bluuebunny/crossref_metadata_2025_split huggingface dataset:
Waist‐hip ratio as a moderator of the effects of hormone therapy on cognitive function in recently menopausal women
Authors: James Taryn T. , Dowling N. Maritza , Simó Carola A. Ferrer , Zuelsdorff Megan , Bouges Shenikqua , Lambrou Nickolas H. , Van Hulle Carol A , Johnson Adrienne L. , Wyman Mary F. , Salazar Hector , Umucu Emre , Kara Firat , Manson JoAnn E. , Brinton Eliot A , Cedars Marcelle I. , Lobo Rogerio A. , Neal‐Perry Genevieve , Santoro Nanette F , Naftolin Frederick , Harman Sherman M. , Pal Lubna , Miller Virginia M. , Kantarci Kejal , Gleason Carey E. 
Published: December 2021

AbstractBackgroundResearch on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive decline or Alzheimer’s disease has been inconsistent. The Women’s Health Initiative Memory Study (WHIMS) revealed elevated incident cognitive impairment for women starting MHT after age >65 with oral conjugated equine estrogens (o‐CEE) treatment, especially among women with diabetes. Subsequently, the Cognitive and Affective substudy of the Kronos Early Estrogen Prevention Study (KEEPS‐Cog) found that MHT initiated soon after menopause caused neither cognitive benefit nor harm. Waist‐to‐hip ratio (WHR) is a measure of central adiposity and a surrogate marker for insulin resistance/prediabetes. To explore effects of MHT in insulin‐resistant states, in younger women, we analyzed WHR as a predictor of cognitive response to MHT in KEEPS‐Cog.MethodsKEEPS‐Cog randomized women less than 36‐months postmenopause to oCEE, transdermal 17‐β‐estradiol (tE2) or placebo for 48 months. Cognitive tests, completed at baseline, 18, 36, and 48 months post‐randomization were summarized as factor scores representing four cognitive domains: verbal learning and memory (VLM), auditory attention and working memory (AAWM), visual attention and executive function (VAEF), and speeded language and mental flexibility (SLMF). WHR, measured at screening and months 12, 36, and 48 was modeled as a time‐varying moderator of MHT on cognitive function over time. Education was included as a time‐invariant covariate.ResultsWHR decreased throughout the study in both the tE2 and oCEE groups compared to placebo. WHR was also inversely associated with all cognitive parameters at baseline. The inverse relationship of WHR on SLMF was significant at baseline and month 18, but decreased at month 48. The inverse relationship of WHR on VLM increased significantly over time. Models including interaction effects were significant for oCEE x WHR effects at months 18, 36, and 48 on SLMF, indicating better performance in MHT vs placebo arms. No other interaction effects were significant.ConclusionsWHR decreased with MHT, and was consistently associated with VLM through 4 years of MHT. Further, women on oCEE performed better on SLMF tasks at a given WHR. Differences between KEEPS‐Cog and WHIMS findings may be related to the timing of MHT administration, and effects on central adiposity/insulin resistance/prediabetes.
Remote neuropsychological assessment using the UDS v3.0 T‐Cog: Preliminary data among participants at the Penn ADRC
Authors: Hackett Katherine , Ferrara Matthew J. , Newman Sidnei , Kelley Melissa , Schankel Laura , McCoubrey Hannah , Best Sharon , Peskin Sara Manning , O’Brien Kyra , Xie Sharon X , Wolk David A. , Mechanic‐Hamilton Dawn 
Published: December 2021

AbstractBackgroundDue to the COVID‐19 pandemic, collection of the Uniform Data Set (UDS) at Alzheimer’s Disease Research Centers (ADRCs) transitioned to remote administration via the T‐Cog. Feasibility of data collection and dissemination of normative data in individuals across the cognitive spectrum will be necessary for accurate utilization of remotely‐captured neurocognitive performance and classification of cognitive function.MethodData was included from individuals who completed a remote T‐Cog protocol during their annual NACC evaluation. Additional data included demographics, informant‐reported functioning, self‐reported depression and consensus diagnosis. Descriptive and general linear model (GLM) statistics were used to characterize the overall sample and test for differences in performance across diagnostic groups.ResultA total of 151 participants with normal cognition (NC; N=103), mild cognitive impairment (MCI; N=32) and Alzheimer’s disease (AD; N=16) were administered the T‐Cog (Age = 75.2+7.2, Education=16.3+3.1; 