bluuebunny/crossref_metadata_2025_split huggingface dataset:
Executive Functions and Episodic Memory are Associated with Extracellular White Matter Microstructure in Early Old Age
Authors: Gustavson Daniel E. , Archer Derek B , Elman Jeremy A. , Fennema‐Notestine Christine , Hagler Donald J. , Panizzon Matthew S. , Shashikumar Niranjana , Hohman Timothy J. , Jefferson Angela L. , Lyons Michael J. , Franz Carol E , Kremen William S. 
Published: December 2022

AbstractBackgroundCortical surface area, cortical thickness, and hippocampal volume are well‐studied in relation to later life cognitive impairments and AD. Fewer studies have investigated how white mater microstructure relates to cognition in late life. Existing work has focused on fractional anisotropy (FA) and mean diffusivity (MD) measures that are thought to capture demyelination and axonal degradation and relate to cognitive decline in normal aging and AD. However, these measures are susceptible to partial volume effects. Here, we evaluated whether executive function and memory are associated with FA and MD after deploying a free‐water (FW) elimination post‐processing method that separates fluid (FW) from tissue (FW‐corrected FA and MD).MethodWe examined 489 non‐demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Executive function was based on 6 tasks spanning inhibition, shifting, and working memory. Memory was based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FW‐corrected FA, and FW‐corrected MD. Analyses controlled for age, scanner, diabetes, hypertension, race, and ethnicity. We used false discovery rate to account for multiple testing.ResultBetter executive functioning was associated with lower FW across all 11 tracts. Better memory was associated with lower FW in 3 tracts: the superior longitudinal fasciculus (SLF) and two sections of the inferior frontal gyrus (opercularis and triangularis). Despite widespread differences with FW, there was only one significant association with intracellular metrics (executive function and FW‐corrected FA in the SLF). Finally, indicators of cognitive reserve (education or general cognitive ability assessed in early adulthood) did not moderate these associations between cognition and white matter microstructure.ConclusionOur findings leveraged a post‐processing method that separates extracellular fluid (FW) from intracellular tissue (FA, MD). We found that cognitive abilities in early old age are associated primarily with extracellular white matter microstructure (FW), which demonstrated global associations with executive function. Finally, there was no evidence that indicators of cognitive reserve influenced the strength of the association between cognition and white matter, at least in this sample of non‐demented men.
NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS): 2022 Update
Authors: Issen Heather , Kuzma Amanda B , Valladares Otto , Greenfest‐Allen Emily , Klamann Conor , Gangadharan Prabhakaran , Katanic Zivadin , Wilk Andrew , Zhao Yi , Qu Liming , Moon Michelle K , Rose Alexis Lerro , Manuel Joseph , Keskinen Peter , Thomas Carlos , Chou Shin‐Yi , Lee Wan‐Ping , Leung Yuk Yee , Naj Adam C. , Stoeckert Christian J , Schellenberg Gerard D. , Wang Li‐San 
Published: December 2022

AbstractBackgroundNIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer’s disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer’s Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer’s Disease Sequencing Project (ADSP), and the Genome Center for Alzheimer’s Disease (GCAD) allow NIAGADS to lead the effort in managing large AD datasets that can be easily accessed and fully utilized by the research community.MethodNIAGADS is supported by National Institute on Aging (NIA) under a cooperative agreement. All data derived from NIA funded AD genetics studies are expected to be deposited in NIAGADS or another NIA approved site. NIAGADS manages a Data Sharing Service (DSS) that facilitates the deposition and sharing of genomic data and association results with approved users in the neurodegenerative research community. In addition, researchers are able to freely use the NIAGADS Alzheimer’s Genomics Database (www.niagads.org/genomics/) to search annotation resources that link published AD studies to AD‐relevant sequence features and genome‐wide annotations.ResultAs of January 2022, NIAGADS houses 82 datasets comprised of >93,000 samples including GWAS, sequencing, gene expression, annotations, deep phenotypes, and summary statistics. Qualified investigators can retrieve ADSP sequencing data with ease and flexibility through the NIAGADS DSS. As of January 2022, the ADSP and other contributing studies have completed whole exome sequencing (WES) of 20,503 samples and whole‐genome sequencing (WGS) of 16,905 samples. Raw WES and WGS files, quality controlled VCF files, and phenotype data files are available via qualified access. The next round of sequencing currently underway will generate around 18,000 additional genomes to be released at the middle of 2022.ConclusionNIAGADS is a rich resource for AD researchers, with the goal of facilitating advances in Alzheimer’s genetics research. By housing datasets from many projects and institutions, NIAGADS enables AD researchers to meet their research goals more efficiently. Datasets, guidelines, and new features are available on our website at https://www.niagads.org.
