bluuebunny/crossref_metadata_2025_split huggingface dataset:
Striatal Amyloid deposition in sporadic Alzheimer’s Disease
Authors: Arena Julieta , Urrutia Leandro , de Leon Magdalena Ponce , Seminara Emiliana , Falasco German , Bérgamo Yanina , Allegri Ricardo Francisco , Sevlever Gustavo , Vazquez Silvia 
Published: December 2023

AbstractBackgroundIt has been shown that disorders associated with early‐life alterations in amyloid production or processing such as in autosomal dominant Alzheimer’s disease (AD) and down syndrome‐associated dementia have a different pattern of Aß deposition, with early striatal accumulation, as compared to sporadic late‐onset cases, in which striatal deposition has been suggested to be a marker of late and advanced amyloidosis. It is not clear, however, if the pattern of amyloid accumulation is related to any other factors or if it has any impact on brain metabolism. We aimed to determine if there are any clinical or demographic predictors of striatal tau accumulation in sporadic AD and whether its presence affects the subjects´ brain metabolism.MethodSubjects that underwent positron emission tomography (PET) scans with 18F‐FDG and 11C‐PIB were analyzed retrospectively. Only those with clinical diagnosis of AD and mild cognitive impairment (MCI) due to AD were considered for the analysis. Visual analyses were performed to exclude subjects without cortical amyloid accumulation. Mean values from cortical volumes of interest (VOIs) and striatum were obtained. Amyloid deposition was correlated with age and disease duration via Pearson’s correlations. Amyloid deposition was also correlated to brain metabolism as assessed by FDG PET.Result150 subjects were included in this study. Neither age nor disease duration was correlated with striatal amyloid accumulation. Subjects with striatal Pib accumulation showed higher cortical amyloid burden. Moreover, higher striatal amyloid burden was positively correlated with higher frontal amyloid burden specifically. Amyloid burden in the striatum did not seem to have an impact on the glucose metabolism in the striatum itself. However, variations in cortical glucose metabolism could be observed. A higher striatal amyloid burden was correlated with cortical glucose hypometabolism, specifically in the precuneus and temporal areas (Figure 1).ConclusionThere seems to be a stage of sporadic Alzheimer’s disease in which amyloid accumulates in the striatum. This, in turn, appears to have an impact on brain functioning. Whether this has a real impact on cognitive performance remains to be elucidated.
Cerebral amyloid angiopathy is associated with higher gray matter regional R2 relaxation rate: An ex‐vivo MRI and pathology study
Authors: Yasar Md Tahmid , Evia Arnold M , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid‐ß (Aß) protein in the walls of cortical and meningeal small vessels. CAA is common in older adults. It has been linked to intracerebral hemorrhage and cognitive decline. In this study, the association of CAA with the transverse relaxation rate R2 values was investigated in gray matter regions from a large number of community‐based older adults.MethodCerebral hemispheres from 802 older adults participating in four cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, and the Clinical Core of the Rush Alzheimer’s Disease Research Center (Fig. 1a) were included in this work. All hemispheres were imaged ex‐vivo using 3T MRI scanners. R2 maps were generated from multi‐echo spin‐echo images. Gray matter was segmented into 34 cortical and 8 subcortical regions. Median R2 values were obtained from each region. Following ex‐vivo MRI, all hemispheres underwent detailed neuropathologic assessment (Fig. 1b). Evaluated neuropathologies included: CAA, Aß plaques, neurofibrillary tangles, gross infarcts, microinfarcts, TDP‐43 pathology, hippocampal sclerosis, Lewy bodies, atherosclerosis, and arteriolosclerosis. Multiple linear regression was conducted in each segmented gray matter region separately to test the association of the corresponding median R2 value with the global CAA score, controlling for all other neuropathologies, age at death, sex, education, postmortem interval to fixation and to imaging, and scanners. False discovery rate (FDR) was used to correct for multiple comparisons. Statistical significance was set at p<0.05.ResultA significant positive association of median R2 with CAA pathology was found in several cortical regions of the temporal and frontal lobes as well as in subcortical structures (Fig. 2,3). No gray matter region showed lower median R2 for higher CAA score. Furthermore, we obtained similar findings when also controlling in the linear regression models for normalized regional volume and for clinical variables such as history of hypertension, diabetes, smoking, blood pressure levels, and the presence of the APOE‐e4 allele.ConclusionThis investigation showed that CAA is independently associated with elongated R2 in cortical regions of the temporal and frontal lobes as well as in subcortical structures.
Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice
Authors: Obenaus Andre , Singh Aditya , Pad Rojina , Iyer Anika , Ketsan Tia , Jullienne Amandine 
Published: December 2023

