bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivariate analysis of white matter crossing fibers reveals correlations with aMCI and dementia diagnoses
Authors: Bender Andrew R. , Weissman Caleb , Scheel Norman , Jung Youjin , Damoiseaux Jessica S. , Peltier Scott J , Hampstead Benjamin M. 
Published: January 2025

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) permits characterizing differences in white matter microstructure associated with amnestic mild cognitive impairment (aMCI) and Alzheimer’s dementia (AD). However, most dMRI measures aggregate signals across multiple axonal fiber populations with varying spatial orientations, which limits the sensitivity and specificity of clinical diagnosis. To overcome this shortcoming, we estimated fiber density (FD) measures, independently from crossing fiber populations, and extracellular cerebral spinal fluid (CSF). We hypothesized that aMCI and AD diagnoses are associated with differential patterns of FD changes in larger and smaller diameter fiber populations.MethodWe evaluated cross‐sectional dMRI data from 179 clinically characterized participants enrolled in the University of Michigan Memory and Aging Project. Image processing leveraged the MRtrix3 multi‐shell multi‐tissue fixel‐based analysis framework to estimate FD, separately for three fiber orientations, and CSF. Data analysis used multi‐block partial least squares correlation (PLS‐C) to estimate factors from multidirectional FD and CSF images correlated with differences between cognitively unimpaired (CU; n = 98) and those diagnosed with aMCI (n = 52) or AD (n = 29).ResultThe PLS‐C model yielded three significant latent variables (LVs; Fig. 1), reflecting patterns of both significant positive and negative associations between diagnosis and FD in crossing fibers. LV1 explained 80% of the differences from CU to aMCI to AD, demonstrating a stepwise reduction of FD and increased CSF with greater disease severity. However, LV2 and LV3 showed FD differences in smaller crossing fibers, distinguishing clinical diagnoses. Intriguingly, participants in the aMCI and AD groups showed different regions with increased or decreased FD in smaller crossing fibers, relative to CU participants. Pairwise PLS‐C models showed aMCI and AD diagnoses were associated with similar patterns of FD changes in smaller crossing fibers in overlapping regions.ConclusionThe present study found distinctive patterns of white matter alterations that systematically differ across diagnostic severity in MCI and Alzheimer’s dementia. These results highlight the value of decomposing signals from crossing fibers as a sensitive neuroimaging correlate to clinical diagnosis. These findings challenge the common perspective that MCI and Alzheimer’s dementia are associated with monotonic declines in white matter integrity.
Novel MRI method enables in vivo quantification of pre‐atrophic neurodegeneration in a mouse model of Alzheimer's Disease
Authors: Tomaszewski Michal R , Sukstansky Alexander L , Haley Hyking D , Meng Xiangjun , Miller Corin O , Yablonskiy Dmitriy A. 
Published: January 2025

AbstractBackgroundRobust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI shows significant promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, with qGRE R2t* metric (tissue‐specific subcomponent of R2*) highlighting areas of low neuronal density (doi:10.3233/JAD‐210503). In this study a novel qGRE method is shown to non‐invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510.MethodTg4510 (n=15) and wild type (WT, n=7) mice underwent MRI (7T field strength) at 3, 5, 6, 7 months old (WT at 3 and 5mo only). Mice were isoflurane‐anesthetized to minimize BOLD contribution to R2* signal. 3D Multi‐GRE sequence was used to generate R2* maps. Light‐sheet microscopy of the brains stained with NeuN and MBP was used to visualize neuronal nuclei and myelin content respectively.ResultSignificant decrease in NeuN staining between 3mo and 6mo was observed in the hippocampus of Tg4510, indicating a decrease of over 30% in neuronal density (p<0.001, Figure 1), validating the mouse model. Longitudinal analysis showed clear changes in R2* values in the Tg4510 hippocampus undergoing neurodegeneration between 3 and 5 months old (Fig. 2). Histogram analysis revealed patterns of increase in low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (Figure 3, p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between myelin content and the DMVF (p=0.01, r=‐0.76) in the hippocampus, suggesting sensitivity of the technique to the loss of myelinated axons.ConclusionIn this study a method is proposed for using R2* relaxometry as a direct biomarker of the neuronal loss. Low R2* volume fraction (DM) and the heterogeneity of R2* both show high sensitivity for capturing longitudinal neurodegeneration. The presented technique, together with accompanying histological validation can be readily applied in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment.
