bluuebunny/crossref_metadata_2025_split huggingface dataset:
Search for protective genetic variants in Alzheimer disease in the U.S. Midwestern Amish
Authors: Main Leighanne R. , Song Yeunjoo E. , Laux Renee A. , Miskimen Kristy , Cuccaro Michael L. , Ogrocki Paula , Lerner Alan J. , Vance Jeffery M. , Fuzzell M. Denise , Fuzzell Sarada L. , Sewell Jane L. , Lynn Audrey , Caywood Laura J. , Prough Michael , Scott Bill , Adams Larry D. , Clouse Jason E. , Herington Sharlene D. , Pericak‐Vance Margaret A. , Haines Jonathan L. 
Published: December 2020

AbstractBackgroundMost genetic studies on Alzheimer’s disease (AD) have focused on finding risk genes and variants. Taking into account the 30+ loci identified to increase risk of AD, still only around 40‐50% of the estimated heritability of AD is explained. Our goal is to identify genetic variants that delay the onset or protect against the development of AD and to find novel gene interactions or pathways associated with AD.MethodOur study focuses on the Amish communities in Ohio and Indiana due to their homogeneous genetics and environment. Studying genetics in the Amish increases our ability to find rare protective variants for AD that do not exist at a detectable frequency in the general population. Our focus is to identify individuals who are cognitively normal (CN), but at high risk for developing AD (i.e. have an affected sibling). Each of these individuals is retested every two years to assess their cognition status.ResultsUsing the extensive genealogical data of families in the Amish population, we have generated a large ∼5,000 person, 13‐generation pedigree. As of January 2020, we have ascertained 652 individuals and are examining over 300,000 SNPs that were retained after preliminary QC. Out of the recently adjudicated enrollments, 55 percent are cognitively normal, 33 percent are borderline or cognitively impaired, and the remainder have been sampled and are awaiting a consensus diagnosis. The frequency of the APOE‐e2 allele in our enrollments is at 5%, while the APOE‐e4 allele is at 14%, is lower than the general European population. We are currently using KING and GENESIS software to QC the data since they take into account more relatedness in a population structure, which is needed for working with the Amish. Association and linkage analyses, taking into account the complex pedigree relationships, is ongoing.ConclusionWe are using a founder population to have an increased chance of finding protective genetic variants in AD. We are specifically targeting individuals who are at high risk for developing AD, but seem to be resilient. This is important in discovering novel pathways in which AD functions, which can lead to further functional and pharmaceutical studies.
Alpha‐frequency synchronization deficits during life predict postmortem neurofibrillary tangle burden in Alzheimer’s disease
Authors: Ranasinghe Kamalini G , Petersen Cathrine , Kudo Kiwamu , Srivatsan Srivatsan , Beagle Alexander J , Mizuiri Danielle , Findlay Anne , Houde John F , Rankin Katherine , Rabinovici Gil D , Seeley William W. , Spina Salvatore , Gorno‐Tempini Marilu , Kramer Joel H , Miller Bruce L , Vossel Keith A , Grinberg Lea Tenenholz , Nagarajan Srikantan S 
Published: December 2020

AbstractBackgroundUsing a multimodal imaging approach with neurophysiological assessments incorporated alongside molecular markers in patients with AD, we have previously demonstrated frequency‐specific neural synchronization deficits distinctly associated with tau and Aβ tracer uptake. Reduced alpha (8‐12 Hz) synchrony (alpha hyposynchrony) closely mapped onto regional patterns of tau uptake and was modulated by the degree of tau uptake. In contrast, increased delta‐theta (2‐8 Hz) synchrony (delta‐theta hypersynchrony) showed strong associations with Aβ tracer uptake. Here, we examined the associations between regional neurofibrillary tangle (NFT) pathology and frequency‐specific neuronal synchrony in patients with AD.MethodsIn a well‐characterized clinicopathological cohort of AD (n=13; Figure 1), we quantified the postmortem NFT density using thioflavin‐S fluorescent microscopy within six selected neocortical and