bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding the effect of fatigue on the association between sleep disturbances and cognitive function ability among cognitively impaired older adults
Authors: Kerner Nancy , Cohen Hannah , Scodes Jennifer , Bell Sophie , Goldberg Terry E. , Westwood Andrew , Devanand Davangere P. 
Published: December 2020

AbstractBackgroundFatigue is associated with neuroinflammation of the brain, one of the signatures of neurodegenerative disorders across preclinical and clinical stages. Substantial research evidence demonstrates a bidirectional link between Alzheimer’s neuropathology and poor sleep. Whether neuroinflammation mediates the association between sleep disturbances and cognitive decline remains to be determined. In this pilot study, we examined whether fatigue impacts the relationship between sleep quality and cognitive function ability.MethodWe prospectively recruited adults aged 55‐90 years with mild cognitive impairment to evaluate their symptoms of Fatigue, Sleep, and Cognitive Function Abilities (CFA), using the NIH PROMIS Fatigue short form (v1.0), Sleep Disturbances (SD, v2.0) and Sleep‐related Impairment short form (SRI v2.0), as well as the NIH Neuro‐QOL Cognitive Function Abilities short form (v1.0). The Poor‐sleep group was defined as a T‐score of >50 on either SD or SRI scale. Depression was defined as a Geriatric Depression Scale score of 5 or greater and was a study exclusion criterion.ResultTwenty‐seven patients enrolled in the study, including 14 women and 13 men. The mean age was 67.37+/‐ 9.00 years. The Poor‐sleep group had significantly lower CFA compared to the Good‐sleep group (b=‐6.28, p=0.019). Greater Fatigue scores were significantly associated with lower Cognitive Function Abilities scores (r=.49, p=0.010). These results remained significant after controlling for age. Further, total scale SRI score was significantly associated with total scale Fatigue score (r=.72, p<0.001).ConclusionBoth fatigue and sleep disturbances were significantly associated with low CFA independently, along with a significant correlation between fatigue and poor sleep. The mechanisms by which fatigue and sleep disturbances contribute to cognitive test performance need to be elucidated in future research.
Efavirenz as a cholesterol‐targeting drug for AD
Authors: Pikuleva Irina A. 
Published: December 2020

AbstractBackgroundCytochrome P450 46A1 (CYP46A1) is the CNS‐specific cholesterol 24‐hydroxylase that controls cholesterol elimination and turnover in the brain. Efavirenz (EFV) is the FDA‐approved reverse transcriptase inhibitor given to HIV subjects at the 600 mg per day dose. We discovered that small doses of EFV allosterically activate CYP46A1 in mice and are evaluating whether CYP46A1 could be a pharmacologic target for Alzheimer’s disease (AD) and EFV as a disease‐modifying anti‐AD medication.MethodClinical and animal studies investigating EFV. Clinical studies include a proof‐of‐concept clinical trial in patients with AD. Animal studies include multiple in vivo and in vitro assessments of 5XFAD mice (an AD model) after the treatment with a small dose (0.1 mg/kg body weight) of EFV.ResultA small dose of EFV activates CYP46A1 and improves behavioral performance of 5XFAD mice; the effect on the amyloid b burden is the treatment paradigm‐specific. The omics and other approaches suggest that the CYP46A1 activity modulation affects multiple signaling pathways and processes via the effects on the physicochemical properties of the plasma membranes. EFV analogs were found, which in vitro are even better CYP46A1 activators than EFV.ConclusionAll our available data suggest that CYP46A1 is a viable therapeutic target for AD, and EFV could be the first generation medication that targets cholesterol metabolism and turnover in AD. Supported by the NIH AG067552 grant and the Alzheimer’s Drug Discovery Foundation grant GC‐2012681.
