bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE genotype, brain imaging, and neuropsychological testing markers of Alzheimer’s disease: Data from the Strong Heart Study
Authors: Suchy‐Dicey Astrid M , Nelson Lonnie A , Su Yi , Howard Barbara , Longstreth WT , Buchwald Dedra , Reiman Eric M 
Published: December 2020

AbstractBackgroundCarrying an APOE ε4 allele increases risk for Alzheimer’s disease and related dementias. However, risk effects and prevalence of risk alleles are not consistent across races/ethnicities. Prevalence of cognitive impairment or dementia and attributable risk from APOE ε4 genotype are unknown in American Indians (AI). This project evaluated associations of APOE genotype with cranial imaging and cognitive testing markers of vascular and Alzheimer’s dementias in a large, prospective, population‐based cohort of AI.MethodThe Strong Heart Study recruited 4,549 AI aged 45‐75 from 13 tribal communities across 3 major geographic regions in 1989‐1991. In 2010‐2013, all eligible surviving participants, then aged 65‐95, underwent cognitive examination including 3MS, WAIS, COWA, and CVLT‐II long delay free recall and cranial magnetic resonance imaging (MRI). APOE was genotyped from blood using ABI PRISM Linkage Mapping and DNA sequencing.ResultMost participants carried either 3.3 (73%) or 4.3 genotypes (23%). Clinical risk factors for dementia were prevalent, including high body mass index (mean>30), hypertension (80%), diabetes (48%), high LDL (39‐44%), chronic kidney disease (27%), and prior stroke (8‐9%). APOE ε4 carriers did not differ from non‐carriers in clinical factors, with the exception of serum LDL (103.9 mg/dL vs 96.7 mg/dL, P=0.015). Findings from MRI were also similar between genotypes, including presence of infarcts or hemorrhages, brain volume, and grade (0‐9) for white matter hyperintensities, sulcal widening, and ventricle enlargement. APOE ε4 carriers had marginally more WMH volume than non‐carriers. Cognitive examination scores were also similar, including Modified Mini Mental Status Examination (3MSE), Weschler Adult Intelligence Scale coding test (WAIS), Controlled Oral Word Association test (COWA), California Verbal Learning Test long delay free recall (CVLT).ConclusionDespite evidence for higher risk of Alzheimer’s and related dementias from presence of APOE ε4 allele among individuals from other populations, our study found little evidence of such an effect in elderly AIs. These findings raise intriguing questions about the presence of as‐yet‐unknown protective factors. Limitations of this study include cross‐sectional analyses and possibility of selective survival before the MRI examination. Future research should directly examine whether longitudinal changes in cognition and brain structure are associated with APOE genotype.
A novel peripheral biomarker for mild cognitive impairment and Alzheimer’s disease
Authors: Parra Mario A , Schumacher Marcela , Fernández Gerardo 
Published: December 2020

AbstractBackgroundRecent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer’s disease (AD). Short‐Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. A combined analysis of oculomotor responses during STMB can enhance the sensitivity of the assessment of patients with AD or at risk of AD such as those with Mild Cognitive Impairment (MCI). We investigated this hypothesis.MethodsUsing eye‐tracking technologies, we measured pupil dilation, fixation, and exploratory eye movement behaviours in patients with AD, MCI and in healthy controls while they performed the STMBT. The STMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding).ResultsExperiment 1 involved 18 healthy older adults and 18 patients with AD dementia. We observed (1) altered pupil dilation linked to poor STMB performance in AD patients. Experiment 2 involved 42 healthy older adults and 63 patients with MCI. Impaired fixation and exploratory eye movement behaviours accompanied poor STMB abilities in MCI patients.ConclusionTaken together, the results above suggest that eye‐tracking measures combined with cognitive markers for AD (STMBT) can (1) enrich the clinical phenotype of this type of dementia, (2) unveil novel features of AD dementia unknown to date, and (2) provide more sensitive tools which can detect and trace aspects of such phenotype in people at risk, thus helping to ascertain the presence of the prodromal stages of the disease.
Working memory training in older adults: COMT Val158Met modulates the transfer of benefits in a virtual reality working memory task
Authors: Boujut Arnaud , Mellah Samira , Verty Lynn Valeyry , Maltezos Samantha , Lussier Maxime , Bherer Louis , Belleville Sylvie 
Published: December 2020

