Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology. - Ramanan, Siddharth; Flanagan, Emma; Leyton, Cristian E; Villemagne, Victor L; Rowe, Christopher C; Hodges, John R; Hornberger, Michael (J Alzheimers Dis, 2016)
Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.
Keywords: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Aphasia, Primary Progressive; Brain; Diagnosis, Differential; Female; Humans; Logistic Models; Male; Memory, Episodic; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Speech Perception; Thiazoles

A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging. - Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L; Annapragada, Ananth (J Alzheimers Dis, 2016)
Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits.

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.

N-truncated Aβ2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models. - Savastano, Adriana; Klafki, Hans; Haußmann, Ute; Oberstein, Timo Jan; Muller, Petr; Wirths, Oliver; Wiltfang, Jens; Bayer, Thomas A (J Alzheimers Dis, 2016)
According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Brain; Cerebral Amyloid Angiopathy; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Transgenic; Plaque, Amyloid

Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention. - Nation, Daniel A; Ho, Jean; Yew, Belinda (J Alzheimers Dis, 2016)
BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-β (Aβ) clearance. OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aβ retention, and reduced progression to dementia. METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aβ and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia. RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aβ and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aβ in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group. DISCUSSION: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aβ, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden.
Keywords: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Chi-Square Distribution; Cross-Sectional Studies; Dementia; Female; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Regression Analysis; tau Proteins; Time Factors

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.

An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers. - Hara, Hideo; Ono, Fumiko; Nakamura, Shinichiro; Matsumoto, Shin-Ei; Jin, Haifeng; Hattori, Nobutaka; Tabira, Takeshi (J Alzheimers Dis, 2016)
With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer's disease when little amyloid is deposited.

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

A Pathway Based Classification Method for Analyzing Gene Expression for Alzheimer's Disease Diagnosis. - Voyle, Nicola; Keohane, Aoife; Newhouse, Stephen; Lunnon, Katie; Johnston, Caroline; Soininen, Hilkka; Kloszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Hodges, Angela; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust. OBJECTIVES: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts. METHODS: Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ4 status were used as covariates for all analysis. RESULTS: Gene and pathway level models performed similarly to each other and to a model based on demographic information only. CONCLUSIONS: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoproteins E; Cohort Studies; Datasets as Topic; Female; Gene Expression; Gene Expression Profiling; Humans; Male; Models, Genetic; Oligonucleotide Array Sequence Analysis; Signal Transduction

Patients that have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer's Disease by Removal of Blood Amyloid. - Sakai, Kazuyoshi; Senda, Takao; Hata, Ryuji; Kuroda, Makoto; Hasegawa, Midori; Kato, Masao; Abe, Masato; Kawaguchi, Kazunori; Nakai, Shigeru; Hiki, Yoshiyuki; Yuzawa, Yukio; Kitaguchi, Nobuya (J Alzheimers Dis, 2016)
As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimer's disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining. Our findings suggest that removal of blood Aβ by hemodialysis results in lower accumulation of Aβ in the brain.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Autopsy; Brain; Case-Control Studies; Humans; Kidney Diseases; Plaque, Amyloid; Renal Dialysis; Silver Staining; Statistics, Nonparametric

Patients with Amyloid-Negative Mild Cognitive Impairment have Cortical Hypometabolism but the Hippocampus is Preserved. - Hanseeuw, Bernard; Dricot, Laurence; Lhommel, Renaud; Quenon, Lisa; Ivanoiu, Adrian (J Alzheimers Dis, 2016)
BACKGROUND: Patients with mild cognitive impairment (MCI) are at risk for Alzheimer's dementia but the presence of amyloid (Aβ) strongly increases this risk. In clinical settings, when Aβ status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Aβ-and Aβ+ MCI is not yet determined. OBJECTIVE: To compare different markers of neurodegeneration in Aβ-and Aβ+ MCI, with an Aβ-elderly control (EC) group. METHODS: Patients with MCI (n = 39) and EC (n = 28) underwent MRI, 18F-FDG PET, and Aβ PET (18F-flutemetamol). We compared FDG and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker. RESULTS: All biomarker values were reduced in Aβ+ MCI compared to EC (p < 0.001). Aβ-MCI had low cortical metabolism (p = 0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Aβ-MCI and EC (p > 0.40). Cortical metabolism best discriminated between MCI and EC (AUC = 0.92/0.86, Aβ+/Aβ-) while hippocampal volume best discriminated between Aβ-MCI and Aβ+ MCI (AUC = 0.79). CONCLUSIONS: Cortical hypometabolism was observed in both Aβ-MCI and Aβ+ MCI whereas hippocampal atrophy was mostly found in Aβ+ MCI. For MCI patients without available Aβ information, hippocampal atrophy is thus more informative about Aβ status than cortical hypometabolism.

Patterns of Brain Iron Accumulation in Vascular Dementia and Alzheimer's Dementia Using Quantitative Susceptibility Mapping Imaging. - Moon, Yeonsil; Han, Seol-Heui; Moon, Won-Jin (J Alzheimers Dis, 2016)
BACKGROUND: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated. OBJECTIVE: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis. RESULTS: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p <  0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups. CONCLUSION: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.
Keywords: Aged; Aging; Alzheimer Disease; Brain; Brain Mapping; Cognition; Dementia, Vascular; Female; Humans; Imaging, Three-Dimensional; Iron; Magnetic Resonance Imaging; Male; Mental Status Schedule; Retrospective Studies; Severity of Illness Index

PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease. - Teich, Andrew F; Sakurai, Mikako; Patel, Mitesh; Holman, Cameron; Saeed, Faisal; Fiorito, Jole; Arancio, Ottavio (J Alzheimers Dis, 2016)
Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease.
Keywords: Blotting, Western; Brain; Cyclic Nucleotide Phosphodiesterases, Type 5; DNA Primers; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Nervous System Diseases; Neurons; Phosphodiesterase 5 Inhibitors; Polymerase Chain Reaction; RNA, Messenger

Performance of Hippocampus Volumetry with FSL-FIRST for Prediction of Alzheimer's Disease Dementia in at Risk Subjects with Amnestic Mild Cognitive Impairment. - Suppa, Per; Hampel, Harald; Kepp, Timo; Lange, Catharina; Spies, Lothar; Fiebach, Jochen B; Dubois, Bruno; Buchert, Ralph (J Alzheimers Dis, 2016)
MRI-based hippocampus volume, a core feasible biomarker of Alzheimer's disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-FIRST for prediction of AD dementia (ADD) in subjects with amnestic mild cognitive impairment (aMCI) from phase 1 of the Alzheimer's Disease Neuroimaging Initiative. Receiver operating characteristic analysis of FSL-FIRST hippocampal volume (corrected for head size and age) revealed an area under the curve of 0.79, 0.70, and 0.70 for prediction of aMCI-to-ADD conversion within 12, 24, or 36 months, respectively. Thus, FSL-FIRST provides about the same power for prediction of progression to ADD in aMCI as other volumetry methods.
Keywords: Aged; Aging; Alzheimer Disease; Area Under Curve; Cognitive Dysfunction; Databases, Factual; Disease Progression; Hippocampus; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Neuropsychological Tests; Organ Size; Pattern Recognition, Automated; Prognosis; Reproducibility of Results; Risk; ROC Curve; Sensitivity and Specificity; Time Factors

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 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.

Phenomenological Reliving and Visual Imagery During Autobiographical Recall in Alzheimer's Disease. - El Haj, Mohamad; Kapogiannis, Dimitrios; Antoine, Pascal (J Alzheimers Dis, 2016)

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.

Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer's Disease. - Waragai, Masaaki; Adame, Anthony; Trinh, Ivy; Sekiyama, Kazunari; Takamatsu, Yoshiki; Une, Kaori; Masliah, Eliezer; Hashimoto, Makoto (J Alzheimers Dis, 2016)
Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.

Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer's Disease Patient with Presenilin-1 Mutation. - Smith, Ruben; Wibom, Moa; Olsson, Tomas; Hägerström, Douglas; Jögi, Jonas; Rabinovici, Gil D; Hansson, Oskar (J Alzheimers Dis, 2016)
It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimer's disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in regions affected by tau aggregates.
Keywords: Adult; Age of Onset; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Presenilin-1; Radiopharmaceuticals; tau Proteins

Posterior Ventricular Enlargement to Differentiate Dementia with Lewy Bodies from Alzheimer's Disease. - Ye, Byoung Seok; Lee, Yoonju; Kwak, Kichang; Park, Yeong-Hun; Ham, Jee Hyun; Lee, Jae Jung; Shin, Na-Young; Lee, Jong-Min; Sohn, Young H; Lee, Phil Hyu (J Alzheimers Dis, 2016)
BACKGROUND: Enlargement of the lateral ventricle is observed in dementia associated with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). OBJECTIVE: The degree of anteroposterior ventricular enlargement and its correlation with clinical and neuropsychological features were investigated in DLB patients. METHODS: Forty-eight patients with DLB, 76 with AD, and 45 subjects with normal cognition (NC) underwent structural brain MRI and detailed neuropsychological tests. Ventricular shape was compared among the groups by visual inspection. Posterior ventricle enlargement (PVE) was defined as the ratio of the distance between the temporal and occipital horns of the lateral ventricle to the distance between the temporal horn of the lateral ventricle and occipital pole of the brain. RESULTS: After controlling for age, sex, and education, higher PVE was observed in the DLB group than in the AD group (68.5 ± 7.9% versus 62.8 ± 9.0%, respectively; p = 0.001) or the NC group (61.9 ± 9.9%, p = 0.002). However, higher PVE was not associated with poorer neuropsychological performance, nor was it associated with any clinical features in the DLB group after controlling for age, sex, and education. CONCLUSION: PVE occurs more often in DLB than in AD and NC. However, it is unclear how PVE is related to the clinical and neuropsychological features of DLB.

Postmortem Adult Human Microglia Proliferate in Culture to High Passage and Maintain Their Response to Amyloid-β. - Guo, Ling; Rezvanian, Aras; Kukreja, Lokesh; Hoveydai, Ramez; Bigio, Eileen H; Mesulam, M-Marsel; El Khoury, Joseph; Geula, Changiz (J Alzheimers Dis, 2016)
Microglia are immune cells of the brain that display a range of functions. Most of our knowledge about microglia biology and function is based on cells from the rodent brain. Species variation in the complexity of the brain and differences in microglia response in the primate when compared with the rodent, require use of adult human microglia in studies of microglia biology. While methods exist for isolation of microglia from postmortem human brains, none allow culturing cells to high passage. Thus cells from the same case could not be used in parallel studies and multiple conditions. Here we report a method, which includes use of growth factors such as granulocyte macrophage colony stimulating factor, for successful culturing of adult human microglia from postmortem human brains up to 28 passages without significant loss of proliferation. Such cultures maintained their phenotype, including uptake of the scavenger receptor ligand acetylated low density lipoprotein and response to the amyloid-β peptide, and were used to extend in vivo studies in the primate brain demonstrating that inhibition of microglia activation protects neurons from amyloid-β toxicity. Significantly, microglia cultured from brains with pathologically confirmed Alzheimer's disease displayed the same characteristics as microglia cultured from normal aged brains. The method described here provides the scientific community with a new and reliable tool for mechanistic studies of human microglia function in health from childhood to old age, and in disease, enhancing the relevance of the findings to the human brain and neurodegenerative conditions.

A Potential VEP Biomarker for Mild Cognitive Impairment: Evidence from Selective Visual Deficit of Higher-Level Dorsal Pathway. - Yamasaki, Takao; Horie, Shizuka; Ohyagi, Yasumasa; Tanaka, Eri; Nakamura, Norimichi; Goto, Yoshinobu; Kanba, Shigenobu; Kira, Jun-Ichi; Tobimatsu, Shozo (J Alzheimers Dis, 2016)
Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.

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.

Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer's Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment. - Babić Leko, Mirjana; Borovečki, Fran; Dejanović, Nenad; Hof, Patrick R; Šimić, Goran (J Alzheimers Dis, 2016)
Visinin-like protein 1 (VILIP-1) recently emerged as a potential biomarker of Alzheimer's disease (AD). This neuronal calcium sensor protein previously used as a marker of acute ischemic stroke is elevated in the cerebrospinal fluid (CSF) of AD patients. The goal of this study was to assess CSF VILIP-1 potential in early AD diagnosis and in differentiating mild cognitive impairment (MCI) patients with and without risk of AD. Additionally, we tested VILIP-1 ability to differentiate AD from other primary causes of dementia, and predict the progression of AD-related cognitive decline. VILIP-1 levels were compared with five CSF AD biomarkers (t-tau, Aβ1-42, p-tau181, p-tau199, and p-tau231). VILIP-1 successfully differentiated two MCI patient groups characterized by absence or presence of pathological levels of these CSF biomarkers, except for t-tau. VILIP-1/Aβ(1-42) and VILIP-1/p-tau181 ratios also differentiated MCI patients with pathological CSF biomarker levels. However, there was no difference in VILIP-1 levels between AD and MCI patients. VILIP-1/Aβ(1-42) and VILIP-1/p-tau231 ratios reached high sensitivities (above 70%) and very high specificities (above 85%) in differentiating AD patients from HC. Additionally, VILIP-1 differentiated AD from patients with Lewy body disease with 77.1% sensitivity and 100% specificity. VILIP-1 potential as a prognostic biomarker of cognitive decline in AD was also proved since VILIP-1/t-tau, VILIP-1/p-tau181, and VILIP-1/p-tau231 ratios correlated with MMSE scores. These data indicate that VILIP-1 alone or in combination with other AD CSF biomarkers represent a valuable marker for the early diagnosis of AD, recognition of MCI patients at higher risk to develop dementia, and in differentiating AD from LBD.
Keywords: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Diagnosis, Differential; Disease Progression; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neurocalcin; Peptide Fragments; Predictive Value of Tests; ROC Curve; Statistics as Topic; tau Proteins

Prevalence and Risk Factor of Cognitive Impairment were Different between Urban and Rural Population: A Community-Based Study. - Tang, Hui-Dong; Zhou, Yi; Gao, Xiang; Liang, Liang; Hou, Miao-Miao; Qiao, Yuan; Ma, Jian-Fang; Chen, Sheng-Di (J Alzheimers Dis, 2016)
BACKGROUND: China is facing a continuously rising numbers of people with cognitive impairment (CI). OBJECTIVES: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities. METHODS: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n = 4,429) and Wuliqiao (urban community, n = 3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate logistic regression was performed to identify risk factors associated with CI. RESULTS: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p = 0.13). In the urban population, risk of having CI was associated with age (OR = 1.04; 95% CI: 1.01-1.08), lack of physical activities (OR = 2.25; 95% CI: 1.11-4.57), presence of diabetes mellitus (OR = 1.79; 95% CI: 1.04-3.07), and having three or more children (OR = 2.39; 95% CI: 1.27-4.50). In contrast, factors associated with rural populations included female gender (OR = 2.03; 95% CI: 1.08-3.82), age (OR = 1.06; 95% CI: 1.03-1.08), exposure to pesticides (OR = 4.68; 95% CI: 1.27-17.21), history of encephalitis or meningitis (OR = 6.02; 95% CI: 1.92-18.85) and head trauma (OR = 1.89; 95% CI: 1.10-3.24). CONCLUSIONS: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed.
Keywords: Aged; Aged, 80 and over; China; Cognition Disorders; Female; Humans; Logistic Models; Male; Mental Status Schedule; Middle Aged; Multivariate Analysis; Prevalence; Risk Factors; Rural Population; Urban Population