62% Female; 75% White). Data were collected via telephone (68%), video‐conference (29%), or a combination (3%). Time to completion ranged from 38‐120 minutes (M=58+14 minutes), with NCs showing a significantly lower (p<0.05) mean completion time (54 minutes) than those with MCI (65 minutes) and AD (69 minutes). Across the battery, 80% of responses were deemed “extremely valid”, 19% were “questionably valid” and <1% were “invalid”. Contributors to poor validity included hearing impairment (34%), distractions (16%), interruptions (6%), lack of effort/disinterest (9%), fatigue (3%), emotional issues (6%), or other reasons (25%). Diagnostic groups varied on tests of global cognition and functioning, as measured by the MoCA‐Blind and Global CDR, with the highest performance among NC, followed by MCI, and AD (p‐values<0.01). Nearly all T‐Cog measures of language, memory, and executive functioning abilities showed expected differences across diagnostic categories (covarying for age, sex and education; p<0.05). Comparisons to prior in‐person UDS neurocognitive testing across all diagnostic groups will also be presented.ConclusionPreliminary feasibility and performance data on the T‐Cog reveals expected differences in T‐Cog performance. Comparisons to within‐subject in‐person testing and deviations from in‐person norms will be presented to further explore the validity of remote cognitive testing and identify tests that show particular promise in discriminating between diagnostic groups.
Associations of TDP‐43 vs. Alzheimer’s disease neuropathology with brain atrophy in the oldest‐old: Initial imaging‐pathological results from The 90+ Study
Authors: Woodworth Davis C. , Nguyen Hannah L. , Phelan Michael J. , Greenia Dana E. , Corrada Maria M. , Kawas Claudia H. , Sajjadi S. Ahmad 
Published: December 2021

AbstractBackgroundBrain atrophy, particularly of the hippocampus and amygdala, is thought to reflect the effects of neurodegenerative proteinopathies such as TAR DNA‐binding protein‐43 (TDP‐43) and Alzheimer’s disease neuropathologic change (ADNC). We sought to test this hypothesis in a cohort of oldest‐old participants.MethodWe used data from participants in The 90+ Study, a study of aging and dementia in individuals aged 90 and older, with both MRI during life and autopsy. Our outcome variables were hippocampus and amygdala volumes calculated from computational anatomy toolbox (CAT12, http://www.neuro.uni‐jena.de/cat/). Proteinopathy variables were dichotomized: TDP‐43 (presence in hippocampus/neo‐cortex), ADNC (NIA‐AA high severity), and Lewy bodies (LB, limbic/neocortical involvement). We examined the association between presence of the proteinopathies and gray matter atrophy using three different methods. First, we compared the volumes between those with vs. without each neuropathology. Then we studied the association between the volumes and proteinopathies in a model containing all neuropathologies, adjusting for age and intracranial volume. Lastly, we calculated voxel‐wise multiple linear regressions of gray matter atrophy across the whole brain (using CAT12) and report results for each proteinopathy. We also repeated the above analyses including cognitive impairment status for comparison.ResultTable‐1 summarizes participant characteristics (N=64). Group differences in hippocampal and amygdala volumes were in the low‐to‐moderate effect‐size range for TDP‐43 (hippocampus d=0.40, amygdala d=0.33) and ADNC (hippocampus d=0.38, amygdala d=0.54, Figure‐1). For associations incorporating all three proteinopathies, semi‐partial correlations were low for TDP‐43 (hippocampus sr=‐0.15, amygdala sr=‐0.10) and ADNC except for the amygdala (hippocampus sr=‐0.12, amygdala sr=‐0.25, Table‐2). For the voxelwise analysis of gray matter atrophy, none of the proteinopathies displayed strong associations (Figure‐3). Generally, LB showed no discernible effect on gray matter atrophy. In contrast to the modest results for the proteinopathies, cognitive impairment was strongly associated with medial temporal atrophy (Figure‐4).ConclusionIn this sample of oldest‐old participants, TDP‐43 and ADNC were only modestly associated with atrophy of the hippocampus and amygdala. While this finding may partly due to low number of participants, strong association of atrophy with cognitive status in the same sample suggests mere presence of degenerative proteinopathies might not be sufficient for brain tissue loss.