AbstractBackgroundIndividuals with the Val/Val homozygous variation of the catechol‐O‐methyltransferase (COMT) gene possess lower prefrontal dopaminergic levels than Met/‐carriers and show more pronounced age‐related cognitive impairment (Papenberg et al., 2015). The aim of this study was to examine the impact of the COMT genotype profile on the transfer of working memory (WM) training effect in older adults.Method60 older adults were randomly assigned to inhibition or updating WM training conditions which were provided over 12 half‐hour sessions (3 sessions per week). Their COMT genotype was determined from a salivary sample collected using an Oragene OG‐500 collection kit. Transfer was measured with untrained complex WM tasks: Alpha‐span, Reading‐span, and a Virtual Reality dual‐task (VR‐WM) involving the detection of a visual road sign and a concurrent verbal memory task. Testing was done weekly, but to limit the bias of regression to the mean with small samples, the first two and the last two assessments were averaged.ResultMixed model analyses showed better performance for COMT Met/‐carriers (n = 43) than Val/Val carriers (n = 11) in the Reading‐Span task and improved performance on the three transfer tasks. There was a COMT x Time interaction on the VR‐WM task. Post‐hoc analyses showed that only the Val/Val group improved their performance following training, allowing them to reach levels similar to that observed in the Met/‐carriers group.ConclusionOur results indicate an effect of the COMT status on WM performance and training transfer. The observed pattern is similar to that previously reported in younger adults (Colzato et al., 2014) and emphasizes the role of dopaminergic regulation in WM and WM malleability. Colzato, L. S., van den Wildenberg, W. P. M., & Hommel, B. (2014). Cognitive control and the COMT Val158Met polymorphism: Genetic modulation of videogame training and transfer to task‐switching efficiency. Psychological Research, 78(5), 670–678. https://doi.org/10.1007/s00426‐013‐0514‐8. Papenberg, G., Lindenberger, U., & Bäckman, L. (2015). Aging‐related magnification of genetic effects on cognitive and brain integrity. Trends in Cognitive Sciences. Elsevier Ltd. https://doi.org/10.1016/j.tics.2015.06.008.
CSF phosphorylated tau‐217 is increased in Alzheimer’s and Creutzfeldt‐Jakob diseases and correlates with amyloid pathology
Authors: Emeršič Andreja , Karikari Thomas K , Rodríguez‐Lantero Juan , Ashton Nicholas J , Rot Uros , Kramberger Milica G , Čučnik Saša , Zetterberg Henrik , Blennow Kaj 
Published: December 2020

AbstractBackgroundCerebrospinal fluid (CSF) phospho‐tau181 (p‐tau181) is an established biomarker of tangle pathology in Alzheimer’s disease (AD), but does not detect aberrant tau phosphorylation in other tauopathies. Recently, tau phosphorylation at threonine‐217 (p‐tau217) was suggested to be a superior biomarker for AD pathology. However, it is unclear if p‐tau217 is increased in other neurodegenerative diseases, including Creutzfeldt–Jakob disease (CJD) with concomitant amyloid/tau pathology or in primary tauopathies such as progressive supranuclear palsy (PSP).MethodWe validated an ultrasensitive Single molecule array (Simoa) p‐tau217 immunoassay and tested its diagnostic performance in the CSF of AD (n=110), CJD (n=22), and PSP (n=22) patients as well as age‐matched controls (n=106). Prospectively recruited patients were classified based on clinical presentation and the core CSF biomarker profile (amyloid‐beta‐42[Aβ1‐42 <650 pg/ml], [Aβ1‐42/Aβ1‐40 ratio<0.08], total‐tau <400 pg/ml and p‐tau181 >60 pg/ml) measured by INNOTEST® immunoassays (Fujirebio). Diagnostic performance was compared against INNOTEST® p‐tau181 using area under the curve (AUC).ResultThe in‐house p‐tau217 assay demonstrated a lower limit of quantification of 1.4pg/ml with robust analytical performance, including dilution linearity (mean recovery=104%), spike recovery (mean recovery=97%) and antibody specificity. P‐tau217 correlated strongly with p‐tau181 in all participants (r=0.82, p<0.0001) and showed six‐fold mean increase in both AD and CJD versus either controls or PSP (p<0.0001). In contrast, p‐tau181 was only increased 2.5‐fold in AD patients (p>0.05), but not CJD. P‐tau217 and p‐tau181 had similar performances in separating AD from controls (AUC>97%), and AD from PSP (AUC>95%). P‐tau217 poorly differentiated AD from CJD (AUC=63%, compared with 87% for p‐tau181) due to the highly overlapping p‐tau217 concentrations in both groups. However, p‐tau217 better distinguished CJD from controls (AUC=96%) compared with p‐tau181 (AUC=76%). Cross‐sectionally, p‐tau217 associated with CSF Aβ1‐42 (r= ‐0.76, p<0.0001). In diagnostic group‐stratified analyses, p‐tau217 correlated with Aβ1‐42/Aβ1‐40 only in AD (r= ‐0.31, p<0.05).ConclusionUnlike the AD‐specific p‐tau181, p‐tau217 had a very high diagnostic accuracy in distinguishing both AD and CJD from controls. P‐tau217 increases in CJD appear independent of amyloidosis. P‐tau217 identifies tau pathology in both diseases whilst p‐tau181 is useful for confirming AD diagnosis.
Relative contribution of white matter hyperintensity to amyloid and neurodegeneration in cognitive decline over time or clinical diagnoses in a diverse, community‐based cohort of older adults
Authors: Lao Patrick J , Chesebro Anthony G , Beato Juliet M , Amarante Erica , Igwe Kay C , Maas Benjamin , Boehme Amelia , Gu Yian , Stern Yaakov , Schupf Nicole , Manly Jennifer J , Mayeux Richard , Brickman Adam M 
Published: December 2020

