Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β40 and Amyloid-β42 Peptides and ABCA7 Transcription in Cell Culture Models. - Bamji-Mirza, Michelle; Li, Yan; Najem, Dema; Liu, Qing Yan; Walker, Douglas; Lue, Lih-Fen; Stupak, Jacek; Chan, Kenneth; Li, Jianjun; Ghani, Mahdi; Yang, Ze; Rogaeva, Ekaterina; et al. (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.

Glutamine and Glutamate Complex, as Measured by Functional Magnetic Resonance Spectroscopy, Alters During Face-Name Association Task in Patients with Mild Cognitive Impairment and Alzheimer's Disease. - Jahng, Geon-Ho; Oh, Janghoon; Lee, Do-Wan; Kim, Hyug-Gi; Rhee, Hak Young; Shin, Wonchul; Paik, Jong-Woo; Lee, Kyung Mi; Park, Soonchan; Choe, Bo-Young; Ryu, Chang-Woo (J Alzheimers Dis, 2016)
BACKGROUND: The metabolite response during a memory task in Alzheimer's disease (AD) patients is unknown. OBJECTIVE: To investigate the metabolite changes in subjects with AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) elderly during a memory task using functional magnetic resonance spectroscopy (fMRS). METHODS: This study involved 23 young normal controls (YC), 24 CN elderly, 24 aMCI, and 24 mild and probable AD individuals. fMRS data were acquired at the precuneus and posterior cingulate brain regions during a face-name association task. Statistical analyses of quantified metabolites were performed to evaluate differences of the metabolite values between the stimulation conditions and among the four subject groups. Receiver operating curve analysis was performed to evaluate whether the metabolic changes after functional activations can differentiate the subject groups. RESULT: Glutamine and glutamate complex (Glx) was statistically significantly different between the fixation and repeat conditions in aMCI (p = 0.0492) as well as between the fixation and the novel conditions in the AD (p = 0.0412) group. The total N-acetylaspartate (tNAA) was statistically significantly different among the four subject groups in the fixation condition (DF = 3, F = 7.673, p <  0.001), the novel condition (DF = 3, F = 6.945, p <  0.001), and the repeat condition (DF = 3, F = 7.127, p <  0.001). tNAA, tCr, and mIns could be used to differentiate CN from aMCI. Furthermore, tNAA, tCr, Glx, and Glu could also differentiate CN from AD, and aMCI from AD. CONCLUSION: Glx was altered during a stimulation that may be used to evaluate neuronal dysfunction in a demented patient. tNAA and tCr were reduced in patients with AD.

GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. - Chu, Dandan; Tan, Jianxin; Xie, Shutao; Jin, Nana; Yin, Xiaomin; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei (J Alzheimers Dis, 2016)
Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9.
Keywords: Animals; Brain; Carboxylic Ester Hydrolases; Cell Line, Transformed; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Kainic Acid; Leucine; Luminescent Proteins; Male; Methylation; Mice; Phosphorylation; Protein O-Methyltransferase; Protein Phosphatase 2; RNA, Small Interfering; Serine; tau Proteins

Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer's Disease Mouse Model. - Manousopoulou, Antigoni; Saito, Satoshi; Yamamoto, Yumi; Al-Daghri, Nasser M; Ihara, Masafumi; Carare, Roxana O; Garbis, Spiros D (J Alzheimers Dis, 2016)
The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.
Keywords: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Functional Laterality; Male; Mice, Transgenic; Nootropic Agents; Proteome; Tetrazoles

Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. - Díaz, Mario; Fabelo, Noemí; Casañas-Sánchez, Verónica; Marin, Raquel; Gómez, Tomás; Quinto-Alemany, David; Pérez, José A (J Alzheimers Dis, 2016)
Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.
Keywords: Acyl Coenzyme A; Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Disease Models, Animal; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Estrogens; Gene Expression Regulation; Hippocampus; Homeostasis; Humans; Lipid Metabolism; Mice; Mice, Transgenic; Mutation; Presenilin-1; RNA, Messenger

A History of In Vivo Neutron Activation Analysis in Measurement of Aluminum in Human Subjects. - Mohseni, Hedieh K; Chettle, David R (J Alzheimers Dis, 2016)
Aluminum, as an abundant metal, has gained widespread use in human life, entering the body predominantly as an additive to various foods and drinking water. Other major sources of exposure to aluminum include medical, cosmetic, and occupational routes. As a common environmental toxin, with well-known roles in several medical conditions such as dialysis encephalopathy, aluminum is considered a potential candidate in the causality of Alzheimer's disease. Aluminum mostly accumulates in the bone, which makes bone an indicator of the body burden of aluminum and an ideal organ as a proxy for the brain. Most of the techniques developed for measuring aluminum include bone biopsy, which requires invasive measures, causing inconvenience for the patients. There has been a considerable effort in developing non-invasive approaches, which allow for monitoring aluminum levels for medical and occupational purposes in larger populations. In vivo neutron activation analysis, a method based on nuclear activation of isotopes of elements in the body and their subsequent detection, has proven to be an invaluable tool for this purpose. There are definite challenges in developing in vivo non-invasive techniques capable of detecting low levels of aluminum in healthy individuals and aluminum-exposed populations. The following review examines the method of in vivo neutron activation analysis in the context of aluminum measurement in humans focusing on different neutron sources, interference from other activation products, and the improvements made in minimum detectable limits and patient dose over the past few decades.
Keywords: Aluminum; Alzheimer Disease; Humans; Neutron Activation Analysis

Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment. - Spalletta, Gianfranco; Cravello, Luca; Gianni, Walter; Piras, Federica; Iorio, Mariangela; Cacciari, Claudia; Casini, Anna Rosa; Chiapponi, Chiara; Sancesario, Giuseppe; Fratangeli, Claudia; Orfei, Maria Donata; Caltagirone, Carlo; et al. (J Alzheimers Dis, 2016)
Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Chi-Square Distribution; Cognitive Dysfunction; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory, Episodic; Mental Status Schedule; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Taurine

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

"I Don't Think Of It As An Illness": Illness Representations in Mild to Moderate Dementia. - Clare, Linda; Quinn, Catherine; Jones, Ian Rees; Woods, Robert T (J Alzheimers Dis, 2016)
The self-regulatory model proposes that illness representations influence adjustment and coping in chronic conditions. Better understanding of the illness representations held by people with dementia could help with targeting information and support so as to optimize adjustment and coping. In this mixed-methods study of illness representations among people with mild to moderate Alzheimer's, vascular, or mixed dementia we aimed to clarify the nature of the representations held, to determine whether specific profiles can be identified based on perceptions of the identity and cause of the condition, and to examine associations between these profiles and other participant characteristics. Data were collected in the second wave of the Memory Impairment and Dementia Awareness Study (MIDAS). Sixty-four people with dementia, who had been told their diagnosis at a memory clinic, completed interviews and responded to questionnaires. In each case a carer was also interviewed. Cluster analysis based on responses about identity and cause identified three profiles. 'Illness' cluster participants saw themselves as living with an illness and used diagnostic labels, 'ageing' cluster participants did not use diagnostic labels and viewed their difficulties as related to ageing, and 'no problem' cluster participants considered that they did not have any difficulties. 'Illness' cluster participants had better cognition and better awareness, but lower mood, and perceived more practical consequences, than 'ageing' cluster participants. Holding an 'illness' model may not be advantageous. Rather than encouraging adoption of such a model, it may be preferable to target information and select interventions in line with the person's representation profile.
Keywords: Adaptation, Psychological; Aged; Aged, 80 and over; Aging; Awareness; Caregivers; Dementia; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Residence Characteristics; Self Concept; Statistics, Nonparametric; Surveys and Questionnaires

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

Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. - Liu, Jieqiong; Zhang, Xinqing; Yu, Chunshui; Duan, Yunyun; Zhuo, Junjie; Cui, Yue; Liu, Bing; Li, Kuncheng; Jiang, Tianzi; Liu, Yong (J Alzheimers Dis, 2016)
BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases. OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists. METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability. RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe. CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.
Keywords: Aged; Alzheimer Disease; Apolipoproteins E; Brain Mapping; Cognitive Dysfunction; Female; Hippocampus; Humans; Limbic System; Magnetic Resonance Imaging; Male; Mental Status Schedule; Neural Pathways; Rest; Severity of Illness Index

Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-β Peptide. - Colin, Julie; Allouche, Ahmad; Chauveau, Fabien; Corbier, Catherine; Pauron-Gregory, Lynn; Lanhers, Marie-Claire; Claudepierre, Thomas; Yen, Frances T; Oster, Thierry; Malaplate-Armand, Catherine (J Alzheimers Dis, 2016)
Oligomeric amyloid-β (Aβ) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer's disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of Aβ demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-AβPP cells expressing the human amyloid-β protein precursor (Aβ-CM), to investigate Aβ-induced neurotoxic and synaptotoxic effects. Characterization of Aβ-CM revealed that it contained picomolar amounts of cell-secreted Aβ in its soluble form. Incubation of primary cortical neurons with Aβ-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-AβPP cells grown in presence of the γ-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of Aβ-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-AβPP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n-3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of Aβ production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment.

Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer's Disease Patients. - Campanari, Maria-Letizia; Navarrete, Francisco; Ginsberg, Stephen D; Manzanares, Jorge; Sáez-Valero, Javier; García-Ayllón, María-Salud (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (qRT-PCR). We found similar protein and mRNA levels of the major cholinergic "tailed"-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic "readthrough" AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine.

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

Intranasal Administration of a Polyethylenimine-Conjugated Scavenger Peptide Reduces Amyloid-β Accumulation in a Mouse Model of Alzheimer's Disease. - Lin, Chih-Yun; Cheng, Yu-Sung; Liao, Tai-Yan; Lin, Chen; Chen, Zih-Ten; Twu, Woan-Ing; Chang, Chi-Wei; Tan, David Tat-Wei; Liu, Ren-Shyan; Tu, Pang-Hsien; Chen, Rita P-Y (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer's disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10-40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10-40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 in the mice's hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice's hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD.

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

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

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

Life's Simple 7's Cardiovascular Health Metrics are Associated with Hispanic/Latino Neurocognitive Function: HCHS/SOL Results. - González, Hector M; Tarraf, Wassim; Gouskova, Natalia; Rodríguez, Carlos J; Rundek, Tatjana; Grober, Ellen; Pirzada, Amber; González, Patricia; Lutsey, Pamela L; Camacho, Alvaro; Daviglus, Martha L; Wright, Clinton; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Hispanics/Latinos are purportedly at increased risk for neurocognitive decline and dementias. Without dementia cures, low-cost, well-tolerated public health means for mitigating neurocognitive decline are needed. OBJECTIVE: We examined associations between neurocognition and cardiovascular health (CVH) metrics (Life's Simple 7; LS7) among diverse Hispanics/Latinos. We hypothesized that higher LS7 would be associated with healthier brain function (neurocognitive performance). METHODS: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; N = 9,623; ages 45-74 years) to examine neurocognition in relation to CVH LS7 scores. RESULTS: In age and sex adjusted models, a one unit LS7 score increase (range = 0-14) was associated with higher neurocognitive function on the B-SEVLT sum (0.23 [p < 0.01]; range = 3-42), B-SEVLT recall (0.12 [p < 0.01]; range = 0-15), Word Fluency (phonemic; 0.46 (p < 0.01); range = 0-49), and Digit Symbol Substitution (0.49 (p < 0.01); range = 0-83) tests, respectively. Stated differently, a change from the minimum LS7 (0) to maximum LS7 (14) score corresponded to higher scores on verbal learning (4.62) and memory (2.24), verbal fluency (7.0), and psychomotor processing speed (12). In fully adjusted models the associations were attenuated, but remained statistically significant. Incremental adjustments indicated that Latino background and, to a lesser extent, education were primary contributors to the evinced attenuations. CONCLUSIONS: We found that higher neurocognitive function was associated with better LS7 CVH metrics among middle-aged and older Hispanics/Latinos. Associations between neurocognitive function and LS7 were strongest among two at-risk groups for neurocognitive decline and dementia, women and Hispanics/Latinos with lower education. Public health efforts to reduce cardiovascular disease morbidity and mortality may have additional neurocognitive benefits among at-risk Hispanics/Latinos.

Longitudinal Alteration of Intrinsic Brain Activity in the Striatum in Mild Cognitive Impairment. - Ren, Ping; Lo, Raymond Y; Chapman, Benjamin P; Mapstone, Mark; Porsteinsson, Anton; Lin, Feng (J Alzheimers Dis, 2016)
The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimer's disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three-year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low-frequency fluctuations (ALFF) (0.01-0.08 Hz) and two subdivided bands (slow-4:0.027-0.073 Hz; slow-5:0.01-0.027 Hz). We calculated Aβ/pTau ratio using baseline cerebrospinal fluid pTau and Aβ1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in the right putamen was significantly related to the memory decline over time and lower baseline Aβ/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Aβ/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Aβ/pTau ratio regardless of clinical diagnosis.

The Longitudinal Association Between a Discrepancy Measure of Anosognosia in Patients with Dementia, Caregiver Burden and Depression. - Perales, Jaime; Turró-Garriga, Oriol; Gascón-Bayarri, Jordi; Reñé-Ramírez, Ramón; Conde-Sala, Josep Lluís (J Alzheimers Dis, 2016)
BACKGROUND: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver's burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients' health. OBJECTIVE: To assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression. METHODS: A convenience cohort of 221 consecutive dementia outpatient and caregiver dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver's socio-demographic and possible confounding factors. RESULTS: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had < 5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient. CONCLUSION: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patient.

Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease. - Serra, Laura; Cercignani, Mara; Mastropasqua, Chiara; Torso, Mario; Spanò, Barbara; Makovac, Elena; Viola, Vanda; Giulietti, Giovanni; Marra, Camillo; Caltagirone, Carlo; Bozzali, Marco (J Alzheimers Dis, 2016)
This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.
Keywords: Aged; Alzheimer Disease; Atrophy; Brain; Brain Mapping; Cognitive Dysfunction; Cross-Sectional Studies; Discriminant Analysis; Disease Progression; Female; Follow-Up Studies; Gray Matter; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neural Pathways; Neuropsychological Tests; Prognosis; Rest

Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. - Raji, Cyrus A; Merrill, David A; Eyre, Harris; Mallam, Sravya; Torosyan, Nare; Erickson, Kirk I; Lopez, Oscar L; Becker, James T; Carmichael, Owen T; Gach, H Michael; Thompson, Paul M; Longstreth, W T; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual. OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons. METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent. RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis. CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

Longitudinal Study of Impaired Intra- and Inter-Network Brain Connectivity in Subjects at High Risk for Alzheimer's Disease. - Zhan, Yafeng; Ma, Jianhua; Alexander-Bloch, Aaron F; Xu, Kaibin; Cui, Yue; Feng, Qianjin; Jiang, Tianzi; Liu, Yong (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is associated with abnormal resting-state network (RSN) architecture of the default mode network (DMN), the dorsal attention network (DAN), the executive control network (CON), the salience network (SAL), and the sensory-motor network (SMN). However, little is known about the disrupted intra- and inter-network architecture in mild cognitive impairment (MCI). Here, we employed a priori defined regions of interest to investigate the intra- and inter-network functional connectivity profiles of these RSNs in longitudinal participants, including normal controls (n = 23), participants with early MCI (n = 26), and participants with late MCI (n = 19). We found longitudinal alterations of functional connectivity within the DMN, where they were correlated with variation in cognitive ability. The SAL as well as the interaction between the DMN and the SAL were disrupted in MCI. Furthermore, our results demonstrate that longitudinal alterations of functional connectivity are more profound in earlier stages as opposed to later stages of the disease. The increased severity of cognitive impairment is associated with increasingly altered RSN connectivity patterns, suggesting that disruptions in functional connectivity may contribute to cognitive dysfunction and may represent a potential biomarker of impaired cognitive ability in MCI. Earlier prevention and treatment may help to delay disease progression to AD.

Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum. - Premi, Enrico; Gualeni, Vera; Costa, Paolo; Cosseddu, Maura; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara (J Alzheimers Dis, 2016)
Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits.

Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease. - Premi, Enrico; Cauda, Franco; Costa, Tommaso; Diano, Matteo; Gazzina, Stefano; Gualeni, Vera; Alberici, Antonella; Archetti, Silvana; Magoni, Mauro; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara (J Alzheimers Dis, 2016)
In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: (1) to identify target regions in different disease stages and (2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporo-parietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease.
Keywords: Adult; Aged; Brain; Brain Mapping; Cohort Studies; Female; Frontotemporal Lobar Degeneration; Humans; Image Processing, Computer-Assisted; Intercellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neural Pathways; Oxygen; Phenylalanine; Threonine

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

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

Measurement Error, Reliability, and Minimum Detectable Change in the Mini-Mental State Examination, Montreal Cognitive Assessment, and Color Trails Test among Community Living Middle-Aged and Older Adults. - Feeney, Joanne; Savva, George M; O'Regan, Claire; King-Kallimanis, Bellinda; Cronin, Hilary; Kenny, Rose Anne (J Alzheimers Dis, 2016)
BACKGROUND: Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test. OBJECTIVE: To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults. METHODS: 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half the group changed rater between assessments and half changed time of day. RESULTS: Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation. CONCLUSION: An individual's score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis.