Development of voice digital biomarkers in AD, their associations with CSF amyloid beta (Aß1‐42) and their underlying neural representations
Authors: Hajjar Ihab , Choi Jinho , Moore Elliot , Calhoun Vince D. , Abrol Anees , Goldstein Felicia C. 
Published: December 2021

AbstractBackgroundSubtle changes in connected speech may be detectable years before symptomatic phases of Alzheimer’s disease (AD). In this study we combine machine learning with innovative natural language processing (NLP) and automatic speech recognition (ASR) to develop digital voice biomarkers. We investigate their associations with levels of Ab (1‐42) and map the significant features to underlying brain networks.MethodData for the current case‐control analysis were drawn from participants in the Brain Stress Hypertension and Aging Research Program (B‐SHARP) at Emory University. B‐SHARP participants undergo cognitive assessments, neuroimaging, and lumbar punctures as well as annual audio recordings to capture connected speech. A picture description task was included for NLP analysis In addition, participants were asked to describe the room they were in and to list events they went through from the moment they arrived at the study site. Each audio recording went through 2 NLP pipelines to obtain lexical‐semantics and acoustic features.ResultThe sample included 206 B‐SHARP participants (age=65.1 years, 51% African Americans, 42% with mild cognitive impairment (MCI), 61% women, follow‐up period =2 years). NLP analysis and to a lesser extent acoustic analysis outperformed traditional cognitive screening in identifying MCI status. NLP based analysis outperformed other screening tools of Ab positive status (defined as <250 pg/ml) status especially in the MCI group. Area under the curve (AUC) for identifying MCI, Ab positive , and MCI/Ab positive and NC/Ab positive vs negative. Results are in the Table. We then assessed the association between baseline digital voice biomarkers and disease progression reflected by CDR‐SOB change/2 years. Both NLP‐based scores (Beta= ‐0.18;p=0.0097) and acoustic scores (beta=0.26,p=0.009) were associated with 2‐year change in CDR‐SOB after adjusting for baseline demographics. Finally functional brain connectivity, based on resting state MRI, was associated with digital voice NLP‐based scores in multiple brain networks (Figure).ConclusionA brief voice recording analysis detected cognitive status, increased likelihood of identifying Abeta positivity, and predicted disease progression over 2 years. Our protocol for digital biomarkers had an underlying neural representation in language‐related neural networks. Our study provides multi‐faceted evidence for validity of using voice recording as a tool for biomarker and cognitive screening.
Meta‐analytic comparison of risk factors for mild cognitive impairment and Alzheimer’s disease between Hispanic and non‐Hispanic White subjects
Authors: Xiao Cally , Neu Scott C , Toga Arthur W 
Published: December 2021

AbstractBackgroundHispanic subjects have been found to have a higher risk for developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD) compared to non‐Hispanic white (NHW) subjects. In addition, having one or two copies of the APOEe4 risk allele, prior stroke, and a history of hypertension have also been shown to be risk factors for developing MCI or AD.MethodIn this meta‐analysis, we compared the differences of the risk factors contributing to MCI or AD between Hispanic and NHW subjects using data available in the Global Alzheimer’s Association Interactive Network (GAAIN), contributed by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the National Alzheimer’s Coordinating Center (NACC).ResultThe odds ratio (OR) for developing a case outcome (MCI or AD) using Hispanic ethnicity as a risk factor is 1.49, which corroborated the existing trend. Interestingly, having one or two copies of the APOEe4 allele is more of a risk factor for NHW subjects (n = 23,148; OR = 2.78) than for Hispanic subjects (n = 2141; OR = 1.89). This OR difference between the two populations is statistically significant (p ≤ 0.001). Additionally, having had a prior stroke is more of a risk factor for NHW subjects, and having a history of hypertension is more of a risk factor for Hispanic subjects, though these differences are not statistically significant.ConclusionHaving one or two copies of the APOEe4 risk allele, prior stroke, and a history of hypertension contribute differently to a case outcome when comparing between Hispanic and NHW subjects. A formal analysis to confirm these findings by matching for age, sex, and education level could further our understanding of the different risk factors that contribute to MCI or AD between Hispanic and NHW subjects.