Improved Disease Subtyping and Staging using Dual Biomarker Amyloid PET
Authors: Scott Catherine J , Coath William , Dickson John C , McQuaid Sarah J , Cash David M , Schott Jonathan M 
Published: January 2025

AbstractBackgroundData‐driven disease progression models of Alzheimer’s disease (AD) have identified subtypes in regional patterns of Aß deposition using amyloid PET. In addition to Aß accumulation, early frame measures of tracer delivery from amyloid PET are strongly correlated with blood flow. This work explores whether combining tracer delivery with amyloid binding measures can improve the subtype and stage characterisation over amyloid binding alone.MethodsData was included from participants in three studies: Insight46, a neuroimaging sub‐study of the Medical Research Council National Survey of Health and Development (n=405), AVID2, a study of patients with a differential diagnosis of Alzheimer’s Disease (n=15), and YOAD, a study of patients with clinically diagnosed young onset Alzheimer’s disease (n=15). All participants underwent a full dynamic 18F‐Florbetapir PET/MR scan. PET images were reconstructed from 0‐2 and 40‐50 minutes post injection to generate the tracer delivery and amyloid binding images, respectively. T1 parcellations were used to calculate regional standardised uptake value ratios (SUVRs) using a cerebellar grey matter reference region. Tracer delivery and amyloid binding SUVRs for 6 cortical regions were converted into z‐scores, assuming unimodal and bimodal distributions respectively, and modelled using subtype and stage inference (SuStaIn). Participants fitted as stage zero were excluded.ResultsFigure 1 shows the three subtypes found using regional amyloid binding SUVR. Subtype 2 accumulates amyloid first in the occipital lobe, while for subtypes 1 and 3, which accumulate Aß first in the precuneus and insula respectively, this is the last area to show Aß deposition. Two distinct subtypes were found with blood flow SUVR; frontal or precuneus first blood flow reduction, Figure 2. When both measures are combined, Figure 3, the data show that subtypes 1 and 2 exhibit amyloid accumulation before blood flow changes, whereas subtype 3 shows blood flow changes in all regions first. The two blood flow subtypes are spread across all three combined subtypes, suggesting that each amyloid subtype may have several blood flow subtypes.ConclusionsCombining blood flow and amyloid SUVR within SuStaIn reveals new patterns of disease progression compared to amyloid alone. This may help us better understand heterogeneity in aging and disease.
Neurobiological and clinical characteristics of amnestic patients with Lewy body pathology
Authors: Silva‐Rodríguez Jesús , Moscoso Alexis , Labrador‐Espinosa Miguel , Sanchez‐Juan Pascual , Schöll Michael , Grothe Michel J. 
Published: January 2025

AbstractBackgroundWhile Lewy body (LB) pathology typically associates with a distinct clinical profile compared to Alzheimer’s disease (AD), early memory deficits are not uncommon and can confound clinical diagnosis of amnestic patients. Moreover, approximately 30‐60% of AD patients have concomitant LB pathology, which has been reported to affect the clinical phenotype and result in a more aggressive disease course. Recently developed a‐synuclein seed amplification assays (aSyn‐SAAs) have demonstrated high diagnostic accuracy for LB diseases, but the role of these novel biomarkers in the context of amnestic presentations typical for AD remains to be investigated in more detail.MethodWe studied 872 patients from the ADNI cohort with a baseline diagnosis of aMCI (N=661) or AD dementia (N=211), who had CSF and FDG‐PET data available. CSF samples were analyzed for peptide levels of Aß1‐42 and p‐tau181, and aSyn positivity was evaluated using a novel aSyn‐SAA. Based on positive/negative results on the different biomarkers, subjects were grouped into “AD‐/LB‐” (A‐T‐aSyn‐, N=106), “AD+/LB‐” (A+T+aSyn‐, N=336), “AD+/LB+” (A+T+aSyn+, N=158) and “AD‐/LB+” ((A‐|T‐)aSyn+, N=68). We analyzed group differences in demographics, APOE4 positivity, neurodegeneration patterns (FDG‐PET), as well as baseline and longitudinal scores of global cognition (MMSE) and domain‐specific function (ADNI_MEM, ADNI_EXEC).ResultAt baseline, AD+/LB+ showed worse global cognition (MMSE: d=‐0.27, p=0.004) and memory performance than AD+/LB‐ (ADNI_MEM: d=‐0.26, p<0.006). AD‐/LB+ were less globally impaired (p<0.001) and characterized by a markedly more dysexecutive profile (d(MEM‐EXEC): p<0.002). AD+/LB+ progressed faster on all cognitive scores, but they did not develop a differential cognitive profile compared to AD+/LB‐ (Figure 1). APOE4 positivity was similar between AD+/LB+ and AD+/LB‐ (72% vs. 75%, p=0.28) but lower in AD‐/LB+ (28%, p<0.001). In FDG‐PET, AD+/LB+ was characterized by a temporo‐parietal hypometabolism pattern similar to that of AD+/LB‐ but with higher effect sizes (Fig‐2). By contrast, AD‐/LB+ showed a strikingly different posterior‐occipital pattern of hypometabolism.ConclusionLB co‐pathology in AD was associated with more severe neurodegeneration and faster cognitive decline, but an amnestic AD‐typical phenotype. By contrast, patients with relatively pure LB pathology were characterized by a more dysexecutive cognitive profile and a distinct hypometabolism pattern typically suggestive of LB disease.