Onset of motor deficits, but not their severity, is augmented by TREM2 reduction in P301S tau transgenic mice
Authors: Feiten Astrid F. , van Hummel Annika , van der Hoven Julia , Przybyla Magdalena , Deng Yuanyuan , Delerue Fabien , Ke Yazi D. , Ittner Lars M. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterised by extracellular amyloid‐β plaques and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. These two pathological hallmarks have been explored for decades however it remains not fully understood how they interact with each other and how they trigger disease onset and progression. Recently, in genome wide association studies other genetic risk factors have been identified. One of them being polymorphisms of the triggering receptor expressed on myeloid cells 2 (TREM2). The effects of TREM2 on disease and especially in the context of tau pathology remain poorly understood and the current literature is conflicting.MethodsHere, we have examined the effect of TREM2 on tau pathology in an P301S tau transgenic mouse model, TAU58/2. TAU58/2 mice are characterised by an early onset and progressive NFT pathology and behavioural, motor and memory deficits. TREM2 knockout (KO) mice were crossed with TAU58/2 transgenic mice and subjected to a variety of functional tests including RotaRod, elevated plus maze, open field and Morris water maze at different age time points. After behavioural assessment brains were collected and histological analysis performed.ResultsAt 2 months of age TAU58/2 mice present with moderate motor deficits on the RotaRod, this phenotype was significantly aggravated upon TREM2 reduction and complete depletion. Further, we found that TREM2 KO induces a disinhibition like phenotype in older TAU58/2 non transgenic animals. Histological analysis revealed an increase in cells positive for tau phosphorylated at serine 422, a late stage pathology marker. Interestingly, knock out of TREM2 impacted on performance of transgenic and non‐transgenic mice differently.ConclusionTaken together, our results show that reducing TREM2 exacerbates the functional deficits of TAU58/2 transgenic mice. Furthermore, we found an accelerated progression of tau phosphorylation. Hence, our work suggests that reduction and loss of TREM2 function could contribute to functional deficits in AD via augmenting tau pathology.
Longer TOMM40 poly‐T variants associated with less regional gray matter in cognitively normal older APOE E3/E3 adults
Authors: Honea Robyn A , Vidoni Eric D , Morris Jill K , Michaelis Elias K , Burns Jeffrey M , Swerdlow Russell H 
Published: December 2020

AbstractBackgroundThe TOMM40 poly‐T is a polymorphism of the TOMM40 gene at rs10524523 (“523”), in linkage disequilibrium with APOE. The role of TOMM40 in Alzheimer’s disease risk is still controversial. We sought to use whole brain voxel‐based methods to investigate if older individuals with the absence of an APOE e4 allele with varying lengths of the TOMM40 Poly‐T allele had gray matter volume differences indicative of Alzheimer’s disease risk.MethodWe studied individuals without cognitive impairment (n = 69) from our KU Alzheimer’s Disease Center whose apolipoprotein (APOE) genotype was e3/e3, and who were Caucasian. The participants were grouped according to poly‐T length polymorphisms at “523” homozygous for S (S/S; n = 25), homozygous for VL (VL/VL; n = 19), and heterozygous (S/VL; n = 25). All individuals were scanned for T1‐weighted MPRAGE structural images using a 3T Skyra Siemens. Images were preprocessed and analyzed using CAT12, a Computational Anatomy Toolbox (http://www.neuro.uni‐jena.de/cat/) running under SPM12 and MATLAB (R2020a). To investigate associations between genotype and regional GM volume, we performed voxel‐based morphometry (VBM). In order to investigate associations between TOMM40 Poly‐T group and gray matter volume differences we included age, sex, and total intracranial volume (TIV), as variables of no interest in our full factorial model. The statistical threshold was set at Pheight < 0.05, corrected (FDR).ResultAll groups were similar and not significantly different in mean age, education, MMSE, and overall brain volume. Individuals with a VL/VL genotype had lower precuneus volumes (p = .023 FDR corrected, k = 213, ‐29, ‐84, 36) and temporal cortex volumes (p = .005 FDR corrected, k = 362, ‐45, ‐40, ‐32) compared to S/S individuals.ConclusionTOMM40 “523” VL variants are related to reduced gray matter volume in the precuneus and the temporal cortex in healthy individuals with an APOE e3/e3genotype. This is especially interesting as the precuneus has been identified in other studies, and it may be particularly sensitive to dysfunction in bioenergetic changes associated with faulty mitochondria. This adds to a growing literature implicating TOMM40 “523” and mitochondrial function in late‐onset Alzheimer’s disease progression.