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aß Knock‐In (hAßKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAßKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.MethodContrast‐enhanced PWI MRI (9.4T) was undertaken from hAßKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.ResultCompared to WT mice at 18mo of age, hAßKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p<0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAßKI only mice.ConclusionThe 18mo hAßKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).
Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan
Authors: Jullienne Amandine , Szu Jenny , Quan Ryan , Trinh Michelle V , Norouzi Tannoz , Noarbe Brenda P , Silvola Rebecca , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Persohn Scott C , Territo Paul R , Obenaus Andre 
Published: December 2023

AbstractBackgroundThe MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐ß deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.MethodMale and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.ResultOur analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.ConclusionThe 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐ß deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.
Individual‐specific change in Alzheimer’s disease vulnerable brain regions across the healthy adult lifespan is associated with genetic AD risk
Authors: Roe James M , Vidal‐Piñeiro Didac , Leonardsen Esten H , Sørensen Øystein , Grydeland Håkon , Iakunchykova Olena , Walhovd Kristine B , Fjell Anders M , Wang Yunpeng 
Published: December 2023

AbstractBackgroundAcross the healthy adult lifespan, our brain’s undergo widespread structural change. Many of these changes – occurring gradually across life – are not qualitatively distinct from atrophy patterns seen in Alzheimer’s disease (AD), raising the possibility accelerated longitudinal brain change across healthy adult life may relate to genetic AD‐risk.MethodWe modelled subject‐specific structural brain change relative to that expected given age, in dense longitudinal adult lifespan data (1430 scans from 420 individuals aged 30 to 89 years; 2‐7 timepoints). Using polygenic AD scores (PRS‐AD) from four GWAS, we tested PRS‐AD associations with age‐relative change in early Braak stage regions – namely hippocampus, entorhinal cortex, amygdala, and medial temporal cortex. Next, to empirically identify features with accelerated change in AD, in ADNI data (scans = 4410; N = 978) we applied machine learning classification on the subject‐specific slopes estimated from individuals classed as consistently healthy over time versus those succumbing to AD. In healthy adult lifespan data, we then tested PRS‐AD associations with age‐relative change, in many combinations of brain features with model‐implied importance. Lastly, we tested whether high PRS‐AD individuals showing more negative brain change exhibit more longitudinal memory decline over healthy adult life.ResultIn healthy adult lifespan data, we observed many significant PRS‐AD associations with age‐relative change in hippocampus (bilateral), right entorhinal cortex, amygdala (bilateral), and left medial temporal cortex, and typically for all four scores (FDR‐corrected). We show that age‐relative change across the healthy adult lifespan in many combinations of AD‐accelerated features is significantly associated with PRS‐AD. As proof‐of‐principle, applying the ADNI‐derived model weights to the healthy adult lifespan data also enabled detection of PRS‐AD associations in healthy adults, but only using models trained on age‐relative change. Most, but not all, of the observed PRS‐AD associations were driven by APOE. Finally, we find high PRS‐AD individuals with more negative brain change exhibit significantly more memory decline, relative to high PRS‐AD individuals with less brain change.ConclusionThe results support a dimensional account linking gradual lifespan brain changes with pathological aging, and demonstrate PRS‐AD impacts the slope of brain aging in most AD‐relevant brain regions in healthy adults.
Aβ accumulation associated with executive function decline and tau accumulation associated with memory decline in cognitively normal older people
Authors: Chen Xi , Juarez Alexis , Baker Suzanne L. , Harrison Theresa M. , Landau Susan M. , Jagust William J. 
Published: December 2023