Metabolic glutamate receptor 5 (mGluR5) is associated with tau pathology in mild Alzheimer's disease
Authors: Wang Yan , Xie Fang , Guan Yihui 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is characterized by the deposition of amyloid plaques and tau neurofibrillary tangles in the brain with continuous cognitive impairment. Although the mechanism underlying AD pathogenesis remains unclear, more evidence suggests that synaptic dysfunction and loss may be an early event in disease progression. Metabotropic glutamate receptor 5 (mGluR5), a kind of G protein–coupled receptor, is involved in AD pathology through modulating synaptic transmission and plasticity and thus exhibits therapeutic effects. However, research on the associations of mGluR5 with the neuropathological hallmarks of AD needs to be completed.MethodIn this single‐center, cross‐sectional study, fifteen patients with mild AD and thirteen normal controls (CN) underwent a PET/MRI scan with [18F] PSS232 (mGluR5 availability) and trouble PET/CT scan with [18F] florbetapir (ß‐amyloid) and [18F] MK6240 (tau deposition). The associations of [18F] PSS232 and [18F] MK6240 binding were investigated. We also investigated the correlations of tau deposition and mGluR5 availability with cognitive performance. Voxel‐wise and volume‐of‐interest (VOI) analyses were performed on PET data.ResultCompared to CN, individuals with mild AD showed smaller clusters of [18F] PSS232 binding in the hippocampus and increased tau deposition in the hippocampus, lateral temporal, posterior cingulate, frontal, occipital, and parietal (Figure 1). Based on Voxel‐wise and VOI analyses, tau deposition in the hippocampus was negatively associated with [18F] PSS232 binding in the hippocampus (r = 0.56, p = 0.002, Figure 2). Lower neuropsychological test scores were associated with decreased [18F] PSS232 and increased [18F] MK6240 binding in the hippocampus (Figure 3).ConclusionPatients with mild AD have significant reductions in mGluR5 availability and have high tau deposition in the hippocampus, which is considered the critical region involved in early cognitive impairment. That means mGluR5 and tau were interrelated in the hippocampus and may apply in tau spreading. The correlation of mGluR5 availability and tau deposition in severe AD patients and more longitudinal data are needed to illustrate the role of mGluR5 in AD pathology.
Perfusion and cerebrovascular reactivity characterization in Alzheimer’s disease and vascular dementia
Authors: Keeling Elizabeth G. , McElvogue Molly M. , Ott Lauren R. , Burke Anna D. , Sabbagh Marwan N. , Bakkar Nadine , Stokes Ashley M. 
