bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross‐Validation of a Novel Apathy Measurement Model in a Diverse Ambulatory Cohort of Older Adults with Memory Complaints
Authors: Ceide Mirnova E , Cantor Aviva , Ayers Emmeline , Verghese Joe , Lounsbury David 
Published: December 2022

AbstractBackgroundApathy is a psychological syndrome characterized by a loss of motivation, goal‐directed activity, and diminished emotion (Marin, 1990), which may mediate the relationship between depression and cognitive impairment (Funes et al., 2018) and be an early risk factor for dementia that precedes predementia syndromes including non‐amnestic mild cognitive impairment (NA‐MCI) and motoric cognitive risk syndrome (MCR) (Ceïde et al., 2020). While there is no gold standard measure of apathy, assessment tools vary from subscales of depression instruments to apathy specific questionnaires. Our group conducted a confirmatory factor analysis (CFA) of the Geriatric Depression Scale (GDS) in a pooled cohort of community and memory clinic older adults which identified a novel 2‐factor model that distinguishes apathy from depression. The goal of this study was to cross‐validate this novel apathy measurement model in a bilingual urban primary care clinical cohort.MethodWe conducted a CFA in the primary care cohort that was composed of participants from the 5‐Cog Battery for Detecting Cognitive Impairment and Dementia clinical trial. We compared the reliability measures and model fit indices of both the previous 2‐factor model and this novel model. Cohort characteristics were compared as well.ResultThe primary care clinical cohort was significantly different from the community and memory clinic cohorts in all baseline characteristics. The CFA of the primary care cohort yielded depression and apathy factors with good reliability (α = .78 and .63, respectively). Despite the fact that the primary care cohort included Spanish speakers, it performed similarly to the reliability of the depression and apathy factors in the community dwelling and memory clinic pooled cohort (α = .75 and .63, respectively). Both the primary care and memory clinic cohorts had higher depression and apathy scale scores compared to the community dwelling cohort, with the primary care cohort scoring in between the community and memory clinic cohorts in both depression and apathy scale measurements.ConclusionOur 2‐factor measurement model demonstrated similar reliability and fit across 3 distinct cohorts (community dwelling, memory clinic and primary care clinic) and 2 languages (English and Spanish), indicating its appropriateness as an apathy measurement model in further clinical trials.
Measuring brain activity associated with subsequent relational memory in typically developing periadolescent children: preliminary data from the PRANK study
Authors: Ramirez Meghan K , Sexton Jennifer N , Phipps Connor J , Behm Lillian , DeCesare Thomas A , Heller Abi M , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E 
Published: December 2022

AbstractBackgroundThe developing brain undergoes significant structural and functional changes that are associated with substantial cognitive changes, and this maturational trajectory continues during the periadolescent epoch. One such change is improvement in relational memory (RM) abilities. Normal RM requires the hippocampus, as demonstrated by the distinct memory deficits of Alzheimer’s disease (AD) associated with AD‐related hippocampal pathology. Lifelong risk factors for late onset AD may affect childhood brain development in ways that affect vulnerability to AD and other memory deficits later in life. This possibility motivates investigation into the brain’s developmental trajectory and correlations with AD‐vulnerable cognitive abilities, especially memory.MethodOur ongoing NIA‐funded study, the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study, measures brain structure, function, and cognitive abilities in periadolescent children (age 8–13 years). Here, we report preliminary data using task‐based fMRI and a subsequent memory (SM) paradigm to measure hippocampal‐dependent RM. A periadolescent sample from the PRANK study provided data for the current project (N = 90). MRI data were collected using protocols adapted from the Human Connectome Project. Hippocampal‐dependent RM was tested using a subsequent memory task where participants were asked to study pairs of common objects while fMRI‐BOLD data were collected. A memory test was completed for the studied materials where participants were presented two types of stimuli (studied match pairs or mismatched pairs of studied items).ResultSuccessful SM was associated with increased activity consistent with the frontoparietal networks in the lateral prefrontal and lateral parietal regions, increased activity in the dorsal attention network, and decreased activity in the so‐called memory retrieval network. There was evidence of increased anterior hippocampal activity associated with successful SM.ConclusionUsing task‐based fMRI to study brains of periadolescent children while they studied pairs of items, we observed SM effects that implicated anterior hippocampus and large‐scale functional brain networks (frontoparietal, dorsal attention, and memory retrieval). Findings from this preliminary analysis are novel in this task and in this population but concordant with previous studies of older and younger individuals. Future work will test whether there is an association in the magnitude of SM effects with polygenic risk for AD among PRANK participants.