AbstractBackgroundThe early accumulation of Aß and tau in cognitively‐normal people is predictive of future cognitive decline. It has been difficult, however, to disentangle their effects. Aß and tau target distinct regions in early stages. Frontal‐parietal regions are among the first to show Aß accumulation and are important for executive control. Temporal regions, especially the medial temporal lobe, are early sites where tau accumulates and are critical for memory. Their differential vulnerability to Aß and tau allows us to examine whether there are specific pathology‐cognitive associations, where faster decline in memory, beyond its expected level based on executive function, may be related to tau accumulation, and that faster executive function decline may be related to Aß accumulation.Method78 cognitively‐normal older adults from the Berkeley Aging Cohort Study underwent longitudinal 11C‐Pittsburgh compound‐B (PiB) PET, 18F‐flortaucipir (FTP) PET, and cognitive assessments of executive function and memory (Fig‐1A). We used linear mixed‐effects models to estimate longitudinal change in Aß (Fig‐1B), temporal tau (Fig‐1C), executive function (Fig‐1D), and memory (Fig‐1E). We focused on within‐individual variability in cognitive decline in different domains and computed two cognitive decline residual scores (executive function controlling for memory, Fig‐2A; memory controlling for executive function, Fig‐2B) to represent domain‐specific performance decline.ResultAß accumulation across wide‐spread regions, especially frontal/parietal cortex, was associated with faster executive function decline, but not memory, even after controlling for meta‐temporal tau change (Fig‐3A). On the other hand, temporal tau accumulation, especially in the medial temporal regions, was related to faster memory decline, but not executive function, even after controlling for global Aß change (Fig‐3B). Using raw cognitive slopes, instead of residual scores, yielded stronger associations with both pathologies but reduced the ability to detect specific pathology‐cognition relationships.ConclusionWe found evidence supporting specific associations between accumulating pathology and domain‐specific cognitive decline. The “Aß‐executive function, tau‐memory” association may reflect specific vulnerabilities in the executive control network and the memory network to different pathology, leading to cognitive decline in different domains. The variability of cognitive decline within the same individual across different domains provides unique information and may be used as behavioral markers for specific pathology.
A CenTauR scale based on 18F‐MK6240
Authors: Dore Vincent , Bourgeat Pierrick , Leuzy Antoine , Huang Kun , Krishnadas Natasha , Feizpour Azadeh , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C 
Published: December 2023

AbstractBackgroundA standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.Method375 18F‐MK6240 PET & T1w scan pairs (HC Aß‐ = 179/MCI Aß+ = 98/AD Aß+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aß‐ (<10CL) and AD Aß+ (>25CL) individuals younger than 75y, with MMSE = 20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aß‐ and 29 AD Aß+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.ResultThe mean and standard deviation (std) for the HC and AD groups are reported in Table 1. Using a single transformation resulted in the following equation: Ct = 100x(SUVR‐0.97)/2.26 Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.ConclusionThe region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.
QyPredict prognostic model enriches selection for faster decliners in mild cognitive impairment
Authors: Gordon Elizabeth , Samper‐González Jorge , Villa Luca , Jubault Thomas , Guizard Nicolas 
Published: December 2023

