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Alzheimer's Research & Therapy

Stephen Salloway, Lee A Honigberg, William Cho, Michael Ward, Michel Friesenhahn, Flavia Brunstein, Angelica Quartino, David Clayton, Deborah Mortensen, Tobias Bittner, Carole Ho, Christina Rabe, Stephen P Schauer, Kristin R Wildsmith, Reina N Fuji, Shehnaaz Suliman, Eric M Reiman, Kewei Chen, Robert Paul
BACKGROUND: We investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer's disease (AD). METHODS: This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18-26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks...
September 19, 2018: Alzheimer's Research & Therapy
Sylvie L Lesuis, Lianne Hoeijmakers, Aniko Korosi, Susanne R de Rooij, Dick F Swaab, Helmut W Kessels, Paul J Lucassen, Harm J Krugers
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a high prevalence among the elderly and a huge personal and societal impact. Recent epidemiological studies have indicated that the incidence and age of onset of sporadic AD can be modified by lifestyle factors such as education, exercise, and (early) stress exposure. Early life adversity is known to promote cognitive decline at a later age and to accelerate aging, which are both primary risk factors for AD...
September 19, 2018: Alzheimer's Research & Therapy
Alberto Benussi, Antonella Alberici, Clarissa Ferrari, Valentina Cantoni, Valentina Dell'Era, Rosanna Turrone, Maria Sofia Cotelli, Giuliano Binetti, Barbara Paghera, Giacomo Koch, Alessandro Padovani, Barbara Borroni
BACKGROUND: Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0-100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis...
September 18, 2018: Alzheimer's Research & Therapy
Yu An, Lingli Feng, Xiaona Zhang, Ying Wang, Yushan Wang, Lingwei Tao, Yanhui Lu, Zhongsheng Qin, Rong Xiao
BACKGROUND: The principal aim of this study was to demonstrate the gender-specific cognitive patterns among middle-aged and elderly Chinese adults, investigate the risk factors on global and domain-specific cognitive performance in men and women, respectively, and report demographically adjusted norms for cognitive tests. METHODS: The Effects and Mechanism of Cholesterol and Oxysterol on Alzheimer's disease (EMCOA) study enrolled 4573 participants aged 50-70 years in three Chinese cities...
September 15, 2018: Alzheimer's Research & Therapy
A Mouton, F Blanc, A Gros, V Manera, R Fabre, E Sauleau, I Gomez-Luporsi, K Tifratene, L Friedman, S Thümmler, C Pradier, P H Robert, R David
BACKGROUND: Gender distribution varies across neurodegenerative disorders, with, traditionally, a higher female frequency reported in Alzheimer's disease (AD) and a higher male frequency in Parkinson's disease (PD). Conflicting results on gender distribution are reported concerning dementia with Lewy bodies (DLB), usually considered as an intermediate disease between AD and PD. The aim of the present study was to investigate gender differences in DLB in French specialized memory settings using data from the French national database spanning from 2010 to 2015 and to compare sex ratio in DLB with that in AD, Parkinson's disease dementia (PDD), and PD...
September 12, 2018: Alzheimer's Research & Therapy
Michael Malek-Ahmadi, Kewei Chen, Sylvia E Perez, Anna He, Elliott J Mufson
BACKGROUND: Cognitive composite scores are used as the primary outcome measures for Alzheimer's disease (AD) prevention trials; however, the extent to which these composite measures correlate with AD pathology has not been fully investigated. Since many on-going AD prevention studies are testing therapies that target either amyloid or tau, we sought to establish an association between a cognitive composite score and the underlying pathology of AD. METHODS: Data from 192 older deceased and autopsied persons from the Rush Religious Order Study were used in this study...
September 11, 2018: Alzheimer's Research & Therapy
Anna Catharina van Loenhoud, Colin Groot, Jacob William Vogel, Wiesje Maria van der Flier, Rik Ossenkoppele
Brain reserve is a concept introduced to explain why Alzheimer's disease (AD) patients with a greater brain volume prior to onset of pathology generally have better clinical outcomes. In this review, we provide a historical background of the emergence of brain reserve and discuss several aspects that need further clarification, including the dynamic or static nature of the concept and its underlying mechanisms and clinical effect. We then describe how brain reserve has been operationalized over the years, and critically evaluate the use of intracranial volume (ICV) as the most widely used proxy for brain reserve...