Primary Progressive Aphasia in the Network of French Alzheimer Plan Memory Centers. - Magnin, Eloi; Démonet, Jean-François; Wallon, David; Dumurgier, Julien; Troussière, Anne-Cécile; Jager, Alain; Duron, Emmanuelle; Gabelle, Audrey; de la Sayette, Vincent; Volpe-Gillot, Lisette; Tio, Gregory; Evain, Sarah; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Few demographical data about primary progressive aphasia (PPA) are available, and most knowledge regarding PPA is based on tertiary centers' results. OBJECTIVE: Our aims were to describe demographical characteristics of the PPA population in a large sample of PPA patients from the network of French Alzheimer plan memory centers (Sample 1), and to describe the stratification of cerebrospinal fluid (CSF) biomarkers in two different samples of PPA patients (Samples 2 and 3). METHODS: All registered PPA patients in the French Alzheimer's disease (AD) databank (Sample 1: n = 2,035) and a subsample (Sample 2: n = 65) derived from a multicentric prospective cohort with CSF biomarker analysis were analyzed. A multicentric retrospective cohort from language expert tertiary centers (Sample 3: n = 97) with CSF biomarker analysis was added. Sample 3 was added to replicate the CSF results of the Sample 2 and to evaluate repartition of AD pathology in the three variant of PPA according to the latest classification. RESULTS: Non-Fluent/Agrammatic, Logopenic, and Unclassifiable PPA patients (NF/A-Logo-Unclass PPA) were older and more frequent than Semantic PPA patients (2.2 versus 0.8/100,000 inhabitants; p < 0.00001). Male predominance occurred after the age of 80 (p < 0.00001). A higher level of education was observed in the PPA population compared to a typical amnesic AD group. No demographical significant difference between PPA due to AD and not due to AD was observed. The Logopenic variant was most frequent with 85% of AD CSF biomarker profiles (35% in NF/A PPA; 20% in Semantic PPA). CONCLUSION: PPA occurs also in an elderly population, especially in male patients over 80. CSF biomarkers are useful to stratify PPA. The epidemiology of PPA should be further investigated to confirm gender and cognitive reserve role in PPA to better understand the factors and mechanisms leading to this language-predominant deficit during neurodegenerative diseases.

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

Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. - Tosto, Giuseppe; Monsell, Sarah E; Hawes, Stephen E; Bruno, Giuseppe; Mayeux, Richard (J Alzheimers Dis, 2016)
BACKGROUND: Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions. OBJECTIVE: To identify clusters of EPS progression over time and their clinical and neuropathological correlates. METHODS: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings. RESULTS: Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies. CONCLUSIONS: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.
Keywords: Aged; Algorithms; Alzheimer Disease; Cluster Analysis; Databases, Factual; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Severity of Illness Index

Prospective Memory Impairments in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates. - Dermody, Nadene; Hornberger, Michael; Piguet, Olivier; Hodges, John R; Irish, Muireann (J Alzheimers Dis, 2016)
BACKGROUND: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown. OBJECTIVE: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). METHODS: Twelve AD, 12 bvFTD, and 12 healthy older Control participants completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI. RESULTS: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy were found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes. CONCLUSION: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life.
Keywords: Aged; Alzheimer Disease; Atrophy; Brain; Brain Mapping; Female; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Middle Aged; Neuropsychological Tests

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 Proteomics Reveals the Mechanism of Oxygen Treatment on Lenses of Alzheimer's Disease Model Mice. - Wang, Hao; Wang, Ying; Hong, Xiaoyu; Li, Shuiming; Wang, Yong (J Alzheimers Dis, 2016)
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with well-characterized pathological features. Yet the underlying mechanisms have not been resolved and an effective therapeutic approach is lacking. Cerebral hypoxia is considered a risk factor of AD. OBJECTIVE: We tested whether oxygen supplementation can relieve AD symptoms and how it affects the expression levels of proteins in the lens. METHODS: Triple transgenic AD model (3xTg-AD) mice were divided into oxygen treated (OT) and control (Ctrl) groups. Their cognitive performances were tested in a Morris water maze (MWM) paradigm. Then, their eye lens tissues were subjected to quantitative proteomics analysis by the iTRAQ (isobaric tags for relative and absolute quantification) method. The up- and downregulated proteins were classified according to a Gene Ontology (GO) database in PANTHER. Behavioral and proteomic data were compared between the groups. RESULTS: Mice in the OT group had better learning and memorizing performance compared with the Ctrl group in MWM test. Lenses from the OT group had 205 differentially regulated proteins, relative to lenses from the Ctrl group, including proteins that are involved in the clearance of amyloid β-protein. CONCLUSION: The results of this study indicate that oxygen treatment can improve cognitive function in AD model mice and alters protein expression in a manner consistent with improved redox regulation.

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

Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice. - Elahi, Montasir; Hasan, Zafrul; Motoi, Yumiko; Matsumoto, Shin-Ei; Ishiguro, Koichi; Hattori, Nobutaka (J Alzheimers Dis, 2016)
Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1β, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.
Keywords: Adaptor Proteins, Signal Transducing; Animals; Antibiotics, Antineoplastic; Brain; Calcium-Binding Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Proliferation; Diabetes Mellitus, Experimental; Disease Models, Animal; Encephalitis; Female; Humans; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Neuroglia; Oxidative Stress; Reactive Oxygen Species; Streptozocin; tau Proteins

Regular Benzodiazepine and Z-Substance Use and Risk of Dementia: An Analysis of German Claims Data. - Gomm, Willy; von Holt, Klaus; Thomé, Friederike; Broich, Karl; Maier, Wolfgang; Weckbecker, Klaus; Fink, Anne; Doblhammer, Gabriele; Haenisch, Britta (J Alzheimers Dis, 2016)
BACKGROUND: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing. OBJECTIVE: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set. METHODS: Using longitudinal German public health insurance data from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. RESULTS: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13-1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed. CONCLUSION: The restricted use of BDZRs may contribute to dementia prevention in the elderly.

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

Retinal oximetry imaging in Alzheimer's disease. - Einarsdottir, Anna Bryndis; Hardarson, Sveinn Hakon; Kristjansdottir, Jona Valgerdur; Bragason, David Thor; Snaedal, Jon; Stefánsson, Einar (J Alzheimers Dis, 2016)
BACKGROUND: Structural and physiological abnormalities have been reported in the retina in Alzheimer's disease (AD). Retinal oximetry detects changes in retinal oxygen metabolism in many eye diseases, where structural changes are seen. OBJECTIVE: To compare oxygen saturation in retinal blood vessels in patients with AD and a healthy cohort. METHODS: Oxygen saturation of hemoglobin was measured in retinal blood vessels, using imaging with spectrophotometric noninvasive retinal oximeter. 18 individuals with mild to moderate dementia of the Alzheimer-type (stage 3-5 according to the Global Deterioration Scale) and 18 healthy subjects underwent retinal oximetry in a case control study. RESULTS: Retinal oxygen saturation in arterioles and venules in patients with moderate AD was significantly elevated compared to healthy individuals. Retinal arterioles have 94.2 ± 5.4% oxygen saturation in moderate AD compared with 90.5 ± 3.1% in healthy subjects (mean ± SD, n = 10, p = 0.028). Retinal venules were 51.9 ± 6.0% saturated in moderate AD compared with 49.7 ± 7.0% in healthy subjects (mean ± SD, n = 10, p = 0.02). CONCLUSION: This is the first study of retinal oxygen metabolism in any central nervous system disease. It discovers abnormalities in retinal oxygen metabolism in AD. The findings are similar to those seen in age-related macular degeneration and diabetic retinopathy. Noninvasive retinal oximetry may offer new insights into pathophysiology of AD. Further studies are needed to confirm and expand these findings.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Hemoglobins; Humans; Male; Middle Aged; Oximetry; Oxygen; Oxygen Consumption; Regional Blood Flow; Retina; Retinal Vessels