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

Metabolic Syndrome and Mild Cognitive Impairment: A Case-Control Study among Elderly in a Shanghai Suburb. - Yao, Qian; Jiang, Guo-Xin; Zhou, Zhi-Ming; Chen, Jin-Mei; Cheng, Qi (J Alzheimers Dis, 2016)
BACKGROUND: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI). OBJECTIVE: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly. METHODS: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current drinking, and physical activities. RESULTS: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR = 2.277; 95% CI: 1.086-4.773). Among MetS components, abdominal obesity (OR = 2.101; 95% CI: 1.224-3.608) and hypertension (OR = 2.075; 95% CI: 1.170-3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR = 2.459; 95% CI: 1.360-4.447). CONCLUSION: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Aging; Case-Control Studies; Chi-Square Distribution; China; Cities; Cognition Disorders; Community Health Planning; Female; Humans; Male; Mental Status Schedule; Metabolic Diseases; Risk Factors

Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. - Son, Sung Min; Shin, Hong-Joon; Byun, Jayoung; Kook, Sun Young; Moon, Minho; Chang, Yu Jin; Mook-Jung, Inhee (J Alzheimers Dis, 2016)
The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Autophagy; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Hypoglycemic Agents; Lysosomes; Metformin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Mutation; Neuroblastoma; Signal Transduction

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. - Luchsinger, Jose A; Perez, Thania; Chang, Helena; Mehta, Pankaj; Steffener, Jason; Pradabhan, Gnanavalli; Ichise, Masanori; Manly, Jennifer; Devanand, Davangere P; Bagiella, Emilia (J Alzheimers Dis, 2016)
Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Brain; Cognitive Dysfunction; Double-Blind Method; Female; Follow-Up Studies; Glucose; Humans; Male; Metformin; Middle Aged; Nootropic Agents; Overweight; Peptide Fragments; Pilot Projects; Positron-Emission Tomography; Psychological Tests; Severity of Illness Index; Treatment Outcome

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

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

Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer's Disease. - Chakrabarti, Mrinmay; McDonald, Alexander J; Will Reed, J; Moss, Melissa A; Das, Bhaskar C; Ray, Swapan K (J Alzheimers Dis, 2016)
Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer's disease (AD). Recent studies demonstrated severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology.
Keywords: Alzheimer Disease; Animals; Brain; Humans; Mice; Neurons; Retinoid X Receptors; Retinoids; Signal Transduction; Tretinoin

Mortality in Mild Cognitive Impairment: A Longitudinal Study in Memory Clinics. - Connors, Michael H; Ames, David; Boundy, Karyn; Clarnette, Roger; Kurrle, Sue; Mander, Alastair; Ward, John; Woodward, Michael; Brodaty, Henry (J Alzheimers Dis, 2016)
BACKGROUND: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival. OBJECTIVE: To identify predictors of mortality in patients with MCI. METHODS: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline. RESULTS: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality. CONCLUSION: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk.

Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study. - Callisaya, Michele L; Ayers, Emmeline; Barzilai, Nir; Ferrucci, Luigi; Guralnik, Jack M; Lipton, Richard B; Otahal, Petr; Srikanth, Velandai K; Verghese, Joe (J Alzheimers Dis, 2016)
BACKGROUND: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints. OBJECTIVES: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people. METHODS: Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts. RESULTS: The mean age of participants was 74.9 (SD 6.8) years and 44% (n = 2728) were male. Overall 33.9% (n = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51). CONCLUSION: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic.

Moving from the Dish to the Clinical Practice: A Decade of Lessons and Perspectives from the Pre-Clinical and Clinical Stem Cell Studies for Alzheimer's Disease. - Salem, Haitham; Rocha, Natalia Pessoa; Colpo, Gabriela Delevati; Teixeira, Antonio Lucio (J Alzheimers Dis, 2016)
To date, there is no definitive treatment for Alzheimer's disease (AD). The realm of stem cells is very promising in regenerative medicine, particularly neurodegenerative disorders. Various types of stem cells have been used in multiple trials on AD models, trying to find an innovative management of this disease. In this systematic review, we trace the published preclinical and clinical data throughout the last decade, to show how much knowledge we gained so far in this field and the future perspectives of stem cells in AD treatment.

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

The Multiple Object Test as a Performance Based Tool to Assess Cognitive Driven Activity of Daily Living Function in Parkinson's Disease. - Glonnegger, Hannah; Beyle, Aline; Cerff, Bernhard; Gräber, Susanne; Csoti, Ilona; Berg, Daniela; Liepelt-Scarfone, Inga (J Alzheimers Dis, 2016)
BACKGROUND: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson's disease (PD). OBJECTIVE: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment. METHODS: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson's disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed. RESULTS: Total time and number of MOT errors was increased in PD patients compared to controls (p < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p < 0.001) and mislocation (p < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function. CONCLUSION: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD.

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

Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer's Disease. - Spilman, Patricia R; Corset, Veronique; Gorostiza, Olivia; Poksay, Karen S; Galvan, Veronica; Zhang, Junli; Rao, Rammohan; Peters-Libeu, Clare; Vincelette, Jon; McGeehan, Andrew; Dvorak-Ewell, Melita; Beyer, Janine; et al. (J Alzheimers Dis, 2016)
Recent studies have shown that inoculation of susceptible mice with amyloid-β (Aβ) peptides accelerates Aβ deposition in the brain, supporting the idea that Aβ may be self-amplifying; however, the exact mechanism is not understood. Here we provide evidence that Aβ may self-amplify, in part, by inhibiting α-secretase ADAM10 (a disintegrin and metalloprotease) cleavage of full-length Aβ precursor protein (FL AβPP) and therefore allow greater β-secretase processing, and that Aβ itself is a substrate for ADAM10. Exposure of primary neuronal cultures from PDAβPP mice to exogenous rat Aβ1- 40 resulted in increased de novo human Aβ1-42 production and exposure of cells to Aβ decreased production of ADAM10 cleavage product soluble AβPPα (sAβPPα). In a cell-free assay, Aβ decreased ADAM10 cleavage of the chimeric substrate MBP-AβPPC125 and Aβ itself was apparently cleaved by the enzyme. The axonal guidance and trophic factor netrin-1, however, reduced the Aβ1- 40-induced Aβ1-42 increase, increased sAβPPα, and reversed the Aβ-induced sAβPPα decrease in vitro. In vivo, induction of netrin-1 expression in PDAβPPSwe/Ind transgenic mice resulted in reductions in both Aβ1-42 and Aβ1- 40, and ICV delivery of netrin-1 to PDAβPPSwe/Ind mice increased sAβPPα, decreased Aβ, and improved working memory. Finally, to support further study of netrin-1's potential as a therapeutic for Alzheimer's disease, pilot gene therapy studies were performed and a netrin mimetic peptide synthesized and tested that, like netrin, can increase sAβPPα and decrease Aβ1-42in vitro. Taken together, these data provide mechanistic insights into Aβ self-amplification and the ability of netrin-1 to disrupt it.

Neuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly. - Malek-Ahmadi, Michael; Perez, Sylvia E; Chen, Kewei; Mufson, Elliott J (J Alzheimers Dis, 2016)
The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ4 status, and Braak stage are taken into consideration.

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

Neurophysiological assessment of Alzheimer's disease individuals by a single electroencephalographic marker. - Lizio, Roberta; Del Percio, Claudio; Marzano, Nicola; Soricelli, Andrea; Yener, Görsev G; Başar, Erol; Mundi, Ciro; De Rosa, Salvatore; Triggiani, Antonio Ivano; Ferri, Raffaele; Arnaldi, Dario; Nobili, Flavio Mariano; et al. (J Alzheimers Dis, 2016)
Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.
Keywords: Aged; Alzheimer Disease; Biomarkers; Brain Mapping; Case-Control Studies; Cognition Disorders; Electroencephalography; Female; Humans; Italy; Magnetic Resonance Imaging; Male; Middle Aged; Occipital Lobe; Rest; ROC Curve; Turkey

Non Fluent Variant of Primary Progressive Aphasia Due to the Novel GRN g.9543delA(IVS3-2delA) Mutation. - Cioffi, Sara M G; Galimberti, Daniela; Barocco, Federica; Spallazzi, Marco; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina; Gardini, Simona; Scarpini, Elio; Caffarra, Paolo (J Alzheimers Dis, 2016)
Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN. Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

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

A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy. - Sassi, Celeste; Capozzo, Rosa; Gibbs, Raphael; Crews, Cynthia; Zecca, Chiara; Arcuti, Simona; Copetti, Massimiliano; Barulli, Maria R; Brescia, Vincenzo; Singleton, Andrew B; Logroscino, Giancarlo (J Alzheimers Dis, 2016)
Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

N-Terminal Pro-B-Type Natriuretic Peptide and Risk of Future Cognitive Impairment in the REGARDS Cohort. - Cushman, Mary; Callas, Peter W; McClure, Leslie A; Unverzagt, Frederick W; Howard, Virginia J; Gillett, Sarah R; Thacker, Evan L; Wadley, Virginia G (J Alzheimers Dis, 2016)
BACKGROUND: Improved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people. OBJECTIVE: To study the association of NT-proBNP with risk of incident cognitive impairment. METHODS: The Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up. RESULTS: Adjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33 pg/ml) had a 1.69-fold increased odds (95% CI 1.11-2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele. CONCLUSION: Higher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimer's disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction.

Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. - Sanders, Chelsea; Behrens, Stephanie; Schwartz, Sarah; Wengreen, Heidi; Corcoran, Chris D; Lyketsos, Constantine G; Tschanz, JoAnn T (J Alzheimers Dis, 2016)
Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β= 0.22, p = 0.017; mMNA by time2 β= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.
Keywords: Age of Onset; Aged, 80 and over; Alzheimer Disease; Dementia, Vascular; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Mental Status Schedule; Nutritional Status; Severity of Illness Index; Sex Factors; Utah

An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid-β Accumulation and Amyloid-β-Mediated Pathology in AβPP/PS1 Double-Transgenic Mice. - Lim, Soonmin; Choi, Jin Gyu; Moon, Minho; Kim, Hyo Geun; Lee, Wonil; Bak, Hyoung-Rok; Sung, Hachang; Park, Chi Hye; Kim, Sun Yeou; Oh, Myung Sook (J Alzheimers Dis, 2016)
The progressive aggregation of amyloid-β protein (Aβ) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aβ accumulation and memory impairment in amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 μg/ml OCGP inhibited Aβ accumulation to the same extent as did 10 μM curcumin. Furthermore, AβPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Aβ plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aβ accumulation and inflammation in the brain.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Ginger; Glial Fibrillary Acidic Protein; Humans; Male; Mice; Mice, Transgenic; Mutation; Paeonia; Phytotherapy; Plant Preparations; Plaque, Amyloid; Presenilin-1

Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes. - Vanderstichele, Hugo Marcel Johan; Janelidze, Shorena; Demeyer, Leentje; Coart, Els; Stoops, Erik; Herbst, Victor; Mauroo, Kimberley; Brix, Britta; Hansson, Oskar (J Alzheimers Dis, 2016)
BACKGROUND: Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimer's disease (AD). OBJECTIVE: To qualify the use of Aβ1-42/Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis. METHODS: Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models. RESULTS: Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42/Aβ1-40 ratio, in contrast to Aβ1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. 'Low binding' tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay. CONCLUSION: The ratio of Aβ1-42/Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, 'low binding' recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42/Aβ1-40 ratio and 'low-binding tubes' into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.

Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls. - Cestari, José Augusto Ferrari; Fabri, Gisele Maria Campos; Kalil, Jorge; Nitrini, Ricardo; Jacob-Filho, Wilson; de Siqueira, José Tadeu Tesseroli; Siqueira, Silvia Regina D T (J Alzheimers Dis, 2016)
BACKGROUND: Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer's disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. OBJECTIVE: The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α, and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. METHODS: Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. RESULTS: Patients with AD had high serum IL-6 levels (p = 0.029), and patients with periodontitis had high serum TNF-α levels (p = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p = 0.023). CONCLUSION: The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation.

The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. - Banerjee, Priyanjalee; Sahoo, Arghyadip; Anand, Shruti; Bir, Aritri; Chakrabarti, Sasanka (J Alzheimers Dis, 2016)
The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.
Keywords: Administration, Oral; Aging; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Benzoates; Brain; Ferritins; Gene Expression Regulation; Iron; Iron Chelating Agents; Neprilysin; NF-kappa B; Oxidative Stress; Peptide Fragments; Protein Carbonylation; Rats; Rats, Wistar; Receptors, Transferrin; Spectrophotometry; Triazoles

Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease. - Manso, Yasmina; Comes, Gemma; López-Ramos, Juan C; Belfiore, Mónica; Molinero, Amalia; Giralt, Mercedes; Carrasco, Javier; Adlard, Paul A; Bush, Ashley I; Delgado-García, José María; Hidalgo, Juan (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.
Keywords: Age Factors; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anxiety; Disease Models, Animal; Exploratory Behavior; Female; Gene Expression Regulation; Humans; Male; Matrix Metalloproteinase 16; Maze Learning; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Phenotype; Psychomotor Disorders

Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. - Malara, Alba; De Biase, Giuseppe Andrea; Bettarini, Francesco; Ceravolo, Francesco; Di Cello, Serena; Garo, Michele; Praino, Francesco; Settembrini, Vincenzo; Sgrò, Giovanni; Spadea, Fausto; Rispoli, Vincenzo (J Alzheimers Dis, 2016)
BACKGROUND: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD). OBJECTIVE: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD. METHODS: A prospective observational study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI). RESULTS: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p = 0.0113), as well as by single items of NPI, such as anxiety (p = 0.0362) and irritability (p = 0.0034), and F1 profile (Aggression) of CMAI (p = 0.01). CONCLUSION: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia.
Keywords: Affect; Aged, 80 and over; Analgesics; Anxiety; Dementia; Depression; Female; Humans; Italy; Logistic Models; Long-Term Care; Male; Multivariate Analysis; Nursing Homes; Pain; Pain Measurement; Prevalence; Prospective Studies; Psychiatric Status Rating Scales; Self Report; Severity of Illness Index

Paired Studies Comparing Clinical Profiles of Lewy Body Dementia with Alzheimer's and Parkinson's Diseases. - Scharre, Douglas W; Chang, Shu-Ing; Nagaraja, Haikady N; Park, Ariane; Adeli, Anahita; Agrawal, Punit; Kloos, Anne; Kegelmeyer, Deb; Linder, Shannon; Fritz, Nora; Kostyk, Sandra K; Kataki, Maria (J Alzheimers Dis, 2016)
Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson's disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer's Disease. - Deng, Yulei; Wei, Jing; Cheng, Jia; Zhong, Ping; Xiong, Zhe; Liu, Aiyi; Lin, Lin; Chen, Shengdi; Yan, Zhen (J Alzheimers Dis, 2016)
The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer's disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD.

Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique. - Fernández, Gerardo; Manes, Facundo; Politi, Luis E; Orozco, David; Schumacher, Marcela; Castro, Liliana; Agamennoni, Osvaldo; Rotstein, Nora P (J Alzheimers Dis, 2016)
Patients with Alzheimer's disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences. The cloze predictability of words N - 1, and N + 1 exerted an influence on the reader's gaze duration. The predictabilities of preceding words in high-predictable sentences served as task-appropriate cues that were used by Control readers. In contrast, these effects were not present in AD patients. In Controls, changes in predictability significantly affected fixation duration along the sentence; noteworthy, these changes did not affect fixation durations in AD patients. Hence, only in healthy readers did predictability of upcoming words influence fixation durations via memory retrieval. Our results suggest that Controls used stored information of familiar texts for enhancing their reading performance and imply that contextual-word predictability, whose processing is proposed to require memory retrieval, only affected reading behavior in healthy subjects. In AD patients, this loss reveals impairments in brain areas such as those corresponding to working memory and memory retrieval. These findings might be relevant for expanding the options for the early detection and monitoring in the early stages of AD. Furthermore, evaluation of eye movements during reading could provide a new tool for measuring drug impact on patients' behavior.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Eye Movements; Female; Humans; Linear Models; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Mental Recall; Mental Status Schedule; Predictive Value of Tests; Semantics; Verbal Learning

Pauses During Autobiographical Discourse Reflect Episodic Memory Processes in Early Alzheimer's Disease. - Pistono, Aurélie; Jucla, Mélanie; Barbeau, Emmanuel J; Saint-Aubert, Laure; Lemesle, Béatrice; Calvet, Benjamin; Köpke, Barbara; Puel, Michèle; Pariente, Jérémie (J Alzheimers Dis, 2016)
There is a large body of research on discourse production in Alzheimer's disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients' episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Brain; Female; Humans; Male; Memory Disorders; Memory, Episodic; Mental Status Schedule; Neuropsychological Tests; Positron-Emission Tomography; Statistics as Topic

Performance Evaluation of an Automated ELISA System for Alzheimer's Disease Detection in Clinical Routine. - Chiasserini, Davide; Biscetti, Leonardo; Farotti, Lucia; Eusebi, Paolo; Salvadori, Nicola; Lisetti, Viviana; Baschieri, Francesca; Chipi, Elena; Frattini, Giulia; Stoops, Erik; Vanderstichele, Hugo; Calabresi, Paolo; et al. (J Alzheimers Dis, 2016)
The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

Performance on Specific Cognitive Domains and Cause of Death: A Prospective Population-Based Study in Non-Demented Older Adults (NEDICES). - Benito-León, Julián; Contador, Israel; Mitchell, Alex J; Domingo-Santos, Ángela; Bermejo-Pareja, Félix (J Alzheimers Dis, 2016)
Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox's proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01-10.7), after which the death certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01-10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p = 0.03); 1.22 (semantic fluency, p = 0.04), 1.32 (delayed free recall, p = 0.003), and 1.23 (delayed logical memory, p = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality.
Keywords: Aged; Cause of Death; Cerebrovascular Disorders; Cognitive Aging; Dementia; Educational Status; Female; Follow-Up Studies; Humans; Intelligence; Longitudinal Studies; Male; Neuropsychological Tests; Prospective Studies; Risk; Spain

Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease. - Tajeddinn, Walid; Persson, Torbjörn; Calvo-Garrido, Javier; Seed Ahmed, Mohammed; Maioli, Silvia; Vijayaraghavan, Swetha; Kazokoglu, Mehmet Selim; Parrado-Fernández, Cristina; Yoshitake, Takashi; Kehr, Jan; Francis, Paul; Winblad, Bengt; et al. (J Alzheimers Dis, 2016)
Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. - Lozano, Andres M; Fosdick, Lisa; Chakravarty, M Mallar; Leoutsakos, Jeannie-Marie; Munro, Cynthia; Oh, Esther; Drake, Kristen E; Lyman, Christopher H; Rosenberg, Paul B; Anderson, William S; Tang-Wai, David F; Pendergrass, Jo Cara; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. OBJECTIVE: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD). METHODS: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. RESULTS: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients  CONCLUSION: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer's Disease. - Malpas, Charles B; Vivash, Lucy; Genc, Sila; Saling, Michael M; Desmond, Patricia; Steward, Christopher; Hicks, Rodney J; Callahan, Jason; Brodtmann, Amy; Collins, Steven; Macfarlane, Stephen; Corcoran, Niall M; et al. (J Alzheimers Dis, 2016)
BACKGROUND: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer's disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain. OBJECTIVE: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials. METHODS: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14-26) were randomized to supranutritional (VEL015 10 mg tds [n = 20]) and control (VEL015 320μg tds [n = 10] or placebo [n = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42). RESULTS: Thirty-six (90%; [supranutritional n = 18, control/placebo n = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p < 0.05). CONCLUSION: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.

PiB-PET Imaging-Based Serum Proteome Profiles Predict Mild Cognitive Impairment and Alzheimer's Disease. - Kang, Seokjo; Jeong, Hyobin; Baek, Je-Hyun; Lee, Seung-Jin; Han, Sun-Ho; Cho, Hyun Jin; Kim, Hee; Hong, Hyun Seok; Kim, Young Ho; Yi, Eugene C; Seo, Sang Won; Na, Duk L; et al. (J Alzheimers Dis, 2016)
Development of a simple, non-invasive early diagnosis platform of Alzheimer's disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD.

A Pilot Study Measuring Aluminum in Bone in Alzheimer's Disease and control Subjects Using in vivo Neutron Activation Analysis. - Mohseni, Hedieh K; Cowan, David; Chettle, David R; Milić, Ana Pejović; Priest, Nicholas; Matysiak, Witold; Atanackovic, Jovica; Byun, Soo Hyun; Prestwich, William V (J Alzheimers Dis, 2016)
Aluminum, being the most abundant metal in the earth's crust, is widely distributed in the environment, and is routinely taken up by the human body through ingestion and inhalation. Aluminum is not considered an essential element and it can be toxic in high concentrations. Most of the body burden of aluminum is stored in the bones. Aluminum has been postulated to be involved in the causality of Alzheimer's disease. A system for non-invasive measurement of bone aluminum using the in vivo neutron activation analysis technique has been developed and previously reported in the literature by our group. The results are reported as ratio of Al to Ca in order to eliminate the variations in beam parameters and geometry as well as the physical variations among the subjects such as size of the hand and bone structure. This pilot study included 30 subjects, 15 diagnosed with Alzheimer's disease in mild and moderate stages and 15 control subjects, all of whom were 60 years of age or older. The mean value of aluminum for the control group was 2.7±8.2μg Al/g Ca (inverse-variance weighted mean 3.5±0.9μg Al/g Ca) and for the Alzheimer's disease subjects was 12.5±13.1μg Al/g Ca (inverse-variance weighted mean 7.6±0.6μg Al/g Ca). The difference between the mean of the Alzheimer's disease group and the mean of the control group was 9.8±15.9μg Al/g Ca, with a p-value of 0.02. An age-dependent linear increase in bone aluminum concentration was observed for all subjects. The difference in serum aluminum levels between the two groups did not reach significance.

PKC Activation Counteracts ADAM10 Deficit in HuD-Silenced Neuroblastoma Cells. - Marchesi, Nicoletta; Amadio, Marialaura; Colombrita, Claudia; Govoni, Stefano; Ratti, Antonia; Pascale, Alessia (J Alzheimers Dis, 2016)
Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an α-secretase involved in the non-amyloidogenic processing of the amyloid-β protein precursor (AβPP) which leads to the production of the neuroprotective sAβPPα peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells. We also studied the effects of Bryostatin-1, a molecule able to activate nELAV protein cascade. The specific HuD/nELAV gene silencing decreased both nELAV and ADAM10 protein contents; similar results were obtained by Aβ40 treatment in wild-type SH-SY5Y cells. In HuD-silenced cells, the exposure to Bryostatin-1 counteracted both nELAV and ADAM10 proteins downregulation, by restoring nELAV/ADAM10 basal levels. We also found that sAβPPα release, which seemed not to be compromised by Aβ40 challenge or HuD-silencing, was favored by Bryostatin-1. Overall, these findings strongly suggest that a deficiency in nELAV content negatively affects ADAM10 expression and may play a role in neurodegenerative diseases, which may benefit by molecules activating ELAV cascade.

Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study. - Chatterjee, Pratishtha; Lim, Wei L F; Shui, Guanghou; Gupta, Veer B; James, Ian; Fagan, Anne M; Xiong, Chengjie; Sohrabi, Hamid R; Taddei, Kevin; Brown, Belinda M; Benzinger, Tammie; Masters, Colin; et al. (J Alzheimers Dis, 2016)
BACKGROUND AND OBJECTIVE: Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). METHODS: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient. RESULTS: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p <  0.05). CONCLUSION: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.
Keywords: Adult; Alzheimer Disease; Apolipoproteins E; Female; Humans; Linear Models; Male; Middle Aged; Mutation; Phospholipids; Pilot Projects; Presenilin-1; Sphingolipids

Plasma Screening for Progranulin Mutations in Patients with Progressive Supranuclear Palsy and Corticobasal Syndromes. - Galimberti, Daniela; Bertram, Kelly; Formica, Alessandra; Fenoglio, Chiara; Cioffi, Sara M G; Arighi, Andrea; Scarpini, Elio; Colosimo, Carlo (J Alzheimers Dis, 2016)
Progranulin gene (GRN) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas association with progressive supranuclear palsy syndrome (PSPS) is rare. Plasma progranulin levels were evaluated in 34 patients, including 19 with PSPS, 12 with CBS, and 3 with mixed signs, with the purpose to screen for the presence of causal mutations, associated with low levels. We found undetectable levels in a patient with CBS. Sequencing confirmed the presence of the Thr272fs deletion. Progranulin mutation screening is suggested in cases of CBS, even in the absence of positive family history for dementia and/or movement disorders.

The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study. - Luccarini, Ilaria; Pantano, Daniela; Nardiello, Pamela; Cavone, Leonardo; Lapucci, Andrea; Miceli, Caterina; Nediani, Chiara; Berti, Andrea; Stefani, Massimo; Casamenti, Fiorella (J Alzheimers Dis, 2016)
Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-week OLE treatment (50 mg/kg of diet) to 6-month-old TgCRND8 mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24 h with either OLE (100μM) or PARP inhibitors. A significant reduction of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90 min; the latter was slightly attenuated by cell treatment for 24 h with PJ-34 or with OLE. In vitro and in vivo, the OLE-induced reduction of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo, by a decrease of NF-κB and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay.

Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. - Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao; Schneider, Lon S (J Alzheimers Dis, 2016)
BACKGROUND: Many post hoc analyses of clinical trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies. OBJECTIVE: We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status. METHODS: We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers. RESULTS: Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm. CONCLUSIONS: Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions.
Keywords: Alzheimer Disease; Apolipoprotein E4; Clinical Trials as Topic; Cognitive Dysfunction; Data Interpretation, Statistical; Humans; Research Design

Potentially Inappropriate Prescribing Among People with Dementia in Primary Care: A Retrospective Cross-Sectional Study Using the Enhanced Prescribing Database. - Barry, Heather E; Cooper, Janine A; Ryan, Cristín; Passmore, A Peter; Robinson, A Louise; Molloy, Gerard J; Darcy, Carmel M; Buchanan, Hilary; Hughes, Carmel M (J Alzheimers Dis, 2016)
BACKGROUND: Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD). OBJECTIVE: To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender. METHODS: A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013-31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender. RESULTS: The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n = 5564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2- 65.5; n = 4393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2-26.2; n = 1718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6-8.7) and 1.3 (95% CI 1.2-1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy. CONCLUSION: This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy.

Prediction of Progressive Mild Cognitive Impairment by Multi-Modal Neuroimaging Biomarkers. - Xu, Lele; Wu, Xia; Li, Rui; Chen, Kewei; Long, Zhiying; Zhang, Jiacai; Guo, Xiaojuan; Yao, Li (J Alzheimers Dis, 2016)
For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer's disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: Volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET).
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Predictive Value of Tests; Psychiatric Status Rating Scales; Sensitivity and Specificity

Predictive factors for disease progression in patients with early-onset Alzheimer's disease. - Yoon, Bora; Shim, Yong S; Park, Hee-Kyung; Park, Sun Ah; Choi, Seong Hye; Yang, Dong Won (J Alzheimers Dis, 2016)
BACKGROUND: Only a few studies have investigated disease progression in patients with early-onset Alzheimer's disease (EOAD). Therefore, the aim of this study was to investigate disease progression in patients with EOAD and the influence of various factors, such as gender, education, and apolipoprotein E (APOE) genotype on disease progression. METHODS: A total of 288 EOAD patients were enrolled in the study. Linear mixed models were used to investigate the rate of cognitive and functional decline in terms of age at onset, gender, education, follow-up period, and APOE genotype. RESULTS: EOAD patients showed an annual decline of -1.54 points/years in the Korean version mini-mental examination score, an annual increase of 3.46 points/year in the Seoul instrumental activities of daily living (SIADL) score, and an annual increase of 1.15 points/year in the clinical dementia rating scale-sum of boxes score. After stratification, higher educated patients showed faster disease progression in all three parameters, and female patients demonstrated faster disease progression as assessed by the SIADL score. Age at onset and APOE genotype had no influence on disease progression. CONCLUSION: We confirmed the rate of disease progression in Korean patients with EOAD in real-life hospital-based clinical practice. The results of this study suggest that education and female gender, not APOE genotype, may be important as independent strong predictive factors for disease progression in patients with EOAD.
Keywords: Activities of Daily Living; Adult; Age Factors; Aged; Alleles; Alzheimer Disease; Apolipoproteins E; Disease Progression; Female; Genotype; Humans; Linear Models; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Risk Factors; Sex Factors

Predictors of Mortality in Dementia: The PRIME Study. - Connors, Michael H; Ames, David; Boundy, Karyn; Clarnette, Roger; Kurrle, Sue; Mander, Alastair; Ward, John; Woodward, Michael; Brodaty, Henry (J Alzheimers Dis, 2016)
BACKGROUND: Dementia is a terminal illness. While various baseline characteristics of patients, such as age, sex, and dementia severity, are known to predict mortality, little research has examined how changes in patients' symptoms over time predict survival. There are also limited data on patients seen in memory clinics, as opposed to other health care settings, and whether antipsychotic medications are associated with mortality in dementia once patients' demographic and clinical features are controlled for. OBJECTIVE: To identify predictors of mortality in patients with dementia. METHOD: Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Patients completed measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use at baseline and at regular intervals over a three-year period. Mortality data were obtained from state registries eight years after baseline. RESULTS: Overall, 447 (57.4%) of the patients with dementia died within the eight years. Older age, male sex, more severe dementia and functional impairment at baseline, greater decline in dementia severity and functional impairment over six months, taking a larger number of medications, and use of atypical antipsychotic medication predicted earlier mortality. CONCLUSIONS: The findings confirm that demographic and diagnostic features predict the survival of patients with dementia. Importantly, the findings indicate that changes in dementia severity and functional impairment over time predict mortality independently of baseline levels, and provide further evidence for the higher mortality risk of patients taking antipsychotic medications.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. - Stern, Robert A; Tripodis, Yorghos; Baugh, Christine M; Fritts, Nathan G; Martin, Brett M; Chaisson, Christine; Cantu, Robert C; Joyce, James A; Shah, Sahil; Ikezu, Tsuneya; Zhang, Jing; Gercel-Taylor, Cicek; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.
Keywords: Adult; Aged; Analysis of Variance; Case-Control Studies; Chronic Traumatic Encephalopathy; Extracellular Vesicles; Humans; Male; Middle Aged; Plasma; tau Proteins

PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. - Oldoni, Emanuela; Fumagalli, Giorgio G; Serpente, Maria; Fenoglio, Chiara; Scarioni, Marta; Arighi, Andrea; Bruno, Giuseppe; Talarico, Giuseppina; Confaloni, Annamaria; Piscopo, Paola; Nacmias, Benedetta; Sorbi, Sandro; et al. (J Alzheimers Dis, 2016)
The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).
Keywords: Aged; Atrophy; Frontal Lobe; Frontotemporal Dementia; Genetic Predisposition to Disease; Humans; Italy; Language; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Prion Proteins; Prions; Temporal Lobe

Prognostic Significance of Mild Cognitive Impairment Subtypes for Dementia and Mortality: Data from the NEDICES Cohort. - Bermejo-Pareja, Félix; Contador, Israel; Trincado, Rocío; Lora, David; Sánchez-Ferro, Álvaro; Mitchell, Alex J; Boycheva, Elina; Herrero, Alejandro; Hernández-Gallego, Jesús; Llamas, Sara; Villarejo Galende, Alberto; Benito-León, Julián (J Alzheimers Dis, 2016)
BACKGROUND: The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable. OBJECTIVE: To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort. METHODS: Retrospect algorithmic MCI subgroups were established in a non-dementia baseline NEDICES cohort using Spanish adaptations of the original Mini-Mental State Examination (MMSE-37) and Pfeffer's Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries. RESULTS: 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%-31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p >  0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative). CONCLUSIONS: Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials.
Keywords: Aged; Aged, 80 and over; Algorithms; Cognitive Dysfunction; Cohort Studies; Dementia; Female; Humans; Male; Mental Status Schedule; Neuropsychological Tests; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Spain

Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias. - Morenas-Rodriguez, Estrella; Cervera-Carles, Laura; Vilaplana, Eduard; Alcolea, Daniel; Carmona-Iragui, María; Dols-Icardo, Oriol; Ribosa-Nogué, Roser; Muñoz-Llahuna, Laia; Sala, Isabel; Belén Sánchez-Saudinós, M; Blesa, Rafael; Clarimón, Jordi; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. OBJECTIVE: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. METHODS: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. RESULTS: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-β42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. CONCLUSIONS: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Biomarkers; Dementia; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; tau Proteins

Prolonged Visual Facial Grasp in Frontotemporal Dementia. - Paholpak, Pongsatorn; Li-Jung, Liang; Carr, Drew R; Jimenez, Elvira; Barrows, Robin J; Sabodash, Valeiry; Mendez, Mario F (J Alzheimers Dis, 2016)
BACKGROUND: Gaze and eye contact is a critical aspect of social interaction. Patients with behavioral variant frontotemporal dementia (bvFTD) may exhibit abnormally prolonged stare toward human faces. OBJECTIVE: To study characteristics of social gaze in patients with bvFTD compared to age and education matched-patients with early-onset Alzheimer's disease (eAD) and healthy controls (HC). METHOD: Fifty picture stimuli were presented to each participant (bvFTD = 12, eAD = 18, HC = 13). Each stimuli contained two properties: face (facial versus non-facial) and valence (positive, negative, and neutral). The "facial" stimuli contained human faces. The participants Visual Fixation Time (VFT) was measured for each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups. RESULTS: The patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p < 0.01). There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p = 0.006 and 0.019, respectively). CONCLUSION: Patients with bvFTD exhibited a prolonged stare toward human faces. This prolonged visual facial grasp may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer's disease and other conditions. Additionally, both dementia groups tended to stare at negative stimuli whether faces or non-faces.

