Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients. - Kirsebom, Bjørn-Eivind; Espenes, Ragna; Waterloo, Knut; Hessen, Erik; Johnsen, Stein Harald; Bråthen, Geir; Aarsland, Dag; Fladby, Tormod (J Alzheimers Dis, 2017)
BACKGROUND: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning. OBJECTIVE: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants. METHODS: We included 431 participants 40-80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34). RESULTS: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group. CONCLUSION: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). - Cardoso, Bárbara R; Hare, Dominic J; Bush, Ashley I; Li, Qiao-Xin; Fowler, Christopher J; Masters, Colin L; Martins, Ralph N; Ganio, Katherine; Lothian, Amber; Mukherjee, Soumya; Kapp, Eugene A; Roberts, Blaine R (J Alzheimers Dis, 2017)
Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.

Sensing of Alzheimer's Disease and Multiple Sclerosis Using Nano-Bio Interfaces. - Hajipour, Mohammad Javad; Ghasemi, Forough; Aghaverdi, Haniyeh; Raoufi, Mohammad; Linne, Uwe; Atyabi, Fatemeh; Nabipour, Iraj; Azhdarzadeh, Morteza; Derakhshankhah, Hossein; Lotfabadi, Alireza; Bargahi, Afshar; Alekhamis, Zahra; et al. (J Alzheimers Dis, 2017)
It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a colorimetric sensor array for the discrimination and detection of two neurodegenerative diseases, Alzheimer's disease (AD) and multiple sclerosis (MS). Applying a variety of techniques, including UV-visible spectra, array response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers. The array responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the sensor to unambiguously identify and discriminate AD and MS. The developed sensor array might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases.

Sex Difference in Aerobic Exercise Efficacy to Improve Cognition in Older Adults with Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial. - Barha, Cindy K; Hsiung, Ging-Yuek R; Best, John R; Davis, Jennifer C; Eng, Janice J; Jacova, Claudia; Lee, Philip E; Munkacsy, Michelle; Cheung, Winnie; Liu-Ambrose, Teresa (J Alzheimers Dis, 2017)
Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer's Disease. - Shen, Yijun; Xia, Yiling; Meng, Shiquan; Lim, Nastasia K H; Wang, Wenan; Huang, Fude (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42. Partial knockout of neuronal SH2B in the Aβ42-expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42, as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42-expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42. Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia.

Situation Model for Situation-Aware Assistance of Dementia Patients in Outdoor Mobility. - Yordanova, Kristina; Koldrack, Philipp; Heine, Christina; Henkel, Ron; Martin, Mike; Teipel, Stefan; Kirste, Thomas (J Alzheimers Dis, 2017)
BACKGROUND: Dementia impairs spatial orientation and route planning, thus often affecting the patient's ability to move outdoors and maintain social activities. Situation-aware deliberative assistive technology devices (ATD) can substitute impaired cognitive function in order to maintain one's level of social activity. To build such a system, one needs domain knowledge about the patient's situation and needs. We call this collection of knowledge situation model. OBJECTIVE: To construct a situation model for the outdoor mobility of people with dementia (PwD). The model serves two purposes: 1) as a knowledge base from which to build an ATD describing the mobility of PwD; and 2) as a codebook for the annotation of the recorded behavior. METHODS: We perform systematic knowledge elicitation to obtain the relevant knowledge. The OBO Edit tool is used for implementing and validating the situation model. The model is evaluated by using it as a codebook for annotating the behavior of PwD during a mobility study and interrater agreement is computed. In addition, clinical experts perform manual evaluation and curation of the model. RESULTS: The situation model consists of 101 concepts with 11 relation types between them. The results from the annotation showed substantial overlapping between two annotators (Cohen's kappa of 0.61). CONCLUSION: The situation model is a first attempt to systematically collect and organize information related to the outdoor mobility of PwD for the purposes of situation-aware assistance. The model is the base for building an ATD able to provide situation-aware assistance and to potentially improve the quality of life of PwD.

Sleep Deprivation Induced Plasma Amyloid-β Transport Disturbance in Healthy Young Adults. - Wei, Meng; Zhao, Beiyu; Huo, Kang; Deng, Yongning; Shang, Suhang; Liu, Jie; Li, Yanbo; Ma, Louyan; Jiang, Yu; Dang, Liangjun; Chen, Chen; Wei, Shan; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD). OBJECTIVE: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-β (Aβ) concentrations. METHODS: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aβ42, Aβ40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA). RESULTS: TSD increased morning plasma Aβ40 levels by 32.6% (p < 0.001) and decreased the Aβ42/Aβ40 ratio by 19.3% (p < 0.001). A positive relationship was found between TSD duration and plasma Aβ40 level (r = 0.51, p < 0.001) and Aβ40/Aβ42 ratio (r = 0.25, p = 0.003). Plasma concentrations of sLRP1 (p = 0.018) and sRAGE (p = 0.001) decreased significantly after TSD. Aβ40 and Aβ42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p = 0.005), whereas serum MDA was increased (p = 0.001). CONCLUSION: Sleep deprivation can lead to an elevation of plasma Aβ40 and decrease of the Aβ42/Aβ40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aβ clearance as pathomechanisms of AD.
Keywords: Adult; Amyloid beta-Peptides; Female; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Male; Malondialdehyde; Peptide Fragments; Receptor for Advanced Glycation End Products; Sleep Deprivation; Superoxide Dismutase; Time Factors; Young Adult

Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity. - Horváth, András; Szűcs, Anna; Barcs, Gábor; Kamondi, Anita (J Alzheimers Dis, 2017)
BACKGROUND: The reported prevalence of epilepsy in Alzheimer's disease (AD) is variable, probably due to the different methodological approaches. OBJECTIVE: We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients. METHODS: We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated. RESULTS: Significant high correlation was identified between the sensitivity of EEG and the length of recordings (r = 0.972, p = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p < 0.001). CONCLUSION: 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease.

Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic. - Cañabate, Pilar; Martínez, Gabriel; Rosende-Roca, Maitee; Moreno, Mariola; Preckler, Silvia; Valero, Sergi; Sotolongo, Oscar; Hernandez, Isabel; Alegret, Montserrat; Ortega, Gemma; Espinosa, Ana; Mauleón, Ana; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies. OBJECTIVE: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply. METHODS: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain. RESULTS: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%). CONCLUSIONS: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations.

Subjective Cognitive Complaints in Cognitively Healthy Older Adults and Their Relationship to Cognitive Performance and Depressive Symptoms. - Marková, Hana; Andel, Ross; Stepankova, Hana; Kopecek, Miloslav; Nikolai, Tomas; Hort, Jakub; Thomas-Antérion, Catherine; Vyhnálek, Martin (J Alzheimers Dis, 2017)
BACKGROUND: Subjective cognitive complaints (SCCs) may be an early marker of prodromal Alzheimer's disease. OBJECTIVES: Using a 10-item yes/no SCCs questionnaire (Le Questionnaire de Plainte Cognitive [QPC]), we evaluated the prevalence and distribution of SCCs in cognitively healthy Czech older adults and examined total score and specific QPC items in relation to depressive symptomology and cognitive performance. METHODS: A sample of 340 cognitively healthy older community-dwelling volunteers aged 60 or older from the third wave of the longitudinal project National Normative Study of Cognitive Determinants of Healthy Aging, who underwent a comprehensive neuropsychological assessment and completed the QPC and the 15-item Geriatric Depression Scale (GDS-15). Regression analysis was controlled for age when GDS-15 was the outcome and for age and GDS-15 with cognitive domains as the outcome. RESULTS: 71% reported 1 + SCCs, with prevalence of individual complaints ranging from 4% to 40%. The number of SCCs was associated with GDS-15 (p < 0.001). Personality change (p < 0.001) and Limitation in daily activities (p = 0.002) were significantly associated with higher GDS-15 score and Spatial orientation difficulties (p = 0.019) and Impression of worse memory in comparison to peers (p = 0.012) were significantly associated with lower memory performance. CONCLUSIONS: We identified some cognitive complaints that were very common in our sample. Overall, a higher number of SCCs in well cognitively functioning individuals was most closely related to depressive symptomatology, while some specific complaints reflected lower memory performance and should be considered when screening for people at risk of cognitive decline.

Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer's Disease. - Ochoa, John Fredy; Alonso, Joan Francesc; Duque, Jon Edinson; Tobón, Carlos Andrés; Mañanas, Miguel Angel; Lopera, Francisco; Hernández, Alher Mauricio (J Alzheimers Dis, 2017)
BACKGROUND: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer's disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. OBJECTIVE: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. METHODS: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. RESULTS: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. CONCLUSION: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD.

A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers. - Lawrence, Emma; Vegvari, Carolin; Ower, Alison; Hadjichrysanthou, Christoforos; De Wolf, Frank; Anderson, Roy M (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes.

Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study. - Tao, Jing; Liu, Jiao; Liu, Weilin; Huang, Jia; Xue, Xiehua; Chen, Xiangli; Wu, Jinsong; Zheng, Guohua; Chen, Bai; Li, Ming; Sun, Sharon; Jorgenson, Kristen; et al. (J Alzheimers Dis, 2017)
The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

Targeted Metabolomic Analysis of Soluble Lysates from Platelets of Patients with Mild Cognitive Impairment and Alzheimer's Disease Compared to Healthy Controls: Is PC aeC40:4 a Promising Diagnostic Tool? - Oberacher, Herbert; Arnhard, Kathrin; Linhart, Caroline; Diwo, Angela; Marksteiner, Josef; Humpel, Christian (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. The use of biological fluids in AD diagnosis remains limited to the analysis of specific protein biomarkers in cerebrospinal fluid. However, metabolomic analysis has recently revealed several metabolites in plasma, especially phosphatidylcholines (PC), as putative biomarkers specific for AD. Following on previous reports of platelet abnormalities in AD, we hypothesized that platelets metabolites released in plasma may offer new biomarkers in AD. The aim of the present study was to apply targeted metabolomics to compare metabolites in soluble lysates of platelets from healthy controls (CO), patients with mild cognitive impairment (MCI), and patients with AD in a cohort of 90 subjects. We could target 163 metabolites and quantitative data were obtained for 91 metabolites. Among these, the lipid PC aeC40:4 significantly differentiated AD from CO (p = 0.0009), while four other lipids (PC aaC32:0, PC ae C32:2, PC aeC34:1, and SM(OH)C14:1) differentiated patients with MCI from CO. The combination of three phosphatidylcholines (PC aeC32:2, PC aeC34:1, PCaaC36:5), two lyso-phosphatidylcholines (lysoPC aC18:1, lysoPC aC16:0), and one sphingomyelin (SM(OH) C14:1) constructed a valuable prediction model using the C4.5 decision tree. The diagnosis accuracy for AD versus CO and MCI was 85%. In a blinded follow up conversion study (10 patients with a second blood collection after 9 months), we could verify the clinical diagnosis in 19 out of 20 cases. We propose that soluble platelet PCaeC40:4 is a promising marker to diagnose AD with a cut-off of <0.30μM and that platelets undergo metabolic processes during AD progression.

Three-Repeat Tau with Grain-Like Structures and Distribution in an 83-Year-Old Man. - Kasahata, Naoki; Sato, Tomohide; Onishi, Iichiroh; Kitagawa, Masanobu; Uchihara, Toshiki; Hirokawa, Katsuiku (J Alzheimers Dis, 2017)
We encountered an 83-year-old man with 3-repeat dominant grain-like tau deposition. Tau-positive lesions exhibited apparent similarity to argyrophilic grains in terms of their distribution in the ambient gyrus, amygdala, and dorsomedial temporal tip and the characteristic comma-like morphology. The abundant oligodendroglial tau immunoreactivities were 3-repeat dominant. Tuft-shaped astrocytes showed partial 3-repeat tau immnoreactivities. These grain-like structures, as well as tuft-shaped astrocytes and oligodendroglia, exhibited predominant 3-repeat tau immunoreactivity, suggesting that grain-like structures and their characteristic distribution are mutually linked and not unique to 4-repeat tau deposition. pTDP immunoreactivity, extensive macrophage infiltration, and spongiosis were associated with these 3-repeat tau deposits.

TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer's Disease. - Siedlak, Sandra L; Jiang, Yinfei; Huntley, Mikayla L; Wang, Luwen; Gao, Ju; Xie, Fei; Liu, Jingyi; Su, Bo; Perry, George; Wang, Xinglong (J Alzheimers Dis, 2017)
Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.

Tocotrienol-Rich Fraction Modulates Amyloid Pathology and Improves Cognitive Function in AβPP/PS1 Mice. - Ibrahim, Nor Faeizah; Yanagisawa, Daijiro; Durani, Lina Wati; Hamezah, Hamizah Shahirah; Damanhuri, Hanafi Ahmad; Wan Ngah, Wan Zurinah; Tsuji, Mayumi; Kiuchi, Yuji; Ono, Kenjiro; Tooyama, Ikuo (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.

Topological Alterations and Symptom-Relevant Modules in the Whole-Brain Structural Network in Semantic Dementia. - Ding, Junhua; Chen, Keliang; Zhang, Weibin; Li, Ming; Chen, Yan; Yang, Qing; Lv, Yingru; Guo, Qihao; Han, Zaizhu (J Alzheimers Dis, 2017)
BACKGROUND: Semantic dementia (SD) is characterized by a selective decline in semantic processing. Although the neuropsychological pattern of this disease has been identified, its topological global alterations and symptom-relevant modules in the whole-brain anatomical network have not been fully elucidated. OBJECTIVE: This study aims to explore the topological alteration of anatomical network in SD and reveal the modules associated with semantic deficits in this disease. METHODS: We first constructed the whole-brain white-matter networks of 20 healthy controls and 19 patients with SD. Then, the network metrics of graph theory were compared between these two groups. Finally, we separated the network of SD patients into different modules and correlated the structural integrity of each module with the severity of the semantic deficits across patients. RESULTS: The network of the SD patients presented a significantly reduced global efficiency, indicating that the long-distance connections were damaged. The network was divided into the following four distinctive modules: the left temporal/occipital/parietal, frontal, right temporal/occipital, and frontal/parietal modules. The first two modules were associated with the semantic deficits of SD. CONCLUSION: These findings illustrate the skeleton of the neuroanatomical network of SD patients and highlight the key role of the left temporal/occipital/parietal module and the left frontal module in semantic processing.

Toward the Automation of Diagnostic Conversation Analysis in Patients with Memory Complaints. - Mirheidari, Bahman; Blackburn, Daniel; Harkness, Kirsty; Walker, Traci; Venneri, Annalena; Reuber, Markus; Christensen, Heidi (J Alzheimers Dis, 2017)
BACKGROUND: The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD). OBJECTIVE: This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated. METHODS: Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD. RESULTS: The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier.Using only the ten best features, the mean correct classification score increased to 95%. CONCLUSION: This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD.

Trajectories of Multidimensional Caregiver Burden in Chinese Informal Caregivers for Dementia: Evidence from Exploratory and Confirmatory Factor Analysis of the Zarit Burden Interview. - Li, Dan; Hu, Nan; Yu, Yueyi; Zhou, Aihong; Li, Fangyu; Jia, Jianping (J Alzheimers Dis, 2017)
BACKGROUND: Despite its popularity, the latent structure of 22-item Zarit Burden Interview (ZBI) remains unclear. There has been no study exploring how caregiver multidimensional burden changed. OBJECTIVE: The aim of the work was to validate the latent structure of ZBI and to investigate how multidimensional burden evolves with increasing global burden. METHODS: We studied 1,132 dyads of dementia patients and their informal caregivers. The caregivers completed the ZBI and a questionnaire regarding caregiving. The total sample was randomly split into two equal subsamples. Exploratory factor analysis (EFA) was performed in the first subsample. In the second subsample, confirmatory factor analysis (CFA) was conducted to validate models generated from EFA. The mean of weighted factor score was calculated to assess the change of dimension burden against the increasing ZBI total score. RESULTS: The result of EFA and CFA supported that a five-factor structure, including role strain, personal strain, incompetency, dependency, and guilt, had the best goodness-of-fit. The trajectories of multidimensional burden suggested that three different dimensions (guilt, role strain and personal strain) became the main subtype of burden in sequence as the ZBI total score increased from mild to moderate. Factor dependency contributed prominently to the total burden in severe stage. CONCLUSION: The five-factor ZBI is a psychometrically robust measure for assessing multidimensional burden in Chinese caregivers. The changes of multidimensional burden have deepened our understanding of the psychological characteristics of caregiving beyond a single total score and may be useful for developing interventions to reduce caregiver burden.

Translational MRI Volumetry with NeuroQuant: Effects of Version and Normative Data on Relationships with Memory Performance in Healthy Older Adults and Patients with Mild Cognitive Impairment. - Stelmokas, Julija; Yassay, Lance; Giordani, Bruno; Dodge, Hiroko H; Dinov, Ivo D; Bhaumik, Arijit; Sathian, K; Hampstead, Benjamin M (J Alzheimers Dis, 2017)
NeuroQuant (NQ) is a fully-automated program that overcomes several existing limitations in the clinical translation of MRI-derived volumetry. The current study characterized differences between the original (NQ1) and an updated NQ version (NQ2) by 1) replicating previously identified relationships between neuropsychological test performance and medial temporal lobe volumes, 2) evaluating the level of agreement between NQ versions, and 3) determining if the addition of NQ2 age-/sex-based z-scores hold greater clinical utility for prediction of memory impairment than standard percent of intracranial volume (% ICV) values. Sixty-seven healthy older adults and 65 mild cognitive impairment patients underwent structural MRI and completed cognitive testing, including the Immediate and Delayed Memory indices from the Repeatable Battery for the Assessment of Neuropsychological Status. Results generally replicated previous relationships between key medial temporal lobe regions and memory test performance, though comparison of NQ regions revealed statistically different values that were biased toward one version or the other depending on the region. NQ2 hippocampal z-scores explained additional variance in memory performance relative to % ICV values. Findings indicate that NQ1/2 medial temporal lobe volumes, especially age- and sex-based z-scores, hold clinical value, though caution is warranted when directly comparing volumes across NQ versions.

Trehalose Improves Cognition in the Transgenic Tg2576 Mouse Model of Alzheimer's Disease. - Portbury, Stuart D; Hare, Dominic J; Sgambelloni, Charlotte; Perronnes, Kali; Portbury, Ashley J; Finkelstein, David I; Adlard, Paul A (J Alzheimers Dis, 2017)
This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels. Trehalose treatment significantly improved performance in the Morris water maze, consistent with enhanced learning and memory. The improvement was not associated with significant modulation of full length amyloid-β protein precursor or other amyloid-β fragments. Trehalose had no effect on autophagy as assessed by western blot of the LC3-1 to LC3-2 protein ratio, and no alteration in biometals that might account for the improved cognition was observed. Biochemical analysis revealed a significant increase in the hippocampus of both synaptophysin, a synaptic vesicle protein and surrogate marker of synapses, and doublecortin, a reliable marker of neurogenesis. The growth factor progranulin was also significantly increased in the hippocampus and cortex with trehalose treatment. This study suggests that trehalose might invoke a suite of neuroprotective mechanisms that can contribute to improved cognitive performance in AD that are independent of more classical trehalose-mediated pathways, such as Aβ reduction and activation of autophagy. Thus, trehalose may have utility as a potential AD therapeutic, with conceivable implications for the treatment of other neurodegenerative disorders.

Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review. - Li, Wei; Huang, Edgar; Gao, Sujuan (J Alzheimers Dis, 2017)
Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia.

Urine Formaldehyde Predicts Cognitive Impairment in Post-Stroke Dementia and Alzheimer's Disease. - Tong, Zhiqian; Wang, Weishan; Luo, Wenhong; Lv, Jihui; Li, Hui; Luo, Hongjun; Jia, Jianping; He, Rongqiao (J Alzheimers Dis, 2017)
Although Alzheimer's disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years. Cognitive abilities of the study participants (n = 577, four groups: 231 controls, 61 stroke, 65 PSD, and 220 AD) were assessed by Mini-Mental State Examination (MMSE). Morning urine formaldehyde concentrations were measured by high performance liquid chromatography (HPLC). Gender- and age-matched participants were selected from the four groups (n = 42 in each group). Both semicarbazide-sensitive amine oxidase (SSAO, a formaldehyde-generating enzyme) and formaldehyde levels in the blood and urine were analyzed by using an enzyme-linked immunosorbent assay (ELISA) and HPLC, respectively. We found that morning urine formaldehyde levels were inversely correlated with MMSE scores. The threshold value (the best Cut-Off value) of formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (Sensitivity: 92.3%; Specificity: 77.1%), and 0.0449 mM in patients with AD (Sensitivity: 94.1%; Specificity: 81.8%), respectively. The results of biochemical analysis revealed that the observed increase in urine formaldehyde resulted from an overexpression of SSAO in the blood. The findings suggest that measuring the concentration of formaldehyde in overnight fasting urine could be used as a potentially noninvasive method for evaluating the likelihood of ensuing cognitive impairment or dementia.

Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. - Dublin, Sascha; Walker, Rod L; Gray, Shelly L; Hubbard, Rebecca A; Anderson, Melissa L; Yu, Onchee; Montine, Thomas J; Crane, Paul K; Sonnen, Josh A; Larson, Eric B (J Alzheimers Dis, 2017)
BACKGROUND: Opioids may influence the development of Alzheimer's disease (AD). Some studies have observed AD pathology in the brains of opioid abusers. No study has examined the association between prescription opioid use and dementia-related neuropathologic changes. OBJECTIVE: To examine the relationship between prescription opioid or NSAID use and dementia-related neuropathologic changes. METHODS: Within a community-based autopsy cohort (N = 420), we ascertained opioid and nonsteroidal anti-inflammatory drug (NSAID) use over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDDs). A neuropathologist assessed outcomes including neuritic plaques, neurofibrillary tangles, and macroscopic infarcts. Outcome measures were dichotomized using established cutpoints. We used modified Poisson regression to calculate adjusted relative risks (RR) and 95% confidence intervals (CI), accounting for participant characteristics and using weighting to account for possible selection bias related to selection into the autopsy sample. RESULTS: Heavier opioid exposure was not associated with greater neuropathologic changes. For neuritic plaques, the adjusted RR [95% CI] was 0.99 [0.64-1.47] for 91+ TSDDs of opioids versus little to no use, and for neurofibrillary tangles, 0.97 [0.49-1.78]. People with heavy NSAID use had higher risk of neuritic plaques (RR 1.39 [1.01-1.89]) than those with little to no use, as we have previously reported. Neither opioid nor NSAID use was associated with higher risk of macroscopic infarcts or with Lewy body disease. CONCLUSION: Prescription opioid use is not associated with dementia-related neuropathologic changes, but heavy NSAID use may be. More research is needed examining chronic pain, its pharmacologic treatments, and neuropathologic changes.