Sleep associated electrophysiological activity in subjects at different levels of risk of developing Alzheimer’s disease
Authors: García‐Colomo Alejandra , Nebreda Alberto , de Frutos Jaisalmer , Carrasco‐Gómez Martín , Fernández Ricardo Bruña , Maestú Fernando 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is tightly associated with sleep alterations: as the disease progresses, sleep quality worsens. Therefore, the study of sleep patterns in interaction with other variables could constitute an early biomarker of AD. It is widely known that sleep alterations lead to an impaired cognitive functioning and performance, and recent studies evidence a positive feedback between amyloid beta (AB) accumulation and sleep. Consequently, sleep could constitute an interesting target for interventions aimed at altering the course of the disease. In the present study, we studied the relationship between self‐reported measures of sleep quality (i.e. number of hours of sleep) and the electrophysiological activity at resting‐state recorded using magnetoencephalography (MEG).MethodThe sample for this study was composed of healthy adults, with varying risks of developing AD (direct relatives vs non‐relatives, and APOE‐E4 carriers vs non‐carriers). All participants completed the Pittsburgh Sleep Quality Index, underwent a MEG scan, and were genotyped for their APOE carriage.ResultPreliminary results show different patterns of brain activation in areas classically associated with the development of AD, in relatives and non‐relatives, in relation with the number of hours of sleep. Non‐relatives present a significant cluster that encompases areas such as the precuneus, where a positive correlation is found between the power in the low beta (12‐20Hz) frequency band and the number of hours of sleep. Relatives do not show clusters where relative power and hours of sleep correlate significantly.ConclusionAlthough further research is needed, a possible interpretation of these results could be the following: non‐relatives’ brain functioning in areas of the default‐mode network, typically associated with AD, are more affected by the number of hours of sleep than relatives, who may not benefit as much due to early damage interfering with the protective effect of sleep.
18F‐MK6240 tau in ento‐ and perihinal cortex is related to episodic memory in the earliest stages of Alzheimer’s disease
Authors: Reinartz Mariska , Schaeverbeke Jolien , Van Laere Koen , Sunaert Stefan , Dupont Patrick , Vandenberghe Rik 
Published: December 2022

AbstractBackgroundIn a previous study, we showed the sensitivity of the Buschke Selective Reminding test Total Retention (BSRT TR) for detecting and predicting 4‐year cognitive change in cognitively intact older adults. Here, we examined how BSRT TR related to tau load.MethodThe study sample consisted of 29 cognitively intact participants of the Flemish Prevent AD cohort KU Leuven (CDR global=0, MMSE=28‐30, mean age=68.5 year) and eight memory‐clinic recruited patients with prodromal AD (CDR global=0.5, MMSE=21‐30, mean age=71 year). All participants underwent neuropsychological testing, MRI and 18F‐MK6240 PET. Structural T1‐weighted MRI images were processed using CAT12. Tau load was quantified as 18F‐MK6240 DVR with the inferior cerebellum used as reference region. The primary analysis was based on voxel‐wise regression analysis between 18F‐MK6240 DVR scans and BSRT TR mean scores, with age as covariate. The second primary endpoint was the correlation between BSRT TR mean scores and tau DVR in an entorhinal and perirhinal volume of interest (VOI) based on the Brainnetome atlas. The secondary analysis was a VOI analysis based on an early metaVOI also containing hippocampus, parahippocampus, fusiform gyrus and inferior temporal cortex. Results were compared to those obtained for other episodic memory scores (BSRT delayed recall (DR), Auditory Verbal Learning Test (AVLT) total learning (TL) and AVLT DR), and an MRI volumetric analysis.ResultVoxel‐wise regression analysis showed a negative correlation between BSRT TR mean and DVR in ento‐ and perirhinal cortex bilaterally (x=22, y=‐4, z=‐32, extent=612 voxels, cluster level pcorr<0.001) (x=‐30, y=‐22, z=‐20, extent=2910 voxels, cluster level pcorr<0.001) (Figure A). This was confirmed by the analysis of the entorhinal/perirhinal VOI (rho=‐0.44, p=0.0063; Figure B). Significant correlations with ento‐ and perirhinal DVR were also present for BSRT DR (rho=‐0.39, p=0.017) and AVLT TL (rho=‐0.41, p=0.012), but not for AVLT DR (rho=‐0.29, p=0.084). No significant correlation was found with tau in the early metaVOI for any of the verbal episodic memory measures. Voxel‐wise regression analysis between gray matter volume and BSRT TR mean scores did not show significant results.ConclusionThe earliest measurable tau aggregate levels in ento‐ and perirhinal cortex correlate with classical episodic memory parameters.