Published: January 2025

AbstractBackgroundCerebrovascular changes are often reported in normal aging, Alzheimer’s disease (AD), and vascular dementia (VaD). Cerebral perfusion and cerebrovascular reactivity (CVR) both decrease with dementia compared to healthy aging; as these changes occur prior to symptomatic onset and in distinct brain regions, perfusion and CVR may act as complementary biomarkers of early cerebrovascular changes. These biomarkers can be measured using MRI methods, yielding macrovascular measures of perfusion and CVR. We recently developed a more advanced method capable of measuring microvascular‐specific measures of perfusion and CVR. Here, we characterized the cerebrovascular profiles of AD and VaD using complementary perfusion and CVR biomarkers representing both macrovascular and microvascular regimes.MethodMRI data were acquired at 3T (Ingenia, Philips) in three cohorts: non‐cognitively impaired cohort (HC), AD, and VaD (Table 1). Perfusion data were acquired with a multi‐echo, multi‐contrast (SAGE) acquisition (5 echoes, 7.7/26/56/74/92 ms), before, during, and after injection of gadolinium‐based contrast agent. Acquisition parameters include: repetition time (TR) = 1.5 s, voxel size = 2.75×2.75×5 mm, 200 volumes, acquisition time = 5 min. SAGE functional MRI (fMRI) data were acquired in the same cohort with the same TEs and the following acquisition parameters: TR = 3.0 s, voxel size = 3 mm3, 160 volumes, acquisition time = 8 min. SAGE data underwent standard pre‐processing. Macro‐ and microvascular cerebral blood flow (CBF), relative cerebral blood volume (rCBV), and relative CVR (rCVR) were calculated using advanced analysis pipelines. The Montreal Cognitive Assessment (MoCA) was administered prior to MRI acquisition.ResultAs expected, microvascular perfusion and rCVR were lower than the corresponding macrovascular metrics for all groups. Macrovascular and microvascular CBF were lower for AD and VaD compared to HC, while there was no difference in CBF between AD and VaD (Figures 1,2). Similar trends were observed for rCBV. There were no differences in macrovascular rCVR between groups; microvascular rCVR was lower for AD and VaD compared to controls.ConclusionMacrovascular and microvascular perfusion decreases with AD and VaD. Enrollment is ongoing, and future directions include analysis of perfusion metrics within cortical and subcortical regions and correlation of neuroimaging findings with cognitive testing.
Cerebral Blood Flow in Midlife Obesity: Associations with Visceral and Subcutaneous Abdominal Adipose Tissue
Authors: Dolatshahi Mahsa , Commean Paul K. , Dai Weiying , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , Sirlin Claude , Mittendorfer Bettina , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A. 
Published: January 2025

AbstractBackgroundObesity and higher adiposity in midlife are recognized as contributors to Alzheimer disease (AD). Neurodegeneration in AD is at least partly mediated by vascular compromise and brain hypoperfusion. In this study, we aimed to investigate the associations between BMI and abdominal visceral and subcutaneous adipose tissue (VAT, SAT) and brain cerebral blood flow (CBF) in cognitively normal midlife individuals.MethodA total of 66 middle‐aged cognitively normal adults (age: 49.86±5.99 years, females: 66.7%, obesity (BMI of 30 kg/m2 or higher): 51.5%, BMI: 31.72±6.96 kg/m2) underwent abdominal and brain MRI. Using an in‐house Matlab program, abdominal VAT and SAT were automatically segmented followed by manual editing. A 3D Pseudo‐Continuous Arterial Spin Labeling (pCASL) sequence, with a single post‐labeling delay of 2.025 s, was used for assessing CBF. SPM12 was used to generate ASL absolute CBF (aCBF) maps with a single compartment model, co‐registered to the gray matter segmentations, and normalized to MNI space, followed by spatial smoothing. Using AAL3 atlas and Matlab, region of interest masks were created for amygdala, hippocampus, posterior cingulate, precuneus, parahippocampal, medial orbitofrontal, and middle temporal cortices and applied to absolute CBF (aCBF) maps. The aCBF differences between the obese vs. non‐obese, high‐VAT vs. low‐VAT, and high‐SAT vs. low‐SAT was assessed, with age and sex as covariates. Also, BMI, VAT, and SAT as separate predictor variables, with age and sex as covariates, were used for voxel‐wise analysis.ResultThere was a lower whole‐brain aCBF in the high‐VAT (p = 0.004) group and obese (p = 0.005) individuals, more prominently in the left middle temporal lobe (p = 0.002). No significant difference was observed in global and regional aCBF in the high‐SAT vs. low‐SAT groups. Voxel‐wise analyses showed significantly lower aCBF in association with BMI in temporal, occipital, and frontal lobe clusters after false discovery rate correction.ConclusionObesity and increased visceral abdominal fat are associated with a lower cerebral blood flow, with a more prominent decrease in the middle temporal cortex, as an AD‐signature area, in cognitively normal midlife individuals. These findings highlight the role of obesity, especially visceral obesity, in brain hypoperfusion and potentially Alzheimer disease risk, as early as midlife.