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 Adiponectin Levels, Neuroimaging, and Cognition in the Mayo Clinic Study of Aging. - Wennberg, Alexandra M V; Gustafson, Deborah; Hagen, Clinton E; Roberts, Rosebud O; Knopman, David; Jack, Clifford; Petersen, Ronald C; Mielke, Michelle M (J Alzheimers Dis, 2016)
BACKGROUND: Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer's disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown. OBJECTIVE: Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample. METHODS: Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 and older enrolled in the Mayo Clinic Study of Aging. RESULTS: Women had higher adiponectin than men (12,631 ng/mL versus 8,908 ng/mL, p < 0.001). Among women, higher adiponectin was associated with smaller HVa (B = -0.595; 95% CI -1.19, -0.005), poorer performance in language (B = -0.676; 95% CI -1.23, -0.121), and global cognition (B = -0.459; 95% CI -0.915, -0.002), and greater odds of a MCI diagnosis (OR = 6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR >1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B = -0.723; 95% CI -1.43, -0.014), poorer performance in memory (B = -1.02; 95% CI -1.73, -0.312), language (B = -0.896; 95% CI -1.58, -0.212), global cognition (B = -0.650; 95% CI -1.18, -0.116), and greater odds of MCI (OR = 19.34; 95% CI 2.72, 137.34). CONCLUSION: Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline.

Sideritis spp. Extracts Enhance Memory and Learning in Alzheimer's β-Amyloidosis Mouse Models and Aged C57Bl/6 Mice. - Hofrichter, Jacqueline; Krohn, Markus; Schumacher, Toni; Lange, Cathleen; Feistel, Bjöorn; Walbroel, Bernd; Pahnke, Jens (J Alzheimers Dis, 2016)
Nowadays, Alzheimer's disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard to their effects on cognition in APP-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aβ deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in APP-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aβ42 load in APP-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α-secretase ADAM10. Moreover, the treatment was able to fully rescue neuronal loss of APP-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer's disease by affecting its most prominent hallmarks: Aβ pathology and cognitive decline.

A Six-Month Cognitive-Motor and Aerobic Exercise Program Improves Executive Function in Persons with an Objective Cognitive Impairment: A Pilot Investigation Using the Antisaccade Task. - Heath, Matthew; Weiler, Jeffrey; Gregory, Michael A; Gill, Dawn P; Petrella, Robert J (J Alzheimers Dis, 2016)
Persons with an objective cognitive impairment (OCI) are at increased risk for progression to Alzheimer's disease and related dementias. The present pilot project sought to examine whether participation in a long-term exercise program involving cognitive-motor (CM) dual-task gait training and aerobic exercise training improves executive function in persons with an OCI. To accomplish our objective, individuals with an OCI (n = 12) as determined by a Montreal Cognitive Assessment (MoCA) score of less than 26 and older adults (n = 11) deemed to be cognitively healthy (i.e., control group: MoCA score ≥26) completed a six-month moderate-to-high intensity (65-85% maximum heart rate) treadmill-based CM and aerobic exercise training program wherein pre- and post-intervention executive control was examined via the antisaccade task. Notably, antisaccades require a goal-directed eye-movement mirror-symmetrical to a target and represent an ideal tool for the study of executive deficits because of its hands- and language-free nature. As well, the cortical networks mediating antisaccades represent regions associated with neuropathology in cognitive decline and dementia (e.g., dorsolateral prefrontal cortex). Results showed that antisaccade reaction times for the OCI group reliably decreased by 30 ms from pre- to post-intervention, whereas the control group did not produce a reliable pre- to post-intervention change in reaction time (i.e., 6 ms). Thus, we propose that in persons with OCI long-term CM and aerobic training improves the efficiency and effectiveness of the executive mechanisms mediating high-level oculomotor control.

So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia. - Bertoux, Maxime; Ramanan, Siddharth; Slachevsky, Andrea; Wong, Stephanie; Henriquez, Fernando; Musa, Gada; Delgado, Carolina; Flanagan, Emma; Bottlaender, Michel; Sarazin, Marie; Hornberger, Michael; Dubois, Bruno (J Alzheimers Dis, 2016)
BACKGROUND: Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties. OBJECTIVE: This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach. METHOD: Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling. RESULTS: Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% - 12.7%) predicted by EF. DISCUSSION: These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.

Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia? - Bertoux, Maxime; de Souza, Leonardo Cruz; O'Callaghan, Claire; Greve, Andrea; Sarazin, Marie; Dubois, Bruno; Hornberger, Michael (J Alzheimers Dis, 2016)
Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.
Keywords: Aged; Alzheimer Disease; Amnesia; Cognition; Diagnosis, Differential; Emotions; Female; Frontotemporal Dementia; Humans; Male; Memory, Episodic; Neuropsychological Tests; Social Perception

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

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor. - Hascup, Kevin N; Hascup, Erin R (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ42 binds the α7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50×100μm) and minimal damage to the surrounding parenchyma (50-100μm). Local application of Aβ42 (0.01, 0.1, 1.0, and 10.0μM; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0μM Aβ42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0μM Aβ42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0μM α-Bungarotoxin, the potent α7nAChR antagonist. Coapplication of 10.0μM tetrodotoxin, indicates Aβ42 - induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ42 isoform evokes glutamate release through the α7nAChR and varies across hippocampal subfields.

Spatial Navigation in Preclinical Alzheimer's Disease. - Allison, Samantha L; Fagan, Anne M; Morris, John C; Head, Denise (J Alzheimers Dis, 2016)
Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.
Keywords: Aged; Alzheimer Disease; Biomarkers; Educational Status; Female; Humans; Learning; Male; Neuropsychological Tests; Prodromal Symptoms; Psychomotor Performance; ROC Curve; Spatial Navigation; tau Proteins; User-Computer Interface

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.

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.

Strong Impact of Chronic Cerebral Hypoperfusion on Neurovascular Unit, Cerebrovascular Remodeling, and Neurovascular Trophic Coupling in Alzheimer's Disease Model Mouse. - Shang, Jingwei; Yamashita, Toru; Zhai, Yun; Nakano, Yumiko; Morihara, Ryuta; Fukui, Yusuke; Hishikawa, Nozomi; Ohta, Yasuyuki; Abe, Koji (J Alzheimers Dis, 2016)
Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer's disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities.

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.

A Systematic Review and Meta-Analysis of On-Road Simulator and Cognitive Driving Assessment in Alzheimer's Disease and Mild Cognitive Impairment. - Hird, Megan A; Egeto, Peter; Fischer, Corinne E; Naglie, Gary; Schweizer, Tom A (J Alzheimers Dis, 2016)
BACKGROUND: Many individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) are at an increased risk of driving impairment. There is a need for tools with sufficient validity to help clinicians assess driving ability. OBJECTIVE: Provide a systematic review and meta-analysis of the primary driving assessment methods (on-road, cognitive, driving simulation assessments) in patients with MCI and AD. METHODS: We investigated (1) the predictive utility of cognitive tests and domains, and (2) the areas and degree of driving impairment in patients with MCI and AD. Effect sizes were derived and analyzed in a random effects model. RESULTS: Thirty-two articles (including 1,293 AD patients, 92 MCI patients, 2,040 healthy older controls) met inclusion criteria. Driving outcomes included: On-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior. Executive function (ES [95% CI]; 0.61 [0.41, 0.81]), attention (0.55 [0.33, 0.77]), visuospatial function (0.50 [0.34, 0.65]), and global cognition (0.61 [0.39, 0.83]) emerged as significant predictors of driving performance. Trail Making Test Part B (TMT-B, 0.61 [0.28, 0.94]), TMT-A (0.65 [0.08, 1.21]), and Maze test (0.88 [0.60, 1.15]) emerged as the best single predictors of driving performance. Patients with very mild AD (CDR = 0.5) mild AD (CDR = 1) were more likely to fail an on-road test than healthy control drivers (CDR = 0), with failure rates of 13.6%, 33.3% and 1.6%, respectively. CONCLUSION: The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients. Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and MCI (amnestic, non-amnestic, single-domain, multiple-domain).

