bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring Microtubule Dynamics in Alzheimer's Disease: Longitudinal Assessment Using [11C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models
Authors: Damuka Naresh , Gollepalli Krishna Kumar , Krizan Ivan , Bhoopal Bhuvanachandra , Miller Mack , Deep Ojasvi , Bashetti Nagaraju , Kumar JV Shanmukha , Orr Miranda E. , Macauley Shannon L , Whitlow Christopher T , Mintz Akiva , Lockhart Samuel N. , Craft Suzanne , Sai Kiran K. Solingapuram 
Published: January 2025

AbstractBackgroundBrains affected by Alzheimer's disease (AD) exhibit senile plaques containing amyloid beta (Aβ) peptides and neurofibrillary tangles, formed when tau becomes hyperphosphorylated and disengages from microtubules (MTs). Early instability in MTs is observed in the AD process, emphasizing its significance in connecting the hallmark pathologies of Aβ/tau‐based degenerative events. While current Aβ and tau PET approaches can characterize disease lesions, they fall short in capturing earlier molecular events. MT‐PET aims to address this gap by targeting these early events, providing crucial insights into AD pathophysiology. The PET radiotracer, [11C]MPC‐6827, capable of tracking and quantifying MT‐based changes in real‐time and in vivo, addresses an urgent unmet need and facilitates the monitoring of MT changes in the early stages of AD. Here we present for the first time a comprehensive longitudinal PET imaging study of [11C]MPC‐6827 in Aβ‐overexpressing (APP/PS1) and tau‐overexpressing (P301S) mouse models of AD.MethodsLongitudinal [11C]MPC‐6827 PET imaging, biodistribution studies, autoradiography, and behavioral assessments were conducted at multiple time points in APP/PS1 (3 to 22 mo old) and P301S (3 to 13‐mo‐old ) transgenic (TG) and age‐matched wild‐type (WT) mice (n=7/group). Whole‐brain standard uptake values for PET, %injected dose/gram for biodistribution, specific brain uptake for autoradiography, and nesting weight for cognitive assessments were determined and PET correlations for TG mice at different age‐points were calculated.ResultsLongitudinal PET imaging demonstrated a 1.3‐fold (***p<0.0001) and 0.9‐fold (**p<0.005) higher brain uptake in APP/PS1 TG mice from 3 to 22 mo and P301S TG mice from 3 to 13 mo respectively (Figure 1) and uptake increased with increasing Aβ and tau loads in AD brains. Longitudinal PET data positively correlated with biodistribution (Pearson r=0.94), and autoradiography results (r=0.55) and negatively correlated with cognitive data (r=‐0.65) in APP/PS1 mice (Figure 2).ConclusionIncreased [11C]MPC‐6827 brain PET uptake with both increasing Aβ and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aβ and tau‐based neurodegeneration processes. These findings highlight the potential of [11C]MPC‐6827 PET as a powerful tool for monitoring MT disintegration early‐on. Ongoing experiments are exploring translational potential in humans.
A clock model of regional tau‐PET accumulation and cognitive decline in sporadic early‐onset Alzheimer’s disease
Authors: Schonhaut Daniel R. , Insel Philip S. , soleimani‐meigooni David N. , Zeltzer Ehud , Windon Charles , Maiti Piyush , Yballa Claire , Zhang Jiaxiuxiu , Mundada Nidhi S , Shankar Ranjani , Amuiri Alinda , Koeppe Robert A. , Dickerson Bradford C. , Carrillo Maria C. , Apostolova Liana G. , Rabinovici Gil D. , Joie Renaud La 
Published: January 2025

AbstractBackgroundThe timing of tau‐PET accumulation and cognitive decline in sporadic early‐onset Alzheimer’s disease (eoAD, age‐at‐onset<65) has not been established and is needed to optimize tau‐PET as an outcome measure in clinical trials. Here we leverage large‐sample, longitudinal data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to model tau‐PET accumulation in three regions relative to cognitive decline.MethodLongitudinal [18F]Flortaucipir‐PET (FTP) and CDR‐SB scores were acquired in 195 amyloid‐PET‐positive, sporadic eoAD patients with MCI or mild dementia due to AD at baseline (Table 1). FTP scans were referenced against inferior cerebellar GM, and mean SUVRs calculated in three meta‐ROIs comprising temporal, parietal, and frontal association cortices (Figure 1A). Generalized additive models estimated nonlinear relations between: (1) baseline SUVRs