Rapidly Progressive Frontotemporal Dementia Associated with MAPT Mutation G389R. - Sun, Lin; Chen, Kathryn; Li, Xia; Xiao, Shifu (J Alzheimers Dis, 2017)
Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease.

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. - Louwersheimer, Eva; Cohn-Hokke, Petra E; Pijnenburg, Yolande A L; Weiss, Marjan M; Sistermans, Erik A; Rozemuller, Annemieke J; Hulsman, Marc; van Swieten, John C; van Duijn, Cock M; Barkhof, Frederik; Koene, Teddy; Scheltens, Philip; et al. (J Alzheimers Dis, 2017)
BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

Recent Increases in Hippocampal Tau Pathology in the Aging Japanese Population: The Hisayama Study. - Hamasaki, Hideomi; Honda, Hiroyuki; Okamoto, Tsuyoshi; Koyama, Sachiko; Suzuki, Satoshi O; Ohara, Tomoyuki; Ninomiya, Toshiharu; Kiyohara, Yutaka; Iwaki, Toru (J Alzheimers Dis, 2017)
BACKGROUND: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer's disease has been observed over the past 18 years. OBJECTIVES: We sought to investigate the increases in brain pathology related to Alzheimer's disease using automated MATLAB morphometric analyses for quantifying tau pathology. METHODS: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies. RESULTS: Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012). CONCLUSION: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology.

Recovery from Proactive Semantic Interference in Mild Cognitive Impairment and Normal Aging: Relationship to Atrophy in Brain Regions Vulnerable to Alzheimer's Disease. - Loewenstein, David A; Curiel, Rosie E; Wright, Clinton; Sun, Xiaoyan; Alperin, Noam; Crocco, Elzabeth; Czaja, Sara J; Raffo, Arlene; Penate, Ailyn; Melo, Jose; Capp, Kimberly; Gamez, Monica; et al. (J Alzheimers Dis, 2017)
BACKGROUND: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer's disease (AD). OBJECTIVE: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults. METHODS: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups. RESULTS: Relative to traditional neuropsychological measures, MCI patients' failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = -0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = -0.49), the failure to recover from PSI (rs = -0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = -0.48). DISCUSSION: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation.

Reduced Cerebrospinal Fluid Concentration of Apolipoprotein A-I in Patients with Alzheimer's Disease. - Johansson, Per; Almqvist, Erik G; Bjerke, Maria; Wallin, Anders; Johansson, Jan-Ove; Andreasson, Ulf; Blennow, Kaj; Zetterberg, Henrik; Svensson, Johan (J Alzheimers Dis, 2017)
BACKGROUND: Apolipoprotein E (ApoE) has been extensively studied in Alzheimer's disease (AD), but little is known of apolipoprotein A-I (ApoA-I) in cerebrospinal fluid (CSF). OBJECTIVE: Plasma lipids as well as ApoA-I and ApoE in plasma and CSF were determined and related to Mini-Mental State Examination (MMSE) score, APOE genotype, and CSF AD biomarkers. METHODS: Consecutive patients with AD (n = 29), stable mild cognitive impairment (n = 13), other dementias (n = 14), and healthy controls (n = 18) were included at a single center. RESULTS: AD patients had higher plasma triglycerides and lower CSF ApoA-I concentration than controls (both p < 0.05). CSF ApoE concentration was reduced in other dementias (p < 0.01). In AD as well as other dementias, the ratios between CSF and plasma concentrations of both ApoA-I and ApoE were lower than those in the controls. ApoA-I and ApoE in plasma and CSF were not influenced by APOEɛ4 allele distribution. In the total study population (n = 74), CSF ApoA-I correlated positively with MMSE score (r = 0.26, p < 0.05) and negatively with CSF P-tau (r = -0.25, p < 0.05). CSF ApoE correlated positively with CSF concentrations of T-tau and P-tau in the total study population and in AD patients. CONCLUSION: CSF ApoA-I was reduced in AD patients and associated with measures of cognitive function and AD disease status. The mechanisms underlying the decreased CSF:plasma ratios of ApoA-I and ApoE in AD and other dementias need to be explored in further studies.

The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer's Disease. - Muszyński, Paweł; Kulczyńska-Przybik, Agnieszka; Borawska, Renata; Litman-Zawadzka, Ala; Słowik, Agnieszka; Klimkowicz-Mrowiec, Aleksandra; Pera, Joanna; Dziedzic, Tomasz; Mroczko, Barbara (J Alzheimers Dis, 2017)
BACKGROUND: It is known that YKL-40- a marker of glial inflammation, and VILIP-1- a marker of neuronal injury, reflect functional and structural changes in AD brains, although there is limited data concerning their potential influence on blood-brain barrier (BBB) homeostasis. OBJECTIVE: Therefore, the aim of our study was to investigate the relationship between markers of inflammation and degeneration in the central nervous system (CNS) of patients with AD and mild cognitive impairment (MCI) as well as immunological response in CNS and BBB function. METHODS: Cerebrospinal fluid (CSF) concentrations of proteins tested were determined in 45 AD patients, 18 MCI subjects, and 23 non-demented controls using ELISA method. RESULTS: CSF concentrations of YKL-40 were significantly higher in MCI and AD patients, whereas CSF levels of VILIP-1 were statistically higher in the AD group as compared to the subjects without cognitive deficits. Elevated concentrations of YKL-40 correlated significantly with increased albumin quotient and decreased Aβ42/40 ratio in AD patients and with IgG quotient in the total study group. We did not find a relationship between VILIP-1 and immunological parameters reflecting BBB dysfunction and humoral immune response. CONCLUSION: Our findings indicate that YKL-40 may contribute to decreased stability and increased permeability of BBB in AD patients. It is assumed that YKL-40 is implicated in the development of brain barriers, although its precise mechanism of action in the BBB disruption remains unrevealed. Further studies on larger groups of patients are required to confirm our hypothesis.

The Relationship of Bilingualism Compared to Monolingualism to the Risk of Cognitive Decline or Dementia: A Systematic Review and Meta-Analysis. - Mukadam, Naaheed; Sommerlad, Andrew; Livingston, Gill (J Alzheimers Dis, 2017)
BACKGROUND: Bilingualism may contribute to cognitive reserve, protect against cognitive decline, and delay the onset of dementia. OBJECTIVE: We systematically reviewed evidence about the effect of bilingualism on subsequent cognitive decline or dementia. METHODS: We searched electronic databases and references for longitudinal studies comparing cognitive decline in people who were bilingual with those who were monolingual and evaluated study quality. We conducted meta-analyses using random effects models to calculate pooled odds ratio of incident dementia. RESULTS: We included 13/1,156 eligible articles. Meta-analysis of prospective studies of the effects of bilingualism on future dementia gave a combined Odds Ratio of dementia of 0.96 (95% CI 0.74-1.23) in bilingual participants (n = 5,527) compared to monolinguals. Most retrospective studies found that bilingual people were reported to develop symptoms of cognitive decline at a later age than monolingual participants. CONCLUSION: We did not find that bilingualism protects from cognitive decline or dementia from prospective studies. Retrospective studies are more prone to confounding by education, or cultural differences in presentation to dementia services and are therefore not suited to establishing causative links between risk factors and outcomes.

The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults. - Bae, Seongryu; Shimada, Hiroyuki; Lee, Sangyoon; Makizako, Hyuma; Lee, Sungchul; Harada, Kazuhiro; Doi, Takehiko; Tsutsumimoto, Kota; Hotta, Ryo; Nakakubo, Sho; Park, Hyuntae; Suzuki, Takao (J Alzheimers Dis, 2017)
BACKGROUND: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear. OBJECTIVE: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults. METHODS: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components and MCI subtypes were analyzed using multiple logistic regression. RESULTS: MetS prevalence was greater in participants with naMCI (men: p = 0.030; women: p = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13-5.32; women: OR: 1.94, 95% CI: 1.12-3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19-2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25-3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03-1.94) and raised glucose (OR: 1.32, 95% CI: 1.02-1.71) were associated with naMCI. CONCLUSION: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components.

Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review. - Solfrizzi, Vincenzo; Custodero, Carlo; Lozupone, Madia; Imbimbo, Bruno P; Valiani, Vincenzo; Agosti, Pasquale; Schilardi, Andrea; D'Introno, Alessia; La Montagna, Maddalena; Calvani, Mariapaola; Guerra, Vito; Sardone, Rodolfo; et al. (J Alzheimers Dis, 2017)
In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

Remyelination: A Potential Therapeutic Strategy for Alzheimer's Disease? - Sun, Junjun; Zhou, Hong; Bai, Feng; Zhang, Zhijun; Ren, Qingguo (J Alzheimers Dis, 2017)
Myelin is a lipid-rich multilamellar membrane that wraps around long segments of neuronal axons and it increases the conduction of action potentials, transports the necessary trophic support to the neuronal axons, and reduces the energy consumed by the neuronal axons. Together with axons, myelin is a prerequisite for the higher functions of the central nervous system and complex forms of network integration. Myelin impairments have been suggested to lead to neuronal dysfunction and cognitive decline. Accumulating evidence, including brain imaging and postmortem and genetic association studies, has implicated myelin impairments in Alzheimer's disease (AD). Increasing data link myelin impairments with amyloid-β (Aβ) plaques and tau hyperphosphorylation, which are both present in patients with AD. Moreover, aging and apolipoprotein E (ApoE) may be involved in the myelin impairments observed in patients with AD. Decreased neuronal activity, increased Aβ levels, and inflammation further damage myelin in patients with AD. Furthermore, treatments that promote myelination contribute to the recovery of neuronal function and improve cognition. Therefore, strategies targeting myelin impairment may provide therapeutic opportunities for patients with AD.

Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data. - Sennik, Simrin; Schweizer, Tom A; Fischer, Corinne E; Munoz, David G (J Alzheimers Dis, 2017)
BACKGROUND: Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. OBJECTIVE: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD. METHODS: Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons. RESULTS: 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. CONCLUSIONS: Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

The Road Less Traveled: Alternative Pathways for Action-Verb Processing in Parkinson's Disease. - Abrevaya, Sofía; Sedeño, Lucas; Fitipaldi, Sol; Pineda, David; Lopera, Francisco; Buritica, Omar; Villegas, Andrés; Bustamante, Catalina; Gomez, Diana; Trujillo, Natalia; Pautassi, Ricardo; Ibáñez, Agustín; et al. (J Alzheimers Dis, 2017)
Action verbs are critically embodied in motor brain networks. In Parkinson's disease (PD), damage to the latter compromises access to such words. However, patients are not fully incapable of processing them, as their performance is far from floor level. Here we tested the hypothesis that action-verb processing in PD may rely on alternative disembodied semantic circuits. Seventeen PD patients and 15 healthy controls listened to action verbs and nouns during functional MRI scanning. Using cluster-mass analysis with a permutation test, we assessed task-related functional connectivity considering seeds differentially engaged by action and non-action words (namely, putamen and M1 versus posterior superior temporal lobe, respectively). The putamen seed showed reduced connectivity within the basal ganglia in patients for both lexical categories. However, only action verbs recruited different cortical networks in each group. Specifically, the M1 seed exhibited more anterior connectivity for controls and more posterior connectivity for patients, with no differences in the temporal seed. Moreover, the patients' level of basal ganglia atrophy positively correlated with their reliance on M1-posterior connectivity during action-verb processing. PD patients seem to have processed action verbs via non-motor cortical networks subserving amodal semantics. Such circuits may afford alternative pathways to process words when default embodied mechanisms are disturbed. Moreover, the greater the level of basal ganglia atrophy, the greater the patients' reliance on this alternative route. Our findings offer new insights into differential neurofunctional mechanisms recruited to process action semantics in PD.

The Role of ADAM10 in Alzheimer's Disease. - Yuan, Xiang-Zhen; Sun, Sen; Tan, Chen-Chen; Yu, Jin-Tai; Tan, Lan (J Alzheimers Dis, 2017)
As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-β protein precursor (AβPP) cleavage and plays a critical role in reducing the generation of the amyloid-β (Aβ) peptides. Recent studies have demonstrated its beneficial role in alleviating the pathologic impairment in Alzheimer's disease (AD) both in vitro and in vivo. However, the role of ADAM10 in AD and the underlying molecular mechanisms are still not well established. Increasing evidence indicates that ADAM10 not only reduces the generation of Aβ but may also affect the pathology of AD through potential mechanisms including reducing tau pathology, maintaining normal synaptic functions, and promoting hippocampal neurogenesis and the homeostasis of neuronal networks. Mechanistically, ADAM10 regulates these functions by interacting with postsynaptic substrates in brain, especially synaptic cell receptors and adhesion molecules. Furthermore, ADAM10 protein in platelets seems to be a promising biomarker for AD diagnosis. This review will summarize the role of ADAM10 in AD and highlight its functions besides its role as the α-secretase in AβPP cleavage. Meanwhile, we will discuss the therapeutic potential of ADAM10 in treating AD.

The Role of Cerebrovascular Disease on Cognitive and Functional Status and Psychosis in Severe Alzheimer's Disease. - Kim, Julia; Schweizer, Tom A; Fischer, Corinne E; Munoz, David G (J Alzheimers Dis, 2017)
BACKGROUND: The pathophysiology behind psychosis in patients with Alzheimer's disease (AD) remains unknown. Vascular risk factors have been recognized as an important modifier of the clinical presentation of AD. OBJECTIVE: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions. METHODS: Data was provided by the National Alzheimer's Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). The Neuropathology Data Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis. RESULTS: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology. CONCLUSION: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis.

Role of Niemann-Pick Type C Disease Mutations in Dementia. - Cupidi, Chiara; Frangipane, Francesca; Gallo, Maura; Clodomiro, Alessandra; Colao, Rosanna; Bernardi, Livia; Anfossi, Maria; Conidi, Maria Elena; Vasso, Franca; Curcio, Sabrina Anna Maria; Mirabelli, Maria; Smirne, Nicoletta; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

The Role of Single-Subject Brain Metabolic Patterns in the Early Differential Diagnosis of Primary Progressive Aphasias and in Prediction of Progression to Dementia. - Cerami, Chiara; Dodich, Alessandra; Greco, Lucia; Iannaccone, Sandro; Magnani, Giuseppe; Marcone, Alessandra; Pelagallo, Elisabetta; Santangelo, Roberto; Cappa, Stefano F; Perani, Daniela (J Alzheimers Dis, 2017)
BACKGROUND AND OBJECTIVE: Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings. MATERIAL AND METHODS: 55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level. RESULTS: FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer's disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline. DISCUSSION: Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic definition of possible endo-phenotypes.

Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice. - Iwahara, Naotoshi; Hisahara, Shin; Kawamata, Jun; Matsumura, Akihiro; Yokokawa, Kazuki; Saito, Taro; Fujikura, Mai; Manabe, Tatsuo; Suzuki, Hiromi; Matsushita, Takashi; Suzuki, Syuuichirou; Shimohama, Shun (J Alzheimers Dis, 2017)
In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cells, Cultured; Disease Models, Animal; Female; Humans; Interleukin-6; Lipopolysaccharides; Male; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurons; Presenilin-1; Suppressor of Cytokine Signaling 3 Protein; Tumor Necrosis Factor-alpha

Rosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis. - Galzitskaya, Oxana V; Selivanova, Olga M (J Alzheimers Dis, 2017)
Deeper understanding of processes of protein misfolding, aggregation, formation of oligomers, protofibrils, and fibrils is crucial for the development of future medicine in treatment of amyloid-related diseases. While numerous reports illuminate the field, the above processes are extremely complex, as they depend on many varying parameters, such as the peptide concentration, temperature, pH, presence of metal ions, lipids, and organic solvents. Different mechanisms of amyloid fibril formation have been proposed, but the process of the oligomer-to-fibril transition is the least agreed upon. Our studies of a number of amyloidogenic proteins and peptides (insulin, Aβ peptides, the Bgl2 protein from the yeast cell wall), as well as their amyloidogenic fragments, have allowed us to propose a model of the fibril structure generation. We have found that the main building block of fibrils of any morphology is a ring-like oligomer. The varying models of interaction of ring oligomers with each other revealed in our studies make it possible to explain their polymorphism. Crucially, the amino acid sequence determines the oligomer structure for the given protein/peptide.