Empirically derived “discourse phenotypes” are associated with neuropsychological performance, cognitive status, and global atrophy: A latent profile analysis of connected speech measures
Authors: Mueller Kimberly D , Koscik Rebecca Langhough , Du Lianlian , Hale Madeline R , Chin Nathaniel A. , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C. , Hermann Bruce P 
Published: December 2022

AbstractBackgroundEvidence suggests that “connected speech” (i.e., spoken language, as in discourse) is related to early cognitive decline and early Alzheimer’s disease and related dementias (ADRD), yet performance on speech tasks and cognitive performance in ADRD are notably heterogeneous. Here we examined whether unique spoken language phenotypes could be ascertained using latent profile analysis (LPA), and we examined the association of identified clusters to demographic, clinical and cognitive characteristics. In the subsets with amyloid PET and structural MR, we analyzed cluster associations with estimated amyloid DVR and/or global atrophy at or near the speech sample.Method1,039 participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) completed comprehensive neuropsychological testing and provided a spoken language digital recording describing the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Cognitive status was determined by consensus conference. Five speech‐language metrics based on previous literature (Table 1) were automatically extracted from transcriptions of recordings utilizing Computerized Language Analysis (CLAN), including: semantic content, sentence length, speaking rate, and fluency. Baseline speech metric Z‐scores were included in the LPA; model fits were evaluated using BIC criteria. T‐tests, chi‐square tests, and ANCOVAs were used to the compare demographic, clinical, cognitive and imaging characteristics of the resulting discourse phenotypes (alpha = .05).ResultFit indices suggested a 3‐profile model: normal content‐normal fluency (n = 558), low content‐normal fluency (n = 224), and low content‐low fluency (n = 257) (Figure 1). The three phenotypes differed on gender and cognitive status, with more men and a higher proportion of MCI in the low content‐low fluency phenotype than the other groups; the phenotypes also differed on concurrent neuropsychological tests of language, memory and executive function. In the subset with imaging, the low content‐low fluency phenotype showed the most global atrophy. There were no differences in concurrent estimated amyloid accumulation (Table 2, Figure 2).ConclusionThree phenotypes of narrative discourse were identified and were associated with multiple neuropsychological tests, overall cognitive status and global brain atrophy. While connected speech metrics are generally viewed as a promising ADRD digital biomarker, the underlying taxonomy identified here suggests a more precision‐based approach is possible.
Initial Reports of ALLFTD Participant Internet and Social Media Usage Survey
Authors: Forsberg Leah K. , Brushaber Danielle , Heuer Hilary W. , Mester Carly T. , Rao Meghana , Manoochehri Masood , Nelson Kevin M , Huey Edward D , Rosen Howard J. , Boxer Adam L. , Boeve Bradley F. 