The Use of Music Playlists for People with Dementia: A Critical Synthesis. - Garrido, Sandra; Dunne, Laura; Chang, Esther; Perz, Janette; Stevens, Catherine J; Haertsch, Maggie (J Alzheimers Dis, 2017)
The use of pre-recorded music to ease behavioral and psychological symptoms associated with dementia is popular in health-care contexts in both formal music therapy settings and in non-therapist led interventions. However, further understanding of how non-therapist led interventions compare to therapist led interventions is needed. This paper reviews 28 studies that used pre-recorded music with people with dementia using a critical interpretive synthesis model. Results revealed that pre-recorded music can be effective in reducing a variety of affective and behavioral symptoms, in particular agitation, even where a trained music therapist is not present. However, the results are not universally positive, suggesting the need for further clarification of protocols for music use and closer investigation of variables that influence individual responseto music.

Using Drugs as Molecular Probes: A Computational Chemical Biology Approach in Neurodegenerative Diseases. - Emon, Mohammad Asif Emran Khan; Kodamullil, Alpha Tom; Karki, Reagon; Younesi, Erfan; Hofmann-Apitius, Martin (J Alzheimers Dis, 2017)
Neurodegenerative diseases including Alzheimer's disease are complex to tackle because of the complexity of the brain, both in structure and function. Such complexity is reflected by the involvement of various brain regions and multiple pathways in the etiology of neurodegenerative diseases that render single drug target approaches ineffective. Particularly in the area of neurodegeneration, attention has been drawn to repurposing existing drugs with proven efficacy and safety profiles. However, there is a lack of systematic analysis of the brain chemical space to predict the feasibility of repurposing strategies. Using a mechanism-based, drug-target interaction modeling approach, we have identified promising drug candidates for repositioning. Mechanistic cause-and-effect models consolidate relevant prior knowledge on drugs, targets, and pathways from the scientific literature and integrate insights derived from experimental data. We demonstrate the power of this approach by predicting two repositioning candidates for Alzheimer's disease and one for amyotrophic lateral sclerosis.

The Utilization of Robotic Pets in Dementia Care. - Petersen, Sandra; Houston, Susan; Qin, Huanying; Tague, Corey; Studley, Jill (J Alzheimers Dis, 2017)
BACKGROUND: Behavioral problems may affect individuals with dementia, increasing the cost and burden of care. Pet therapy has been known to be emotionally beneficial for many years. Robotic pets have been shown to have similar positive effects without the negative aspects of traditional pets. Robotic pet therapy offers an alternative to traditional pet therapy. OBJECTIVE: The study rigorously assesses the effectiveness of the PARO robotic pet, an FDA approved biofeedback device, in treating dementia-related symptoms. METHODS: A randomized block design with repeated measurements guided the study. Before and after measures included reliable, valid tools such as: RAID, CSDD, GDS, pulse rate, pulse oximetry, and GSR. Participants interacted with the PARO robotic pet, and the control group received standard activity programs. Five urban secure dementia units comprised the setting. RESULTS: 61 patients, with 77% females, average 83.4 years in age, were randomized into control and treatment groups. Compared to the control group, RAID, CSDD, GSR, and pulse oximetry were increased in the treatment group, while pulse rate, pain medication, and psychoactive medication use were decreased. The changes in GSR, pulse oximetry, and pulse rate over time were plotted for both groups. The difference between groups was consistent throughout the 12-week study for pulse oximetry and pulse rate, while GSR had several weeks when changes were similar between groups. CONCLUSIONS: Treatment with the PARO robot decreased stress and anxiety in the treatment group and resulted in reductions in the use of psychoactive medications and pain medications in elderly clients with dementia.

Validation of Suspected Somatic Single Nucleotide Variations in the Brain of Alzheimer's Disease Patients. - Gomez-Ramos, Alberto; Picher, Angel J; García, Esther; Garrido, Patricia; Hernández, Félix; Soriano, Eduardo; Avila, Jesús (J Alzheimers Dis, 2017)
Next-generation sequencing techniques and genome-wide association study analyses have provided a huge amount of data, thereby enabling the identification of DNA variations and mutations related to disease pathogenesis. New techniques and software tools have been developed to improve the accuracy and reliability of this identification. Most of these tools have been designed to discover and validate single nucleotide variants (SNVs). However, in addition to germ-line mutations, human tissues bear genomic mosaicism, which implies that somatic events are present only in low percentages of cells within a given tissue, thereby hindering the validation of these variations using standard genetic tools. Here we propose a new method to validate some of these somatic mutations. We combine a recently developed software with a method that cuts DNA by using restriction enzymes at the sites of the variation. The non-cleaved molecules, which bear the SNV, can then be amplified and sequenced using Sanger's technique. This procedure, which allows the detection of alternative alleles present in as few as 10% of cells, could be of value for the identification and validation of low frequency somatic events in a variety of tissues and diseases.

Validation of the Korean Version of the Lewy Body Composite Risk Score (K-LBCRS). - Ryu, Hui Jin; Kim, Minyoung; Moon, Yeonsil; Choi, Yeji; Han, Jee-Young; Galvin, James E; Han, Seol-Heui (J Alzheimers Dis, 2017)
The Lewy body composite risk score (LBCRS) is a useful clinical screening tool to help determine whether the dementia is related to Lewy body pathology. The purpose of this study is to verify reliability, validity, and diagnostic usefulness of Korean version of LBCRS (K-LBCRS). CDR-sum of boxes, Mini-Mental State Examination, and standardized scales related to cognition, mood, behavior, and motor function were administered to a total of 107 subjects, including 30 dementia with Lewy bodies (DLB), 54 Alzheimer's disease (AD), and 23 cognitively normal elderly people and their collateral informants. Internal consistency of the K-LBCRS was good with Cronbach's alpha of 0.85, and concurrent validity was also satisfactory, with K-LBCRS correlating highly with CDR-SB and other scales. The test-retest reliability was very high with a Pearson correlation coefficient of 0.97. The mean scores of K-LBCRS were significantly different among three groups, with DLB (6.2±2.4), AD (1.4±1.3), and controls (0.3±0.6). We identified a cut-off score of 3 as best to differentiate between DLB and AD, having AUC of 0.97 (95% CI 0.94-1.00), sensitivity 97%, specificity 83%, positive predictive value 76%, negative predictive value 98%, which is the same score suggested in the original study. This study shows K-LBCRS as a new useful screening tool for Korean DLB patients in clinical settings.

Validation of the Spanish Version of the LASSI-L for Diagnosing Mild Cognitive Impairment and Alzheimer's Disease. - Matías-Guiu, Jordi A; Curiel, Rosie E; Rognoni, Teresa; Valles-Salgado, María; Fernández-Matarrubia, Marta; Hariramani, Roshan; Fernández-Castro, Alejandro; Moreno-Ramos, Teresa; Loewenstein, David A; Matías-Guiu, Jorge (J Alzheimers Dis, 2017)
BACKGROUND: The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer's disease (AD). OBJECTIVE: To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD. METHODS: We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize the sample size and to provide age- and education-adjusted normative data using a logistic regression analysis. RESULTS: Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy. CONCLUSIONS: The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia.

Visit-to-Visit Blood Pressure Variability and Alzheimer's Disease: Links and Risks. - Nagai, Michiaki; Dote, Keigo; Kato, Masaya; Sasaki, Shota; Oda, Noboru; Kagawa, Eisuke; Nakano, Yoshinori; Yamane, Aya; Higashihara, Tasuku; Miyauchi, Shunsuke; Tsuchiya, Akane (J Alzheimers Dis, 2017)
While hypertension has been shown to be a risk factor for vascular dementia, several studies have also demonstrated that hypertension also increases the risk of Alzheimer's disease (AD). Although the relationship between visit-to-visit blood pressure variability (VVV) and cognitive impairment, including AD, have been provided, the mechanisms remain poorly understood. This review paper focuses on the relationship of VVV with AD and summarizes the pathophysiology underlying that relationship, which appears to be mediated by arterial stiffness.

Visual Selective Attention Toward Novel Stimuli Predicts Cognitive Decline in Alzheimer's Disease Patients. - Chau, Sarah A; Herrmann, Nathan; Sherman, Chelsea; Chung, Jonathan; Eizenman, Moshe; Kiss, Alex; Lanctôt, Krista L (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression. OBJECTIVE: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients. METHODS: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners' Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years. RESULTS: Multivariate linear regressions of 32 AD patients (14 females, age = 77.9±7.8, baseline sMMSE = 22.2±4.4) indicated that reduced time spent on novel images (t = 2.78, p = 0.010) was also associated with greater decline in sMMSE scores (R2 = 0.41, Adjusted R2 = 0.35, F3,28 = 6.51, p = 0.002), adjusting for attention and baseline sMMSE. CONCLUSION: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired.

von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion. - Yang, Yue; Halliday, Glenda M; Hodges, John R; Tan, Rachel H (J Alzheimers Dis, 2017)
BACKGROUND: The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. OBJECTIVE: To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls. METHODS: Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9). RESULTS: von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. CONCLUSION: The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

What Drives Country Differences in Cost of Alzheimer's Disease? An Explanation from Resource Use in the GERAS Study. - Reed, Catherine; Happich, Michael; Argimon, Josep Maria; Haro, Josep Maria; Wimo, Anders; Bruno, Giuseppe; Dodel, Richard; Jones, Roy W; Vellas, Bruno; Belger, Mark (J Alzheimers Dis, 2017)
BACKGROUND: Country differences in resource use and costs of Alzheimer's disease (AD) may be driven by differences in health care systems and resource availability. OBJECTIVE: To compare country resource utilization drivers of societal costs for AD dementia over 18 months. METHODS: GERAS is an observational study in France (n = 419), Germany (n = 550), and the UK (n = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics. RESULTS: Mean 18-month societal costs per patient were France €33,339, Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support. CONCLUSION: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Caregivers; Cohort Studies; Cost of Illness; Europe; Female; Health Resources; Humans; International Cooperation; Male; Surveys and Questionnaires

White Matter Degradation is Associated with Reduced Financial Capacity in Mild Cognitive Impairment and Alzheimer's Disease. - Gerstenecker, Adam; Hoagey, David A; Marson, Daniel C; Kennedy, Kristen M (J Alzheimers Dis, 2017)
Financial capacity (FC) is a cognitively complex activity of daily living that declines in mild cognitive impairment (MCI) and Alzheimer's disease (AD), limiting an individual's ability to manage one's finances and function independently. The neural underpinnings of this decline in function are poorly understood but likely involve age-related and disease-related degradation across structural networks. The purpose of the current study was to determine if altered white matter integrity is associated with declining FC in persons with MCI and AD compared to older controls. Individuals with MCI due to AD (n = 31), mild dementia (n = 39), and cognitively healthy older adults (n = 60) were administered a neuropsychological battery including the FC Instrument, a performance-based measure of FC. All 130 participants also underwent diffusion tensor imaging (DTI) upon which tract-based spatial statistics were performed. Both FC and white matter integrity decreased in accordance with disease severity with little to no effect in healthy elderly, significant effects in MCI, and greater effects in AD. Regional white matter degradation (increased diffusivities and decreased fractional anisotropy) was associated with reduced FC in both MCI and AD groups even after controlling for age, education, and gender. Specifically, in MCI, decreased fractional anisotropy, but not increased diffusivities, was associated with poorer FC in widespread cingulo-parietal-frontal and temporo-occipital areas. In AD, rather than anisotropy, increased mean and axial diffusivities in anterior cingulate, callosum, and frontal areas associated with poorer FC. These findings suggest a severity gradient of white matter degradation across DTI metrics and AD stages that predict declining financial skill and knowledge.

ABCA7 Genotypes Confer Alzheimer's Disease Risk by Modulating Amyloid-β Pathology. - Zhao, Qing-Fei; Wan, Yu; Wang, Hui-Fu; Sun, Fu-Rong; Hao, Xiao-Ke; Tan, Meng-Shan; Tan, Chen-Chen; Zhang, Dao-Qiang; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2016)
ABCA7 gene has been identified as a strong genetic locus for Alzheimer's disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.

ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain. - Fu, YuHong; Hsiao, Jen-Hsiang T; Paxinos, George; Halliday, Glenda M; Kim, Woojin Scott (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.

Aberrant Spontaneous Brain Activity in Patients with Mild Cognitive Impairment and concomitant Lacunar Infarction: A Resting-State Functional MRI Study. - Ni, Ling; Liu, Renyuan; Yin, Zhenyu; Zhao, Hui; Nedelska, Zuzana; Hort, Jakub; Zhou, Fei; Wu, Wenbo; Zhang, Xin; Li, Ming; Yu, Haiping; Zhu, Bin; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear. OBJECTIVE: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) methods. RESULTS: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r = 0.432, p = 0.045) (of borderline significance after Bonferroni correction). CONCLUSIONS: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage.
Keywords: Aged; Aged, 80 and over; Brain; Brain Mapping; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Rest; Stroke, Lacunar

Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype. - Tramutola, Antonella; Pupo, Gilda; Di Domenico, Fabio; Barone, Eugenio; Arena, Andrea; Lanzillotta, Chiara; Broekaart, Diede; Blarzino, Carla; Head, Elizabeth; Butterfield, D Allan; Perluigi, Marzia (J Alzheimers Dis, 2016)
Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.
Keywords: Acetylation; Alzheimer Disease; Animals; Apoptosis; Blotting, Western; Disease Models, Animal; Down Syndrome; Female; Frontal Lobe; Humans; Immunoprecipitation; Male; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phenotype; Phosphorylation; Tumor Suppressor Protein p53; Young Adult

Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. - Durazzo, Timothy C; Korecka, Magdalena; Trojanowski, John Q; Weiner, Michael W; O' Hara, Ruth; Ashford, John W; Shaw, Leslie M (J Alzheimers Dis, 2016)
Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD). Smoking and non-smoking CN (n = 83), MCI (n = 164), and probable AD (n = 101) were compared on cerebrospinal fluid (CSF) iPF2α-III and 8,12, iso-iPF2α-VI F2-isoprostane concentrations. Associations between F2-isoprostane levels and hippocampal volumes were also evaluated. In CN and AD, smokers had higher iPF2α-III concentration; overall, smoking AD showed the highest iPF2α-III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2α-III concentration. No group differences were apparent on 8,12, iso-iPF2α-VI concentration, but across AD, higher 8,12, iso-iPF2α-VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2-isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan.

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort. - Handels, Ron L H; Joore, Manuela A; Vos, Stephanie J B; Aalten, Pauline; Ramakers, Inez H G B; Rikkert, Marcel Olde; Scheltens, Philip; Jansen, Willemijn J; Visser, Pieter-Jelle; van Berckel, Bart M N; van Domburg, Peter; Smid, Machiel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup. OBJECTIVE: This study aims to investigate the added prognostic value of AD CSF biomarkers. METHODS: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information. RESULTS: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment. CONCLUSION: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

Adults at Increased Alzheimer's Disease Risk Display Cognitive-Motor Integration Impairment Associated with Changes in Resting-State Functional Connectivity: A Preliminary Study. - Hawkins, Kara M; Sergio, Lauren E (J Alzheimers Dis, 2016)
BACKGROUND: Many neuroimaging parameters have demonstrated utility as biomarkers in preclinical AD, including resting-state functional connectivity in the default mode network. However, neuroimaging is not a practical, cost effective screening instrument. OBJECTIVE: Here we investigate the relationship between performance on a cognitive-motor integration assessment and alterations in resting-state functional connectivity in an at-risk population. METHODS: Three groups of ten adults (young: mean age = 26.6 ± 2.7, low AD risk: mean age = 58.7 ± 5.6, and high AD risk: mean age = 58.5 ± 6.9) performed a simple cognitive-motor integration task using a dual-touchscreen laptop and also underwent functional magnetic resonance imaging at rest. RESULTS: We found poorer cognitive-motor integration performance in high AD risk participants, as well as an association with lower resting-state functional connectivity in this group. CONCLUSION: These findings provide novel insight into underlying AD-related brain alterations associated with a behavioral assessment that can be easily administered clinically.

Age-Related Effects of the Apolipoprotein E Gene on Brain Function. - Matura, Silke; Prvulovic, David; Hartmann, Daniel; Scheibe, Monika; Sepanski, Beate; Butz, Marius; Oertel-Knöchel, Viola; Knöchel, Christian; Karakaya, Tarik; Fußer, Fabian; Hattingen, Elke; Pantel, Johannes (J Alzheimers Dis, 2016)
The apolipoprotein E (ApoE) ɛ4 allele is a well-established genetic risk factor for sporadic Alzheimer's disease. Some evidence suggests a negative role of the ApoE ɛ4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4±4.6 years, 25 ɛ4 carriers) and old (n = 40; age 66.1±7.0 years, 20 ɛ4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ4 carriers. The increased BOLD response in old ɛ4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

Alcohol Consumption and Incident Dementia: Evidence from the Sydney Memory and Ageing Study. - Heffernan, Megan; Mather, Karen A; Xu, Jing; Assareh, Amelia A; Kochan, Nicole A; Reppermund, Simone; Draper, Brian; Trollor, Julian N; Sachdev, Perminder; Brodaty, Henry (J Alzheimers Dis, 2016)
Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE) genotype, an established risk factor for Alzheimer's dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOEɛ4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOEɛ4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption.

All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity. - Midorikawa, Akira; Leyton, Cristian E; Foxe, David; Landin-Romero, Ramon; Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2016)
BACKGROUND: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. OBJECTIVE: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). METHODS: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. RESULTS: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. CONCLUSIONS: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia.

Alterations in the Levels of Amyloid-β, Phospholipid Hydroperoxide, and Plasmalogen in the Blood of Patients with Alzheimer's Disease: Possible Interactions between Amyloid-β and These Lipids. - Yamashita, Shinji; Kiko, Takehiro; Fujiwara, Hironori; Hashimoto, Michio; Nakagawa, Kiyotaka; Kinoshita, Mikio; Furukawa, Katsutoshi; Arai, Hiroyuki; Miyazawa, Teruo (J Alzheimers Dis, 2016)
Aside from accumulation of amyloid-β (Aβ) peptide in the brain, Alzheimer's disease (AD) has been reported as being associated with peroxidation of major phospholipids (e.g., phosphatidylcholine (PtdCho)) and degradation of antioxidative phospholipids (e.g., ethanolamine plasmalogen (PlsEtn)). In addition to its presence in the brain, Aβ is also found in blood; however, there is still little information about the levels of PtdCho hydroperoxide (PCOOH) and PlsEtn in the blood of patients with AD. In this study, by assuming a possible interaction among Aβ, PCOOH, and PlsEtn in blood circulation, we evaluated the levels of these molecules and correlations in blood samples that had been obtained from our former AD study for PCOOH measurement (Kiko et al., J Alzheimers Dis28, 593-600, 2012). We found that when compared to controls, plasma from patients with AD showed lower concentrations of PlsEtn species, especially PlsEtn bearing the docosahexaenoic acid (DHA) moiety. In addition, lower PlsEtn and higher PCOOH levels were observed in red blood cells (RBCs) of patients with AD. In both AD and control blood samples, RBC PCOOH levels tended to correlate with plasma levels of Aβ40, and each PlsEtn species showed different correlations with plasma Aβ. These results, together with in vitro data suggesting Aβ aggregation due to a decrease in levels of PlsEtn having DHA, led us to deduce that Aβ is involved in alterations in levels of PCOOH and PlsEtn species observed in the blood of patients with AD.
Keywords: Aged; Amyloid beta-Peptides; Female; Humans; Hydrogen Peroxide; Male; Phosphatidylcholines; Plasmalogens

Altered Topology in Information Processing of a Narrated Story in Older Adults with Mild Cognitive Impairment. - Yogev-Seligmann, Galit; Oren, Noga; Ash, Elissa L; Hendler, Talma; Giladi, Nir; Lerner, Yulia (J Alzheimers Dis, 2016)
The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.

Analysis of Cerebrospinal Fluid and [11C]PIB PET Biomarkers for Alzheimer's Disease with Updated Protocols. - Wang, Min Jeong; Yi, SangHak; Han, Jee-Young; Park, So Young; Jang, Jae-Won; Chun, In Kook; Giau, Vo Van; Bagyinszky, Eva; Lim, Kun Taek; Kang, Sung Min; An, Seong Soo A; Park, Young Ho; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer's Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers. OBJECTIVE: Here, we analyzed fluid and imaging biomarkers of Alzheimer's disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD. METHODS: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD = 26, NC = 29) following the Korea consensus protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed. RESULTS: The cutoff values of CSF amyloid beta 1-42 (Aβ42), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ= 0.849, CI 0.71-0.99) than CSF Aβ42 alone (κ= 0.703, CI 0.51-0.89). CONCLUSIONS: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis.