AbstractBackgroundThe suboptimal selection of patients is a key challenge for disease‐modifying trials in mild cognitive impairment (MCI) and Alzheimer’s disease. Improved selection strategies are urgently needed to better power trials. Recent advances in AI predictive modeling, such as the QyPredict® algorithm, are promising tools to improve the selection of patients likely to clinically progress during the clinical trial timeframe.MethodQyPredict® was applied to 519 MCI patients from ADNI: age: (71.8(±7.1), 303 Male, MMSE range 24‐30, CDR = 0.5, with available amyloid and APOE‐e4 + status. QyPredict®, a tunable machine learning model, incorporated baseline QyScore® volumetric MRI results, demographic (age and sex) and clinical (MMSE and CDR) inputs. A QyPredict® score (0‐1) was produced for each individual, representing the probability they will demonstrate a modelled outcome (here an increase in CDR‐SOB of 0.5+ over 24 months). A score close to zero indicating very low probability of change. Predictive performance was evaluated using positive predictive value (PPV), sensitivity and specificity. Mean and standard deviation for change in CDR‐SOB over 24 months were calculated and compared using Mann‐Whitney test at increasing QyPredict® cut‐offs (0.1, 0.2, 0.3, 0.4 and 0.5). Actual change versus predicted change in CDR‐SB scores was further investigates for ‘Stable’ (QyPredict®<0.5) versus ‘Decliners’ (QyPredict®>0.5) (Figure 1). Sample sizes to detect a 30% treatment effect (reduction in change in CDR‐SOB) were calculated for the full sample and a cohort enriched with only ‘Decliners’.ResultFor the full sample without QyPredict® enrichment, change in CDR‐SOB at 24 months was 2.3 (±2.11), which significantly increase (p<0.001) from a QyPredict®>0.2, reaching a change of 3.4 (±2.30) points for MCI patients with QyPredict®>0.5. PPV, sensitivity and specificity were: 0.76, 0.70 and 0.75 (the full cohort); 0.83, 0.77 and 0.70 (Amyloid positive patients) and 0.82, 0.75 and 0.74 (APOE‐e4 + patients). Sample sizes for a putative trial where 304 (full sample) compared with 110 (enriched cohort) per treatment arm.ConclusionUsing baseline QyScore® metrics, basic demographic, and typical clinical data available at screening visits, QyPredict® accurately modelled the likelihood of future clinical decline, resulting in substantially reduced patient cohorts to detect treatment effects when enriched with ‘decliners’.
Microstructural integrity and structural connectivity of medial temporal lobe subregions is related to Alzheimer’s pathology
Authors: Adams Jenna N. , Granger Steven J. , Taylor Lisa M. , Kim Soyun , Harrison Theresa M. , Harris Alyssa L. , McMillan Liv , Colon‐Perez Luis , Keator David B. , Yassa Michael A. 
Published: December 2023

AbstractBackgroundThe earliest effects of Alzheimer’s disease pathology on medial temporal lobe (MTL) gray matter microstructure and white matter connectivity are still unknown. Here, we applied ultra‐high‐resolution diffusion MRI to characterize microstructural integrity and structural connectivity of the MTL, and tested associations with Alzheimer’s pathology and memory performance in cognitively normal older adults.Method83 participants (M = 71.7yrs, 66% female) received structural and ultra‐high‐resolution diffusion MRI (0.67×0.67×3mm). Subsamples received [18F]‐florbetapir (FBP) to measure Aß (n = 77; global summary SUVR), [18F]‐MK6240 to measure tau (n = 23; entorhinal SUVR), and performed an object mnemonic discrimination task (n = 74). Structural MRI was processed with ASHS to obtain MTL ROIs (Fig1). Diffusion MRI was processed with FSL DTIfit to calculate mean diffusivity (MD), an index of cellular integrity. Tractography was performed with DSI Studio. ROI‐to‐ROI streamlines were calculated (Fig3A) and used for structural connectivity graph analyses of the MTL network. Analyses controlled for age and sex, with scan interval and education in relevant models.ResultEntorhinal MK6240 SUVR was associated with increased MD in transentorhinal cortex (BA35; r = 0.72, p<0.001), entorhinal cortex (EC; r = 0.61, p = 0.004), and dentate gyrus (DG; r = 0.46, p = 0.04; Fig2A), while global FBP SUVR was associated with higher MD in EC (r = 0.25, p = 0.03). Worse mnemonic discrimination performance was associated with increased MD in DG (r = ‐0.29, p = 0.01), with trends in EC (r = ‐0.23, p = 0.06) and CA3 (r = ‐0.20, p = 0.09; Fig2B). The number of streamlines between EC and DG was not significantly associated with entorhinal MK6240 SUVR (r = ‐0.32, p = 0.17), FBP SUVR, or mnemonic discrimination (ps>0.37). Lower global efficiency of the MTL network was associated with increased entorhinal MK6240 SUVR (r = ‐0.50, p = 0.025) yet better mnemonic discrimination performance (r = ‐0.28, p = 0.02; Fig3B).ConclusionEntorhinal tau pathology and memory performance are closely related to microstructural integrity and structural connectivity of the MTL, suggesting tau‐related MTL neurodegeneration may drive early memory decline.