Published: December 2022

AbstractBackgroundThe ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study, is the unification of prior FTD research studies, ARTFL and LEFFTDS. ALLFTD aims to evaluate sporadic (s‐) and familial (f‐) frontotemporal lobar degeneration (FTLD) patients and asymptomatic family members of f‐FTLD patients, characterizing the cohorts longitudinally and informing clinical trial design.MethodALLFTD participants completed the ALLFTD‐specific, Internet and Social Media (ISM) Usage Survey. This survey was created to learn more about participants’ ISM habits. The survey asks participants to report on the frequency with which they use ISM for personal reasons and contains additional questions about reasons for use and general gaming and social media habits.ResultIn conjunction with their scheduled ALLFTD visit, 194 participants completed the ALLFTD ISM Usage Survey. Fifty one percent of participants identified as female. The mean age was 56.6 (SD 14.61), and the mean education level was 15.9 (SD 3.53). Most participants reported using ISM 1‐5 hours per day (56.7%). Participants also reported using ISM at less common frequencies: more than 5 hours per day (12.9%), less than 1 hour per day (13.9%), weekly (3.1%), 2‐3 times a week (2.1%), 2‐3 times a month (2.1%), and never (9.3%). “Moderate and Severely impaired” participants (CDR© + NACC FTLD > = 2) reported using ISM less frequently than “mildly symptomatic” participants (CDR© + NACC FTLD = 1, p<0.0001), and those who are “normal and questionably impaired” CDR© + NACC FTLD < = 0.5, p<0.0001). Those who are mildly symptomatic reported using ISM at a similar frequency to those who are normal or questionably impaired (p<0.01). When reporting on personal use, most participants stated that they used the internet for email (45.5%), news (37.5%), social media (32.4%), and entertainment (33.5%). Additionally, most participants reported playing games (56.2%) and using social media (59.8%). Participants predominantly indicated that they use social media to connect with family and friends (90.5%). Comparison of ISM usage frequency to reported anxiety, agitation, or depression on the NPI‐Q found evidence of a difference in ISM usage frequency; directional comparison studies are forthcoming.ConclusionFrequency of ISM usage is consistent between ALLFTD participants. Additional analyses of ISM usage are forthcoming.
Adverse Childhood Experiences and Poor Sleep Quality in Older Adults: The Influence of Cognitive Reappraisal
Authors: Sheffler Julia L , Pickett Scott 
Published: December 2022

AbstractBackgroundPoor sleep quality is associated with increased risk for developing mild cognitive impairment and Alzheimer’s disease and related dementias in older age. Adverse childhood experiences (ACEs) are associated with sleep impairment across the lifespan, but little is known about modifiable factors that may ameliorate this relationship.MethodData were obtained from an online questionnaire completed by a community sample of older adults (N = 267). The questionnaire included the Pittsburgh Sleep Quality Inventory, an Adverse Childhood Experiences questionnaire, the Cognitive Emotion Regulation Questionnaire (CERQ), and measures of pain, health conditions, and other psychosocial information. Moderation analyses were used to examine the interaction between ACEs and the positive reappraisal facet of CERQ on sleep quality in older adults, while accounting for the effects of sex, income, pain, body mass index, and health.ResultACEs were significantly associated with worse sleep quality in older adults, and this effect was moderated by positive reappraisal (ps<.05). For individuals reporting greater use of positive reappraisal skills, ACEs had no effect on sleep quality, whereas for individuals reporting less frequent use of positive reappraisal, ACEs were associated with substantially worse sleep quality. This relationship remained significant after accounting for sex, income, pain, body mass index, and health conditions in the model.ConclusionThe effects of early adversity on sleep quality persist into older age and may ultimately contribute to further health and cognitive problems. However, the modifiable emotion regulation skill of positive reappraisal appears to protect against sleep impairment in individuals with higher ACEs. These findings provide valuable information on techniques that may be beneficial for developing lifestyle interventions for high‐risk older adults.
Spatial Distribution of Rare Missense Variants Within Protein Structures is Associated with AD Risk
Authors: Jin Bowen , Capra John A , Benchek Penelope , Wheeler Nicholas R. , Naj Adam C. , Hamilton‐Nelson Kara L. , Farrell John , Leung Yuk Yee , Kunkle Brian W. , Vardarajan Badri N , Schellenberg Gerard D. , Mayeux Richard , Wang Li‐San , Farrer Lindsay A. , Pericak‐Vance Margaret A. , Martin Eden R. , Haines Jonathan L. , Crawford Dana , Bush William S. 