and annualized rates‐of‐change in each meta‐ROI, and (2) baseline CDR‐SB and annualized rates‐of‐change in cognition. Integrating these baseline‐by‐change functions yielded regional FTP and CDR‐SB trajectories over time. An exhaustive search algorithm identified optimal time‐shifts between each regional tau trajectory and CDR‐SB progression that minimized the error between model‐predicted and observed data at baseline. This time‐shifting procedure was repeated in a held‐out dataset of 184 eoAD patients to assess out‐of‐sample reproducibility (Table 1).ResultFTP SUVRs and CDR‐SB scores increased longitudinally in most patients (Figure 1B,C). Baseline SUVR by rate‐of‐change associations were inverted U‐shaped in each meta‐ROI (Figure 1D), and similar associations were found for CDR‐SB progression (Figure 1E). Time‐shift estimation in the training dataset converged on a single, best‐fitting model in which temporal and parietal FTP accumulation led clinical onset by 4.5 years, while frontal FTP accumulation began 0.5 years before clinical onset (Figure 2A). The replication dataset yielded nearly identical results (Figure 2B). We estimate that the full timecourse of FTP accumulation and cognitive decline occurs over ∼16 years from earliest detectable change in FTP.ConclusionTau‐PET accumulation in the frontal meta‐ROI immediately precedes cognitive decline and tracks closely with clinical progression in eoAD, while temporoparietal tau‐PET is prominent at clinical onset and plateaus as dementia worsens. For clinical trials in symptomatic patients, temporal and parietal tau‐PET may therefore aid staging and inclusion criteria, while frontal tau‐PET is likely superior for monitoring longitudinal change.
Unsupervised online reaction time test improves estimation of cognitive function in a large sample of cognitively‐asymptomatic older adults
Authors: Wang Xinyi , Bindoff Aidan , George Rebecca J St , Roccati Eddy , Bartlett Larissa , Lawler Katherine , Noyce Alastair J , Tran Son , King Anna E , Vickers James C , Bai Quan , Alty Jane E 
Published: January 2025

AbstractBackgroundFinding low‐cost, accessible methods to detect people at risk of preclinical Alzheimer’s disease (AD) is a research priority for neuroprotective drug development and clinical trials. Sub‐clinical asymptomatic decline in episodic memory is a proxy measure of preclinical AD and there is emerging evidence that analysis of motor patterns using laboratory apparatus may detect this stage. There has been little investigation of whether self‐administrated simple hand motor tests using personal computers in an unsupervised environment can detect preclinical AD. This study evaluated how home‐based reaction time tests predict cognitive performance in a sample of cognitively asymptomatic older adults.Method894 community participants (66.2 +/‐ 7.46 years old, 71.0 % female) who self‐reported an absence of cognitive symptoms were recruited from the ISLAND cohort study. In an unsupervised environment such as their home, they completed a simple reaction time test and a five‐choice reaction time test from the TAS Test website, and validated online cognitive tests (CANTAB) of episodic memory, working memory and executive function. Reaction time was measured in milliseconds. Test failure was defined as a delay of > 2000 milliseconds. We fitted hurdle linear mixed models to examine associations between reaction time, and test failure, with cognitive performance, adjusted for choice (simple or 5‐choice).ResultHigher episodic and working memory errors, and worse executive function scores were associated with test failure (episodic memory log‐odds = 0.135, p < 0.001, working memory log‐odds = 0.130, p = 0.002, and executive function log‐odds= 0.132, p < 0.001). There was no significant association between cognitive test scores and reaction time on successful trials (episodic memory p = 0.438, working memory and executive function models would not converge).ConclusionTest failure in brief self‐administered online reaction time tests were associated with cognitive test performance across three domains, in a cognitively asymptomatic older cohort. This provides a potential low‐cost and brief home‐based method for risk stratification of enriched cohorts for further assessment.
