bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of plasma GFAP, NfL, and p‐tau231 with early‐onset Alzheimer’s Disease pathology
Authors: Logan Paige E. , Dage Jeff L. , Hammers Dustin B. , Manchella Mohit K. , Eloyan Ani , Mundada Nidhi S. , La Joie Renaud , Iaccarino Leonardo , Fagan Anne M. , Foroud Tatiana M. , Zetterberg Henrik , Blennow Kaj , Koeppe Robert A. , Aisen Paul S. S , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Brad C. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundIncreased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD).Method183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐e4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐e4; Model 3: age, sex, APOE‐e4 and MMSE. All models are displayed at a family‐wise error adjustment of p<.05.ResultHigher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 & 3). When controlling for APOE‐e4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not.ConclusionThese results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐e4 and dementia severity.
Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities
Authors: Cha Woo‐Jin , Yi Dahyun , Ahn Hyejin , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2023

AbstractBackgroundWhite matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aß) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.MethodA total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aß deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aß or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aß or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.ResultBaseline Aß deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (ß = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aß deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female (ß = 0.427, p = 0.001), but not in male.ConclusionOur findings suggest that Aß deposition, but not tau, accelerates cerebral white matter injury, particularly in female.
Machine‐learning derived MRI‐based atrophy biomarker predicts long‐term cognitive decline in stroke or transient ischemic attack
Authors: Yuan CAI , Lam Bonnie Y.K. , Fan Xiang , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong 
Published: December 2023

AbstractBackgroundAlzheimer’s disease‐resemblance atrophy index (AD‐RAI) is a machine‐learning derived MRI‐based brain atrophy biomarker that is valid in predicting cognitive decline in subjects with AD. We investigated the performance of AD‐RAI in predicting long‐term cognitive decline in subjects with stroke or transient ischemic attack (TIA).MethodWe recruited consecutive dementia‐free stroke/TIA subjects who had brain MRI at baseline (i.e., within 3‐6 months after the index event) and cognitive data at both baseline and 3 years. We defined cognitive decline as an increase in clinical dementia rating scale from 0 to 0.5 or above or from 0.5 to 1 or above at 3 years when compared with baseline. We investigated the association between AD‐RAI, traditional brain atrophy biomarkers (hippocampus volume [HV], hippocampal fraction [HF], total brain volume [TBV], TBV/intracranial volume [ICV] ratio, ventricular‐brain‐ratio, presence of medial temporal lobe atrophy [MTLA]), and cerebral small vessel disease biomarkers (white matter hyperintensity [WMH]) volume, WMHV/ICV ratio presence of confluent WMH, presence of >/ = 3 lacunes) with cognitive decline.ResultOf 231 participants (mean age 66.0 ± 10.9, 124 [53.7] male), 55(23.8) had cognitive decline at 3 years. Among all the imaging biomarkers, AD‐RAI and HV were associated with cognitive decline in univariate regression. Such a relationship was still significant with AD‐RAI after adjusted for age, gender, and education (aOR [95%CI] 3.900 [1.221‐12.458]). Among all imaging biomarkers, only AD‐RAI was associated with slope of Montreal cognitive assessment (MoCA) after adjusted to age, gender, education (ß(SE) ‐0.742[0.242], p = 0.002).ConclusionAD‐RAI predicted long term cognitive decline in subjects with stroke/TIA.
Individuals from Memory Clinic were Associated with Severer Amyloid Deposition in the Chinese Population in Urban Cities
Authors: He Kun , Li Binyin , Huang Lin , Zhao Jun , Hua Fengchun , Wang Tao , Li Junpeng , Wang Jie , Wang Mengjie , Huang Qi , Xu Shasha , Chen Ke‐Liang , Ren Shuhua , Cai Huawei , Jiang Donglang , Hu Jingchao , Han Xinmin , Guan Yihui , Guo Qihao , Xie Fang 
Published: December 2023