Published: December 2022

AbstractBackgroundDespite large genome‐wide association studies, only ∼30% of the heritability of Alzheimer’s disease is explained. The Alzheimer’s Disease Sequencing Project Whole Exome Sequencing (ADSP WES) has identified millions of genetic variants, over 97% of which are rare (MAF<1%), with 23% appearing in only one person. These rare variants could provide valuable information about new and previously identified risk loci for AD. However, current analysis strategies do not have power to detect associations for such rare variants.MethodWe have developed a protein structure‐based approach that evaluates rare missense variants based on their spatial distribution in a known protein structure rather than on their allele frequency. We hypothesize that AD cases exhibit clustering of rare variants within a protein structure relative to cognitive normal controls. We applied our approach to the ADSP WES Discovery Dataset with 5,522 AD cases and 4,919 controls on 5,969 genes with known structures from the Protein Data Bank (PDB) and 17,450 genes with Alpha Fold2 predicted structures. Only rare variants(MAF<0.05) were included in the analysis. We validated the identified genes within an independent dataset with multi‐ancestry individuals (ADSP WGS Replication) and a European‐ancestry dataset with 15,078 individuals (ADSP validation dataset).ResultWe identified three significant genes (TREM2, SORL1, and EXOC3L4) and one suggestive gene (CSF1R) with AD‐associated spatial clusterings from the ADSP WES data. For TREM2(PDB:6XDS; p‐value = 3.592E‐07) and SORL1(PDB:3WSY;p‐value = 6.701E‐05), two known AD genes, the spatial clusters are significant after excluding known AD risk variants, indicating the presence of additional low‐frequency risk variants within these genes. EXOC3L4(AlphaFold2:Q17RC7;p‐value = 2.504E‐05) is a novel AD risk gene that has a cluster of variants primarily shared by AD cases around the C terminal end of the Sec6 domain. This cluster replicated with significant associations in the ADSP WGS Replication and ADSP validation dataset.ConclusionOur result suggests multiple rare missense variants in TREM2, SORL1, EXOC3L4, and likely CSF1R are associated with AD risk by spatial clustering within the protein structure. These spatial clusterings have been replicated in two additional datasets. These spatial patterns may indicate potential functional regions in the protein structure associated with AD risk and are prime targets for further experimental validation.
Neurodegenerative Pathways in Alzheimer's Disease Subtypes
Authors: Wheatley Sophia , Mohanty Rosaleena , Ferreira Daniel , Muehlboeck J‐Sebastian , Levin Fedor , Grothe Michel J. , Westman Eric 
Published: December 2022

AbstractBackgroundBiological heterogeneity in Alzheimer’s disease (AD) has been observed and described as subtypes in measures of neurodegeneration (e.g., hypometabolism and atrophy). However, the relationship between these AD subtypes have not been studied. Thus, we aimed to compare and identify pathways associated with hypometabolism‐based and atrophy‐based subtypes.MethodCross‐sectional FDG‐PET and MRI scans from 173 amyloid‐positive AD individuals and 120 amyloid‐negative cognitively normal control individuals from the ADNI were included. Subtypes were identified in each neuroimaging modality by random forest hierarchical clustering using FDG‐PET uptake (measuring hypometabolism) and MRI volumes (measuring atrophy) in cortical and subcortical regions. We performed cross‐modal comparisons of atrophy patterns in hypometabolism‐based subtypes and hypometabolism patterns in atrophy‐based subtypes. To identify neurodegenerative pathways corresponding to each subtype, we used event‐based modelling to predict sequential progression of abnormality in hypometabolism and atrophy across brain regions (hippocampus, AD signature, frontal, posterior areas).ResultClustering revealed four hypometabolism‐based (two relatively limbic‐predominant: 25.7%, 19.8% and two relatively cortical‐predominant: 25.7%, 28.6%) and three atrophy‐based (diffuse: 18.7%, relatively limbic‐predominant: 28.6%, minimal: 52.6%) subtypes of AD with distinct spatial patterns and demographic and clinical characteristics. Cross‐modally, we found comparable AD‐typical atrophy patterns (involving the hippocampus and temporal regions) across the four hypometabolism‐based subtypes and comparable AD‐typical hypometabolism patterns (involving the retrosplenial cortex) across the three atrophy‐based subtypes. Event‐based modelling showed that each hypometabolism‐based subtype was associated with a unique sequential progression of regional hypometabolism, but not regional atrophy (sequence always initiated with frontal atrophy across all subtypes). Similarly, each atrophy‐based subtype was associated with a unique sequential progression of regional atrophy, but not regional hypometabolism (sequence always initiated with hypometabolism in AD signature areas across all subtypes).ConclusionOur findings suggest that hypometabolism‐based and atrophy‐based AD subtypes are not interchangeable. We identified unique metabolic and atrophy pathways specific to each subtype, which supports the notion that neurodegeneration manifests and progresses differentially across subtypes of AD. Despite being measures of neurodegeneration, hypometabolism and atrophy may not share the same extent of heterogeneity, bearing a complex multimodal relationship. Disentangling such relationships and combining complementary biomarkers to investigate heterogeneity could aid personalized treatment of AD.