Screening for Mild Cognitive Impairment and Dementia with Automated, Anonymous Online and Telephone Cognitive Self-Tests. - Van Mierlo, Lisa D; Wouters, Hans; Sikkes, Sietske A M; van der Flier, Wiesje M; Prins, Niels D; Bremer, Jonne A E; Koene, Teddy; Van Hout, Hein P J (J Alzheimers Dis, 2017)
BACKGROUND: Many older people worry about cognitive decline. Early cognitive screening in an anonymous and easily accessible manner may reassure older people who are unnecessarily worried about normal cognitive aging while it may also expedite help seeking in case of suspicious cognitive decline. OBJECTIVE: To develop and validate online and telephone-based automated self-tests of cognitive function. METHODS: We examined the feasibility and validity of the self-tests in a prospective study of 117 participants of whom 34 had subjective cognitive decline (SCD), 30 had mild cognitive impairment (MCI), and 53 had dementia. The ability of these self-tests to accurately distinguish MCI and dementia from SCD was examined with ROC curves. Convergent validity was examined by calculating rank correlations between the self-tests and neuropsychological tests. RESULTS: Both the online and telephone cognitive self-tests were feasible, because the majority of participants (86% and 80%, respectively) were able to complete them. The online self-test had adequate diagnostic accuracy in the screening for MCI and dementia versus SCD with an Area under the Curve (AUC) of 0.86 (95% CI: 0.78-0.93). The AUC of the MMSE was 0.82 (95% CI: 0.74-0.89). By contrast, the telephone self-test had lower diagnostic accuracy (AUC = 0.75, 95% CI: 0.64-0.86). Both self-tests had good convergent validity as demonstrated by moderate to strong rank correlations with neuropsychological tests. CONCLUSION: We demonstrated good diagnostic accuracy and convergent validity for the online self-test of cognitive function. It is therefore a promising tool in the screening for MCI and dementia.

Secular Trends in the Incidence of Dementia in a Multi-Ethnic Community. - Noble, James M; Schupf, Nicole; Manly, Jennifer J; Andrews, Howard; Tang, Ming-Xin; Mayeux, Richard (J Alzheimers Dis, 2017)
BACKGROUND: Determination of secular trends in cognitive aging is important for prioritization of resources, services, and research in aging populations. Prior studies have identified declining dementia incidence associated with changes in cardiovascular risk factors and increased educational attainment. However, few studies have examined these factors in multi-ethnic cohorts. OBJECTIVE: To identify secular trends in the incidence rate of dementia in an elderly population. METHODS: Participants in this study were drawn from the Washington Heights-Inwood Columbia Aging Project, a multi-ethnic cohort study of northern Manhattan residents aged 65 years and older. Cox proportional hazards models were used to examine differences in the incidence of dementia in cohorts recruited in 1992 and 1999, with age at dementia or age at last follow-up visit as the "time-to-event" variable. RESULTS: Overall, there was a 41% reduction in the hazard ratio for dementia among participants in the 1999 cohort compared with those in the 1992 cohort, adjusting for age, sex, race, and baseline memory complaints (HR = 0.59). The reduction in incidence was greatest among non-Hispanic Whites and African-Americans and lowest among Hispanic participants (HRs = 0.60, 0.52 and 0.64, respectively), and was associated with increases in level of educational attainment, especially among African-Americans. Reduction in incidence of dementia was also greater among persons 75 years or older than among younger participants (HR = 0.52 versus HR = 0.69). CONCLUSIONS: Our results support previous findings that secular trends in dementia incidence are changing, including in aging minority populations.

Selenomethionine Attenuates the Amyloid-β Level by Both Inhibiting Amyloid-β Production and Modulating Autophagy in Neuron-2a/AβPPswe Cells. - Zhang, Zhong-Hao; Wu, Qiu-Yan; Chen, Chen; Zheng, Rui; Chen, Yao; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aβ clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD.

Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD). - Nave, Stephane; Doody, Rachelle S; Boada, Merce; Grimmer, Timo; Savola, Juha-Matti; Delmar, Paul; Pauly-Evers, Meike; Nikolcheva, Tania; Czech, Christian; Borroni, Edilio; Ricci, Benedicte; Dukart, Juergen; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD). OBJECTIVE: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. METHODS: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. RESULTS: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p = 0.014; 1 mg) and - 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). CONCLUSIONS: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

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-Dependent Associations of Serum Uric Acid with Brain Function During Aging. - Kueider, Alexandra M; An, Yang; Tanaka, Toshiko; Kitner-Triolo, Melissa H; Studenski, Stephanie; Ferrucci, Luigi; Thambisetty, Madhav (J Alzheimers Dis, 2017)
Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer's disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26-99 (N = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β= 0.006; p = 0.03) and visuospatial abilities (β= 0.007; p = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women.

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.

Shape-Attributes of Brain Structures as Biomarkers for Alzheimer's Disease. - Glozman, Tanya; Solomon, Justin; Pestilli, Franco; Guibas, Leonidas (J Alzheimers Dis, 2017)
We describe a fully automatic framework for classification of two types of dementia based on the differences in the shape of brain structures. We consider Alzheimer's disease (AD), mild cognitive impairment of individuals who converted to AD within 18 months (MCIc), and normal controls (NC). Our approach uses statistical learning and a feature space consisting of projection-based shape descriptors, allowing for canonical representation of brain regions. Our framework automatically identifies the structures most affected by the disease. We evaluate our results by comparing to other methods using a standardized data set of 375 adults available from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our framework is sensitive to identifying the onset of Alzheimer's disease, achieving up to 88.13% accuracy in classifying MCIc versus NC, outperforming previous methods.

Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer's Disease: A "Real World" Study. - Boccardi, Virginia; Baroni, Marta; Smirne, Nicoletta; Clodomiro, Alessandra; Ercolani, Sara; Longo, Annalisa; Ruggiero, Carmelinda; Bruni, Amalia C; Mecocci, Patrizia (J Alzheimers Dis, 2017)
BACKGROUND: Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population. OBJECTIVE: We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting. METHODS: This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively. RESULTS: In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p < 0.0001), respectively. Old-old non-responders had a slower rate of cognitive (p < 0.0001) and functional decline (p < 0.0001) as compared with responders after three years of observation. CONCLUSION: Discontinuing ChEI treatment solely for the absence of an initial response is not appropriate, especially in old-old subjects.

Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer's Disease. - Sheng, Min; Lu, Hanzhang; Liu, Peiying; Li, Yang; Ravi, Harshan; Peng, Shin-Lei; Diaz-Arrastia, Ramon; Devous, Michael D; Womack, Kyle B (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. OBJECTIVE: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. METHODS: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. RESULTS: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. CONCLUSION: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

Silicic Acid and Beer Consumption Reverses the Metal Imbalance and the Prooxidant Status Induced by Aluminum Nitrate in Mouse Brain. - González-Muñoz, María José; Garcimartán, Alba; Meseguer, Isabel; Mateos-Vega, Carmen José; Orellana, José María; Peña-Fernández, Antonio; Benedí, Juana; Sánchez-Muniz, Francisco J (J Alzheimers Dis, 2017)
BACKGROUND: Emerging evidence suggests that by affecting mineral balance, aluminum (Al) may enhance some events associated with neurodegenerative diseases. AIM: To examine the effect of Al(NO3)3 exposure on brain Al, cooper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), silicon (Si), and zinc (Zn) levels, and the metal-change implication in brain oxidant and inflammatory status. METHODS: Four groups of six-week-old male NMRI mice were treated for three months: i) controls, administrated with deionized water; ii) Al, which received Al(NO3)3; iii) Al+silicic acid, which were given Al(NO3)3 plus silicic acid; and iv) Al+beer, which received Al(NO3)3 plus beer. RESULTS: Brain Al and TBARS levels and TNFα and GPx expressions increased, while Cu, Mn, and Zn levels, and catalase and CuZn-SOD expression decreased (at least, p < 0.05) in Al versus control animals. Al, Si, and TBARS levels and TNFα expression decreased (p < 0.05) in Al+silicic acid and Al+beer specimens while Cu, Mn, and Zn levels and antioxidant expression increased versus the Al group. Brain Al levels correlated negatively with those of Cu, Fe, Mn, and Zn, and catalase, CuZn-SOD, and GPx enzyme expressions but positively with Si and TBARS levels and TNFα expression. Two components of the principal component analysis (PCA) explained 71.2% of total data variance (p < 0.001). PCA connected the pro-oxidant markers with brain Al content, while brain Zn and Cu levels were closer to antioxidant enzyme expression. CONCLUSION: Administration of Al(NO3)3 induced metal imbalance, inflammation, and antioxidant status impairment in the brain. Those effects were blocked to a significant extent by silicic acid and beer administration.

Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship. - Buratti, Laura; Viticchi, Giovanna; Baldinelli, Sara; Falsetti, Lorenzo; Luzzi, Simona; Pulcini, Alessandra; Petrelli, Cristina; Provinciali, Leandro; Silvestrini, Mauro (J Alzheimers Dis, 2017)
BACKGROUND: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. OBJECTIVE: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. METHODS: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. RESULTS: At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. CONCLUSIONS: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

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.

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload. - Cascella, Roberta; Evangelisti, Elisa; Bigi, Alessandra; Becatti, Matteo; Fiorillo, Claudia; Stefani, Massimo; Chiti, Fabrizio; Cecchi, Cristina (J Alzheimers Dis, 2017)
An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by Aβ42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by Aβ42 oligomers with low solvent-exposed hydrophobicity (A-) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. - Liu, Guiyou; Sun, Jing-Yi; Xu, Meiling; Yang, Xiao-Yi; Sun, Bao-Liang (J Alzheimers Dis, 2017)
A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer's disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer's disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk.

Specific Verbal Memory Measures May Distinguish Alzheimer's Disease from Dementia with Lewy Bodies. - Bussè, Cinzia; Anselmi, Pasquale; Pompanin, Sara; Zorzi, Giovanni; Fragiacomo, Federica; Camporese, Giulia; Di Bernardo, Gian Antonio; Semenza, Carlo; Caffarra, Paolo; Cagnin, Annachiara (J Alzheimers Dis, 2017)
BACKGROUND: Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory. OBJECTIVE: To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). METHODS: Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting (VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance. RESULTS: DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB. DISCUSSION: DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions.

Sporadic Cases with Novel Mutations and Pedigree in Hereditary Leukoencephalopathy with Axonal Spheroids. - Wu, Liyong; Liu, Jia; Sha, Longze; Wang, Xianling; Li, Jieying; Dong, Jing; Jia, Jianping (J Alzheimers Dis, 2017)
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant hereditary disease, featured by cerebral white matter degeneration with demyelination and axonal spheroids. We collected three gene-confirmed HDLS cases in our neurodegenerative clinic. Two HDLS cases were sporadic with novel mutations, while another case had a family history with previously described mutations. All three cases suffered memory problems with white matter lesions and pyramid signs. No obvious clinical differences were observed between sporadic and familial HDLS cases. Distinct features, such as subcortical calcification in brain computed tomography and asymmetric abnormal MRI signal along the pyramid tracts throughout brainstem and spinal cord (cervical, thoracic, and lumbar segments), were observed in one sporadic case with novel mutation. Therefore, the interactions of genotype-phenotype still need to be further investigated.

Stress-Induced Synaptic Dysfunction and Neurotransmitter Release in Alzheimer's Disease: Can Neurotransmitters and Neuromodulators be Potential Therapeutic Targets? - Jha, Saurabh Kumar; Jha, Niraj Kumar; Kumar, Dhiraj; Sharma, Renu; Shrivastava, Abhishek; Ambasta, Rashmi K; Kumar, Pravir (J Alzheimers Dis, 2017)
The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer's disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca2+ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as a potential therapeutic approach in synaptopathy associated with AD.

Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β. - Salgado-Puga, Karla; Rodríguez-Colorado, Javier; Prado-Alcalá, Roberto A; Peña-Ortega, Fernando (J Alzheimers Dis, 2017)
In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.

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.

Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer's Disease. - Cansev, Mehmet; Turkyilmaz, Mesut; Sijben, John W C; Sevinc, Cansu; Broersen, Laus M; van Wijk, Nick (J Alzheimers Dis, 2017)
Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors' effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer's disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

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.

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases. - Nilson, Ashley N; English, Kelsey C; Gerson, Julia E; Whittle, T Barton; Crain, C Nicolas; Xue, Judy; Sengupta, Urmi; Castillo-Carranza, Diana L; Zhang, Wenbo; Gupta, Praveena; Kayed, Rakez (J Alzheimers Dis, 2017)
It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

Tau Oligomers in Sera of Patients with Alzheimer's Disease and Aged Controls. - Kolarova, Michala; Sengupta, Urmi; Bartos, Ales; Ricny, Jan; Kayed, Rakez (J Alzheimers Dis, 2017)
Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer's disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels positively correlated with aging (Spearman r = 0.26, p = 0.016). On the contrary, we found lower levels of tau oligomers in the serum of mild cognitive impairment (MCI) (p = 0.033) and MCI-AD (p = 0.006) patients. These results could suggest that clearance of extracellular tau proteins takes place, in part, in the periphery. In the case of MCI patients, the lower levels of tau oligomers could be the result of impaired clearance of tau protein from interstitium to blood and consequent accumulation of tau aggregates in the brain.

Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer's Disease. - Slachevsky, Andrea; Guzmán-Martínez, Leonardo; Delgado, Carolina; Reyes, Pablo; Farías, Gonzalo A; Muñoz-Neira, Carlos; Bravo, Eduardo; Farías, Mauricio; Flores, Patricia; Garrido, Cristian; Becker, James T; Lopez, Oscar L; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Intracellular neurofibrillary tangles are part of the core pathology of Alzheimer's disease (AD), which are mainly composed of hyperphosphorylated tau protein. OBJECTIVES: The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects. METHODS: We examined 53 AD patients and 37 cognitively normal subjects recruited from two Memory Clinics at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI scans were analyzed using voxel-based morphometry in 41 AD patients. RESULTS: The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region. CONCLUSIONS: This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.

Tau Proteins Cross the Blood-Brain Barrier. - Banks, William A; Kovac, Andrej; Majerova, Petra; Bullock, Kristin M; Shi, Min; Zhang, Jing (J Alzheimers Dis, 2017)
Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease.

Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study. - Kuiperij, H Bea; Versleijen, Alexandra A M; Beenes, Marijke; Verwey, Nicolaas A; Benussi, Luisa; Paterlini, Anna; Binetti, Giuliano; Teunissen, Charlotte E; Raaphorst, Joost; Schelhaas, Helenius J; Küsters, Benno; Pijnenburg, Yolande A L; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies. OBJECTIVE: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes. METHODS: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers. RESULTS: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients. CONCLUSION: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice. - Shukla, Varsha; Seo, Jinsoo; Binukumar, B K; Amin, Niranjana D; Reddy, Preethi; Grant, Philip; Kuntz, Susan; Kesavapany, Sashi; Steiner, Joseph; Mishra, Santosh K; Tsai, Li-Huei; Pant, Harish C (J Alzheimers Dis, 2017)
It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.

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.

TOMM40 and APOE Gene Expression and Cognitive Decline in Japanese Alzheimer's Disease Subjects. - Mise, Ayano; Yoshino, Yuta; Yamazaki, Kiyohiro; Ozaki, Yuki; Sao, Tomoko; Yoshida, Taku; Mori, Takaaki; Mori, Yoko; Ochi, Shinichiro; Iga, Jun-Ichi; Ueno, Shu-Ichi (J Alzheimers Dis, 2017)
BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD). OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects. RESULTS: TOMM40 mRNA expression was significantly lower in AD subjects (0.87±0.18 versus 1.0±0.23, p = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5±0.61 versus 1.0±0.52, p < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r = 0.290, p = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p = 0.32). Methylation rates in the upstream region of TOMM40exon 1 were not different between AD and control subjects (average rate: 1.37±0.99 versus 1.39±1.20, p = 0.885), and TOMM40523 polyT genotypes were also not different between AD and control subjects (p = 0.67). CONCLUSION: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction.