Association of APOE/TOMM40 Haplotypes and Limbic System White Matter Microstructure in Black and White Individuals
Authors: Mooney Katelyn Elizabeth , Archer Derek B. , Hohman Timothy J. , Sathe Aditi , Kadiri Ose , Barnes Lisa L. , Deters Kacie 
Published: January 2025

AbstractBackgroundAPOE is in linkage disequilibrium with the length of poly‐T repeats at the rs10524523 (‘523) locus of the TOMM40 gene. APOE‐ε3 is associated with short (S) and (VL) variants of ‘523 in white and Black individuals. In white individuals, APOE‐ε4 is associated with the long (L) ‘523 variant, but is associated with ‘523‐S, ‘523‐L, and ‘523‐VL variants in Black individuals. Black ε3‐’523‐S carriers have faster rates of cognitive decline while Black ε4‐’523‐S carriers have slower rates of cognitive decline. Little is known about the association of these haplotypes with white matter integrity. This study aims to determine the association between APOE/TOMM40 haplotypes and white matter microstructure (WMM) in tracts important for cognition and risk of AD.MethodsData comes from participants without cognitive impairment from the Rush Memory and Aging Project and the Minority Aging Research Study who self‐identified as non‐Hispanic white (N=500) and non‐Hispanic Black (N=144). WMM was measured using diffusion MRI (dMRI). dMRI was preprocessed using PreQual and microstructural metrics were calculated in DTIFIT and MATLAB. Data was harmonized using Longitudinal ComBat. We assessed free‐water (FW; higher values are abnormal) and FW‐corrected fractional anisotropy (FAFW‐corr; lower values are abnormal) in five limbic tracts that are associated with AD: the inferior longitudinal fasciculus, cingulum, fornix, inferior temporal gyrus, and uncinate fasciculus. The effect of 0, 1, or 2 copies of ‘523‐S on FW and FAFW‐corr was assessed using linear regression models, controlling for age, sex/gender, and education.ResultsWhite ε3/ε3 participants with two copies of ‘523‐S had lower FAFW‐corr in the cingulum (β=−0.006, SE=0.003, P=0.031) and inferior temporal gyrus (β=−0.007, SE=0.003, P=0.042) (Table). Black ε4+ participants with one‐‘523‐S had lower FW in cingulum (β=−0.024, SE=0.01, P=0.020) and inferior longitudinal fasciculus (β=−0.0304, SE=0.013, P=0.026) (Table).ConclusionsThis is the first study examining APOE/‘523 variation on WMM in Black participants, and the first to examine this association using FW‐corrected metrics. These results support prior findings that ‘523‐S copy‐number is deleterious in White‐ε3/ε3 participants, but protective in Black‐ε4+ participants. These findings suggest a differential effect by racialized background of APOE on brain microstructural integrity in older adults.
Investigation of blood‐brain barrier water exchange rate as a novel early indicator of neurovascular dysfunction and Alzheimer’s disease
Authors: Rowsthorn Ella , Sim Ming Ann , O'Brien William , McDonald Stuart , Vivash Lucy , O'Brien Terence J , Law Meng , Chong Trevor T.‐J. , Shao Xingfeng , Wang Danny JJ , Pase Matthew P. , Harding Ian H 
Published: January 2025

AbstractBackgroundGrowing evidence shows neurovascular dysfunction occurs early in Alzheimer’s disease (AD) and may be a useful early marker of pathology. Blood‐brain barrier water exchange rate (BBB kw) is a novel measure of fluid transport through the neurovascular unit. Lower BBB kw has been associated with vascular risk factors, but its relationship with age, vascular brain health and biomarkers of AD remains equivocal. The present study investigated the relationships between BBB kw, age, MRI measures of neurovascular integrity, and cerebrospinal fluid amyloid‐beta (Aβ).MethodThe Brain and Cognitive Health (BACH) Cohort Study recruited 108 participants without dementia, aged 55‐80 (68.5% female; mean age=67 years) from the general community. Participants underwent a suite of MRI scans (3T Siemens Prisma) that allowed for quantification of BBB kw, enlarged perivascular space volume (ePVS), diffusion free water (FW), cerebral blood flow (CBF), and white matter hyperintensity volume (WMH). A subsample of 35 individuals also completed an optional lumbar puncture for Aβ42 and Aβ40 quantification. Linear regression models and linear mixed‐effects models were used to investigate the association between BBB kw and the outcomes. We also investigated whether there was an interaction effect of age on MRI measure relationships. All analyses were adjusted for age, sex and intracranial volume.ResultBBB kw was negatively associated with age (B(SE)=‐44.74(20.91), R2
partial =.04, p=.04), negatively associated with FW (B(SE)=‐87.86(29.03), R2
marginal=.128, p=.006; Figure 1), and positively associated with CBF (B(SE)=0.02(0.08), R2
marginal=.128, p=.018; Figure 2). BBB kw was not associated with ePVS or WMH (p>.05). The association between BBB kw and CBF was modified by age (R2
partial=.06, p=.047), such that the relationship was stronger in younger participants (Figure 3). BBB kw was not associated with Aβ42/Aβ40 ratio (B(SE)=59.89(205.30), R2
partial=<.01, p=.773) in the small subsample.ConclusionLower efficiency of fluid transport through the neurovascular unit was associated with markers of neurovascular health, including cerebral perfusion and fluid accumulation/white matter integrity. These findings suggest BBB kw as a useful imaging tool for studying neurovascular unit integrity in the context of brain aging. Associations of BBB kw across the continuum of AD requires further investigation.