AbstractBackgroundAmyloid deposition is considered the initial pathology in Alzheimer’s disease (AD), investigation of amyloid pathology and the risk factor for amyloid pathology and cognitive declines in the Chinese population is critical for personalized management. However, the prevalence of amyloid deposition and the risk factors for amyloid pathology are unknown in the Chinese population.MethodParticipants were recruited from urban communities and memory clinics in Shanghai and Zhengzhou, China. A total of 246 AD individuals, 274 Mild cognitive impairment (MCI) individuals, and 506 Normal cognition (NC) individuals were identified: 106 AD, 156 MCI and 506 NC from the Community‐based cohort (COMC) as well as 140 AD and 118 MCI from the Clinic‐based cohort (CLIC). Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET) scans. We also performed a partial least squares (PLS) analysis to evaluate the associations of cohort, age, sex, education level, and ApoE genotype with amyloid qualification, quantification results and global cognition in all 1026 participants.ResultAcross the two cohorts, the AD group displayed the significantly highest rate of amyloid positivity (211/246, 85.8%), followed by the MCI (122/274, 44.5%) and NC groups (136/506, 26.9%, all P < 0.001). Participants from the CLIC displayed a higher rate of amyloid positivity than those from the COMC in the MCI (68/118, 57.6% vs. 54/156, 34.6%, P < 0.001) and AD groups (128/140, 91.4% vs. 83/106, 78.3%, P = 0.006). MCI (SUVr: 1.37 ± 0.25 vs. 1.25 ± 0.18, P < 0.001), Aß+ MCI (SUVr: 1.48 ± 0.27 vs. 1.37 ± 0.24, P = 0.03) and AD individuals (SUVr: 1.47 ± 0.23 vs. 1.39 ± 0.23, P = 0.01) in the CLIC displayed significantly greater amyloid deposition than those in the COMC. According to the PLS model, we found that the CLIC was significantly associated with positive amyloid deposition and severer amyloid deposition.ConclusionWe found that individuals from CLIC displayed a higher amyloid positive rate and severer amyloid deposition. Specifically, in a PLS model, The CLIC, was strongly associated with amyloid pathology.
Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with greater WMH more than a decade later in the KEEPS Continuation
Authors: Kara Firat , Tosakulwong Nirubol , Lesnick Timothy G. , Fought Angela J. , Schwarz Christopher G. , Senjem Matthew L. , Fields Julie A. , Min Paul H , Lowe Val J. , Jack Clifford R. , Bailey Kent R. , James Taryn T. , Lobo Rogerio A. , Manson JoAnn E. , Pal Lubna , Hammers Dustin B. , Malek‐Ahmadi Michael H. , Cedars Marcelle I. , Naftolin Frederick N. , Miller Virginia M. , Harman Sherman M. , Dowling Maritza N. , Gleason Carey E. , Kantarci Kejal 
Published: December 2023

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p = 0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.
Effects of de‐facing T1 MRI, FLAIR MRI, Amyloid PET, and Tau PET scans on imaging‐clinical correlations analyses
Authors: Schwarz Christopher G. , Kremers Walter K. , Weigand Stephen D. , Prakaashana Carl M. , Senjem Matthew L. , Lowe Val J. , Gunter Jeffrey L. , Kantarci Kejal , Vemuri Prashanthi , Petersen Ronald C. , Knopman David S. , Jack Clifford R. 
Published: December 2023

AbstractBackgroundAutomated face recognition can potentially re‐identify de‐identified research brain MRI, PET, and CT, and direct differences of brain measurements from original and de‐faced images are statistically significant but very minor, i.e. below scan‐rescan differences. Their effects on analyses correlating brain imaging biomarkers with clinical variables remain unknown.MethodWe sampled 3 age‐and‐sex‐matched groups (CU, MCI, and clinical AD) from Mayo Clinic aging studies, each with 61 participants with same‐visit 3D T1‐weighted and 3D T2‐FLAIR MRI, PiB amyloid PET, and Flortaucipir tau PET (total n = 183). We automatically measured hippocampal volume, PIB global SUVR, and tau temporal meta‐ROI SUVR using a) our in‐house pipeline with SPM12, MCALT, and ANTs, and b) FreeSurfer 7.3.2 (PETSurfer), and we measured voxels associated with clinical group separation using SPM12. We also measured WMH from FLAIR using a) our in‐house pipeline, b) Lesion Segmentation Tool (LST), and c) FreeSurfer’s Samseg. For each measurement, we calculated pair‐wise group separation AUC values and Spearman’s rho with age and CDR‐SOB. We then de‐faced all PET and MRI using mri_reface, our top‐performing automated de‐facing software that replaces imaged faces with an average face (“re‐facing”), and we repeated all measurements and analyses with de‐faced images. We then compared the magnitudes of clinical correlations with original images and those of de‐faced images.ResultAnalyses of original and de‐faced images had very high agreement. Only 2/55 paired comparisons were significant (Tables 1‐2): FreeSurfer‐measured global PIB SUVR from de‐faced images was more correlated with age (rho 0.003 vs ‐0.227, p = 0.046), and Mayo‐measured WMH volume from original images was more correlated with CDR‐SOB (rho 0.321 vs 0.308, p = 0.020). Another comparison‐pair tested p = 0.041 for an AUC change +0.008, which we consider not practically meaningful. All others had p>0.05. In voxel‐based analyses of CU vs AD participants, all comparisons were qualitatively similar between original and de‐faced variants (Figure 1).ConclusionDe‐facing PET and MRI using mri_reface did not significantly affect 53/55 correlations between imaging and clinical variables; of the two affected, one became stronger with re‐faced images. Stronger correlations with clinical variables may be explained by de‐facing’s standardizing face voxels and artifacts that irrelevantly affect brain segmentations.
Synaptic density is correlated with Aβ plaques and neurofibrillary tau tangles across the clinical and biologic Alzheimer’s disease continuum
Authors: DiFilippo Alexandra H , McLachlan Max , McVea Andrew K , Bettcher Brecca , Jonaitis Erin M. , Ennis Gilda E. , Pasquesi Mary‐Elizabeth , Davenport Nancy J , Thor Yer , Grover Ethan , Hudson Sarah , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J , Johnson Sterling C , Bendlin Barbara B , Christian Bradley T. 
Published: December 2023