Anemia and Mild Cognitive Impairment in the German General Population. - Dlugaj, Martha; Winkler, Angela; Weimar, Christian; Dürig, Jan; Broecker-Preuss, Martina; Dragano, Nico; Moebus, Susanne; Jöckel, Karl-Heinz; Erbel, Raimund; Eisele, Lewin (J Alzheimers Dis, 2016)
There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50-80 years) of the second examination (t1) of a cohort study (baseline (t0) 2000-2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin <13 g/dl in men (n = 84) and <12 g/dl in women (n = 79). Group comparisons were used to compare the cognitive subtests. To determine the association of MCI with anemia at t1, with anemia five years prior to the cognitive assessment (t0) and anemia at both time points, we used logistic regression models and included 579 participants with MCI and 1,438 cognitively normal participants out of the total cohort. Anemic participants showed lower performances in verbal memory and executive functions. The fully adjusted odds ratios (OR) for MCI, aMCI, and naMCI in anemic versus non-anemic participants were 1.92 (95% -CI, 1.09-3.39), 1.96 (1.00-3.87), and 1.88 (0.91-3.87). Anemia at both times points showed a non-significant association with naMCI (OR 3.74, 0.94-14.81, fully adjusted). Our results suggest that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. The association of anemia and MCI has important clinical relevance, because many causes of anemia can be treated effectively.
Keywords: Aged; Aged, 80 and over; Anemia; Cognitive Dysfunction; Cohort Studies; Executive Function; Female; Follow-Up Studies; Germany; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Prevalence; Speech Perception

The Anti-Amyloid-β Monoclonal Antibody 4G8 Recognizes a Generic Sequence-Independent Epitope Associated with α-Synuclein and Islet Amyloid Polypeptide Amyloid Fibrils. - Hatami, Asa; Monjazeb, Sanaz; Glabe, Charles (J Alzheimers Dis, 2016)
Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18-23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution.
Keywords: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal; Brain; Epitopes; Humans; Islet Amyloid Polypeptide

Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose. - Huang, Han-Chang; Zheng, Bo-Wen; Guo, Yu; Zhao, Jian; Zhao, Jiang-Yan; Ma, Xiao-Wei; Jiang, Zhao-Feng (J Alzheimers Dis, 2016)
Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

Apathy and Attentional Biases in Alzheimer's Disease. - Chau, Sarah A; Chung, Jonathan; Herrmann, Nathan; Eizenman, Moshe; Lanctôt, Krista L (J Alzheimers Dis, 2016)
BACKGROUND: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. OBJECTIVE: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. METHODS: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. RESULTS: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023). CONCLUSION: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.
Keywords: Aged; Alzheimer Disease; Apathy; Attentional Bias; Cognition; Cross-Sectional Studies; Emotions; Eye Movement Measurements; Eye Movements; Female; Humans; Linear Models; Male; Neuropsychological Tests; Photic Stimulation; Severity of Illness Index; Social Perception

Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease. - Singhrao, Sim K; Harding, Alice; Chukkapalli, Sasanka; Olsen, Ingar; Kesavalu, Lakshmyya; Crean, StJohn (J Alzheimers Dis, 2016)
The primary goal of advancement in clinical services is to provide a health care system that enhances an individual's quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual's lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer's disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia.
Keywords: Aging; Alzheimer Disease; Animals; Apolipoprotein E4; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus, Type 2; Humans; Mice; Periodontal Diseases

Apolipoprotein ɛ4 is Associated with Dementia and Cognitive Impairment Predominantly Due to Alzheimer's Disease and Not with Vascular Cognitive Impairment: A Singapore-Based Cohort. - Chai, Yuek Ling; Yeo, Hazel Kai-Hui; Wang, Jiehao; Hilal, Saima; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Wong, Boon-Seng; Chen, Christopher Li-Hsian (J Alzheimers Dis, 2016)
BACKGROUND AND OBJECTIVE: While the association for apolipoprotein ɛ4 allele (APOE4) with Alzheimer's disease (AD) has been consistently confirmed, the association with vascular cognitive impairment (VCI) is unclear. We therefore explored the relationship of APOE with both AD and cerebrovascular disease (CeVD) by examining the prevalence of APOE4 in AD, AD with CeVD and vascular dementia (VaD), as well as in cognitive impairment no dementia (CIND) with and without CeVD. METHODS: We performed a case-control study with subjects recruited from memory clinics and the community. All subjects underwent standardized brain neuroimaging, clinical and neuropsychological assessments, following which they were classified using research criteria. RESULTS: A total of 411 subjects; 92 controls with no cognitive impairment (NCI), 77 CIND without CeVD, 87 CIND with CeVD, 55 AD without CeVD, 68 AD with CeVD, and 32 VaD patients were recruited. Compared to NCI (16.3%), the prevalence of APOE4 carriers was significantly higher only in CIND (37.7%) and AD in the absence of CeVD (45.5%), but not in the three subgroups of VCI, namely CIND with CeVD (20.7%), AD with CeVD (27.9%) and VaD (25.0%). Logistic regression analyses also showed that APOE4 carriers were more likely to have CIND without CeVD (Odds Ratio [OR]: 3.34; 95% Confidence Interval [CI]: 1.59-7.03) and AD without CeVD (OR: 7.21; 95% CI: 2.74-18.98), but no such association was observed in the VCI subgroups. CONCLUSION: APOE4 is significantly associated with dementia and CIND due to AD pathology, but not with VCI.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Apolipoprotein E4; Cognition Disorders; Cohort Studies; Dementia; Female; Genetic Association Studies; Genotype; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Psychiatric Status Rating Scales; Singapore; Vascular Diseases

Aquaporin-4 and Alzheimer's Disease. - Yang, Canhong; Huang, Xiaomin; Huang, Xiaoyu; Mai, Hantao; Li, Jie; Jiang, Tao; Wang, Xiaofeng; Lü, Tianming (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most common form of dementia. Although the pathogenesis of AD remains unclear, AD is thought to result from an imbalance in the production and clearance of amyloid-β protein (Aβ). Aquaporin-4 (AQP4) is the major aquaporin in the mammalian brain, is mostly expressed on astrocytic endfeet, and functions as a water transporter. However, the distribution and expression of AQP4 are altered in both AD clinical populations and animal models. Recent studies have revealed that AQP4 is important to the clearance of Aβ in brain via lymphatic clearance, transcytotic delivery, and glial degradation, as well as to the synaptic function. Thus, AQP4 likely plays an important role in the pathogenesis of AD. Further studies would provide new targets for prevention, ultimately leading to improved treatment options for AD.

Association between Coffee Consumption and Incident Risk of Disabling Dementia in Elderly Japanese: The Ohsaki Cohort 2006 Study. - Sugiyama, Kemmyo; Tomata, Yasutake; Kaiho, Yu; Honkura, Kenji; Sugawara, Yumi; Tsuji, Ichiro (J Alzheimers Dis, 2016)
Epidemiological studies of the association between coffee consumption and dementia have yielded inconsistent results. Therefore, we investigated the association between coffee consumption and incident risk of dementia in an elderly Japanese population. 23,091 subjects aged ≥65 y living in Ohsaki City, northeastern Japan, responded to the baseline survey in 2006. Of these, we analyzed 13,137 subjects who gave informed consent and were not disabled at baseline. The outcome was the incidence of disabling dementia defined by usage of the Long-term Care Insurance database. We used the Cox proportional hazards regression model for multivariate analysis. During 5.7 y of follow-up period, we identified 1,107 cases of incident dementia. Overall, coffee consumption was significantly associated with a lower risk of incident dementia. The multivariate-adjusted HRs for the incidence of dementia according to coffee consumption categories (never, occasionally, 1-2 cups/d, and ≥3 cups/d) were 1.00, 0.73 (95% CI, 0.62-0.86), 0.72 (95% CI, 0.61-0.84), and 0.82 (95% CI, 0.65-1.02; p for trend = 0.009), respectively. In addition, this significant inverse association was more remarkable among women, non-smokers, and non-drinkers. Coffee consumption is significantly associated with a lower risk of incident dementia.
Keywords: Aged; Aged, 80 and over; Coffee; Dementia; Female; Health Surveys; Humans; Incidence; Japan; Male; Prospective Studies; Risk Factors

The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer's Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging. - Mielke, Michelle M; Haughey, Norman J; Han, Dingfen; An, Yang; Bandaru, Veera Venkata Ratnam; Lyketsos, Constantine G; Ferrucci, Luigi; Resnick, Susan M (J Alzheimers Dis, 2016)
BACKGROUND: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. OBJECTIVE: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. METHODS: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. RESULTS: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers. CONCLUSION: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

The Association Between Retinal Neuronal Layer and Brain Structure is Disrupted in Patients with Cognitive Impairment and Alzheimer's Disease. - Liu, Siwei; Ong, Yi-Ting; Hilal, Saima; Loke, Yng Miin; Wong, Tien Y; Chen, Christopher Li-Hsian; Cheung, Carol Y; Zhou, Juan (J Alzheimers Dis, 2016)
Both healthy and pathological aging due to Alzheimer's disease (AD) are associated with decreased brain grey matter volume (GMV) and disrupted white matter (WM) microstructure. Thinner macular ganglion cell-inner plexiform layer (GC-IPL) measured by spectral-domain optical coherence tomography has been reported in patients with AD and mild cognitive impairment. Emerging evidence suggested a link between thinner GC-IPL and lower GMV in subjects with no dementia using region-of-interest-based approach. However, it remains unknown whether GC-IPL thickness is associated with brain WM microstructure and how such association differed between normal and cognitively impaired subjects. Here, for subjects with no cognitive impairment (NCI), thinner GC-IPL was associated with lower WM microstructure integrity in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tracts, anterior thalamic radiation, and cingulum regions, while it was weakly associated with lower GMV in visual cortex and cerebellum. Nevertheless, these retina-brain associations were disrupted in the presence of cognitive impairment. Correlations between GMV and GC-IPL were lost in patients with cognitive impairment but no dementia (CIND) and AD patients. GC-IPL was related to WM microstructural disruption in similar regions with decreased significance. In contrast, lower WM microstructure integrity in the fornix showed a trend of correlation with thinner GC-IPL in both CIND and AD but not NCI. Collectively, our findings suggest the possible physiological retina-brain relationship in healthy aging, which might be disrupted by disease-induced changes in patients with cognitive impairment. Longitudinal study with larger patient sample should follow to confirm the disease mechanism behind these retina-brain relationship changes.

Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study. - Araújo, Larissa Fortunato; Mirza, Saira Saeed; Bos, Daniel; Niessen, Wiro J; Barreto, Sandhi Maria; van der Lugt, Aad; Vernooij, Meike W; Hofman, Albert; Tiemeier, Henning; Ikram, M Arfan (J Alzheimers Dis, 2016)
BACKGROUND: Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia. OBJECTIVE: To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance. METHODS: In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0-1, >1-3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders. RESULTS: We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95% CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95% CI:0.39;1.88)], Word Fluency test [0.74(95% CI:0.04,1.45)], Stroop interference task [1.82(95% CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95% CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally. CONCLUSION: We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.

Association of Plasma Aβ40 Peptides, But Not Aβ42, with Coronary Artery Disease and Diabetes Mellitus. - Roeben, Benjamin; Maetzler, Walter; Vanmechelen, Eugeen; Schulte, Claudia; Heinzel, Sebastian; Stellos, Konstantinos; Godau, Jana; Huber, Heiko; Brockmann, Kathrin; Wurster, Isabel; Gaenslen, Alexandra; Grüner, Eva; et al. (J Alzheimers Dis, 2016)
BACKGROUND/OBJECTIVE: Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals. METHODS: Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records. RESULTS: Plasma Aβ1 - 40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOEɛ4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype. DISCUSSION: Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer's disease.

Association of Platelet Serotonin Levels in Alzheimer's Disease with Clinical and Cerebrospinal Fluid Markers. - Tajeddinn, Walid; Fereshtehnejad, Seyed-Mohammad; Seed Ahmed, Mohammed; Yoshitake, Takashi; Kehr, Jan; Shahnaz, Tasmin; Milovanovic, Micha; Behbahani, Homira; Höglund, Kina; Winblad, Bengt; Cedazo-Minguez, Angel; Jelic, Vesna; et al. (J Alzheimers Dis, 2016)
INTRODUCTION: Serotonin (5-HT) is involved in the pathology of Alzheimer's disease (AD). OBJECTIVE: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-β 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms. METHODS: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD). RESULTS: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normalization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/Aβ42 ratio (p = 0.001), compared to those with high 5-HT levels. CONCLUSION: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.

Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. - Karakis, Ioannis; Pase, Matthew P; Beiser, Alexa; Booth, Sarah L; Jacques, Paul F; Rogers, Gail; DeCarli, Charles; Vasan, Ramachandran S; Wang, Thomas J; Himali, Jayandra J; Annweiler, Cedric; Seshadri, Sudha (J Alzheimers Dis, 2016)
BACKGROUND: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts. OBJECTIVE: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function. METHODS: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n = 1663), multiple neuropsychological tests (n = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139). RESULTS: In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β= -0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. CONCLUSIONS: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.
Keywords: Adult; Aging; Brain; Cohort Studies; Dementia; Female; Humans; Incidence; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Regression Analysis; Risk; Sensitivity and Specificity; Vitamin D

Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study. - Nishihira, Junko; Tokashiki, Takashi; Higashiuesato, Yasushi; Willcox, Donald Craig; Mattek, Nora; Shinto, Lynne; Ohya, Yusuke; Dodge, Hiroko H (J Alzheimers Dis, 2016)
BACKGROUND: Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known. OBJECTIVE: To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old. METHODS: The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1±3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating <1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letter). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia. RESULTS: Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders. CONCLUSIONS: Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.
Keywords: Age Factors; Aged, 80 and over; Arachidonic Acid; Blood Chemical Analysis; Cognition; Cross-Sectional Studies; Educational Status; Fatty Acids, Omega-3; Female; Humans; Japan; Logistic Models; Male; Mental Status Schedule; Obesity; Prospective Studies; Sex Factors

AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. - Eketjäll, Susanna; Janson, Juliette; Kaspersson, Karin; Bogstedt, Anna; Jeppsson, Fredrik; Fälting, Johanna; Haeberlein, Samantha Budd; Kugler, Alan R; Alexander, Robert C; Cebers, Gvido (J Alzheimers Dis, 2016)
A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.
Keywords: Administration, Oral; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Blood Chemical Analysis; Blood-Brain Barrier; Brain; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Guinea Pigs; Humans; Imidazoles; Kinetics; Male; Mice, Inbred C57BL; Peptide Fragments; Spiro Compounds

AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging. - Ordoñez-Gutierrez, Lara; Fernandez-Perez, Ivan; Herrera, Jose Luis; Anton, Marta; Benito-Cuesta, Irene; Wandosell, Francisco (J Alzheimers Dis, 2016)
Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease. - Ibarria, Marta; Alegret, Montserrat; Valero, Sergi; Morera, Amèrica; Guitart, Marina; Cañabate, Pilar; Moreno, Mariola; Lara, Susana; Diego, Susana; Hernández, Joan; Tantinyá, Natàlia; Vera, Maribel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied. OBJECTIVE: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP. METHODS: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years). CONCLUSIONS: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Combined Modality Therapy; Disease Progression; Female; Humans; Male; Neuropsychological Tests; Psychotherapy; Severity of Illness Index; Treatment Outcome

Biofunctionalized Silica Nanoparticles: Standards in Amyloid-β Oligomer-Based Diagnosis of Alzheimer's Disease. - Hülsemann, Maren; Zafiu, Christian; Kühbach, Katja; Lühmann, Nicole; Herrmann, Yvonne; Peters, Luriano; Linnartz, Christina; Willbold, Johannes; Kravchenko, Kateryna; Kulawik, Andreas; Willbold, Sabine; Bannach, Oliver; et al. (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) oligomers represent a promising biomarker for the early diagnosis of Alzheimer's disease (AD). However, state-of-the-art methods for immunodetection of Aβ oligomers in body fluids show a large variability and lack a reliable and stable standard that enables the reproducible quantitation of Aβ oligomers. At present, the only available standard applied in these assays is based on a random aggregation process of synthetic Aβ and has neither a defined size nor a known number of epitopes. In this report, we generated a highly stable standard in the size range of native Aβ oligomers that exposes a defined number of epitopes. The standard consists of a silica nanoparticle (SiNaP), which is functionalized with Aβ peptides on its surface (Aβ-SiNaP). The different steps of Aβ-SiNaP synthesis were followed by microscopic, spectroscopic and biochemical analyses. To investigate the performance of Aβ-SiNaPs as an appropriate standard in Aβ oligomer immunodetection, Aβ-SiNaPs were diluted in cerebrospinal fluid and quantified down to a concentration of 10 fM in the sFIDA (surface-based fluorescence intensity distribution analysis) assay. This detection limit corresponds to an Aβ concentration of 1.9 ng l-1 and lies in the sensitivity range of currently applied diagnostic tools based on Aβ oligomer quantitation. Thus, we developed a highly stable and well-characterized standard for the application in Aβ oligomer immunodetection assays that finally allows the reproducible quantitation of Aβ oligomers down to single molecule level and provides a fundamental improvement for the worldwide standardization process of diagnostic methods in AD research.

Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab. - Russu, Alberto; Samtani, Mahesh N; Xu, Steven; Adedokun, Omoniyi J; Lu, Ming; Ito, Kaori; Corrigan, Brian; Raje, Sangeeta; Liu, Enchi; Brashear, H Robert; Styren, Scot; Hu, Chuanpu (J Alzheimers Dis, 2016)
BACKGROUND: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients. OBJECTIVE: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. METHODS: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. RESULTS: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. CONCLUSIONS: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-β-Induced Neuronal Death. - Fernandez, Ana M; Hervas, Ruben; Dominguez-Fraile, Manuel; Garrido, Victoria Navarro; Gomez-Gutierrez, Patricia; Vega, Miguel; Vitorica, Javier; Perez, Juan J; Torres Aleman, Ignacio (J Alzheimers Dis, 2016)
Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.

Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. - Westwood, Sarah; Leoni, Emanuela; Hye, Abdul; Lynham, Steven; Khondoker, Mizanur R; Ashton, Nicholas J; Kiddle, Steven J; Baird, Alison L; Sainz-Fuertes, Ricardo; Leung, Rufina; Graf, John; Hehir, Cristina Tan; et al. (J Alzheimers Dis, 2016)
Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Brain Atrophy of Secondary REM-Sleep Behavior Disorder in Neurodegenerative Disease. - Kim, Hee-Jin; Im, Hyung Kyun; Kim, Juhan; Han, Jee-Young; de Leon, Mony; Deshpande, Anup; Moon, Won-Jin (J Alzheimers Dis, 2016)
BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy. OBJECTIVE: We investigated that dementia with RBD might show distinctive cortical atrophic patterns. METHODS: A total of 31 patients with idiopathic Parkinson's disease (IPD), 23 with clinically probable Alzheimer's disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects. RESULTS: Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes. CONCLUSION: The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α-synucleinopathy.

Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer's Disease Risk by Altering Neuronal Degeneration. - Wang, Hui-Fu; Wan, Yu; Hao, Xiao-Ke; Cao, Lei; Zhu, Xi-Chen; Jiang, Teng; Tan, Meng-Shan; Tan, Lin; Zhang, Dao-Qiang; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2016)
BACKGROUND: Bridging integrator 1 (BIN1) has been identified as one of the most associated loci for Alzheimer's disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro. However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed. OBJECTIVE: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis. METHODS: We calculated the associations of BIN1 loci with these markers at baseline and follow-up in multiple linear models in 812 ADNI subjects. RESULTS: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc = 0.047, rs13031703: pc = 0.042) and P-tau (rs744373: pc = 0.044, rs13031703: pc = 0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc = 0.011), CA1 (rs1469980: pc = 0.029) and parahippocampus (rs72838284, pc = 0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals. CONCLUSION: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology.
Keywords: Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Databases, Factual; European Continental Ancestry Group; Female; Follow-Up Studies; Genetic Predisposition to Disease; Glucose; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Degeneration; Nuclear Proteins; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Risk; tau Proteins; Tumor Suppressor Proteins

Cerebral Arterial Occlusion Did Not Promote the Prevalence of Cerebral Amyloid Angiopathy. - Honda, Kazuhiro (J Alzheimers Dis, 2016)
BACKGROUND: An impairment of amyloid-β (Aβ) clearance has been suggested in Alzheimer's disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. OBJECTIVE: This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). METHODS: Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain. RESULTS: Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. CONCLUSION: In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA.

Cerebral Microbleeds and Cerebrovascular Reactivity in the General Population: The EDAN Study. - Akoudad, Saloua; Gurol, M Edip; Fotiadis, Panagiotis; Koudstaal, Peter J; Hofman, Albert; Ikram, M Arfan; Greenberg, Steven M; Vernooij, Meike W (J Alzheimers Dis, 2016)
BACKGROUND: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA. OBJECTIVE: We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds. METHODS: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all≥55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student's t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds. RESULTS: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p = 0.179 and p = 0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds. CONCLUSIONS: In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA.

Cerebral White Matter Changes on Therapeutic Response to Rivastigmine in Alzheimer's Disease. - Ho, Bo-Lin; Kao, Yi-Hui; Chou, Mei-Chuan; Yang, Yuan-Han (J Alzheimers Dis, 2016)
BACKGROUND: Rivastigmine has been approved in the treatment of Alzheimer's disease (AD) patients as it can inhibit acetyl- and butyryl-cholinesterase and provide neuroprotective effects involving the synapses. White matter changes (WMCs) are frequently observed in AD, and clinical-pathological correlations imply their possible impacts on cognitive function by interference with cortical and subcortical neuronal pathways. OBJECTIVE: To evaluate the therapeutic effects of rivastigmine in AD patients with cerebral WMCs. METHODS: Clinically diagnosed AD patients from Kaohsiung Municipal Ta-Tung hospital were recruited together with their cranial magnetic resonance imaging and a series of annual psychometric tests, including Mini-Mental State Examination (MMSE) and sum of boxes of clinical dementia rating scale (CDR-SB). WMCs were rated through the modified Fazekas scale for the periventricular and deep WMCs. RESULTS: In total, 87 AD patients treated with rivastigmine were enrolled. Patients at severe stage of WMCs, compared to mild stage ones, had significant improvement evaluated by MMSE (periventricular WMCs, p = 0.025; deep WMCs, p = 0.030), but not CDR-SB. Compared to the worsening group, the clinically improving group had a significant higher ratio of pre-existing hypertension in terms of cognitive performance [p = 0.016, odds ratio (OR) = 3.48, 95% CI = 1.25-10.34], while having younger age (p = 0.043, OR = 0.11, 95% CI = 0.01-1.12) in terms of global status. CONCLUSION: Rivastigmine may provide better benefits in cognitive function, but not global status, for AD patients with more advanced WMCs. The detailed mechanisms still have to be determined in future studies.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation. - Renard, Dimitri; Wacongne, Anne; Ayrignac, Xavier; Charif, Mahmoud; Fourcade, Genevieve; Azakri, Souhayla; Le Floch, Anne; Bouly, Stephane; Marelli, Cecilia; Arquizan, Caroline; Hirtz, Christophe; Gabelle, Audrey; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). RESULTS: For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aβ40 (p <  0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cerebral Amyloid Angiopathy; Female; Humans; Inflammation; Male; Middle Aged; Retrospective Studies; tau Proteins

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis. - Renard, Dimitri; Gabelle, Audrey; Hirtz, Christophe; Demattei, Christophe; Thouvenot, Eric; Lehmann, Sylvain (J Alzheimers Dis, 2016)
We evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40), amyloid-β 1-42 (Aβ42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n = 13), Alzheimer's disease patients (AD, n = 42), and controls (n = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p = 0.019) and lower Aβ42 (p = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD (p = 0.0063, p = 0.0004, and p = 0022, respectively), and higher p-tau compared to LH-CAA (p = 0.012).

Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future "Non-Cognitive" Outcomes of Alzheimer's Disease. - Ingber, Adam P; Hassenstab, Jason; Fagan, Anne M; Benzinger, Tammie L S; Grant, Elizabeth A; Holtzman, David M; Morris, John C; Roe, Catherine M (J Alzheimers Dis, 2016)
BACKGROUND: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood. OBJECTIVE: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. METHODS: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. RESULTS: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. CONCLUSIONS: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease. - Melah, Kelsey E; Lu, Sharon Yuan-Fu; Hoscheidt, Siobhan M; Alexander, Andrew L; Adluru, Nagesh; Destiche, Daniel J; Carlsson, Cynthia M; Zetterberg, Henrik; Blennow, Kaj; Okonkwo, Ozioma C; Gleason, Carey E; Dowling, N Maritza; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. OBJECTIVE: To determine whether neuroinflammation exacerbates neural damage in preclinical AD. METHODS: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. RESULTS: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. CONCLUSION: Inflammation may play a role in neural damage in preclinical AD.
Keywords: Adipokines; Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Chemokine CCL2; Chitinase-3-Like Protein 1; Diffusion Tensor Imaging; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Lectins; Male; Microglia; Middle Aged; Peptide Fragments; tau Proteins; White Matter

CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease. - Shankle, William R; Hara, Junko; Barrentine, Lori W; Curole, Melanie V (J Alzheimers Dis, 2016)
We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease. - Rosenberg, Paul B; Lanctôt, Krista L; Herrmann, Nathan; Mintzer, Jacobo E; Porsteinsson, Anton P; Sun, Xiaoying; Raman, Rema (J Alzheimers Dis, 2016)
BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). OBJECTIVE: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). METHODS: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. RESULTS: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. CONCLUSION: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

Cholesteryl Ester Transfer Protein Intimately Involved in Dyslipidemia-Related Susceptibility to Cognitive Deficits in Type 2 Diabetic Patients. - Sun, Jie; Cai, Rongrong; Huang, Rong; Wang, Pin; Tian, Sai; Sun, Haixia; Xia, Wenqing; Wang, Shaohua (J Alzheimers Dis, 2016)
BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia. OBJECTIVE: We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients. METHODS: We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification. RESULTS: There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r = -0.638; p < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r = -0.266; p = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level ≥2.59 mmol/L, or high density lipoproteins level ≤1.0 mmol/L for men and ≤1.3 mmol/L for women, or TG level ≥1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all ps < 0.05). CONCLUSIONS: CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients.

Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model. - Zhai, Yun; Yamashita, Toru; Nakano, Yumiko; Sun, Zhuoran; Shang, Jingwei; Feng, Tian; Morihara, Ryuta; Fukui, Yusuke; Ohta, Yasuyuki; Hishikawa, Nozomi; Abe, Koji (J Alzheimers Dis, 2016)
Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action.

Chronic Stress Aggravates Cognitive Impairment and Suppresses Insulin Associated Signaling Pathway in APP/PS1 Mice. - Han, Bing; Yu, Lulu; Geng, Yuan; Shen, Li; Wang, Hualong; Wang, Yanyong; Wang, Jinhua; Wang, Mingwei (J Alzheimers Dis, 2016)
Differences in brain function are a central determinant of individual variability in the stress response. Brain dysfunction, resulting from aging, illness, or genetic mutations, could reduce the tolerance of glucocorticoid stress hormones. When glucocorticoids exceed tolerable limits in the brain, especially in the hippocampus, this state can cause or aggravate structural or functional damage. However, the underlying mechanisms are not well understood. This study investigated the effects of chronic unpredictable mild stress (CUMS) in APP/PS1 and control mice. We showed that 4 weeks of CUMS exposure increased the levels of glucocorticoids, reduced glucocorticoids receptor expression, and promoted senile plaque deposition, neuronal injury, and cognitive impairment in APP/PS1 mice compared to controls. The phosphorylation of insulin receptor, insulin receptor substrate 1 and associated signaling pathways (Akt, mTOR, p70S6K, ERK1/2, and PTEN) were decreased in hippocampus in APP/PS1 mice compared to control mice, while no changes were found in GSK3 and TSC2 phosphorylation. Furthermore, insulin and Akt/mTOR signaling pathways were further decreased in APP/PS1 mice after CUMS, which may be related to the activation of the stress-activated protein kinase JNK, while no alterations in the levels of phosphorylated ERK1/2, GSK3, PTEN, or TSC2 were observed. These results suggest that chronic stress may affect the insulin and Akt/mTOR pathway, accelerating the progression of Alzheimer's disease in vulnerable individuals.

Classification of Neuropsychiatric Symptoms Requiring Antipsychotic Treatment in Patients with Alzheimer's Disease: Analysis of the CATIE-AD Study. - Nagata, Tomoyuki; Shinagawa, Shunichiro; Nakajima, Shinichiro; Plitman, Eric; Mihashi, Yukiko; Hayashi, Shogo; Mimura, Masaru; Nakayama, Kazuhiko (J Alzheimers Dis, 2016)
BACKGROUND: The Neuropsychiatric Inventory (NPI) comprises 12 items, which were conventionally determined by psychopathological symptoms of patients with dementia. The clinical rating scales with structured questionnaires have been useful to evaluate neuropsychiatric symptoms (NPSs) of patients with dementia over the past twenty year. OBJECTIVE: The aim of this study was to classify the conventional NPSs in patients with Alzheimer's disease (AD) requiring antipsychotic treatment for their NPSs into distinct clusters to simplify assessment of these numerous symptoms. METHODS: Twelve items scores (product of severity and frequency of each symptom) in the NPI taken from the baseline visit were classified into subgroups by principle component analysis using data from 421 outpatients with AD enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Phase 1. Chi square tests were conducted to examine the co-occurrence of the subgroups. RESULTS: We found four distinct clusters: aggressiveness (agitation and irritabilities), apathy and eating problems (apathy and appetite/eating disturbance), psychosis (delusions and hallucinations), and emotion and disinhibition (depression, euphoria, and disinhibition). Anxiety, aberrant motor behavior, and sleep disturbance were not included by these clusters. Apathy and eating problems, and emotion and disinhibition co-occurred (p = 0.002), whereas aggressiveness and psychosis occurred independent of the other clusters. CONCLUSIONS: Four distinct category clusters were identified from NPSs in patients with AD requiring antipsychotic treatment. Future studies should investigate psychosocial backgrounds or risk factors of each distinct cluster, in addition to their longitudinal course over treatment intervention.
Keywords: Aged; Aged, 80 and over; Aggression; Alzheimer Disease; Antipsychotic Agents; Apathy; Cluster Analysis; Female; Humans; Male; Psychiatric Status Rating Scales; Psychomotor Agitation; Psychotic Disorders; Retrospective Studies; Severity of Illness Index

Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease. - Bonet-Costa, Vicent; Herranz-Pérez, Vicente; Blanco-Gandía, MariCarmen; Mas-Bargues, Cristina; Inglés, Marta; Garcia-Tarraga, Patricia; Rodriguez-Arias, Marta; Miñarro, Jose; Borras, Consuelo; Garcia-Verdugo, Jose Manuel; Viña, Jose (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. Treatment of an Alzheimer's disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer's disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Astrocytes; Avoidance Learning; Brain; Cells, Cultured; Disease Models, Animal; Female; Genistein; Habituation, Psychophysiologic; Maze Learning; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Nootropic Agents; Olfactory Perception; Plaque, Amyloid; PPAR gamma; Recognition (Psychology); Tetrahydronaphthalenes

Clinical Conversion or Reversion of Mild Cognitive Impairment in Community versus Hospital Based Studies: GDEMCIS (Gwangju Dementia and Mild Cognitive Impairment Study) and CREDOS (Clinical Research Center for Dementia of South Korea). - Roh, Hyun Woong; Hong, Chang Hyung; Lee, Yunhwan; Lee, Kang Soo; Chang, Ki Jung; Kang, Dae Ryong; Lee, Jung-Dong; Choi, Seong Hye; Kim, Seong Yoon; Na, Duk L; Seo, Sang Won; Kim, Doh Kwan; et al. (J Alzheimers Dis, 2016)
BACKGROUND: In keeping with increasing interest in dementia, few recent studies suggest that clinical course of mild cognitive impairment vary across different studies with hospital-based subjects showing higher rates of conversion than community-based subjects. OBJECTIVE: The main objective of the present study was to assess whether the clinical conversion or reversion rates differ according to recruitment source. METHODS: The baseline study subjects comprised of patients who were diagnosed with mild cognitive impairment in community-based GDEMCIS or hospital-based CREDOS. The two studies had nearly the same protocol and were performed over a similar period. We used propensity score matching for baseline comparability. After that, Cox proportional hazards regression analyses were conducted to estimate the hazard ratios and 95% confidence intervals of clinical conversion or reversion. RESULTS: Based on 89 GDEMCIS subjects, 1 : 4 propensity score matching was conducted and 356 CREDOS subjects were selected. After adjusting for covariates including baseline demographics, comorbidity, depression, disability, and neuropsychological result, Cox proportional hazard regression analysis for time to clinical conversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 2.13 (95% CI, 1.08-4.21), as compared to recruitment from community-based GDEMCIS. Similarly, Cox proportional hazard regression analysis for time to reversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 0.34 (95% CI, 0.20-0.59), as compared to recruitment from community-based GDEMCIS. CONCLUSION: The present study demonstrated that even after the matching process and adjustments for baseline covariates, recruitment source greatly affected the course of mild cognitive impairment.

Clinical Impact of a Second FDG-PET in Atypical/Unclear Dementia Syndromes. - Bergeron, David; Beauregard, Jean-Mathieu; Guimond, Jean; Fortin, Marie-Pierre; Houde, Michèle; Poulin, Stéphane; Verret, Louis; Bouchard, Rémi W; Laforce, Robert (J Alzheimers Dis, 2016)
Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management.
Keywords: Adult; Brain; Dementia; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies

Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers. - Bensaïdane, Mohamed Reda; Beauregard, Jean-Mathieu; Poulin, Stéphane; Buteau, François-Alexandre; Guimond, Jean; Bergeron, David; Verret, Louis; Fortin, Marie-Pierre; Houde, Michèle; Bouchard, Rémi W; Soucy, Jean-Paul; Laforce, Robert (J Alzheimers Dis, 2016)
Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer's disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers' outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones.

Clinical utility of the informant AD8 as a dementia case finding instrument in primary healthcare. - Chan, Qun Lin; Xu, Xin; Shaik, Muhammad Amin; Chong, Steven Shih Tsze; Hui, Richard Jor Yeong; Chen, Christopher Li-Hsian; Dong, YanHong (J Alzheimers Dis, 2016)
The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91-0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79-0.94), p = 0.04; MoCA AUC (95% CI): 0.88 (0.82-0.95), p = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings.
Keywords: Aged; Aged, 80 and over; Dementia; Female; Humans; Language; Logistic Models; Male; Mass Screening; Middle Aged; Neuropsychological Tests; Primary Health Care; Reproducibility of Results; ROC Curve; Sensitivity and Specificity; Singapore; Surveys and Questionnaires

Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer's Disease: Comparison and Contrast with Microtubule-Associated Protein Tau. - Hensley, Kenneth; Kursula, Petri (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit.
Keywords: Alzheimer Disease; Animals; Humans; Intercellular Signaling Peptides and Proteins; Nerve Tissue Proteins; tau Proteins

Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients. - Ritter, Kerstin; Lange, Catharina; Weygandt, Martin; Mäurer, Anja; Roberts, Anna; Estrella, Melanie; Suppa, Per; Spies, Lothar; Prasad, Vikas; Steffen, Ingo; Apostolova, Ivayla; Bittner, Daniel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease. OBJECTIVE: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients. METHODS: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer's disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. RESULTS: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p≤0.001). Integration of all modalities resulted in 76% accuracy (p≤0.001). CONCLUSION: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process.

Community-Dwelling People Screened Positive for Dementia in Primary Care: A Comprehensive, Multivariate Descriptive Analysis Using Data from the DelpHi-Study. - Thyrian, Jochen René; Eichler, Tilly; Michalowsky, Bernhard; Wucherer, Diana; Reimann, Melanie; Hertel, Johannes; Richter, Steffen; Dreier, Adina; Hoffmann, Wolfgang (J Alzheimers Dis, 2016)
BACKGROUND: Efficient help and care for people with dementia (PWD) is dependent on knowledge about PWD in primary care. OBJECTIVE: This analysis comprehensively describes community-dwelling PWD in primary care with respect to various dementia care specific variables. METHODS: The analyses are based on baseline data of the ongoing general practitioner-based, randomized, controlled intervention trial DelpHi-MV (Dementia: life- and person-centered help). 6,838 patients were screened for dementia in 136 GP practices; 17.1% were screened positive, 54.4% of those agreed to participate and data could be assessed in n = 516 subjects. We assessed age, sex, living situation, cognitive status, functional status, level of impairment, comorbidities, formal diagnosis of dementia, depression, neuropsychiatric symptoms, quality of life, utilization of medical support, and pharmacological therapy. RESULTS: Concerning clinical-, dementia-, and health-related variables, the sample under examination was on average mildly cognitively and functionally impaired (MMSE, m = 22.2; BADL, m = 3.7). A level of care was assigned in 38.0%. Depression was identified in 15.4% and other frequent comorbidities were high blood pressure (83.3%), coronary heart diseases (37.1%), cerebrovascular diseases (22.3%), among others. In 48.6%, neuropsychiatric symptoms were present in a clinically relevant severity. Pharmacological treatment with antidementia medication was received by 25.8% and antidepressant medication by 14.0%. Utilization of services was generally low. CONCLUSION: The comprehensive description of people screened positive for dementia in primary care reveals a complex and unique population of patients. They are considerably underdiagnosed and in their majority mildly to moderately affected. More in-depth analyses are needed to study relations, associations and interactions between different variables.

Comorbid Mild Cognitive Impairment and Depressive Symptoms Predict Future Dementia in Community Older Adults: A 24-Month Follow-Up Longitudinal Study. - Makizako, Hyuma; Shimada, Hiroyuki; Doi, Takehiko; Tsutsumimoto, Kota; Hotta, Ryo; Nakakubo, Sho; Makino, Keitaro; Suzuki, Takao (J Alzheimers Dis, 2016)
BACKGROUND: Older adults with mild cognitive impairment (MCI) are non-demented, but demonstrate cognitive dysfunction, and have significantly higher risk of progressing to dementia. A better understanding of more sensitive risk factors, such as combination of cognitive and psychological status, for progression of MCI to dementia may be crucial for prevention of development of dementia. OBJECTIVE: To examine MCI, depressive symptoms, and comorbid MCI and depressive symptoms as risk factors for development of dementia. METHODS: A total of 3,663 community-dwelling older people were included in this prospective longitudinal study. MCI was determined by age- and education-adjusted objective cognitive impairment using computerized comprehensive cognitive measures including memory, attention/executive function, and processing speed. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) and defined by a GDS score of 6 or more. RESULTS: During the 24-month follow-up period, 72 participants (2.0%) developed dementia. Baseline MCI was significantly associated with an increased risk of incident dementia (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.8-5.5) but depressive symptoms were not (2.0; 1.0-4.2) after adjusting for age, sex, education, prescribed medications, and walking speed. Participants with comorbid MCI and depressive symptoms at baseline had a higher risk of developing dementia (HR, 4.8; 2.3-10.5). CONCLUSION: Although MCI and depressive symptoms may be associated with increased risk for incident dementia independently, comorbid MCI and depressive symptoms have a significantly greater impact on dementia development among community-dwelling older adults.

Comparing Longitudinal Behavior Changes in the Primary Progressive Aphasias. - Van Langenhove, Tim; Leyton, Cristian E; Piguet, Olivier; Hodges, John R (J Alzheimers Dis, 2016)
BACKGROUND: Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants. OBJECTIVE: To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time. METHODS: We measured behavioral changes in 73 prospectively recruited PPA (30 sv-PPA, 22 nfv-PPA, and 21 lv-PPA), as well as 33 behavioral variant frontotemporal dementia (bv-FTD) and 31 Alzheimer's disease (AD) patients, at baseline and after 1 year, using the Cambridge Behavioural Inventory Revised. All included patients had mild dementia severity at baseline. RESULTS: Both at baseline and follow-up, sv-PPA exhibited significantly more behavioral disturbances of the type characteristic of bv-FTD compared with other PPA variants. 74% of sv-PPA patients with mild dementia severity exhibited at least one behavior disturbance at baseline, which increased to 84% during follow-up. Behavioral symptoms did not differ between nfv-PPA and lv-PPA groups at baseline. At follow-up, however, empathy loss was significantly more pronounced in nfv-PPA. The prevalence and course of behavioral symptoms in lv-PPA was similar to that found in AD. CONCLUSIONS: sv-PPA show more prominent FTD-like behavioral disturbances compared with other PPA variants which typically emerge already early in the disease course. Empathy loss may be an important factor that helps differentiating nfv-PPA from lv-PPA. Our results may allow improved prediction of likely progression in behavioral symptoms across the PPA variants.

Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. - Lelental, Natalia; Brandner, Sebastian; Kofanova, Olga; Blennow, Kaj; Zetterberg, Henrik; Andreasson, Ulf; Engelborghs, Sebastiaan; Mroczko, Barbara; Gabryelewicz, Tomasz; Teunissen, Charlotte; Mollenhauer, Brit; Parnetti, Lucilla; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.
Keywords: Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Biomarkers; Cattle; Clinical Chemistry Tests; Dementia; Humans; Peptide Fragments; Quality Control; Reference Standards; Serum Albumin, Bovine; Sodium Azide; tau Proteins; Time Factors; Tissue Preservation

Comparison of Prefrontal Atrophy and Episodic Memory Performance in Dysexecutive Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia. - Wong, Stephanie; Bertoux, Maxime; Savage, Greg; Hodges, John R; Piguet, Olivier; Hornberger, Michael (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) sometimes presents with prominent executive dysfunction and associated prefrontal cortex atrophy. The impact of such executive deficits on episodic memory performance as well as their neural correlates in AD, however, remains unclear. The aim of the current study was to investigate episodic memory and brain atrophy in AD patients with relatively spared executive functioning (SEF-AD; n = 12) and AD patients with relatively impaired executive functioning (IEF-AD; n = 23). We also compared the AD subgroups with a group of behavioral-variant frontotemporal dementia patients (bvFTD; n = 22), who typically exhibit significant executive deficits, and age-matched healthy controls (n = 38). On cognitive testing, the three patient groups showed comparable memory profiles on standard episodic memory tests, with significant impairment relative to controls. Voxel-based morphometry analyses revealed extensive prefrontal and medial temporal lobe atrophy in IEF-AD and bvFTD, whereas this was limited to the middle frontal gyrus and hippocampus in SEF-AD. Moreover, the additional prefrontal atrophy in IEF-AD and bvFTD correlated with memory performance, whereas this was not the case for SEF-AD. These findings indicate that IEF-AD patients show prefrontal atrophy in regions similar to bvFTD, and suggest that this contributes to episodic memory performance. This has implications for the differential diagnosis of bvFTD and subtypes of AD.
Keywords: Aged; Alzheimer Disease; Atrophy; Databases, Factual; Diagnosis, Differential; Executive Function; Female; Frontotemporal Dementia; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory, Episodic; Middle Aged; Neuropsychological Tests; Prefrontal Cortex

Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease. - Hakobyan, Svetlana; Harding, Katharine; Aiyaz, Mohammed; Hye, Abdul; Dobson, Richard; Baird, Alison; Liu, Benjamine; Harris, Claire Louise; Lovestone, Simon; Morgan, Bryan Paul (J Alzheimers Dis, 2016)
There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

Connected Language in Late Middle-Aged Adults at Risk for Alzheimer's Disease. - Mueller, Kimberly Diggle; Koscik, Rebecca L; Turkstra, Lyn S; Riedeman, Sarah K; LaRue, Asenath; Clark, Lindsay R; Hermann, Bruce; Sager, Mark A; Johnson, Sterling C (J Alzheimers Dis, 2016)
Connected language is often impaired among people with Alzheimer's disease (AD), yet little is known about when language difficulties first emerge on the path to a clinical diagnosis. The objective of this study was to determine whether individuals with psychometric (preclinical) evidence of amnestic mild cognitive impairment (pMCI) showed deficits in connected language measures. Participants were 39 pMCI and 39 cognitively healthy (CH) adults drawn from the Wisconsin Registry for Alzheimer's Prevention, who were matched for age, literacy, and sex. Participants completed a connected language task in which they described the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Language samples were analyzed across three language domains: content, syntactic complexity, and speech fluency. Paired t-tests were used to compare CH and pMCI groups on all variables, and Cohen's d effect sizes were calculated for each comparison. The CH and pMCI groups differed significantly on measures of content (e.g., CH group produced more semantic units, more unique words and had larger idea density, on average, than the pMCI group). The picture description findings are consistent with previous retrospective studies showing semantic language differences in adults with autopsy-confirmed AD. Given that these comparisons are between cognitively healthy and pMCI individuals (before a clinical MCI diagnosis), these findings may represent subtle language difficulty in spontaneous speech, and may be predictive of larger language changes over time.