A weakly‐supervised, MRI‐guided clustering of cognitive decline: A post‐hoc analysis of the EXPEDITION‐3 clinical trial
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Demirsoy Idris , Lipton Richard B. , Davatzikos Christos , Rabin Laura , Sajjadi S. Ahmad , Ezzati Ali 
Published: January 2025

AbstractBackgroundAlzheimer's disease exhibits heterogeneity through varied phenotypic and pathological manifestations. Here, we aimed to investigate the potential of semi‐supervised pattern classification applied to volumetric MRI data in identifying relatively homogeneous subgroups of individuals exhibiting cognitive decline (CD) throughout the study period.MethodWe used data from the placebo arm of trial of Solanezumab for mild dementia due to AD (EXPEDITION‐3 trial). Participants were classified as showing CD if there was any increase in Clinical Dementia Rating (CDR, Sum of Boxes) from baseline to the 80 weeks of follow‐up, and as stable cognition (SC) otherwise. We applied a non‐linear, semi‐supervised clustering algorithm, HYDRA, that captures subtypes within the decliner group accounting for the heterogeneous variations that are also present in the stable group. Two models with different feature‐sets were developed: model I used only baseline volumetric MRI measures, while the model II included both baseline volumetric MRI measures and longitudinal changes observed after 80 weeks.ResultParticipants were 710 individuals with longitudinal MRI and CDR measures (mean age: 72.57[±7.69] years, 60.1% Female). Models I and II each produced two distinct subgroups of CD with notable differences in their baseline MRI volumes, and different rates of change in cognitive outcomes over the course of trial (Table 1). In both the models, one of the subgroups (Slow Decliner) had significantly lower change in scores than the other (Fast Decliner) on the 11‐item version of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS‐Cog) at the end of Week 80 (Figure 1). In Model‐I, both the decliner subgroups had smaller temporal and parietal lobe volumes at baseline compared to the Stable group (Figure 2). In Model‐II, the Slow Decliner group had higher baseline MRI volumes than the stable group and significantly lower change in ADAS‐Cog compared to that of the Fast Decliner group (Figure 2).ConclusionHeterogeneity in brain atrophy is linked to distinct patterns of cognitive decline. Using longitudinal changes in MRI measures revealed decliner subgroups with greater difference in ADAS‐cog scores compared to those obtained by baseline measures only.
Deletion of α5 integrin in endothelial cells ameliorates age–associated cognitive decline and increases survival in mice
Authors: Hall Gregory W , Ismael Saifudeen , Bix Gregory J 
Published: January 2025

AbstractBackgroundLevels of inflammatory components gradually rise in tissues and blood as we age. This “inflammageing” process is often debilitating and even fatal. Cognitive impairment is one example of inflammageing’s incapacitating nature. Excessive permeation of inflammatory markers in the brain gradually erodes the blood‐brain barrier (BBB) over time. Consequently, enhanced cerebral inflammatory processes contribute to neurological senescence. Neurological inflammageing may be partly due to a5 integrin, a receptor found primarily in brain endothelial cells during brain development, cerebrovascular injury (e.g. stroke), neuroinflammation and neurodegenerative disease (e.g. ALS). We hypothesize that deletion of a5 integrin in endothelial cells helps maintain BBB integrity and leads to improved cognitive performance with age. In the past we have shown that endothelial cell selective a5 knockout (a5‐EC‐KO) mice are more resilient to ischemic stroke. Enhanced stroke recovery in a5‐EC‐KO mice is due to less a5‐related BBB deterioration and subsequently less brain edema and infiltration of peripheral inflammatory cells. Therefore, we used aged a5‐EC‐KO and wild type (WT) litter mate mice to investigate how a5 integrin influences cognitive performance and survival probability over time.Methods25‐32‐month‐old male and female a5‐EC‐KO mice and aged‐matched WT mice were used in the study. Cognitive function was analyzed using Y‐maze and open field. Additionally, Kaplan Meier curves were used to assess probability of survival.ResultsFor Y maze, results indicate a trend towards greater alteration rate and total alteration for a5‐EC‐KO mice. Open field test shows greater center time and less peripheral time for a5‐EC‐KO. WT and a5‐EC‐KO mice have nearly identical mean speed. Additionally, Kaplan‐Meier curves indicate a greater probability of survival for a5‐EC‐KO mice between the ages of 26 to 30 months. Interestingly, 26‐30 months is the average life expectancy of a lab mouse.ConclusionsObservations from Y maze and open field tests suggest that a5‐EC‐KO mice have improved spatial memory and less anxiety behavior when compared to aged‐matched WT mice. Moreover, the Kaplan‐Meier curves depict a greater probability of survival for aged a5‐EC‐KO mice. Thus, a5 integrin expression may significantly influence age‐related cognitive decline. Preliminary data suggests that inhibition of a5 integrin may improve symptoms of age‐associated cognitive impairment.