AbstractBackgroundThe 2018 NIA‐AA Alzheimer’s disease (AD) research framework moves towards a multiple biomarker approach to explain AD development and progression more fully. This research framework has the flexibility to incorporate various biomarkers into a full or partial amyloid‐tau‐neurodegeneration (A/T/N) profile. The objective of this study was to determine the relative contribution of white matter hyperintensities (WMH) to amyloid and neurodegeneration on cognition in a diverse, community‐based cohort of older adults.MethodA subset of cognitively healthy participants (n=155; age=69‐99yrs; 65% women, 30%/44%/26% Non‐Hispanic White/Non‐Hispanic Black/Hispanic) from the Washington Heights‐Inwood Columbia Aging Project underwent baseline Florbetaben PET (amyloid SUVR), T1‐weighted (cortical thickness[mm]) and T2‐weighted FLAIR MRI (WMH volume[cm3]), as well as subsequent neuropsychological assessments and consensus diagnoses every 1.5 years (up to 6 visits). Linear mixed effects models were used to test for change over time in language, memory, executive function, and visuospatial ability, while cox proportional hazard models were used to test for risk of developing MCI or AD. Biomarkers of interest included amyloid, cortical thickness, and WMH, adjusted for demographics (sex/gender, race/ethnicity, education). Interactions between biomarkers and time (e.g., slope differences) were evaluated as significant below 0.1.ResultIn A/N/V models, higher amyloid was associated with faster rates of decline in language (B [95%CI]: ‐0.08 [‐0.13, ‐0.02]), memory (‐0.13 [‐0.21, ‐0.05]), and visuospatial ability (‐0.05 [‐0.12, 0.01]), higher WMH was associated with faster rates of decline in executive function (‐0.05 [‐0.11, 0.009]) and visuospatial ability (‐0.02 [‐0.05, 0.005]), and lower cortical thickness was associated with lower executive function scores (1.6 [0.10, 3.0]). Individuals were more likely to develop MCI or AD with higher amyloid (Hazard Ratio=4.2, [1.1, 15.9]), but not with higher WMH (1.2 [0.83, 1.7]) or lower cortical thickness (0.03 [4E‐4, 2]).ConclusionIn this imaging subsample of older community‐dwelling adults, cognitive decline is differentially associated by domain with amyloid or vascular burden, while broader, multi‐domain cognitive impairment necessary for MCI or AD diagnoses is associated with amyloid, one of the hallmark AD pathologies. Results support the use of complementary information from biomarker profiles, including traditional AD, vascular, and neurodegenerative biomarkers, to investigate AD and related dementias.
Cognitive performance effects following a single dose of the M1 muscarinic positive allosteric modulator VU319
Authors: Conley Alexander C. , Key Alexandra P. , Blackford Jennifer U. , Rook Jerri M. , Conn Jeffrey , Lindsley Craig W. , Jones Carrie K. , Newhouse Paul A. 
Published: December 2020