Whole genome sequence association analyses of brain volumes in the TOPMed program
Authors: Sarnowski Chloé , Satizabal Claudia L. , Yanek Lisa R. , Bis Joshua C. , Smith Jennifer A , DeCarli Charles , Arnett Donna K. , Psaty Bruce M. , Nyquist Paul , Mathias Rasika A. , Destefano Anita L. , Seshadri Sudha ,   TOPMed Neurocognitive Working Group
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing whole genome association analyses using sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program.MethodsWe analyzed up to 3,975 participants (58% women; 78% Europeans, 22% African‐Americans), mean age of 62.5 (13.9), from four TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, and GENOA). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or any other finding affecting the scan. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes with individual genetic variants using mixed‐effect linear regression models adjusted for age, age2, sex, study and principal components. Models including HV, TBV and LVV were adjusted for ICV. We accounted for relatedness using a kinship matrix and trait variance variability using a random effects model. We retained variants with a minor allele count greater than 40.ResultsWe detected new genome‐wide significant (P < 5 × 10−8) low frequency or rare variants in five regions associated with HV (5q31, P = 10−9) and TBV (2p22, P = 10−8; 17q25, P = 4 × 10−9; Xp11, P = 2 × 10−10; Xq21, P = 4 × 10−8). We also confirmed previously observed common variants in GWAS loci for HV (12q14 & 12q24), LVV (3q28, 12q23 & 16q24) and ICV (6q21, 6q22 & 17q21). The top 5q31 hit for HV (rs246587) lies at 19kb from the PCDHAC2 gene, encoding neural cadherin‐like cell adhesion proteins that most likely play a critical role in the establishment and maintenance of specific neuronal connections in the brain.ConclusionsOur whole genome analysis revealed intriguing new loci associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, gene‐based and burden tests as well as the inclusion of additional TOPMed cohorts. Supported by: U01s AG058589, AG052409, R01s AG054076, AG033040 AG049607, HL112064, NS062059, FHS contracts HHSN268201500001I and 75N92019D00031, R01HL131136 (Analysis Commons).
Associations between ambient air pollution and Alzheimer pathologic change in humans: A secondary analysis of IDEAS study data
Authors: Iaccarino Leonardo , La Joie Renaud , Lesman‐Segev Orit H. , Lee Eunice , Hanna Lucy , Gatsonis Constantine , Rabinovici Gil D. 
Published: December 2020

AbstractBackgroundAmyloid accumulation is a defining feature of Alzheimer’s Disease (AD) and is a risk factor for cognitive decline and dementia. Previous cerebrospinal fluid and autopsy studies in humans have showed that brain β‐amyloid pathology may be promoted by exposure to air pollutants, possibly because of resulting chronic microglia activation and oxidative stress.MethodsWe tested the association between local concentrations of fine particulate matter (PM2.5) and ground‐level ozone (O3) and probability of amyloid‐PET positivity in 18,178 cognitively‐impaired participants from the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) study (age 75.8±6.3, N=10,991 Mild Cognitive Impairment (MCI) and N=7,187 Dementia, see Table 1 and Figure 1). The ambient concentration of airborne pollutants was estimated proximate to recorded patient residence zipcodes, using daily predictions from the Environmental Protection Agency (EPA) Downscaler model, which combines pollutant concentrations, photochemical properties and atmospheric data. Air quality data was collected considering two biennial time‐windows, i.e. 14‐years and 1‐year prior to amyloid‐PET (average quality in 2002‐2003 and 2015‐2016), to model early‐ and late exposure. Adjusted logistic models included demographic, lifestyle and socioeconomical factors as well as respiratory, cardiovascular, cerebrovascular, psychiatric and general health comorbidities.ResultsPeople residing in areas with higher predicted PM2.5 concentrations had a higher probability of being amyloid‐PET positive 14‐years later (odds ratio ‐ OR 1.10 [per 4 μg/m3 increase], 95%CI 1.05‐1.15, p<0.001). In sub‐group analyses, the association between PM2.5 and positive amyloid‐PET were significant in White/Caucasian, female and MCI participants. Exposure to higher predicted O3 concentrations was not associated with amyloid‐PET positivity overall (OR 1.03 [increase by 5 ppb], 95%CI 0.99‐1.06, p=0.11), but showed a significant association in females and in dementia patients. Similar relationships were observed with 2015‐2016 data. See Figure 2 for a complete summary of all logistic regression models.ConclusionsIncreasing air pollution, even within EPA standards, may directly impact brain health by promoting the accumulation of β‐amyloid plaques.