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.

Transport of Non-Transferrin Bound Iron to the Brain: Implications for Alzheimer's Disease. - Tripathi, Ajai K; Karmakar, Shilpita; Asthana, Abhishek; Ashok, Ajay; Desai, Vilok; Baksi, Shounak; Singh, Neena (J Alzheimers Dis, 2017)
A direct correlation between brain iron and Alzheimer's disease (AD) raises questions regarding the transport of non-transferrin-bound iron (NTBI), a toxic but less researched pool of circulating iron that is likely to increase due to pathological and/or iatrogenic systemic iron overload. Here, we compared the distribution of radiolabeled-NTBI (59Fe-NTBI) and transferrin-bound iron (59Fe-Tf) in mouse models of iron overload in the absence or presence of inflammation. Following a short pulse, most of the 59Fe-NTBI was taken up by the liver, followed by the kidney, pancreas, and heart. Notably, a strong signal of 59Fe-NTBI was detected in the brain ventricular system after 2 h, and the brain parenchyma after 24 h. 59Fe-Tf accumulated mainly in the femur and spleen, and was transported to the brain at a much slower rate than 59Fe-NTBI. In the kidney, 59Fe-NTBI was detected in the cortex after 2 h, and outer medulla after 24 hours. Most of the 59Fe-NTBI and 59Fe-Tf from the kidney was reabsorbed; negligible amount was excreted in the urine. Acute inflammation increased the uptake of 59Fe-NTBI by the kidney and brain from 2-24 hours. Chronic inflammation, on the other hand, resulted in sequestration of iron in the liver and kidney, reducing its transport to the brain. These observations provide direct evidence for the transport of NTBI to the brain, and reveal a complex interplay between inflammation and brain iron homeostasis. Further studies are necessary to determine whether transient increase in NTBI due to systemic iron overload is a risk factor for AD.

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.

Trends, Predictors, and Outcomes of Healthcare Resources Used in Patients Hospitalized with Alzheimer's Disease with at Least One Procedure: The Nationwide Inpatient Sample. - Beydoun, May A; Gamaldo, Alyssa A; Beydoun, Hind A; Shaked, Danielle; Zonderman, Alan B; Eid, Shaker M (J Alzheimers Dis, 2017)
We assessed trends, predictors and outcomes of resource utilization in hospital inpatient discharges with a principal diagnosis of Alzheimer's disease (AD) with at least one procedure. Using Nationwide Inpatient Sample data (NIS, 2002-2012), discharges primarily diagnosed with AD, aged ≥60 y and with ≥1 procedure, were selected (Weighted N = 92,300). Hospital resource utilization were assessed using ICD-9-CM codes, while hospitalization outcomes included total charges (TC, 2012$), length of stay (LOS, days), and mortality risk (MR, %). Brain and respiratory/gastrointestinal procedure utilization both dropped annually by 3-7%, while cardiovascular procedures/evaluations, blood evaluations, blood transfusion, and resuscitation ("CVD/Blood") as well as neurophysiological and psychological evaluation and treatment ("Neuro") procedures increased by 5-8%. Total charges, length of stay, and mortality risk were all markedly higher with use of respiratory/gastrointestinal procedures as opposed to being reduced with use of "Brain" procedures. Procedure count was positively associated with all three hospitalization outcomes. In sum, patterns of hospital resources that were used among AD inpatients changed over-time, and were associated with hospitalization outcomes such as total charges, length of stay, and mortality risk.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Female; Health Resources; Hospitalization; Humans; Inpatients; Length of Stay; Male; Middle Aged; Morbidity; Outcome Assessment (Health Care); Predictive Value of Tests; United States

Triceps and Subscapular Skinfold in Men Aged 40-65 and Dementia Prevalence 36 Years Later. - Ravona-Springer, Ramit; Schnaider-Beeri, Michal; Goldbourt, Uri (J Alzheimers Dis, 2017)
BACKGROUND: The relationship of obesity with risk for dementia is complex and may change with age. OBJECTIVE: To analyze the relationship between measures of obesity at age 40-65 and dementia prevalence in survivors 36 years later. METHODS: Obesity-related measures of triceps and subscapular skinfold thickness were assessed in 1963 in n = 9,760 men aged 40-65 participating in the Israel Ischemic Heart Disease study. Cognitive evaluation and assessment of dementia prevalence were performed in n = 1,643 participants of the original cohort who survived until 1999/2000 (age ≥76 years) and had anthropometric measures in 1963. RESULTS: Age-adjusted prevalence of dementia in survivors in 1999/2000 by baseline triceps skinfold quintile was 20.5%, 21.2%, 17.6%, 15.6%, and 14.5%, respectively, from lowest to highest (p = 0.006 in trend test). Using logistic regression, a 6-mm increment of triceps skinfold was associated with an age and BMI-adjusted odds ratio of 0.81 (95% CI, 0.70-0.94) for dementia prevalence among survivors. Age-adjusted risk for dementia by subscapular skinfold quintile demonstrated 20.5%, 17.1%, 15.7%, 19.4%, and 18.1%, respectively, in groups of subjects by subscapular skinfold quintile from lowest to highest (p = 0.6 in trend test). CONCLUSIONS: Lower triceps skinfold at age 40-65, reflecting diminished peripheral fat, was associated with higher dementia prevalence in late life, potentially suggesting a protective role of peripheral fat to brain health.
Keywords: Adipose Tissue; Aged; Anthropometry; Arm; Body Mass Index; Dementia; Exercise; Humans; Israel; Leisure Activities; Longitudinal Studies; Male; Middle Aged; Muscle, Skeletal; Obesity; Odds Ratio; Prevalence; Shoulder; Skinfold Thickness; Social Class

Upregulated Expression of Heparanase and Heparanase 2 in the Brains of Alzheimer's Disease. - Garcia, Beatriz; Martin, Carla; Garcia-Suarez, Olivia; Muniz-Alonso, Barbara; Ordiales, Helena; Fernandez-Menendez, Santiago; Santos-Juanes, Jorge; Lorente-Gea, Laura; Castanon, Sonia; Vicente-Etxenausia, Ikerne; Pina Batista, Kelvin Manuel; Ruiz-Diaz, Irune; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer's disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity. OBJECTIVE: To analyze HPSE and HPSE2 expressions at different stages of AD. METHODS: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain. RESULTS: Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well. CONCLUSION: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

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.

Utility of Molecular and Structural Brain Imaging to Predict Progression from Mild Cognitive Impairment to Dementia. - Lan, Martin J; Ogden, R Todd; Kumar, Dileep; Stern, Yaakov; Parsey, Ramin V; Pelton, Gregory H; Rubin-Falcone, Harry; Pradhaban, Gnanavalli; Zanderigo, Francesca; Miller, Jeffrey M; Mann, J John; Devanand, D P (J Alzheimers Dis, 2017)
This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

The Utility of the Cognitive Function Instrument (CFI) to Detect Cognitive Decline in Non-Demented Older Adults. - Li, Clara; Neugroschl, Judith; Luo, Xiaodong; Zhu, Carolyn; Aisen, Paul; Ferris, Steven; Sano, Mary (J Alzheimers Dis, 2017)
BACKGROUND: Subjective cognitive complaint is a sensitive marker of decline. OBJECTIVE: This study aimed to (1) examine reliability of subjective cognitive complaint using the Cognitive Function Instrument (CFI), and (2) assess the utility of the CFI to detect cognitive decline in non-demented elders. METHODS: Data from a four-year longitudinal study at multiple Alzheimer's Disease Cooperative Study (ADCS) sites were extracted (n = 644). Of these, 497 had Clinical Dementia Rating (CDR) global scores of 0 and 147 had a CDR of 0.5. Mean age and education were 79.5±3.6 and 15.0±3.1 years, respectively. All participants and their study partners completed the subject and study partner CFI yearly. Modified Mini-Mental State Exam (mMMSE) and Free and Cued Selective Reminding Test (FCSRT) were administered. Scores below the predetermined cut-off scores on either measure at annual visit were triggers for a full diagnostic evaluation. Cognitive decline was defined by the absence/presence of the trigger. RESULTS: Three-month test retest reliability showed that inter-class coefficients for subject and study partner CFI were 0.76 and 0.78, respectively. Generalized estimating equation method revealed that both subject and study partner CFI change scores and scores from previous year were sensitive to cognitive decline in the CDR 0 group (p < 0.05). In the CDR 0.5 group, only the study partner CFI change score predicted cognitive decline (p < 0.05). CONCLUSION: Cognitive decline was predicted differentially by CDR level with subject CFI scores providing the best prediction for those with CDR 0 while study partner CFI predicted best for those at CDR 0.5.

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 by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier. - André, Séverine; Ansciaux, Emilie; Saidi, Elamine; Larbanoix, Lionel; Stanicki, Dimitri; Nonclercq, Denis; Vander Elst, Luce; Laurent, Sophie; Muller, Robert N; Burtea, Carmen (J Alzheimers Dis, 2017)
The diagnosis of Alzheimer's disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls'-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

Validation of a Latent Construct for Dementia in a Population-Wide Dataset from Singapore. - Peh, Chao Xu; Abdin, Edimansyah; Vaingankar, Janhavi A; Verma, Swapna; Chua, Boon Yiang; Sagayadevan, Vathsala; Seow, Esmond; Zhang, YunJue; Shahwan, Shazana; Ng, Li Ling; Prince, Martin; Chong, Siow Ann; et al. (J Alzheimers Dis, 2017)
BACKGROUND: The latent variable δ has been proposed as a proxy for dementia. Previous validation studies have been conducted using convenience samples. It is currently unknown how δ performs in population-wide data. OBJECTIVE: To validate δ in Singapore using population-wide epidemiological study data on persons aged 60 and above. METHODS: δ was constructed using items from the Community Screening Instrument for Dementia (CSI'D) and World Health Organization Disability Assessment Schedule (WHODAS II). Confirmatory factor analysis (CFA) was conducted to examine δ model fit. Convergent validity was examined with the Clinical Dementia Rating scale (CDR) and GMS-AGECAT dementia. Divergent validity was examined with GMS-AGECAT depression. RESULTS: The δ model demonstrated fit to the data, χ2(df) = 249.71(55), p < 0.001, CFI = 0.990, TLI = 0.997, RMSEA = 0.037. Latent variable δ was significantly associated with CDR and GMS-AGECAT dementia (range: β= 0.32 to 0.63), and was not associated with GMS-AGECAT depression. Compared to unadjusted models, δ model fit was poor when adjusted for age, gender, ethnicity, and education. CONCLUSION: The study found some support for δ as a proxy for dementia in Singapore based on population data. Both convergent and divergent validity were established. In addition, the δ model structure appeared to be influenced by age, gender, ethnicity, and education covariates.

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.

Varying Degrees of Temporoparietal Hypometabolism on FDG-PET Reveal Amyloid-Positive Logopenic Primary Progressive Aphasia is not a Homogeneous Clinical Entity. - Krishnan, Kamini; Machulda, Mary M; Whitwell, Jennifer L; Butts, Alissa M; Duffy, Joseph R; Strand, Edythe A; Senjem, Matthew L; Spychalla, Anthony J; Jack, Clifford R; Lowe, Val J; Josephs, Keith A (J Alzheimers Dis, 2017)
BACKGROUND: The logopenic variant of primary progressive aphasia (lvPPA) manifests due to a breakdown of the language network with prominent hypometabolism of the left temporoparietal region. LvPPA is strongly associated with amyloid deposition, yet there is question as to whether it is a homogeneous clinical entity. OBJECTIVE: This study investigated whether differences in temporoparietal metabolic patterns on 18F fludeoxyglucose positron emission tomography (FDG-PET) could elucidate brain regions preferentially affected in lvPPA. METHOD: We used differences in FDG-PET metabolic z-scores relative to controls for means of left lateral temporal, left inferior parietal, and left superior parietal regions to classify 53 amyloid-positive lvPPA patients into temporal, parietal, or temporoparietal predominate groups. Clinical features and FDG-PET regions of hypometabolism outside of the temporoparietal region were then compared across the three groups; the latter using statistical parametric mapping. RESULTS: Of the 53 lvPPA patients, 15 were classified as temporal, 14 as temporoparietal, and 22 as parietal predominate. There were no significant differences between the groups on demographic measures, language evaluation, or apolipoprotein E genotype. Compared to the other two groups, individuals with the parietal predominate pattern had extensive hypometabolism in left frontal lobe and the precuneus. Furthermore, this group had greater behavioral dyscontrol and deficits in executive function, visuospatial skills, visual memory retention, working memory, and cognitive flexibility (Bonferronip < 0.05). CONCLUSIONS: This study demonstrates that there is clinical heterogeneity within amyloid-positive lvPPA. Patients with lvPPA with predominant parietal hypometabolism, unlike those with temporal or temporoparietal predominant hypometabolism, demonstrated widespread cognitive and behavioral changes.

Violation of Laws in Frontotemporal Dementia: A Multicenter Study in Japan. - Shinagawa, Shunichiro; Shigenobu, Kazue; Tagai, Kenji; Fukuhara, Ryuji; Kamimura, Naoto; Mori, Takaaki; Yoshiyama, Kenji; Kazui, Hiroaki; Nakayama, Kazuhiko; Ikeda, Manabu (J Alzheimers Dis, 2017)
Although violations of laws, such as shoplifting, are considered to be common in frontotemporal dementia (FTD) patients, there have been few studies on this subject and the frequencies and types of such violations have not been clarified. The objective of this study was to conduct a retrospective investigation of FTD patients in the psychiatry departments of multiple institutions to determine the types and frequencies of any law violations and compare them with those of AD patients. All patients were examined between January 2011 and December 2015 at the specialized dementia outpatient clinics of 10 facilities (5 psychiatry departments of university hospitals, 5 psychiatric hospitals). According to diagnostic criteria, 73 behavior variant FTD (bvFTD) patients, 84 semantic variant of primary progressive aphasia (svPPA) patients, and 255 age- and sex-matched AD subjects as the control group were selected. The findings revealed a higher rate of law violations in the bvFTD and svPPA patients before the initial consultation as compared to the AD group (bvFTD: 33%, svPPA: 21%, AD: 6%) and that many patients had been referred due to such violations. Laws had been broken 4 times or 5 or more times in several cases in the FTD group before the initial consultation. Regarding rates for different types of violation, in bvFTD subjects, the highest rate was for theft, followed by nuisance acts and hit and run. In svPPA, theft had the highest rate, followed by ignoring road signs. There was no gender difference in law violations but they were more frequent when the disease was severe at the initial consultation in the FTD group. As the rates of law violations after the initial consultation were lower than before it, interventions were considered to have been effective. These findings may be useful for future prevention as well as to the legal system.

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.

Voluptuary Habits and Risk of Frontotemporal Dementia: A Case Control Retrospective Study. - Tremolizzo, Lucio; Bianchi, Elisa; Susani, Emanuela; Pupillo, Elisabetta; Messina, Paolo; Aliprandi, Angelo; Salmaggi, Andrea; Cosseddu, Maura; Pilotto, Andrea; Borroni, Barbara; Padovani, Alessandro; Bonomini, Cristina; et al. (J Alzheimers Dis, 2017)
Alcohol, coffee, and tobacco consumption was assessed on 151 FTD outpatients and 151 matched controls in a multicenter retrospective case-control design. No association was found for smoking and coffee intake. The risk of FTD was decreased by alcohol consumption (adj. OR 0.30, 95% CI 0.14-0.63); risk reduction was significant in current alcohol consumers (adj. OR 0.22, 95% CI 0.10-0.51). The risk of FTD inversely correlated with the duration of exposure (adj. OR 0.88, 95% CI 0.81-0.95, for every 5 years of exposure increase). Retrospective information and the unknown amount of consumed alcohol are limits of the present work.

