bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropathologic underpinnings of PET and fluid biomarker measures
Authors: Murray Melissa E. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) biomarkers can be broadly considered to inform upon regional or global changes occurring in‐vivo. Investigation of neuropathologic underpinnings of regional and global biomarker measures may require differing strategies to validate in the postmortem brain. The goal of this presentation will be to discuss potential neuropathologic strategies to validate AD biomarkers and consider how we may leverage our understanding of the biology to inform upon disease stages.MethodA neuropathologic overview of amyloid‐β composition, neurofibrillary tangle maturity, and glial activation will be provided in a didactic format with an emphasis on disease spectrum. The relevant AD biomarker literature with neuropathologic validation will be highlighted.ResultRegional AD biomarker measures can be visualized and quantified using positron emission tomography (PET). Neuropathologic validation is performed using PET‐to‐autopsy studies or via autoradiographic studies in the postmortem brain tissue. Global AD biomarker measures can be assessed using PET, or fluid biomarkers that include cerebrospinal fluid and blood. Interpretation of these global AD biomarker measures can be further examined in individuals followed to autopsy, which enables a direct comparison with global neuropathologic staging scales (e.g. Braak stage, Thal phase). Neuropathologic validation of global measures and disease stage may be especially useful in identifying contributors to biomarker variability owing to the presence of multiple comorbidities that are a common finding in the AD brain.ConclusionThe direct target of AD biomarkers (e.g. N‐terminal tau phosphorylation) may impact the sensitivity to early or advanced disease stages, both of which may be critical for disease monitoring depending upon the setting or study question. Quantitative digital pathology studies investigating regional, global, or disease stages measured by PET and fluid biomarkers provide an invaluable opportunity to inform upon the neuropathologic underpinnings of longitudinal biomarker changes.
Frequent leisure activity participation and cognitive change in the Study of Healthy Aging in African Americans (STAR)
Authors: Peterson Rachel L , George Kristen M , Gilsanz Paola , Mayeda Elizabeth Rose , Meyer Oanh L , Barnes Lisa L , Glymour M Maria , Mungas Dan M , Whitmer Rachel A 
Published: December 2021

AbstractBackgroundParticipation in leisure activities improves quality of life and is associated with lower dementia risk but has not been well studied in diverse populations. We examine type of leisure activities and cognitive change in older Black‐Americans.MethodIn the STAR cohort, an ongoing study that characterizes predictors of cognitive aging in Black‐Americans, 631 participants ages 50‐102 reported engagement in 13 leisure activities that require cognitive, social, or physical skills on a 5‐point Likert‐type scale (almost daily, weekly, monthly, yearly, or <yearly). Linear regression models examined the association of ≥weekly versus <weekly (reference) participation in individual activities measured at wave 1 with cognition assessed at wave 2 and cognitive change between waves 1‐2. Executive function, semantic memory, and verbal episodic memory were assessed using the Spanish and English Neuropsychological Assessment Scales (SENAS) and z‐standardized to wave 1 cohort distribution. Linear regression models adjusted for wave 1 age, gender, education, retirement status, time between waves, Southern state birth, and interview mode (phone/in person).ResultMean age was 68.3 (SD 8.6) years, 70% female, 36% <college educated, 56% retired and 37% Southern state birth (Table 1). Weekly activity participation ranged from >90% (reading, socializing) to 6% (attending cultural events; Table 2). Participants had better executive function scores in wave 2 if they reported they played games ≥weekly (β=0.18; 95% CI=0.05, 0.32) or read ≥weekly (β=0.30; 95% CI=0.03, 0.58) in wave 1 (Table 3). Playing games ≥weekly in wave 1 was also associated with higher wave 2 verbal episodic memory (β=0.15; 95% CI=0.004, 0.29), while ≥weekly arts and crafts participation was associated with lower Wave 2 verbal episodic memory (β=‐0.21; 95% CI=‐0.41, ‐0.01). Among participants who read ≥weekly in wave 1, executive function scores improved from wave 1 to wave 2 (β=0.20; 95% CI=0.02, 0.39; Table 4).ConclusionIn this cohort of Black‐Americans, those who read or play games weekly or more had better executive function; those who read weekly or more also had improved executive function from waves 1‐2. Participation in leisure activities can be a way to maintain brain health and potentially reduce risk of cognitive decline.