Towards a universal cortical tau sampling mask
Authors: Dore Vincent , Rowe Christopher C , Bourgeat Pierrick , Burnham Samantha C , Huang Kun , Krishnadas Natasha , Masters Colin L , Fripp Jurgen , Villemagne Victor LL 
Published: December 2020

AbstractBackgroundThe introduction of the A/T/(N) framework raised several issues regarding the definition of T+. In which region should tau scans be sampled? Based on which tracer? In this work, we developed a “universal” cortical tau mask derived from three major tau ligands for the AD continuum, over which several different global/regional sampling VOI or composites can be applied.Method221 healthy elderly controls (HC) and 67 Alzheimer’s disease (AD) patients underwent tau scans with either 18F‐AV1451 (HC=54/AD=24), 18F‐MK6240 (HC=157/AD=22) or 18F‐PI2620 (HC=10/AD=21). All HC were Ab‐ (<20CL) and all AD were Ab+(20CL). The tau scans were spatially normalized using CapAIBL and the cerebellum cortex was used as reference region. For each tracer, a difference image between the means of the Ab‐HC and Ab+AD patients was then generated. Difference images were subsequently thresholded at 1/3 of the difference between Ab‐HC and Ab+AD in the inferior temporal lobe.A MRI‐derived grey matter mask at PET resolution was applied to the composite mask to only sample cortical region. The mask was finally mirrored and fused to remove the hemispherical asymmetry due to the distribution of tau deposits in the assessed participants. Agreement between masks was assessed by dice‐scores.ResultVisually, the three tracer‐specific masks appeared very similar (Fig 1, rows 1‐3). None of the known off‐target binding regions was discernible in the resulting masks. There was good agreement between all masks, with dice‐scores of 0.60 and 0.66 for cortical regions.ConclusionWe constructed an “universal” tau mask for the AD continuum based on three commonly used tau tracers aiming at standardizing tau sampling (and quantification) across tracers and across centres. The “universal” tau mask can also be sub‐segmented into smaller regions to focus on specific areas or to construct a subset of composite masks that might better capture early tau deposition and spreading. Further refinement of the tau mask will require the addition of more tau tracers. (RO948, GTP1, PBB3, etc.).
Patterns of change in subjective cognitive complaints are associated with cognitive decline and dementia risk: Findings from the Sydney Memory and Ageing Study
Authors: Numbers Katya T. , Lam Ben C.P. , Crawford John D. , Kochan Nicole A. , Sachdev Perminder S. , Brodaty Henry 
Published: December 2020

AbstractBackgroundSubjective cognitive complaints (SCCs) are now an established risk factor for dementia, however, little is known about whether changing patterns in SCCs over time are associated with cognitive decline and dementia risk. We examine the trajectory of SCCs over a 6‐year period to determine whether intraindividual patterns of reporting SCCs over time is related to cognitive decline and incident dementia.MethodParticipants were 1037 older adults without dementia (M
age = 78.65 years; 55% females) from the Sydney Memory and Ageing Study who were followed‐up biennially. Global cognition was measured using a comprehensive neuropsychological battery, and clinical diagnoses were made by an expert consensus panel. SCCs were obtained as participants’ response to a single question concerning their subjective report of memory decline. Patterns of SCCs over time were modelled by conducting categorical latent growth curve analysis using the logit transformation (Figure 1). We examined the associations between average level of SCC likelihood and change in SCC likelihood, with global cognition over six years using latent growth curve analysis, and with risk of incident dementia over 10 years using Cox regression.ResultIn this community‐dwelling older adult sample, there was an annual 10% increase in the odds of reporting SCCs (Figure 2). After controlling for demographics, depression, and personality, results revealed a negative longitudinal association between the slope of SCCs and the slope of global cognition scores, such that participants with an increasing propensity of reporting SCCs over time also showed a steeper rate of decline in global cognition (Figure 4). Cox regression revealed an association between increased SCCs and incident dementia risk (Table 1). That is, participants with an increasing propensity of reporting SCCs over time are also at greater risk for developing dementia (Figure 5).ConclusionThis is the first study to use latent growth curve analysis to examine patterns of change in SCCs overtime. Traditionally, studies examining SCCs longitudinally categorise people as ‘stable’ versus ‘not stable’, however, important information may be lost this way. Understanding patterns of change in SCC reporting over time has significant potential to identify individuals at greater risk of cognitive decline and incident dementia.