Predictors of Usual Gait Speed in Persons with Mild‐Moderate Alzheimer’s Dementia
Authors: Salisbury Dereck , Yu Fang 
Published: December 2022

AbstractBackgroundGait speed, the time needed to walk a specified distance at normal pace, is a strong predictor of adverse outcomes. Usual gait speed ≥1.0 meters/second (m/s) is associated with better survival in community‐dwelling older adults. The purpose of this cross‐sectional study was to 1) evaluate usual gait speed and their predictors in community‐dwelling older adults with mild‐to‐moderate Alzheimer’s dementia (AD) participating in a pilot study investigating the effects of aerobic exercise on cognitive function.MethodUsual gait speed was calculated from the 4‐meter walk test (4mWT) (part of the short physical performance battery test [SPPB] according to published guidelines. Potential predictors were selected based on the literature and included: demographics (age, sex, cognition [Mini‐Mental State Examination (MMSE) score], body mass index [BMI], balance (balance score from SPPB), aerobic fitness (peak oxygen consumption [VO2peak] from cycling‐based cardiopulmonary exercise test and walking distance from shuttle walk test [SWT]), and muscle strength/power (repeated chair rise test [RCR] of the SPPB). Data were analyzed using descriptive statistics (means/SD) and multiple linear regression.ResultThe sample (n = 90) averaged 76.9±6.6 years old, 44% female, 21.71±6.6 MMSE, and 24.6±11.2 BMI. Usual gait speed was 0.96±0.24 m/s, with 61% having a usual gait speed ≥1.0 m/s. Regression analysis showed that aerobic fitness (SWT distance) and muscular strength/power (RCR) were significant predictors of usual gait speed. Specifically, 45% of the variability in usual gait speed was accounted for by aerobic fitness (SWT distance) and muscle strength/power (RCR) (R2 = 0.449; SEE = 0.175; p≤0.001). In the subset with usual gait speed <1.0 m/s (n = 45), seventy‐three percent of the variability in usual gait speed was accounted for by aerobic fitness (SWT distance and VO2peak) and muscle strength (RCR) (R2 = 0.728; SEE = 0.07; p≤0.001).ConclusionOur findings suggest that aerobic fitness and muscular strength/power are significant determinants of usual gait speed in community‐dwelling older adults with mild‐to‐moderate AD and particularly in persons usual gait speed <1.0 m/s. Exercise interventions that have the capacity to enhance aerobic fitness and muscular strength/power will be important in preventing adverse outcomes associated with reduced usual gait speed in persons with AD.