Neural somatosensory dysfunction is masked by variable executive declines across the Alzheimer’s disease spectrum
Authors: Wiesman Alex I , Mundorf Victoria M , Wolfson Sara L , Johnson Craig M , May Pamela E , Murman Daniel L , Wilson Tony W 
Published: December 2021

AbstractBackgroundDespite decades of research suggesting that primary somatosensory cortical function is spared until relatively late in the progression of Alzheimer’s disease (AD), very few of these studies have considered the role of domain‐specific cognitive function. This is essential, as recent literature has established a robust neurocognitive relationship between attention and executive functions and somatosensory neurophysiology, and patients with AD exhibit highly variable inter‐individual declines in these cognitive domains.MethodIn this study, we combine the high spatio‐temporal resolution of source imaged magnetoencephalography (MEG) with an extensive battery of neuropsychological tests to examine the potential mediating role of domain‐specific cognitive declines on somatosensory neural dysfunction in AD. In a sample of 38 biomarker‐confirmed patients on the AD spectrum and a group of 18 biomarker‐negative older adults, we model mediation/suppression effects of five distinct cognitive composite domains on group differences in two neurophysiological metrics of somatosensory function using a nonparametric bootstrapping approach.ResultInitial models that did not consider cognitive abilities provided weak or null support for somatosensory dysfunction in patients on the AD spectrum. However, the addition of domain‐specific cognitive scores to these models significantly increased their predictive capacity, and revealed robust differences in somatosensory function between these patients and their cognitively‐normal counterparts. The indirect effects of these cognitive variables on somatosensory group differences were significant as well, indicating a suppression effect. Specifically, across‐participant variability in processing speed declines was found to mask groupwise differences in mean somatosensory response amplitude, and similar variability in both processing speed and attention function was found to mask differences in the functional gating of redundant somatosensory information.ConclusionBy considering an important potential confounder in our models of somatosensory dysfunction in patients on the AD spectrum, we show that both general somatosensory responses and the functional gating of incoming somatosensory information exhibit profound alterations in these patients. These findings hold important implications for both our understanding of functional somatosensory pathology in AD, as well as for the importance of considering the role of domain‐specific cognitive variability in future AD‐neuroimaging research.
Augmenting Alzheimer’s Research: Schol‐AR
Authors: Ard Tyler , Toga Arthur W. 
Published: December 2021

AbstractBackgroundThe multi‐disciplinary field of Alzheimer’s disease research relies on many modern forms of data, from neuroimaging volumes and cellular image‐stacks to population and genetic information. Unfortunately, much of this information is difficult to communicate through the standard communication of scientific articles and static images, often resulting in incomplete data reporting and suboptimal comprehension for many readers.MethodWe introduce an augmented reality technique to layer modern digital information ontop of printable scientific figures, enabling full datasets to be attached to scientific articles. This system is additionally paired with an uploading framework that allows authors to create and disseminate augmentations from their own data.ResultThe capabilities provided through both the augmented viewing and augmentation creating systems facilitate communication and comprehension of the complex information underlying Alzheimer’s research.ConclusionAugmented reality technologies can improve and modernize the state of scientific communication in Alzheimer’s research, bridging the gap between modern digital data and journal article communications.