AbstractBackgroundVU319 is an investigational positive allosteric modulator of the M1 muscarinic acetylcholine receptor developed for cognitive enhancement in Alzheimer’s disease (AD) and other disorders. Cognitive tasks including test of attention, speed, and memory and event‐related potentials (ERPs) were used during the double‐blind, placebo controlled Single Ascending Dose (SAD) study of VU319. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state.MethodVU319 was given orally to 52 healthy volunteers aged 18‐55 years. The SAD study tested 40 participants in five dose escalating cohorts (60‐600 mg), in which 6 received VU319 and 2 received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. Cognitive and electrophysiological tasks testing attention, memory and psychomotor speed were examined pre‐dosing and at 5 hours post‐dose. The tasks were selected for their sensitivity to cholinergic tone.ResultSingle dose treatment showed improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants responded significantly faster to targets on the continuous performance test after 600 mg compared to placebo (p = 0.03, effect size d = 1.2). On the incidental memory task, participants who received 400 and 600 mg VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d > 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that response time of psychomotor speed measures improved with increasing blood concentration of VU319 across doses (r>0.38).ConclusionWe conclude that these results demonstrate likely enhancement of the cholinergic system functioning in healthy adults following a single oral dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by M1 allosteric modulators and provide a framework to examine the cognitive impact of multiple doses of VU319 in AD patients.
The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease
Authors: Solders Seraphina K. , Clark Alexandra L. , Weigand Alexandra J. , Sorg Scott F. , Galinsky Vitaly , Frank Lawrence R. , Bondi Mark W. 
Published: December 2020

AbstractBackgroundThe locus coeruleus (LC) is the brain’s main source of norepinephrine and plays a key role in modulating attention and memory processes. In Alzheimer’s disease (AD), the LC has been identified as an early site of tau accumulation and this tau pathology may spread via its connections to the transentorhinal cortex (TEC). Historically, this region has been nearly impossible to study in vivo. However, recent advances in structural magnetic resonance imaging (MRI) have provided opportunities to capture the integrity of LC neurons and their projections. We utilized a combination of neuromelanin‐sensitive and diffusion tensor MRI to examine LC integrity and its role in memory.Method31 older adults (26 cognitively normal; 5 MCI) underwent T1 fast spin echo and diffusion MRI scans as well as neuropsychological testing. Bilateral LC contrast ratios (CRs) were calculated as neuromelanin‐related signal intensities relative to a reference region. In a subset of participants (n=12; 10 cognitively normal, 2 MCI) LC‐TEC white matter pathways were reconstructed using probabilistic tractography in FSL and average fractional anisotropy (FA) was extracted. Logical Memory and CVLT‐2 were used to assess verbal learning and memory.ResultResults revealed lower bilateral LC‐CRs was associated with poorer performance on measures of story learning (LMI; r=0.425, p=.045) and word‐list recall (CVLT‐2 Short Delay Recall: r=.481, p=.006; CVLT‐2 Long Delay Recall: r=.375, p=.038). Tractography analyses indicated that higher FA of the left LC‐TEC tract was associated with poorer story learning (LM1: r=‐.651, p=.02), whereas higher FA of the right LC‐TEC tract was associated with poorer word‐list recall (CVLT‐2 Short Delay Recall: r=‐.599, p=.039; CVLT‐2 Short Delay Cued Recall, r=‐.705, p=.01).ConclusionPreliminary results indicate that neuromelanin and tractography MRI methods can be utilized for in vivo characterization of the human LC. Lower neuromelanin signal, but higher FA is associated with poorer memory performance in a sample of cognitively normal and MCI adults. Greater tau pathology may alter the LC signal and encroaching tau accumulation in the LC‐TEC pathway may initiate neuroinflammatory processes reflected by increased FA. Future work is needed to understand the temporal course and nature of LC changes across the aging‐MCI‐AD continuum.
A biorepository for the in‐depth validation of pre‐analytical sample handling effects on novel blood‐based biomarkers for Alzheimer’s disease: The first results
Authors: Verberk Inge M.W. , Misdorp Els O. , Koelewijn Jannet MW , Shan Dandan , Lambrechts Charlotte , Shaw Leslie M. , Rissman Robert A. , Blennow Kaj , Zetterberg Henrik , Ball Andrew J. , Edelmayer Rebecca M. , Teunissen Charlotte E. 
Published: December 2020