TREM2 Variants in Parkinson’s Disease: Results from the Parkinson’s Progression Markers Initiative (PPMI) Study
Authors: Nudelman Kelly N. H. , Brumm Michael C. , Marek Kenneth , Foroud Tatiana M. ,   for the Parkinson's Progression Markers Initiative (PPMI) Study
Published: December 2022

AbstractBackgroundWhile TREM2 coding variants are known risk factors for Alzheimer’s disease, their contribution to Parkinson’s disease (PD) risk is less clear. We hypothesized that rare coding variants in TREM2 are associated with increased risk for Parkinson’s disease (PD), and that carriers of TREM2 coding variants represent a subtype of PD cases with different clinical characteristics and disease trajectory.Method
TREM2 coding variants were obtained from the whole genome sequencing data available on LONI (https://ida.loni.usc.edu/) using VCFtools and annotated using Annovar for all individuals enrolled in the Parkinson’s Progression Markers Initiative (PPMI, N=1736), a longitudinal study of biomarkers of PD onset and progression. Of the 12 coding variants obtained, 8 variants that had reported or predicted pathogenic function were further analyzed. Fischer’s Exact 2‐sided tests were used to investigate enrichment of all variant carriers, as well as enrichment of specific variants with >20 carriers in the cohort, in sporadic (non‐genetic) PD (sPD) cases compared to controls. Enriched variants were tested for association with PD‐related measures including the MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) total score, Montreal Cognitive Assessment (MoCA) score, Geriatric Depression Scale (GDS)‐15 score, and the University of Pennsylvania Smell Identification Test (UPSIT) score.Result
TREM2 variant carriers (total N=77) were enriched in PD cases compared to controls (p=0.002). Within variant analysis showed enrichment of p.R62H carriers (p=0.027), but not p.R47H carriers (p=0.667) in sPD. While there was no significant difference in MDS‐UPDRS (p=0.763) or MoCA (p=0.815) at baseline between p.R62H sPD carriers and non‐carriers, p.R62H carriers were more likely to have a MoCA score <21 at a subsequent visit [HR (95% CI) = 2.78 (1.19‐6.49)], though this effect was not significant in an age‐adjusted model [HR (95% CI) = 2.28 (0.97‐5.34]. Compared to non‐carriers, p.R62H carriers showed a trend for more depressive symptoms (p=0.078) and had worse anosmia (p=0.002).Conclusion
TREM2 rare coding variants are more common in PD, suggesting that TREM2 may contribute to the genetic etiology of this disease. Interestingly, p.R47H, a risk factor for Alzheimer’s disease, does not appear to contribute to sPD risk, whereas p.R62H may be a novel risk factor for PD.
CSF Alzheimer’s biomarkers in clinical practice
Authors: Agüero Pablo , Querejeta Agustín , Sainz María José , Téllez Raquel , Gómez‐Tortosa Estrella 
Published: December 2022

AbstractBackgroundCSF biomarkers are well validated and a useful tool for the diagnosis of Alzheimer’s disease (AD). However, in some cases results are not consistent. In this study we examine to which extent CSF biomarkers support diagnosis in clinical practice.MethodAnalysis of 141 consecutive CSF samples of patients referred to our memory clinic with suspected cognitive decline, using the Lumipulse G600II chemiluminescent immunoassay (Fujirebio, Spain) to determine Ab‐42/Ab‐40 ratio (A+ if <0.068), total Tau (N+ if >410 pg/ml), and phospho‐Tau (T+ if >59 pg/ml).Clinical diagnosis was classified into three categories: AD, degenerative non‐AD, and non degenerative, considering current clinical criteria at last visit.Based on biomarkers, we separated the groups as follows: negative for AD (A‐T‐N‐ and A‐T‐N+), positive for AD (A+T+N+ and A+T+N‐), cases with amyloidosis A+ but T‐ (A+T‐N+; A+T‐N‐), and cases without amyloidosis A‐ but T+ (A‐T+N+).Result50,5% of the patients had a positive AD result that correlated in a majority of cases with a clinical amnestic AD phenotype or other highly related phenotypes (logopenic aphasia and posterior cortical atrophy). The exceptions were 5 cases meeting diagnostic criteria for non‐fluent/agrammatic aphasia or corticobasal syndrome.37% had a negative AD result which correlated with a clinical diagnosis of non‐AD neurodegeneration (25 cases) or non degenerative (27 cases).Therefore, in 87% of the cases CSF biomarkers supported a clinical diagnosis.On the other hand, 18 cases (13%) had some inconsistencies within biomarkers: 7 with A‐ and 11 with A+ results. As regards clinical diagnosis, all A‐T+N+ and many of the patients with A+ biomarkers (8/11) had been considered AD phenotypes. In two of the cases with A+T‐N‐, an AD diagnosis was later confirmed, respectively, by a positive PET‐amyloid study and full positive CSF biomarkers analyzed two years later.No differences were found in family history, age of onset, or age at lumbar puncture between the groups of AD positive biomarkers and just amyloidosis A+.ConclusionCSF biomarkers were clearly supportive of the clinical diagnosis in a majority of the cases of our cohort. However, in 13% of the cases, most of them with an AD type phenotype, biomarkers were unclear.