AbstractBackgroundThe extent to which amyloid‐ß burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐ß plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer’s disease continuum.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer’s disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson’s r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR.ResultGlobal [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005).ConclusionBoth amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed.
Cerebral Blood Flow and Arterial Transit Time Variations in Elders with Long COVID
Authors: Patel Milan , Cohen Alexander D , Pommy Jessica , Umfleet Laura Glass , Franczak Malgorzata , Swanson Sara J , Obarski Shawn , Agarwal Mohit , Wang Yang 
Published: December 2023

AbstractBackgroundMany COVID‐19 patients experience persistant neurological symptoms that often extend beyond the period of acute infection, referred to as “Long COVID”, where most patients reported brain fog and cognitive dysfunction. While elderly individuals are more vulnerable to possible enduring cognitive impairments after acute COVID‐19 requiring hospitalization, there is increasing concern that older patients with Long COVID will be at high risk for developing Alzheimer’s disease (AD) and dementia. Although there is emerging recognition of Long COVID, its underlying neuropathology remains unknown. This study aimed to investigate neurovascular function using advanced MRI perfusion in elder patients with Long COVID.MethodWell‐matched elderly Long COVID patients (n = 14, mean age = 60.1±4.3 years, 12F, 2M) and control subjects (n = 25, mean age = 60.4±7.2 years, 19F, 6M) underwent neurocognitive testing as well as neuroimaging. Patients were seen 711.57 ± 165.02 days after the initial mild non‐hospitalized COVID‐19 infection. Clinical cognitive complaints of Long COVID patients included memory changes (n = 12, 85.7%), attention (n = 12, 85.7%), speech/writing (n = 9, 64.3%), and multitasking (n = 9, 64.3%). Brain perfusion was evaluated using an advanced 3D pseudo‐continuous arterial spin labeling (pCASL) sequence with Hadamard encoded multiple post‐labeling delays (PLDs), enabling estimation of Cerebral Blood Flow (CBF) and Arterial Transit Time (ATT) ATT and ATT corrected CBF.ResultConventional MRI scans (T1, T2, and FlAIR) appear normal in all subjects. Voxelwise comparisons between Long‐COVID and control subjects showed a significant global decrease in the ATT (p < 0.05, cluster corrected at a < 0.05), along default mode and other key networks, where there is a trend of decreased CBF (p<0.05, uncorrected) specifically in the frontal lobe in those with Long COVID.ConclusionThese preliminary results in an aging group indicate that neurocognitive effects of Long COVID could be attributed to neurovascular dysfunction, even in those cases with initial non‐hospitalized mild COVID‐19 of more than 500 days. The novel finding of diffusely decreased ATT could be something attributable to the unique neurovascular mechanism of Long COVID. Future longitudinal research following the progression of those elderly Long COVID patients with known abnormal neurovascular function to fully evaluate their risk for developing AD and dementia.
Testing bidirectional relationships between functional brain networks and preclinical Alzheimer disease biomarkers
Authors: Millar Peter R , Singhe Nawang , Macharia Kiana Angela , Metcalf Nicholas V , Roman June , Morris John C , Benzinger Tammie L.S. , Ances Beau 
Published: December 2023

AbstractBackgroundResting‐state functional connectivity (RSFC) provides estimates of brain networks using fMRI. There are conflicting reports regarding the effects of amyloid‐ß (Aß) and tau on RSFC networks in cognitively normal participants. These inconsistencies might be explained by a recently‐proposed theoretical model that Aß and tau have an interactive effect on RSFC, marked first by hyper‐connectivity in association with Aß, then by hypo‐connectivity in association with tau. Although there is preliminary support for this model, independent validations and further characterizations of the effects of Aß and tau on RSFC are needed.MethodWe analyzed RSFC, Aß PET, and tau PET data from the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal (Clinical Dementia Rating®: 0). RSFC was collected on two scanners in partly‐overlapping samples (PETMR N: 190, TRIO N: 149). RSFC data were processed with framewise censoring and global signal regression. RSFC networks were defined using 298 regions of interest. Aß was measured with PET PiB and AV‐45 tracers, which were harmonized using a Centiloid conversion. Tau was measured with a PET AV‐1451 tracer and was summarized in pre‐defined regions. Main effect and interaction relationships between Aß, tau PET, and RSFC were tested with linear regression models, controlling for age, sex, education, and head motion as covariates, with a false discovery rate correction.ResultWe did not observe a bidirectional interaction effect in any of the hypothesized networks (default mode [DMN], salience [SAL], frontoparietal [FPN]). Aß was positively associated with RSFC, independent of tau, in the DMN and SAL, while tau was negatively associated with RSFC, independent of Aß, in the SAL only. Exploratory analyses of FC within and between all networks did not identify clear patterns of interactive biomarker effects, nor consistent patterns of main effect relationships within any of the other networks.ConclusionThese results do not support an interactive model of RSFC in preclinical AD. Inconsistencies with previous interactions may be driven by sample‐specific or methodological differences, or the low reliability of FC and brain‐behavior relationships. Prominent biomarker relationships in the DMN and SAL are consistent with regional overlap with Aß deposition in early AD.