hippocampal regions including, angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1 and subiculum. In the same patients, using resting‐state magnetoencephalography (MEG) we quantified the degree of alpha and delta‐theta neural synchrony abnormalities, compared to an age‐matched control group (n=23). We used linear mixed effects statistical models to investigate the associations between frequency‐specific neurophysiological indices and NFT burden. The duration between MEG scan and death, Clinical Dementia Rating (CDR) at death, and the difference of CDR‐Sum‐of‐Boxes between MEG scan and death were included into the mixed models as additional variables, together with the subject identity as a repeated factor.ResultsWe found that alpha hyposynchrony negatively predicted the NFT burden in patients with AD, in contrast, delta‐theta hypersynchrony did not show significant associations with the NFT burden (b=‐7.42, F=10.17, P=0.01 for alpha‐hyposynchrony; b=0.73, F=0.07, P=0.8 for delta‐theta hypersynchrony; Figure 2). Results were similar with a restricted analysis on neocortical regions after exclusion of subcortical regions (b=‐13.13, F=8.75, P=0.02 for alpha‐hyposynchrony; b=‐1.79, F=0.00, P=0.97 for delta‐theta hypersynchrony).ConclusionsThe current study characterizes the frequency‐specific nature of neurophysiological signatures in AD pathophysiology and demonstrates that alpha hyposynchrony is a sensitive index of network disruptions mediated by abnormally phosphorylated tau proteins. These findings suggest that neurophysiological indices may be useful biomarkers to detect earliest manifestations of dysfunctional neural networks as well as to gauge therapeutic efficacy in clinical trials.
Exploring the causes of MMSE scoring and administration errors in the clinical trial screening period
Authors: Miller David S. , Wang XIngmei , Kott Alan 
Published: December 2020

AbstractBackgroundAudio recording of eCOA MMSE administration enables identification of both administration and scoring errors. Either can result in incorrect MMSE scores, potentially leading to inclusion of inappropriate subjects and/or biased assessment of change after randomization. Our current analysis explores the effect of protocol design, MMSE scores close to inclusion criteria and visit type on MMSE scoring and/or administration errors.MethodData were pooled from 2 types of early dementia protocols – Type A where MMSE inclusion criteria need only be met at screening, and type B where they needed to be met at both screening and baseline. All assessments were audio recorded and reviewed by independent clinicians for the presence of administration and scoring errors. Operationally, subjects were defined as close to inclusion criteria if their MMSE scores were within 2 points of specified thresholds. Logistic regression with 3‐way interaction was used to explore the hypotheses.Result11,391 MMSE assessments were reviewed, and 2,706 (23.8%) had either an administration and/or scoring error. In both protocol types, administration errors were significantly less likely at baseline than screening, regardless of MMSE score proximity to inclusion threshold. In type A protocols, administration errors were more likely if scores were close to inclusion criteria. For type B protocols this was true only at screening. Scoring errors were significantly less likely at baseline, if MMSE scores were close to inclusion (both protocol types) or not (type A). Scoring errors were significantly more likely at screening but not baseline when scores were close to inclusion (only type A). No direct effect of protocol design was observed on the likelihood of either scoring or administration errors.ConclusionOur data indicate that scoring and administration errors occur more frequently at screening and in subjects with scores close to inclusion criteria. Despite some differences, the effect of protocol design seems less likely to result in errors to the same extent as the other 2 parameters. Given that data coming from subjects close to inclusion criteria at screening are at the highest risk of having a scoring or administration error indicates that data may be manipulated to meet inclusion criteria.