Diffusion MRI alterations coincide with memory deficits in a novel hAβKI mouse model of Alzheimer’s Disease
Authors: Jullienne Amandine , Noarbe Brenda P , Keiser Ashley , Trinh Michelle V , Pad Rojina , Kramár Enikö , Dong Tri , Beardwood Joy , Al‐Shammari Ameer , Wood Marcelo A , Obenaus Andre 
Published: December 2022

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse. These mice exhibit age‐dependent cognitive and synaptic impairments. Preclinical neuroimaging was performed, specifically diffusion MRI (dMRI) to investigate brain‐wide structural alterations in conjunction with connectomic analyses across the hAβKI mouse lifespan.MethodhAβKI and WT mice were compared at 4, 12, and 18 months (mo) of age. Two cohorts were generated for: 1) behavior and long‐term potentiation (LTP), and 2) high resolution diffusion tensor imaging at 9.4T (30 directions b=3000 mm2/sec) to assess regional white and gray matter changes. Regional tissue features based on the AMBMC atlas were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps.ResultSignificant impairments in hippocampal LTP were observed in male hAβKI mice at 4mo of age relative to WT but not at 12 or 18mo. In contrast, in female hAβKI mice, LTP impairments were observed only at 12 and 18mo relative to WT. dMRI heatmaps of MD highlighted regional differences between sexes across time and genotype, with MD progressively decreasing with time. Male hAβKI mice had progressive changes within the brain with advancing age whereas the largest changes in females was at 12mo of age. AxD in 18mo male hAβKI mice was increased in 4 of 7 white matter regions but not in female hAβKI mice compared to WT.ConclusionIn summary, using the newly developed hAβKI mouse model of AD, we identified progressive altered regional dMRI tissue metrics. The hippocampal CA1 region appeared to be particularly vulnerable, findings consistent with observed impairments in LTP and behavior. MRI of new mouse models is a powerful tool to investigate tissue level modifications to brain structure and function to inform human disease.
Costs of dementia in Europe: a systematic literature review and meta‐analysis
Authors: Jönsson Linus , Frisell Oskar , Wimo Anders 
Published: December 2022

AbstractBackgroundReliable data on costs of dementia care is critically important for estimating the value of novel therapies, technologies and methods in dementia care. The costs of dementia have been described in an increasing number of studies, however many are limited by small, selected samples and incomplete scope of cost categories included. Comparison of results has been challenged by considerable methodological heterogeneity, however increasing standardization of how resource utilization is measured and valued is increasing opportunities for systematic compilation of results. In this study we summarize available evidence on the costs of dementia in Europe through meta‐analysis on individual cost items.MethodWe conducted a systematic literature review to identify studies that collect and report costs of care in individuals with dementia. Costs were assessed in seven categories covering direct medical care (inpatient care, outpatient care, drugs), direct non‐medical care (institutional care, home care) and informal care (caregiver time loss, caregiver work loss). Data on study methodology, patient populations, care setting and disease severity was abstracted and harmonized across studies, and costs were converted to 2021 EUR.Result115 studies were included in the final review and meta‐analysis, reporting data for 631,281 patients from 17 countries. Annual total costs vary between regions within Europe, from approximately €6,000 EUR in Eastern Europe to €50,000 in Northern Europe, but consistently increase with disease severity and for institutionalized patients. Costs are dominated by informal care and non‐medical direct costs, while the balance of these two vary between regions. About half of the studies used a standardized scale for collecting resource utilization and cost data, the most common of which was the Resource Use in Dementia (RUD) instrument.ConclusionIn this study we construct the most comprehensive database to date of costs of dementia in relation to disease severity and care setting. Meta‐analytical estimates of care costs are possible but require categorization of resource use items and cross‐mapping of different measures of disease severity.
