bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between the Harvard automated phone task and Alzheimer’s disease pathology in clinically normal older adults
Authors: Gonzalez Christopher , Premnath Pranitha Y. , Kuppe Madeline K. , Fitzpatrick Colleen D. , Properzi Michael J. , Becker Alex , Johnson Keith A. , Rentz Dorene M. , Gatchel Jennifer R. , Vannini Patrizia , Amariglio Rebecca E. , Marshall Gad A. 
Published: February 2022

AbstractBackgroundWith the advent of prevention trials in preclinical Alzheimer’s disease (AD), evaluating novel and sensitive methods to measure instrumental activities of daily living (IADL) is becoming increasingly important in order to detect these clinically meaningful changes at the earliest stages of disease. The objective of the current exploratory study was to examine the cross‐sectional relationship between a phone performance‐based IADL test, the Harvard Automated Phone Task (APT), and regional cerebral tau and cortical amyloid burden in clinically normal (CN) older adults.MethodThirty‐one CN participants (mean age 70.0 (SD 4.8), 70% female) underwent flortaucipir (FTP) tau and Pittsburgh Compound B (PiB) amyloid positron emission tomography (PET). IADL were assessed using the 3 Harvard APT tasks: refilling a prescription (APT‐Script), calling the health insurance company to select a new primary care physician (APT‐PCP), and making a bank account transfer and payment (APT‐Bank). Linear regression models were used in the primary analyses to determine the associations between each APT task rate (correct responses/time) as the dependent variable and cortical amyloid aggregate, entorhinal cortex, inferior temporal, or precuneus tau as predictors of interest in separate analyses. In secondary analyses, models were repeated with an interaction between cortical amyloid and regional tau. Analyses included age, sex, and education as covariates.ResultA significant association was found between the APT‐Script rate and entorhinal cortex tau (β=‐0.08, 95% CI=‐0.14, ‐0.21, t value=‐2.78, p=0.01). No significant associations were found between other APT tasks and amyloid and tau regions. Additionally, no significant associations were found with the interaction between amyloid and tau regions.ConclusionOur preliminary findings suggest an association between a region of early tau accumulation in CN adults, the entorhinal cortex, and a real‐life IADL test. Moreover, APT‐Script task was more normally distributed, and had overall larger variability compared to the other two tasks, suggesting that it may be a more sensitive IADL measurement in CN individuals. Further analyses should explore this relationship in larger samples and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.
Neuropsychological correlates of plasma NfL in adults with Down syndrome
Authors: Carmona‐Iragui Maria , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Barroeta Isabel , Altuna Miren , Fernandez Susana , Garzón Diana , Padilla Concepción , Iulita M. Florencia , Bejanin Alexandre , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan 
Published: February 2022

AbstractBackgroundThe diagnosis of symptomatic Alzheimer’s disease (AD) in Down syndrome (DS) is challenging, mainly because the variability in cognitive performance associated with the different levels of intellectual disability. Plasma NfL levels are a promising biomarker of axonal damage with good diagnostic and prognostic performance, but its impact on cognitive performance has not been assessed. We aimed to explore this association between NfL levels and both baseline cognitive performance and the longitudinal cognitive decline.MethodProspective longitudinal cohort study. We included adults with DS from the Down Alzheimer Barcelona Neuroimaging Initiative cohort with mild and moderate levels of intellectual disability (ID) who had available plasma and a neuropsychological evaluation (Cambridge Cognitive Examination for Older Adults with Down's syndrome [CAMCOG‐DS] and/or modified Cued Recall Test [mCRT]). Plasma NfL levels were determined by Simoa SR‐XTM. We performed correlation analysis between baseline NfL levels and cognitive scores and linear mixed models to account for longitudinal cognitive measures. Age, sex and cognitive status (asymptomatic, prodromal AD, AD dementia) were considered as co‐variables in the analysis. The analyses were stratified in mild and moderate ID separately.ResultWe selected 378 individuals (mean age: 43.1 [sd 10.9], 46.6% female): 287 had CAMCOG‐DS scores and 224 had mCRT scores. We observed a significant correlation between baseline NfL levels and both CAMCOG‐DS and mCRT (R2=0.18 and R2=0.30, respectively, both p<0.001) (Figure). This correlation remained significant after stratification by ID (R2=0.17 and R2=0.19 for mild ID, R2=0.19 and R2=0.32 for moderate ID, all p<0.001). There was a significant association between longitudinal cognitive scores and baseline NfL levels (β=‐0.0035, p=0.011 for CAMCOG‐DS; β=‐0.015, p<0.001 for mCRT).ConclusionCognitive performance is inversely correlated to plasma NfL levels in adults with DS. This study supports the potential role of plasma NfL levels to identify and track AD‐related cognitive decline in DS.
Exploring the ATN classification system using brain morphology
Authors: Heinzinger Nils , Maass Anne , Yakupov Renat , Schütze Hartmut , Spottke Annika , Ramirez Alfredo , Schneider Anja , Metzger Coraline D. , Laske Christoph , Bittner Daniel , Brosseron Frederic , Priller Josef , Wiltfang Jens , Buerger Katharina , Fließbach Klaus , Heneka Michael T. , Peters Oliver , Speck Oliver , Nestor Peter J. , Teipel Stefan J. , Pross Verena , Glanz Wenzel , Wagner Michael , Jessen Frank , Düzel Emrah , Ziegler Gabriel 
Published: February 2022

AbstractBackgroundThe NIA‐AA proposed ATN (Amyloid/Tau/Neurodegeneration) as a classification system for AD pathology. The Amyloid Cascade Hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (Amyloid‐conversion first, Tau‐conversion second, N‐conversion last; therefore ‘ATN’) and alternative progressions (ANT, TAN, TNA, NAT, NTA) using Voxel‐based Morphometry (VBM) of brain anatomy in a large MRI sample.MethodWe used the DELCODE cohort of 437 subjects (49% female) which underwent lumbar puncture, MRI scanning and neuropsychological assessment. ATN classification was performed using (A+/‐) CSF‐Abeta42over40, (T+/‐) CSF‐phospho‐Tau, and (N+/‐) adjusted hippocampal volume. We compared voxel‐based model evidence for monotonic decline of gray matter volume across various sequences over ATN groups accounting for age, sex, education, TIV and WMH. The evidence of each progression was assessed using the Bayesian Information Criterion on voxel‐ and ROI‐level. First, face validity of the ACH transition trajectory A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ for VBM was compared against 23 biologically less plausible (permuted) sequences among AD‐continuum ATN groups. Then we evaluated the evidence for 6 brain volume progressions from A‐T‐N‐ towards A+T+N+ (ATN, ANT, TAN, TNA, NAT, NTA) including also non‐AD continuum ATN groups.ResultThe ACH‐based progression A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ is in line with cognitive decline and clinical diagnosis (Figure 1&2). It also has highest evidence in 9% of the gray matter voxels (especially MTL; Figure 3&4). Many (especially cortical) regions were compatible with alternative non‐monotonic volume progressions (‘AP 1’: 16%, ‘AP 2’: 14%; see Figure 3) over ACH progression sequence, compatible with early amyloid‐related tissue expansion or sampling effects due to brain‐reserve (Figure 5). Volume decline in 65% of voxels was more compatible with ATN/ANT progression (A flips first) when compared to alternative sequences (TAN, TNA, NAT, NTA).ConclusionEarly Amyloid status conversion (before Tau and Neurodegeneration) is compatible with brain volume loss observed during AD progression. The ATN classification and the ACH are compatible with monotonic progress of MTL atrophy.
Neural correlates of executive functions in people with amnestic mild cognitive impairment
Authors: Lejko Nena , Tumati Shankar , Opmeer Esther M. , Marsman Jan‐Bernard C. , Reesink Fransje E. , De Deyn Peter Paul , Aleman André , Ćurčić‐Blake Branislava 
Published: February 2022

AbstractBackgroundPeople with amnestic mild cognitive impairment (aMCI) often experience difficulties in cognitive domains other than memory, including executive functioning. Though these deficits are well documented, their neural correlates remain unknown. The aim of this study was to: (1) identify differences in brain activity and connectivity during planning in people with aMCI and cognitively healthy older adults, and (2) find whether planning‐related activity and connectivity are associated with cognitive performance.MethodTwenty‐five people with aMCI (67.6 ± 5.2 y, 6 F, 3 left‐handed) and 15 cognitively healthy older adults (66.4 ± 4.3 y, 5 F, all right‐handed) performed a visuospatial planning task (Tower of London; ToL) during functional magnetic resonance imaging (fMRI). Task‐related brain activation and connectivity were compared between the two groups and regressed against measures of executive functions (Digit Symbol Substitution Test, DSST; Trail Making Test difference score, TMT B‐A) and delayed recall (Rey Auditory Verbal Learning). All fMRI analyses were controlled for scores on the Geriatric Depression Scale, the Apathy Evaluation Scale, the DSST, and the TMT B‐A, and corrected for multiple comparisons at cluster‐level.ResultAs expected, people with aMCI had significantly poorer delayed recall than cognitively healthy older adults (F = 15.8, p < 0.0001). They also scored worse on the DSST (F = 5.5, p = 0.025) and the TMT B‐A (U = 77.5, p = 0.012), and were less accurate on the ToL task (F = 10.7, p = 0.002).During planning, people with aMCI had less activation in two clusters, both located in the precentral gyrus (p = 0.013 and p = 0.047). Across all participants, better performance on the DSST was associated with stronger anti‐correlation between a seed in the left middle frontal gyrus and a cluster in bilateral frontal poles (p = 0.012).ConclusionImpaired planning in people with aMCI appears to be underpinned by less activation in areas associated with sequence planning and visuospatial attention. Interestingly, more negative connectivity between the left middle frontal gyrus and frontal areas involved in working memory and task flexibility was associated with better performance on a task of executive functions.
7T locus coeruleus imaging correlates of apathy and cognition in patients with Parkinson’s disease and progressive supranuclear palsy
Authors: Ye Rong , O'Callaghan Claire , Rua Catarina , Hezemans Frank H. , Holland Negin , Malpetti Maura , Jones P. Simon , Passamonti Luca , Rowe James B. 
Published: February 2022

AbstractBackgroundApathy is a common neuropsychiatric feature of both Parkinson’s disease and progressive supranuclear palsy (PSP) (Aarsland, et al., 2001). Early neuropathology in the locus coeruleus (LC) and consequent noradrenergic deficiency are proposed to be key contributors to the pathogenesis of apathy (Passamonti et al., 2018). Here we test the hypothesis that in vivo LC integrity measured by ultra‐high field 7T‐MRI is predictive of apathy in Parkinson’s disease and PSP.MethodSixty‐three participants aged 50‐80 years were recruited: 25 people with idiopathic Parkinson’s disease, 14 patients with PSP Richardson’s syndrome and 24 age‐ and sex‐matched healthy controls (HC). Patients underwent clinical assessments for apathy, impulsivity, global cognition, motor severity, mood and sleep (Figure 2A&B). The LC was measured in vivo using a sensitive magnetisation transfer (MT) weighted sequence with ultra‐high 7T‐MRI (0.1mm3 voxels). The contrast‐to‐noise ratio of an atlas‐based signal was used to estimate the LC structural integrity (Ye et al., 2021). The LC integrity was correlated with clinical assessments. To estimate the spatial extent of the correlation within LC, voxelwise analyses used FSL randomise for localising the group differences and the clinical correlations.ResultReduced LC integrity was observed along the rostrocaudal axis for both PD and PSP patients, most prominently in the caudal subregion (Figure 1A‐D). This was confirmed by significant voxelwise comparisons between the patient groups and controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels; FWE‐corrected p<0.05), Figures 1E&F. Patients with PSP and PD showed similar levels of LC degeneration relative to controls, but this was more spatially widespread in PSP. The variability of LC integrity in both disease groups was associated with ACER, MoCA and apathy (Figure 2C&D). Distinctive spatial patterns were identified for the correlations, with the caudal LC consistently associated with cognitive impairment and apathy.ConclusionReduced LC integrity was confirmed in both PD and PSP using in vivo 7T‐MRI. LC degeneration, particularly in the caudal subregion, was associated with apathy and cognitive impairment. Our results suggest, noradrenergic therapies may be beneficial in targeting cognitive and behavioural features of Parkinson’s disease and PSP.
Effect of APOE4 and APOE2 genotype on white matter microstructure
Authors: Nir Talia M. , Nabulsi Leila , Lawrence Katherine E. , Villalon‐Reina Julio E. , Abaryan Zvart , Gari Iyad Ba , Zhu Alyssa H. , Haddad Elizabeth , Muir Alexandra M. , Thompson Paul M. , Jahanshad Neda 
Published: February 2022

AbstractBackgroundThe apolipoprotein E4 (APOE4) genotype is a major risk factor for late‐onset Alzheimer’s disease (AD). APOE2, on the other hand, has a protective effect. While there is evidence supporting an association between APOE genotype and white matter (WM) microstructure, findings have been inconsistent. Studies assessing AD risk in WM microstructure have largely used diffusion tensor imaging (DTI), but more recent diffusion MRI models may offer additional sensitivity to microstructural properties. Here, we characterized the effects of APOE4 and APOE2 genotypes on WM microstructure in a large, population‐based sample of adults from the UK Biobank.MethodDiffusion MRI data from 17,896 UK Biobank participants (age range: 45‐80 years; Fig 1a) were analyzed. Ten diffusion measures were derived from 4 models: 1) DTI, 2) the tensor distribution function (TDF), 3) mean apparent propagator MRI (MAPMRI), and 4) neurite orientation dispersion and density imaging (NODDI). Each measure was averaged across voxels within 25 WM regions (Fig 1c). Linear regressions were used to compare regional measures between individuals with an E3E3 genotype and E4 (E3E4+E4E4) or E2 (E2E3+E2E2) carriers, adjusting for age, sex, age‐by‐sex interaction, education, parents with dementia, and the first four genetic ancestry principal components. E4 or E2 carrier‐by‐age interactions were also tested, covarying for APOE genotype. FDR (q=0.05) was used to correct for multiple comparisons across 25 regions.ResultCompared to E3E3 carriers, E4 carriers showed widespread, yet subtle WM differences (Fig 2). The largest effects were detected with signal‐based model measures that reflect increased mean diffusivity (higher DTI‐MD, higher MSD, lower TDF‐FA). Significant E4‐by‐age interactions were detected with NODDI‐ISOVF, with E4 carriers showing a greater age‐related increase in ISOVF (Fig 3). Compared to E3E3 carriers, E2 carriers showed higher NODDI‐ICVF throughout the WM; differences were not detected with other measures. No significant E2‐by‐age interactions were detected (Fig 4).ConclusionAPOE4 carriers showed microstructural WM differences in measures reflecting less restricted diffusion, which could indicate neuronal loss or inflammation, particularly in posterior WM. Age‐dependent APOE4 effects were only detected with multi‐compartment diffusion measures. Greater neuronal density in APOE2 carriers may suggest a protective effect in WM, which was also detectable only with a multi‐compartment model.
Sex‐specific cerebral blood flow trajectories in mouse models of Alzheimer’s disease
Authors: Zhao Yifan , Jin Tao , Fitz Nicholas F. , Koldamova Radosveta , Vazquez Alberto L. , Iordanova Bistra 
Published: February 2022

AbstractBackgroundAlzheimer’s disease (AD) therapies targeting the aggregation of amyloid‐beta during the late stages have been largely unsuccessful. Growing evidence indicates that cerebral blood flow (CBF) plays a key role during the early AD stages by limiting the energy supply to the brain and impairing the clearance of harmful metabolites1. Recent studies suggest that CBF can be used as a predictor of AD2. Despite the CBF potential as a biomarker, its sex‐specific changes during AD progression are still poorly characterized. In the present study we quantify CBF trajectories in male and female mouse model of AD across lifespan. We also measure the tissue plaques and the vascular deposits in the form of cerebral amyloid angiopathy (CAA) to assess their relationship with CBF.MethodWe used 9.4T MRI of APPswe.PSEN1dE9 mice (12 male,10 female, 6‐24 months) and matched controls (n=15). We quantified CBF (qCBF) using T1‐weighted mapping (TE=12ms, TR=10 sec, 9 inversion times between 15‐8000ms and continuous arterial spin labeling (CASL) with TE=0.32ms and TR=2625ms with a label offset 12mm, duration 2.4s. Both had 64×64 matrix with 210 μm/voxel. We computed qCBF as previously described.3 Smooth muscle actin (SMA) and X34 staining was performed on free floating sections. Two‐way ANOVA was used to evaluate the age and sex effects on parenchymal plaques, CAA and qCBF.ResultWe found CBF to be significantly reduced in AD mice compared to controls (Fig 1, t‐test p=0.00017). Two‐way ANOVA showed a significance in the effects of sex and AD as factors on CBF (p=0.015) and an impact of both sex and age on the tissue plaque accumulation (Fig 2A), CAA was affected by age, with trend for higher CAA in females (Fig 2B), particularly after 13 months when qCBF declined.ConclusionWhen interpreting blood flow as AD biomarker both age and sex should be taken into consideration. The accumulation of tissue and vascular plaques appears to occur at different rates and depends both on age and sex. Further studies are needed on the CAA and CBF interaction and the sex‐specific vascular contributions to AD onset and progression. 1.Kisler et al. (2017). 2.Iturria‐Medina et al. (2015). 3.Zhang et al. (1992).
Association of Hispanic/Latino background and brain structure in Hispanics/Latinos from the SOL‐INCA MRI study
Authors: DeCarli Charles S. , Tarraf Wassim , Gonzalez Kevin A , Stickel Ariana M , Fletcher Evan M , Knaack Alexander , Maillard Pauline , Gallo Linda C , Daviglus Martha L , Testai Fenando D , Isasi Carmen R , Schneiderman Neil , Sofer Tamar , Fornage Myriam , Gonzalez Hector M 
Published: February 2022

AbstractBackgroundThe Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a representative, community‐based study of Hispanics and Latinos across the US that seeks to understand health disparities within this heterogeneous population. The Study of Latinos ‐ Investigation of Neurocognitive Aging MRI (SOL‐INCA MRI) is an ancillary MRI study to HCHS/SOL focused on the genetic influence and cognitive impact of age‐ and disease‐related brain measures. Brain structure undergoes substantial development and remodeling from birth through adulthood. Intracranial volume is a measure of maximum brain development, which is under substantial genetic and environmental influences, and is an independent marker of cognitive resilience. We report the influence of self‐described background on intracranial volume, brain tissue and cortical thickness measures for 1388 individuals studied to date.MethodHispanics and Latinos (ages 35.9‐85.2 years; 66% female) underwent MRI and analysis at the Imaging of Dementia and Aging (IDeA) laboratory using previously published methods. MRI outcomes of interest included supratentorial intracranial volume (TCV), image segmentation into white matter, gray matter, total brain, and regional cortical thickness. Background was categorized as Cuban, Central American, Dominican, Mexican, Puerto Rican and South American. We performed association analysis using linear regression models accounting for sex, height, background, and their interactions.ResultHeight was positively associated with TCV. Women had significantly smaller TCV than men (Table 1). TCV did not vary significantly with age. After adjusting for age, gender, height, and interactions, TCV measures varied significantly by background, and were greatest for Dominicans. Cuban’s and Mexican’s TCV measures were significantly smaller than Dominican’s (Figure 1). Cerebral gray matter volume as a residual of TCV was also significantly greater for Dominicans as compared to all other backgrounds (Table 2). Residuals of brain, gray and white matter varied significantly across backgrounds (Figure 2). Finally, cortical thickness measures varied significantly by background and brain region, being greatest for both Dominicans and Puerto Ricans (Figure 3).ConclusionBrain development results from multiple factors including gene, environment, and gene‐environment interactions. Investigating the genetic and environmental causes of the heterogeneity of brain measures in SOL‐INCA‐MRI are likely to lead to discoveries related to both brain development and possibly brain aging.
Investigating the effects of antihypertensive medication use in AD patients using multi‐modal neuroimaging
Authors: Dake Manmohi D , Marco Matteo , Soininen Hilkka , Venneri Annalena 
Published: February 2022

AbstractBackgroundHypertension is a known risk factor for Alzheimer’s disease (AD). Both conditions cause significant irreversible damage to cerebral constituents that can result in a more severe AD phenotype. Although there are no effective treatments available for AD, hypertension is a modifiable risk factor and its detrimental effects can be alleviated with antihypertensive drug treatments and through primary prevention.MethodPatients with mild to moderate AD (N = 133) were divided into two groups to examine differences in cerebral constituents and cognitive function in patients who were medicated (n = 71) and unmedicated (n = 62) for hypertension. Within the medicated patient group, a post hoc analysis was conducted to examine differences in patients based on the class of antihypertensive treatment. We used multi‐modal neuroimaging to explore these differences in cerebral blood flow (CBF), white matter integrity, grey matter volume (GMV) and vascular burden.ResultNo differences were detected between the medicated and unmedicated AD patients in the multi‐modal comparisons, although the medicated group showed a slightly better cognitive profile than the unmedicated group, despite having a higher burden of cardiovascular comorbidities and similar blood pressure readings to the unmedicated group. In the post hoc analysis, AD patients who were on beta‐blockers only, presented with higher GMV, CBF and neuropsychological scores and also a lower vascular burden compared to AD patients on other classes of antihypertensive treatment or a combination of the two. In the post hoc analysis of the unmedicated AD patient subgroup, variability in pulse pressure (the difference between systolic and diastolic blood pressure) was linked with lower CBF in subcortical structures.ConclusionThe use of antihypertensive treatment in AD could mitigate progression of damage to cerebral constituents related to chronically elevated blood pressure. The class of antihypertensive treatment used has varied effects on cerebral constituents in AD patients, pointing towards the need for future longitudinal studies exploring these effects. Evidence from this study also suggests that implementation of antihypertensive treatment could be beneficial in AD patients with uncontrolled hypertension. Measures to promote early identification of comorbidities and targeted interventions could thus help reduce AD severity in patients.