Contribution of the Cholinergic System to Verbal Memory Performance in Mild Cognitive Impairment. - Peter, Jessica; Lahr, Jacob; Minkova, Lora; Lauer, Eliza; Grothe, Michel J; Teipel, Stefan; Köstering, Lena; Kaller, Christoph P; Heimbach, Bernhard; Hüll, Michael; Normann, Claus; Nissen, Christoph; et al. (J Alzheimers Dis, 2016)
Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

Cost Related to Dementia in the Young and the Impact of Etiological Subtype on Cost. - Kandiah, Nagaendran; Wang, Vivian; Lin, Xuling; Nyu, Mei Mei; Lim, Linda; Ng, Adeline; Hameed, Shahul; Wee, Hwee Lin (J Alzheimers Dis, 2016)
BACKGROUND: Young onset dementia (YOD) presents in individuals who are economically productive and socially active. While the cost related to dementia in the elderly has been widely studied, the cost related to YOD is largely unknown. OBJECTIVE: To study the economic burden of community dwelling YOD in relation to late onset dementia (LOD) and cost of YOD based on etiology. METHODS: In this prospective cross-sectional study of 255 patients attending a tertiary neurology center, data on economic burden, clinical features, and caregiver burden were collected using structured financial questionnaire, standard cognitive and neuropsychiatric measures, and Zarit caregiver burden scale. Cost components were grouped into those relating to direct medical costs, direct non-medical costs, and those related to indirect costs. Cost was also categorized based on etiology of YOD. RESULTS: The mean age at symptom onset in the YOD and LOD cohort was 57.0 (SD 5.1) and 75.0 (SD 5.9) years, respectively. The median annual cost for patients with YOD was almost twice that of LOD (USD 15,815 versus USD 8,396). Indirect cost contributed heavily to cost related to YOD. Even when grouped by dementia etiology, YOD patients with Alzheimer's disease, frontotemporal dementia (FTD), and vascular dementia had higher cost compared to their elderly counterparts. Young onset FTD had the highest cost. 43.2% of YOD reported loss of employment due to dementia, which was significantly higher than that in LOD (2.4%). CONCLUSION: Patients with YOD have a high economic burden. Young patients with FTD have the highest cost followed by vascular dementia and Alzheimer's disease.
Keywords: Age of Onset; Aged; Cohort Studies; Costs and Cost Analysis; Cross-Sectional Studies; Dementia; Female; Humans; Independent Living; Male; Mental Disorders; Middle Aged; Perceptual Disorders; Prospective Studies; Psychiatric Status Rating Scales; Severity of Illness Index; Surveys and Questionnaires; Young Adult

Death Preparation and Boredom Reduction as Functions of Reminiscence in Alzheimer's Disease. - El Haj, Mohamad; Antoine, Pascal (J Alzheimers Dis, 2016)
Reminiscence, or the process of thinking or telling about past experience, is thought to serve social, instrumental, and integrative functions. Our paper investigated these functions in Alzheimer's disease (AD). Twenty-six participants with a clinical diagnosis of probable mild AD and 28 control older adults filled in a French adaptation of the Reminiscence Functions Scale. Eight specific functions were assessed: death preparation, identity, problem-solving, teaching/informing, conversation, boredom reduction, bitterness revival, and intimacy maintenance. Both older adults and AD participants reported reminiscence about their past to prepare themselves for the idea of their own mortality. All participants also reported reminiscence "to reduce boredom" and "for something to do". However, reminiscence for death preparation and boredom reduction was reported more by AD participants than by older adults. In all participants, the death preparation function of reminiscence was significantly correlated with depression. Individuals with AD seem to reminiscence to cope with thoughts about their own mortality. This helps them to see that they have lived a full life and can therefore accept death more calmly. Individuals with AD also seem to cope with boredom by using reminiscence, probably as a tool to fill time or simply to create ease of conversation.

Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ4 Carriers: A Preliminary Study. - Luo, Xiao; Qiu, Tiantian; Xu, Xiaojun; Huang, Peiyu; Gu, Quanquan; Shen, Zhujing; Yu, Xinfeng; Jia, YunLu; Guan, Xiaojun; Song, Ruirui; Zhang, Minming (J Alzheimers Dis, 2016)
The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimer's disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p <  0.05; r = 0.65, p <  0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p <  0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.
Keywords: Aged; Aging; Apolipoprotein E4; Brain; Brain Mapping; Female; Functional Laterality; Genotyping Techniques; Heterozygote; Humans; Magnetic Resonance Imaging; Male; Memory; Neuropsychological Tests; Rest

Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. - Vallortigara, Julie; Whitfield, David; Quelch, William; Alghamdi, Amani; Howlett, David; Hortobágyi, Tibor; Johnson, Mary; Attems, Johannes; O'Brien, John T; Thomas, Alan; Ballard, Clive G; Aarsland, Dag; et al. (J Alzheimers Dis, 2016)
Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.
Keywords: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Analysis of Variance; Cognition Disorders; Dementia; Female; Humans; Male; Mental Status Schedule; Neuropsychological Tests; Regression Analysis; Synaptophysin; tau Proteins; Vesicle-Associated Membrane Protein 2

A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders. - Johnson, Leigh A; Gamboa, Adriana; Vintimilla, Raul; Edwards, Melissa; Hall, James; Weiser, Brent; Yadav, Menaka; Dickensheets, Tony; O'Bryant, Sid E (J Alzheimers Dis, 2016)
BACKGROUND: Late life depression is a prodromal feature and a risk factor for Alzheimer's disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating. OBJECTIVE: Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans. METHODS: Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis. RESULTS: Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p < 0.05) in women, with no significant differences on delay recall in either gender. CONCLUSION: DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline.

Describing the Sequence of Cognitive Decline in Alzheimer's Disease Patients: Results from an Observational Study. - Henneges, Carsten; Reed, Catherine; Chen, Yun-Fei; Dell'Agnello, Grazia; Lebrec, Jeremie (J Alzheimers Dis, 2016)
BACKGROUND: Improved understanding of the pattern of cognitive decline in Alzheimer's disease (AD) would be useful to assist primary care physicians in explaining AD progression to patients and caregivers. OBJECTIVE: To identify the sequence in which cognitive abilities decline in community-dwelling patients with AD. METHODS: Baseline data were analyzed from 1,495 patients diagnosed with probable AD and a Mini-Mental State Examination (MMSE) score ≤ 26 enrolled in the 18-month observational GERAS study. Proportional odds logistic regression models were applied to model MMSE subscores (orientation, registration, attention and concentration, recall, language, and drawing) and the corresponding subscores of the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), using MMSE total score as the index of disease progression. Probabilities of impairment start and full impairment were estimated at each MMSE total score level. RESULTS: From the estimated probabilities for each MMSE subscore as a function of the MMSE total score, the first aspect of cognition to start being impaired was recall, followed by orientation in time, attention and concentration, orientation in place, language, drawing, and registration. For full impairment in subscores, the sequence was recall, drawing, attention and concentration, orientation in time, orientation in place, registration, and language. The sequence of cognitive decline for the corresponding ADAS-cog subscores was remarkably consistent with this pattern. CONCLUSION: The sequence of cognitive decline in AD can be visualized in an animation using probability estimates for key aspects of cognition. This might be useful for clinicians to set expectations on disease progression for patients and caregivers.

Development of a Proxy-Free Objective Assessment Tool of Instrumental Activities of Daily Living in Mild Cognitive Impairment Using Smart Home Technologies. - Jekel, Katrin; Damian, Marinella; Storf, Holger; Hausner, Lucrezia; Frölich, Lutz (J Alzheimers Dis, 2016)
BACKGROUND: The assessment of activities of daily living (ADL) is essential for dementia diagnostics. Even in mild cognitive impairment (MCI), subtle deficits in instrumental ADL (IADL) may occur and signal a higher risk of conversion to dementia. Thus, sensitive and reliable ADL assessment tools are important. Smart homes equipped with sensor technology and video cameras may provide a proxy-free assessment tool for the detection of IADL deficits. OBJECTIVE: The aim of this paper is to investigate the potential of a smart home environment for the assessment of IADL in MCI. METHOD: The smart home consisted of a two-room flat equipped with activity sensors and video cameras. Participants with either MCI or healthy controls (HC) had to solve a standardized set of six tasks, e.g., meal preparation, telephone use, and finding objects in the flat. RESULTS: MCI participants needed more time (1384 versus 938 seconds, p <  0.001) and scored less total points (48 versus 57 points, p <  0.001) while solving the tasks than HC. Analyzing the subtasks, intergroup differences were observed for making a phone call, operating the television, and retrieving objects. MCI participants showed more searching and task-irrelevant behavior than HC. Task performance was correlated with cognitive status and IADL questionnaires but not with participants' age. CONCLUSION: This pilot study showed that smart home technologies offer the chance for an objective and ecologically valid assessment of IADL. It can be analyzed not only whether a task is successfully completed but also how it is completed. Future studies should concentrate on the development of automated detection of IADL deficits.

Development of a Standardized Approach to Disclosing Amyloid Imaging Research Results in Mild Cognitive Impairment. - Lingler, Jennifer H; Butters, Meryl A; Gentry, Amanda L; Hu, Lu; Hunsaker, Amanda E; Klunk, William E; Mattos, Meghan K; Parker, Lisa A; Roberts, J Scott; Schulz, Richard (J Alzheimers Dis, 2016)
The increased use of PET amyloid imaging in clinical research has sparked numerous concerns about whether and how to return such research test results to study participants. Chief among these is the question of how best to disclose amyloid imaging research results to individuals who have cognitive symptoms that could impede comprehension of the information conveyed. We systematically developed and evaluated informational materials for use in pre-test counseling and post-test disclosures of amyloid imaging research results in mild cognitive impairment (MCI). Using simulated sessions, persons with MCI and their family care partners (N = 10 dyads) received fictitious but realistic information regarding brain amyloid status, followed by an explanation of how results impact Alzheimer's disease risk. Satisfaction surveys, comprehension assessments, and focus group data were analyzed to evaluate the materials developed. The majority of persons with MCI and their care partners comprehended and were highly satisfied with the information presented. Focus group data reinforced findings of high satisfaction and included 6 recommendations for practice: 1) offer pre-test counseling, 2) use clear graphics, 3) review participants' own brain images during disclosures, 4) offer take-home materials, 5) call participants post-disclosure to address emerging questions, and 6) communicate seamlessly with primary care providers. Further analysis of focus group data revealed that participants understood the limitations of amyloid imaging, but nevertheless viewed the prospect of learning one's amyloid status as valuable and empowering.
Keywords: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Brain; Brain Chemistry; Cognitive Dysfunction; Disclosure; Family; Female; Focus Groups; Health Communication; Humans; Male; Middle Aged; Patient Satisfaction; Pilot Projects; Positron-Emission Tomography

Diagnostic Value of Cerebrospinal Fluid Biomarkers (Phospho-Tau181, total-Tau, Aβ42, and Aβ40) in Prodromal Stage of Alzheimer's Disease and Dementia with Lewy Bodies. - Bousiges, Olivier; Cretin, Benjamin; Lavaux, Thomas; Philippi, Nathalie; Jung, Barbara; Hezard, Sylvie; Heitz, Camille; Demuynck, Catherine; Gabel, Aurelia; Martin-Hunyadi, Catherine; Blanc, Frédéric (J Alzheimers Dis, 2016)
BACKGROUND: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer's disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1 - 42, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease. OBJECTIVE: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage. METHODS: A total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF. RESULTS: At the prodromal stage, contrary to AD patients, DLB patients' biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients. CONCLUSIONS: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Middle Aged; Peptide Fragments; Prodromal Symptoms; Psychiatric Status Rating Scales; Retrospective Studies; Statistics, Nonparametric; tau Proteins

Differences in Depressive Patterns According to Disease Severityin Early-Onset Alzheimer's Disease. - Yoon, Bora; Yang, Dong Won; Hong, Yun Jeong; Choi, Seong Hye; Park, Sun Ah; Park, Hee Kyung; Kim, Yong Duk; Shim, Yong S (J Alzheimers Dis, 2016)
BACKGROUND & OBJECTIVE: Depression frequently combines with dementia, including early-onset Alzheimer's disease (EOAD). We investigated differences in prevalence and characteristics of depressive symptoms according to dementia severity in EOAD patients. METHODS: The 15-item Korean version of the Geriatric Depression Scale (GDS-15) was administered to 412 EOAD patients. Factor analysis was used to assess GDS-15 factor structure. We subdivided participants into three groups by disease severity, then compared the frequencies and scores of individual GDS-15 items and performed logistic regression analysis to assess associations between depressive symptoms and EOAD stage. RESULTS: Factor analysis yielded three factor categories: 1) "hopelessness and ominousness" (symptoms no. 6, 8, 12, 14, 15); 2) "unhappiness and dissatisfaction" (no. 1, 3, 5, 7, 11); and 3) "monotony and lack of energy" (no. 2, 4, 9, 10, 13). Factor 2 depressive symptoms (no. 1, 5, 11) were less common in moderate EOAD. The risk of Factor 1 symptoms: no. 12 (OR, 2.04; 95% CI, 1.19-3.50; p = 0.010) and 14 (OR, 1.84; 95% CI, 1.07-3.16; p = 0.028) was higher in mild than very mild EOAD. The risk of Factor 2 symptoms: no. 9 (OR, 2.69; 95% CI, 1.08-6.71; p = 0.033) and 13 (OR, 2.12; 95% CI, 1.02-4.40; p = 0.043) was higher in moderate than mild EOAD. CONCLUSION: We confirmed that depressive symptoms differ according to EOAD severity. When assessing depressive symptoms related to dementia progression, we recommend focusing on "hopelessness and ominousness" in very mild EOAD and "unhappiness and dissatisfaction" in mild EOAD.

Different Clinical and Neuroimaging Characteristics in Early Stage Parkinson's Disease with Dementia and Dementia with Lewy Bodies. - Takemoto, Mami; Sato, Kota; Hatanaka, Noriko; Yamashita, Toru; Ohta, Yasuyuki; Hishikawa, Nozomi; Abe, Koji (J Alzheimers Dis, 2016)
Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p = 0.013 and 8.6±4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in "orientation to place" tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients' lower average scores for "repetition" (MMSE), "recent memory" (HDS-R), and "lexical fluency" (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients' poorer average subscale scores of "orientation to place" (MMSE) and "similarities", "conflicting instructions", and "go-no go" (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.

Different Expression Patterns of Amyloid-β Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-β Pathogenesis. - Xu, Zhi-Qiang; Huang, Huang; Chen, Ya-Li; Gao, Yun-Ying; Xu, Jun; Marshall, Charles; Cai, Zhi-You; Xiao, Ming (J Alzheimers Dis, 2016)
Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AβPPα, but low levels of amyloidogenic β-secretase and γ-secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ-secretase, but not α-secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.
Keywords: ADAM10 Protein; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Antibodies; Aspartic Acid Endopeptidases; Cell Count; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Hippocampus; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Mice, Transgenic; Middle Aged; Mutation; Neurons; Peptide Fragments; Presenilin-1; Species Specificity; Time Factors

Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein. - Grangeon, Lou; Paquet, Claire; Bombois, Stephanie; Quillard-Muraine, Muriel; Martinaud, Olivier; Bourre, Bertrand; Lefaucheur, Romain; Nicolas, Gaël; Dumurgier, Julien; Gerardin, Emmanuel; Jan, Mary; Laplanche, Jean-Louis; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses. OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD. METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria. RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001). CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.
Keywords: Adult; Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Creutzfeldt-Jakob Syndrome; Dementia, Vascular; Diagnosis, Differential; Female; France; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Mental Status Schedule; Middle Aged; Phosphorylation; Retrospective Studies; Sex Factors; tau Proteins

Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies. - Barthélemy, Nicolas R; Gabelle, Audrey; Hirtz, Christophe; Fenaille, François; Sergeant, Nicolas; Schraen-Maschke, Susanna; Vialaret, Jérôme; Buée, Luc; Junot, Christophe; Becher, François; Lehmann, Sylvain (J Alzheimers Dis, 2016)
Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer's disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles. Following and understanding the complexity of Tau's molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge. Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies. Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ). To study Tau proteins, which are found at very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment. We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders. We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection. While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution. Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Chromatography, Liquid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Mental Status Schedule; Middle Aged; Neuroimaging; Neuropsychological Tests; Peptide Fragments; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Statistics as Topic; Supranuclear Palsy, Progressive; tau Proteins

Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease. - Kasza, Ágnes; Hunya, Ákos; Frank, Zsuzsa; Fülöp, Ferenc; Török, Zsolt; Balogh, Gábor; Sántha, Miklós; Bálind, Árpád; Bernáth, Sándor; Blundell, Katie L I M; Prodromou, Chrisostomos; Horváth, Ibolya; et al. (J Alzheimers Dis, 2016)
Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer's disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD.

Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo. - Bolós, Marta; Llorens-Martín, María; Jurado-Arjona, Jerónimo; Hernández, Félix; Rábano, Alberto; Avila, Jesús (J Alzheimers Dis, 2016)
The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons-a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer's disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.
Keywords: Alzheimer Disease; Analysis of Variance; Animals; Animals, Newborn; Calcium-Binding Proteins; Cells, Cultured; Cerebral Cortex; Glial Fibrillary Acidic Protein; Hippocampus; Humans; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Phosphorylation; Protein Transport; Rats; tau Proteins; Time Factors

Disrupted Brain Network in Progressive Mild Cognitive Impairment Measured by Eigenvector Centrality Mapping is Linked to Cognition and Cerebrospinal Fluid Biomarkers. - Qiu, Tiantian; Luo, Xiao; Shen, Zhujing; Huang, Peiyu; Xu, Xiaojun; Zhou, Jiong; Zhang, Minming (J Alzheimers Dis, 2016)
Mild cognitive impairment (MCI) is a heterogeneous condition associated with a high risk of progressing to Alzheimer's disease (AD). Although functional brain network alterations have been observed in progressive MCI (pMCI), the underlying pathological mechanisms of network alterations remain unclear. In the present study, we evaluated neuropsychological, imaging, and cerebrospinal fluid (CSF) data at baseline across a cohort of: 21 pMCI patients, 33 stable MCI (sMCI) patients, and 29 normal controls. Fast eigenvector centrality mapping (fECM) based on resting-state functional MRI (rsfMRI) was used to investigate brain network organization differences among these groups, and we further assessed its relation to cognition and AD-related pathology. Our results demonstrated that pMCI had decreased eigenvector centrality (EC) in left temporal pole and parahippocampal gyrus, and increased EC in left middle frontal gyrus compared to sMCI. In addition, compared to normal controls, patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus, and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule. Correlation analysis showed that EC in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory (WMS-LM) delay score (r = 0.467, p = 0.044) and total tau (t-tau) level in CSF (r = -0.509, p = 0.026) in pMCI. Our findings implicate EC changes of different brain network nodes in the prognosis of pMCI and sMCI. Importantly, the association between decreased EC of brain network node and pathological changes may provide a deeper understanding of the underlying pathophysiology of pMCI.

Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer's Disease Mouse Model. - Zhai, Yun; Yamashita, Toru; Nakano, Yumiko; Sun, Zhuoran; Morihara, Ryuta; Fukui, Yusuke; Ohta, Yasuyuki; Hishikawa, Nozomi; Abe, Koji (J Alzheimers Dis, 2016)
A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.

Distinct Patterns of Cognitive Aging Modified by Education Level and Gender among Adults with Limited or No Formal Education: A Normative Study of the Mini-Mental State Examination. - Xie, Haiqun; Zhang, Chengguo; Wang, Yukai; Huang, Shuyun; Cui, Wei; Yang, Wenbin; Koski, Lisa; Xu, Xiping; Li, Youbao; Zheng, Meili; He, Mingli; Fu, Jia; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia. OBJECTIVE: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low-educated populations. METHODS: This community-based study included data from 2,280 individuals aged 40 years or older from two rural areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function. RESULTS: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated. CONCLUSION: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered.
Keywords: Adult; Aged; Aged, 80 and over; China; Cognition Disorders; Cognitive Aging; Educational Status; Female; Humans; Male; Mental Status Schedule; Middle Aged; Reference Values; Rural Population; Sex Characteristics

Divergent Longitudinal Propagation of White Matter Degradation in Logopenic and Semantic Variants of Primary Progressive Aphasia. - Tu, Sicong; Leyton, Cristian E; Hodges, John R; Piguet, Olivier; Hornberger, Michael (J Alzheimers Dis, 2016)
BACKGROUND: Clinico-pathological distinction of primary progressive aphasia (PPA) can be challenging at clinic presentation. In particular, cross-sectional neuroimaging signatures across the logopenic (lvPPA) and semantic (svPPA) variants are difficult to establish, with longitudinal profiles showing greater divergence. OBJECTIVE: Assess longitudinal propagation of white matter degradation in lvPPA and svPPA to determine disease progression over time, and whether this reflects distinct underlying pathology. METHOD: A cohort of 27 patients with dementia (12 lvPPA; 15 svPPA) and 12 healthy controls were assessed at baseline and 1-year follow-up on the Addenbrooke's Cognitive Examination-Revised and Sydney Language Battery. Diffusion weighted images were collected at both time-points and analyzed for longitudinal white matter change using DTI-TK and TBSS. RESULTS: LvPPA patients showed a significant decline in naming and repetition, over 1 year, while svPPA patients declined in naming and comprehension. Longitudinal imaging revealed widespread bilateral degradation of white matter tracts in lvPPA over a 1-year period with early involvement of the left posterior inferior longitudinal fasciculus (ILF). SvPPA demonstrated focal left lateralized white matter degradation involving the uncinate fasciculus (UF) and anterior ILF, propagating to the right UF with disease progression. CONCLUSIONS: LvPPA and svPPA cohorts showed distinct longitudinal cognitive and white matter profiles. We propose differences in multi-centric and focal white matter dysfunction in lvPPA and svPPA, respectively, reflect underlying pathological differences. The clinical relevance of white matter degradation and mechanisms underlying disease propagation are discussed.
Keywords: Aged; Analysis of Variance; Aphasia, Primary Progressive; Brain; Cohort Studies; Cross-Sectional Studies; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Middle Aged; Names; Neuropsychological Tests; Semantics

Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers. - Schütt, Trine; Helboe, Lone; Pedersen, Lars Østergaard; Waldemar, Gunhild; Berendt, Mette; Pedersen, Jan Torleif (J Alzheimers Dis, 2016)
Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer's disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology.
Keywords: Aging; Alzheimer Disease; Animals; Brain; Cognitive Dysfunction; Cytokines; Denmark; Disease Models, Animal; Disease Progression; Dog Diseases; Dogs; Female; Humans; Immunohistochemistry; Longitudinal Studies; Male; Plaque, Amyloid; Severity of Illness Index; Species Specificity; tau Proteins; Translational Medical Research

Dual Kinase Inhibition Affords Extended in vitro Neuroprotection in Amyloid-β Toxicity. - Gourmaud, Sarah; Mouton-Liger, François; Abadie, Claire; Meurs, Eliane F; Paquet, Claire; Hugon, Jacques (J Alzheimers Dis, 2016)
In Alzheimer's disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR-/-) mice neurons, we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR-/- neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth being tested in in vivo AD and oxidative stress models.