The prevalence of vascular risk factors in different AD biomarker profiles
Authors: Kučikienė Domantė , Costa Ana Sofia , Banning Leonie C.P. , van Gils Veerle , Schulz Jörg B. , Ramakers Inez H.G.B. , Verhey Frans R.J. , Vos Stephanie J.B. , Reetz Kathrin 
Published: December 2021

AbstractBackgroundThe relation between vascular risk factors and Alzheimer’s disease (AD) pathophysiology has been gaining an increasing research interest. Our aim was to investigate the prevalence of vascular factors in regard to different AD biomarker profiles in a memory clinic setting.MethodWe performed a retrospective analysis of patients of two memory clinics (University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands)) in between 2008 and 2019. We included patients, who were older than 45 years and had data on demographics, vascular risk factors, cerebrospinal fluid (CSF) and brain magnetic resonance imaging (MRI). The individuals were assigned an ATN profile according to Jack et al. (2018), with “A” referring to amyloid‐pathology (CSF Aβ 1‐42/ Aβ 1‐40 ratio or CSF Aβ 1‐42), “T” to tauopathy (CSF phosphorylated Tau) and “N” ‐ neurodegeneration (CSF total Tau and/or medial temporal atrophy (MTA) score). All patients were categorised into normal ATN profile (A‐T‐N‐), non‐AD change (A‐T+N‐, A‐T‐N+, A‐T+N+) and AD‐continuum (A+T‐N‐, A+T+N‐, A+T‐N+, A+T+N+) groups.ResultOf the 838 subjects included into the analysis, 53.2% were men; mean age was 68.7 ± 9.7 years. The most common vascular risk factors in the cohort were smoking (60.9%), hypertension (54.6%) and dyslipidemia (37.8%). A higher prevalence in the AD‐continuum group than in the normal ATN and non‐AD‐change groups was found for coronary heart disease (11,9% vs. 4,8% and 9.6% respectively, Pearson χ2 = 9.788, p=.007) and carotid artery stenosis (30.6% vs. 15.8 % and 17.1 % respectively, Pearson χ2 = 22.326, p<.001). Alcohol abuse and smoking were the most prevalent in non‐AD‐change group (alcohol abuse: 23.9% vs. 15.0% and 9.1%, Pearson χ2 = 7.501, p=.024; smoking: 69.4% vs. 60.3% and 52.1%, Pearson χ2 = 7.871, p=.020). Depression was more prevalent in the normal ATN group than in other groups (19.3% vs. 10.8% and 10.1%, Pearson χ2 = 12.930, p=.002).ConclusionVascular risk factors are very common in memory clinic patients, showing distinct differences between different AD biomarker profiles. This implies the need for controlling vascular factors in memory clinics and urges to further investigate this field to improve the prevention and treatment of dementia.
The prospective association between physical activity and memory in the Canadian Longitudinal Study on Aging (CLSA)
Authors: Hammond Nicole G , Stinchcombe Arne 
Published: December 2021

AbstractBackgroundPhysical activity is a recommended health behaviour and there exists a literature base linking physical activity and cognition in mid‐life and older adulthood. Yet, longitudinal study of physical activity and cognition is needed in order to account for determinants of health which may affect participation in physical activity and attenuate previously observed relationships. The aim of this study was to examine the longitudinal relationship between different intensities of physical activity and memory at first three‐year follow‐up in a large prospective survey of Canadian adults.MethodData were drawn from the Canadian Longitudinal Study of Aging (CLSA), an ongoing prospective cohort study. Participants self‐reported a number of health behaviours, health‐professional diagnosed conditions, and social and demographic factors. Physical activity was measured using the Physical Activity Scale for the Elderly (PASE). Past‐week activity was classified according to type of intensity (e.g., strenuous) and duration (e.g., minutes [mins] and hours [hrs]). Memory was assessed using the Rey Auditory Verbal Learning Test, with higher scores reflective of better memory performance. We used linear regression modelling to examine associations between physical activity at baseline and memory three‐years later, after adjustment for an array of potential confounders.ResultIn fully adjusted models, the pattern of findings across type of activity and duration was mixed. We observed a protective relationship of physical activity at some levels of walking (30mins to <1 hr: b= 0.14, p=0.021, 1hr to <2 hrs: b= 0.14, p=0.029), light activity (1hr to <2 hrs: b= 0.17, p=0.035, 2 hours or more: b= 0.15, p=0.050), moderate activity (1hr to <2 hrs: b= 0.38, p<0.001, 2 hours or more: b= 0.35, p<0.001), and strenuous activity (1hr to <2 hrs: b= 0.18, p=0.004). No prospective relationships were observed for strength‐based activities.ConclusionCertain types of physical activity were associated with better memory at follow‐up. On average, activities within the 1 to 2 hour range were most beneficial. Potential benefits of physical activity on memory may only be realized after other health considerations are first considered.