An 18-mer Peptide Derived from Prosaposin Ameliorates the Effects of Aβ1-42 Neurotoxicity on Hippocampal Neurogenesis and Memory Deficit in Mice. - Gao, Hui-Ling; Li, Cheng; Nabeka, Hiroaki; Shimokawa, Tetsuya; Wang, Zhan-You; Cao, Ya-Ming; Matsuda, Seiji (J Alzheimers Dis, 2016)
The pathological hallmarks of Alzheimer's disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1-42 peptide. Seven days after Aβ1-42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1-42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked by Aβ1-42. Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1-42-induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD.

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.

Accurate Prediction of Conversion to Alzheimer's Disease using Imaging, Genetic, and Neuropsychological Biomarkers. - Dukart, Juergen; Sambataro, Fabio; Bertolino, Alessandro (J Alzheimers Dis, 2016)
A variety of imaging, neuropsychological, and genetic biomarkers have been suggested as potential biomarkers for the identification of mild cognitive impairment (MCI) in patients who later develop Alzheimer's disease (AD). Here, we systematically evaluated the most promising combinations of these biomarkers regarding discrimination between stable and converter MCI and reflection of disease staging. Alzheimer's Disease Neuroimaging Initiative data of AD (n = 144), controls (n = 112), stable (n = 265) and converter (n = 177) MCI, for which apolipoprotein E status, neuropsychological evaluation, and structural, glucose, and amyloid imaging were available, were included in this study. Naïve Bayes classifiers were built on AD and controls data for all possible combinations of these biomarkers, with and without stratification by amyloid status. All classifiers were then applied to the MCI cohorts. We obtained an accuracy of 76% for discrimination between converter and stable MCI with glucose positron emission tomography as a single biomarker. This accuracy increased to about 87% when including further imaging modalities and genetic information. We also identified several biomarker combinations as strong predictors of time to conversion. Use of amyloid validated training data resulted in increased sensitivities and decreased specificities for differentiation between stable and converter MCI when amyloid was included as a biomarker but not for other classifier combinations. Our results indicate that fully independent classifiers built only on AD and controls data and combining imaging, genetic, and/or neuropsychological biomarkers can more reliably discriminate between stable and converter MCI than single modality classifiers. Several biomarker combinations are identified as strongly predictive for the time to conversion to AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoproteins E; Area Under Curve; Brain; Cognitive Dysfunction; Disease Progression; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; ROC Curve; Sensitivity and Specificity

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.

Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. - Stogmann, Elisabeth; Moser, Doris; Klug, Stefanie; Gleiss, Andreas; Auff, Eduard; Dal-Bianco, Peter; Pusswald, Gisela; Lehrner, Johann (J Alzheimers Dis, 2016)
BACKGROUND: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest. OBJECTIVES: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS: We included 752 consecutive patients suffering from SCD, non-amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed. RESULTS: SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls-SCD-naMCI-aMCI-AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6-1.7). CONCLUSIONS: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Cognitive Dysfunction; Depression; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Odds Ratio; Perception; Prospective Studies

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.

Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus: A New/Old Potential Target. - Arosio, Beatrice; Casati, Martina; Gussago, Cristina; Ferri, Evelyn; Abbate, Carlo; Scortichini, Valeria; Colombo, Elena; Rossi, Paolo Dionigi; Mari, Daniela (J Alzheimers Dis, 2016)
As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies.

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-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD). - Do, Tuan Minh; Dodacki, Agnès; Alata, Wael; Calon, Frederic; Nicolic, Sophie; Scherrmann, Jean-Michel; Farinotti, Robert; Bourasset, Fanchon (J Alzheimers Dis, 2016)
The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.
Keywords: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Blood-Brain Barrier; Brain; Carbon Isotopes; Cholesterol; Disease Models, Animal; Humans; Lipoproteins; Mice; Mice, Transgenic; P-Glycoproteins; Peptide Fragments; Receptors, LDL; Sucrose; Tritium; Tumor Suppressor Proteins

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.

Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid. - Shan, Ye; Wang, Dan-Dan; Xu, Yu-Xia; Wang, Chu; Cao, Lan; Liu, Yun-Sheng; Zhu, Cui-Qing (J Alzheimers Dis, 2016)
Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.
Keywords: Aging; Animals; Antioxidants; Brain; Cinnamates; Corticotropin-Releasing Hormone; Depsides; Disease Models, Animal; HEK293 Cells; HSP90 Heat-Shock Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Microscopy, Immunoelectron; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphorylation; Precipitating Factors; Receptors, Corticotropin; Restraint, Physical; Stress, Psychological; tau Proteins; Transfection

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.

Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers. - Perkins, Michelle; Wolf, Andrew B; Chavira, Bernardo; Shonebarger, Daniel; Meckel, J P; Leung, Lana; Ballina, Lauren; Ly, Sarah; Saini, Aman; Jones, T Bucky; Vallejo, Johana; Jentarra, Garilyn; et al. (J Alzheimers Dis, 2016)
The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.

Altered Executive Function in Pre-Mild Cognitive Impairment. - Seo, Eun Hyun; Kim, Hoowon; Lee, Kun Ho; Choo, Il Han (J Alzheimers Dis, 2016)
BACKGROUND: For the early detection of Alzheimer's disease (AD), there is increasing interest in pre-mild cognitive impairment (pre-MCI). OBJECTIVE: We explored the neuropsychological characteristics in a group of pre-MCI and cognitively normal (CN) elderly individuals, with the aim of providing measures sensitive to cognitive change in pre-MCI. METHODS: We included 188 CN elderly and 77 individuals with pre-MCI. All participants underwent comprehensive clinical and neuropsychological assessment. We compared 17 cognitive tests between the CN and pre-MCI groups by using one-way ANOVAs with false discovery rate correction for multiple comparisons. Pearson's correlations were also obtained between episodic memory and executive function tests in the pre-MCI group. RESULTS: The pre-MCI group showed significantly lower scores for visual immediate recall, fluency tests, and Stroop color naming in the color-word incongruent condition than the CN group (p < 0.05). Most of these executive function measures were significantly correlated with episodic memory (p < 0.05). There were no significant group-differences in other tests assessing attention, verbal memory, visuospatial ability, and language. CONCLUSION: Our findings indicate that poor executive function especially demanding inhibition and goal-directed behaviors within time limit could be the characteristics of the very early cognitive sign in the course of AD.

Altered sense of humor in dementia. - Clark, Camilla N; Nicholas, Jennifer M; Gordon, Elizabeth; Golden, Hannah L; Cohen, Miriam H; Woodward, Felix J; Macpherson, Kirsty; Slattery, Catherine F; Mummery, Catherine J; Schott, Jonathan M; Rohrer, Jonathan D; Warren, Jason D (J Alzheimers Dis, 2016)
Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer's disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Cognition Disorders; Emotions; Female; Frontotemporal Dementia; Humans; Male; Middle Aged; Neuropsychological Tests; Primary Progressive Nonfluent Aphasia; Psychiatric Status Rating Scales; Surveys and Questionnaires

Amyloid-β Increases Activity of Proteasomes Capped with 19S and 11S Regulators. - Morozov, Alexey V; Kulikova, Alexandra A; Astakhova, Tatiana M; Mitkevich, Vladimir A; Burnysheva, Ksenia M; Adzhubei, Alexei A; Erokhov, Pavel A; Evgen'ev, Michail B; Sharova, Natalia P; Karpov, Vadim L; Makarov, Alexander A (J Alzheimers Dis, 2016)
Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer's disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators. Modulation of proteasome activity is mainly determined by the C-terminal segment of Aβ (amino acids 17-42). This study demonstrated an important role of proteasome regulators in the interplay between Aβ and the proteasomes.

Antioxidants Rescue Mitochondrial Transport in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. - Yu, Qing; Fang, Du; Swerdlow, Russell Howard; Yu, Haiyang; Chen, John Xi; Yan, Shirley ShiDu (J Alzheimers Dis, 2016)
Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer's disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD.

The Anti-Prion Antibody 15B3 Detects Toxic Amyloid-β Oligomers. - Stravalaci, Matteo; Tapella, Laura; Beeg, Marten; Rossi, Alessandro; Joshi, Pooja; Pizzi, Erika; Mazzanti, Michele; Balducci, Claudia; Forloni, Gianluigi; Biasini, Emiliano; Salmona, Mario; Diomede, Luisa; et al. (J Alzheimers Dis, 2016)
15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42, an aggregating peptide implicated in the pathogenesis of Alzheimer's disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD.

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

Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer's Disease. - Grossi, Enzo; Stoccoro, Andrea; Tannorella, Pierpaola; Migliore, Lucia; Coppedè, Fabio (J Alzheimers Dis, 2016)
BACKGROUND: There is increasing interest in DNA methylation studies in Alzheimer's disease (AD), but little is still known concerning the relationship between gene-promoter methylation and circulating biomarkers of one-carbon metabolism in patients. OBJECTIVE: To detect the connections among circulating folate, homocysteine (hcy) and vitamin B12 levels and promoter methylation levels of PSEN1, BACE1, DNMT1, DNMT3A, DNMT3B, and MTHFR genes in blood DNA. METHODS: We applied a data mining system called Auto Contractive Map to an existing database of 100 AD and 100 control individuals. RESULTS: Low vitamin B12 was linked to the AD condition, to low folates, and to high hcy. Low PSEN1 methylation was linked to low folate levels as well as to low promoter methylation of BACE1 and DNMTs genes. Low hcy was linked to controls, to high folates and vitamin B12, as well as to high methylation levels of most of the studied genes. CONCLUSIONS: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12.

Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. - Mandecka, Monika; Budziszewska, Magdalena; Barczak, Anna; Pepłońska, Beata; Chodakowska-Żebrowska, Małgorzata; Filipek-Gliszczyńska, Anna; Nesteruk, Marta; Styczyńska, Maria; Barcikowska, Maria; Gabryelewicz, Tomasz (J Alzheimers Dis, 2016)
In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aβ1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aβ1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aβ1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

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

Association Between Serum Ceruloplasmin Specific Activity and Risk of Alzheimer's Disease. - Siotto, Mariacristina; Simonelli, Ilaria; Pasqualetti, Patrizio; Mariani, Stefania; Caprara, Deborah; Bucossi, Serena; Ventriglia, Mariacarla; Molinario, Rossana; Antenucci, Mirca; Rongioletti, Mauro; Rossini, Paolo Maria; Squitti, Rosanna (J Alzheimers Dis, 2016)
Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-ɛ4 allele (p <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.
Keywords: Aged; Alzheimer Disease; Apolipoprotein E4; Area Under Curve; Biomarkers; Blood Chemical Analysis; Ceruloplasmin; Copper; Female; Genotype; Genotyping Techniques; Humans; Logistic Models; Male; Multivariate Analysis; Prognosis; Risk; ROC Curve; Sensitivity and Specificity; Transferrin

Association of Butyrylcholinesterase-K Allele and Apolipoprotein E ɛ4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease. - Vijayaraghavan, Swetha; Darreh-Shori, Taher; Rongve, Arvid; Berge, Guro; Sando, Sigrid B; White, Linda R; Auestad, Bjørn H; Witoelar, Aree; Andreassen, Ole A; Ulstein, Ingun D; Aarsland, Dag (J Alzheimers Dis, 2016)
BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias. OBJECTIVE: To determine the association of BCHE-K and APOEɛ4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients. METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOEɛ4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years. RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEɛ4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOEɛ4 allele than in the absence of these polymorphisms. CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEɛ4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEɛ4 and BCHE-K alleles require prospective confirmation in well-controlled trials.
Keywords: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoprotein E4; Butyrylcholinesterase; Cognition; Disease Progression; Female; Gene Frequency; Genotype; Humans; Lewy Body Disease; Male; Neuropsychological Tests

Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer's Disease in a Northern Han Chinese Population. - Tan, Chen-Chen; Wan, Yu; Tan, Meng-Shan; Zhang, Wei; Wang, Zi-Xuan; Sun, Fu-Rong; Miao, Dan; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2016)
BACKGROUND: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD. OBJECTIVE: To explore whether these SNPs are associated with AD risk. METHODS: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects. RESULTS: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088). CONCLUSION: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.
Keywords: Age of Onset; Aged; Alzheimer Disease; Apolipoprotein E4; Asian Continental Ancestry Group; Case-Control Studies; China; Female; Frontotemporal Dementia; Gene Frequency; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Genotyping Techniques; Humans; Linkage Disequilibrium; Male; Mental Status Schedule; Polymorphism, Single Nucleotide

Association of Physical Function with Clinical and Subclinical Brain Disease: The Framingham Offspring Study. - Camargo, Erica C; Weinstein, Galit; Beiser, Alexa S; Tan, Zaldy S; DeCarli, Charles; Kelly-Hayes, Margaret; Kase, Carlos; Murabito, Joanne M; Seshadri, Sudha (J Alzheimers Dis, 2016)
BACKGROUND: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking. OBJECTIVE: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer's disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample. METHODS: Framingham Offspring (n = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors. RESULTS: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12-2.70/SDU, p = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction. CONCLUSION: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.

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

The Associations between a Capsaicin-Rich Diet and Blood Amyloid-β Levels and Cognitive Function. - Liu, Cheng-Hui; Bu, Xian-Le; Wang, Jun; Zhang, Tao; Xiang, Yang; Shen, Lin-Lin; Wang, Qing-Hua; Deng, Bo; Wang, Xin; Zhu, Chi; Yao, Xiu-Qing; Zhang, Meng; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Capsaicin-rich diets are common worldwide. Capsaicin has been shown to have favorable effects on various diseases including atherosclerosis, cardiovascular diseases, stroke, obesity, hypertension, cancer, and gastrointestinal and inflammatory diseases. The impact of capsaicin on Alzheimer's disease (AD), which is the most common form of dementia in the elderly, remains unknown. OBJECTIVE: To investigate the correlations of capsaicin intake with cognition and blood markers of AD. METHODS: A total of 338 participants aged 40 years or older were enrolled from communities. Dietary habits regarding chili pepper consumption were collected using a Food Frequency Questionnaire (FFQ). Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Blood amyloid-β (Aβ)40 and Aβ42 were measured with ELISA kits. RESULTS: In univariate analysis, MMSE scores (r = 0.209, p < 0.001), serum Aβ40 levels (r = -0.149, p = 0.006), the ratio of Aβ42/Aβ40 (r = 0.11, p = 0.043) and total serum Aβ levels (r = -0.097, p = 0.075), but not serum Aβ42 levels (r = 0.17, p = 0.757), were significantly correlated with total capsaicin diet scores. In multivariate analysis, total capsaicin diet scores were positively associated with MMSE scores and inversely associated with serum Aβ40 levels, and total serum Aβ levels, but not serum Aβ42 levels and the ratio of Aβ42/Aβ40, after adjustment for age, gender, educational level, smoking history, alcohol consumption, body mass index (BMI) and comorbidities. CONCLUSION: These findings suggest that a capsaicin-rich diet may exert favorable effects on AD blood biomarkers and cognitive function in middle-aged and elderly adults.

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

Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells. - Li, Yan; Chang, Lirong; Song, Yizhi; Gao, Xianghong; Roselli, Francesco; Liu, Jinping; Zhou, Wei; Fang, Yuan; Ling, Wei; Li, Hui; Almeida, Osborne F X; Wu, Yan (J Alzheimers Dis, 2016)
Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer's disease, in which Aβ and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor β (β-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD.