Promising Role of Neuromodulation in Predicting the Progression of Mild Cognitive Impairment to Dementia. - Naro, Antonino; Corallo, Francesco; De Salvo, Simona; Marra, Angela; Di Lorenzo, Giuseppe; Muscarà, Nunzio; Russo, Margherita; Marino, Silvia; De Luca, Rosaria; Bramanti, Placido; Calabrò, Rocco Salvatore (J Alzheimers Dis, 2016)
The differential diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is not always straightforward, and the rate of progression of MCI to dementia is not negligible. Thus, there is a need for para-clinical approaches that can improve the differential diagnosis and identify patients that are at risk of progression. There is a growing interest, at present, in the role of the deterioration of brain oscillations as a predictor of MCI-to-AD conversion. For this reason, we experimentally modulated γ-band oscillations (GBO) in a sample of MCI and AD patients and an age-matched healthy elderly group, using a transcranial alternating current stimulation (tACS) protocol that was applied to different cortical sites. We correlated the after-effects of tACS on the GBO and the neuropsychological data, in an attempt to differentiate MCI from AD patients and identify, among the MCI patients, those that could be at potential risk of MCI-to-dementia conversion. MCI patients showed a partial GBO increase and improvement in some neuropsychological tests whereas AD individuals did not show significant tACS after-effects. Notably, some MCI subjects lacked significant neuropsychological and electrophysiological after-effects, similar to AD individuals. In a two-year follow-up, such MCI individuals had converted into AD. Therefore, our data suggest that tACS may support the clinical differential diagnosis of MCI and AD and identify MCI patients who could be at risk of developing dementia. This prediction index may help the clinician to adopt a better prevention/follow-up strategy in such a disabling neurodegenerative disease.

Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. - Rosenberger, Andrea F N; Hilhorst, Riet; Coart, Elisabeth; García Barrado, Leandro; Naji, Faris; Rozemuller, Annemieke J M; van der Flier, Wiesje M; Scheltens, Philip; Hoozemans, Jeroen J M; van der Vies, Saskia M (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cohort Studies; Female; Hippocampus; Humans; Male; Middle Aged; Phosphorylation; Protein Kinases; Protein-Serine-Threonine Kinases; Severity of Illness Index

Puerarin Ameliorates D-Galactose Induced Enhanced Hippocampal Neurogenesis and Tau Hyperphosphorylation in Rat Brain. - Hong, Xiao-Ping; Chen, Tao; Yin, Ni-Na; Han, Yong-Ming; Yuan, Fang; Duan, Yan-Jun; Shen, Feng; Zhang, Yan-Hong; Chen, Ze-Bin (J Alzheimers Dis, 2016)
Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer's disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus of D-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD.
Keywords: Animals; Cognition Disorders; Disease Models, Animal; Fibroblast Growth Factor 2; Galactose; Glycogen Synthase Kinase 3; Hippocampus; Isoflavones; Male; Maze Learning; Neurogenesis; Neurons; Neuroprotective Agents; Phosphorylation; Random Allocation; Rats, Sprague-Dawley; Signal Transduction; Spatial Memory; tau Proteins

Quantitative phosphoproteomic analyses of the inferior parietal lobule from three different pathological stages of Alzheimer's disease. - Triplett, Judy C; Swomley, Aaron M; Cai, Jian; Klein, Jon B; Butterfield, D Allan (J Alzheimers Dis, 2016)
Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is clinically characterized by progressive neuronal loss resulting in loss of memory and dementia. AD is histopathologically characterized by the extensive distribution of senile plaques and neurofibrillary tangles, and synapse loss. Amnestic mild cognitive impairment (MCI) is generally accepted to be an early stage of AD. MCI subjects have pathology and symptoms that fall on the scale intermediately between 'normal' cognition with little or no pathology and AD. A rare number of individuals, who exhibit normal cognition on psychometric tests but whose brains show widespread postmortem AD pathology, are classified as 'asymptomatic' or 'preclinical' AD (PCAD). In this study, we evaluated changes in protein phosphorylation states in the inferior parietal lobule of subjects with AD, MCI, PCAD, and control brain using a 2-D PAGE proteomics approach in conjunction with Pro-Q Diamond phosphoprotein staining. Statistically significant changes in phosphorylation levels were found in 19 proteins involved in energy metabolism, neuronal plasticity, signal transduction, and oxidative stress response. Changes in the disease state phosphoproteome may provide insights into underlying mechanisms for the preservation of memory with expansive AD pathology in PCAD and the progressive memory loss in amnestic MCI that escalates to the dementia and the characteristic pathology of AD brain.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Disease Progression; Female; Humans; Male; Memory; Neurofibrillary Tangles; Oxidative Stress; Parietal Lobe; Phosphorylation; Plaque, Amyloid; Proteome

Reduction of Amyloid-β Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy? - Tholen, Susanne; Schmaderer, Christoph; Chmielewski, Stefan; Förstl, Hans; Heemann, Uwe; Baumann, Marcus; Steubl, Dominik; Grimmer, Timo (J Alzheimers Dis, 2016)
BACKGROUND: Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ). OBJECTIVE: To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients. METHODS: Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously. RESULTS: Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001). CONCLUSION: In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.
Keywords: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognition Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Renal Dialysis

Reduction of Blood Amyloid-β Oligomers in Alzheimer's Disease Transgenic Mice by c-Abl Kinase Inhibition. - Estrada, Lisbell D; Chamorro, David; Yañez, María José; Gonzalez, Marcelo; Leal, Nancy; von Bernhardi, Rommy; Dulcey, Andrés E; Marugan, Juan; Ferrer, Marc; Soto, Claudio; Zanlungo, Silvana; Inestrosa, Nibaldo C; et al. (J Alzheimers Dis, 2016)
One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates.

Reelin in Alzheimer's Disease, Increased Levels but Impaired Signaling: When More is Less. - Cuchillo-Ibañez, Inmaculada; Balmaceda, Valeria; Mata-Balaguer, Trinidad; Lopez-Font, Inmaculada; Sáez-Valero, Javier (J Alzheimers Dis, 2016)
In the continuing search for proteins that play a role in Alzheimer's disease (AD) and that are related to the pathological hallmarks, those that influence cognitive function and that constitute potential therapeutic targets deserve special interest. Reelin is a signaling protein that is involved in a cascade of cytoplasmic events that control tau phosphorylation and that regulate synaptic neurotransmission, plasticity, and memory. Both Reelin expression and glycosylation are modulated by amyloid-β (Aβ), suggesting that the activity of Reelin could be affected in AD and hence, its possible influence on this pathology should be taken into consideration. The levels of Reelin in the brain of AD patients appear to be altered and interestingly, disrupted Reelin signaling is associated with increased tau phosphorylation as well as with amyloid-β protein precursor processing. We discuss here the somewhat contradictory data regarding Reelin levels in AD and we evaluate the processing of the Reelin receptor, ApoER2, and other downstream events, such as the phosphorylation of the intracellular adapter Dab1. Together with brain Reelin levels, these changes may represent a relevant read-out of Reelin signaling in the human brain.

Relative Alterations in Blood-Based Levels of Sestrin in Alzheimer's Disease and Mild Cognitive Impairment Patients. - Rai, Nitish; Kumar, Rahul; Desai, Gaurav Rajesh; Venugopalan, G; Shekhar, Shashank; Chatterjee, Prasun; Tripathi, Manjari; Upadhyay, Ashish Datt; Dwivedi, Sadanand; Dey, Aparajit B; Dey, Sharmistha (J Alzheimers Dis, 2016)
Sestrins (sesn) are highly conserved proteins that play an important neuroprotective role, in part as a consequence of their antioxidative capacity, which prevents reactive oxygen species formation. In this study, we evaluated the concentrations of sesn1 and sesn2 in the serum of 41 Alzheimer's disease (AD) patients, 27 mild cognitive impairment (MCI), and 60 elderly controls, by surface plasmon resonance, which was validated by using western blot. Moreover, the mRNA level of sestrins in all the study groups was determined by real time polymerase chain reaction. The results showed significant overexpression of serum sesn2 protein and mRNA levels in the AD group compared to MCI and elderly control groups. A difference in serum sesn2 concentration between MCI and the control group was also evident. ROC analysis showed highly sensitive, selective cutoff values for sens2 in the differentiation of AD, MCI, and controls. No significant difference in sesn1 level was observed among the study groups. This study highlights the important role of sesn2 in the progression of the AD, indicating its potential utility as a protein marker in this devastating disease.

Reproductive history and risk of cognitive impairment in elderly women: a cross-sectional study in eastern China. - Li, Fu-Dong; He, Fan; Chen, Ting-Rui; Xiao, Yuan-Yuan; Lin, Shang-Tong; Shen, Wei; Wang, Xin-Yi; Zhai, Yu-Jia; Shang, Xiao-Peng; Lin, Jun-Fen (J Alzheimers Dis, 2016)
BACKGROUND: Epidemiological studies suggest that proxies of higher lifetime estrogen exposure are associated with better cognitive function in postmenopausal women, but this has not been found consistently. OBJECTIVE: To determine whether reproductive history, an important modifier of estrogen exposure across the lifetime, is associated with risk of cognitive impairment in postmenopausal women. METHODS: We analyzed the baseline data from Zhejiang Major Public Health Surveillance Program (ZPHS) including 4,796 postmenopausal women. Cognitive impairment was assessed through the application of Mini-Mental State Examination questionnaire. Logistic regression models, controlled for an extensive range of potential confounders, were generated to examine the associations between women's reproductive history and risk of cognitive impairment in their later life. RESULTS: The length of reproductive period was inversely associated with risk of cognitive impairment (p = 0.001). Odds ratio (OR) of cognitive impairment were 1.316 (95% CI 1.095∼1.582) for women with 5 or more times of full-term pregnancies, compared with those with 1∼4 times of full-term pregnancies. Women without incomplete pregnancy had a significant higher risk of cognitive impairment (OR = 1.194, 95% CI 1.000∼1.429), compared with the reference (1∼2 times of incomplete pregnancies). Oral contraceptive use (OR = 0.489, 95% CI 0.263∼0.910) and intrauterine device (IUD) use (OR = 0.684, 95% CI 0.575∼0.815) were associated with significantly reduced risk of cognitive impairment. CONCLUSION: Our results indicated that shorter reproductive period, higher number of full-term pregnancies and no incomplete pregnancy history were associated with an increased risk of cognitive impairment. In contrast, oral contraceptive and IUD use corresponded to reduced risk of cognitive impairment.
Keywords: Aged; Aged, 80 and over; China; Cognition; Cognition Disorders; Contraceptives, Oral; Cross-Sectional Studies; Estrogens; Female; Humans; Intrauterine Devices; Logistic Models; Middle Aged; Neuropsychological Tests; Odds Ratio; Postmenopause; Psychiatric Status Rating Scales; Reproductive History

Reversal of LTP-Like Cortical Plasticity in Alzheimer's Disease Patients with Tau-Related Faster Clinical Progression. - Koch, Giacomo; Di Lorenzo, Francesco; Del Olmo, Miguel Fernandez; Bonní, Sonia; Ponzo, Viviana; Caltagirone, Carlo; Bozzali, Marco; Martorana, Alessandro (J Alzheimers Dis, 2016)
Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Cognition; Disease Progression; Evoked Potentials, Motor; Female; Humans; Male; Motor Cortex; Neuronal Plasticity; Neuropsychological Tests; Phosphorylation; tau Proteins; Transcranial Magnetic Stimulation

Reversible Mild Cognitive Impairment: The Role of Comorbidities at Baseline Evaluation. - Grande, Giulia; Cucumo, Valentina; Cova, Ilaria; Ghiretti, Roberta; Maggiore, Laura; Lacorte, Eleonora; Galimberti, Daniela; Scarpini, Elio; Clerici, Francesca; Pomati, Simone; Vanacore, Nicola; Mariani, Claudio (J Alzheimers Dis, 2016)
The prognostic value of mild cognitive impairment (MCI) is being questioned, with some MCI subjects reverting to normal cognition (NC). The reversion rate varies mostly depending on the study design, the setting, and both MCI and NC definitions. Previous studies have focused on the profile of subjects who revert to NC, but the role of comorbidities has not been entirely investigated. We aimed to evaluate the proportion of MCI subjects who revert to NC in a memory clinic context, focusing on the role of comorbidities. Between 2004 and 2013, 374 MCI subjects were recruited. During a mean time of 32 ± 25.5 months, 21 subjects (5.6%) reverted to NC. Subjects who reverted to NC were younger (p = 0.0001), more educated (p = 0.0001), had a better global cognition (p = 0.0001), as assessed by the Mini-Mental State Examination (MMSE) and suffered from more comorbidities (p = 0.002), as assessed by Cumulative Illness Rating Scale (CIRS) than those who developed dementia. The Cox Regression Model, constructed to adjust for the confounders, showed that the higher were the MMSE (HR = 1.83, CI 95%: 1.07-3.11) and the CIRS score (HR = 1.3, CI 95% 0.88-1.92) at baseline, the higher was the probability of returning to NC than developing dementia, though the last association was not significant. Subjects who reverted to NC were more frequently affected by respiratory (p = 0.002), urologic (p = 0.012), and psychiatric (p = 0.012) diseases. The cognitive performance of subjects with medical comorbidities could benefit from preventive strategies aimed at treating the underlying diseases.
Keywords: Analysis of Variance; Cognitive Dysfunction; Cohort Studies; Comorbidity; Female; Humans; Male; Memory; Mental Status Schedule; Neuropsychological Tests; Reference Values; Verbal Learning

Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings. - Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero (J Alzheimers Dis, 2016)
The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).
Keywords: Aged; Aged, 80 and over; Brain; Creutzfeldt-Jakob Syndrome; Female; Genotype; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phenotype; Prions

The Role of Cerebrovascular Disease in Amyloid Deposition. - Noh, Young; Seo, Sang Won; Jeon, Seun; Lee, Jong Min; Kim, Jae Seung; Lee, Jae-Hong; Kim, Jung-Hyun; Kim, Geon Ha; Ye, Byoung Seok; Cho, Hanna; Kim, Hee Jin; Yoon, Cindy W; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Some patients clinically diagnosed with subcortical vascular cognitive impairment (SVCI) have co-morbidity with AD pathology. OBJECTIVE: We investigated topographical differences in amyloid burden between SVCI and Alzheimer's disease type cognitive impairment (ADCI) using [11C] Pittsburgh compound B (PiB) positron emission tomography (PET). The purpose of this study was to investigate the role of cerebrovascular disease (CVD) in amyloid deposition. METHODS: We recruited 44 patients with SVCI and 44 patients with ADCI (amnestic mild cognitive impairment or Alzheimer's disease) with absent or minimal white matter hyperintensities, all with PiB-positive PET scans [PiB+]. As controls, we included 13 participants with normal cognition and PiB-negative scans. We divided the SVCI and ADCI patients into three groups according to global PiB retention ratio of SVCI, and then compared the tertiles in terms of the distribution of PiB retention using statistical parametric mapping analyses. Lobar to global PiB retention ratio and asymmetry indices were also compared between SVCI and ADCI groupsResults: Compared to PiB+ ADCI patients, PiB+ SVCI patients exhibited: 1) increased left-right asymmetry, and increased anterior-posterior difference; and 2) increased PiB retention in the parietal cortex, the occipital cortex and the precuneus-posterior cingulate cortex. In contrast, ADCI patients showed increased PiB retention in the striatum. When stratified by level of PiB retention, each group showed different characteristics. CONCLUSION: Our results showed that the distribution of amyloid deposition differed between patients with PiB+ SVCI and ADCI. These suggest that CVD contribute to and alter the known progression pattern in amyloid deposition in Alzheimer's disease.