Hidden objective test
Authors: Kim Ko Woon , Choi Jong Doo , Chin Juhee , Lee Byung Hwa , Choi Jee Hyun , Na Duk L. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease patients frequently complaint that they lose things and be unable to find them again because of deficit in visuospatial memory. In this study we aimed to develop a novel visuospatial memory tests called the Hidden Objective Test (HOT) based on the ideas of patients’ complaint. Virtual reality (VR) is an optimal tool for developing this visuospatial memory tests in that real‐life settings implementation.MethodWe designed a pleasant and cozy living room. The photorealistic virtual environment interface with 360‐degree panoramas was rendered through HMD. The VR system enables the users to turn their head, to walk around, to open and close the furniture doors using controllers, and to track their movement in the VR living room. When the participant starts the test, the VR living room is shown and instructions for the prospective memory test are given. Nine items appeared on the white panel in order, and one by one, the item moved to the each furniture space and were hided. Memory test composed of 1) Item Free‐recall test, 2) Place Free‐recall test, 3) Item Recognition test, 4) Place‐item matching test, and 5) Prospective memory test.Participants were selected from those who visited the Memory Disorder Clinic at Samsung Medical Center in Seoul, Korea, between November 1st, 2019 and January 30th, 2020. This study group comprised 16 AD, 15 AMCI, and 15 NC participants.ResultThe performance of memory test was NC>AMCI (p<0.001), AMCI>AD (p<0.05), and NC > AD (p<0.001) in the Item Free‐recall test; NC>AMCI (p<0.01) and NC > AD (p<0.001) in the Place Free‐recall test; NC>AMCI (p<0.05), AMCI>AD (p<0.01), and NC > AD (p<0.001) in the Item Recognition test; NC>AMCI (p<0.001) and NC > AD (p<0.001) in the Place‐item matching test; NC > AD (p<0.05) in the Prospective memory test. Interestingly, the average movement path showed that NC participants went straight toward the target point whereas AD patients wandered to the target point when searching for hidden objects.ConclusionThe Hidden Objective Test (HOT) developed in this study, which incorporated virtual reality to experience real‐life events, showed potential to be used as a new memory screening test.
Clinical characterization of a large Caribbean Hispanic family linked to chromosome 9 without ApoE4
Authors: Tejada Sergio J , Mena Pedro Ramon , Silva‐Vergara Concepcion , Adams Larry D. , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. 
Published: December 2021

AbstractBackgroundThe ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to discovering ancestry‐specific genetic factors in Alzheimer's disease. As part of the Puerto Rican Alzheimer Disease Initiative (PRADI), we ascertained 80+ multigenerational families with multiple AD family members and reported linkage to 9p21. Here we present the clinical phenotype of the largest 9p21 linked family.MethodThe 18 members of this family were screened using neuropsychological test (e.g., CDR, 3MS), history of medical conditions, Apolipoprotein e4 were obtained and AD diagnosis was done by a panel of experts. Results were reported as frequencies and percentage and the associations were determined using Chi‐square.ResultThe family consisted of 17 participating family members, 76% females, a mean age of 70 years (SD=14 years). 1 participant was diagnosed with Parkinson’s disease, 6 with AD possible diagnosis, 1 as MCI and 6 were cognitively normal. No known causal genes for AD were observed through whole genome sequencing. The prevalence for APOE genotypes, 2/2, 2/3, 2/4 and 3/3, were 6%, 47%, 6% and 41% respectively. None of the AD cases in the family had an APOE4 allele. The average age of onset of AD cases was 79 years (SD=12 years) with a minimum of 60 years and maximum of 90 years. The average 3MS score for the cases was 49/100 (SD=33) and 90/100 (SD=4) for controls. CDR scores for all controls were 0 and between 2 and 1 for all cases. Depression was present in 33% of the participants, 22% diagnosed with diabetes, 25% with high cholesterol and 44% with hypertension.ConclusionIn this family, 8 individuals had neurodegenerative disorders, 5 of which had at least 1 APOE2 allele. The only APOE4 carrier is a unaffected participant (APOE 2/4) whose age at exam was 57 years. This supports a novel AD risk factor segregating in this family. Pedigree studies remain a useful tool to help unravel the pathophysiologic pathways involved in neurodegeneration.