Attitudes and Perceptions of Research in Aging and Dementia in an Urban Minority Population. - Neugroschl, Judith; Sewell, Margaret; De La Fuente, Angelica; Umpierre, Mari; Luo, Xiaodong; Sano, Mary (J Alzheimers Dis, 2016)
In dementia trials, minority participation is low. We assessed attitudes toward research in a community based urban poor minority sample of elderly adults attending senior center talks using the 7-item Research Attitudes Questionnaire (RAQ). Presentations on cognitive aging were given at senior centers, and 123 attendees completed the RAQ-7. On trust and safety questions, a significant minority (42-48%) responded neutrally or negatively. Encouragingly, on questions concerning the importance of research, 72-81% answered positively. More work can be done to capitalize on these findings to engage and foster trust, and this can be a focus of outreach.

Biochemical and Radiological Markers of Alzheimer's Disease Progression. - Dziedzic, Tomasz; Pera, Joanna; Klimkowicz-Mrowiec, Aleksandra; Mroczko, Barbara; Slowik, Agnieszka (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a neurodegenerative, inevitably progressive disease with a rate of cognitive, functional, and behavioral decline that varies highly from patient to patient. Although several clinical predictors of AD progression have been identified, to our mind in clinical practice there is a lack of a reliable biomarker that enables one to stratify the risk of deterioration. Identification of biomarkers that allow the monitoring of AD progression could change the way physicians and caregivers make treatment decisions. This review summarizes the results of studies on potential biochemical and radiological markers related to AD progression.
Keywords: Alzheimer Disease; Biomarkers; Disease Progression; Humans; Neuroimaging; Radionuclide Imaging

Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions. - Martire, Sara; Fuso, Andrea; Mosca, Luciana; Forte, Elena; Correani, Virginia; Fontana, Mario; Scarpa, Sigfrido; Maras, Bruno; d'Erme, Maria (J Alzheimers Dis, 2016)
Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.

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.

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.

Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer's Disease Biomarkers. - Malishkevich, Anna; Marshall, Gad A; Schultz, Aaron P; Sperling, Reisa A; Aharon-Peretz, Judith; Gozes, Illana (J Alzheimers Dis, 2016)
Biomarkers for Alzheimer's disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Chi-Square Distribution; Cognitive Dysfunction; Cohort Studies; Female; Homeodomain Proteins; Humans; Independent Living; Intelligence; Male; Mental Status Schedule; Middle Aged; Nerve Tissue Proteins; Peptide Fragments; RNA, Messenger; tau Proteins

Brain Metabolism Correlates of the Free and Cued Selective Reminding Test in Mild Cognitive Impairment. - Caffarra, Paolo; Ghetti, Caterina; Ruffini, Livia; Spallazzi, Marco; Spotti, Annamaria; Barocco, Federica; Guzzo, Caterina; Marchi, Massimo; Gardini, Simona (J Alzheimers Dis, 2016)
Free and Cued Selective Reminding Test (FCSRT) measures immediate and delayed episodic memory and cueing sensitivity and is suitable to detect prodromal Alzheimer's disease (AD). The present study aimed at investigating the segregation effect of FCSRT scores on brain metabolism of memory-related structures, usually affected by AD pathology, in the Mild Cognitive Impairment (MCI) stage. A cohort of forty-eight MCI patients underwent FCSRT and 18F-FDG-PET. Multiple regression analysis showed that Immediate Free Recall correlated with brain metabolism in the bilateral anterior cingulate and delayed free recall with the left anterior cingulate and medial frontal gyrus, whereas semantic cueing sensitivity with the left posterior cingulate. FCSRT in MCI is associated with neuro-functional activity of specific regions of memory-related structures connected to hippocampal formation, such as the cingulate cortex, usually damaged in AD.
Keywords: Aged; Brain; Cognitive Dysfunction; Cues; Female; Fluorodeoxyglucose F18; Humans; Male; Memory Disorders; Memory, Episodic; Mental Recall; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography

Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease. - Vermeiren, Yannick; Janssens, Jana; Aerts, Tony; Martin, Jean-Jacques; Sieben, Anne; Van Dam, Debby; De Deyn, Peter P (J Alzheimers Dis, 2016)
Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link Between Diabetes Mellitus and Alzheimer's Disease. - Goldwaser, Eric L; Acharya, Nimish K; Sarkar, Abhirup; Godsey, George; Nagele, Robert G (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology. Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke, have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose of this review is to highlight investigations into the role of the cerebrovasculature in the development and progression of AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that is common to both.

Cerebral Amyloid Angiopathy (CAA)-Related Inflammation: Comparison of Inflammatory CAA and Amyloid-β-Related Angiitis. - Chu, Shuguang; Xu, Feijia; Su, Ya; Chen, Hong; Cheng, Xin (J Alzheimers Dis, 2016)
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ɛ4/ɛ4. More clinical markers for diagnosis of CAA-ri warrant further researches.
Keywords: Apolipoproteins E; Cerebral Amyloid Angiopathy; Headache; Humans; Inflammation; Magnetic Resonance Imaging; Male; Middle Aged; Seizures; Vasculitis, Central Nervous System

Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults. - Gardener, Samantha L; Sohrabi, Hamid R; Shen, Kai-Kai; Rainey-Smith, Stephanie R; Weinborn, Michael; Bates, Kristyn A; Shah, Tejal; Foster, Jonathan K; Lenzo, Nat; Salvado, Olivier; Laske, Christoph; Laws, Simon M; et al. (J Alzheimers Dis, 2016)
Increasing evidence suggests that Alzheimer's disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.

Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation. - Carmona-Iragui, María; Fernández-Arcos, Ana; Alcolea, Daniel; Piazza, Fabrizio; Morenas-Rodriguez, Estrella; Antón-Aguirre, Sofía; Sala, Isabel; Clarimón, Jordi; Dols-Icardo, Oriol; Camacho, Valle; Sampedro, Frederic; Munuera, Josep; et al. (J Alzheimers Dis, 2016)
We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.
Keywords: Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Autoantibodies; Cerebral Amyloid Angiopathy; Ethylene Glycols; Female; Humans; Magnetic Resonance Imaging; Male; Meningoencephalitis; Peptide Fragments; Positron-Emission Tomography; Statistics, Nonparametric; tau Proteins

Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years. - Bjerke, Maria; Kern, Silke; Blennow, Kaj; Zetterberg, Henrik; Waern, Margda; Börjesson-Hanson, Anne; Östling, Svante; Kern, Jürgen; Skoog, Ingmar (J Alzheimers Dis, 2016)
BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking. OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181, and CSF: serum albumin ratio. METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aβ42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria. RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aβ42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism.
Keywords: Aged; Aged, 80 and over; Albumins; Amyloid beta-Peptides; Community Health Planning; Dementia; Fatty Acid-Binding Proteins; Female; Humans; Longitudinal Studies; Peptide Fragments; Sweden; tau Proteins

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

The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease. - De Vos, Ann; Struyfs, Hanne; Jacobs, Dirk; Fransen, Erik; Klewansky, Tom; De Roeck, Ellen; Robberecht, Caroline; Van Broeckhoven, Christine; Duyckaerts, Charles; Engelborghs, Sebastiaan; Vanmechelen, Eugeen (J Alzheimers Dis, 2016)
BACKGROUND: In diagnosing Alzheimer's disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42/tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. OBJECTIVE: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42, Aβ1-40, and Aβ1-38. All six analytes were considered as single parameters as well as ratios. METHODS: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychological (MMSE) examinations for at least one year. RESULTS: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio. CONCLUSION: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline.

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 Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study. - Eyre, Harris A; Acevedo, Bianca; Yang, Hongyu; Siddarth, Prabha; Van Dyk, Kathleen; Ercoli, Linda; Leaver, Amber M; Cyr, Natalie St; Narr, Katherine; Baune, Bernhard T; Khalsa, Dharma S; Lavretsky, Helen (J Alzheimers Dis, 2016)
BACKGROUND: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity. OBJECTIVES: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI). METHODS: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active "gold-standard" control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance. RESULTS: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex. CONCLUSION: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies.

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.

Changes of Cerebral Perfusion and Functional Brain Network Organization in Patients with Mild Cognitive Impairment. - Lou, Wutao; Shi, Lin; Wong, Adrian; Chu, Winnie C W; Mok, Vincent C T; Wang, Defeng (J Alzheimers Dis, 2016)
Disruptions of the functional brain network and cerebral blood flow (CBF) have been revealed in patients with mild cognitive impairment (MCI). However, the neurophysiological mechanism of hypoperfusion as well as the reorganization of the intrinsic whole brain network due to the neuropathology of MCI are still unclear. In this study, we aimed to investigate the changes of CBF and the whole brain network organization in MCI by using a multimodal MRI approach. Resting state ASL MRI and BOLD MRI were used to evaluate disruptions of CBF and underlying functional connectivity in 27 patients with MCI and 35 cognitive normal controls (NC). The eigenvector centrality mapping (ECM) was used to assess the whole brain network reorganization in MCI, and a seed-based ECM approach was proposed to reveal the contributions of the whole brain network on the ECM alterations. Significantly decreased perfusion in the posterior parietal cortex as well as its connectivity within the default mode network and occipital cortex were found in the MCI group compared to the NC group. The ECM analysis revealed decreased EC in the middle cingulate cortex, parahippocampal gyrus, medial frontal gyrus, and increased EC in the right calcarine sulcus, superior temporal gyrus, and supplementary motor area in the MCI group. The results of this study indicate that there are deficits in cerebral blood flow and functional connectivity in the default mode network, and that sensory-processing networks might play a compensatory role to make up for the decreased connections in MCI.

Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. - Kleinschmidt, Martin; Schoenfeld, Robby; Göttlich, Claudia; Bittner, Daniel; Metzner, Jürgen Erich; Leplow, Bernd; Demuth, Hans-Ulrich (J Alzheimers Dis, 2016)
BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. RESULTS: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.
Keywords: Activities of Daily Living; Adolescent; Adult; Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Analysis of Variance; Apolipoproteins E; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Cytokines; Dementia; Female; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Young Adult

Characterizing White Matter Tract Degeneration in Syndromic Variants of Alzheimer's Disease: A Diffusion Tensor Imaging Study. - Madhavan, Ajay; Schwarz, Christopher G; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Drubach, Daniel A; Kantarci, Kejal; Przybelski, Scott A; Reid, Robert I; Senjem, Matthew L; Gunter, Jeffrey L; Apostolova, Liana G; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). OBJECTIVE: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. METHODS: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. RESULTS: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. CONCLUSION: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.
Keywords: Aged; Alzheimer Disease; Aniline Compounds; Anisotropy; Aphasia, Primary Progressive; Case-Control Studies; Diffusion Tensor Imaging; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Nerve Fibers, Myelinated; Neurodegenerative Diseases; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Retrospective Studies; Thiazoles; White Matter

Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis. - Wang, Hua-Long; Wang, Yan-Yong; Liu, Xin-Gang; Kuo, Sheng-Han; Liu, Na; Song, Qiao-Yun; Wang, Ming-Wei (J Alzheimers Dis, 2016)
Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.
Keywords: Alzheimer Disease; Cholesterol; Cognitive Dysfunction; Databases, Bibliographic; Humans; Hydroxycholesterols

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.

CHRNA7 Gene and Response to Cholinesterase Inhibitors in an Italian Cohort of Alzheimer's Disease Patients. - Clarelli, Ferdinando; Mascia, Elisabetta; Santangelo, Roberto; Mazzeo, Salvatore; Giacalone, Giacomo; Galimberti, Daniela; Fusco, Federica; Zuffi, Marta; Fenoglio, Chiara; Franceschi, Massimo; Scarpini, Elio; Forloni, Gianluigi; et al. (J Alzheimers Dis, 2016)
Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) patients. We sought to replicate the association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR = 1.4; p = 0.17), which after meta-analysis with previous study yielded a significant result (OR = 1.57, p = 0.02, I2 = 0%).

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 Obstructive Pulmonary Disease as a Risk Factor for Cognitive Dysfunction: A Meta-Analysis of Current Studies. - Zhang, Ximeng; Cai, Xiaoying; Shi, Xiaolei; Zheng, Zhenyang; Zhang, Aiwu; Guo, Junliang; Fang, Yannan (J Alzheimers Dis, 2016)
Cognitive dysfunction has been shown to be associated with many risk factors, such as smoking, diabetes, and body mass index. Chronic obstructive pulmonary disease (COPD), a common disease within the elderly population, has also been found to be related to cognitive decline. However, whether COPD is a risk factor of cognitive dysfunction is not well established. The purpose of this meta-analysis is to investigate the role COPD plays in cognitive dysfunction. PubMed, Cochrane library and Web of Science databases were searched. Three cohort studies and eleven cross-sectional studies were found to be eligible. According to our results, COPD patients had a higher risk of cognitive dysfunction than controls (OR [odds ratio]: 1.72; 95% CI, 1.12-2.65; p = 0.01). The exacerbation of COPD was strongly correlated with cognitive decline. COPD patients performed worse than controls on the Mini- Mental State Examination test, but the results were not statistically significant (OR: -0.79; 95% CI, [-1.78, 0.19]; p = 0.11). Thus, more attention should be given to the occurrence of cognitive decline in COPD patients. The prevention and control of COPD exacerbation are critical.
Keywords: Cognitive Dysfunction; Humans; Pulmonary Disease, Chronic Obstructive; Risk Factors

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.

Circulating microRNAs as Biomarkers of Alzheimer's Disease: A Systematic Review. - Wu, Helen Zong Ying; Ong, Kwok Leung; Seeher, Katrin; Armstrong, Nicola J; Thalamuthu, Anbupalam; Brodaty, Henry; Sachdev, Perminder; Mather, Karen (J Alzheimers Dis, 2016)
BACKGROUND: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases. OBJECTIVE: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers. METHODS: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies. RESULTS: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75. CONCLUSION: Individual studies suggest that miRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation.
Keywords: Alzheimer Disease; Biomarkers; Databases, Bibliographic; Humans; MicroRNAs

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

Clinical and Demographic Factors Associated with the Cognitive and Emotional Efficacy of Regular Musical Activities in Dementia. - Särkämö, Teppo; Laitinen, Sari; Numminen, Ava; Kurki, Merja; Johnson, Julene K; Rantanen, Pekka (J Alzheimers Dis, 2016)
Recent evidence suggests that music-based interventions can be beneficial in maintaining cognitive, emotional, and social functioning in persons with dementia (PWDs). Our aim was to determine how clinical, demographic, and musical background factors influence the cognitive and emotional efficacy of caregiver-implemented musical activities in PWDs. In a randomized controlled trial, 89 PWD-caregiver dyads received a 10-week music coaching intervention involving either singing or music listening or standard care. Extensive neuropsychological testing and mood and quality of life (QoL) measures were performed before and after the intervention (n = 84) and six months later (n = 74). The potential effects of six key background variables (dementia etiology and severity, age, care situation, singing/instrument playing background) on the outcome of the intervention were assessed. Singing was beneficial especially in improving working memory in PWDs with mild dementia and in maintaining executive function and orientation in younger PWDs. Music listening was beneficial in supporting general cognition, working memory, and QoL especially in PWDs with moderate dementia not caused by Alzheimer's disease (AD) who were in institutional care. Both music interventions alleviated depression especially in PWDs with mild dementia and AD. The musical background of the PWD did not influence the efficacy of the music interventions. Our findings suggest that clinical and demographic factors can influence the cognitive and emotional efficacy of caregiver-implemented musical activities and are, therefore, recommended to take into account when applying and developing the intervention to achieve the greatest benefit.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Caregivers; Case-Control Studies; Cognition Disorders; Dementia; Executive Function; Female; Follow-Up Studies; Humans; Male; Memory, Short-Term; Middle Aged; Mood Disorders; Music Therapy; Neuropsychological Tests; Orientation; Outcome Assessment (Health Care); Psychiatric Status Rating Scales; Quality of Life

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 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

The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests. - Rattanabannakit, Chatchawan; Risacher, Shannon L; Gao, Sujuan; Lane, Kathleen A; Brown, Steven A; McDonald, Brenna C; Unverzagt, Frederick W; Apostolova, Liana G; Saykin, Andrew J; Farlow, Martin R (J Alzheimers Dis, 2016)
BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms. OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms. METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models. RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant. CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.
Keywords: Adult; Aged; Aged, 80 and over; Analysis of Variance; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Perception; Self Report

Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit. - Xiong, Li; Davidsdottir, Sigurros; Reijmer, Yael D; Shoamanesh, Ashkan; Roongpiboonsopit, Duangnapa; Thanprasertsuk, Sekh; Martinez-Ramirez, Sergi; Charidimou, Andreas; Ayres, Alison M; Fotiadis, Panagiotis; Gurol, Edip; Blacker, Deborah L; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized. OBJECTIVE: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA. METHODS: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed. RESULTS: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p = 0.03) and executive function (β= 0.394, p = 0.01). CONCLUSIONS: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.
Keywords: Aged; Atrophy; Brain; Cerebral Amyloid Angiopathy; Cognition; Cognition Disorders; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Stroke

Cognitive Reserve in Alzheimer's Dementia: Diagnostic Accuracy of a Testing-the-Limits Paradigm. - Küster, Olivia C; Kösel, Jonas; Spohn, Stephanie; Schurig, Niklas; Tumani, Hayrettin; von Arnim, Christine A F; Uttner, Ingo (J Alzheimers Dis, 2016)
Individuals with higher cognitive reserve are more able to cope with pathological brain alterations, potentially due to the application of more efficient cognitive strategies. The extent to which an individual's cognitive performance can be increased by advantageous conditions differs substantially between patients with Alzheimer's dementia (AD) and healthy older adults and can be assessed with the Testing-the-Limits (TtL) approach. Thus, TtL has been proposed as a tool for the early diagnosis of AD. Here, we report the diagnostic accuracy of a memory TtL paradigm to discriminate between AD patients and controls. The TtL paradigm was administered to 57 patients with clinically diagnosed AD and 94 controls. It consisted of a pre-test condition, representing baseline cognitive performance, the presentation of an encoding strategy, and two subsequent post-test conditions, representing learning potential. Receiver operating characteristic (ROC) curves were analyzed for each condition in order to receive optimal cutoff points along with their sensitivity and specificity and to compare the diagnostic accuracy of the conditions. Differentiation between AD patients and controls, indicated by the area under the ROC curve, increased significantly for the TtL post-test and total error scores compared to the pre-test score. The combined error score in the two post-tests could differentiate between AD patients and controls with a sensitivity of 0.93 and a specificity of 0.80. The presented approach can be carried out in 25 minutes and thus constitutes a time- and cost-effective way to diagnose AD with high accuracy.

Cohort Effects in the Prevalence and Survival of People with Dementia in a Rural Area in Northern Sweden. - Wimo, Anders; Sjölund, Britt-Marie; Sköldunger, Anders; Qiu, Chengxuan; Klarin, Inga; Nordberg, Gunilla; von Strauss, Eva (J Alzheimers Dis, 2016)
BACKGROUND: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare. OBJECTIVES: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area. METHODS: Participants were from the 1995-1998 Nordanstig Project (NP) (n = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death. RESULTS: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48-1.04) in SNAC-N; the OR was 0.47 (0.24-0.90) for men and 0.88 (0.54-1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39-0.99) and in men (0.34; 0.15-0.79), but not in women (0.81; 0.46-1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population. CONCLUSIONS: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men.
Keywords: Aged; Aged, 80 and over; Aging; Cohort Effect; Dementia; Female; Humans; Male; Prevalence; Risk Factors; Rural Population; Sex Factors; Survival Rate; Sweden

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.

Combining Cerebrospinal Fluid Biomarkers and Neuropsychological Assessment: A Simple and Cost-Effective Algorithm to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease Dementia. - Mazzeo, Salvatore; Santangelo, Roberto; Bernasconi, Maria Paola; Cecchetti, Giordano; Fiorino, Agnese; Pinto, Patrizia; Passerini, Gabriella; Falautano, Monica; Comi, Giancarlo; Magnani, Giuseppe (J Alzheimers Dis, 2016)
BACKGROUND: Correctly diagnosing Alzheimer's disease (AD) in prodromal phases would allow the adoption of experimental therapeutic strategies that could selectively interrupt the pathogenetic process before neuronal damage becomes irreversible. Therefore, great efforts have been aimed at finding early reliable disease markers. OBJECTIVE: The aim of this study was to identify a simple, cost effective, and reliable diagnostic algorithm to predict conversion from mild cognitive impairment (MCI) to AD. METHODS: 96 consecutive MCI patients admitted to the Neurology department of San Raffaele Hospital in Milan between January 2009 and January 2015 were included. All patients underwent neuropsychological assessment and lumbar puncture with CSF analysis of amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Each patient underwent clinical and neuropsychological follow-up, in order to identify a possible progression from MCI to AD. The mean follow up time was 36.73 months. RESULTS: 37 out of 96 MCI converted to AD during follow up. CSF analysis and neuropsychological assessment reliably detected MCI patients who developed AD. In a subsample of 43 subjects, a Composite Cognitive Score (CCS) was calculated including episodic memory, executive function, and verbal fluency tests. Combining together CSF biomarkers and CCS increased the accuracy of the single predictors, correctly classifying 86% of patients with a specificity of 96% and a Positive Predictive Value of 93%. DISCUSSION: Even if preliminary, our data seem to suggest that CSF analysis and neuropsychological assessment could detect MCI patients who will convert to AD with high confidence. Their relative low cost and availability could make them worldwide essential tools in future clinical trials.

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 the Effects of Multisensory Stimulation and Individualized Music Sessions on Elderly People with Severe Dementia: A Randomized Controlled Trial. - Sánchez, Alba; Maseda, Ana; Marante-Moar, M Pilar; de Labra, Carmen; Lorenzo-López, Laura; Millán-Calenti, José Carlos (J Alzheimers Dis, 2016)
The objective of this study was to compare the effects of a multisensory stimulation environment (MSSE) and individualized music sessions on agitation, emotional and cognitive status, and dementia severity in a sample of institutionalized patients with severe dementia. Twenty-two participants with a diagnosis of severe or very severe dementia were randomly assigned to two groups: MSSE and individualized music sessions. Both groups participated in two 30-min weekly sessions over 16 weeks. Outcomes were agitation (Cohen-Mansfield Agitation Inventory, CMAI), mood (Cornell Scale for Depression in Dementia, CSDD), anxiety (Rating Anxiety in Dementia, RAID), cognitive function (Severe Mini-Mental State Examination, SMMSE), and the overall severity of dementia (Bedford Alzheimer Nursing Severity Scale, BANS-S). They were assessed at baseline (pre-trial), in the middle (mid-trial), at the end of the intervention (post-trial), and 8 weeks after the intervention (follow-up). Patients in the MSSE group showed significant improvement in their RAID and BANS-S scores compared with the individualized music group post- versus pre-trial. With regard to agitation, there was improvement during the intervention in both the MSSE and individualized music groups in the CMAI total score after 16 weeks of intervention, with no significant differences between the groups. The results suggest that MSSE could have better effects on anxiety symptoms and dementia severity in comparison with individualized music sessions in elderly patients with severe dementia.
Keywords: Affect; Aged; Aged, 80 and over; Anxiety; Cognition; Dementia; Environment; Female; Follow-Up Studies; Humans; Male; Mental Status Schedule; Music Therapy; Precision Medicine; Sensory Art Therapies; Severity of Illness Index; Treatment Outcome

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

Concanavalin agglutinin levels are decreased in peripheral blood of Alzheimer's disease patients. - Sun, Xuying; Ma, Ronghong; Yao, Xiuqing; Shang, Xiaoling; Wang, Qun; Wang, Jian-Zhi; Liu, Gongping (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) seriously threatens patients' lives and causes severe burden to the families. Early prevention and treatment can alleviate the development of the disease; therefore it is important to find new effective and non-traumatic biomarkers for early diagnosis. In this study, peripheral blood samples were collected from 24 AD patients and the same number of age- and gender-matched control subjects. Lectin reactive glycosylation levels including beta-D-galactosyl ricinus communis agglutinin 120 (RCA), peanut agglutinin (PNA), concanavalin agglutinin (Con A), alpha-L-fucosyl ulex europeus agglutinin (UEA), dolichos biflorus agglutinin (DBA), and galanthus nivalis (GNL), in the red blood cells of peripheral blood were examined by western blotting. We found that lectin levels were altered with aging and gender; some lectin levels were different between AD patients and the control subjects. Only Con A levels were significantly decreased in AD patients compared to age-matched control subjects. These results suggest that Con A levels in peripheral blood may be a potent diagnostic marker for AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Case-Control Studies; Concanavalin A; Female; Humans; Lectins; Male; Plant Lectins

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.

The Cytome Assay as a Tool to Investigate the Possible Association Between Exposure to Extremely Low Frequency Magnetic Fields and an Increased Risk for Alzheimer's Disease. - Maes, Annemarie; Anthonissen, Roel; Wambacq, Sheleen; Simons, Koen; Verschaeve, Luc (J Alzheimers Dis, 2016)
Exposure to extremely low frequency magnetic fields (ELF-MF) has been identified as one of the potential environmental risk factors for Alzheimer's disease (AD). However, this is far from being established. So far there is no experimental evidence supporting this alleged association. We have performed an in vitro cytogenetic laboratory investigation to explore the plausibility of such association. Our investigation was based on possible similarities found in cells from AD patients and in cells exposed to ELF-MF. We especially found that 50  Hz ELF-MF increase the frequency of cells with (large) micronuclei and nuclear buds indicating that fields above 50 μT may induce chromosome instabilities as those found in AD patients. It should be stressed yet that results from the few published experimental studies on ELF-MF and AD are rather reassuring. Thus, our findings certainly do not prove anything. They only suggest that further investigations might be necessary.
Keywords: Apoptosis; Carcinoma; Cell Line, Tumor; Chromosome Aberrations; Cytokinesis; Dose-Response Relationship, Radiation; Humans; Magnetic Fields; Risk Factors

Daily Function as Predictor of Dementia in Cognitive Impairment, No Dementia (CIND) and Mild Cognitive Impairment (MCI): An 8-Year Follow-Up in the ILSA Study. - Di Carlo, Antonio; Baldereschi, Marzia; Lamassa, Maria; Bovis, Francesca; Inzitari, Marco; Solfrizzi, Vincenzo; Panza, Francesco; Galluzzo, Lucia; Scafato, Emanuele; Inzitari, Domenico (J Alzheimers Dis, 2016)
BACKGROUND: Preclinical cognitive changes may predict an increased risk of dementia, allowing selection of subgroups as possible targets for preventive or therapeutic interventions. OBJECTIVE: To evaluate the predictive effect of daily functioning and motor performance (MP) on the progression to dementia in normal cognition, cognitive impairment, no dementia (CIND), and mild cognitive impairment (MCI). METHODS: The Italian Longitudinal Study on Aging is a large population-based survey on age-related diseases of the cardiovascular and nervous systems. After the baseline assessment, to detect prevalent cases of cognitive impairment and dementia, participants were re-examined at 4-year and 8-year follow-ups. Functional independence was evaluated using the Index of Activities of Daily Living (ADL) and the Instrumental Activities of Daily Living (IADL) Scale. A six-test battery was used to assess MP. RESULTS: Overall, 2,386 individuals were included, for a total of 16,545 person-years. Eight-year incidence of dementia (per 1,000 person-years) was 12.69 in total sample, 9.86 in subjects with normal cognition at baseline, 22.99 in CIND, and 21.43 in MCI. Progression to dementia was significantly higher with increasing baseline ADL and IADL impairment, and with a worse MP. In Cox regression analyses controlled for demographics and major age-related conditions, increased IADL impairment was the stronger predictor of progression to dementia (p < 0.001), with HR ranging from 2.16 (95% CI, 0.82-5.70) to 9.57 (95% CI, 3.40-26.91) in subjects with MCI at baseline. CONCLUSIONS: Inclusion of IADL in the MCI construct significantly improves the prediction of dementia. Individuation of different transition rates is required to plan cost-effective interventions.

A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Belgium. - Somers, Charisse; Struyfs, Hanne; Goossens, Joery; Niemantsverdriet, Ellis; Luyckx, Jill; De Roeck, Naomi; De Roeck, Ellen; De Vil, Bart; Cras, Patrick; Martin, Jean-Jacques; De Deyn, Peter-Paul; Bjerke, Maria; et al. (J Alzheimers Dis, 2016)
During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

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

Delusions in Patients with Alzheimer's Disease: A Multidimensional Approach. - D'Onofrio, Grazia; Panza, Francesco; Sancarlo, Daniele; Paris, Francesco F; Cascavilla, Leandro; Mangiacotti, Antonio; Lauriola, Michele; Paroni, Giulia H; Seripa, Davide; Greco, Antonio (J Alzheimers Dis, 2016)
In Alzheimer's disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Delusions; Female; Humans; Male; Mental Status Schedule; Neuropsychological Tests; Prognosis; Risk; Severity of Illness Index; Time Factors

Dementia and Rapid Mortality: Who is at Risk? - Staekenborg, Salka S; Pijnenburg, Yolande A L; Lemstra, Afina W; Scheltens, Philip; Vd Flier, Wiesje M (J Alzheimers Dis, 2016)
BACKGROUND: Dementia is typically known for its insidious onset and slowly progressive course, but a subgroup deteriorates fast and dies within years or even months. OBJECTIVE: The purpose of this study was to characterize dementia patients with a rapidly progressive course to death and evaluate their cause of death. METHODS: We retrospectively included all patients from the Amsterdam Dementia Cohort who died within two years after diagnosis. We evaluated the characteristics of these rapid progressors and compared them to patients known to be alive two years after diagnosis ('non-rapid mortality'). RESULTS: We included 129 dementia patients (13% of our total cohort with known follow-up) with rapid mortality (age 72±10 y [29%  <65 y], 70[55%]M, MMSE 20±5). Mean(SD) survival was 12±7 months. Compared to non-rapid mortality patients (n = 892; age 68±9, 503(56%)M, MMSE 22±5), patients with rapid mortality were slightly older at time of diagnosis, had lower MMSE scores, more depressive symptoms and higher prevalence of a cardiovascular history (all p < 0.05). Alzheimer's disease (AD, 43%) was most frequent in patients with rapid mortality, but the occurrence was much lower compared to non-rapid mortality patients (71%), while all other dementia diagnoses, especially Creutzfeldt-Jakob disease (CJD), vascular dementia (VaD), and frontotemporal dementia (FTD), were more frequent (p < 0.001). There were no specific characteristics for AD patients with rapid versus non-rapid mortality, especially APOE genotypes and CSF-profiles were comparable (p > 0.70). Cause of death was highly variable without a clear relation to dementia diagnosis, with exception of dementia itself in CJD, intracerebral hematoma in VaD, and motor neuron disease in FTD. CONCLUSIONS: Short survival is relatively common (∼13% in our cohort) and occurs in all different types of dementia, with overrepresentation of non-AD dementias like CJD, VaD, and FTD.

Dementia Risk and Protective Factors Differ in the Context of Memory Trajectory Groups. - Zahodne, Laura B; Schupf, Nicole; Brickman, Adam M; Mayeux, Richard; Wall, Melanie M; Stern, Yaakov; Manly, Jennifer J (J Alzheimers Dis, 2016)
BACKGROUND: Previous research has identified multiple risk and protective factors for late onset Alzheimer's disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines. OBJECTIVE: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles. METHODS: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories ("Stable-High," "Stable-Low," "Decliner," "Rapid Decliner") using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington Heights-Inwood Columbia Aging Project. RESULTS: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-ɛ4 only incurred independent risk in the rapidly declining group. CONCLUSION: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient's unique cognitive history.