Timing of school desegregation experience and late‐life cognition in the Study of Healthy Aging in African Americans (STAR) cohort
Authors: Peterson Rachel , George Kristen M. , Barnes Lisa L. , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundPrior studies suggest segregated school experiences are associated with poorer late‐life cognition among African Americans. However, less is known about how the timing of school desegregation in the individual’s lifecourse or historically is associated with cognition for younger cohorts.MethodThe Study of Healthy Aging in African Americans (STAR) is a cohort of community‐dwelling Kaiser Permanente members residing in the San Francisco Bay area and Sacramento valley. The study has enrolled 722 African Americans (half ages 50‐64, half 65+) and aims to understand lifecourse processes that contribute to cognitive aging disparities. Experiences of segregation were self‐reported and modeled three ways: 1) having attended only segregated schools vs. only integrated; 2) by life stage when first transitioned to a desegregated school (i.e. 1st‐6th, 7th‐9th or 10th‐12th grades); and 3) the historical timing of school desegregation relative to the 1954 Brown vs. Board of Education decision mandating school integration (many districts were reluctant to integrate in a timely manner). Executive function, semantic memory and verbal memory measured with the Spanish and English Neuropsychological Assessment Scales (SENAS) were z‐standardized and averaged for overall cognition. Linear regression was used for analysis; models controlled for age, gender, and education.ResultParticipant mean age was 68 (8.7) and 69% were female. Compared with participants who only attended integrated schools (ref.; n=438), those who only attended segregated schools (n=145) had significantly lower overall cognition, executive function and semantic memory (see table). Those who transitioned from segregated to integrated schools between 7th and 9th grade (n=51) had worse executive function and semantic memory than those who only attended integrated schools; we did not observe significant associations for those who transitioned to integrated schools in 1st‐6th grades (n=44), or 10th‐12th grades (n=43). We observed no differences in cognition by historical timing of desegregation.ConclusionOlder African Americans who attended only segregated schools or experienced desegregation in 7th‐9th grades had worse later‐life cognitive test scores than those who attended racially integrated schools. Our findings suggest that only attending segregated schools and the timing of school desegregation in the lifecourse may have implications for understanding cognitive aging among African Americans.
Variability in every day pain is associated with mild cognitive impairment (MCI): Results from the Einstein Aging Study (EAS)
Authors: Lipton Richard B , Wang Cuiling , Hyun Jinshil , Katz Mindy J , Derby Carol A , Pavlovic Jelena 
Published: December 2020

AbstractBackgroundHalf of older adults have chronic pain. Pain is a common, biologically plausible, remediable risk factor for cognitive decline and incident dementia. The relation of pain and MCI is under‐explored. Commonly measured dimensions of pain include intensity (how severe is the pain) and interference (how much does pain interfere with activities). Traditional pain measures use recall intervals of 1 week to 3 months, are subject to recall bias, and cannot measure pain variability.MethodsThe EAS enrolled a systematically‐recruited, community residing sample of adults, age 70+. Annual in‐person visits included neuropsychological and neurologic assessments, and recall‐based pain measures (Table 1). MCI was diagnosed using Jak‐Bondi criteria. Ecological Momentary Assessment (EMA) via smartphone was used to measure pain intensity and pain interference with activities and concentration 6 times per day for 14 days. We calculated mean daily pain (DP) intensity and mean DP interference as well as the standard deviations of these measures across days (i.e., variability). Logistic models were used to calculate odds ratios for associations between pain indices and MCI status, adjusting for age, sex and education.ResultsThe study sample included 243 individuals (mean age 77.5, 65.4% females) including 68 with MCI and 175 normal controls (NC). On average, participants completed 84% of the daily EMA assessments (86% in NC, 78 % in MCI). There were no differences in the mean recall‐based pain measures between MCI and NC participants (Table1). Variability in DP intensity and interference with concentration were significantly higher in the MCI group compared to NC, while variability in DP interference with activities did not differ between groups (Table1). In logistic regression models, higher variability of DP intensity and DP interference with concentration was significantly associated with higher odds of having MCI status in logistic models (Table 2).ConclusionEMA‐based measures of variability in DP intensity and interference with concentration are associated at cross‐section with MCI while recall‐based pain measures are not. Future work will assess the predictive validity of pain intensity and interference for cognitive decline and incident MCI.
Klotho‐VS decreases probability of amyloid pet positivity in APOE4+ controls
Authors: Eger Sarah J. , Belloy Michael E. , Guen Yann Le , Napolioni Valerio , Deters Kacie D. , Mormino Elizabeth C. , Greicius Michael D. 