The Role of Ethnicity in Alzheimer's Disease: Findings From The C-PATH Online Data Repository. - Chen, Huei-Yang; Panegyres, Peter K (J Alzheimers Dis, 2016)
BACKGROUND: Ethnic minorities seem to be at an increased risk of Alzheimer's disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD). OBJECTIVE: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression. METHODS: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities--including Native Alaskans, Americans, and Hawaiians. RESULTS: Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p <  0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2-3.5) were significantly higher, compared with Caucasians. CONCLUSIONS: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.
Keywords: African Americans; Age Factors; Aged; Alaska Natives; Alzheimer Disease; Apolipoproteins E; Asian Continental Ancestry Group; Clinical Trials as Topic; Comorbidity; Databases, Factual; European Continental Ancestry Group; Female; Hispanic Americans; Humans; Indians, North American; Internet; Logistic Models; Male; Oceanic Ancestry Group; Risk; Sex Factors

The Savvy Caregiver Program: A Probe Multicenter Randomized Controlled Pilot Trial in Caregivers of Patients Affected by Alzheimer's Disease. - Sepe-Monti, Micaela; Vanacore, Nicola; Bartorelli, Luisa; Tognetti, Alessandra; Giubilei, Franco (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a major cause of disability in the elderly, leading to a considerable burden on caregivers and high costs to society. Psycho-education programs such as the Savvy Caregiver Program (SCP) are reported to be a successful means of reducing caregivers' distress through various intervention strategies. The aim of the present study was to assess the efficacy of the SCP in reducing the burden and psychological symptoms in caregivers of AD patients and to analyze the coping strategies adopted by the caregivers. The study was designed as a multicenter, randomized, controlled, pilot clinical trial. One hundred and sixty-four caregivers of patients with probable AD were randomized. The SCP was structured in six, weekly, two-hour sessions. All the clinical scales were administered before treatment, two weeks and six months after treatment. Caregivers in the SCP group displayed better coping strategies adopted to positive attitudes, and they tended to be less anxious and less depressed than those in the control group. However, caregiver burden levels were not reduced in SCP caregivers. The patients of SCP caregivers received a lower number of new prescriptions of neuroleptics during the 6 months of follow-up than the patients of control caregivers and apathy was the neuropsychiatric symptom that improved most as a result of the SCP. The results of this study suggest that the SCP may improve coping strategies of caregivers of people affected by AD, influencing their psychological symptoms and those of their patients.

Searching for Primary Predictors of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Multivariate Follow-Up Study. - López, María Eugenia; Turrero, Agustín; Cuesta, Pablo; López-Sanz, David; Bruña, Ricardo; Marcos, Alberto; Gil, Pedro; Yus, Miguel; Barabash, Ana; Cabranes, José Antonio; Maestú, Fernando; Fernández, Alberto (J Alzheimers Dis, 2016)
Recent proposals of diagnostic criteria within the healthy aging-Alzheimer's disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The "stable" MCI group (sMCI, 21 subjects) and the "progressive" MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as "first order" predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role.

Self-Perceived Quality of Life Among Patients with Alzheimer's Disease: Two Longitudinal Models of Analysis. - Conde-Sala, Josep L; Turró-Garriga, Oriol; Portellano-Ortiz, Cristina; Viñas-Diez, Vanesa; Gascón-Bayarri, Jordi; Reñé-Ramírez, Ramón (J Alzheimers Dis, 2016)
The objective was to analyze the factors that influence self-perceived quality of life (QoL) in patients with Alzheimer's disease (AD), contrasting two different longitudinal models. A total of 127 patients were followed up over 24 months. The instruments applied were: Quality of Life in Alzheimer's Disease scale (QoL-AD), Geriatric Depression Scale-15, Anosognosia Questionnaire-Dementia, Disability Assessment in Dementia, Neuropsychiatric Inventory, and the Mini-Mental State Examination. Two models for grouping patients were tested: 1) Baseline score on the QoL-AD (QoL-Baseline), and 2) Difference in QoL-AD score between baseline and follow-up (QoL-Change). Generalized estimating equations were used to analyze longitudinal data, and multinomial regression analyses were performed. Over the follow-up period the QoL-Baseline model showed greater variability between groups (Wald χ2 = 172.3, p < 0.001) than did the QoL-Change model (Wald χ2  = 1.7, p = 0.427). In the QoL-Baseline model the predictive factors were greater depression (odds ratio [OR] = 1.20; 95% CI: 1.00- 1.45) and lower functional ability (OR = 0.92; 95% CI: 0.85- 0.99) for the Low QoL group (< 33 QoL-AD), and less depression (OR = 0.68; 95% CI: 0.52- 0.88), more anosognosia (OR = 1.07; 95% CI: 1.01- 1.13), and fewer neuropsychiatric symptoms (OR = 0.95; 95% CI: 0.91- 0.99) for the High-QoL group (>37 QoL-AD). The model based on baseline scores (QoL-Baseline) was better than the QoL-Change model in terms of identifying trajectories and predictors of QoL in AD.

Self-Reported Traumatic Brain Injury and Mild Cognitive Impairment: Increased Risk and Earlier Age of Diagnosis. - LoBue, Christian; Denney, David; Hynan, Linda S; Rossetti, Heidi C; Lacritz, Laura H; Hart, John; Womack, Kyle B; Woon, Fu L; Cullum, C Munro (J Alzheimers Dis, 2016)
This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n = 3,187) and normal cognition (n = 3,244) were obtained from the National Alzheimer's Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ɛ4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated age of onset differed between those with (TBI+) and without (TBI-) a history of TBI. TBI history was a significant predictor (p <  0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI = 1.05-1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10-1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94-1.37; p = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p <  0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation.
Keywords: Age of Onset; Aged; Apolipoproteins E; Brain Injuries, Traumatic; Cognitive Dysfunction; Cohort Studies; Databases, Factual; Depression; Educational Status; Female; Humans; Logistic Models; Male; Risk Factors; Self Report; United States

Serum Uric Acid and Its Association with Longitudinal Cognitive Change Among Urban Adults. - Beydoun, May A; Canas, Jose-Atilio; Dore, Gregory A; Beydoun, Hind A; Rostant, Ola S; Fanelli-Kuczmarski, Marie T; Evans, Michele K; Zonderman, Alan B (J Alzheimers Dis, 2016)
Uric acid, a waste metabolite among humans, was linked to various cognitive outcomes. We describe sex and age-group specific associations of baseline serum uric acid (SUAbase) and significant change in SUA (ΔSUA: 1 versus 0 = decrease versus no change; 2 versus 0 = increase versus no change) with longitudinal annual rate of cognitive change among a large sample of urban adults. Data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2004-2009 (visit 1) and 2009-2013 (visit 2) were used. Of 3,720 adults selected at baseline (age range: 30-64 y), complete data were available for N = 1,487-1,602 with a mean repeat of 1.5-1.7 visits/participant. Cognitive test domains spanned attention, processing speed, learning/memory, executive function, visuo-spatial/visuo-construction ability, language/verbal, and global cognitive function. SUA was measured at both visits. Multiple mixed-effects regression analyses were conducted. In the total population, a higher SUAbase was associated with a faster annual rate of decline on a measure of visual memory/visuo-construction ability (the Benton Visual Retention Test) by γ= 0.07 with a standard error of 0.02, p < 0.001. Among older men, a significant increase in SUA was associated with slower decline on a test of attention/processing speed, namely Trailmaking test, Part A, measured in seconds to completion (γ= -6.91 ± 1.73, p < 0.001). In sum, a higher SUAbase was associated with faster cognitive decline over-time in a visual memory/visuo-construction ability test. ΔSUA had particular beneficial effects of an increasing ΔSUA on the domain of attention/processing speed among older men. More longitudinal studies are needed to examine cognitive domain-specific effects of over-time change in SUA within sex and age groups.

Shared Genetic Etiology between Type 2 Diabetes and Alzheimer's Disease Identified by Bioinformatics Analysis. - Gao, Lei; Cui, Zhen; Shen, Liang; Ji, Hong-Fang (J Alzheimers Dis, 2016)
Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs), gene, and pathway levels, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD.
Keywords: Alzheimer Disease; Apolipoprotein C-I; Computational Biology; Databases, Factual; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Lipid Metabolism; Male; Polymorphism, Single Nucleotide

Short-Term Effects of Rhythmic Sensory Stimulation in Alzheimer's Disease: An Exploratory Pilot Study. - Clements-Cortes, Amy; Ahonen, Heidi; Evans, Michael; Freedman, Morris; Bartel, Lee (J Alzheimers Dis, 2016)
This study assessed the effect of stimulating the somatosensory system of Alzheimer's disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.

Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer's Disease Mouse Models. - Biella, Gloria; Fusco, Federica; Nardo, Emanuele; Bernocchi, Ottavia; Colombo, Alessio; Lichtenthaler, Stefan F; Forloni, Gianluigi; Albani, Diego (J Alzheimers Dis, 2016)
The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.

The Societal Cost of Dementia in Singapore: Results from the WiSE Study. - Abdin, Edimansyah; Subramaniam, Mythily; Achilla, Evanthia; Chong, Siow Ann; Vaingankar, Janhavi Ajit; Picco, Louisa; Sambasivam, Rajeswari; Pang, Shirlene; Chua, Boon Yiang; Ng, Li Ling; Chua, Hong Choon; Heng, Derrick; et al. (J Alzheimers Dis, 2016)
BACKGROUND: There is currently limited evidence on the economic burden that dementia exerts on multi-ethnic Asian populations. OBJECTIVE: The present study aimed to estimate the economic cost of dementia in Singapore. METHODS: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above. Generalized linear modeling was used to estimate factors associated with costs. RESULTS: The total cost of dementia in 2013 was estimated at S$532 million (95% CI, S$361 million to S$701 million) while the annual cost per person was estimated at S$10,245 per year (95% CI, S$6,954 to S$12,495). Apart from dementia, higher total societal cost were also significantly associated with older age, Indian ethnicity, and those who were diagnosed with heart problems, stroke, diabetes or depression, whereas being divorced/separated, lower education, and those who were diagnosed with hypertension were significantly associated with lower total societal cost. CONCLUSION: The study provides a rich body of information on healthcare utilization and cost of dementia, which is essential for future planning of services for the elderly population.
Keywords: Adult; Aged, 80 and over; Cost of Illness; Dementia; Female; Humans; Linear Models; Male; Middle Aged; Singapore

Spatial Memory Impairment is Associated with Intraneural Amyloid-β Immunoreactivity and Dysfunctional Arc Expression in the Hippocampal-CA3 Region of a Transgenic Mouse Model of Alzheimer's Disease. - Morin, Jean-Pascal; Cerón-Solano, Giovanni; Velázquez-Campos, Giovanna; Pacheco-López, Gustavo; Bermúdez-Rattoni, Federico; Díaz-Cintra, Sofía (J Alzheimers Dis, 2016)
Dysfunction of synaptic communication in cortical and hippocampal networks has been suggested as one of the neuropathological hallmarks of the early stages of Alzheimer's disease (AD). Also, several lines of evidence have linked disrupted levels of activity-regulated cytoskeletal associated protein (Arc), an immediate early gene product that plays a central role in synaptic plasticity, with AD "synaptopathy". The mapping of Arc expression patterns in brain networks has been extensively used as a marker of memory-relevant neuronal activity history. Here we evaluated basal and behavior-induced Arc expression in hippocampal networks of the 3xTg-AD mouse model of AD. The basal percentage of Arc-expressing cells in 10-month-old 3xTg-AD mice was higher than wild type in CA3 (4.88% versus 1.77% , respectively) but similar in CA1 (1.75% versus 2.75% ). Noteworthy, this difference was not observed at 3 months of age. Furthermore, although a Morris water maze test probe induced a steep (∼4-fold) increment in the percentage of Arc+ cells in the CA3 region of the 10-month-old wild-type group, no such increment was observed in age-matched 3xTg-AD, whereas the amount of Arc+ cells in CA1 increased in both groups. Further, we detected that CA3 neurons with amyloid-β were much more likely to express Arc protein under basal conditions. We propose that in 3xTg-AD mice, intraneuronal amyloid-β expression in CA3 could increase unspecific neuronal activation and subsequent Arc protein expression, which might impair further memory-stabilizing processes.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Benzeneacetamides; CA3 Region, Hippocampal; Cytoskeletal Proteins; Disease Models, Animal; Gene Expression Regulation; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Neurons; Presenilin-1; Pyridines; tau Proteins

Specific Triazine Herbicides Induce Amyloid-β42 Production. - Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloϊse; Oumata, Nassima; Galons, Hervé; Lee, Jung Yeol; Chang, Young-Tae; Stϋber, Kathrin; et al. (J Alzheimers Dis, 2016)
Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifying products of the 'human chemical exposome' (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD iPSCs-derived neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.

Staging Alzheimer's Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers. - Chen, Guangyu; Shu, Hao; Chen, Gang; Ward, B Douglas; Antuono, Piero G; Zhang, Zhijun; Li, Shi-Jiang (J Alzheimers Dis, 2016)
This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer's disease (AD) on an individual level. We selected 144 subjects from the Alzheimer's Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal). We identified the numerical order of the Soptimal as the characterizing Alzheimer's disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal, hippocampal and posterior cingulate cortex network biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD.

Standardized Uptake Value Ratio-Independent Evaluation of Brain Amyloidosis. - Chincarini, Andrea; Sensi, Francesco; Rei, Luca; Bossert, Irene; Morbelli, Silvia; Guerra, Ugo Paolo; Frisoni, Giovanni; Padovani, Alessandro; Nobili, Flavio (J Alzheimers Dis, 2016)
The assessment of in vivo18F images targeting amyloid deposition is currently carried on by visual rating with an optional quantification based on standardized uptake value ratio (SUVr) measurements. We target the difficulties of image reading and possible shortcomings of the SUVr methods by validating a new semi-quantitative approach named ELBA. ELBA involves a minimal image preprocessing and does not rely on small, specific regions of interest (ROIs). It evaluates the whole brain and delivers a geometrical/intensity score to be used for ranking and dichotomic assessment. The method was applied to adniimages 18F-florbetapir images from the ADNI database. Five expert readers provided visual assessment in blind and open sessions. The longitudinal trend and the comparison to SUVr measurements were also evaluated. ELBA performed with area under the roc curve (AUC) = 0.997 versus the visual assessment. The score was significantly correlated to the SUVr values (r = 0.86, p < 10-4). The longitudinal analysis estimated a test/retest error of ≃2.3%. Cohort and longitudinal analysis suggests that the ELBA method accurately ranks the brain amyloid burden. The expert readers confirmed its relevance in aiding the visual assessment in a significant number (85) of difficult cases. Despite the good performance, poor and uneven image quality constitutes the major limitation.

Stem Cell Therapy for Alzheimer's Disease: A Review of Recent Clinical Trials. - Kang, Jae Myeong; Yeon, Byeong Kil; Cho, Seong-Jin; Suh, Yoo-Hun (J Alzheimers Dis, 2016)
Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer's disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials.

Strategies for improving memory: a randomized trial of memory groups for older people, including those with mild cognitive impairment. - Kinsella, Glynda J; Ames, David; Storey, Elsdon; Ong, Ben; Pike, Kerryn E; Saling, Michael M; Clare, Linda; Mullaly, Elizabeth; Rand, Elizabeth (J Alzheimers Dis, 2016)
BACKGROUND: Governments are promoting the importance of maintaining cognitive health into older age to minimize risk of cognitive decline and dementia. Older people with amnestic mild cognitive impairment (aMCI) are particularly vulnerable to memory challenges in daily activities and are seeking ways to maintain independent living. OBJECTIVE: To evaluate the effectiveness of memory groups for improving memory strategies and memory ability of older people, especially those with aMCI. METHODS: 113 healthy older adults (HOA) and 106 adults with aMCI were randomized to a six-week memory group or a waitlist control condition. Outcome was evaluated through knowledge and use of memory strategies, memory ability (self-report and neuropsychological tests), and wellbeing. Assessments included a six-month follow-up. RESULTS: Using intention to treat analyses, there were intervention effects for HOA and aMCI groups in strategy knowledge (HOA: η2= 0.20; aMCI: η2= 0.06), strategy use (HOA: η2= 0.18; aMCI: η2= 0.08), and wellbeing (HOA: η2= 0.11; aMCI: η2= 0.05). There were also intervention effects in the HOA group, but not the aMCI group, in self-reported memory ability (η2= 0.06) and prospective memory tests (η2= 0.02). By six-month follow-up, gains were found on most HOA outcomes. In the aMCI group gains were found in strategy use, and by this stage, gains in prospective memory were also found. CONCLUSION: Memory groups can engage older people in techniques for maintaining cognitive health and improve memory performance, but more modest benefits are seen for older adults with aMCI.
Keywords: Aged; Aged, 80 and over; Aging; Cognitive Dysfunction; Cross-Over Studies; Female; Humans; Male; Memory, Episodic; Neuropsychological Tests; Self Report

Streptozotocin Induces Mild Cognitive Impairment at Appropriate Doses in Mice as Determined by Long-Term Potentiation and the Morris Water Maze. - Li, Dong; Huang, Yan; Cheng, Bin; Su, Jie; Zhou, Wen-Xia; Zhang, Yong-Xiang (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is a progressive neurodegenerative disease, and effective therapeutic drugs in the clinic are still lacking. Ideally, AD progression could be stopped at an early stage, such as at the mild cognitive impairment (MCI) stage. MCI refers to the clinical condition between normal aging and dementia. Patients with MCI experience memory loss but do not meet the criteria for the diagnosis of clinically probable AD. However, few MCI animal models have been established. Here, we used in vivo long-term potentiation (LTP) recording and the Morris water maze (MWM) to evaluate the effects of intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. We found a relationship between cognitive behavior and LTP in vivo and determined the appropriate doses of STZ for a putative MCI animal model. Animals that received≥150μg of STZ exhibited cognitive impairment in the MWM test, and few changes in behavior tests were observed in animals receiving less than 150μg of STZ. In vivo LTP recordings revealed that the induction of LTP decreased significantly in STZ-treated animals, even at the lowest dose (25μg/mouse), in a dose-dependent manner. Pathology analysis revealed STZ-induced neuron loss in a dose-dependent manner, both in the cortex and in the hippocampus, as evidenced by a significantly decreased neuronal number in the cohort treated with 75μg of STZ/mouse. Our study indicated that a low dose (25μg/mouse) of STZ impaired neural plasticity; at a higher dose of 75μg/mouse STZ, further LTP deficits were noted along with induced neuronal loss in both the cortex and the hippocampus, which could be considered a possible MCI or pre-MCI animal model; and finally, at 150μg/mouse STZ, dementia was induced, feasibly indicating a state of AD.

STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity. - Gray, Nora E; Zweig, Jonathan A; Kawamoto, Colleen; Quinn, Joseph F; Copenhaver, Philip F (J Alzheimers Dis, 2016)
Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer's disease.
Keywords: Acrylamides; Adenosine Triphosphate; Amyloid beta-Peptides; Animals; Cell Death; Cell Line, Tumor; Drug Evaluation, Preclinical; Estrogen Receptor Modulators; Genes, Mitochondrial; Hippocampus; Humans; Mice, Transgenic; Mitochondria; Neurons; Neuroprotective Agents

The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory. - Tang, Wei; Cheng, Juan; Wang, Zheng-Yu; Chen, Ke-Yang; Han, Zhen-Min; Wang, Qi-Hong; Yao, Yu-You (J Alzheimers Dis, 2016)
In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene.

Tau Accumulation in Primary Motor Cortex of Variant Alzheimer's Disease with Spastic Paraparesis. - Lyoo, Chul Hyoung; Cho, Hanna; Choi, Jae Yong; Hwang, Mi Song; Hong, Sang Kyoon; Kim, Yun Joong; Ryu, Young Hoon; Lee, Myung Sik (J Alzheimers Dis, 2016)
We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.
Keywords: Adult; Aged; Alzheimer Disease; Aniline Compounds; Brain Mapping; Carbolines; Female; Humans; Male; Motor Cortex; Mutation, Missense; Paraparesis, Spastic; Positron-Emission Tomography; Presenilin-1; Radiopharmaceuticals; Stilbenes; tau Proteins

Tau in Late-Life Depression: A Systematic Review and Meta-Analysis. - Brown, Eric E; Iwata, Yusuke; Chung, Jun Ku; Gerretsen, Philip; Graff-Guerrero, Ariel (J Alzheimers Dis, 2016)
A lifetime history of major depressive disorder (MDD) increases the risk of developing Alzheimer's disease, of which neurofibrillary tangles due to abnormal tau proteins are a hallmark. We systematically reviewed the literature on tau in MDD and identified 49 relevant articles spanning a number of modalities, including cerebrospinal fluid (CSF) analysis, positron emission tomography, and clinicopathological correlation. We compared CSF total and phosphorylated tau proteins in MDD and controls using a meta-analytic approach. We found no difference in total or phosphorylated tau in MDD. We also found no difference in a comparison of a subgroup excluding studies with significant age differences. Positron emission tomography studies lacked specificity. Clinicopathological studies failed to associate neurofibrillary tangles with MDD. The available data on tau in MDD is limited. The involvement of tau in a subset of MDD cannot be ruled out and requires prospective exploration.

Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration. - Deochand, Chetram; Tong, Ming; Agarwal, Amit R; Cadenas, Enrique; de la Monte, Suzanne M (J Alzheimers Dis, 2016)
BACKGROUND: Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. OBJECTIVE: This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. METHODS: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. RESULTS: CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. CONCLUSION: Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.
Keywords: Animals; Brain; Insulin; Male; Mice; Nerve Degeneration; Neurons; Phosphorylation; Receptor, IGF Type 1; Signal Transduction; Somatomedins; Tobacco Smoke Pollution

Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration. - Yu, Rosa; Deochand, Chetram; Krotow, Alexander; Leão, Raiane; Tong, Ming; Agarwal, Amit R; Cadenas, Enrique; de la Monte, Suzanne M (J Alzheimers Dis, 2016)
BACKGROUND: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. OBJECTIVE: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. METHODS: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis. RESULTS: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. CONCLUSION: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.
Keywords: 2',3'-Cyclic-Nucleotide Phosphodiesterases; AC133 Antigen; Animals; Antigens, CD; Brain; Disease Models, Animal; Galactosylceramides; Gene Expression Regulation; Glycoproteins; Leukoencephalopathies; Male; Mice; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Neurons; Oligodendroglia; Papain; Peptides; Smoking; Tobacco; Transcription Factors

Topographical APOE ɛ4 Genotype Influence on Cerebral Metabolism in the Continuum of Alzheimer's Disease: Amyloid Burden Adjusted Analysis. - Seo, Eun Hyun; Kim, Sang Hoon; Park, Sang Hag; Kang, Seong-Ho; Choo, Il Han (J Alzheimers Dis, 2016)
BACKGROUND: APOE ɛ4 contributes to Alzheimer's disease (AD) pathogenesis by amyloid-beta (Aβ)-dependent and Aβ-independent processes. OBJECTIVE: We investigated the APOE ɛ4 influence on regional cerebral glucose metabolism (rCMglc) in the continuum of AD after Aβ adjustment. METHODS: We included 318 cognitively normal (CN) elderly, 498 mild cognitive impairment (MCI), and 178 AD from the Alzheimer's Disease Neuroimaging Initiative database. They had [18F] florbetapir positron emission tomography (PET) and [18F] fluorodeoxyglucose (FDG)-PET conducted within 3 months of a clinical and cognitive assessment visit and APOE genotype. At first, the rCMglc differences between APOE ɛ4 carriers (ɛ4+) and non-carriers (ɛ4-) were estimated on a voxel-based analysis using a 'two-sample t-test' design. In the second analysis, Aβ was added as covariate. RESULTS: In CN, ɛ4+ showed reduced rCMglc compared to ɛ4-in the bilateral frontal, temporal, and the left parietal regions. In MCI, ɛ4+ showed reduced rCMglc compared to ɛ4- in the bilateral posterior parietal, temporal, and left frontal regions. In AD, ɛ4+ showed reduced rCMglc in the left hippocampus, right insular, and right temporal gyrus. However, after Aβ adjustment, the significant differences in the temporal regions were absent in CN and MCI, and none of the areas detected as significant in the first analysis were statistically significant in AD. CONCLUSIONS: Our study demonstrated that Aβ-independent APOE ɛ4 influence on rCMglc is limited to the parietal and frontal, but not temporal lobes. These results suggest that APOE ɛ4 may predispose for regional vulnerability according to Aβ-independent and Aβ-dependent processes.

Topographical Information-Based High-Order Functional Connectivity and Its Application in Abnormality Detection for Mild Cognitive Impairment. - Zhang, Han; Chen, Xiaobo; Shi, Feng; Li, Gang; Kim, Minjeong; Giannakopoulos, Panteleimon; Haller, Sven; Shen, Dinggang (J Alzheimers Dis, 2016)
Temporal synchronization-based functional connectivity (FC) has long been used by the neuroscience community. However, topographical FC information may provide additional information to characterize the advanced relationship between two brain regions. Accordingly, we proposed a novel method, namely high-order functional connectivity (HOFC), to capture this second-level relationship using inter-regional resemblance of the FC topographical profiles. Specifically, HOFC first calculates an FC profile for each brain region, notably between the given brain region and other brain regions. Based on these FC profiles, a second layer of correlations is computed between all pairs of brain regions (i.e., correlation's correlation). On this basis, we generated an HOFC network, where "high-order" network properties were computed. We found that HOFC was discordant with the traditional FC in several links, indicating additional information being revealed by the new metrics. We applied HOFC to identify biomarkers for early detection of Alzheimer's disease by comparing 77 mild cognitive impairment patients with 89 healthy individuals (control group). Sensitivity in detection of group difference was consistently improved by ∼25% using HOFC compared to using FC. An HOFC network analysis also provided complementary information to an FC network analysis. For example, HOFC between olfactory and orbitofrontal cortices was found significantly reduced in patients, besides extensive alterations in HOFC network properties. In conclusion, our results showed promise in using HOFC to comprehensively map the human brain connectome.

Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers. - García Barrado, Leandro; Coart, Els; Vanderstichele, Hugo M J; Burzykowski, Tomasz (J Alzheimers Dis, 2016)
Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Bayes Theorem; Biomarkers; Cognitive Dysfunction; Datasets as Topic; Humans; Linear Models; Multivariate Analysis; Peptide Fragments; tau Proteins

Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment. - Ye, Byoung Seok; Jang, Eun Young; Kim, Seong Yoon; Kim, Eun-Joo; Park, Sun Ah; Lee, Yunhwan; Hong, Chang Hyung; Choi, Seong Hye; Yoon, Bora; Yoon, Soo Jin; Na, Hae Ri; Lee, Jae-Hong; et al. (J Alzheimers Dis, 2016)
BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD. CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Body Mass Index; Body Weight; Cognitive Dysfunction; Dementia; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Neuropsychological Tests; Registries

Upregulation of Connexin 43 Expression Via C-Jun N-Terminal Kinase Signaling in Prion Disease. - Lee, Geon-Hwi; Jang, Byungki; Choi, Hong-Seok; Kim, Hee-Jun; Park, Jeong-Ho; Jeon, Yong-Chul; Carp, Richard I; Kim, Yong-Sun; Choi, Eun-Kyoung (J Alzheimers Dis, 2016)
Prion infection leads to neuronal cell death, glial cell activation, and the accumulation of misfolded prion proteins. However, the altered cellular environments in animals with prion diseases are poorly understood. In the central nervous system, cells connect the cytoplasm of adjacent cells via connexin (Cx)-assembled gap junction channels to allow the direct exchange of small molecules, including ions, neurotransmitters, and signaling molecules, which regulate the activities of the connected cells. Here, we investigate the role of Cx43 in the pathogenesis of prion diseases. Upregulated Cx43 expression, which was dependent on c-Jun N-Terminal Kinase (JNK)/c-Jun signaling cascades, was found in prion-affected brain tissues and hippocampal neuronal cells. Scrapie infection-induced Cx43 formed aggregated plaques within the cytoplasmic compartments at the cell-cell interfaces. The ethidium bromide (EtBr) uptake assay and scrape-loading dye transfer assay demonstrated that increased Cx43 has functional consequences for the activity of Cx43 hemichannels. Interestingly, blockade of PrPSc accumulation reduced Cx43 expression through the inhibition of JNK signaling, indicating that PrPSc accumulation may be directly involved in JNK activation-mediated Cx43 upregulation. Overall, our findings describe a scrapie infection-mediated novel regulatory signaling pathway of Cx43 expression and may suggest a role for Cx43 in the pathogenesis of prion diseases.
Keywords: Animals; Brain; Cell Membrane; Cells, Cultured; Connexin 43; Disease Models, Animal; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mesocricetus; Mice, Inbred C57BL; Mice, Knockout; PrPSc Proteins; RNA, Messenger; Scrapie; Up-Regulation

The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration. - Shi, Zhongyong; Zhu, Yingbo; Wang, Meijuan; Wu, Yujie; Cao, Jing; Li, Chunbo; Xie, Zhongcong; Shen, Yuan (J Alzheimers Dis, 2016)
Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 ± 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n = 60) or converted participants whose cognitive status deteriorated (n = 18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 ± 0.30 versus 0.12 ± 0.19, p <  0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer's disease.
Keywords: Aged; Cognition Disorders; Female; Humans; Logistic Models; Longitudinal Studies; Male; Nerve Fibers; Neuropsychological Tests; Predictive Value of Tests; Retina; ROC Curve; Statistics, Nonparametric; Tomography, Optical Coherence

Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aβ40 and Aβ42 Peptides in Plasma. - Pérez-Grijalba, Virginia; Fandos, Noelia; Canudas, Jesús; Insua, Daniel; Casabona, Diego; Lacosta, Ana M; Montañés, María; Pesini, Pedro; Sarasa, Manuel (J Alzheimers Dis, 2016)
Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer's disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-β (Aβ) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of Aβ40 and Aβ42 in human plasma. The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using Aβ peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both Aβ40 and Aβ42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification Aβ40 and Aβ42 in plasma.

Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study. - Müller, Mareike; Kuiperij, H Bea; Versleijen, Alexandra A M; Chiasserini, Davide; Farotti, Lucia; Baschieri, Francesca; Parnetti, Lucilla; Struyfs, Hanne; De Roeck, Naomi; Luyckx, Jill; Engelborghs, Sebastiaan; Claassen, Jurgen A; et al. (J Alzheimers Dis, 2016)
MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.

Validation of the Total Cerebrovascular Disease Burden Scale in a Community Sample. - Xu, Xin; Hilal, Saima; Collinson, Simon L; Chan, Qun Lin; Yi Chong, Eddie Jun; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Cheng, Ching-Yu; Wong, Tien Yin; Chen, Christopher Li-Hsian (J Alzheimers Dis, 2016)
BACKGROUND: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined. OBJECTIVE: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample. METHODS: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established. RESULTS: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1-6.4) times higher odds of dementia compared to dementia-free. DISCUSSION: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale.

Vascular Risk Factors and Cognition in Parkinson's Disease. - Pilotto, Andrea; Turrone, Rosanna; Liepelt-Scarfone, Inga; Bianchi, Marta; Poli, Loris; Borroni, Barbara; Alberici, Antonella; Premi, Enrico; Formenti, Anna; Bigni, Barbara; Cosseddu, Maura; Cottini, Elisabetta; et al. (J Alzheimers Dis, 2016)
Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.
Keywords: Age of Onset; Aged; Attention; Disability Evaluation; Educational Status; Executive Function; Female; Humans; Male; Motor Activity; Neuropsychological Tests; Parkinson Disease; Prevalence; Risk Factors; Sex Factors; Time Factors; Vascular Diseases

Vitamin D and Memory Decline: Two Population-Based Prospective Studies. - Kuźma, Elżbieta; Soni, Maya; Littlejohns, Thomas J; Ranson, Janice M; van Schoor, Natasja M; Deeg, Dorly J H; Comijs, Hannie; Chaves, Paulo H M; Kestenbaum, Bryan R; Kuller, Lewis H; Lopez, Oscar L; Becker, James T; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively. RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34). CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.
Keywords: Humans; Memory Disorders; Netherlands; Prospective Studies; United States; Vitamin D; Vitamin D Deficiency

Volumetric and shape analysis of the thalamus and striatum in amnestic mild cognitive impairment. - Leh, Sandra E; Kälin, Andrea M; Schroeder, Clemens; Park, Min Tae M; Chakravarty, M Mallar; Freund, Patrick; Gietl, Anton F; Riese, Florian; Kollias, Spyros; Hock, Christoph; Michels, Lars (J Alzheimers Dis, 2016)
Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Corpus Striatum; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thalamus

White Matter and Hippocampal Volume Predict the Risk of Dementia in Patients with Cerebral Small Vessel Disease: The RUN DMC Study. - van Uden, Ingeborg W M; van der Holst, Helena M; Tuladhar, Anil M; van Norden, Anouk G W; de Laat, Karlijn F; Rutten-Jacobs, Loes C A; Norris, David G; Claassen, Jurgen A H R; van Dijk, Ewoud J; Kessels, Roy P C; de Leeuw, Frank-Erik (J Alzheimers Dis, 2016)
BACKGROUND: The relationship between cerebral small vessel disease (SVD) and dementia has been studied without considering white matter (WM) volume, the microstructural integrity of the WM surrounding the SVD, and grey matter (GM). OBJECTIVE: We prospectively investigated the relationship between these structures and the risk of dementia, and formed a prediction model to investigate which characteristics (macro- or microstructural) explained most of the variance. METHODS: The RUN DMC study is a prospective cohort study among 503 non-demented participants with an age between 50 and 85 years at baseline, with baseline assessment in 2006 and follow-up assessment in 2012. Two were lost to follow-up (yielding a 99.6% response-rate). Cox regression analysis was used, to calculate hazard ratios for dementia, of baseline MRI characteristics. Tract-Based Spatial Statistics (TBSS) analysis was used to assess the added value of microstructural integrity of the WM. RESULTS: Mean age at baseline was 65.6 years (SD 8.8) and 56.8% was male. 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95% CI 7.7-14.6). Low WM and hippocampal volume are significant predictors for dementia. WM, WM hyperintensities, and hippocampal volume explained most of the variance. TBSS analyses showed no additional value of diffusion parameters. CONCLUSIONS: WM and hippocampal volume were the main predictors for the development of incident dementia at 5-year follow-up in elderly with SVD. There was no additional diagnostic value of the diffusion tensor imaging parameters on top of the macrostructural characteristics.
Keywords: Aged; Cerebral Small Vessel Diseases; Cohort Studies; Dementia; Diffusion Tensor Imaging; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Statistics, Nonparametric; White Matter

White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. - Coutu, Jean-Philippe; Goldblatt, Alison; Rosas, H Diana; Salat, David H (J Alzheimers Dis, 2016)
White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.
Keywords: Aged; Aging; Alzheimer Disease; Cognitive Dysfunction; Diffusion Tensor Imaging; Factor Analysis, Statistical; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Male; Mental Status Schedule; Neuropsychological Tests; White Matter

Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. - Li, Qiao-Xin; Villemagne, Victor L; Doecke, James D; Rembach, Alan; Sarros, Shannon; Varghese, Shiji; McGlade, Amelia; Laughton, Katrina M; Pertile, Kelly K; Fowler, Christopher J; Rumble, Rebecca L; Trounson, Brett O; et al. (J Alzheimers Dis, 2015)
BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. METHODS: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. RESULTS: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

The APOE Gene is Differentially Methylated in Alzheimer's Disease. - Foraker, Jessica; Millard, Steven P; Leong, Lesley; Thomson, Zachary; Chen, Sunny; Keene, C Dirk; Bekris, Lynn M; Yu, Chang-En (J Alzheimers Dis, 2015)
The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.