Detection of Striatal Amyloid Plaques with [18F]flutemetamol: Validation with Postmortem Histopathology. - Beach, Thomas G; Thal, Dietmar Rudolf; Zanette, Michelle; Smith, Adrian; Buckley, Christopher (J Alzheimers Dis, 2016)
Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- β (Aβ) plaques and dementia. Autopsy studies suggest that Aβ plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aβ plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aβ deposits with a visually positive panel consensus decision of a positive [18F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aβ deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aβ plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD.

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

Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid? - Weston, Philip S J; Paterson, Ross W; Dickson, John; Barnes, Anna; Bomanji, Jamshed B; Kayani, Irfan; Lunn, Michael P; Mummery, Catherine J; Warren, Jason D; Rossor, Martin N; Fox, Nick C; Zetterberg, Henrik; et al. (J Alzheimers Dis, 2016)
Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer's disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist's working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains.

Diagnostic Accuracy of MRI and Additional [18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes. - Vijverberg, Everard G B; Wattjes, Mike P; Dols, Annemiek; Krudop, Welmoed A; Möller, Christiane; Peters, Anne; Kerssens, Cora J; Gossink, Flora; Prins, Niels D; Stek, Max L; Scheltens, Philip; van Berckel, Bart N M; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown. OBJECTIVE: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes. METHODS: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging. RESULTS: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52-85%) with a specificity of 93% (95% CI 86-97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66-100%) with a specificity of 68% (95% CI 56-79%). The sensitivity of combined neuroimaging was 96% (95% CI 85-100%) with a specificity of 73% (95% CI 63-81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis. CONCLUSION: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.

Diagnostic Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer's Disease. - Niemantsverdriet, Ellis; Goossens, Joery; Struyfs, Hanne; Martin, Jean-Jacques; Goeman, Johan; De Deyn, Peter Paul; Vanderstichele, Hugo; Engelborghs, Sebastiaan (J Alzheimers Dis, 2016)
Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer's disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Cognitive Dysfunction; Enzyme-Linked Immunosorbent Assay; Exercise; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Retrospective Studies; Statistics, Nonparametric; tau Proteins

Dietary high cholesterol and trace metals in the drinking water increase levels of ABCA1 in the rabbit hippocampus and temporal cortex. - Schreurs, Bernard G; Sparks, D Larry (J Alzheimers Dis, 2016)
BACKGROUND: Cholesterol-fed rabbits have been documented to show increased amyloid-β (Aβ) deposits in the brain that can be exacerbated by the quality of drinking water especially if rabbits drink tap water or distilled water containing copper. One mechanism of cholesterol and Aβ clearance may be through the ATP-binding cassette transporter A1 (ABCA1). OBJECTIVE AND METHODS: Using an ABCA1 antibody, we determined the number of ABCA1-immunopositive neurons in three areas of rabbit brain as a function of feeding 2% cholesterol and providing tap water, distilled water, or distilled water to which aluminum, copper, or zinc was added. RESULTS: The number of neurons with ABCA1 immunoreactivity was increased significantly as a result of dietary cholesterol in the rabbit hippocampus and inferior and superior temporal cortex. The number of neurons with ABCA1 immunoreactivity was further increased in all three areas as a result of cholesterol-fed rabbits drinking tap water or distilled water with copper. Finally, cholesterol-fed rabbits that drank distilled water with aluminum also showed an increased number of ABCA1-immunopositive neurons in inferior and superior temporal cortex. CONCLUSIONS: These data suggest that ABCA1 levels increase in parallel with previously documented increases in Aβ levels as a result of high dietary cholesterol and copper in the drinking water. Addition of aluminum to distilled water may have a similar effect in the temporal cortex. ABCA1 has been proposed as a means of clearing Aβ from the brain and manipulations that increase Aβ also result in an increase of clearance machinery.
Keywords: Aluminum; Alzheimer Disease; Animals; ATP-Binding Cassette Transporters; Brain Chemistry; Cholesterol, Dietary; Copper; Drinking Water; Hippocampus; Male; Neurons; Rabbits; Temporal Lobe; Zinc

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 Patterns of Correlation between Grey and White Matter Integrity Account for Behavioral and Psychological Symptoms in Alzheimer's Disease. - Makovac, Elena; Serra, Laura; Spanò, Barbara; Giulietti, Giovanni; Torso, Mario; Cercignani, Mara; Caltagirone, Carlo; Bozzali, Marco (J Alzheimers Dis, 2016)
Behavioral disorders and psychological symptoms (BPSD) in Alzheimer's disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Brain; Depression; Female; Gray Matter; Hallucinations; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; White Matter

Differential Effects of APOE Genotypes on the Anterior and Posterior Subnetworks of Default Mode Network in Amnestic Mild Cognitive Impairment. - Yuan, Baoyu; Xie, Chunming; Shu, Hao; Liao, Wenxiang; Wang, Zan; Liu, Duan; Zhang, Zhijun (J Alzheimers Dis, 2016)
BACKGROUND: The apolipoprotein E (APOE) ɛ4 carriers are at increased risk of developing Alzheimer's disease (AD) while the ɛ2 carriers appear to be protected against the disease. The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), consists of functionally differentiable anterior and posterior subnetworks. OBJECTIVE: This study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in amnestic mild cognitive impairment (aMCI). METHODS: Functional connectivity (FC) analyses were performed in DMN subnetworks in 74 aMCI (9 APOE ɛ2ɛ3, 44 ɛ3ɛ3, and 21 ɛ3ɛ4) and 105 healthy controls (HC; 32 APOE ɛ2ɛ3, 39 ɛ3ɛ3, and 34 ɛ3ɛ4). Logistic regression analysis was performed to obtain a model for classifying aMCI and HC. RESULTS: Significant interactions of APOE by aMCI on FCs were found in right cerebellum posterior lobe, left lingual gyrus, and right middle cingulate cortex in the vmPFC subnetwork, and bilateral fusiform gyrus, left inferior frontal gyrus, and left precuneus in the PCC subnetwork. The impairment of episodic memory for ɛ4-carriers in aMCI negatively correlated with altered FC between vmPFC and right middle cingulate cortex, while positively correlated with altered FC between PCC and left fusiform gyrus. A model composed of episodic memory and FCs dexterity correctly classified 89.4% of aMCI and HC. CONCLUSIONS: APOE ɛ4 and ɛ2 alleles differentially mediate anterior and posterior DMN subnetworks. Furthermore, it further suggests that the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory.

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

Differential Regulation of N-Methyl-D-Aspartate Receptor Subunits is an Early Event in the Actions of Soluble Amyloid-β(1-40) Oligomers on Hippocampal Neurons. - Chang, Lirong; Zhang, Yali; Liu, Jinping; Song, Yizhi; Lv, Angchu; Li, Yan; Zhou, Wei; Yan, Zhen; Almeida, Osborne F X; Wu, Yan (J Alzheimers Dis, 2016)
Synaptic dysfunction during early stages of Alzheimer's disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits to synaptotoxicity and demonstrate that Aβ exerts differential effects on the levels and distribution of GluN2A and GluN2B subunits of NMDAR in dendrites. Treatment of cultured hippocampal neurons with Aβ1-40 (10 μM, 1 h) induced a significant increase of dendritic and synaptic GluN2B puncta densities with parallel decreases in the puncta densities of denritic and synaptic pTyr1472-GluN2B. Conversely, Aβ significantly decreased dendritic and synaptic GluN2A and dendritic pTyr1325-GluN2A puncta densities and increased synaptic pTyr1325-GluN2A puncta densities. Unexpectedly, Aβ treatment resulted in a significant reduction of GluN2B and pTyr1472-GluN2B protein levels but did not influence GluN2A and pTyr1325-GluN2A levels. These results show that Aβ exerts complex and distinct regulatory effects on the trafficking and phosphorylation of GluN2A and GluN2B, as well as on their localization within synaptic and non-synaptic sites. Increased understanding of these early events in Aβ-induced synaptic dysfunction is likely to be important for the development of timely preventive and therapeutic interventions.
Keywords: Amyloid beta-Peptides; Animals; Animals, Newborn; Cells, Cultured; Dendrites; Gene Expression Regulation; Hippocampus; Male; Neurons; Peptide Fragments; Phosphorylation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Differential Risk of Incident Alzheimer's Disease Dementia in Stable Versus Unstable Patterns of Subjective Cognitive Decline. - Wolfsgruber, Steffen; Kleineidam, Luca; Wagner, Michael; Mösch, Edelgard; Bickel, Horst; Lϋhmann, Dagmar; Ernst, Annette; Wiese, Birgitt; Steinmann, Susanne; König, Hans-Helmut; Brettschneider, Christian; Luck, Tobias; et al. (J Alzheimers Dis, 2016)
BACKGROUND: It is unknown whether longitudinal stability versus instability in subjective cognitive decline (SCD) is a modifying factor of the association between SCD and risk of incident Alzheimer's disease (AD) dementia. OBJECTIVE: We tested the modifying role of temporal stability of the SCD report on AD dementia risk in cognitively normal elderly individuals. METHODS: We analyzed data of 1,990 cognitively normal participants from the longitudinal AgeCoDe Study. We assessed SCD with/without associated worries both at baseline and first follow-up 18 months later. Participants were then classified either as (a) Controls (CO, with no SCD at both baseline and follow-up 1, n = 613), (b) inconsistent SCD (with SCD reported only at baseline or at follow-up 1, n = 637), (c) consistent SCD but without/or with inconsistent worries (n = 610) or (d) consistent SCD with worries (n = 130). We estimated incident AD dementia risk over up to 6 years for each group with Cox-Proportional Hazard Regression analyses adjusted for age, gender, education, ApoE4 status, and depression. RESULTS: Compared to CO, inconsistent SCD was not associated with increased risk of incident AD dementia. In contrast, risk was doubled in the group of consistent SCD without/ with inconsistent worries, and almost 4-fold in the group of consistent SCD with worries. These results could be replicated when using follow-up 1 to follow-up 2 response patterns for group definition. CONCLUSION: These findings suggest that longitudinal stability versus instability is an important modifying factor of the association between SCD and AD dementia risk. Worrisome SCD that is also consistently reported over time is associated with greatly increased risk of AD dementia.

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.

Diminished CRE-Induced Plasticity is Linked to Memory Deficits in Familial Alzheimer's Disease Mice. - Bartolotti, Nancy; Segura, Laura; Lazarov, Orly (J Alzheimers Dis, 2016)
The mechanism underlying impaired learning and memory in Alzheimer's disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer's disease.
Keywords: Alzheimer Disease; Animals; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Hippocampus; Maze Learning; Memory Disorders; Mice; Neuronal Plasticity; Neurons; Phosphorylation

Discovering New Genes in the Pathways of Common Sporadic Neurodegenerative Diseases: A Bioinformatics Approach. - Kim, Yong Hwan; Beak, Seung Han; Charidimou, Andreas; Song, Min (J Alzheimers Dis, 2016)
Late onset Alzheimer's disease (AD) and Parkinson's disease (PD) are mostly "sporadic" age-related neurodegenerative disorders, but with a clear genetic component. However, their genetic architecture is complex and heterogeneous, largely remaining a conundrum, with only a handful of well-established genetic risk factors consistently associated with these diseases. It is possible that numerous, yet undiscovered, AD and PD related genes might exist. We focused on the 'gene' as a mediator to find new potential genes that might have a relationship with both disorders using bio-literature mining techniques. Based on Entrez Gene, we extracted the genes and directional gene-gene relation in the entire MEDLINE records and then constructed a directional gene-gene network. We identified common genes associated with two different but related diseases by performing shortest path analysis on the network. With our approach, we were able to identify and map already known genes that have a direct relationship with PD and AD. In addition, we identified 7 genes previously unknown to be a bridge between these two disorders. We confirmed 4 genes, ROS1, FMN1, ATP8A2, and SNORD12C, by biomedical literature and further checked 3 genes, ERVK-10, PRS, and C7orf49, that might have a high possibility to be related with both diseases. Additional experiments were performed to demonstrate the effectiveness of our proposed method. Comparing to the co-occurrence approach, our approach detected 25% more candidate genes and verified 10% more genes that have the relationship between both diseases than the co-occurrence approach did.
Keywords: Computational Biology; Female; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Male; MEDLINE; Neurodegenerative Diseases

Discovery and Subsequent Confirmation of Novel Serum Biomarkers Diagnosing Alzheimer's Disease. - Shah, Dipti Jigar; Rohlfing, Frederick; Anand, Swati; Johnson, W Evan; Alvarez, MeiHwa Tanielle Bench; Cobell, Jesse; King, Jackson; Young, Sydney A; Kauwe, John S K; Graves, Steven W (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts. OBJECTIVE: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers. METHODS: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS. RESULTS: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified. CONCLUSION: These results suggest novel serum AD diagnostic biomarkers can be found using this approach.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Case-Control Studies; Chromatography, Liquid; Female; Humans; Male; Psychiatric Status Rating Scales; Reproducibility of Results; ROC Curve; Tandem Mass Spectrometry

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.

Disrupted White Matter Network and Cognitive Decline in Type 2 Diabetes Patients. - Zhang, Junying; Liu, Zhen; Li, Zixiao; Wang, Yunxia; Chen, Yaojing; Li, Xin; Chen, Kewei; Shu, Ni; Zhang, Zhanjun (J Alzheimers Dis, 2016)
Type 2 diabetes mellitus is accompanied by cognitive impairment and is associated with an increased risk of dementia. Damage to brain structures such as white matter network disruption may underlie this cognitive disturbance. In the present study, 886 non-diabetic and 163 type 2 diabetic participants completed a battery of neuropsychological tests. Among them, 38 diabetic patients and 34 non-diabetic participants that matched the patients for age/sex/education received a magnetic resonance imaging-based diffusion tensor imaging. Then we calculated the topological properties of the white matter network using a graph theoretical method to investigate network efficiency differences between groups. We found that type 2 diabetic patients had inferior performances compared to the non-diabetic controls, in several cognitive domains involving executive function, spatial processing, memory, and attention. We also found that diabetic patients exhibited a disrupted topological organization of the white matter network (including the global network properties, i.e., network strength, global efficiency, local efficiency and shortest path length, and the nodal efficiency of the right rolandic operculum) in the brain. Moreover, those global network properties and the nodal efficiency of the right rolandic operculum both had positive correlations with executive function in the patient group. The results suggest that type 2 diabetes mellitus leads to an alteration in the topological organization of the cortical white matter network and this alteration may account for the observed cognitive decline.