Targretin Improves Cognitive and Biological Markers in a Patient with Alzheimer's Disease. - Pierrot, Nathalie; Lhommel, Renaud; Quenon, Lisa; Hanseeuw, Bernard; Dricot, Laurence; Sindic, Christian; Maloteaux, Jean-Marie; Octavea, Jean-Noël; Ivanoiu, Adrian (J Alzheimers Dis, 2016)
We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimer's disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage of AD.
Keywords: Aged; Alzheimer Disease; Amyloidogenic Proteins; Biomarkers; Cognition Disorders; Humans; Male; Mental Recall; Neuropsychological Tests; Receptors, Retinoic Acid; tau Proteins; Tetrahydronaphthalenes

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

A Theoretical Analysis of the Synergy of Amyloid and Tau in Alzheimer's Disease. - Han, Pengcheng; Shi, Jiong (J Alzheimers Dis, 2016)
Amyloid plaques and Tau protein neurofibrillary tangles are considered the two most important pathogenic factors in Alzheimer's disease. The prevailing amyloid cascade hypothesis suggests that amyloid-β (Aβ) elevation induces downstream Tau hyperphosphorylation and aggregation, synaptic dysfunction, and neuronal loss that ultimately results in cognitive impairment. Alternatively, the dual-pathway hypothesis suggests that Aβ and abnormal Tau are two independent factors that exert synergistic effects on synaptic dysfunction and neuronal loss. We hypothesize that the intrinsic interaction of Aβ and Tau would better predict cognitive impairment. Herein, we propose an Aβ-Tau interactive model based on a review of the medical literature, mathematic modeling, and analysis of our clinicopathological data.

Time Orientation and 10 Years Risk of Dementia in Elderly Adults: The Three-City Study. - Dumurgier, Julien; Dartigues, Jean-François; Gabelle, Audrey; Paquet, Claire; Prevot, Magali; Hugon, Jacques; Tzourio, Christophe (J Alzheimers Dis, 2016)
Time disorientation is commonly observed in dementia, however very little is known about the pathological significance of minor time errors in community-dwelling population. Our objective was to investigate the relationship between time orientation and risk of dementia in a population of older adults. Analyses relies on 8611 dementia-free subjects from the Three-City Study, France. Participants were followed up for 10 years for incident dementia. Time orientation was assessed by asking for the date, the day of the week, the month, the season and the year. At baseline, 905 subjects made at least one error in time orientation. During 57,073 person-years of follow-up, 827 participants developed dementia. After controlling for age, gender and education level, subjects with one error in time had a greater risk of dementia (hazard ratio [HR] 1.44 [1.18-1.77]), while those with at least 2 errors had a more than three-fold increased risk (HR 3.10 [1.98-4.83]). This association was particularly marked for the diagnosis of probable Alzheimer's disease. Time disorientation was associated with an increased risk of dementia in a large population of cognitively normal older people followed during up to 10 years and should not be underestimated in clinical setting.

Time trends in antipsychotic drug use in patients with dementia: a nationwide study. - Nørgaard, Ane; Jensen-Dahm, Christina; Gasse, Christiane; Hansen, Hanne Vibe; Waldemar, Gunhild (J Alzheimers Dis, 2016)
BACKGROUND: Antipsychotics are often used to treat neuropsychiatric symptoms in dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety regulations worldwide. OBJECTIVE: To investigate time trends in use of antipsychotics and other psychotropic drugs in dementia care. METHODS: The study included longitudinal data on all Danish residents ≥65 years. The study population was defined on January 1 of each year from 2000-2012. Data included prescriptions, discharge diagnoses, and somatic and psychiatric comorbidities. Multivariate time trend analyses of psychotropic drug use in patients with dementia within 4-year age bands were performed. RESULTS: Overall, among patients with dementia the prevalence of antipsychotic drug use decreased from 31.3% in 2000 to 20.4% in 2012. The decreasing use of antipsychotics was accompanied by decreasing use of anxiolytics and hypnotics/sedatives, but an increase in the use of antidepressants from 43.3% in 2000 to 53.8% in 2012. These changes were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD. CONCLUSIONS: The changing patterns of psychotropic drug use may be caused by warnings against use of antipsychotics. Further research is needed to explore the implications for patient safety.
Keywords: Aged; Aged, 80 and over; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Dementia; Denmark; Drug Prescriptions; Female; Homes for the Aged; Humans; Hypnotics and Sedatives; Longitudinal Studies; Male; Multivariate Analysis; Nursing Homes; Registries

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.

Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration. - Iyappan, Anandhi; Gündel, Michaela; Shahid, Mohammad; Wang, Jiali; Li, Hui; Mevissen, Heinz-Theodor; Müller, Bernd; Fluck, Juliane; Jirsa, Viktor; Domide, Lia; Younesi, Erfan; Hofmann-Apitius, Martin (J Alzheimers Dis, 2016)
Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.

Tract-Specific Correlates of Neuropsychological Deficits in Patients with Subcortical Vascular Cognitive Impairment. - Jung, Na-Yeon; Han, Cheol E; Kim, Hee Jin; Yoo, Sang Wook; Kim, Hee-Jong; Kim, Eun-Joo; Na, Duk L; Lockhart, Samuel N; Jagust, William J; Seong, Joon-Kyung; Seo, Sang Won (J Alzheimers Dis, 2016)
The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI.
Keywords: Aged; Brain; Cerebrovascular Disorders; Cognitive Dysfunction; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Female; Gray Matter; Humans; Male; Neural Pathways; Neuropsychological Tests; White Matter

Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease. - Pasquier, Florence; Sadowsky, Carl; Holstein, Ann; Leterme, Ghislaine Le Prince; Peng, Yahong; Jackson, Nicholas; Fox, Nick C; Ketter, Nzeera; Liu, Enchi; Ryan, J Michael (J Alzheimers Dis, 2016)
Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx-40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.
Keywords: Adjuvants, Immunologic; Aged; Alzheimer Disease; Amyloid beta-Peptides; Antipsychotic Agents; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Interferon-gamma; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Recombinant Fusion Proteins; Saponins; Single-Blind Method; Treatment Outcome

UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. - Xie, Min; Han, Yun; Yu, Quntao; Wang, Xia; Wang, Shaohui; Liao, Xiaomei (J Alzheimers Dis, 2016)
Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer's disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau.
Keywords: Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Immunoprecipitation; Indoles; Mice; Microtubules; Neuroblastoma; Oximes; Protein Binding; Proteolysis; RNA, Small Interfering; tau Proteins; Ubiquitin Thiolesterase; Ubiquitination

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. - Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R; Irish, Muireann (J Alzheimers Dis, 2016)
Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