Early in vivo Effects of the Human Mutant Amyloid-β Protein Precursor (hAβPPSwInd) on the Mouse Olfactory Bulb. - Rusznák, Zoltán; Kim, Woojin Scott; Hsiao, Jen-Hsiang T; Halliday, Glenda M; Paxinos, George; Fu, YuHong (J Alzheimers Dis, 2016)
The amyloid-β protein precursor (AβPP) has long been linked to Alzheimer's disease (AD). Using J20 mice, which express human AβPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AβPP/amyloid-β (Aβ) was examined in mice aged 3 months (before the onset of hippocampal Aβ deposition) and over 5 months (when hippocampal Aβ deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AβPP is overexpressed in some of the mitral cells, widespread Aβ deposition and microglia aggregates are not prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57±0.13 million versus 6.59±0.36 million neurons; p = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617±425 versus 4455±623 cells; p = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AβPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AβPP/Aβ-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical.
Keywords: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Humans; Ki-67 Antigen; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Neurogenesis; Neurons; Olfactory Bulb; Piriform Cortex

Economic Analysis of Formal Care, Informal Care, and Productivity Losses in Primary Care Patients who Screened Positive for Dementia in Germany. - Michalowsky, Bernhard; Thyrian, Jochen René; Eichler, Tilly; Hertel, Johannes; Wucherer, Diana; Flessa, Steffen; Hoffmann, Wolfgang (J Alzheimers Dis, 2016)
BACKGROUND: The majority of people with dementia (PwD) live at home and require professional formal care and informal care that is generally provided by close relatives. OBJECTIVE: To determine the utilization and costs of formal and informal care for PwD, indirect costs because of productivity losses of caregivers, and the associations between cost, socio-demographic and clinical variables. METHODS: The analysis includes the data of 262 community-dwelling PwD and their caregivers. Socio-demographics, clinical variables, and the utilization of formal care were assessed within the baseline assessment. To evaluate informal care costs, the Resource Utilization in Dementia (RUD) questionnaire was used. Costs were calculated from a social perspective. Associations were evaluated using multiple linear and logistic regression models. RESULTS: Formal care services were utilized less (26.3%) than informal care (85.1%), resulting in a cost ratio of one to ten(1,646 €; 16,473 €, respectively). In total, 29% of caregivers were employed, and every seventh (14.3%) experienced productivity losses, which corresponded to 1,258 € annually. Whereas increasing deficits in daily living activities were associated with higher formal and higher informal costs, living alone was significantly associated with higher formal care costs and the employment of a caregiver was associated with lower informal care costs. CONCLUSION: Informal care contributes the most to total care costs. Living alone is a major cost driver for formal costs because of the lower availability of potential informal care. The availability of informal care is limited and productivity losses are increased when a caregiver is employed.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Caregivers; Cost of Illness; Cross-Sectional Studies; Dementia; Female; Germany; Health Care Costs; Home Care Services; Humans; Male; Patient Care; Sensitivity and Specificity; Surveys and Questionnaires

Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People. - Hisatsune, Tatsuhiro; Kaneko, Jun; Kurashige, Hiroki; Cao, Yuan; Satsu, Hideo; Totsuka, Mamoru; Katakura, Yoshinori; Imabayashi, Etsuko; Matsuda, Hiroshi (J Alzheimers Dis, 2016)
Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60-78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p = 0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed.
Keywords: Adult; Aged; Aging; Anserine; Brain; Carnosine; Cytokines; Dietary Supplements; Double-Blind Method; Female; Gene Expression Regulation; Humans; Image Processing, Computer-Assisted; Male; Memory, Episodic; Middle Aged; Neuropsychological Tests; Oligonucleotide Array Sequence Analysis; Verbal Learning

Effect of Continuous Propofol Infusion in Rat on Tau Phosphorylation with or without Temperature Control. - Huang, Chunxia; Ng, Olivia Tsz-Wa; Ho, Yuen-Shan; Irwin, Michael Garnet; Chang, Raymond Chuen-Chung; Wong, Gordon Tin-Chun (J Alzheimers Dis, 2016)
Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8-10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3β, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions.
Keywords: Amyloid beta-Peptides; Analysis of Variance; Anesthetics, Intravenous; Animals; Body Temperature; Brain; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Hypothermia, Induced; Male; Peptide Fragments; Phosphorylation; Propofol; Rats; Rats, Sprague-Dawley; Signal Transduction; tau Proteins

Effect of Early Referral to Specialist in Dementia on Institutionalization and Functional Decline: Findings from a Population-Based Study. - Pimouguet, Clément; Le-Goff, Mélanie; Rizzuto, Debora; Berr, Claudine; Leffondré, Karen; Pérès, Karine; Dartigues, Jean François; Helmer, Catherine (J Alzheimers Dis, 2016)
BACKGROUND: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until now studies evaluating the effect of early dementia diagnosis are lacking. OBJECTIVE: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL). METHODS: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional decline. RESULTS: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09- 3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71- 1.67). CONCLUSIONS: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home.
Keywords: Activities of Daily Living; Cognition Disorders; Community Health Planning; Dementia; Disability Evaluation; Female; Finland; Follow-Up Studies; Humans; Institutionalization; Male; Psychiatric Status Rating Scales; Referral and Consultation; Specialization

Effect of Tween-20 on Core Biomarkers Measured in Cerebrospinal Fluid from Patients with Alzheimer's Disease, Mild Cognitive Impairment, or Healthy Control Individuals. - Berge, Guro; Lauridsen, Camilla; Sando, Sigrid Botne; Holder, Daniel Joseph; Møller, Ina; Aasly, Jan Olav; Bråthen, Geir; Savage, Mary Josephine; White, Linda Rosemary (J Alzheimers Dis, 2016)
BACKGROUND: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reported in the literature. OBJECTIVE: Determine whether the detergent Tween-20 improves diagnostic accuracy. METHODS: CSF proteins (Aβ42, Aβ40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined. RESULTS: 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30% ), Aβ40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube. CONCLUSION: Addition of Tween-20 to CSF did not improve differentiation of patients from controls.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Phosphorylation; Polysorbates; ROC Curve; Surface-Active Agents; tau Proteins

The Effects of Amnestic Mild Cognitive Impairment on Go/NoGo Semantic Categorization Task Performance and Event-Related Potentials. - Mudar, Raksha A; Chiang, Hsueh-Sheng; Eroh, Justin; Nguyen, Lydia T; Maguire, Mandy J; Spence, Jeffrey S; Kung, Fanting; Kraut, Michael A; Hart, John (J Alzheimers Dis, 2016)
We examined the effects of amnestic mild cognitive impairment (aMCI) on behavioral (response times and error rates) and scalp-recorded event-related potential (ERP) measures of response execution and inhibition, using Go/NoGo tasks involving basic and superordinate semantic categorization. Twenty-five aMCI (16 F; 68.5±8 years) and 25 age- and gender-matched normal control subjects (16 F; 65.4±7.1 years) completed two visual Go/NoGo tasks. In the single car task, responses were made based on single exemplars of a car (Go) and a dog (NoGo) (basic). In the object animal task, responses were based on multiple exemplars of objects (Go) and animals (NoGo) (superordinate). The aMCI subjects had higher commission errors on the NoGo trials compared to the control subjects, whereas both groups had comparable omission errors and reaction times during the Go trials. The aMCI subjects had significantly prolonged N2 ERP latency during Go and NoGo trials across tasks compared to the controls. Both groups showed similar categorization effects and response type effects in N2/P3 ERP latencies and P3 amplitude. Our findings indicate that altered early neural processing indexed by N2 latency distinguishes subjects with aMCI from controls during the Go/NoGo task. Prolonged Go-N2 latency in aMCI appears to precede behavioral changes in response execution, whereas prolonged NoGo-N2 latency underlies behavioral deterioration in response inhibition.
Keywords: Aged; Aged, 80 and over; Amnesia; Brain; Brain Mapping; Cognitive Dysfunction; Electroencephalography; Evoked Potentials; Female; Humans; Inhibition (Psychology); Male; Middle Aged; Neuropsychological Tests; Reaction Time

Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer's Disease: A Randomized, Double-Blind Trial. - Homma, Akira; Atarashi, Hirotsugu; Kubota, Naoki; Nakai, Kenya; Takase, Takao (J Alzheimers Dis, 2016)
BACKGROUND: Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD. OBJECTIVE: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD). METHODS: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety. RESULTS: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: -1.7, 1.8; p = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil. CONCLUSION: SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD.
Keywords: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Indans; Japan; Male; Mental Status Schedule; Nootropic Agents; Outpatients; Piperidines; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline. - Hochstetler, Helen; Trzepacz, Paula T; Wang, Shufang; Yu, Peng; Case, Michael; Henley, David B; Degenhardt, Elisabeth; Leoutsakos, Jeannie-Marie; Lyketsos, Constantine G (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Apolipoprotein E4; Cognition Disorders; Databases, Factual; Dementia; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Surveys and Questionnaires

Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease. - Ongali, Brice; Nicolakakis, Nektaria; Tong, Xing-Kang; Aboulkassim, Tahar; Imboden, Hans; Hamel, Edith (J Alzheimers Dis, 2016)
The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Analysis of Variance; Animals; Antihypertensive Agents; Cerebrovascular Disorders; Cholinesterases; Disease Models, Animal; Drug Combinations; Enalapril; Female; Glial Fibrillary Acidic Protein; Humans; Losartan; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation

Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. - Chouraki, Vincent; Reitz, Christiane; Maury, Fleur; Bis, Joshua C; Bellenguez, Celine; Yu, Lei; Jakobsdottir, Johanna; Mukherjee, Shubhabrata; Adams, Hieab H; Choi, Seung Hoan; Larson, Eric B; Fitzpatrick, Annette; et al. (J Alzheimers Dis, 2016)
Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

The Evolution of Caregiver Burden in Frontotemporal Dementia with and without Amyotrophic Lateral Sclerosis. - Hsieh, Sharpley; Leyton, Cristian E; Caga, Jashelle; Flanagan, Emma; Kaizik, Cassandra; O'Connor, Claire M; Kiernan, Matthew C; Hodges, John R; Piguet, Olivier; Mioshi, Eneida (J Alzheimers Dis, 2016)
BACKGROUND AND AIMS: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent a disease spectrum. Caregiver burden in subtypes of FTD has not yet been directly compared with those patients who have co-existent FTD and ALS (ALSFTD). METHOD: Perceived caregiver burden was evaluated using the short Zarit Burden Interview (ZBI) in patients with behavioral-variant FTD (bvFTD, n = 21), semantic dementia (SD, n = 18), and ALSFTD (n = 15) at the initial clinical presentation and follow-up assessments. The Mini-Addenbrooke's Cognitive Examination (M-ACE) and the Motor Neuron Disease Behaviour Scale (MiND-B) were also used. Linear mixed effects models examined longitudinal changes on the ZBI, M-ACE, and MiND-B across groups. RESULTS: Burden at baseline was highest for the bvFTD group. Longitudinally, perceived burden increased for the SD and ALSFTD groups whereas in bvFTD, the level of burden which was high at baseline and remained high with disease progression. The severity of abnormal behaviors at baseline, as assessed by the MiND-B, correlated with baseline levels of caregiver burden and further accounted for 23% of the variance in caregiver burden at clinical follow-up. CONCLUSIONS: The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease progression.
Keywords: Adaptation, Psychological; Aged; Amyotrophic Lateral Sclerosis; Analysis of Variance; Caregivers; Case-Control Studies; Cost of Illness; Disease Progression; Female; Frontotemporal Dementia; Humans; Interviews as Topic; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Surveys and Questionnaires

Examining the Relationship Between Autobiographical Memory Impairment and Carer Burden in Dementia Syndromes. - Kumfor, Fiona; Teo, Drusilla; Miller, Laurie; Lah, Suncica; Mioshi, Eneida; Hodges, John R; Piguet, Olivier; Irish, Muireann (J Alzheimers Dis, 2016)
BACKGROUND: Autobiographical memory (ABM) refers to the capacity to remember one's own past, and is known to be central for supporting one's identity and sense of self. This capacity is commonly affected in Alzheimer's disease (AD), as well as semantic dementia (SD) and behavioral-variant frontotemporal dementia (bvFTD). Importantly, ABM plays a critical social function, facilitating relationship intimacy and empathy, and thus loss of ABM may also negatively affect families and carers. OBJECTIVE: To explore the relationship between ABM disruption and carer burden in AD, SD, and bvFTD, and establish whether characteristic ABM profiles differentially relate to carer burden across dementia syndromes. METHODS: We recruited 12 AD, 10 SD, and 13 bvFTD patients and their primary carer. All participants completed the Autobiographical Interview to assess memory for recent and remote events. Carers completed: the Zarit Burden Interview; Depression, Anxiety and Stress Scale (DASS-21); and the Intimate Bond Measure (IBM). RESULTS: In AD, loss of recent ABM was associated with worse psychological wellbeing of carers on the DASS-21. In contrast in SD, remote ABM dysfunction was associated with SD patients showing greater controlling behavior within their intimate relationships. In bvFTD, surprisingly, despite pervasive ABM impairment, no relationship between extent of ABM loss and carer burden was observed. CONCLUSION: These preliminary results reveal that ABM impairment impacts on patients' families and carers and suggest that these influences vary according to the pattern of ABM dysfunction. Disease-specific interventions focusing on preserved aspects of ABM may improve quality of life for both patients and carers.
Keywords: Adaptation, Psychological; Aged; Alzheimer Disease; Analysis of Variance; Behavioral Symptoms; Caregivers; Female; Frontotemporal Dementia; Humans; Male; Memory Disorders; Memory, Episodic; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Statistics as Topic

Excess Costs Associated with Possible Misdiagnosis of Alzheimer's Disease Among Patients with Vascular Dementia in a UK CPRD Population. - Happich, Michael; Kirson, Noam Y; Desai, Urvi; King, Sarah; Birnbaum, Howard G; Reed, Catherine; Belger, Mark; Lenox-Smith, Alan; Price, David (J Alzheimers Dis, 2016)
BACKGROUND: Prior diagnosis of Alzheimer's disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis. OBJECTIVE: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK. METHODS: Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis. RESULTS: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter. CONCLUSION: Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD.

Expression of the Alzheimer's Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs. - Jakobsen, Jannik E; Johansen, Marianne G; Schmidt, Mette; Liu, Ying; Li, Rong; Callesen, Henrik; Melnikova, Margarita; Habekost, Mette; Matrone, Carmela; Bouter, Yvonne; Bayer, Thomas A; Nielsen, Anders Lade; et al. (J Alzheimers Dis, 2016)
Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer's disease.

Extracellular Tau Paired Helical Filaments Differentially Affect Tau Pathogenic Mechanisms in Mitotic and Post-Mitotic Cells: Implications for Mechanisms of Tau Propagation in the Brain. - Varghese, Merina; Santa-Maria, Ismael; Ho, Lap; Ward, Libby; Yemul, Shrishailam; Dubner, Lauren; Księżak-Reding, Hanna; Pasinetti, Giulio Maria (J Alzheimers Dis, 2016)
The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer's disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons. In a mitotic cell line (HEK 293T), extracellular exposure to AD PHFs leads to an intracellular "aggresomal" type deposition of tau, coincidental with redistribution of dynein, a retrograde motor protein. We also observed that PHFs impaired proteasome degradation, but not autophagy. Exposure of cells to proteasome inhibitors was sufficient to induce intracellular tau aggregate formation as well as reorganization of dynein and the intermediate filament protein, vimentin. Thus, in mitotic cells, extracellular PHFs promote cellular tau aggregation, in part, by interfering with cellular proteasome degradation processes. In contrast with our observations with proliferating cells, exposure of post-mitotic primary neuronal cultures to AD PHFs did not promote "aggresomal" tau deposition, but instead resulted in a widespread accumulation of phosphorylated tau-immunoreactive swellings in neuritic processes, characterized by disturbed cytoskeletal organization of dynein and vimentin. Collectively, our observations suggest that extracellular PHFs may contribute to the propagation of tau pathology by independent mechanisms in post-mitotic and mitotic brain cells. These outcomes indicate that in addition to post-mitotic brain neurons, mitotic brain cells should also be considered as targets for therapeutic interventions to attenuate propagation of tauopathy.

Fluoxetine Treatment Induces Seizure Behavior and Premature Death in APPswe/PS1dE9 Mice. - Sierksma, Annerieke S R; de Nijs, Laurence; Hoogland, Govert; Vanmierlo, Tim; van Leeuwen, Fred W; Rutten, Bart P F; Steinbusch, Harry W M; Prickaerts, Jos; van den Hove, Daniel L A (J Alzheimers Dis, 2016)
Treatment of Alzheimer's disease (AD) patients with the antidepressant fluoxetine is known to improve memory and cognitive function. However, the mechanisms underlying these effects are largely unknown. To unravel these mechanisms, we aimed to treat APPswe/PS1dE9 mice with fluoxetine. Unexpectedly, with time, an increased number of animals displayed seizure behavior and died. Although spontaneous behavioral seizures have been reported previously in this mouse model, the observation of seizures and death consequential to fluoxetine treatment is new. Our results warrant further research on the underlying mechanisms as this may refine the treatment of AD patients.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anticonvulsants; Body Weight; Disease Models, Animal; Fluoxetine; Humans; Logistic Models; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Presenilin-1; Seizures

FTIR and Raman Spectroscopy Applied to Dementia Diagnosis Through Analysis of Biological Fluids. - Lopes, Jéssica; Correia, Marta; Martins, Ilka; Henriques, Ana Gabriela; Delgadillo, Ivonne; da Cruz E Silva, Odete; Nunes, Alexandra (J Alzheimers Dis, 2016)
To date, it is still difficult to perform an early and accurate diagnosis of dementia, therefore significant research has focused on finding new dementia biomarkers that can aid in this respect. There is an urgent need for non-invasive, rapid, and relatively inexpensive procedures for early diagnostics. Studies have demonstrated that of spectroscopic techniques, such as Fourier Transform Infrared Spectroscopy (FTIR) and Raman Spectroscopy could be a useful and accurate procedure to diagnose dementia. Given that several biochemical mechanisms related to neurodegeneration and dementia can lead to changes in plasma components and others peripheral body fluids; blood-based samples coupled to spectroscopic analyses can be used as a simple and less invasive approach.

Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease. - Weissmann, Robert; Hüttenrauch, Melanie; Kacprowski, Tim; Bouter, Yvonne; Pradier, Laurent; Bayer, Thomas A; Kuss, Andreas W; Wirths, Oliver (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Gene Expression Profiling; Male; Mice; Mice, Transgenic; Nerve Degeneration; Presenilin-1; Transcriptome

Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians. - Kim, Sungeun; Nho, Kwangsik; Ramanan, Vijay K; Lai, Dongbing; Foroud, Tatiana M; Lane, Katie; Murrell, Jill R; Gao, Sujuan; Hall, Kathleen S; Unverzagt, Frederick W; Baiyewu, Olusegun; Ogunniyi, Adesola; et al. (J Alzheimers Dis, 2016)
Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
Keywords: Adaptor Proteins, Signal Transducing; African Americans; African Continental Ancestry Group; Aged; Aged, 80 and over; Cohort Studies; Cystathionine beta-Synthase; Cytoskeletal Proteins; Female; Genetic Variation; Genome-Wide Association Study; Heterozygote; Homocysteine; Humans; Indiana; Longitudinal Studies; Male; Nigeria; Prospective Studies

A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease. - Andersson, Carl-Henrik; Hansson, Oskar; Minthon, Lennart; Andreasen, Niels; Blennow, Kaj; Zetterberg, Henrik; Skoog, Ingmar; Wallin, Anders; Nilsson, Staffan; Kettunen, Petronella (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.

The Gesture Imitation in Alzheimer's Disease Dementia and Amnestic Mild Cognitive Impairment. - Li, Xudong; Jia, Shuhong; Zhou, Zhi; Hou, Chunlei; Zheng, Wenjing; Rong, Pei; Jiao, Jinsong (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease dementia (ADD) has become an important health problem in the world. Visuospatial deficits are considered to be an early symptom besides memory disorder. OBJECTIVES: The gesture imitation test was devised to detect ADD and amnestic mild cognitive impairment (aMCI). METHODS: A total of 117 patients with ADD, 118 with aMCI, and 95 normal controls were included in this study. All participants were administered our gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Clinical Dementia Rating Scale (CDR). RESULTS: Patients with ADD performed worse than normal controls on global scores and had a lower success rate on every item (p < 0.001). The area under the curve (AUC) for the global scores when comparing the ADD and control groups was 0.869 (p < 0.001). Item 4 was a better discriminator with a sensitivity of 84.62% and a specificity of 67.37%. The AUC for the global scores decreased to 0.621 when applied to the aMCI and control groups (p = 0.002). After controlling for age and education, the gesture imitation test scores were positively correlated with the MMSE (r = 0.637, p < 0.001), the MoCA (r = 0.572, p < 0.001), and the CDT (r = 0.514, p < 0.001) and were negatively correlated with the CDR scores (r = -0.558, p < 0.001). CONCLUSIONS: The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics.

Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation. - Mead, Emma; Kestoras, Dimitra; Gibson, Yolanda; Hamilton, Lucy; Goodson, Ross; Jones, Sophie; Eversden, Sarah; Davies, Peter; O'Neill, Michael; Hutton, Michael; Szekeres, Philip; Wolak, Joanna (J Alzheimers Dis, 2016)
Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.