Published: December 2020

AbstractBackground
Klotho‐VS heterozygosity (KL‐VSHET) has been linked to increased longevity and decreased rate of cognitive decline. In Alzheimer’s disease (AD), KL‐VSHET was recently shown to decrease both AD risk and amyloid burden, specifically, in APOE4+ controls of Northwestern European descent within the age range of 60 to 80 years (Belloy et al., 2020). We investigated whether this protective effect of KL‐VSHET could be replicated in a larger, independent cohort of cognitively normal subjects.MethodThe A4 study provides genotypic data and cross‐sectional amyloid PET cortical composite standard uptake value ratios (SUVr) of a large group of cognitively healthy older controls (CDR = 0 and MMSE 25‐30). We performed identity‐by‐decent analysis and SNPweights ancestry determination to select only unrelated individuals of Northwestern European ancestry (n = 2453) (Figure 1). With this sample, we examined the association between KL‐VSHET and amyloid positivity (SUVr equal to or greater than 1.17, as determined by a Gaussian Mixture Modeling approach with a 2‐cluster solution), for each of the age strata (60‐80, 80+, full sample) and within the APOE4+ and APOE4‐ groups. A logistic regression model was implemented using the amyloid positive phenotype as the target outcome variable, KL‐VSHET as the covariate of interest, adjusting for age, sex, and the first three genetic principal components to account for population structure.ResultAs predicted, KL‐VSHET significantly reduced the odds of being amyloid positive for APOE4+ controls within the age range of 60 to 80 years (OR = 0.72 [0.53, 0.98]; p = 0.041) (Table 1). This was not the case in APOE4‐ controls in the same age range (OR = 0.93 [CI = 0.65, 0.13]; p = 0.703), nor in either of the 80+ age‐stratified analyses (Table 1). Figure 2 shows the logistic model for amyloid positivity and demonstrates the difference in probabilities of amyloid positivity between the APOE4+ KL‐VSHET carriers and non‐heterozygotes (wild type homozygotes and minor allele homozygotes combined).ConclusionThese findings provide additional evidence that for APOE4+ controls KL‐VSHET is associated with decreased amyloid burden. Elucidating the molecular mechanisms underlying this protective effect may lead to novel drug targets for AD.
White matter hyperintensities in Alzheimer’s disease: Topography of lesions and association with cognition
Authors: Garnier‐Crussard Antoine , Bougacha Salma , Wirth Miranka , Paly Léo , Sherif Siya , Landeau Brigitte , Gonneaud Julie , Sayette Vincent De , Vivien Denis , Salmon Pierre Krolak , Chetelat Gael 
Published: December 2020

AbstractBackgroundWhite matter hyperintensities (WMH) are frequent in the older adults and are associated to worse cognitive performances and to dementia. Alzheimer’s disease is associated with greater brain WMH volume, particularly in posterior regions, compared to cognitively unimpaired older adults. The aim of this study was to assess in details the topography of brain WMH and their links with cognition in amyloid‐positive cognitively impaired older adults, i.e. patients in the Alzheimer’s continuum (ALZ), compared to amyloid‐negative cognitively unimpaired adults (controls).MethodFifty‐four ALZ and forty controls matched for age and cardiovascular risk factors were included in the IMAP cohort (Caen, France). Amyloid status was based on Florbetapir PET scans. In addition, each participant underwent 1) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of WMH in the frontal, parietal, temporal, occipital lobes and in the corpus callosum (CC) region and subregions; 2) a comprehensive neuropsychological assessment of global cognition, episodic memory, working memory and executive functions. The regional volumes of WMH were compared between groups and the relationship of regional WMH to cognition was assessed within the ALZ patients.ResultWMH volumes were significantly higher in ALZ patients than in controls in all brain regions, with highest differences in the splenium of the CC (p= 0.00005, size effect r = 0.42) and lowest effects in the frontal lobe (p = 0.025, size effect r = 0.23) (Figure 1). Within the ALZ patient group, WMH volumes of the CC, particularly in the splenium, were negatively associated with global cognition, working memory and executive functions (Figure 2). Total and frontal WMH volumes were also negatively associated with working memory, but this relationship did not survive correction for multiple comparisons.ConclusionWMH in the splenium of the CC most specifically characterize amyloid‐positive patients in the Alzheimer’s continuum and correlate to worse cognition especially in frontal cognitive functions. These specific ALZ‐related WMH are probably not only due to small vessel disease and could be secondary to neurodegenerescence.