First Comprehensive Intranasal PET imaging of Insulin using the Aptar device in Nonhuman Primates
Authors: Sai Kiran K. Solingapuram , Gollepalli Krishna Kumar , Erichsen Jennifer M. , Krizan Ivan , Miller Mack , Jorgensen Matthew J. , Craft Suzanne 
Published: January 2025

AbstractBackgroundInsulin resistance (IR) is associated with abnormal tau‐phosphorylation and IR markers in AD brain co‐localize with neurofibrillary tangles. One strategy to overcome brain IR is to increase brain insulin is via intranasal insulin (INI) administration using specialized intranasal devices that deliver insulin to the brain. Our recent INI vs. placebo‐controlled double‐blinded clinical trial in MCI/AD showed that INI improved CSF biomarkers and slowed symptom progression over the placebo group treated with one type of delivery device (with no benefit with another). While these studies highlight the potential of INI for therapeutic applications, methods are needed to verify the successful INI delivery with specific devices. Here we report our novel [68Ga]‐NOTA‐insulin‐based brain PET imaging and whole‐body dosimetry through intranasal route in healthy vervets using the Aptar Cartridge Pump System (CPS) device for the first time.MethodHuman‐grade insulin was chelated with NOTA and radiolabeled with [68Ga]. 0‐90min and 0‐3h PET scans were conducted for brain and whole‐body dosimetry in healthy vervets (n=4/sex, 9‐12 y) after intranasal administration (2 puffs per nostril) of [68Ga]‐NOTA‐insulin (25‐37 MBq) through the Aptar device. Blood glucose, oxygen, heartbeat, and temperature were collected throughout the scan. Standard uptake values (SUVs), time‐activity curves (TACs), and standard dosimetry organ doses were calculated.Result[68Ga]‐NOTA‐insulin radiochemistry was fully‐optimized: shorter reaction times (∼6‐7min), lower insulin mass (2‐4 units), high radiochemical purity (>99%), and molar activity (108 GBq/µmol). No significant changes were observed in vitals recorded. PET/MRI images showed brain penetration; SUV whole‐brain=0.29±0.11, hippocampus=0.18±0.05, cortex=0.21±0.08, choroid plexus=0.38±0.11, and cerebellum=0.09±0.01. TACs showed that radioactivity peaked in brain within 15‐20min of radiotracer administration and washed out by 90 min. Dosimetry showed nasal cavity and eyes as critical organs and effective dose=0.11 mSv/MBq. No sex differences were seen in brain uptake or dosimetry parameters.ConclusionBrain PET and whole‐body dosimetry PET scans of [68Ga]‐NOTA‐insulin in vervets demonstrate brain penetration and favorable distribution of INI respectively. This preliminary data provides critical information for translating [68Ga]‐NOTA‐insulin PET with intranasal delivery to humans using the Aptar device. This strategy will create a new paradigm for understanding the INI in AD pathogenesis and advance novel therapeutic platforms.