Health-Related Quality of Life in Patients with Alzheimer's Disease in Different German Health Care Settings. - Heßmann, Philipp; Seeberg, Greta; Reese, Jens Peter; Dams, Judith; Baum, Erika; Müller, Matthias J; Dodel, Richard; Balzer-Geldsetzer, Monika (J Alzheimers Dis, 2016)
The purpose of this study is to evaluate the health-related quality of life (HrQoL) of patients with Alzheimer's disease (AD) in different care settings (institutionalized versus community-dwelling) across all severity stages of dementia. Patients were consecutively recruited with their primary caregivers (123 inpatients and 272 outpatients), and the impact of patient-related parameters such as behavioral and psychological symptoms of dementia (BPSD) (Geriatric Depression Scale [GDS] and Neuropsychiatric Inventory [NPI]) and functional capacity (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]) on HrQoL was analyzed. Patients' HrQoL was assessed using self-reported and caregiver-rated generic (EuroQoL Instrument) and dementia-specific (Quality of Life-Alzheimer's Disease [Qol-AD]) scales. Patients reported a considerably higher HrQoL than their caregivers on the QoL-AD, EQ-5D, and EQ VAS (p <  0.001). Different dementia severity groups showed significantly worse results in HrQoL for patients with lower MMSE scores. The mean self-reported QoL-AD decreased from 32.3±5.7 in the group with the highest MMSE scores to 27.1±5.5 in patients with the lowest MMSE scores (p <  0.001). A considerably lower HrQoL was shown for institutionalized patients versus participants in outpatient settings (proxy-rated QoL-AD 19.7±4.6 versus 26.0±7.1, p <  0.001). Depressive symptoms (GDS), BPSD (NPI), and reduced functional capacity (ADCS-ADL) were evaluated for their impact on patients' HrQoL. Multivariate models explained between 22% and 54% of the variance in patients' HrQoL. To analyze the causative direction of the reported associations, further longitudinal studies should be conducted.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Depression; Female; Germany; Humans; Inpatients; Male; Multivariate Analysis; Neuropsychological Tests; Outpatients; Psychiatric Status Rating Scales; Quality of Life; Residential Facilities; Self Report; Severity of Illness Index

Heart Rate Spectra Confirm the Presence of Autonomic Dysfunction in Dementia Patients. - Struhal, Walter; Mahringer, Christoph; Lahrmann, Heinz; Mörtl, Christoph; Buhl, Peter; Huemer, Mario; Ransmayr, Gerhard (J Alzheimers Dis, 2016)
Recent data suggest autonomic dysfunction in patients suffering dementia. This study evaluated autonomic modulation in dementia patients with and without autonomic involvement, employing ECG spectral analysis in the time-frequency domain (wavelet transform) in supine resting and head-up tilt (HUT) position. Thirty-six patients were prospectively evaluated at the Department of Neurology and Psychiatry, General Hospital of the City of Linz, between 2009 and 2014. A standard cardiovascular autonomic test series (Ewing battery) was performed to screen for autonomic dysfunction. The Ewing battery diagnoses were used as reference standard and compared to the diagnostic results obtained by spectral analysis (time-frequency domain) of ECG recordings. Based on the Ewing battery results, 14 patients suffered autonomic dysfunction, while 22 did not. Time frequency domain was accessed by using the continuous wavelet transformation (CWT) with an analytical Morlet mother wavelet in supine resting and HUT position. Within each cohort the modification of spectral components from supine resting to HUT was analyzed reflecting the autonomic modulation. For patients without autonomic dysfunction, a significant increase of autonomic modulation was detected by wavelet transformed ECG recordings (8%, p < 0.05; low frequency content) during HUT compared to supine resting. There was no significant modulation between HUT and supine resting in patients suffering autonomic dysfunction. In dementia patients suffering autonomic dysfunction, CWT identified blunted autonomic regulation only by analysis of ECG recordings without the need to assess other biosignals or tests depending on the patient's cooperation. Further studies are needed to evaluate whether CWT is a suitable method to support the standard Ewing battery in demented patients.

Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer's Disease Patients. - Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Del Turco, Domenico; Ghebremedhin, Estifanos; Seidel, Kay; den Dunnen, Wilfred; Korf, Horst-Werner (J Alzheimers Dis, 2016)
In spite of considerable progress in neuropathological research on Alzheimer's disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.
Keywords: Alzheimer Disease; Cytoskeleton; Humans; tau Proteins; Thalamus

Homocysteine and Alzheimer's Disease: Evidence for a Causal Link from Mendelian Randomization. - Hu, Qingting; Teng, Wenhui; Li, Jiajia; Hao, Fangfang; Wang, Naidong (J Alzheimers Dis, 2016)
BACKGROUND/OBJECTIVE: The relationship between plasma homocysteine (Hcy) levels and Alzheimer's disease (AD) has been studied for many years, but remains controversial. While a recent meta-analysis of epidemiological studies, which included observational studies, indicated that homocysteine may be a risk factor for AD, there remains a need to further demonstrate this link due to the large degree of heterogeneity between studies. Epidemiological studies have certain limitations, as their results can be affected by confounding factors and reverse causation. In this study, we evaluated the relationship between plasma homocysteine and AD by using a Mendelian randomization method to avoid problems of confounding bias and reverse causality. METHODS: We searched the PubMed and EMBASE databases for reports regarding the MTHFR C677T polymorphism (rs1801133) from the time of their inception to September 2015. These reports were combined with related observational studies, and used to evaluate the effect of MTHFR C677T (rs1801133) on the risk for AD. A recent meta-analysis of genome-wide association studies had previously suggested a relationship between homocysteine and MTHFR C677T (rs 1801133). RESULTS: Our met-analysis included 34 studies with 9397 subjects, and demonstrated a significant relationship between plasma total homocysteine levels and the risk for AD (OR = 3.37; 95% CI = 1.90-5.95; p = 2.9×10-5). CONCLUSION: Our meta-analysis demonstrated a causal link between plasma total homocysteine and the risk for AD, and provides a new insight into the etiology and prevention of AD.

Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy. - Zimova, Ivana; Brezovakova, Veronika; Hromadka, Tomas; Weisova, Petronela; Cubinkova, Veronika; Valachova, Bernadeta; Filipcik, Peter; Jadhav, Santosh; Smolek, Tomas; Novak, Michal; Zilka, Norbert (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model. - Jul, Pia; Volbracht, Christiane; de Jong, Inge E M; Helboe, Lone; Elvang, Anders Brandt; Pedersen, Jan Torleif (J Alzheimers Dis, 2016)
Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.
Keywords: Age Factors; Analysis of Variance; Animals; Brain; Cognition Disorders; Disease Models, Animal; Doxycycline; Exploratory Behavior; Humans; Hyperkinesis; Male; Maze Learning; Mice; Mice, Transgenic; Motor Activity; Mutation; Psychomotor Agitation; tau Proteins; Tauopathies; Time Factors

Identification of Physician-Diagnosed Alzheimer's Disease and Related Dementias in Population-Based Administrative Data: A Validation Study Using Family Physicians' Electronic Medical Records. - Jaakkimainen, R Liisa; Bronskill, Susan E; Tierney, Mary C; Herrmann, Nathan; Green, Diane; Young, Jacqueline; Ivers, Noah; Butt, Debra; Widdifield, Jessica; Tu, Karen (J Alzheimers Dis, 2016)
BACKGROUND: Population-based surveillance of Alzheimer's and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD. OBJECTIVE: We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data in identifying older adults with AD-RD over time. METHODS: This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared. RESULTS: The highest performing algorithm was "one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication" with sensitivity 79.3% (confidence interval (CI) 72.9-85.8%), specificity 99.1% (CI 98.8-99.4%), positive predictive value 80.4% (CI 74.0-86.8%), and negative predictive value 99.0% (CI 98.7-99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11. CONCLUSION: Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD.

Immunization with Small Amyloid-β-derived Cyclopeptide Conjugates Diminishes Amyloid-β-Induced Neurodegeneration in Mice. - Mulder, Cornelis K; Dong, Yun; Brugghe, Humphrey F; Timmermans, Hans A M; Tilstra, Wichard; Westdijk, Janny; van Riet, Elly; van Steeg, Harry; Hoogerhout, Peter; Eisel, Ulrich L M (J Alzheimers Dis, 2016)
BACKGROUND: Soluble oligomeric (misfolded) species of amyloid-β (Aβ) are the main mediators of toxicity in Alzheimer's disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aβ is a promising disease modifying strategy. However, eliciting an immune response against Aβ in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aβ, inducing a specific antibody response. OBJECTIVE: Here we investigate the protective effects of the experimental vaccine against oligomeric Aβ1-42-induced neuronal fiber loss in vivo. METHODS: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aβ1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aβ1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain. RESULTS: Immunized responders (79%) showed 23% less cholinergic fiber loss (p = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2 = 0.29, p = 0.02). CONCLUSION: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms.

Impact of Depressive Symptoms on Memory for Emotional Words in Mild Cognitive Impairment and Late-Life Depression. - Callahan, Brandy L; Simard, Martine; Mouiha, Abderazzak; Rousseau, François; Laforce, Robert; Hudon, Carol (J Alzheimers Dis, 2016)
BACKGROUND: Amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) are associated with increased risk of Alzheimer's disease (AD). This is also true for aMCI with concomitant depressive symptoms (aMCI/D+), but few studies have investigated this syndrome. OBJECTIVES: We aimed to clarify the association between cognitive and depressive symptoms in individuals at risk for AD by examining episodic memory for emotional stimuli in aMCI, aMCI/D+, and LLD. METHODS: Participants were 34 patients with aMCI, 20 patients with aMCI/D+, 19 patients with LLD, and 28 healthy elderly adults. In an implicit encoding task, participants rated the emotional valence of 12 positive, 12 negative, and 12 neutral words. Immediately and 20 minutes later, participants recalled as many words as possible. They were also asked to identify previously presented words during a yes/no recognition trial. RESULTS: At immediate recall, aMCI participants displayed better recall of emotional words, particularly positive words. aMCI/D+ and control participants displayed better recall of positive and negative words compared to neutral words. LLD participants recalled more negative than neutral words. At delayed recall, emotional words were generally better-remembered than neutral words by all groups. At recognition, all subjects responded more liberally to emotional than to neutral words. CONCLUSION: We find that the type of emotional information remembered by aMCI patients at immediate recall depends on the presence or absence of depressive symptoms. These findings contribute to identifying sources of heterogeneity in individuals at risk for AD, and suggest that the cognitive profile of aMCI/D+ is different from that of aMCI and LLD. Future studies should systematically consider the presence of depressive symptoms in elderly at-risk individuals.

Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. - Külzow, Nadine; Witte, A Veronica; Kerti, Lucia; Grittner, Ulrike; Schuchardt, Jan Philipp; Hahn, Andreas; Flöel, Agnes (J Alzheimers Dis, 2016)
As the process of Alzheimer's disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.
Keywords: Aged; Apolipoproteins E; Auditory Perception; Blood Chemical Analysis; Cognitive Aging; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Feeding Behavior; Female; Humans; Learning; Male; Memory; Middle Aged; Neuropsychological Tests; Nootropic Agents; Treatment Outcome

Impacts of Illiteracy on the Risk of Dementia: A Global Health Perspective. - Suh, Seung Wan; Han, Ji Won; Park, Jae Young; Hong, Jong Woo; Kim, Kayoung; Kim, Taehyun; Lee, Kyoung Hwan; Han, Guehee; Jeong, Hyeon; Seo, Jiyeong; Kim, Tae Hui; Lee, Dong Young; et al. (J Alzheimers Dis, 2016)
Despite its significance as a contributing factor for late-life dementia risk, illiteracy is frequently underappreciated in the management of dementia. In this study, we estimated the proportion of dementia cases attributable to illiteracy using the population attributable fraction (PAF), and calculated to what extent the monetary cost of dementia could be saved in the future by reducing illiteracy from the South Korean, Latin American, South Asian/Middle Eastern, and African populations. We collected necessary data from the 2011 United Nations Human Development Report and prevalence studies conducted in these regions. Additional variables not included in the above sources were estimated using a logit model under a "trend scenario"-based assumption. Around 16% of the total number of dementia cases in South Korea in 2015 can be attributed to illiteracy, with this figure predicted to decline to around 2% by 2050. This translates to a saving in dementia care costs of approximately 52 billion USD, providing we are successful in theoretically eradicating illiteracy as of 2015, in the population aged 65 years or under. Likewise, reducing illiteracy to 50% in Latin America, South Asia/The Middle East, and Africa by 2050 could generate further cost savings of between 71 and 244 billion, 13 and 94 billion, and 17 and 78 billion USD, respectively. Even public policies aimed solely at reducing illiteracy in the childhood, adolescent, or middle-aged population could potentially have a role in the primary prevention of dementia. Moving forward, governments will need to address this issue in a purposeful and systematic manner.

Impaired Autophagy in APOE4 Astrocytes. - Simonovitch, Shira; Schmukler, Eran; Bespalko, Alina; Iram, Tal; Frenkel, Dan; Holtzman, David M; Masliah, Eliezer; Michaelson, Danny M; Pinkas-Kramarski, Ronit (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.
Keywords: Amyloid beta-Peptides; Animals; Apolipoprotein E3; Apolipoprotein E4; Astrocytes; Autophagy; Brain; Cells, Cultured; Central Nervous System Agents; Chloroquine; Disease Models, Animal; Humans; Mice, Transgenic; Plaque, Amyloid; Sirolimus; Time Factors

Incidence and Duration of Cumulative Bisphosphonate Use among Community-Dwelling Persons with or without Alzheimer's Disease. - Tiihonen, Miia; Taipale, Heidi; Tanskanen, Antti; Tiihonen, Jari; Hartikainen, Sirpa (J Alzheimers Dis, 2016)
We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer's disease (AD). The MEDALZ-2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002-2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD (n = 3121, 12.3%) than among persons with AD (n = 2,920, 11.2%) (p = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p <  0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD.

The Incidence of Benzodiazepine and Related Drug Use in Persons with and without Alzheimer's Disease. - Saarelainen, Laura; Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa (J Alzheimers Dis, 2016)
BACKGROUND: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer's disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population. OBJECTIVE: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up. METHODS: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005-2011 (n = 70,718) and their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated. RESULTS: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5-2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1-4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis. CONCLUSION: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Benzodiazepines; Cohort Studies; Female; Finland; Humans; Incidence; Male; Middle Aged; Substance-Related Disorders

Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain. - Musunuri, Sravani; Khoonsari, Payam Emami; Mikus, Maria; Wetterhall, Magnus; Häggmark-Mänberg, Anna; Lannfelt, Lars; Erlandsson, Anna; Bergquist, Jonas; Ingelsson, Martin; Shevchenko, Ganna; Nilsson, Peter; Kultima, Kim (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. OBJECTIVE: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. METHODS: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. RESULTS: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. CONCLUSIONS: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

Influence of Low-Dose Aspirin on Cerebral Amyloid Angiopathy in Mice. - Hattori, Yorito; Maki, Takakuni; Saito, Satoshi; Yamamoto, Yumi; Nagatsuka, Kazuyuki; Ihara, Masafumi (J Alzheimers Dis, 2016)
Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer's dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA.

Insight into the Dissociation of Behavior from Histology in Synucleinopathies and in Related Neurodegenerative Diseases. - Sekiyama, Kazunari; Takamatsu, Yoshiki; Koike, Wakako; Waragai, Masaaki; Takenouchi, Takato; Sugama, Shuei; Hashimoto, Makoto (J Alzheimers Dis, 2016)
Recent clinical trials using immunization approaches against Alzheimer's disease (AD) have failed to demonstrate improved cognitive functions in patients, despite potent suppression in the formation of both senile plaques and other amyloid-β deposits in postmortem brains. Similarly, we observed that treatment with ibuprofen, a non-steroidal anti-inflammatory drug, was effective in improving the histopathology, such as reducing both protein aggregation and glial activation, in the brains of transgenic mice expressing dementia with Lewy bodies-linked P123H β-synuclein. In contrast, only a small improvement in cognitive functions was observed in these mice. Collectively, it is predicted that histology does not correlate with behavior that is resilient and resistant to therapeutic stimuli. Notably, such a 'discrepancy between histology and behavior' is reminiscent of AD-like pathologies and incidental Lewy bodies, which are frequently encountered in postmortem brains of the elderly who had been asymptomatic for memory loss and Parkinsonism during their lives. We suggest that 'the discrepancy between histology and behavior' may be a universal feature that is associated with various aspects of neurodegenerative diseases. Furthermore, given that the cognitive reserve is specifically observed in human brains, human behavior may be evolutionally distinct from that in other animals, thus, contributing to the differential efficiency of therapy between human and lower animals, an important issue in the therapy of neurodegenerative diseases. Overall, it is important to better understand 'the discrepancy between histology and behavior' in the mechanism of neurodegeneration for the development of effective therapies against neurodegenerative diseases.

Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults. - Hoscheidt, Siobhan M; Starks, Erika J; Oh, Jennifer M; Zetterberg, Henrik; Blennow, Kaj; Krause, Rachel A; Gleason, Carey E; Puglielli, Luigi; Atwood, Craig S; Carlsson, Cynthia M; Asthana, Sanjay; Johnson, Sterling C; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Type 2 diabetes is associated with an increased risk for Alzheimer's disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. OBJECTIVE: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOEɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance. METHODS: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer's Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOEɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOEɛ4 status. RESULTS: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 . APOEɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. CONCLUSION: Overall, the findings suggest that IR and APOEɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.

Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory. - Li, Wen-Xing; Dai, Shao-Xing; Liu, Jia-Qian; Wang, Qian; Li, Gong-Hua; Huang, Jing-Fei (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.
Keywords: Adult; Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Bayes Theorem; Brain; Datasets as Topic; Gene Expression Profiling; Humans; Learning; Memory; Microarray Analysis; Middle Aged; Schizophrenia; Schizophrenic Psychology; Young Adult

Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology. - Bangen, Katherine J; Himali, Jayandra J; Beiser, Alexa S; Nation, Daniel A; Libon, David J; Fox, Caroline S; Seshadri, Sudha; Wolf, Philip A; McKee, Ann C; Au, Rhoda; Delano-Wood, Lisa (J Alzheimers Dis, 2016)
Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer's Disease. - Uekawa, Ken; Hasegawa, Yu; Senju, Satoru; Nakagata, Naomi; Ma, Mingjie; Nakagawa, Takashi; Koibuchi, Nobutaka; Kim-Mitsuyama, Shokei (J Alzheimers Dis, 2016)
This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer's disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer's disease.

Intranasal TAT-haFGF Improves Cognition and Amyloid-β Pathology in an AβPP/PS1 Mouse Model of Alzheimer's Disease. - Lou, Guofeng; Zhang, Qihao; Xiao, Fei; Xiang, Qi; Su, Zhijian; Huang, Yadong (J Alzheimers Dis, 2016)
Neurotoxic amyloid-β (Aβ) peptide causing cognitive function disabilities is one of the most characteristic pathological features in Alzheimer's disease (AD). A novel fusion protein, TAT-haFGF, was administrated to AβPP/PS1 transgenic mice by intravenous (IV) injection and intranasal (IN) delivery, respectively, for 5 weeks to compare the pharmacodynamics between the two routes of administration. Our results showed that IN administration of TAT-haFGF improved cognition and reduced Aβ plaques more significantly in AβPP/PS1 mice, when compared with IV injection. Our new findings suggest that TAT-haFGF might be a promising new therapy to attenuate AD pathological process.
Keywords: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cognition Disorders; Disease Models, Animal; Fibroblast Growth Factors; Gene Products, tat; Humans; Injections, Intraventricular; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Movement; Mutation; Peptide Fragments; Plaque, Amyloid; Presenilin-1

Intraneuronal Amylin Deposition, Peroxidative Membrane Injury and Increased IL-1β Synthesis in Brains of Alzheimer's Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats. - Verma, Nirmal; Ly, Han; Liu, Miao; Chen, Jing; Zhu, Haining; Chow, Martin; Hersh, Louis B; Despa, Florin (J Alzheimers Dis, 2016)
Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.

Lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer's disease. - Agostini, Simone; Mancuso, Roberta; Baglio, Francesca; Cabinio, Monia; Hernis, Ambra; Guerini, Franca Rosa; Calabrese, Elena; Nemni, Raffaello; Clerici, Mario (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD), the most common form of dementia worldwide, is associated with impairment in the mechanisms of the clearing of amyloid-β within a scenario of neuroinflammation. The etiopathogenesis of the AD is unclear, but a role for viral infection is suspected to play a role in initiating the disease. We recently described a positive correlation between high titers of HSV-1-specific antibodies (Ab) and the volumes of brain regions typically affected in disease. OBJECTIVE: The exploration of a possible role for Herpesviridae in AD was extended by analyzing HHV-6-specific humoral immunity in individuals with AD or a diagnosis of amnestic mild cognitive impairment (aMCI), a condition that is often prodromic of the development of AD. METHODS: 59 AD, 60 aMCI, and 61 age-matched healthy controls were enrolled in the study. Serum HHV-6 IgG antibody titers and avidity index were tested by ELISA. Two randomly selected subgroups of AD and aMCI in whom HHV-6 serum antibodies were detected underwent brain magnetic resonance imaging (MRI) by 1.5 T scanner. RESULTS: HHV-6 seroprevalence, antibody titers, and avidity were similar in the three groups. No correlation was found between Ab titers or avidity and brain volumes, either overall or in the regions typically affected by disease. CONCLUSIONS: The lack of any relation between humoral immune response against HHV-6 and AD and aMCI seems to rule out a role for this virus in the pathogenesis of AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Antibodies; Case-Control Studies; Cognitive Dysfunction; Female; Herpesvirus 1, Human; Herpesvirus 6, Human; Humans; Immunity, Humoral; Magnetic Resonance Imaging; Male; Seroepidemiologic Studies; Temporal Lobe

The Language Profile of Behavioral Variant Frontotemporal Dementia. - Hardy, Chris J D; Buckley, Aisling H; Downey, Laura E; Lehmann, Manja; Zimmerer, Vitor C; Varley, Rosemary A; Crutch, Sebastian J; Rohrer, Jonathan D; Warrington, Elizabeth K; Warren, Jason D (J Alzheimers Dis, 2016)
BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group. METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images. RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.
Keywords: Aged; Aphasia, Primary Progressive; Atrophy; Brain; Cognition; Comprehension; Female; Frontotemporal Dementia; Humans; Language; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Primary Progressive Nonfluent Aphasia

Late-Life Depressive Symptoms and Lifetime History of Major Depression: Cognitive Deficits are Largely Due to Incipient Dementia rather than Depression. - Heser, Kathrin; Bleckwenn, Markus; Wiese, Birgitt; Mamone, Silke; Riedel-Heller, Steffi G; Stein, Janine; Lühmann, Dagmar; Posselt, Tina; Fuchs, Angela; Pentzek, Michael; Weyerer, Siegfried; Werle, Jochen; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Late-life depression is frequently accompanied by cognitive impairments. OBJECTIVE: Whether these impairments indicate a prodromal state of dementia, or are a symptomatic expression of depression per se is not well-studied. METHODS: In a cohort of very old initially non-demented primary care patients (n = 2,709, mean age = 81.1 y), cognitive performance was compared between groups of participants with or without elevated depressive symptoms and with or without subsequent dementia using ANCOVA (adjusted for age, sex, and education). Logistic regression analyses were computed to predict subsequent dementia over up to six years of follow-up. The same analytical approach was performed for lifetime major depression. RESULTS: Participants with elevated depressive symptoms without subsequent dementia showed only small to medium cognitive deficits. In contrast, participants with depressive symptoms with subsequent dementia showed medium to very large cognitive deficits. In adjusted logistic regression models, learning and memory deficits predicted the risk for subsequent dementia in participants with depressive symptoms. Participants with a lifetime history of major depression without subsequent dementia showed no cognitive deficits. However, in adjusted logistic regression models, learning and orientation deficits predicted the risk for subsequent dementia also in participants with lifetime major depression. CONCLUSION: Marked cognitive impairments in old age depression should not be dismissed as "depressive pseudodementia", but require clinical attention as a possible sign of incipient dementia. Non-depressed elderly with a lifetime history of major depression, who remained free of dementia during follow-up, had largely normal cognitive performance.