Unmet Needs of Community-Dwelling Primary Care Patients with Dementia in Germany: Prevalence and Correlates. - Eichler, Tilly; Thyrian, Jochen René; Hertel, Johannes; Richter, Steffen; Wucherer, Diana; Michalowsky, Bernhard; Teipel, Stefan; Kilimann, Ingo; Dreier, Adina; Hoffmann, Wolfgang (J Alzheimers Dis, 2016)
BACKGROUND: To provide an optimal care for persons with dementia (PWD), their individual unmet needs have to be identified and comprehensively addressed. OBJECTIVES: Present analyses aim to describe the number and types of unmet needs of German primary care patients screened positive for dementia and factors associated with the number of unmet needs. METHODS: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, cluster-randomized controlled intervention trial. Analyses are based on the baseline data of 227 PWD (≥70 years, living at home) of the intervention group who had screened positive for dementia (DemTect<9) and received a standardized computer-assisted needs assessment. RESULTS: PWD had on average 8.77±5.04 unmet needs (Range = 0-31). More than 90% of the PWD had three or more unmet needs. Unmet needs were identified across all predefined 26 subcategories. The majority of unmet needs occurred in the domains "nursing treatment and care" (38%), "social counseling and legal support" (20%), and "pharmacological treatment and care" (15%). More impairment in the activities of daily living was the only factor that was significantly associated with a higher number of unmet needs, independent of age, gender, living situation, presence of an informal caregiver, cognitive impairment, and depression. CONCLUSIONS: Present results demonstrate that community-dwelling PWD had a broad range of varying unmet needs. These findings emphasize the importance of a comprehensive needs assessment that allows the identification of individual needs as the basis for a tailored intervention- such as Dementia Care Management- that can address these needs.
Keywords: Aged, 80 and over; Caregivers; Cross-Sectional Studies; Dementia; Depression; Female; Germany; Health Services Needs and Demand; Humans; Male; Needs Assessment; Prevalence

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

An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia. - Li, Wei; Huang, Edgar (J Alzheimers Dis, 2016)
With the rapidly expanding evidence on brain structural and functional changes in type 2 diabetes mellitus (T2DM) patients, there is an increasing need to update our understanding on how T2DM associates with dementia as well as the underlying pathophysiological mechanisms. A literature search of T2DM and dementia or cognition impairments was carried out in electronic databases Medline, EMBASE, and Google Scholar. In this review, the chosen evidence was limited to human subject studies only, and data on either type 1 diabetes mellitus (T1DM) or non-classified diabetes were excluded. T2DM is a risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), although AD pathological marker studies have not provided sufficient evidence. T2DM interacts additively or synergistically with many factors, including old age, hypertension, total cholesterol, and APOEɛ4 carrier status for impaired cognition functions seen in patients with T2DM. In addition, comorbid T2DM can worsen the clinical presentations of patients with either AD or VaD. In summary, T2DM increases the risk for AD through different mechanisms for VaD although some mechanisms may overlap. Tau-related neurofibrillary tangles instead of amyloid-β plaques are more likely to be the pathological biomarkers for T2DM-related dementia. Degeneration of neurons in the brain, impaired regional blood supply/metabolism, and genetic predisposition are all involved in T2DM-associated dementia or cognitive impairments.

Validation of a Commercial Chemiluminescence Immunoassay for the Simultaneous Measurement of Three Different Amyloid-β Peptides in Human Cerebrospinal Fluid and Application to a Clinical Cohort. - Klafki, Hans-W; Hafermann, Henning; Bauer, Chris; Haussmann, Ute; Kraus, Inga; Schuchhardt, Johannes; Muck, Stephan; Scherbaum, Norbert; Wiltfang, Jens (J Alzheimers Dis, 2016)
A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloid-β peptides Aβ38, Aβ40, and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n = 203) were statistically significantly correlated with available ELISA data of Aβ1-40 (n = 158) and Aβ1-42 (n = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42/Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer's disease due to a normalization to total Aβ levels.

Validation of the Spanish version of the Baylor Profound Mental Status Examination. - Salmerón, Sergio; Huedo, Isabel; López-Utiel, Melisa; Soler-Moratalla, Isabel; Flores-Ruano, Teresa; Fernández-Sánchez, Miguel; Noguerón, Alicia; Doody, Rachelle S; Abizanda, Pedro (J Alzheimers Dis, 2016)
BACKGROUND: There are no short valid instruments to evaluate cognitive status in severe Alzheimer's disease (AD) patients in the Spanish language. OBJECTIVE: To validate the Spanish version of the Baylor Profound Mental Status Examination (BPMSE-Sp). METHODS: The Baylor Profound Mental Status Examination (BPMSE) was translated to Spanish and back translated. Validation was conducted in 100 patients with severe probable AD with a Mini-Mental State Examination (MMSE) <12. We assessed internal consistency (Cronbach's alpha), concurrent validity (Pearson's correlations) with the MMSE, Severe Impairment Battery (SIB), Neuropsychiatric Inventory Short Form (NPI-Q) and the Functional Assessment Staging and reliability. RESULTS: The mean age of patients was 84.9; 74% were female; 64% were institutionalized. The mean MMSE was 5.6; the mean BPMSE-Sp was 13.6; the mean BPMSE-Sp behavior was 1.2; the mean SIB was 42.2; and the mean NPI-Q was 4.7. BPMSE-Sp presented good internal consistency (Cronbach α= 0.84). There were significant correlations between the BPMSE-Sp and MMSE (r = 0.86, p <  0.001), and between the BPMSE-Sp and SIB (r = 0.92, p <  0.001). Inter-rater and test-retest reliability were in both cases excellent, ranging between 0.96 and 0.99 (p <  0.001). BPMSE-Sp had fewer floor and ceiling effects than the MMSE. CONCLUSIONS: The BPMSE-Sp is a valid tool for use in daily practice and research in the evaluation of cognitive function of patients with severe AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Cognition Disorders; Female; Humans; Language; Male; Mental Status Schedule; Neuropsychological Tests; Reproducibility of Results; Severity of Illness Index; Spain

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.

The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. - Jefferson, Angela L; Gifford, Katherine A; Acosta, Lealani Mae Y; Bell, Susan P; Donahue, Manus J; Davis, L Taylor; Gottlieb, JoAnn; Gupta, Deepak K; Hohman, Timothy J; Lane, Elizabeth M; Libon, David J; Mendes, Lisa A; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Blood Pressure Monitoring, Ambulatory; Brain; Case-Control Studies; Cerebral Angiography; Cognitive Dysfunction; Echocardiography; Epidemiologic Research Design; Female; Follow-Up Studies; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Research Design

Vascular Contributions in Alzheimer's Disease-Related Neuropathological Changes: First Autopsy Evidence from a South Asian Aging Population. - Wijesinghe, Printha; Shankar, S K; Yasha, T C; Gorrie, Catherine; Amaratunga, Dhammika; Hulathduwa, Sanjayah; Kumara, K Sunil; Samarasinghe, Kamani; Suh, Yoo-Hun; Steinbusch, Harry W M; De Silva, K Ranil D (J Alzheimers Dis, 2016)
BACKGROUND: Evidence from various consortia on vascular contributions has been inconsistent in determining the etiology of sporadic Alzheimer's disease (AD). OBJECTIVE: To investigate vascular risk factors and cerebrovascular pathologies associated in manifestation of AD-related neuropathological changes of an elderly population. METHODS: Postmortem brain samples from 76 elderly subjects (≥50 years) were used to study genetic polymorphisms, intracranial atherosclerosis of the circle of Willis (IASCW), and microscopic infarcts in deep white matters. From this cohort, 50 brains (≥60 years) were subjected to neuropathological diagnosis using immunohistopathological techniques. RESULTS: Besides the association with age, the apolipoprotein E ɛ4 allele was significantly and strongly associated with Thal amyloid-β phases ≥1 [odds ratio (OR) = 6.76, 95% confidence interval (CI) 1.37-33.45] and inversely with Braak neurofibrillary tangle (NFT) stages ≥III (0.02, 0.0-0.47). Illiterates showed a significant positive association for Braak NFT stages ≥IV (14.62, 1.21-176.73) and a significant negative association for microscopic infarcts (0.15, 0.03-0.71) in deep white matters. With respect to cerebrovascular pathologies, cerebral small vessel lesions (white matter hyperintensities and cerebral amyloid angiopathy) showed a higher degree of associations among them and with AD-related neuropathological changes (p < 0.05) compared to large vessel pathology (IASCW), which showed a significant association only with Braak NFT stages ≥I (p = 0.050). CONCLUSION: These findings suggest that besides age, education, and genetic factors, other vascular risk factors were not associated with AD-related neuropathological changes and urge prompt actions be taken against cerebral small vessel diseases since evidence for effective prevention is still lacking.

Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder. - Takahashi, Sho; Mizukami, Katsuyoshi; Arai, Tetsuaki; Ogawa, Ryoko; Kikuchi, Norihiro; Hattori, Satoshi; Darby, David; Asada, Takashi (J Alzheimers Dis, 2016)
BACKGROUND: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB. OBJECTIVE: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD. METHODS: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy. RESULTS: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters. CONCLUSION: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.
Keywords: 3-Iodobenzylguanidine; Aged; Aged, 80 and over; Depressive Disorder, Major; Follow-Up Studies; Heart Rate; Humans; Hypercapnia; Hypotension, Orthostatic; Kaplan-Meier Estimate; Lewy Body Disease; Middle Aged; Partial Pressure; Psychiatric Status Rating Scales; Retrospective Studies; Ventilators, Mechanical

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

Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus. - Herukka, Sanna-Kaisa; Rummukainen, Jaana; Ihalainen, Jouni; von Und Zu Fraunberg, Mikael; Koivisto, Anne M; Nerg, Ossi; Puli, Lakshman K; Seppälä, Toni T; Zetterberg, Henrik; Pyykkö, Okko T; Helisalmi, Seppo; Tanila, Heikki; et al. (J Alzheimers Dis, 2015)
Background: Amyloid-β (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1-42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1-42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1-42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.

Ankle-Brachial Index but Neither Intima Media Thickness Nor Coronary Artery Calcification is Associated With Mild Cognitive Impairment. - Weimar, Christian; Winkler, Angela; Dlugaj, Martha; Lehmann, Nils; Hennig, Frauke; Bauer, Marcus; Kröger, Knut; Kälsch, Hagen; Mahabadi, Amir-Abass; Dragano, Nico; Moebus, Susanne; Hoffmann, Barbara; et al. (J Alzheimers Dis, 2015)
BACKGROUND: Several studies have reported an association of atherosclerosis with mild cognitive impairment (MCI) and dementia independent of cardiovascular risk factors. OBJECTIVE: To compare the cross-sectional association of the ankle-brachial index (ABI), intima media thickness (IMT), and coronary artery calcification (CAC) with MCI and its subtypes, amnestic MCI (aMCI) and non-amnestic MCI (naMCI) in the population-based Heinz Nixdorf Recall cohort study. METHODS: 4,086 participants performed a validated brief cognitive assessment at the first follow-up examination (2006-2008). MCI was diagnosed according to previously published criteria. Prevalence ratio (PR) regression models adjusted for age, gender, education, cardiovascular risk factors, and APOE genotype were used to compare the association of the ABI, the CAC-Agatston score and the IMT with MCI and its subtypes. RESULTS: We identified 490 participants with MCI (mean age 66.1 ± 7.8, 46.9 % male, aMCI n = 249, naMCI n = 241) and 1,242 cognitively normal participants. A decreasing ABI (per 0.1) was significantly associated with a higher MCI prevalence in fully adjusted models (PR 1.06; 95% confidence interval (CI) 1.01-1.11), whereas an increasing CAC (log(CAC+1)) or IMT (per 0.1 mm) were not associated after adjustment. A decreasing ABI was also significantly associated with naMCI in fully adjusted models (PR 1.12; CI 1.03-1.21) but not with aMCI. CONCLUSIONS: Our data show that the degree of generalized atherosclerosis as measured by the ABI is associated with MCI and with naMCI in a population-based cohort.

APOE Affects the Volume and Shape of the Amygdala and the Hippocampus in Mild Cognitive Impairment and Alzheimer's Disease: Age Matters. - Tang, Xiaoying; Holland, Dominic; Dale, Anders M; Miller, Michael I (J Alzheimers Dis, 2015)
This paper examines how age intervenes in the effects of APOE ɛ4 allele on the volume and shape morphometrics of the hippocampus and the amygdala in mild cognitive impairment (MCI) and Alzheimer's disease. We evaluate the structural morphological differences between ɛ4 carriers and non-carriers in two age-dependent subgroups; younger than 75 years (Young-Old) and older than 80 years (Very-Old). While we show that the four structures of interest atrophy significantly in the ɛ4 carriers, relative to the non-carriers, of the Young-Old group, this effect is not observed in their Very-Old counterparts. The structures in the right hemisphere are found to be more affected by the APOE genotype than those in the left hemisphere and we identify the relevant regions in which significant atrophy occurs to be parts of the basolateral, centromedial, and lateral nucleus subregions of the amygdala and the CA1 and subiculum subregions of the hippocampus. We also observe that the APOE genotype only affects MCI patients that deteriorated to dementia within 3 years while leaving their "non-converting" counterparts unaffected.

AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer's Disease. - Bielarczyk, Hanna; Jankowska-Kulawy, Agnieszka; Hofling, Corinna; Ronowska, Anna; Gul-Hinc, Sylwia; Rossner, Steffen; Schliebs, Reinhard; Pawelczyk, Tadeusz; Szutowicz, Andrzej (J Alzheimers Dis, 2015)
The pyruvate-derived acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of pyruvate dehydrogenase in the neocortex are common features of Alzheimer's disease and other age-related encephalopathies in humans. Therefore, amyloid-β overload in brains of diverse transgenic Alzheimer's disease model animals was investigated as one of neurotoxic compounds responsible for pyruvate dehydrogenase inhibition yielding deficits of cholinergic neurotransmission and cognitive functions. Brains of aged, 14-16-month-old Tg2576 mice contained 0.6 μmol/kg levels of amyloid-β 1-42. Activities of pyruvate dehydrogenase complex, choline acetyltransferase, and several enzymes of acetyl-CoA and energy metabolism were found to be unchanged in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least cholinergic neuronal cells. However, in transgenic brain synaptosomes, pyruvate utilization, mitochondrial levels, and cytoplasmic acetyl-CoA levels, as well as acetylcholine content and its quantal release, were all found to be decreased by 25-40% . On the contrary, activation of pyruvate utilization was detected and no alterations in acetyl-CoA content and citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that amyloid-β evoked deficits in acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving path for further stages of neurodegeneration. On the other hand, acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite amyloid-β accumulated in transgenic brains.

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.

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.

Clinical Benefits for Older Alzheimer's Disease Patients: Okayama Late Dementia Study (OLDS). - Matsuzono, Kosuke; Yamashita, Toru; Ohta, Yasuyuki; Hishikawa, Nozomi; Sato, Kota; Kono, Syoichiro; Deguchi, Kentaro; Nakano, Yumiko; Abe, Koji (J Alzheimers Dis, 2015)
BACKGROUND/OBJECTIVE: There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting. METHODS: "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy. RESULTS: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p <  0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p <  0.05), and memantine (3 and 6 months,  *p <  0.05) and rivastigmine (3 months,  **p <  0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p <  0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p <  0.05), as did female Geriatric Depression Scale scores at 6 months ( *p <  0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p <  0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p <  0.05). CONCLUSION: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

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.

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.

Depressive Symptoms and Biomarkers of Alzheimer's Disease in Cognitively Normal Older Adults. - Donovan, Nancy J; Hsu, David C; Dagley, Alexander S; Schultz, Aaron P; Amariglio, Rebecca E; Mormino, Elizabeth C; Okereke, Olivia I; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A (J Alzheimers Dis, 2015)
Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, "subthreshold symptoms of depression" are associated with Alzheimer's disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS >10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p = 0.03) was significantly associated with lower HV and was marginally related (p = 0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p = 0.02) and Apathy-Anhedonia (p = 0.05) were related to lower HV while higher Apathy-Anhedonia (p = 0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden.

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.

The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. - Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Niehoff, Michael L; Morley, John E; Jelsing, Jacob; Pyke, Charles; Bjerre Knudsen, Lotte; Farr, Susan A; Vrang, Niels (J Alzheimers Dis, 2015)
Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by Aβ plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of Aβ plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.