Associations between basal forebrain volume and cognitive decline in GBA and LRRK2 mutation carriers from asymptomatic stages to Parkinson’s disease
Authors: Schumacher Julia , Teipel Stefan , Storch Alexander 
Published: January 2025

AbstractBackgroundIn people with Parkinson’s disease (PD), mutations in GBA and LRRK2 are associated with different clinical phenotypes which might be related to differential involvement of the cholinergic system. We aimed to investigate cholinergic basal forebrain (cBF) volume in asymptomatic and symptomatic mutation carriers in comparison to idiopathic PD and healthy controls and associations with cognitive decline.MethodThis study included 149 asymptomatic GBA and 169 asymptomatic LRRK2 mutation carriers, 112 LRRK2 carriers and 60 GBA carriers with PD, 492 idiopathic PD, and 180 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI). cBF volumes were extracted using an established automated MRI volumetry approach based on a stereotactic atlas (Figure 1A). We also estimated hippocampal volumes as a control analysis. Bayesian ANCOVAs were used to compare volumes between (1) asymptomatic carriers and controls including covariates for age, sex, and years of education and (2) mutation carriers with PD and idiopathic PD with an additional covariate for disease duration.ResultWe found evidence for an increase in cBF volume in asymptomatic GBA (Bayes Factor against the null hypothesis (BF10)=75.2) and LRRK2 mutation carriers (BF10=57.0) compared to controls and for no group differences between the two mutation groups (BF10=0.17) (Figure 1B). At the PD stage, cBF volumes were increased in LRRK2 compared to GBA mutation carriers (BF10=14.5) and idiopathic PD (BF10=3.6*107), with no difference between idiopathic PD and PD‐GBA (BF10=0.25). Whole‐brain voxelwise comparisons confirmed that increased volume in asymptomatic mutation carriers was mainly found in the region of the cBF (Figure 1C). There were no group differences in hippocampal volume (Figure 1B).Over five years, idiopathic PD and PD‐GBA declined across all cognitive domains whereas the PD‐LRRK2 group only declined in processing speed. Linear mixed models revealed a significant interaction between cBF volume and time in predicting multiple cognitive domains in idiopathic PD and PD‐GBA, but not in PD‐LRRK2.ConclusionWhile LRRK2 and GBA mutations are both associated with increased cBF volume at the asymptomatic stage, at the PD stage this increase persists only in LRRK2 carriers and might be related to the slower rate of cognitive decline in these patients.
Preliminary Evaluation of the African American Alzheimer’s Caregiver Training and Support Project 2 (ACTS2) Facebook Live Workshop Series: A Mixed Methods Analysis
Authors: Lampe Nik M. , Nowakowski Alexandra C. H. , Norton‐Brown Tomeka , Paredes Joshua , Bastow Skyler , Savage‐Paik Marin , Bakshi Jayson , Patel Amar , Glueckauf Robert L. 
Published: January 2025

AbstractBackgroundThe African‐American Alzheimer’s Caregiver Training and Support Project 2 (ACTS2) is a faith‐integrated, skills‐training and support program for Black family caregivers of persons living with dementia in Florida. In response to the COVID‐19 pandemic, ACTS2 initiated a bi‐monthly Facebook Live Workshop series, offering practical information and resources for Black communities on dementia caregiving topics (e.g., caregiver self‐care and negotiating stressful caregiving situations). Using mixed assessment methods, we evaluated viewer reach, engagement, and satisfaction with the workshops.MethodsWe used quantitative (Facebook and YouTube usage statistics, online pre‐registrations, online evaluation surveys) and qualitative data (viewer engagement during workshops, online evaluation surveys) to evaluate viewer reach, engagement, and satisfaction with 22 workshops from bi‐monthly ACTS2 Facebook Live Workshops series, delivered from May 2020 to August 2023.ResultsThe ACTS2 Facebook Live Workshop series reached a total of 1,193 individuals who pre‐registered (averaging 52 per workshop) and at least 1,032 individuals who attended the virtual workshops in live time (averaging 45 per workshop). To date, the series reached at least 9,697 Facebook user views and 274 YouTube user views. Thematic analysis of attendee engagement revealed three themes: (1) requesting additional information and community resources; (2) sharing personal information about caregiving experiences; and (3) gratitude towards workshop presenters and presentations. From the pool of 1,193 workshop pre‐registrants, 98 completed evaluation surveys. Nine out of ten survey completers reported the workshops were “extremely informative” or “very informative” (92.9%) and rated the overall quality of workshops as “excellent” or “good” (90.8%). Four themes emerged from the qualitative analysis of survey data: (1) gratitude for workshop presenters’ testimonies; (2) satisfaction with ACTS2 and other community resources; (3) centering Black dementia caregiver experiences; and (4) concerns with attendee/presenter communication format during workshops.ConclusionInitial findings of the mixed methods analysis suggested that the ACTS2 Facebook Live Workshop series was successful in reaching and engaging community members across Florida and the U.S., while serving as a useful tool in providing information and community resources for Black dementia caregivers. Further research is needed to enhance online communication between participants and presenters during live workshops and accrual of evaluation surveys.