Older adults with underidentified dementia exhibit a fragile clinical and neuropsychiatric profile
Authors: Formoso Carolina Rodrigues , Borelli Wyllians Vendramini , Castilhos Raphael Machado , Chaves Marcia L Fagundes 
Published: December 2022

AbstractBackgroundWorldwide prevalence of dementia in older adults ranges from 5‐7%, with higher rates observed in Latin America (8.5%). However, underdiagnosis remains frequent. Our aim is to identify the profile of individuals with probable dementia that were underidentified using an epidemiological cohort.MethodAn epidemiological study named ELSI‐Brazil was evaluated for potential underidentification of dementia. Individuals at or above 60 years of age with probable dementia were selected using semantic fluency test scores (adjusted for age and education) and loss of any basic activity of daily living (Katz scale<6). Groups were divided into reported and unreported diagnosis of dementia (UpD), according to previous history of Alzheimer’s disease. UpD group compounds individuals potentially living with probable dementia without a proper medical evaluation. Individuals were evaluated for self‐reported risk factors, previous medical history, frailty scores, cognitive tests and neuropsychiatric symptoms. A multivariate logistic regression was performed to demonstrate predictors of UpD.ResultAmong 5221 older adults of the ELSI‐Brazil sample, 474 individuals (mean age 73.30±8.65, 67% females) were classified as probable dementia (pD), and 4747 individuals (mean age 69.6±7.42, 59% females) as probable not dementia (pND). Among probable dementia, unreported dementia (UpD) comprehended 459 older adults (96.4%), with significantly more clinical comorbidities, such as hypertension, diabetes, ischemic events (stroke or myocardial infarction), hearing loss and malignancy (p < 0.001). They also presented higher neuropsychiatric symptoms, such as poor quality of sleep, frequent usage of sleep drugs, and depression (p<0.001). Strong predictors of UpD included frailty score (OR: 2.06 [1.58 ‐ 2.68]), poor sleep quality (OR: 1.46 [1.13 ‐ 1.90]), frequent usage of sleep drugs (OR: 1.54 [1.15 ‐ 2.05]), and recent hospitalization (OR: 1.67 [1.20 ‐ 2.30]).ConclusionA specific profile of vulnerability was demonstrated in older adults with unidentified probable dementia in this cohort. Frailty, poor sleep quality, frequent usage of sleep drugs, and recent hospitalization were important predictors of UpD. This study provides insights to guide public health policies and target individuals more vulnerable to underidentified dementia.
Integrating music‐based interventions with gamma‐frequency stimulation for Subjective Cognitive Decline and Mild Cognitive Impairment
Authors: Tichko Parker , Kim Ji Chul , Zappi Victor , Large Edward , Loui Psyche 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized by disrupted, synchronous neural activity in the gamma‐band range (30‐100 Hz) and atypical cross‐frequency coupling between gamma and other bands of brain activity1‐3. In non‐human‐animal models, restoring aberrant gamma activity with non‐invasive gamma sensory stimulation remediates multiple pathophysiologies of AD (e.g., amyloid‐beta, tau tangles) and improves cognition4,5. While promising, gamma sensory stimulation may be difficult to use with human patients. We theorize that combining gamma sensory stimulation with natural music may increase the efficacy of gamma interventions for dementia, as music naturally drives gamma brain activity; engages multiple brain networks that are important for learning, memory, and reward processing; and music‐based interventions can reduce distress and agitation in older adults with dementia6.MethodWe developed a non‐invasive, gamma‐ and music‐based intervention for dementia, called SynchronyGamma (SynG). SynG delivers synchronized bursts of gamma‐frequency visual stimulation during natural music listening, cross‐frequency coupled to delta (0.5 – 4 Hz) and theta (4 – 8 Hz) visual rhythms, which adapt in real‐time to musical rhythms. In a preclinical experiment featuring older adults with and without Mild Cognitive Impairment (MCI) and Subjective Cognitive Decline (SCD) (N = 19 experimental group, 3 with MCI/SCD; N = 18 control group, 2 with MCI/SCD), we tested whether a single‐dose of music listening with SynG, relative to a control intervention, drives gamma neural activity; induces cross‐frequency coupling between delta, theta, and gamma brain activity; and improves cognition (e.g., delayed‐match‐to‐sample working‐memory task)ResultsSynG was found to drive scalp‐recorded gamma brain activity (p<0.05), and induce stronger cross‐frequency coupling, relative to the control condition (p<0.05). Additionally, enhanced gamma activity was observed during the working‐memory task that followed the intervention. Finally, SynG participants performed more accurately on a visual working memory task compared to their control counterparts, although this improvement fell short of statistical significance following a single dose (p>0.05).ConclusionTogether, these findings suggest that combining self‐selected music with delta, theta, and gamma frequency visual stimulation is effective at driving gamma neural activity, inducing cross‐frequency coupling, and it may improve cognitive functioning. Future research will assess the effects of a longitudinal implementation of the intervention.