Healthcare expenditures attributable to Alzheimer's disease in Japan: Life study
Authors: Fukuda Haruhisa , Maeda Megumi , Ono Rei 
Published: December 2020

AbstractBackgroundThe number of older adults with dementia in Japan is projected to exceed 7 million by 2025. This increase will place a heavy economic strain on Japan’s public insurance system as its population ages and workforce shrinks. Although the estimation of this economic burden is crucial to understanding the societal importance of dementia prevention, little is known about the additional healthcare expenditures attributable to dementia in Japan. This study aimed to quantify the healthcare expenditures attributable to Alzheimer's disease (AD).MethodThe analysis was conducted using the Longevity Improvement & Fair Evidence Study (LIFE Study) database, which comprises municipality‐level information centred on claims data. Claims data from April 2014 to March 2019 were obtained from one rural city. The study subjects were individuals who had received new diagnoses of AD in October 2014 or later. The healthcare expenditures for one year were estimated for subjects with adequate follow‐up data for the respective periods. Using the expenditures incurred during the six‐month period before AD diagnosis as a comparator, the additional expenditures incurred after AD diagnosis were estimated through fixed‐effects models.ResultA total of 1,283 patients with new diagnoses of AD were identified from the LIFE Study database. Their mean age was 83.2 years, 67.1% were women, and the mean healthcare expenditure during the six months before AD diagnosis was US$1,038. For subjects with one‐year follow‐up data, the fixed‐effects model estimated that the first, second, and third months after AD diagnosis were associated with additional expenditures of US$1,787 (P < 0.001), US$1,388 (P < 0.001), and US$952 (P < 0.001), respectively, when compared with the pre‐AD period. The additional expenditures stabilized at approximately US$300 in the fourth month and later.ConclusionAD onset was associated with additional monthly healthcare expenditures of approximately US$300 per patient. The substantial economic burden of AD underscores the societal importance of implementing effective and efficient preventive measures.
Protocol of a clinical trial to implement physical activity for cognitive health in two aged persons' mental health services in Melbourne: The EXCEL study
Authors: Ellis Kathryn A , Curran Eleanor , Cox Kay L , Chong Terence WH , Palmer Victoria J , Anstey Kaarin J , Southam Jennifer , Coulson Brett , Moss Francine , Lautenschlager Nicola T 
Published: December 2020

AbstractBackgroundPhysical inactivity is a key contributor to chronic disease burden. Physical activity (PA) offers significant health benefits, including for brain health, and to groups with increased dementia risk such as older people with mental illness, Mild Cognitive Impairment or Subjective Cognitive Decline. There is a global call for dementia risk reduction interventions to be implemented into clinical practice. Older people with mental health problems experience significant barriers to PA and are a ‘hard to reach’ group for health promotion. Specific programs, integrated into mental health services, are needed. We will implement behaviour change theories to investigate the effectiveness, acceptability, feasibility and sustainability of an intervention to assist consumers of public Aged Persons Mental Health Services to follow PA clinical guidelines.MethodThis three‐phased study will involve consumers, mental health clinicians and General Practitioners (GPs). An optimisation phase includes initial theory‐based design, using a comprehensive intervention logic model that identifies key anticipated behavioural determinants and matched strategies to support change. The proposed intervention will be presented to consumers and clinicians for consideration. Their feedback will inform tailoring of the intervention prior to implementation. The implementation phase involves a trial of the intervention’s effectiveness compared to usual care for increasing consumer PA levels. Clinicians will be supported to incorporate PA guidelines into clinical practice using tailored behaviour change strategies over 12‐weeks. An individual PA prescription, relevant equipment and exercise demonstrations will be offered to consumers. We will measure PA levels using a validated questionnaire (the CHAMPS) to determine the number of participants meeting PA guidelines, along with measuring changes to quality of life, psychiatric symptom burden and dementia risk. An evaluation phase will use a mixed‐methods approach to evaluate change in the identified key behavioural determinants, as well as qualitative evaluation of the intervention across the three participant groups.ResultsThis study will provide pragmatic evidence‐based information for clinical practice, supporting the design of implementation programs to enhance PA in older consumers with mental health problems.ConclusionThis research addresses the need for integrated mental, cognitive and physical healthcare, facilitating holistic healthcare for groups at increased risk of cognitive decline.