Randomized controlled trial of gamma sensory stimulation treatment maintains functional ability and decreases sleep fragmentation in Alzheimer’s disease patients
Authors: Cimenser Aylin , Hempel Evan , Travers Taylor , Strozewski Nathan , Malchano Zach , Hajos Mihaly 
Published: December 2021

AbstractBackgroundDaily, at‐home gamma sensory stimulation consisting of EEG‐calibrated auditory and visual stimuli is a new therapeutic approach for the treatment of Alzheimer’s Disease (AD). Based on experimental studies demonstrating that sensory‐evoked gamma oscillation halts or reverses AD‐related pathology, improves cognitive function, and normalizes circadian rhythm in transgenic mice carrying human AD pathological genes, this clinical trial evaluated the effects of 40Hz sensory stimulation on functional ability and sleep quality of AD patients.MethodPatients with mild‐to‐moderate AD (MMSE 14‐26, inclusive; n=74) were randomized to receive either 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Functional abilities of patients were measured by Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale at baseline and every four weeks during the study and follow‐up period. Sleep quality was assessed from nighttime activities of a subgroup of patients (n=7 in treatment, n=6 in sham groups) who were monitored continuously via a wrist worn actigraphy watch throughout the 6‐month period.ResultAdjusted ADCS‐ADL scores from beginning and end of the trial were compared in patients who completed the trial. Over the 6‐month period, patients in the sham group (n=19) showed the expected decline, a 5.40‐point drop in ADCS‐ADL scores, whereas patients in the treatment group (n=33) receiving therapy exhibited only a 0.57‐point decline. Changes in ADCS‐ADL scores were statistically significant between the sham and treatment groups (P<0.01). Nighttime active durations in the treatment group were significantly (p<0.03) reduced in the second 3 months compared to the first 3 months but the opposite change was observed in the sham group. After normalizing the active durations by the corresponding nighttime period of each patient, the analysis confirmed opposite changes in nighttime active durations between the two groups (p<0.001).ConclusionPatients in gamma sensory stimulation therapy maintained their activities of daily living and showed an improved sleep quality over a 6‐month treatment period; two outcome measures, functional ability and sleep quality known to be strongly linked in AD. Maintenance of functional ability represents an important treatment and management goal for AD patients, reducing formal and informal care, and delaying time to institutionalization.
Area‐level deprivation is associated with rate of memory decline in late life within a community‐based cohort
Authors: Williams Victoria J. , Herd Pamela , Sicinski Kamil , Johnson Sterling C. , Asthana Sanjay 
Published: December 2021

AbstractBackgroundResiding in a disadvantaged neighborhood is associated with adverse health outcomes, as well as increased risk for dementia. However, it remains unclear whether area‐level deprivation impacts the rate of age‐related memory decline, especially in community‐based populations.MethodWe quantified late life neighborhood level disadvantage using the 2013 Area Deprivation Index (ADI) for 2,554 participants with complete data of interest within the Wisconsin Longitudinal Study – a same‐aged, community‐based cohort of randomly selected 1957 Wisconsin high school graduates. Delayed recall for a 10‐item word list was assessed at two timepoints in mid to late life (Time 1 (∼2004): age 64.39 + 0.74 years; and Time 2 (∼2011): age 71.28 + 0.97 years). We used multivariate linear regression models to evaluate whether ADI was associated with memory performance at each time point, and with the annualized rate of change in memory performance over time.ResultIncreasing ADI was significantly correlated with lower adolescent IQ, less educational attainment, lower net worth, higher vascular risk scores, elevated depression metrics, and increasing age (all p<0.001). Mean ADI did not differ by sex, but was significantly higher in ApoE‐4 positive carriers (t(2552) =2.257, p=0.024). Results of multivariate regression indicated that greater area‐level deprivation (higher ADI) was not associated with delayed recall performance at Time 1 (b = 0.001; 95% CI: ‐0.003 to 0.005, P=0.790), but was associated with poorer delayed recall performance at Time 2 (B = ‐0.004; 95% CI: ‐0.007 to ‐0.001, P=0.019). Higher ADI also predicted greater annualized rate of decline in delayed recall between timepoints (B = ‐0.001; 95% CI: ‐0.001 to ‐9.9^10‐5, P=0.025). These findings held after controlling for individual‐level demographic and socioeconomic variables (age, sex, adolescent IQ, years of education, net worth), genetic risk (ApoE‐4 carrier status), depression, hearing loss, and a modified CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) risk score calculated at Time 1.ConclusionEven after accounting for established individual‐level demographic, socioeconomic, health, and genetic risk factors for cognitive decline, greater neighborhood disadvantage is associated with an accelerated rate of annualized decline in delayed recall performance across mid to late life in a community sample.