September 11, 2018: Alzheimer's Research & Therapy
Shraddha Sapkota, Joel Ramirez, Donald T Stuss, Mario Masellis, Sandra E Black
BACKGROUND: Interindividual differences in cognitive reserve (CR) are associated with complex and dynamic clinical phenotypes observed in cognitive impairment and dementia. We tested whether (1) CR early in life (E-CR; measured by education and IQ), (2) CR later in life (L-CR; measured by occupation), and (3) CR panel (CR-P) with the additive effects of E-CR and L-CR, act as moderating factors between baseline ventricular size and clinical dementia severity at baseline and across 2 years...
September 5, 2018: Alzheimer's Research & Therapy
Piotr Lewczuk, Amélie Gaignaux, Olga Kofanova, Natalia Ermann, Fay Betsou, Sebastian Brandner, Barbara Mroczko, Kaj Blennow, Dominik Strapagiel, Silvia Paciotti, Jonathan Vogelgsang, Michael H Roehrl, Sandra Mendoza, Johannes Kornhuber, Charlotte Teunissen
BACKGROUND: In this study, we tested to which extent possible between-center differences in standardized operating procedures (SOPs) for biobanking of cerebrospinal fluid (CSF) samples influence the homogeneity of the resulting aliquots and, consequently, the concentrations of the centrally analyzed selected Alzheimer's disease biomarkers. METHODS: Proficiency processing samples (PPSs), prepared by pooling of four individual CSF samples, were sent to 10 participating centers, which were asked to perform aliquoting of the PPSs into two secondary aliquots (SAs) under their local SOPs...
August 28, 2018: Alzheimer's Research & Therapy
Taylor J Maxwell, Chris Corcoran, Jorge L Del-Aguila, John P Budde, Yuetiva Deming, Carlos Cruchaga, Alison M Goate, John S K Kauwe
BACKGROUND: A relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus. Relationship quantitative trait loci (rQTL) are often involved in gene-by-gene (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G. METHODS: We performed genome-wide association studies to identify rQTL between tau and Aβ42 and ptau and Aβ42 with over 3000 individuals using age, gender, series, APOE ε2, APOE ε4, and two principal components for population structure as covariates...
August 28, 2018: Alzheimer's Research & Therapy
Roy W E Van Hooren, Joost M Riphagen, Heidi I L Jacobs
BACKGROUND: Amyloid-beta (Aβ) has a dose-response relationship with cognition in healthy adults. Additionally, the levels of functional connectivity within and between brain networks have been associated with cognitive performance in healthy adults. Aiming to explore potential synergistic effects, we investigated the relationship of inter-network functional connectivity, Aβ burden, and memory decline among healthy individuals and individuals with preclinical, prodromal, or clinical Alzheimer's disease...
August 28, 2018: Alzheimer's Research & Therapy
Maarten Timmers, Johannes Rolf Streffer, Alberto Russu, Yushin Tominaga, Hiroko Shimizu, Ayako Shiraishi, Kanaka Tatikola, Pascale Smekens, Anne Börjesson-Hanson, Niels Andreasen, Jorge Matias-Guiu, Miquel Baquero, Mercè Boada, Ina Tesseur, Luc Tritsmans, Luc Van Nueten, Sebastiaan Engelborghs
BACKGROUND: β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS: In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0...
August 23, 2018: Alzheimer's Research & Therapy
Dahyun Yi, Younghwa Lee, Min Soo Byun, Jun Ho Lee, Kang Ko, Bo Kyung Sohn, Young Min Choe, Hyo Jung Choi, Hyewon Baek, Chul-Ho Sohn, Yu Kyeong Kim, Dong Young Lee
BACKGROUND: Recently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer's disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks-the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)-on AD-related brain changes in cognitively normal (CN) middle-aged and older adults. METHODS: [11 C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [18 F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE)...