Self‐reported OSA risk, but not daytime sleepiness, is related to memory decline in autosomal dominant Alzheimer’s disease: Preliminary findings from the COLBOS biomarker study
Authors: Pardilla‐Delgado Enmanuelle , Baena Ana Y. , Ramirez‐Gomez Liliana A. , Martínez Jairo E. , Lopera Francisco , Quiroz Yakeel T. 
Published: December 2021

AbstractBackgroundSleep disturbances may increase the risk of developing Alzheimer’s Disease (AD). Research suggests that excessive daytime sleepiness and obstructive sleep apnea (OSA) may be linked to increased AD pathology and cognitive dysfunction. This study aimed to investigate the relation between subjective sleepiness and OSA risk, memory, and amyloid and tau, as measured by PET in preclinical AD.MethodOur ongoing sleep study includes members of a Colombian kindred with a Presenilin1 (PSEN1) E280A mutation for autosomal dominant AD. PSEN1 mutation carriers develop dementia in their late forties. 19 carriers (mean age 38+‐6,12 females) and 15 non‐carrier family members (mean age 36+‐5,10 females) completed the Epworth Sleepiness Scale and the STOP‐BANG for OSA risk, and underwent cognitive testing and PET examinations. A subset (n=15, 8 carriers, 7 non‐carriers) also completed these tests after 18mo. Mann‐Whitney tests were used to test between‐group differences in sleepiness and OSA risk. Spearman correlations were used to examine associations among outcome measures and cortical amyloid, entorhinal tau, and verbal memory (delayed word list recall). Change scores between baseline and follow‐up were calculated (timepoint2‐timepoint1) to assess longitudinal relations.ResultCross‐sectional results showed no differences between carriers and non‐carriers in daytime sleepiness or OSA risk (p’s<0.34). Sleep metrics were not related to cortical amyloid, entorhinal tau, or verbal memory (r’s>0.14, p’s<0.62). Longitudinal results revealed an increase in OSA risk score from baseline to 1.5‐year follow‐up was correlated to lower verbal memory performance for all subjects who had two time points (r=‐0.73,p=0.002). A change in sleepiness score was not associated with any of the variables of interest (r’s>0.44,p’s<0.10).ConclusionPreliminary baseline results showed that carriers and non‐carriers from a kindred with autosomal dominant AD did not differ in sleep‐related risk factors, such as self‐reported daytime sleepiness and OSA risk. These results suggest that baseline daytime sleepiness and OSA risk may not be related to pathology burden in early AD. In contrast, preliminary longitudinal results suggest that an increase in self‐reported OSA risk within a 1.5‐year timeframe may be related to memory decline. Future research with a larger sample is required to further assess sleep metrics in this population.
Baseline characteristics for CLARITY AD: A phase 3 placebo‐controlled, double‐blind, parallel‐group, 18‐month study evaluating lecanemab (ban2401) in early Alzheimer's disease
Authors: Lynch Shau Yu , Irizarry Michael C , Dhadda Shobha , Li David JianJun , Kanekiyo Michio , Bogoslovsky Tanya , Gee Michelle , Reyderman Larisa , Kaplow June , Rabe Martin , Hodgkinson Mark , Kramer Lynn D , Hampel Harald , Swanson Chad J 
Published: December 2021

AbstractBackgroundLecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ. In a recent multinational, phase 2, double‐blind, placebo‐controlled, study utilizing a Bayesian design with response adaptive randomization, 10‐mg/kg bi‐weekly lecanemab reduced brain Ab levels and slowed decline in cognition and function on Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐cog), and Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) at 18 months in participants with early Alzheimer’s disease (AD). Following these results, the CLARITY AD phase 3 study was designed to confirm the efficacy and safety of lecanemab in participants with early Alzheimer’s disease. Herein, we describe the baseline characteristics for participants in the ongoing CLARITY AD study.MethodsCLARITY AD is an 18‐month treatment, multicenter, double‐blind, placebo‐controlled, parallel‐group study with open‐label extension in participants with early AD. Baseline clinical and demographic data were summarized descriptively and compared to the lecanemab phase 2 study population.ResultsAs of a data cutoff of January 6, 2021, 1540 participants were randomized in CLARITY AD. The median age of participants was 72 years (range: 50‐90 years), with 81% of participants 65 years of age or older. Overall, 52% of participants were female and 75% were Caucasian. Mean (SD) baseline values for clinical endpoints were 3.2 (1.3) for CDR‐SB, 0.4 (0.1) for ADCOMS, 25.4 (7.3) for ADAS‐Cog, 25.6 (2.2) for MMSE, and 0.6 (0.2) for Global CDR. Aggregate baseline characteristics are similar to the lecanemab phase 2 study (median age 72 years [range: 50‐90 years]; 80% 65 years of age or older; 50% female; 90% Caucasian; clinical endpoints: 3.0 [1.4] for CDR‐SB, 0.4 [0.2] for ADCOMS, 22.2 [7.4] for ADAS‐Cog, 25.6 [2.4] for MMSE, and 0.6 [0.2] for Global CDR). Comparisons of the study populations will be presented.ConclusionBuilding on the encouraging findings from the lecanemab phase 2 study, the phase 3 CLARITY AD study is designed to confirm clinical efficacy and safety of lecanemab versus placebo in participants with early AD. Baseline characteristics after enrollment of 1540 participants are consistent with the phase 2 study and representative of an early AD population. Enrollment is ongoing.
Integrative analysis of eQTL and GWAS summary statistics reveals novel genes related to Alzheimer's disease
Authors: Varathan Pradeep , Gorijala Priyanka , Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Yan Jingwen 
Published: December 2021

AbstractBackgroundLarge‐scale genome wide association studies (GWASs) have identified many genetic variants associated with Alzheimer’s disease (AD) and related traits. While many GWAS findings were found to co‐localize with expression quantitative trait loci (eQTL), it is of great interest to investigate the functional effect of GWAS hits on the downstream transcriptomic level. Considering the lack of gene expression data from the brain tissue, we propose to integrate the summary statistics from AD GWAS and brain eQTL analysis to investigate potential transcriptomic alterations inside AD brains. We further validate our findings using the brain gene expression data from the ROS/MAP cohort.MethodWe used the GWAS summary statistics from IGAP[1] and brain eQTL results from BRAINEAC[2]. Summary Mendelian Randomization (SMR) and Heterogeneity in Dependent Instruments (HEIDI) tests were applied to identify highly significant genes related to AD in temporal cortex, frontal cortex and hippocampal regions. For significant genes identified from each region, we further performed differential gene expression analysis using the RNA‐Seq data from the corresponding brain tissue in the Mayo Clinic cohort. SNPs from these genes were tested for association with FDG intensity and thickness of corresponding brain regions using the data from ADNI. Finally, we performed pathway analysis using ClueGO.ResultSMR and HEIDI test identified 32 genes significantly associated with AD in the transcriptomic level, but only in temporal cortex. 10 of them were further validated with altered expression in AD temporal cortex region in the Mayo cohort (Fig.1). 19 SNPs from these genes were significantly related to the FDG intensity and thickness of temporal cortex regions, predominantly present in TOMM40 and NECTIN genes. Top pathways enriched by these genes are Neutrophil degranulation and cell surface interactions at vascular wall (Fig.2).ConclusionWe identified several SNPs with potential regulatory role in mediating the expression level of genes, which are found altered in AD brains and associated with multiple neuroimaging phenotypes. With evidence from multiple sources, these SNPs, their downstream genes and related pathways could serve as potential targets for further therapeutic intervention of AD.