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.

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

C9orf72 nucleotide repeat structures initiate molecular cascades of disease. - Haeusler, Aaron R; Donnelly, Christopher J; Periz, Goran; Simko, Eric A J; Shaw, Patrick G; Kim, Min-Sik; Maragakis, Nicholas J; Troncoso, Juan C; Pandey, Akhilesh; Sattler, Rita; Rothstein, Jeffrey D; Wang, Jiou (Nature, 2014)
A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Keywords: Amyotrophic Lateral Sclerosis; B-Lymphocytes; Base Sequence; Cell Nucleolus; DNA; DNA Repeat Expansion; Frontotemporal Dementia; G-Quadruplexes; HEK293 Cells; Humans; Models, Molecular; Neurons; Open Reading Frames; Phosphoproteins; Ribonucleoproteins; RNA; RNA-Binding Proteins; Stress, Physiological; Transcription, Genetic

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

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

Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. - Salloway, Stephen; Sperling, Reisa; Fox, Nick C; Blennow, Kaj; Klunk, William; Raskind, Murray; Sabbagh, Marwan; Honig, Lawrence S; Porsteinsson, Anton P; Ferris, Steven; Reichert, Marcel; Ketter, Nzeera; et al. (N Engl J Med, 2014)
BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Apolipoproteins E; Biomarkers; Brain; Cognition; Double-Blind Method; Edema; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Neuropsychological Tests; Phosphorylation; Positron-Emission Tomography; Severity of Illness Index; tau Proteins; Treatment Failure

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

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

Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. - Buchhave, Peder; Minthon, Lennart; Zetterberg, Henrik; Wallin, Asa K; Blennow, Kaj; Hansson, Oskar (Arch Gen Psychiatry, 2012)
CONTEXT: Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease. OBJECTIVES: To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD. DESIGN: A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years). SETTING: Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia. RESULTS: During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%. CONCLUSIONS: Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Follow-Up Studies; Humans; Male; Mild Cognitive Impairment; Peptide Fragments; Predictive Value of Tests; tau Proteins; Time Factors

Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. - Talbot, Konrad; Wang, Hoau-Yan; Kazi, Hala; Han, Li-Ying; Bakshi, Kalindi P; Stucky, Andres; Fuino, Robert L; Kawaguchi, Krista R; Samoyedny, Andrew J; Wilson, Robert S; Arvanitakis, Zoe; Schneider, Julie A; et al. (J Clin Invest, 2012)
While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Brain; Cerebellar Cortex; Cognition Disorders; Diabetes Complications; Drug Resistance; Female; Glucose; Hippocampus; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Like Growth Factor I; Male; Middle Aged; Phosphorylation; Phosphoserine; Protein Processing, Post-Translational; Recombinant Proteins; Signal Transduction

An epigenetic blockade of cognitive functions in the neurodegenerating brain. - Gräff, Johannes; Rei, Damien; Guan, Ji-Song; Wang, Wen-Yuan; Seo, Jinsoo; Hennig, Krista M; Nieland, Thomas J F; Fass, Daniel M; Kao, Patricia F; Kahn, Martin; Su, Susan C; Samiei, Alireza; et al. (Nature, 2012)
Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
Keywords: Acetylation; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Epigenesis, Genetic; Gene Expression Regulation; Gene Knockdown Techniques; Hippocampus; Histone Deacetylase 2; Histones; Humans; Hydrogen Peroxide; Memory Disorders; Mice; Neurodegenerative Diseases; Neuronal Plasticity; Peptide Fragments; Phosphorylation; Promoter Regions, Genetic; Receptors, Glucocorticoid; RNA Polymerase II

Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. - Head, Denise; Bugg, Julie M; Goate, Alison M; Fagan, Anne M; Mintun, Mark A; Benzinger, Tammie; Holtzman, David M; Morris, John C (Arch Neurol, 2012)
OBJECTIVE: APOE ε4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. DESIGN: APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. SETTING: Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri. PARTICIPANTS: A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer's Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants. RESULTS: APOE ε4 carriers evidenced higher [(11)C]PiB binding (P<.001) and lower CSF Aβ42 levels (P<.001) than did noncarriers. Our previous findings of higher [(11)C]PiB binding (P=.005) and lower CSF Aβ42 levels (P=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [(11)C]PiB binding (P=.008) such that a more sedentary lifestyle was significantly associated with higher [(11)C]PiB binding for ε4 carriers (P=.013) but not for noncarriers (P=.20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments. CONCLUSION: Collectively, these results suggest that cognitively normal sedentary APOE ε4-positive individuals may be at augmented risk for cerebral amyloid deposition.
Keywords: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Cognition; Cohort Studies; Exercise; Female; Genetic Association Studies; Genotype; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Regression Analysis; Surveys and Questionnaires; Thiazoles

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. - Jonsson, Thorlakur; Atwal, Jasvinder K; Steinberg, Stacy; Snaedal, Jon; Jonsson, Palmi V; Bjornsson, Sigurbjorn; Stefansson, Hreinn; Sulem, Patrick; Gudbjartsson, Daniel; Maloney, Janice; Hoyte, Kwame; Gustafson, Amy; et al. (Nature, 2012)
The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.
Keywords: Aging; Alleles; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cognition; Cognition Disorders; Genetic Predisposition to Disease; HEK293 Cells; Humans; Mutation; Plaque, Amyloid

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

Astrocyte-neuron lactate transport is required for long-term memory formation. - Suzuki, Akinobu; Stern, Sarah A; Bozdagi, Ozlem; Huntley, George W; Walker, Ruth H; Magistretti, Pierre J; Alberini, Cristina M (Cell, 2011)
We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.
Keywords: Animals; Arabinose; Astrocytes; Glycogen; Hippocampus; Imino Furanoses; Lactic Acid; Memory, Long-Term; Monocarboxylic Acid Transporters; Muscle Proteins; Neurons; Rats; Sugar Alcohols; Symporters

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

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

Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. - Petersen, R C; Aisen, P S; Beckett, L A; Donohue, M C; Gamst, A C; Harvey, D J; Jack, C R; Jagust, W J; Shaw, L M; Toga, A W; Trojanowski, J Q; Weiner, M W (Neurology, 2010)
BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally. OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures. METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials. RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures. CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cross-Sectional Studies; Diagnostic Imaging; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged

APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. - Morris, John C; Roe, Catherine M; Xiong, Chengjie; Fagan, Anne M; Goate, Alison M; Holtzman, David M; Mintun, Mark A (Ann Neurol, 2010)
OBJECTIVE: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging. METHODS: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE. RESULTS: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181). INTERPRETATION: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Brain; Female; Follow-Up Studies; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Phosphorylation; Plaque, Amyloid; tau Proteins; Thiazoles

Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. - Miller, Jeremy A; Horvath, Steve; Geschwind, Daniel H (Proc Natl Acad Sci U S A, 2010)
Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human, we took a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression across multiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.
Keywords: Alzheimer Disease; Animals; Brain; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Mice; Presenilin-1; Systems Biology

Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. - He, Gen; Luo, Wenjie; Li, Peng; Remmers, Christine; Netzer, William J; Hendrick, Joseph; Bettayeb, Karima; Flajolet, Marc; Gorelick, Fred; Wennogle, Lawrence P; Greengard, Paul (Nature, 2010)
Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer's disease. Formation of amyloid-beta is catalysed by gamma-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective gamma-secretase inhibitors that can reduce amyloid-beta formation without impairing cleavage of other gamma-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increases amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-beta and plaque development. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-beta formation without affecting Notch cleavage, achieves its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Benzamides; Cell Line; Disease Models, Animal; Gene Knockdown Techniques; Humans; Imatinib Mesylate; Mice; Peptide Fragments; Piperazines; Proteins; Pyrimidines; Receptor, Notch1; RNA Interference

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

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