August 23, 2018: Alzheimer's Research & Therapy
Ashwati Vipin, Yng Miin Loke, Siwei Liu, Saima Hilal, Hee Youn Shim, Xin Xu, Boon Yeow Tan, Narayanaswamy Venketasubramanian, Christopher Li-Hsian Chen, Juan Zhou
BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns...
August 18, 2018: Alzheimer's Research & Therapy
Monica H Breitve, Kolbjørn Brønnick, Luiza J Chwiszczuk, Minna J Hynninen, Dag Aarsland, Arvid Rongve
BACKGROUND: Little is known about the consequences of apathy in dementia with Lewy bodies (DLB), because previous research on apathy in dementia focused mainly on Alzheimer's disease (AD). METHODS: In this longitudinal study, we included patients with AD (n = 128) and patients with DLB (n = 81). At baseline, we analyzed the associations between apathy and cognition in the total sample and in AD and DLB separately. Generalized linear mixed models were used to investigate the association between apathy and Mini Mental State Examination (MMSE) over 4 years, and the Kaplan-Meier method was used to assess the association between apathy and survival or nursing home admission...
August 18, 2018: Alzheimer's Research & Therapy
Hua Zhang, Joseph Therriault, Min Su Kang, Kok Pin Ng, Tharick A Pascoal, Pedro Rosa-Neto, Serge Gauthier
BACKGROUND: There is accumulating evidence that synaptic loss precedes neuronal loss and correlates best with impaired memory formation in Alzheimer's disease (AD). Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) is a newly discovered marker indicating synaptic damage. We here test CSF SNAP-25 and SNAP-25/amyloid-β42 (Aβ42) ratio as a diagnostic marker for predicting cognitive decline and brain structural change in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database...
August 16, 2018: Alzheimer's Research & Therapy
Sudhanshu Agrawal, Edsel M Abud, Shikha Snigdha, Anshu Agrawal
BACKGROUND: The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (Aβ) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of Aβ. METHODS: We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjects to Aβ peptide 1-42, Aβ fibrils, and recombinant, nonaggregated tau-4 protein with a view to understand the role of peripheral immunity in AD...
August 16, 2018: Alzheimer's Research & Therapy
Ione O C Woollacott, Jennifer M Nicholas, Amanda Heslegrave, Carolin Heller, Martha S Foiani, Katrina M Dick, Lucy L Russell, Ross W Paterson, Ashvini Keshavan, Nick C Fox, Jason D Warren, Jonathan M Schott, Henrik Zetterberg, Jonathan D Rohrer
BACKGROUND: Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer's disease (AD), but they have not been fully explored in FTD. METHODS: We investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers)...
August 16, 2018: Alzheimer's Research & Therapy
Carolyn W Zhu, Bote Gosse Bruinsma, Yaakov Stern
BACKGROUND: The concept of dependence has been proposed as a unified representation of disease severity to quantify and stage disease progression in a manner more informative to patients, caregivers, and healthcare providers. METHODS: This paper provides a review of the Dependence Scale (DS) as a quantitative measure of Alzheimer's disease severity, its properties as an outcome measure, a metric of disease progression, and a correlate of medical costs. RESULTS: The literature supports the notion that the DS is related to, but distinct from, key severity measures, including cognition, function, and behavior, and captures the full spectrum of patient needs...
August 13, 2018: Alzheimer's Research & Therapy
Niklas Mattsson, Rik Ossenkoppele, Ruben Smith, Olof Strandberg, Tomas Ohlsson, Jonas Jögi, Sebastian Palmqvist, Erik Stomrud, Oskar Hansson
BACKGROUND: Alzheimer's disease is characterized by aggregated β-amyloid and tau proteins, but the clinical presentations and patterns of brain atrophy vary substantially. A part of this heterogeneity may be linked to the risk allele APOE ε4. The spread of tau pathology is related to atrophy and cognitive decline, but little data exist on the effects of APOE ε4 on tau. The objective of this preliminary study was therefore to test if tau load and brain structure differ by APOE ε4 in Alzheimer's disease...
August 7, 2018: Alzheimer's Research & Therapy
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