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

Distinctive Resting State Network Disruptions Among Alzheimer's Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients. - Kim, Hee Jin; Cha, Jungho; Lee, Jong-Min; Shin, Ji Soo; Jung, Na-Yeon; Kim, Yeo Jin; Choe, Yearn Seong; Lee, Kyung Han; Kim, Sung Tae; Kim, Jae Seung; Lee, Jae Hong; Na, Duk L; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer's disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. OBJECTIVE: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. METHODS: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. RESULTS: When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. CONCLUSIONS: Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cerebral Cortex; Cross-Sectional Studies; Dementia; Dementia, Vascular; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Models, Neurological; Neural Pathways; Neuropsychological Tests; Oxygen; Psychiatric Status Rating Scales; Radionuclide Imaging; Rest; Thiazoles

Diversity of Cognitive Phenotypes Associated with C9ORF72 Hexanucleotide Expansion. - Gómez-Tortosa, Estrella; Prieto-Jurczynska, Cristina; Serrano, Soledad; Franco-Macías, Emilio; Olivié, Laura; Gallego, Jesús; Guerrero-López, Rosa; Trujillo-Tiebas, María José; Ayuso, Carmen; García Ruiz, Pedro; Pérez-Pérez, Julián; Sainz, María José (J Alzheimers Dis, 2016)
For diagnostic purposes, we screened for the C9ORF72 mutation in a) 162 FTLD cases, and b) 145 cases with other diagnoses but with some frontotemporal features or manifestations previously reported in C9 carriers. Ten cases (onset 50 to 75 years) harbored the expansion: seven had FTLD syndromes (4.3% of total, 11% of familial cases), and three (2%) had a different diagnosis. All positive cases had family history of dementia, psychiatric disease, or ALS, but only 20% of families with mixed FTLD/ALS phenotypes carried the expansion. Language impairment was the most common symptom, followed by behavioral changes, memory deficits, and parkinsonism. C9ORF72 mutation has a low frequency in our dementia series and very diverse clinical manifestations.
Keywords: Adult; Age of Onset; Apolipoprotein E4; Cognition; DNA Repeat Expansion; Family; Female; Follow-Up Studies; Frontotemporal Lobar Degeneration; Genetic Association Studies; Genetic Predisposition to Disease; Genotyping Techniques; Humans; Male; Middle Aged; Prevalence; Proteins; Spain

Do Microglia Default on Network Maintenance in Alzheimer's Disease? - Southam, Katherine A; Vincent, Adele J; Small, David H (J Alzheimers Dis, 2016)
Although the cause of Alzheimer's disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain's immune cells. They play an important role in maintaining the brain's extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.
Keywords: Alzheimer Disease; Animals; Humans; Microglia; Synapses

Does the Interplay Between Aging and Neuroinflammation Modulate Alzheimer's Disease Clinical Phenotypes? A Clinico-Pathological Perspective. - Taipa, Ricardo; Sousa, Ana Luísa; Melo Pires, Manuel; Sousa, Nuno (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of dementia worldwide. Cumulative data suggests that neuroinflammation plays a prominent and early role in AD, and there is compelling data from different research groups of age-associated dysregulation of the neuroimmune system. From the clinical point of view, despite clinical resemblance and neuropathological findings, there are important differences between the group of patients with sporadic early-onset (<65 years old) and late-onset AD (>65 years old). Thus, it seems important to understand the age-dependent relationship between neuroinflammation and the underlying biology of AD in order to identify potential explanations for clinical heterogeneity, interpret biomarkers, and promote the best treatment to different clinical AD phenotypes. The study of the delicate balance between pro-inflammatory or anti-inflammatory sides of immune players in the different ages of onset of AD would be important to understand treatment efficacy in clinical trials and eventually, not only direct treatment to early disease stages, but also the possibility of establishing different treatment approaches depending on the age of the patient. In this review, we would like to summarize what is currently known about the interplay between "normal" age associated inflammatory changes and AD pathological mechanisms, and also the potential differences between early-onset and late-onset AD taking into account the age-related neuroimmune background at disease onset.

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

Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Aβ 1-42. - Jin, Huafeng; Chen, Tingting; Li, Guoxi; Wang, Conghui; Zhang, Baofeng; Cao, Xinyuan; Sha, Sha; Wan, Qi; Chen, Ling (J Alzheimers Dis, 2016)
BACKGROUND: Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer's disease (AD), however there are conflicting reports. OBJECTIVE & METHODS: Intracerebroventricular injection of aggregated Aβ1-42 in mice (Aβ1-42-mice) caused spatial cognitive deficits, long-term potentiation (LTP) impairment, and death of hippocampal pyramidal cells. The present study focused on exploring the dose-dependent effects of SV (10-80 mg/kg) on Aβ1-42-impaired spatial memory and the underlying mechanisms. RESULTS: The treatment of Aβ1-42-mice with SV for continuous 15 days could attenuate the spatial cognitive deficits and recover the LTP induction in a "U" type dose-dependent manner. The death of pyramidal cells in Aβ1-42-mice was significantly reduced by the SV-treatment at 20 mg/kg, but not at a dose of 10 or 40 mg/kg, even was aggravated at a dose of 80 mg/kg. Hippocampal NMDA receptor (NMDAr) NR2B phosphorylation (phospho-NR2B) was elevated in Aβ1-42-mice, which was further dose-dependently increased by SV-treatment. Replenishment of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the SV-increased phospho-NR2B in Aβ1-42-mice, but had no effect on the Aβ1-42-enhanced phospho-NR2B. NMDAr antagonist blocked the neurotoxicity of Aβ1-42 and SV (80 mg/kg) in Aβ1-42-mice, whereas FOH only inhibited SV (80 mg/kg)-neurotoxicity. The SV-treatment in Aβ1-42-mice corrected the decrease in hippocampal Akt phosphorylation. The PI3K inhibitor abolished the SV (20 mg/kg)-neuroprotection in Aβ1-42-mice. CONCLUSION: SV-treatment in Aβ1-42-mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt.
Keywords: Amyloid beta-Peptides; Animals; Dose-Response Relationship, Drug; Hippocampus; Injections, Intraventricular; Male; Maze Learning; Mice; Neuroprotective Agents; Peptide Fragments; Phosphorylation; Polyisoprenyl Phosphates; Receptors, N-Methyl-D-Aspartate; Sesquiterpenes; Simvastatin; Spatial Memory

Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study. - Marseglia, Anna; Fratiglioni, Laura; Laukka, Erika J; Santoni, Giola; Pedersen, Nancy L; Bäckman, Lars; Xu, Weili (J Alzheimers Dis, 2016)
Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β - 1.10 [95% CI - 1.98, - 0.23]), category fluency (β - 1.27 [95% CI - 2.52, - 0.03]), and digit span forward (β - 0.35 [95% CI - 0.54, - 0.17]). Critically, these associations were present only among APOEɛ4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations.

Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition. - Kantarci, Kejal; Lowe, Val J; Lesnick, Timothy G; Tosakulwong, Nirubol; Bailey, Kent R; Fields, Julie A; Shuster, Lynne T; Zuk, Samantha M; Senjem, Matthew L; Mielke, Michelle M; Gleason, Carey; Jack, Clifford R; et al. (J Alzheimers Dis, 2016)
BACKGROUND: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD). OBJECTIVE: To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women. METHODS: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. RESULTS: Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers. CONCLUSION: In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

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

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial. - Berger, Miles; Nadler, Jacob W; Friedman, Allan; McDonagh, David L; Bennett, Ellen R; Cooter, Mary; Qi, Wenjing; Laskowitz, Daniel T; Ponnusamy, Vikram; Newman, Mark F; Shaw, Leslie M; Warner, David S; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

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

Effectiveness of Exercise- and Cognitive-Based Treatments on Salivary Cortisol Levels and Sundowning Syndrome Symptoms in Patients with Alzheimer's Disease. - Venturelli, Massimo; Sollima, Alessio; Cè, Emiliano; Limonta, Eloisa; Bisconti, Angela V; Brasioli, Anna; Muti, Ettore; Esposito, Fabio (J Alzheimers Dis, 2016)
Sundowning syndrome (SDS) in patients with Alzheimer's disease (AD) is characterized by the intensification of behavioral disorders at sunset. Despite SDS etiology being unclear, a strong relationship between high cortisol levels and SDS has been reported. Aerobic exercise (AE) and cognitive training (CT) can reduce cortisol levels. However, whether SDS would benefit from AE and CT is still unknown. Therefore, the aim of this study was to investigate whether AE and CT treatments are effective in reducing SDS via downregulation of cortisol levels. The possible additive effects of combined AE+CT were also assessed. Eighty AD patients were randomly assigned to AE (n = 20), CT (n = 20), AE+CT (n = 20), and standard therapy (no treatment, NT; n = 20). Treatments were administered for 3 months, 5 days/week, 1 hour before sunset. Before and after treatments, salivary cortisol levels were sampled at 7, 11, 15, at sunset, and 20 (time of day). Blind assessment of behavioral disorders (neuropsychiatric inventory, NPI) and agitation (agitated behavior scale, ABS) were also performed. After interventions, cortisol levels were reduced in AE and AE+CT by ∼26%. In the same groups, NPI and ABS decreased by ∼50%. By contrast, cortisol and behavioral disorders were similar to baseline in CT and NT. Changes in NPI and ABS were significantly correlated with the reduction in cortisol levels. AE or AE+CT effects on SDS and cortisol levels and the lack of effect of CT alone indicate the effectiveness of an exercise-based treatment on SDS, suggesting a possible hypothalamic-pituitary-adrenal axis dysregulation underpinning SDS.

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

Effects of Meditation versus Music Listening on Perceived Stress, Mood, Sleep, and Quality of Life in Adults with Early Memory Loss: A Pilot Randomized Controlled Trial. - Innes, Kim E; Selfe, Terry Kit; Khalsa, Dharma Singh; Kandati, Sahiti (J Alzheimers Dis, 2016)
BACKGROUND: Older adults with subjective cognitive decline (SCD) are at increased risk not only for Alzheimer's disease, but for poor mental health, impaired sleep, and diminished quality of life (QOL), which in turn, contribute to further cognitive decline, highlighting the need for early intervention. OBJECTIVE: In this randomized controlled trial, we assessed the effects of two 12-week relaxation programs, Kirtan Kriya Meditation (KK) and music listening (ML), on perceived stress, sleep, mood, and health-related QOL in older adults with SCD. METHODS: Sixty community-dwelling older adults with SCD were randomized to a KK or ML program and asked to practice 12 minutes daily for 12 weeks, then at their discretion for the following 3 months. At baseline, 12 weeks, and 26 weeks, perceived stress, mood, psychological well-being, sleep quality, and health-related QOL were measured using well-validated instruments. RESULTS: Fifty-three participants (88%) completed the 6-month study. Participants in both groups showed significant improvement at 12 weeks in psychological well-being and in multiple domains of mood and sleep quality (p's≤0.05). Relative to ML, those assigned to KK showed greater gains in perceived stress, mood, psychological well-being, and QOL-Mental Health (p's≤0.09). Observed gains were sustained or improved at 6 months, with both groups showing marked and significant improvement in all outcomes. Changes were unrelated to treatment expectancies. CONCLUSIONS: Findings suggest that practice of a simple meditation or ML program may improve stress, mood, well-being, sleep, and QOL in adults with SCD, with benefits sustained at 6 months and gains that were particularly pronounced in the KK group.

Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. - Tsolaki, Magda; Karathanasi, Elina; Lazarou, Ioulietta; Dovas, Kostas; Verykouki, Eleni; Karacostas, Anastasios; Georgiadis, Kostas; Tsolaki, Anthoula; Adam, Katerina; Kompatsiaris, Ioannis; Sinakos, Zacharias (J Alzheimers Dis, 2016)
There is evidence to suggest the efficacy of Crocus (saffron) in the management of cognitive decline. This study examined the efficacy of Crocus in patients with amnesic and multi domain MCI (aMCImd). The participants included 17 patients on Crocus and 18 on a waiting list, who were examined with a short neuropsychological battery, MRI 3T, while some patients were examined via 256-channel electroencephalogram (HD-EEG) at baseline and after 12 months. The results showed that patients on Crocus had improved Mini-Mental State Examination scores (p = 0.015), while the control group deteriorated. Also, MRI, EEG, and ERP showed improvement in specific domains. This led us to conclude that Crocus is a good choice for management of aMCImd.

Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. - Liu, Guosong; Weinger, Jason G; Lu, Zhong-Lin; Xue, Feng; Sadeghpour, Safa (J Alzheimers Dis, 2016)
BACKGROUND: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents. OBJECTIVE: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50-70) with cognitive impairment. Subjects were treated with MMFS-01 (n = 23) or placebo (n = 21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains. RESULTS: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p = 0.003; Cohen's d = 0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined. CONCLUSIONS: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults.
Keywords: Aged; Anxiety; Butyrates; Cognition; Cognition Disorders; Double-Blind Method; Emotions; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Sleep; Synapses; Treatment Outcome

Elevated mRNA Expression and Low Methylation of SNCA in Japanese Alzheimer's Disease Subjects. - Yoshino, Yuta; Mori, Takaaki; Yoshida, Taku; Yamazaki, Kiyohiro; Ozaki, Yuki; Sao, Tomoko; Funahashi, Yu; Iga, Jun-Ichi; Ueno, Shu-Ichi (J Alzheimers Dis, 2016)
Despite the continuing debate about the amyloid hypothesis in Alzheimer's disease (AD), the precise pathogenesis is still unclear. Mixed pathology is common and multiple different protein aggregates are seen in human postmortem brains. Aggregates consisting of the alpha-synuclein protein encoded by the Synuclein Alpha gene (SCNA) are common in both dementia with Lewy bodies and AD. We examined SNCA mRNA expression and methylation rates of the CpG island at intron 1 of SNCA in peripheral leukocytes in 50 AD and age- and sex-matched control subjects to verify whether alpha-synuclein pathology affects the AD pathogenesis. SNCA mRNA expression in AD subjects was significantly higher than that in control subjects (1.62±0.73 versus 0.98±0.50, p < 0.001). We found significant differences between AD and control subjects at seven CpG sites (average rate; 8.8±2.7 versus 9.5±2.5, respectively: p = 0.027). The methylation rates tended to be lower in AD subjects at all CpG sites. We conclude that mRNA expression and methylation of SNCA intron 1 are altered in AD, which may be caused by Lewy body pathology in AD.

Epileptic Prodromal Alzheimer's Disease, a Retrospective Study of 13 New Cases: Expanding the Spectrum of Alzheimer's Disease to an Epileptic Variant? - Cretin, Benjamin; Sellal, François; Philippi, Nathalie; Bousiges, Olivier; Di Bitonto, Laure; Martin-Hunyadi, Catherine; Blanc, Frédéric (J Alzheimers Dis, 2016)
BACKGROUND: Aside from rare case reports, only one study, with 12 patients, has addressed the phenotypic presentation of epilepsy in clinically defined amnestic mild cognitive impairment (aMCI, presumed to correspond to the AD prodromal stage): the authors highlighted a pharmacosensitive non-convulsive partial epileptic syndrome most probably related to the temporal or temporo-frontal cortices. OBJECTIVE: The objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic. METHODS: We conducted a retrospective, single-center study of the electro-radio-clinical features of 13 cases of epileptic prodromal AD patients (3.1% of a cohort of MCI, n = 430 subjects), selected on both clinical criteria and CSF biomarkers. RESULTS: In our patients, a pharmacosensitive temporal lobe epilepsy syndrome, inaugurating prodromal AD, started at a mean age of 63 years (±12.8 years) and preceded MCI diagnosis by 4 to 7 years. At the stage of aMCI, median MMSE score was 26 and imaging showed mild hippocampal atrophy. After almost one year under treatment, cognitive complaints were not relieved but the MMSE score remained stable at 26 for 11 patients (2 patients were excluded from analysis because of the onset of aphasic or neurovisual symptoms altering MMSE scoring). CONCLUSION: Our data, in conjunction with those of the 12 previously described subjects, suggest the existence of a currently unrecognized inaugural epilepsy syndrome of sporadic AD. Such a syndrome could be called the epileptic variant of AD because seizures are its sole feature for more than 2.5 years.

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.

Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. - White, Matthew T; Shaw, Leslie M; Xie, Sharon X (J Alzheimers Dis, 2016)
Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Area Under Curve; Biomarkers; Databases, Factual; Female; Humans; Likelihood Functions; Male; Peptide Fragments; Phosphorylation; ROC Curve; tau Proteins

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease. - Jayne, Tanya; Newman, Morgan; Verdile, Giuseppe; Sutherland, Greg; Münch, Gerald; Musgrave, Ian; Moussavi Nik, Seyyed Hani; Lardelli, Michael (J Alzheimers Dis, 2016)
The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (AβPP/APP) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and AβPP) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity.

Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment. - Sacco, Guillaume; Caillaud, Corinne; Ben Sadoun, Gregory; Robert, Philippe; David, Renaud; Brisswalter, Jeanick (J Alzheimers Dis, 2016)
BACKGROUND: Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments. OBJECTIVES: The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI). METHOD: Eight participants with MCI (72 ± 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no-Go) before, immediately after, and 1 month after each intervention. RESULTS: The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 ± 1% ; p >  0.05), when compared with exercise alone (4 ± 0.5% ,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance. CONCLUSION: Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results.
Keywords: Aged; Analysis of Variance; Cognitive Dysfunction; Cognitive Therapy; Exercise; Exercise Therapy; Female; Humans; Inhibition (Psychology); Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Reaction Time; Retrospective Studies; Treatment Outcome

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.