The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. - Koppara, Alexander; Wolfsgruber, Steffen; Kleineidam, Luca; Schmidtke, Klaus; Frölich, Lutz; Kurz, Alexander; Schulz, Stefanie; Hampel, Harald; Heuser, Isabella; Peters, Oliver; Reischies, Friedel M; Jahn, Holger; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Dementia; Disease Progression; Female; Humans; Logistic Models; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Phenotype; Predictive Value of Tests; Retrospective Studies; tau Proteins

Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. - Le Bouc, Raphael; Marelli, Cecilia; Beaufils, Emilie; Berr, Claudine; Hommet, Caroline; Touchon, Jacques; Pasquier, Florence; Deramecourt, Vincent (J Alzheimers Dis, 2016)
Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.
Keywords: Autopsy; Brain; France; Health Knowledge, Attitudes, Practice; Humans; Neurodegenerative Diseases; Physicians; Retrospective Studies

Living Alone with Dementia: Prevalence, Correlates and the Utilization of Health and Nursing Care Services. - Eichler, Tilly; Hoffmann, Wolfgang; Hertel, Johannes; Richter, Steffen; Wucherer, Diana; Michalowsky, Bernhard; Dreier, Adina; Thyrian, Jochen René (J Alzheimers Dis, 2016)
BACKGROUND: Little is known about the proportion and the characteristics of community-dwelling people with dementia (PWD) living alone in Germany. OBJECTIVES: To analyze the prevalence of PWD living alone (with and without the support of an informal caregiver) and socio-demographical and clinical characteristics as well as health and nursing care utilization associated with living alone. METHODS: DelpHi-MV (Dementia: Life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, randomized controlled intervention trial. The present analyses are based on baseline data of 511 patients (≥70 years, community-dwelling) who had screened positive for dementia (DemTect <9). RESULTS: N = 251 (51%) of the patients lived alone. PWD living alone were statistically significantly more often female, older, and more often widowed than those not living alone. About 9% of the patients (n = 24) were not supported by any informal caregiver. Regarding the clinical variables (cognitive and functional impairment, depression, falls, number of drug-related problems, malnutrition, quality of life), there were no statistically significant group differences. Patients living alone utilized professional services such as home care, help with medication, home-delivered meals, or housekeeping assistance significantly more often. Multivariate analyses confirmed these findings. CONCLUSION: Our results reveal the high proportion of PWD living alone in Germany. PWD living alone did not seem to be at an increased health risk. Our findings indicate that living alone with dementia is possible. In order to ensure the sufficient provision of health and nursing care services for PWD living alone, providers should consider the present results for future planning.

Longitudinal Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease. - Schubert, Samantha; Leyton, Cristian E; Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation. OBJECTIVE: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD. METHODS: Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts. RESULTS: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group. CONCLUSIONS: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.
Keywords: Alzheimer Disease; Aniline Compounds; Brain; Diagnosis, Differential; Disease Progression; Executive Function; Female; Follow-Up Studies; Frontotemporal Dementia; Humans; Longitudinal Studies; Male; Memory; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Low Plasma Cholinesterase Activities are Associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer's Disease. - Dingova, Dominika; Fazekas, Tomas; Okuliarova, Petra; Strbova, Jaroslava; Kucera, Matej; Hrabovska, Anna (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.
Keywords: Acetylcholinesterase; Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Blood Chemical Analysis; Body Mass Index; Butyrylcholinesterase; Female; Hospitalization; Humans; Male; Middle Aged; Orientation, Spatial

Low Prevalence of Mixed Dementia in a Cohort of 2,000 Elderly Patients in a Memory Clinic Setting. - Claus, Jules J; Staekenborg, Salka S; Roorda, Jelmen J; Stevens, Martijn; Herderschee, Dirk; van Maarschalkerweerd, Willy; Schuurmans, Lilly; Tielkes, Caroline E M; Koster, Pieter; Bavinck, Chris; Scheltens, Philip (J Alzheimers Dis, 2016)
BACKGROUND: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer's disease (AD) becomes more mixed, i.e., co-existence of amyloid plaques and cerebrovascular pathology. OBJECTIVE: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer's disease (AD) in a single-center memory clinic population. METHODS: Patients included had diagnoses of AD (n = 832), subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492), vascular dementia (VaD, n = 57), other dementia (n = 53), or other diagnosis (n = 233). Prevalence of severe white matter lesions (WML) was defined as a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML. RESULTS: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages. CONCLUSION: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease.
Keywords: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Cognitive Dysfunction; Cohort Studies; Dementia; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Prevalence; Regression Analysis; Risk Factors; Tomography Scanners, X-Ray Computed

Low Serum Insulin-Like Growth Factor-I Predicts Cognitive Decline in Alzheimer's Disease. - Vidal, Jean-Sébastien; Hanon, Olivier; Funalot, Benoît; Brunel, Nadège; Viollet, Cécile; Rigaud, Anne-Sophie; Seux, Marie-Laure; le-Bouc, Yves; Epelbaum, Jacques; Duron, Emmanuelle (J Alzheimers Dis, 2016)
BACKGROUND: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer's disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD. OBJECTIVE: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline. METHODS: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every 6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function. RESULTS: Among the 200 AD participants, 146 (mean age = 81.1 (standard deviation (SD) = 5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7)/30 and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline. CONCLUSION: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period.

Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly. - Hsu, David C; Mormino, Elizabeth C; Schultz, Aaron P; Amariglio, Rebecca E; Donovan, Nancy J; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A (J Alzheimers Dis, 2016)
BACKGROUND: Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer's disease (AD) dementia. OBJECTIVE: To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia. METHODS: Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62-90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein E ɛ4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction. RESULTS: In the primary analysis, greater PiB retention was associated with lower BMI (β  =  -0.14, p = 0.02). In the secondary analyses, APOE4 carrier status (β= -0.27, p = 0.02) and normal BMI (β= -0.25, p = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= -0.14, p = 0.04). CONCLUSIONS: This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers.

Lower Prevalence of Alzheimer's Disease among Tibetans: Association with Religious and Genetic Factors. - Huang, Fukai; Shang, Ying; Luo, Yuandai; Wu, Peng; Huang, Xue; Tan, Xiaohui; Lu, Xingyi; Zhen, Lifang; Hu, Xianda (J Alzheimers Dis, 2016)
BACKGROUND: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2-4%). The most common type of dementia is Alzheimer's disease (AD). OBJECTIVE: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors. METHODS: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, and BIN1. Logistic regression models were used to ascertain the associations with AD. RESULTS: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98-1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069-18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038-0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046-0.896) were negatively correlated with AD. CONCLUSION: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind-body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Clusterin; Cognition Disorders; Cross-Sectional Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Logistic Models; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Religion; Risk Factors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tibet

MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. - Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustin; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; et al. (J Alzheimers Dis, 2016)
The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Female; Frontotemporal Dementia; Genetic Predisposition to Disease; Haplotypes; Humans; Logistic Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Spain; tau Proteins

Measuring Information Processing Speed in Mild Cognitive Impairment: Clinical Versus Research Dichotomy. - Haworth, Judy; Phillips, Michelle; Newson, Margaret; Rogers, Peter J; Torrens-Burton, Anna; Tales, Andrea (J Alzheimers Dis, 2016)
A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer's disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI.
Keywords: Aged; Aged, 80 and over; Attention; Cognitive Dysfunction; Electroencephalography; Female; Humans; Male; Mental Processes; Mental Status Schedule; Middle Aged; Neuroimaging; Neuropsychological Tests; Photic Stimulation; Reaction Time; Residence Characteristics

Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy. - Ahmed, Samrah; Baker, Ian; Husain, Masud; Thompson, Sian; Kipps, Christopher; Hornberger, Michael; Hodges, John R; Butler, Christopher R (J Alzheimers Dis, 2016)
Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway. - Song, Jung Min; Sung, You Me; Nam, Jin Han; Yoon, Hyejin; Chung, Andrew; Moffat, Emily; Jung, Mira; Pak, Daniel T S; Kim, Jungsu; Hoe, Hyang-Sook (J Alzheimers Dis, 2016)
BACKGROUND: The accumulation of amyloid-β (Aβ) leads to the loss of dendritic spines and synapses, which is hypothesized to cause cognitive impairments in Alzheimer's disease (AD) patients. In our previous study, we demonstrated that a novel mercaptoacetamide-based class II histone deacetylase inhibitor (HDACI), known as W2, decreased Aβ levels and improved learning and memory in mice. However, the underlying mechanism of this effect is unknown. OBJECTIVE: Because dendritic spine formation is associated with cognitive performance, here we investigated whether HDACI W2 regulates dendritic spine density and its molecular mechanism of action. METHODS: To examine the effect of HDACI W2 on dendritic spine density, we conducted morphological analysis of dendritic spines using GFP transfection and Golgi staining. In addition, to determine the molecular mechanism of W2 effects on spines, we measured the levels of mRNAs and proteins involved in the Ras signaling pathway using quantitative real-time PCR, immunocytochemistry, and western analysis. RESULTS: We found that HDACI W2 altered dendritic spine density and morphology in vitro and in vivo. Additionally, W2 increased the mRNA or protein levels of Ras GRF1 and phospho-ERK. Moreover, knockdown of RasGRF1 and inhibition of ERK activity prevented the W2-mediated spinogenesis in primary hippocampal neurons. CONCLUSION: Our Class II-selective HDACI W2 promotes the formation and growth of dendritic spines in a RasGRF1 and ERK dependent manner in primary hippocampal neurons.
Keywords: Acetamides; Animals; Blotting, Western; Cells, Cultured; Cerebral Cortex; Dendritic Spines; Gene Knockdown Techniques; Green Fluorescent Proteins; Hippocampus; Histone Deacetylase Inhibitors; Immunohistochemistry; MAP Kinase Signaling System; Mice, Inbred C57BL; ras-GRF1; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Thioglycolates; Transfection

Metallothioneins in Prion- and Amyloid-Related Diseases. - Adam, Pavlína; Křížková, Soňa; Heger, Zbyněk; Babula, Petr; Pekařík, Vladimír; Vaculovičoá, Markéta; Gomes, Cláudio M; Kizek, René; Adam, Vojtěch (J Alzheimers Dis, 2016)
Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.
Keywords: Amyloidosis; Animals; Brain Diseases; Humans; Metallothionein; Prion Diseases

Midlife Physical Activity and Cognition Later in Life: A Prospective Twin Study. - Iso-Markku, Paula; Waller, Katja; Vuoksimaa, Eero; Heikkilä, Kauko; Rinne, Juha; Kaprio, Jaakko; Kujala, Urho M (J Alzheimers Dis, 2016)
BACKGROUND: Physical activity has been associated with a reduced risk of cognitive decline but the nature of this association remains obscure. OBJECTIVE: To study associations between midlife physical activity and cognition in old age for a prospective cohort of Finnish twins. METHODS: Physical activity in the Finnish Twin Cohort was assessed using questionnaire responses collected in 1975 and 1981. After a mean follow-up of 25.1 years, the subjects' (n = 3050; mean age 74.2; range 66-97) cognition was evaluated with a validated telephone interview. Both participation in vigorous physical activity, and the volume of physical activity, divided into quintiles, were used as predictors of cognitive impairment. Metrics collected by TELE were used to categorize participants as: cognitively impaired, suffering mild cognitive impairment, or cognitively healthy. RESULTS: Participation in vigorous physical activity compared to non-participation for both 1975 and 1981 was associated with a lower risk of cognitive impairment in individual-based analyses (fully adjusted OR 0.50, 95% CI 0.35-0.73). Pairwise analyses yielded similar but statistically non-significant associations. In terms of the volume of physical activity, the most active quintile of individuals (OR 0.69, 95% CI 0.46-1.04) had a reduced risk of cognitive decline compared with the most sedentary quintile in the fully adjusted model although no clear dose-response was found. CONCLUSION: Vigorous midlife physical activity was associated with less cognitive impairment but without a clear dose-response association between the volume of physical activity and cognition.

Mild Cognitive Impairment and Susceptibility to Scams in Old Age. - Han, S Duke; Boyle, Patricia A; James, Bryan D; Yu, Lei; Bennett, David A (J Alzheimers Dis, 2016)
BACKGROUND: Falling victim to financial scams can have a significant impact upon social and financial wellbeing and independence. A large proportion of scam victims are older adults, but whether older victims with mild cognitive impairment (MCI) are at higher risk remains unknown. OBJECTIVE: We tested the hypothesis that older persons with MCI exhibit greater susceptibility to scams compared to those without cognitive impairment. METHODS: Seven hundred and thirty older adults without dementia were recruited from the Rush Memory and Aging Project, a community-based epidemiologic study of aging. Participants completed a five-item self-report measure of susceptibility to scams, a battery of cognitive measures, and clinical diagnostic evaluations. RESULTS: In models adjusted for age, education, and gender, the presence of MCI was associated with greater susceptibility to scams (B = 0.125, SE = 0.063, p-value = 0.047). Further, in analyses of the role of specific cognitive systems in susceptibility to scams among persons with MCI (n = 144), the level of performance in two systems, episodic memory and perceptual speed abilities, were associated with susceptibility. CONCLUSIONS: Adults with MCI may be more susceptible to scams in old age than older persons with normal cognition. Lower abilities in specific cognitive systems, particularly perceptual speed and episodic memory, may contribute to greater susceptibility to scams in those with MCI.
Keywords: Aged; Aged, 80 and over; Aging; Cognitive Dysfunction; Crime Victims; Disease Susceptibility; Female; Humans; Male; Memory, Episodic; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Residence Characteristics; Self Report

miR-302 Attenuates Amyloid-β-Induced Neurotoxicity through Activation of Akt Signaling. - Li, Hsin-Hua; Lin, Shi-Lung; Huang, Chien-Ning; Lu, Fung-Jou; Chiu, Pai-Yi; Huang, Wen-Nung; Lai, Te-Jen; Lin, Chih-Li (J Alzheimers Dis, 2016)
Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer's disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients' blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Female; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1; Humans; Insulin; Male; Membrane Potential, Mitochondrial; MicroRNAs; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Reactive Oxygen Species; Ribonucleoproteins

Mismatch Negativity and Ear Laterality in Alzheimer's Disease and in Mild Cognitive Impairment. - Idrizbegovic, Esma; Hederstierna, Christina; Rosenhall, Ulf (J Alzheimers Dis, 2016)
BACKGROUND: Cortical auditory event-related potentials (ERPs) were studied in order to measure mismatch negativity (MMN). Three groups of subjects were studied: patients with Alzheimer's disease (AD, n = 32), mild cognitive impairment (MCI, n = 44), and subjective memory complaints without cognitive decline (SMC, n = 27). A bottom up strategy was applied, and the right and left ears were stimulated monaurally. OBJECTIVE: To investigate MMN in AD and MCI, and in a clinical reference group. METHODS: ERPs were carried out with 500 tone pulses at 80 dBnHL. Each sequence included 80% standard tones (500 Hz) (f), and 20% deviant tones (1000 Hz) (r). MMN measurements were carried out by comparing the amplitudes of (f) and (r) recordings and to calculate the amplitude difference in μV for each group. The right and the left ears were analyzed separately. RESULTS: A left ear advantage (LEA) of MMN amplitude was demonstrated in the two groups with better cognition (the MCI and the SMC groups), but not in the AD group. DISCUSSION: The absence of MMN asymmetry in the AD group is possibly caused by a dysfunction to apprehend changes of tonal stimuli.

Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial. - Hoffmann, Kristine; Sobol, Nanna A; Frederiksen, Kristian S; Beyer, Nina; Vogel, Asmus; Vestergaard, Karsten; Brændgaard, Hans; Gottrup, Hanne; Lolk, Annette; Wermuth, Lene; Jacobsen, Søren; Laugesen, Lars P; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent. OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Depression; Exercise; Exercise Therapy; Female; Humans; Male; Middle Aged; Quality of Life; Treatment Outcome

Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier. - Merino-Zamorano, Cristina; Fernández-de Retana, Sofía; Montañola, Alex; Batlle, Aina; Saint-Pol, Julien; Mysiorek, Caroline; Gosselet, Fabien; Montaner, Joan; Hernández-Guillamon, Mar (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) accumulation in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Aβ elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Aβ1-40 to track its efflux across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Aβ1-40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Aβ1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Aβ1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Aβ1-40, rApoA1 trafficking was restricted when it was bound to the Aβ peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Aβ elimination across the BBB.

Modulation of miR-19 in Aluminum-Induced Neural Cell Apoptosis. - Zhu, Mingming; Huang, Cong; Ma, Xiao; Wu, Rui; Zhu, Weiwei; Li, Xiaoting; Liang, Zhaofeng; Deng, Feifei; Zhu, Jianyun; Xie, Wei; Yang, Xue; Jiang, Ye; et al. (J Alzheimers Dis, 2016)
Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer's disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer's disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis.
Keywords: Aluminum; Animals; Apoptosis; Brain; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Male; MicroRNAs; Neurons; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats, Sprague-Dawley; Tumor Suppressor Protein p53

Molecular markers of amnestic mild cognitive impairment among Mexican Americans. - Edwards, Melissa; Hall, James; Williams, Benjamin; Johnson, Leigh; O'Bryant, Sid (J Alzheimers Dis, 2016)
BACKGROUND: Mexican Americans face a significant health disparity when it comes to Alzheimer's disease (AD) as they present with higher rates of the disease and develop AD at an earlier age compared to other ethnic groups. Recent work identified a proteomic profile of AD among this population; however, no work to date has sought to examine the biological profile of pre-AD among Mexican Americans. OBJECTIVE: This study aims to identify an amnestic mild cognitive impairment (aMCI) proteomic profile among Mexican Americans. METHODS: Data were analyzed from 284 Mexican American participants (aMCI, n = 73; normal controls, n = 211) from the Health & Aging Brain among Latino Elders study. Fasting serum samples were analyzed using a multi-plex biomarker assay platform. A biomarker profile was generated using random forest analyses. RESULTS: Among aMCI cases, the biomarker profile was found to be largely inflammatory with the top three markers shown to include TNFα, IL10, and TARC. The overall diagnostic accuracy of the biomarkers in detecting aMCI was 96% (sensitivity = 0.82; specificity = 0.97). Inclusion of clinical variables with the selected biomarkers did not impact the overall detection accuracy (area under the curve = 0.96) but led to a slight improvement in specificity (specificity = 0.99) and decrease in sensitivity (sensitivity = 0.74). CONCLUSION: The biomarker profile of aMCI was shown to be different from our previously generated AD profile among Mexican Americans, which was largely metabolic in nature. The findings implicate a possible interplay between inflammatory and metabolic processes and additional work is needed to further examine this.
Keywords: Aged; Alzheimer Disease; Area Under Curve; Biomarkers; Cognitive Dysfunction; Female; Humans; Male; Mexican Americans; Middle Aged; Neuropsychological Tests; Proteome; Sensitivity and Specificity; United States

Multimodal Classification of Mild Cognitive Impairment Based on Partial Least Squares. - Wang, Pingyue; Chen, Kewei; Yao, Li; Hu, Bin; Wu, Xia; Zhang, Jiacai; Ye, Qing; Guo, Xiaojuan (J Alzheimers Dis, 2016)
In recent years, increasing attention has been given to the identification of the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Brain neuroimaging techniques have been widely used to support the classification or prediction of MCI. The present study combined magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose PET (FDG-PET), and 18F-florbetapir PET (florbetapir-PET) to discriminate MCI converters (MCI-c, individuals with MCI who convert to AD) from MCI non-converters (MCI-nc, individuals with MCI who have not converted to AD in the follow-up period) based on the partial least squares (PLS) method. Two types of PLS models (informed PLS and agnostic PLS) were built based on 64 MCI-c and 65 MCI-nc from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The results showed that the three-modality informed PLS model achieved better classification accuracy of 81.40%, sensitivity of 79.69%, and specificity of 83.08% compared with the single-modality model, and the three-modality agnostic PLS model also achieved better classification compared with the two-modality model. Moreover, combining the three modalities with clinical test score (ADAS-cog), the agnostic PLS model (independent data: florbetapir-PET; dependent data: FDG-PET and MRI) achieved optimal accuracy of 86.05%, sensitivity of 81.25%, and specificity of 90.77%. In addition, the comparison of PLS, support vector machine (SVM), and random forest (RF) showed greater diagnostic power of PLS. These results suggested that our multimodal PLS model has the potential to discriminate MCI-c from the MCI-nc and may therefore be helpful in the early diagnosis of AD.

Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice. - Yu, Lixia; Chen, Yuan; Wang, Weiguang; Xiao, Zhonghai; Hong, Yan (J Alzheimers Dis, 2016)
Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model. - Zhou, Xiao; Huang, Jianou; Pan, Suyue; Xu, Miaojing; He, Rongni; Ji, Zhong; Hu, Yafang (J Alzheimers Dis, 2016)
BACKGROUND: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models. OBJECTIVE: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9). METHODS: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed. RESULTS: GFP expression was detected by in vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression. CONCLUSION: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo, as well as an alternative tool for development of drugs against neurotoxic of p25.

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations. - Luis, Elkin; Ortiz, Alexandra; Eudave, Luis; Ortega-Cubero, Sara; Borroni, Barbara; van der Zee, Julie; Gazzina, Stefano; Caroppo, Paola; Rubino, Elisa; D'Agata, Federico; Le Ber, Isabelle; Santana, Isabel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia. - Hirni, Daniela I; Kivisaari, Sasa L; Krumm, Sabine; Monsch, Andreas U; Berres, Manfred; Oeksuez, Fatma; Reinhardt, Julia; Ulmer, Stephan; Kressig, Reto W; Stippich, Christoph; Taylor, Kirsten I (J Alzheimers Dis, 2016)
Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

Non-Fibrillar Oligomeric Amyloid-β within Synapses. - Pickett, Eleanor K; Koffie, Robert M; Wegmann, Susanne; Henstridge, Christopher M; Herrmann, Abigail G; Colom-Cadena, Marti; Lleo, Alberto; Kay, Kevin R; Vaught, Melissa; Soberman, Roy; Walsh, Dominic M; Hyman, Bradley T; et al. (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue.