bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi‐Parametric MRI assessment of biomarkers in a non‐human primate model exhibiting sporadic cerebral amyloid angiopathy
Authors: Khan Suleiman , Murray Sean , Szabo Jakub , Soliman Muhammad T , Goldman Hannah , Llanos Michael , Cho Olivia , Schissler Emily , Kingsley Charles , Swain Jody , Gray Stanton B , Hopkins William D , Veraart Jelle , Wisniewski Thomas , Zaim‐Wadghiri Youssef , Scholtzova Henrieta 
Published: January 2025

AbstractBackgroundCerebral amyloid angiopathy (CAA) has been recognized as one of the morphologic hallmarks of Alzheimer disease (AD). The development of new AD drugs has brought unforeseen challenges that manifest as amyloid‐related imaging abnormalities (ARIA) appearing as vasogenic edema/effusion (ARIA‐E) and cerebral microhemorrhage/hemosiderosis (ARIA‐H). The prominence of CAA pathology in aged squirrel monkeys (SQMs), a New World non‐human primate model, underlines the importance of advancing this unique species for use in AD and dementia research. Previously, we demonstrated the effectiveness of atlas‐based R2* mapping, a measure of transverse tissue relaxation rate sensitive to the presence of iron, to discern age‐associated changes in SQM neuropathology along with validation of multiparametric in‐vivo MRIs to identify spontaneous ARIA in geriatric SQMs. The present study examined SQMs at distinct stages of aging by combining quantitative R2* mapping, T2‐weighted (T2‐w) sequences, and multi‐shell diffusion weighted imaging (DWI) to evaluate microstructural tissue integrity, in addition to histological assessment of the brain pathology correlates.MethodSQMs underwent 2D T2‐w Turbo Spin Echo (TSE) RARE/FLAIR MRI scans, in addition to multi‐shell DWI acquisitions. In vivo multi‐gradient echo (MGE) scans across three age cohorts were utilized to generate R2* maps for atlas‐based quantitative assessments of neuropathology. Coronal brain sections were examined to characterize histopathological features of MRI lesions.ResultMultiple instances of ARIA‐E‐like signal hyperintensities have been identified in brains of geriatric SQMs using T2‐w TSE RARE/FLAIR and DWI MRI. Furthermore, DWI revealed white matter (WM) abnormalities undetectable by conventional MRI. Absolute R2* values significantly increased with age in several brain regions, both in GM and WM. However, some regions experienced a reversal of this trend, suggesting a multi‐factorial model. Histological assessment of brain tissue corresponding to MRI abnormalities/hyperintensities revealed extravascular fibrinogen, diffuse IgG deposits, reactive gliosis, and disruptions of axons and myelin. In ARIA‐H regions, Perls’ stain confirmed hemosiderin depositions surrounding CAA‐positive blood vessels. Ferritin staining revealed microglial cells with characteristic morphology alongside colocalization of iron within microglia cell bodies.ConclusionOverall, this study demonstrates the complex interplay between ARIA, CAA, and age‐related brain changes in SQMs, highlighting the utility of this model for translational research on CAA/AD and innovative therapeutic interventions.
Assessing the feasibility of dried blood spot (DBS) collection for blood‐based biomarkers of Alzheimer’s Disease in rural South Africa
Authors: Gao Sarah , Bassil Darina T. , Wagner Ryan G. , du Toit Jacques , Huber Hanna , Ashton Nicholas J. , Cotton‐Samuel Dejania , Farrell Meagan T. , Mngomezulu Victor , Manly Jennifer J. , Tollman Stephen , Berkman Lisa F. , Zetterberg Henrik , Brickman Adam M. 
Published: January 2025

AbstractBackgroundThe characterization of Alzheimer’s disease (AD) and AD related dementias (ADRD) pathophysiology has been revolutionized by the development of highly sensitive blood‐based biomarkers. Although blood‐based biomarkers allow for greater access, cost effectiveness, and scalability, there are limitations for their implementation in resource‐constrained low‐ and middle‐income countries (LMICs) and rural settings, where access to equipment, freezers, and assays is often limited. Dried blood spot (DBS) collection emerges as a promising, convenient, and cost‐effective method for acquiring blood samples in these contexts, but it is unclear whether highly sensitive assays typically applied to cerebrospinal fluid (CSF), plasma, or serum can detect biomarker concentrations accurately. This pilot study assessed the feasibility of using DBS to measure blood‐based AD biomarkers by examining the agreement between ADRD biomarker concentrations derived from DBS and from plasma in older adults in rural South Africa.MethodData were collected from the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), an ongoing population cohort of 5,059 adults aged ≥40 years living in Agincourt, South Africa. This study focuses on a sub‐sample of 95 participants, whose venous blood and DBS were collected during the HAALSI visit and later tested for blood‐based ADRD biomarkers, including neurofilament light chain (NfL), phosphorylated‐tau181 (p‐tau181), and glial fibrillary acidic protein (GFAP). Plasma and DBS markers were analyzed using commercially available Single molecule array assays (Quanterix) at the University of Gothenburg. We ran pairwise correlations that examined the association between the plasma and DBS measures of p‐tau181, NfL, and GFAP.ResultThe sample consisted of 70.5% women, with an average age of 67.53 years (SD=9.69). We observed a positive correlation between plasma and DBS GFAP concentrations (r=0.78, p‐value<0.001). However, DBS and plasma concentrations were not correlated for p‐tau181 (r=0.05, p‐value=0.62) or for NfL (r=‐0.04, p‐value=0.68).ConclusionThese preliminary analyses suggest that GFAP concentration, a marker of astrogliosis, can be measured consistently in DBS. These findings have important implications for the selection and analysis of AD blood‐based biomarkers in low‐resource and LMIC settings, where venous blood draws may not be feasible.
Genome‐wide association of Tau imaging and plasma biomarkers in adults with Down Syndrome
Authors: Fan Kang‐Hsien , Aslam Muhammad Muaaz , Dang Lam‐Ha T , Gorijala Priyanka , Shi Ruyu , Feingold Eleanor , Kamboh M. Ilyas , Lee Joseph H. , Xicota Laura , Cohen Ann D , Handen Benjamin L , Christian Bradley T. , Head Elizabeth , Mapstone Mark , Cruchaga Carlos ,   Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS)
Published: January 2025

AbstractBackgroundAdults with Down Syndrome (DS) clearly show a higher risk of developing Alzheimer's disease (AD) when compared with the general population. Thus, it is important to investigate the role AD‐related biomarkers in adults with DS. Here we have performed genome‐wide association analyses on Tau‐PET and plasma Tau levels in the participants of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS).MethodGenome‐wide analyses were performed on 320 individuals of European descent DS (ranging in age from 25 to 81, Male 54.1%) having biomarker data from Tau‐PET as well as plasma p‐tau 181, p‐tau 217, and total tau. The association of these biomarkers with two APOE SNPs, rs429358 (E4) and rs7412 (E2) was also examined. We used a joint model of multiple phenotypes to investigate the genetic factors contributing to all Tau biomarkers simultaneously in those participants having complete phenotypic and genotypic data.ResultIn the APOE association analysis, APOE4 was not significantly associated with any biomarker. However, individuals carrying APOE2 had lower plasma p‐tau‐181 levels (p= 0.0017) than non‐carriers. In a genome‐wide analysis, we identified three novel genome‐wide significant (GWS) associations. The first association was with plasma total Tau on chromosome 11 near JHY (top SNP= rs77264104; MAF=0.017; p=1.75E‐08; β=‐1.52). The second association was with Tau‐PET on trisomy chromosome 21 near a long coding RNA LOC105372747 (top SNP= rs76523946; MAF=0.034; p=2.04E‐08; β=0.61). Lastly, the multiple phenotype analysis revealed association with all Tau AD biomarkers on chromosome 7 in the intronic region of SEM1 (Top SNP= rs78223947; MAF= 0.039; p=1.44E‐08).ConclusionWe have identified three novel associations with Tau biomarkers in adults with DS associated with either lower tau or higher tau biomarkers. Two of these associations (JHY and SEM1) have also been implicated potentially with Tau pathology and AD risk, respectively, in non‐DS participants. This investigation underscores the potential of leveraging the DS population as a valuable resource for discerning genetic elements that contribute to AD or AD‐related biomarkers.
Examination of Sex‐dependent sleep disruptions and OSA severity on Limbic System Integrity in Community‐Dwelling Cognitively Unimpaired Older Adults
Authors: Gills Joshua L , Cesar Oliver , Kovbasyuk Zanetta , Dharmapuri Anhiti , McBride Julian , Mbah Alfred , Valkanova Elena , Figueredo Luisa F , Parekh Ankit , Jean‐Louis Girardin A , Varga Andrew , Osorio Ricardo S. , Bubu Omonigho M 
Published: January 2025

AbstractBackgroundMicrostructure impairments of the limbic tracts are seen in early stages of the Alzheimer’s disease (AD) continuum. Sleep disruptions differ between sexes and have been linked with AD. We examined sex differences between measures of limbic white matter tracts and objective sleep parameters in cognitively unimpaired older adults.MethodThis cross‐sectional study included 170 community‐dwelling cognitively unimpaired older adults (mean±SD: age=67.2±5.2y) participating in NYU studies of sleep, aging, and memory. Subjects completed polysomnography (NPSG) and brain MRI. Sleep measures of interest included total sleep time (TST), NREM stages 2, 3 and REM sleep duration, sleep efficiency and fragmentation, and AHI4% and REM AHI4%. Microstructural properties of the cingulum, uncinate fasciculus (UF), and fornix were estimated using diffusional tensor imaging (DTI) metrics including radial kurtosis (RK), radial diffusivity (RD), and fractional anisotropy (FA). Linear mixed‐effects regression models examined associations between sex*sleep variables and DTI metrics. Models were adjusted for age, race, education, BMI, time between NPSG and MRI.ResultParticipants were 71.2% female, 44.1% Black/African‐American, and had 16.8±2.5y of education. In the cingulum, females showed increased fragmentation associated with decreased FA(β[IV]= β[SE}; β[fragmentation Left] =‐0.0023[0.00097], p=0.021), higher RD (β[fragmentation Right] =0.0021[0.00087], p=0.016; β [fragmentation Left] =0.0032[0.00096], p=0.001), and lower RK (β[fragmentation Right] =‐0.0055[0.00253], p=0.039). Additionally in the cingulum, females demonstrated higher AHI4% being associated with lower FA (β[AHI4% left]=‐0.0005[0.00026], p=0.054), higher RD (β [AHI4% left] =0.0006[0.00036], p=0.029), and lower RK (β [AHI4% Right] =‐0.0014[0.00069], p=0.052); and, less time spent in REM was associated with higher RD (β [REM left] =‐0.0016[0.00077], p=0.042). In the UF, females showed greater sleep fragmentation being related to higher RD (β[Fragmentation Left]=0.0045[0.00173], p=0.010) and lower RK (β[Fragmentation]=‐0.00077[0.00034], p=0.027), higher AHI4% was related to higher RD (β[AHI4% Right]=0.00072[0.00030], p=0.015). In the cingulum, men showed more NREM stage 3 sleep being associated with greater RK β[NREM 3 Left]=0.0065[0.00279], p=0.021). In the UF, men with higher AHI4% demonstrated associations with lower RK β[AHI4% Right]=‐0.0016[0.00080], p=0.046).ConclusionIn this sample of community‐dwelling cognitively unimpaired older adults. Sex‐specific sleep disruption associations were observed with limbic white matter tract alterations. Thus, highlighting possible sleep related underpinnings of sex differences in Alzheimer disease risk.
Relationship of retinal vasculature with measures of amyloid, tau, and neurodegeneration across the AD continuum
Authors: Mathew Sunu , Mackay Devin , Tallman Eileen F. , Deardorff Rachael , Hottle Savannah , Vosmeier Aaron , Clark David G. , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L. 
Published: January 2025

AbstractBackgroundThe eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of retinal vasculature measured using optical coherence tomography angiography (OCTA) with temporal lobe neurodegeneration, and cerebral amyloid and tau deposition, in older adults along the Alzheimer’s disease (AD) continuum.MethodParticipants included 13 cognitively normal subjects, 5 with subjective cognitive decline (SCD), 7 with cognitive impairment (mild cognitive impairment [MCI] and AD) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCTA, non‐AD dementia, or exclusion for MRI or PET. OCTA scans were obtained from each eye to measure retinal vessel density and perfusion density. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Finally, the association between retinal perfusion and vessel density with hippocampal volume, MTL tau, and lateral parietal amyloid was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.ResultRetinal vessel and perfusion density were decreased in patients with AD. The right and left hippocampal volume were significantly correlated with retinal vessel density and perfusion density in the right eye and left hippocampal volume was correlated with vessel density in the left eye, but it did not reach significance. The retinal vessel density and perfusion density in the right eye correlated significantly with lateral parietal lobe amyloid and medial temporal lobe tau. Finally, the total gray matter volume correlated significantly with the retinal vessel density and perfusion density in the right eye and inversely with the foveal avascular zone in the right eye.ConclusionRetinal perfusion and vessel density correlates with hippocampal atrophy, and general atrophy of the gray matter. It is also significantly correlated with the deposition of amyloid and tau in the brain. Imaging the retinal vasculature may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.
Neuroimaging features of CSF α‐synuclein seed amplification assay positivity in elderly individuals in AD continuum
Authors: Tosun Duygu , Landau Susan M. , Weiner Michael S. W. , Blauwendraat Cornelis ,   Alzheimer's Disease Neuroimaging Initiative
Published: January 2025

AbstractBackgroundWhile Aβ and tau pathologies are central to AD, emerging evidence suggests the coexistence of Lewy body pathology (α‐synuclein aggregates), further contributing to neurodegenerative processes. Our objective was to investigate the association between CSF α‐synuclein seed amplification assay (SAA) positivity and in vivo neuroimaging metrics of florbetapir‐PET and flortaucipir‐PET retention, as well as atrophy measured by structural‐MRI, with a focus on Aβ+ cognitively impaired (MCI and Dementia due to AD) individuals.MethodParticipants from ADNI who were Aβ+ (CSF Aβ42<980 pg/mL) and had undergone SAA analysis, along with based on florbetapir‐PET, flortaucipir‐PET, or structural‐MRI scans within one year of CSF sample collection, were included in the analysis (Table 1). Utilizing generalized ridge regression with connectivity‐informed adaptive regularization, SAA‐associated patterns of cross‐sectional neuroimaging features, as well as SAA‐associated patterns of the longitudinal rate of change in neuroimaging features were modeled, adjusting for age, sex, APOE ε4 status, and clinical diagnosis with additional adjustments for CSF Aβ42 levels in flortaucipir models and CSF Aβ42 and p‐tau181 levels in atrophy models. Significant associations (95% CI) were determined through 50,000 bootstrap‐based sampling.ResultIn cross‐sectional analysis (Figure 1; top row), compared to SAA‐ individuals, SAA+ was associated with: (1) greater florbetapir‐SUVR, observed in the bilateral middle and superior temporal, banks of superior temporal, left middle frontal and postcentral cortices; (2) elevated flortaucipir‐SUVR in bilateral insula, left superior temporal and postcentral cortices; and (3) greater atrophy in left middle frontal and lateral orbitofrontal, right anterior cingulate and banks of superior temporal cortices, as well as greater GM tissue volume in right inferior temporal cortex. Although the longitudinal sample size was limited, SAA+ was associated with: (1) lower rates of change in florbetapir in bilateral middle/lateral orbitofrontal and anterior cingulate cortices; and (2) higher rates of atrophy in bilateral middle frontal, right inferior parietal, left pre/postcentral and inferior frontal cortices, and lower rates of atrophy in right anterior and posterior cingulate cortices (Figure 1; bottom row).ConclusionOur results reveal that SAA‐positivity in individuals on the AD continuum is associated with distinctive patterns of neuroimaging features, highlighting the multifaceted nature of neurodegeneration in AD.
Low Incidence of Amyloid Related Imaging Abnormalities over 104 Weeks in a Phase 2 Study of Amyloid Anti‐Oligomer Agent ALZ‐801: Phase 2 Study Results in Biomarker Positive APOE4 Carriers with Early Alzheimer’s Disease (AD)
Authors: Kesslak Patrick , Abushakra Susan , Bracoud Luc , Hey John A. , Barakos Jerome , Hort Jakub , Prins Niels D. , Suhy Joyce , Power Aidan , Tolar Martin 
Published: January 2025

AbstractBackgroundOral ALZ‐801 (valiltramiprosate), a brain‐penetrant agent that inhibits amyloid‐oligomer formation is being evaluated in a fully enrolled APOLLOE4 Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer’s disease (AD). ALZ‐801 effects on plasma AD biomarkers were evaluated in a 104‐week Phase 2 study in APOE4‐carriers with CSF+ AD biomarkers. APOE4 is a major risk factor for amyloid‐related imaging abnormalities (ARIA) in AD patients. Incidence of ARIA‐H (microhemorrhages, MH; superficial siderosis, SS) and of ARIA‐E (edema/effusion) was analyzed.MethodThis study enrolled 84 subjects (31 APOE4/4, 53 APOE3/4) MMSE ≥22 and CDR‐G 0.5 or 1.0, with positive amyloid and CSF p‐tau181 ≥60 pg/ml. Subjects received ALZ‐801 at 265 mg BID over 104 weeks, with MRI at baseline, 52 and 104 weeks following a standardized protocol including 2D FLAIR and T2* Gradient Echo. Study allowed subjects with any number of MH, but ARIA‐E and SS lesions >1cm were exclusionary. Data were evaluated centrally by Clario neuroradiologists for eligibility assessment and ARIA safety monitoring. The study’s primary outcome was plasma p‐tau181 reduction at 104 weeks.ResultAt baseline, mean age and MMSE were 69 years and 26 respectively, with 52% female and 70% MCI subjects. Of 84 enrolled, 83, 75 and 69 subjects had baseline, 52‐week and 104‐week MRI. Baseline MRIs showed >1 MH in 7/83 (8%), and 6/75 subjects (8%) with post‐treatment MRI developed new MH, all asymptomatic. At baseline, 5 subjects had 1‐4 MH, of whom 2 developed new MH (3‐4); 1 subject had >10 MH and developed 29 new MH. 3 subjects developed de novo MH (1‐3). There was no SS or ARIA‐E. Study primary outcome was achieved with significant p‐tau181 reduction (31%, p = 0.045) and 4% Aβ42 reduction (p = 0.042), with memory stabilization over 2 years (Hey, ADPD 2024).ConclusionThe Phase 2 APOE4‐carrier population with positive CSF biomarkers showed low incidence of microhemorrhage (8%) over 2 years, all asymptomatic, with no siderosis or ARIA‐E. This 265 mg BID ALZ‐801 dose showed significant target engagement and promising cognitive effects in this study. These data suggest a low risk of ARIA with ALZ‐801 in APOE4 carriers with Early AD.
Clinical Impact of Amyloid PET in Diverse Medicare Beneficiaries with Cognitive Impairment: Preliminary Results from New IDEAS
Authors: Rabinovici Gil D. , Gatsonis Constantine , Dilworth‐Anderson Peggye , Gareen Ilana F , Glavin Emily , Hanna Lucy , Hillner Bruce E , March Andrew , Romanoff Justin , Siegel Barry A , Smith Karen , Weber Christopher J. , Windon Charles , Whitmer Rachel A. , Wilkins Consuelo H. , Carrillo Maria C. 
Published: January 2025

AbstractBackgroundThe Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study demonstrated that amyloid PET changes patient management in >60% of Medicare beneficiaries with MCI/atypical dementia. IDEAS had limited racial/ethnic diversity and excluded patients with “typical” amnestic clinical presentations. Here we present preliminary results from the New IDEAS study, which evaluates the clinical impact of amyloid PET in a more racially, ethnically and clinically diverse cohort.MethodLaunched in December 2020, the New IDEAS study (NCT04426539) is recruiting Medicare beneficiaries with typical (amnestic) and atypical (non‐amnestic) MCI/dementia at 142 dementia specialty clinics across the U.S. Multifaceted, community‐engaged and culturally‐tailored strategies are implemented to enhance the diversity of the cohort. Based on self‐identified race/ethnicity, patients are enrolled into 1 of 3 cohorts: Black/African‐American (BAA), Latino/Hispanic (LAT), or not BAA or LAT (NBL, all other racial/ethnic identities). Patients undergo amyloid PET using an FDA‐approved tracer with local visual read at 127 imaging facilities. Changes in management are measured between the pre‐PET visit (intended management, assuming no access to amyloid PET) and 90‐day post‐PET visit (implemented management, incorporating amyloid PET results). A composite management endpoint captures changes in one or more of the following: AD drug therapy, non‐AD drug therapy, counseling about safety and future planning.ResultOut of 5,209 registered participants, 3,328 (63.9%) participants completed amyloid PET, pre‐ and post‐PET visits at time of analysis (median age 74; 55.2% female; 22.6% BAA/17.5% LAT). Demographic and clinical features by cohort are shown in Table 1. Compared to NBL, BAA and LAT cohorts presented with greater clinical impairment, more frequent atypical clinical presentations and lower rates of amyloid PET positivity. Changes in the composite management endpoint occurred in 57.5% of all participants (57.2% MCI, 58.1% dementia), with similar rates across cohorts (Table 2). Following PET, anti‐amyloid antibodies were newly recommended in 7.0% of BAA, 7.4% of LAT and 9.0% of NBL. Changes in management were more frequent in typical than atypical clinical presentations (Table 3).ConclusionThese preliminary findings highlight the clinical utility of amyloid PET in a diverse and representative sample of cognitively impaired patients recruited in real‐world practice.