AbstractBackgroundVariation in pre‐analytical sample handling can critically affect biomarker concentrations in biofluids. A study on pre‐analytical effects on novel blood‐based biomarkers is therefore of importance to facilitate their swift introduction in clinical settings. Guided by the Alzheimer’s Association, we established a biorepository of systematically “mistreated” blood samples for analysis of various biomarkers using various technologies. Here we present the first results.MethodBlood samples were collected from 90 volunteers presenting at the hospital for any disease. Blood was mistreated according to 8 pre‐analytical protocols, resulting in n=10 sample sets per protocol with several aliquots per set to be shared among labs for biomarker analysis. The protocols were designed to test the effects of type of collection tube, and the effects on K2‐EDTA plasma of delayed centrifugation (at room temperature (RT) or 4°C), centrifugation temperature (RT or 4°C), delayed freezing after centrifugation (RT or 4°C), two‐week intermittent storage at low temperature (4°C or ‐20°C), freezing‐thawing (up to 4x) and aliquot tube filling (250µl, 500µl or 1000µl in 1.5‐mL tube). Using a novel 4‐plex Simoa assay simultaneously measuring Abeta(1‐42), Abeta(1‐40), GFAP and NfL, we obtained the first results on our sample sets. A decline was regarded relevant when a change of at least a 10% was observed in the biomarker value compared to the reference conditions.ResultCollection tube type affected the levels of the assessed markers Abeta(1‐42/1‐40), GFAP and NfL (Figure 1). Delayed centrifugation affected only plasma Abeta(1‐42/1‐40), and only when kept at RT for 24h (average ‐18% decline compared to no delay) and not when kept at 4°C (Figure 2). This same pattern was observed for hold time after centrifugation (Abeta(1‐42/1‐40): ‐16% for 24h hold at RT). Two‐week storage at 4°C but not at ‐20°C affected only Abeta(1‐42/1‐40) (average ‐15%). Centrifugation temperature, up to four freeze‐thaw cycles and aliquot tube filling did not affect the biomarker values Abeta(1‐42/1‐40), GFAP and NfL.ConclusionThese first results of the project on pre‐analytical effects on novel blood‐based biomarker concentrations show that relevant pre‐analytical effects exist and that it is essential to work towards unified standard operating procedures for blood sample collection, handling and storage.
Developing feedback methods for caregivers of persons with cognitive impairment using a home‐based sensing and computing system
Authors: Thomas Neil W , Ault Laura , Goubran Rafik , Wallace Bruce , Knoefel Frank , Kaye Jeffrey 
Published: December 2020

AbstractBackgroundConventional methods assessing activities related to caregiving rely on self‐report with caregivers providing estimations of time and resources directed to these activities, which vary over time and can be difficult to reliably estimate retrospectively. Home‐based assessment platforms using sensors to collect objective information on daily activities represent a novel method to evaluate caregivers.MethodThis pilot study is an observational trial using the Collaborative Aging Research Using Technology (CART) sensor platform to assess cognitive and functional outcome measures. The study is enrolling individuals with cognitive impairment living with a caregiver. All participants’ complete questionnaires on functional status and behavioral symptoms, and undergo cognitive testing at baseline. These conventional measures are compared to the sensor‐based outcome measures. Caregivers complete an additional survey on burden level, the Zarit Burden Inventory (ZBI‐12). Additionally, focus group sessions will be held including caregivers enrolled in the pilot study and caregivers of individuals with cognitive impairment in the community.ResultData is currently being collected on daily functional activities in caregivers. Enrollment is ongoing for participant homes installing the sensor system. Three caregivers are enrolled, with an average age of 61.7 years (± 5.0), and 14 (± 3.4) years of education. Baseline mean ZBI‐12 scores were 15 (±4.6). Data has been collected for 9672 hours in total for the 3 participants. Caregivers slept on average 8.8 (±2.3) hrs/night and took 3868 (± 592) steps per day. Sensor data will be compared to ZBI‐12 scores to identify those activities correlated with higher levels of burden. Information from the focus group sessions will be used to guide development of a feedback system to inform caregivers of their activities related to time and effort spent in caregiving.ConclusionA home‐based sensing and computing system could provide objective information on activity and effort related to caregiving activities. The design of the feedback system is being developed using input from end‐users. The information provided by this system could help to inform caregivers of changes in their level of caregiving activities associated with higher levels of stress and more promptly identify whether they should seek increased external or community support.