Tau‐dependent regulation of neuronal activity by the Alzheimer’s disease risk gene BIN1
Authors: Voskobiynyk Yuliya , Roth Jonathan R. , Cochran J. Nicholas , Rush Travis , Carullo Nancy V.N. , Waqas Mohammad , Vollmer Rachael , McMahon Lori L. , Day Jeremy J. , Roberson Erik D. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) affects about five million Americans and the underlying causes of the disease remain uncertain. Genome wide association studies (GWAS) have identified bridging integrator 1 (BIN1) as one of the leading genetic risk factors in AD. Neurons express unique BIN1 isoforms, but their function is unknown. Thus, one key question that may contribute to a deeper understanding of AD pathophysiology is how BIN1 affects neuronal function.MethodsTo address this question, we determined the effects of expressing human BIN1 neuronal isoform 1 in primary hippocampal cultures.ResultsFirst, we observed that higher BIN1 increased spike and burst frequency using multielectrode arrays. On patch‐clamp recordings of transduced neurons, higher BIN1 increased frequency of both excitatory and inhibitory synaptic transmission. Higher BIN1 also increased calcium spikes in neurons co‐transfected with the calcium indicator GCaMP6f. To understand the potential mechanism of increased calcium influx, we explored potential interactions with L‐type voltage gated calcium channels (LVGCCs). BIN1 interacted with LVGCCs in neurons in a Tau‐dependent manner, assessed by both co‐immunoprecipitation and proximity ligation assay. Finally, using a high throughput multielectrode array system, we showed that Tau reduction prevents network hyperexcitability induced by BIN1.ConclusionsTogether, these data show Tau‐dependent regulation of neuronal activity by the Alzheimer’s disease risk gene BIN1 and generate fundamental insights about the mechanistic role BIN1 may play in AD.
Caregiver’s position creating dementia care networks in a rural area in Mexico
Authors: Ibarrola Mariana Longoria , Acosta‐Castillo Gilberto Isaac , Cañongo Guadalupe , Sosa‐Ortíz Ana Luisa , Institute Global Brain Health 
Published: December 2020

AbstractBackgroundDementia prevalence in Mexico is 9% over 65 years old, 28% of those patients live in rural areas, dementia care in rural communities face special challenges due to often geographical, economical, sociocultural, functional and inaccessibility1. Although in the country dementia care is mostly family dependent and locally integrated there is a scarcity of data about their networks2.ObjectiveTo describe the dementia caregiver´s position given the possibility of creating a network of care in a rural area in Mexico.MethodWe analyzed information from 13 dyads (patient and primary caregiver), evaluated in incidence phase of Dementia Research Group 10/66 protocol in Mexico. Dementia was established according to the 10/66 algorithm. We asked about: 1) relationship with neighbors, 2) with other relatives, 3) willingness to spend time with relatives of other dementia patients, 4) and to participate in a scheme of rotation of care among other families with dementia patients.ResultsMean age of patients was 84.4±4.2 years and 61.5% were women. Caregiver´s mean age was 54.8±16.0 years, 69.2% were female. Regarding employment, 38.5% merchants, and 53.8% homemakers, 23.7% were widowers, single or separated, and 69.2% were married. 93.2% have economic dependents and their average monthly income was 146±84 USD. There were no differences by gender in spend‐time and relationships with neighbors and relatives. 66.7% spend‐time with their neighbors, 83.3% believe their relationship with the neighbors is good or very good. Half of the relatives say they do not know other families of dementia patients, 66.7% would spend‐time with these families and 91.7% are willing to share their experiences. 83.3% would be willing to spend time in group sessions, but only 41.7% would be willing to care for other patients and only 25.0% would leave others take care of their patients.ConclusionDementia care networks are highly influenced by caregivers, patients, and community surrounding their characteristics. In our study, despite a good relationship within the community and the desire to share experiences, the provision both to care and to let care is low, understanding this phenomenon could be crucial in the implementation of strategies for dementia care in these rural areas.