Blood Protein Markers of Neocortical Amyloid-β Burden: A Candidate Study Using SOMAscan Technology. - Voyle, Nicola; Baker, David; Burnham, Samantha C; Covin, Antonia; Zhang, Zhanpan; Sangurdekar, Dipen P; Tan Hehir, Cristina A; Bazenet, Chantal; Lovestone, Simon; Kiddle, Steven; Dobson, Richard J B (J Alzheimers Dis, 2015)
BACKGROUND: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-β burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer's disease (AD) therapeutics. OBJECTIVE: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort. METHODS: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOE ε4 carriage were used as covariates for all analysis. RESULTS: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects. CONCLUSIONS: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of further replication, further studies are required.

A Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease. - Olazarán, Javier; Gil-de-Gómez, Luis; Rodríguez-Martín, Andrés; Valentí-Soler, Meritxell; Frades-Payo, Belén; Marín-Muñoz, Juan; Antúnez, Carmen; Frank-García, Ana; Jiménez, Carmen Acedo; Gracia, Lorenzo Morlén; Torregrossa, Roberto Petidier; Guisasola, María Concepción; et al. (J Alzheimers Dis, 2015)
Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid (22:6n-3, DHA), one bile acid (deoxycholic acid), one phosphatidylethanolamine [PE(36:4)], and one sphingomyelin [SM(39:1)]. Detailed analysis ruled out the influence of potential confounding variables, including comorbidities and treatments, on each of the seven biomarkers. The final model accurately distinguished AD from NC patients (AUC, 0.918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.

Body Mass Index and Mortality Rate in Korean Patients with Alzheimer's Disease. - Jang, Hyemin; Kim, Jong Hun; Choi, Seong Hye; Lee, Yunhwan; Hong, Chang Hyung; Jeong, Jee Hyang; Han, Hyun Jeong; Moon, So Young; Park, Kyung Won; Han, Seol-Hee; Park, Kee Hyung; Kim, Hee Jin; et al. (J Alzheimers Dis, 2015)
Background: A relationship between body weight, cognitive impairment, and the onset of Alzheimer's disease (AD) was recently reported. However, to our knowledge, no studies have investigated the relationship between body weight and mortality in Asian AD patients. Objective: We evaluated the relationship between body mass index (BMI) and mortality rate in Korean AD cohorts. Methods: Participants were consecutively included from two Korean representative registries: 579 AD patients from Samsung Medical Center and 1911 AD patients from the Clinical Research Center for Dementia of South Korea study. We combined these two AD cohorts to evaluate the association between BMI and mortality. BMI was used to categorize the participants into underweight, normal-weight, overweight, and obesity subgroups. All deaths were confirmed through the nationwide mortality database of Statistics Korea. Results: 53 of 181 (29.3%), 208 of 1,127 (18.5%), 88 of 626 (14.1%), and 115 of 556 (20.7%) patients died in the underweight, normal-weight, overweight, and obese subgroups during 43.7 months of follow-up. The time-dependent cox proportional hazards model showed that, relative to the normal-weight subgroup, the underweight group had higher mortality (HR 1.82 (95% CI, 1.07-3.09)) while overweight group had lower mortality rate (HR 0.60 (95% CI, 0.38-0.95)) The effects of underweight and overweight were prominent in younger and older elderly group, respectively. However, there were no interactive effects of dementia severity or gender and BMI on survival rate. Conclusion: Relative to AD patients of normal weight, those who were underweight had an increased mortality rate, and overweight predicted decreased mortality in AD patients. Furthermore, our findings may help facilitate mortality stratification in AD patients by using baseline BMI.

Cognitive Effects of Soy Isoflavones in Patients with Alzheimer's Disease. - Gleason, Carey E; Fischer, Barbara L; Dowling, N Maritza; Setchell, Kenneth D R; Atwood, Craig S; Carlsson, Cynthia M; Asthana, Sanjay (J Alzheimers Dis, 2015)
BACKGROUND: In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction abilities, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults. OBJECTIVE: The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer's disease. METHODS: Sixty-five men and women over the age of 60 were treated with 100 mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, and at two additional time points: three and six months after baseline. RESULTS: Of the sixty-five participants enrolled, thirty-four (52.3% ) were women, and 31 (47.7% ) were APOEɛ4 positive. Average age was 76.3 (SD = 7.2) years. Fifty-nine (90.8% ) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency. CONCLUSIONS: Six months of 100 mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer's disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones.

Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids. - Kelly, David; Coen, Robert F; Akuffo, Kwadwo Owusu; Beatty, Stephen; Dennison, Jessica; Moran, Rachel; Stack, Jim; Howard, Alan N; Mulcahy, Riona; Nolan, John M (J Alzheimers Dis, 2015)
BACKGROUND: Macular pigment (MP) levels correlate with brain concentrations of lutein (L) and zeaxanthin (Z), and have also been shown to correlate with cognitive performance in the young and elderly. OBJECTIVE: To investigate the relationship between MP, serum concentrations of L and Z, and cognitive function in subjects free of retinal disease with low MP (Group 1, n = 105) and in subjects with AMD (Group 2, n = 121). METHODS: MP was measured using customized heterochromatic flicker photometry and dual-wavelength autofluorescence; cognitive function was assessed using a battery of validated cognition tests; serum L and Z concentrations were determined by HPLC. RESULTS: Significant correlations were evident between MP and various measures of cognitive function in both groups (r = -0.273 to 0.261, p≤0.05, for all). Both serum L and Z concentrations correlated significantly (r = 0.187, p≤0.05 and r = 0.197, p≤0.05, respectively) with semantic (animal) fluency cognitive scores in Group 2 (the AMD study group), while serum L concentrations also correlated significantly with Verbal Recognition Memory learning slope scores in the AMD study group (r = 0.200, p = 0.031). Most of the correlations with MP, but not serum L or Z, remained significant after controlling for age, gender, diet, and education level. CONCLUSION: MP offers potential as a non-invasive clinical biomarker of cognitive health, and appears more successful in this role than serum concentrations of L or Z.

Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease. - Liu-Seifert, Hong; Siemers, Eric; Price, Karen; Han, Baoguang; Selzler, Katherine J; Henley, David; Sundell, Karen; Aisen, Paul; Cummings, Jeffrey; Raskin, Joel; Mohs, Richard (J Alzheimers Dis, 2015)
BACKGROUND: The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. OBJECTIVE: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. METHODS: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. RESULTS: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. CONCLUSIONS: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.

Comorbid Depression and Diabetes as a Risk for Mild Cognitive Impairment and Alzheimer's Disease in Elderly Mexican Americans. - Johnson, Leigh A; Gamboa, Adriana; Vintimilla, Raul; Cheatwood, Austin J; Grant, Alyann; Trivedi, Ashesh; Edwards, Melissa; Hall, James R; O'Bryant, Sid E (J Alzheimers Dis, 2015)
BACKGROUND: The links between diabetes, depression, and Alzheimer's disease (AD) has been established, but they are still poorly understood. However, little research has examined the effect that comorbidity of depression and diabetes has on cognitive impairment in an ethnically diverse sample. OBJECTIVE: The purpose of this study was to investigate the relationship between comorbid diabetes and depression on cognitive dysfunction; and examine the relationship in an ethnically diverse population. METHODS AND RESULTS: Analyses of data from 2,436 participants (914 men and 1,522 women) of three separate cohorts: HABLE, FRONTIER, and TARCC. In the HABLE cohort, comorbidity (odds ratio [OR] = 3.008; 95% CI = 1.358-6.667), age (OR = 1.138; 95% CI = 1.093-1.185), and education (OR = 0.915; 95% CI = 0.852-0.982) increased the risk of mild cognitive impairment (MCI) diagnosis among elderly Mexican American. In the TARCC cohort, results showed an increase risk of MCI in both non-Hispanic whites (OR = 18.795; 95% CI = 2.229-158.485) and Mexican Americans (OR = 8.417; 95% CI = 2.967-23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (OR = 2.754; 95% CI = 1.084-6.995) and age (OR = 1.069; 95% CI = 1.023-1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI. CONCLUSIONS: Among elderly Mexican Americans, comorbid depression and diabetes significantly increased risk for MCI and AD across cohorts. Effects of comorbid diabetes and depression on MCI were inconclusive. Our results support the link between comorbid diabetes and depression and risk for cognitive decline among Mexican Americans. This finding is of critical importance as the Hispanic population is at higher risk of developing AD.

Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults. - Nho, Kwangsik; Ramanan, Vijay K; Horgusluoglu, Emrin; Kim, Sungeun; Inlow, Mark H; Risacher, Shannon L; McDonald, Brenna C; Farlow, Martin R; Foroud, Tatiana M; Gao, Sujuan; Callahan, Christopher M; Hendrie, Hugh C; et al. (J Alzheimers Dis, 2015)
Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we PERFORMED genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease. - Coart, Els; Barrado, Leandro García; Duits, Flora H; Scheltens, Philip; van der Flier, Wiesje M; Teunissen, Charlotte E; van der Vies, Saskia M; Burzykowski, Tomasz (J Alzheimers Dis, 2015)
BACKGROUND: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers. OBJECTIVE: To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account. METHODS: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β1-42, Total tau, and P-tau181) by including the clinical diagnosis as imperfect reference test into the analysis. RESULTS: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively. CONCLUSIONS: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.

Cortical Transcriptional Profiles in APOE4 Carriers with Alzheimer's Disease: Patterns of Protection and Degeneration. - Conejero-Goldberg, Concepcion; Hyde, Thomas M; Chen, Shufen; Herman, Mary M; Kleinman, Joel E; Davies, Peter; Goldberg, Terry E (J Alzheimers Dis, 2015)
Transcriptional profiling of postmortem Alzheimer's disease (AD) brain tissue has yielded important insights into disease. We recently described a novel approach to understand transcriptional changes in AD designed to identify both neurosusceptibility and intrinsic neuroprotective factors in young non-AD E4 carriers. Here we extend our work to APOE4-related AD itself. In temporal cortex (BA 21), a region known to be vulnerable to AD pathology, we identified over 1,400 transcripts that differed between APOE4 controls and APOE4 carriers diagnosed with AD. Results from somatosensory cortex (BA 1/2/3), a region relatively preserved in AD differed strikingly from temporal cortex in that differences were far fewer (37 versus 1,492). We also conducted another set of contrasts involving APOE3 AD cases and APOE4 AD cases to better understand what transcriptional differences were dependent on genotype, but independent of disease status. When analyzing interregional differences, ten pathways differed between both brain areas in the APOE4 AD cases to APOE4 controls contrast and two pathways differed between both brain areas in the APOE4 cases to APOE3 controls contrast. Base excision repair pathway was found in common for both contrasts. In summary, our results indicate that many of the molecular changes identified in the brains of patients with AD reflect the non-specific consequences of neurodegeneration, rather than causative processes. Additionally, the molecular signatures specific to somatosensory cortex may make it uniquely resistant to AD pathology and thereby could provide important leads for treatment.

A Critical Proton MR Spectroscopy Marker of Alzheimer's Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents. - Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Sánchez, Gastón Melo; Rodríguez-Díaz, Joel; Torres-Jardón, Ricardo; Styner, Martin; Mukherjee, Partha S; Lin, Weili; Jewells, Valerie (J Alzheimers Dis, 2015)
Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer's disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ4 MC children and in left hippocampus in MC APOE ɛ4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

Diabetes is Associated with Worse Executive Function in Both Eastern and Western Populations: Shanghai Aging Study and Mayo Clinic Study of Aging. - Zhao, Qianhua; Roberts, Rosebud O; Ding, Ding; Cha, Ruth; Guo, Qihao; Meng, Haijiao; Luo, Jianfeng; Machulda, Mary M; Shane Pankratz, V; Wang, Bei; Christianson, Teresa J H; Aakre, Jeremiah A; et al. (J Alzheimers Dis, 2015)
BACKGROUND AND OBJECTIVES: It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations. METHODS: The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN, USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance. RESULTS: A total of 3,348 Chinese participants in the SAS and 3,734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ɛ4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, gender, education, and vascular covariates, DM was associated with worse performance in executive function (β=-0.15, p = 0.001 for SAS, and β=-0.10, p = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA. CONCLUSIONS: Diabetes is associated with cognitive dysfunction and, in particular, exerts a negative impact on executive function regardless of race, age, and prevalence of vascular risk factors.

Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment. - Hanson, Angela J; Bayer, Jennifer L; Baker, Laura D; Cholerton, Brenna; VanFossen, Brian; Trittschuh, Emily; Rissman, Robert A; Donohue, Michael C; Moghadam, Setareh H; Plymate, Stephen R; Craft, Suzanne (J Alzheimers Dis, 2015)
BACKGROUND: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer's disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions. OBJECTIVE: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor. METHODS: 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW (25% total fat, 7% SF, GI <55) and a HIGH meal (50% total fat, 25% SF, GI >70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimer's disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations. RESULTS: E4-adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4- groups had higher scores after the HIGH meal (ANOVA p = 0.03). These findings were associated with meal-induced changes in glucose (p = 0.05), insulin (p = 0.004), triglycerides (p <  0.01), and plasma Aβ42 (p = 0.05). CONCLUSIONS: These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation.

Identification of Novel Tau Interactions with Endoplasmic Reticulum Proteins in Alzheimer's Disease Brain. - Meier, Shelby; Bell, Michelle; Lyons, Danielle N; Ingram, Alexandria; Chen, Jing; Gensel, John C; Zhu, Haining; Nelson, Peter T; Abisambra, Jose F (J Alzheimers Dis, 2015)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the formation of extracellular amyloid plaques and intraneuronal tau tangles. We recently identified that tau associates with proteins known to participate in endoplasmic reticulum (ER)-associated degradation (ERAD); consequently, ERAD becomes dysfunctional and causes neurotoxicity. We hypothesized that tau associates with other ER proteins, and that this association could also lead to cellular dysfunction in AD. Portions of human AD and non-demented age matched control brains were fractionated to obtain microsomes, from which tau was co-immunoprecipitated. Samples from both conditions containing tau and its associated proteins were analyzed by mass spectrometry. In total, we identified 91 ER proteins that co-immunoprecipitated with tau; 15.4% were common between AD and control brains, and 42.9% only in the AD samples. The remainder, 41.8% of the proteins, was only seen in the control brain samples. We identified a variety of previously unreported interactions between tau and ER proteins. These proteins participate in over sixteen functional categories, the most abundant being involved in RNA translation. We then determined that association of tau with these ER proteins was different between the AD and control samples. We found that tau associated equally with the ribosomal protein L28 but more robustly with the ribosomal protein P0. These data suggest that the differential association between tau and ER proteins in disease could reveal the pathogenic processes by which tau induces cellular dysfunction.

Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease. - Migliaccio, Raffaella; Agosta, Federica; Possin, Katherine L; Canu, Elisa; Filippi, Massimo; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Gorno-Tempini, Maria Luisa (J Alzheimers Dis, 2015)
The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate.

The Multi-Target Drug M30 Shows Pro-Cognitive and Anti-Inflammatory Effects in a Rat Model of Alzheimer's Disease. - Pimentel, Luisa S; Allard, Simon; Do Carmo, Sonia; Weinreb, Orly; Danik, Marc; Hanzel, Cecilia E; Youdim, Moussa B; Cuello, A Claudio (J Alzheimers Dis, 2015)
Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.

sAβPPα is a Potent Endogenous Inhibitor of BACE1. - Peters-Libeu, Clare; Campagna, Jesus; Mitsumori, Michael; Poksay, Karen S; Spilman, Patricia; Sabogal, Alex; Bredesen, Dale E; John, Varghese (J Alzheimers Dis, 2015)
Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer's disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα, the product of the cleavage of AβPP by α-secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ.

Variants in Antiviral Genes are Risk Factors for Cognitive Decline and Dementia. - Licastro, Federico; Raschi, Elena; Carbone, Ilaria; Porcellini, Elisa (J Alzheimers Dis, 2015)
A gene association study of factors regulating antiviral response such as interferon (IFN)-λ3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer's disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE ε4 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly.

Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. - Dubois, Bruno; Feldman, Howard H; Jacova, Claudia; Hampel, Harald; Molinuevo, José Luis; Blennow, Kaj; DeKosky, Steven T; Gauthier, Serge; Selkoe, Dennis; Bateman, Randall; Cappa, Stefano; Crutch, Sebastian; et al. (Lancet Neurol, 2014)
In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
Keywords: Alzheimer Disease; Biomarkers; Humans; International Cooperation; Phenotype; Practice Guidelines as Topic; Societies, Medical

Plasma phospholipids identify antecedent memory impairment in older adults. - Mapstone, Mark; Cheema, Amrita K; Fiandaca, Massimo S; Zhong, Xiaogang; Mhyre, Timothy R; MacArthur, Linda H; Hall, William J; Fisher, Susan G; Peterson, Derick R; Haley, James M; Nazar, Michael D; Rich, Steven A; et al. (Nat Med, 2014)
Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.
Keywords: Aged; Alzheimer Disease; Asparagine; Biomarkers; Carnitine; Cohort Studies; Dipeptides; Female; Humans; Longitudinal Studies; Lysophosphatidylcholines; Malates; Male; Memory Disorders; Metabolome; Mild Cognitive Impairment; Neuropsychological Tests; Phosphatidylcholines; Phosphatidylinositols; Phospholipids; Proline; Prospective Studies; Sensitivity and Specificity; Sphingomyelins; Ursodeoxycholic Acid

REST and stress resistance in ageing and Alzheimer's disease. - Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, X Shirley; Bennett, David A; Colaiácovo, Monica P; et al. (Nature, 2014)
Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Brain; Caenorhabditis elegans Proteins; Cell Death; Cell Nucleus; Chromatin Immunoprecipitation; Cognition; DNA-Binding Proteins; Down-Regulation; Frontotemporal Dementia; Gene Expression Regulation; Humans; Lewy Body Disease; Longevity; Mice; Mild Cognitive Impairment; Neurons; Neuroprotective Agents; Oxidative Stress; Phagosomes; Repressor Proteins; Transcription Factors; Up-Regulation; Wnt Signaling Pathway; Young Adult

A three-dimensional human neural cell culture model of Alzheimer's disease. - Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; Lee, Seungkyu; D'Avanzo, Carla; Chen, Hechao; Hooli, Basavaraj; Asselin, Caroline; Muffat, Julien; Klee, Justin B; Zhang, Can; et al. (Nature, 2014)
Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Cell Culture Techniques; Cell Differentiation; Drug Evaluation, Preclinical; Extracellular Space; Glycogen Synthase Kinase 3; Humans; Microtubule-Associated Proteins; Models, Biological; Neural Stem Cells; Neurites; Phosphorylation; Presenilin-1; Protein Aggregation, Pathological; Reproducibility of Results; tau Proteins

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. - Villeda, Saul A; Plambeck, Kristopher E; Middeldorp, Jinte; Castellano, Joseph M; Mosher, Kira I; Luo, Jian; Smith, Lucas K; Bieri, Gregor; Lin, Karin; Berdnik, Daniela; Wabl, Rafael; Udeochu, Joe; et al. (Nat Med, 2014)
As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
Keywords: Age Factors; Aging; Animals; Blood Transfusion; Blotting, Western; Cell Line; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; DNA Primers; Hippocampus; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microarray Analysis; Neuronal Plasticity; Parabiosis; Polymerase Chain Reaction

Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. - Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R; Lesinski, Andrea N; Asselin, Caroline N; Mullin, Kristina; Hooli, Basavaraj; Choi, Se Hoon; Hyman, Bradley T; Tanzi, Rudolph E (Neuron, 2013)
The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Case-Control Studies; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Matched-Pair Analysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia; Polymorphism, Single Nucleotide; Reference Values; RNA, Messenger; Sialic Acid Binding Ig-like Lectin 3

Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. - Piazza, Fabrizio; Greenberg, Steven M; Savoiardo, Mario; Gardinetti, Margherita; Chiapparini, Luisa; Raicher, Irina; Nitrini, Ricardo; Sakaguchi, Hideya; Brioschi, Monica; Billo, Giuseppe; Colombo, Antonio; Lanzani, Francesca; et al. (Ann Neurol, 2013)
OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri. METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated. RESULTS: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.
Keywords: Adult; Aged; Amyloid beta-Peptides; Apolipoproteins E; Autoantibodies; Brain; Case-Control Studies; Cerebral Amyloid Angiopathy; Female; Humans; Inflammation; Male; Middle Aged; Peptide Fragments; Phosphorylation; Retrospective Studies; Steroids; tau Proteins

Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. - Zhang, Bin; Gaiteri, Chris; Bodea, Liviu-Gabriel; Wang, Zhi; McElwee, Joshua; Podtelezhnikov, Alexei A; Zhang, Chunsheng; Xie, Tao; Tran, Linh; Dobrin, Radu; Fluder, Eugene; Clurman, Bruce; et al. (Cell, 2013)
The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
Keywords: Adaptor Proteins, Signal Transducing; Alzheimer Disease; Animals; Bayes Theorem; Brain; Gene Regulatory Networks; Humans; Membrane Proteins; Mice; Microglia

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. - Lambert, J C; Ibrahim-Verbaas, C A; Harold, D; Naj, A C; Sims, R; Bellenguez, C; DeStafano, A L; Bis, J C; Beecham, G W; Grenier-Boley, B; Russo, G; Thorton-Wells, T A; et al. (Nat Genet, 2013)
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Keywords: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cohort Studies; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. - Kondo, Takayuki; Asai, Masashi; Tsukita, Kayoko; Kutoku, Yumiko; Ohsawa, Yutaka; Sunada, Yoshihide; Imamura, Keiko; Egawa, Naohiro; Yahata, Naoki; Okita, Keisuke; Takahashi, Kazutoshi; Asaka, Isao; et al. (Cell Stem Cell, 2013)
Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Cell Differentiation; Cerebral Cortex; Docosahexaenoic Acids; Humans; Induced Pluripotent Stem Cells; Intracellular Space; Models, Biological; Mutant Proteins; Neurons; Oxidative Stress; Phenotype; Protein Structure, Quaternary

TREM2 variants in Alzheimer's disease. - Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S K; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; et al. (N Engl J Med, 2013)
BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
Keywords: Aged; Alzheimer Disease; Animals; Brain; Exome; Genetic Variation; Genome-Wide Association Study; Genotype; Genotyping Techniques; Heterozygote; Humans; Membrane Glycoproteins; Mice; Mice, Inbred A; Mutation; Receptors, Immunologic; Risk Factors; RNA, Messenger; Sequence Analysis, DNA

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. - Hyman, Bradley T; Phelps, Creighton H; Beach, Thomas G; Bigio, Eileen H; Cairns, Nigel J; Carrillo, Maria C; Dickson, Dennis W; Duyckaerts, Charles; Frosch, Matthew P; Masliah, Eliezer; Mirra, Suzanne S; Nelson, Peter T; et al. (Alzheimers Dement, 2012)
A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.
Keywords: Alzheimer Disease; Brain; Consensus Development Conferences, NIH as Topic; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; Societies, Medical; United States

Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. - Calderón-Garcidueñas, Lilian; Kavanaugh, Michael; Block, Michelle; D'Angiulli, Amedeo; Delgado-Chávez, Ricardo; Torres-Jardón, Ricardo; González-Maciel, Angelica; Reynoso-Robles, Rafael; Osnaya, Norma; Villarreal-Calderon, Rodolfo; Guo, Ruixin; Hua, Zhaowei; et al. (J Alzheimers Dis, 2012)
Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.
Keywords: Adolescent; Adult; Age Factors; Air Pollution; Child; Child, Preschool; Cohort Studies; Down-Regulation; Encephalitis; Female; Frontal Lobe; Gene Regulatory Networks; Humans; Infant; Male; Mexico; Phosphorylation; Plaque, Amyloid; Prions; tau Proteins; Young Adult

Propagation of tau pathology in a model of early Alzheimer's disease. - de Calignon, Alix; Polydoro, Manuela; Suárez-Calvet, Marc; William, Christopher; Adamowicz, David H; Kopeikina, Kathy J; Pitstick, Rose; Sahara, Naruhiko; Ashe, Karen H; Carlson, George A; Spires-Jones, Tara L; Hyman, Bradley T (Neuron, 2012)
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.
Keywords: Age Factors; Alzheimer Disease; Animals; Disease Models, Animal; Disease Progression; Entorhinal Cortex; Epitopes; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Gliosis; Hippocampus; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; RNA, Messenger; Serine; tau Proteins; Tauopathies

18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. - Fodero-Tavoletti, Michelle T; Okamura, Nobuyuki; Furumoto, Shozo; Mulligan, Rachel S; Connor, Andrea R; McLean, Catriona A; Cao, Diana; Rigopoulos, Angela; Cartwright, Glenn A; O'Keefe, Graeme; Gong, Sylvia; Adlard, Paul A; et al. (Brain, 2011)
While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.
Keywords: Alzheimer Disease; Analysis of Variance; Aniline Compounds; Animals; Autoradiography; Binding Sites; Brain; Female; Fluorodeoxyglucose F18; Humans; Immunohistochemistry; Male; Mice; Quinolines; Radiopharmaceuticals; tau Proteins

Caspase signalling controls microglia activation and neurotoxicity. - Burguillos, Miguel A; Deierborg, Tomas; Kavanagh, Edel; Persson, Annette; Hajji, Nabil; Garcia-Quintanilla, Albert; Cano, Josefina; Brundin, Patrik; Englund, Elisabet; Venero, Jose L; Joseph, Bertrand (Nature, 2011)
Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
Keywords: Alzheimer Disease; Animals; Caspase 3; Caspase 7; Caspase 8; Caspase Inhibitors; Caspases; Cell Death; Cells, Cultured; Dopamine; Enzyme Activation; Frontal Lobe; Gene Knockdown Techniques; Humans; Lipopolysaccharides; Mice; Microglia; Neostriatum; Neurotoxicity Syndromes; Parkinson Disease; Protein Kinase C-delta; Rats; Signal Transduction; Substantia Nigra; Toll-Like Receptor 4

The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - McKhann, Guy M; Knopman, David S; Chertkow, Howard; Hyman, Bradley T; Jack, Clifford R; Kawas, Claudia H; Klunk, William E; Koroshetz, Walter J; Manly, Jennifer J; Mayeux, Richard; Mohs, Richard C; Morris, John C; et al. (Alzheimers Dement, 2011)
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Keywords: Alzheimer Disease; Biomarkers; Diagnosis, Differential; Diagnostic Imaging; Disease Progression; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; Societies, Medical; United States

The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - Albert, Marilyn S; DeKosky, Steven T; Dickson, Dennis; Dubois, Bruno; Feldman, Howard H; Fox, Nick C; Gamst, Anthony; Holtzman, David M; Jagust, William J; Petersen, Ronald C; Snyder, Peter J; Carrillo, Maria C; et al. (Alzheimers Dement, 2011)
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.
Keywords: Alzheimer Disease; Biomarkers; Cognition Disorders; Diagnosis, Differential; Diagnostic Imaging; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; Societies, Medical; United States

Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. - Qiang, Liang; Fujita, Ryousuke; Yamashita, Toru; Angulo, Sergio; Rhinn, Herve; Rhee, David; Doege, Claudia; Chau, Lily; Aubry, Laetitia; Vanti, William B; Moreno, Herman; Abeliovich, Asa (Cell, 2011)
Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Cell Transdifferentiation; Cells, Cultured; Fibroblasts; Humans; Neurons; Presenilin-1; Presenilin-2; Regenerative Medicine; Skin

Exercise training increases size of hippocampus and improves memory. - Erickson, Kirk I; Voss, Michelle W; Prakash, Ruchika Shaurya; Basak, Chandramallika; Szabo, Amanda; Chaddock, Laura; Kim, Jennifer S; Heo, Susie; Alves, Heloisa; White, Siobhan M; Wojcicki, Thomas R; Mailey, Emily; et al. (Proc Natl Acad Sci U S A, 2011)
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Keywords: Aged; Aging; Brain-Derived Neurotrophic Factor; Enzyme-Linked Immunosorbent Assay; Exercise; Hippocampus; Humans; Magnetic Resonance Imaging; Memory; Middle Aged; Organ Size; Space Perception

Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. - Castellano, Joseph M; Kim, Jungsu; Stewart, Floy R; Jiang, Hong; DeMattos, Ronald B; Patterson, Bruce W; Fagan, Anne M; Morris, John C; Mawuenyega, Kwasi G; Cruchaga, Carlos; Goate, Alison M; Bales, Kelly R; et al. (Sci Transl Med, 2011)
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.
Keywords: Adult; Aged; Alleles; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoprotein E4; Biomarkers; Brain; Female; Genotype; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis; Middle Aged; Protein Isoforms

Neuronal activity regulates the regional vulnerability to amyloid-β deposition. - Bero, Adam W; Yan, Ping; Roh, Jee Hoon; Cirrito, John R; Stewart, Floy R; Raichle, Marcus E; Lee, Jin-Moo; Holtzman, David M (Nat Neurosci, 2011)
Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Disease Models, Animal; Extracellular Fluid; Female; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis; Neurons; Plaque, Amyloid; Sensory Deprivation; Somatosensory Cortex

Report of the task force on designing clinical trials in early (predementia) AD. - Aisen, P S; Andrieu, S; Sampaio, C; Carrillo, M; Khachaturian, Z S; Dubois, B; Feldman, H H; Petersen, R C; Siemers, E; Doody, R S; Hendrix, S B; Grundman, M; et al. (Neurology, 2011)
BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.
Keywords: Advisory Committees; Alzheimer Disease; Amyloidogenic Proteins; Biomarkers; Clinical Trials as Topic; Cognition; Consensus; Disease Progression; Drug Industry; Early Diagnosis; Europe; Humans; Indans; International Cooperation; Nootropic Agents; Outcome Assessment (Health Care); Patient Selection; Piperidines; Positron-Emission Tomography; Research Design; Treatment Outcome; United States; United States Food and Drug Administration; Vitamin E

Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. - Jin, Ming; Shepardson, Nina; Yang, Ting; Chen, Gang; Walsh, Dominic; Selkoe, Dennis J (Proc Natl Acad Sci U S A, 2011)
Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Chromatography, Gel; Dimerization; Genetic Vectors; Hippocampus; Humans; Immunohistochemistry; Immunoprecipitation; In Situ Nick-End Labeling; Lentivirus; Microscopy, Confocal; Microtubules; Neurites; Phosphorylation; Rats; Rats, Sprague-Dawley; tau Proteins

Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. - Sperling, Reisa A; Aisen, Paul S; Beckett, Laurel A; Bennett, David A; Craft, Suzanne; Fagan, Anne M; Iwatsubo, Takeshi; Jack, Clifford R; Kaye, Jeffrey; Montine, Thomas J; Park, Denise C; Reiman, Eric M; et al. (Alzheimers Dement, 2011)
The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
Keywords: Alzheimer Disease; Biomarkers; Cognition Disorders; Humans; National Institute on Aging (U.S.); Practice Guidelines as Topic; United States

Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. - Li, J; Wang, Y J; Zhang, M; Xu, Z Q; Gao, C Y; Fang, C Q; Yan, J C; Zhou, H D (Neurology, 2011)
OBJECTIVE: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. METHODS: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion. RESULTS: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion. CONCLUSION: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.
Keywords: Aged; Alzheimer Disease; Cerebrovascular Disorders; Cognition Disorders; Disease Progression; Female; Humans; Incidence; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptides; Regression Analysis; Residence Characteristics; Retrospective Studies; Risk Factors; Statistics, Nonparametric

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. - Jones, Lesley; Holmans, Peter A; Hamshere, Marian L; Harold, Denise; Moskvina, Valentina; Ivanov, Dobril; Pocklington, Andrew; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Pahwa, Jaspreet Singh; et al. (PLoS One, 2010)
BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Keywords: Alzheimer Disease; Apolipoproteins E; Cholesterol; Chromosome Mapping; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Immune System; Polymorphism, Single Nucleotide

Memory impairment in transgenic Alzheimer mice requires cellular prion protein. - Gimbel, David A; Nygaard, Haakon B; Coffey, Erin E; Gunther, Erik C; Laurén, Juha; Gimbel, Zachary A; Strittmatter, Stephen M (J Neurosci, 2010)
Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Avoidance Learning; Brain; Disease Models, Animal; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration; Presenilin-1; PrPC Proteins; Random Allocation; Serotonin; Survival Analysis

National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. - Daviglus, Martha L; Bell, Carl C; Berrettini, Wade; Bowen, Phyllis E; Connolly, E Sander; Cox, Nancy Jean; Dunbar-Jacob, Jacqueline M; Granieri, Evelyn C; Hunt, Gail; McGarry, Kathleen; Patel, Dinesh; Potosky, Arnold L; et al. (Ann Intern Med, 2010)
The National Institute on Aging and the Office of Medical Applications of Research of the National Institutes of Health convened a State-of-the-Science Conference on 26-28 April 2010 to assess the available scientific evidence on prevention of cognitive decline and Alzheimer disease. This article provides the panel's assessment of the available evidence.
Keywords: Aged; Alzheimer Disease; Cognition Disorders; Evidence-Based Medicine; Humans; Risk Factors; Risk Reduction Behavior