bluuebunny/crossref_metadata_2025_split huggingface dataset:
MTL networks are differentially affected by tau pathology
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Wisse Laura E.M. , Kelley Melissa , Lane Jacqueline , Sherin Monica , DiCalogero Michael , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A 
Published: January 2025

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional alterations in the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. Here, we examined the relationship between tau accumulation in the (trans)entorhinal cortex and functional connectivity (FC) in two MTL‐affiliated brain networks — the Anterior‐Temporal (AT) and Posterior‐Medial (PM) — in normal agers, individuals with preclinical AD, and patients with symptomatic AD.MethodIn this cross‐sectional study, we analyzed data from 125 individuals from the Penn ADRC (Table 1). All participants underwent structural and functional MRI on a Siemens 3 T Prisma system, as well as 18F‐Florbetaben and 18F‐Flortaucipir (FTP) PET imaging. We used the AT/PM network architecture from our previous work (Figure 1; PMID37767219) and analyzed the effects of (trans)entorhinal tau accumulation on the AT/PM FC as a function of distance to the MTL (Figure 1). Guided by our previous findings of an inverted U‐shaped FC pattern in the AT network over the course of the disease, we performed separate analyses of the AT FC in cognitively normal and symptomatic individuals.ResultsFC between the anterior MTL and its direct neighbors in the AT network was positively correlated with tau accumulation in the MTL (r = 0.201, p = 0.031; Figure 2a). Associations with tau were not present in other MTL‐AT connections (Figures 2b‐c) or in individuals with symptomatic AD. In contrast, the PM FC was broadly affected by tau pathology with both direct MTL‐PM and more distant connections showing a negative relationship to (trans)entorhinal tau (Figure 2d‐e). Excluding amyloid‐negative controls, the relationship between MTL tau and AT/PM FC remained statistically significant in the PM [one‐hop connections: r = ‐0.323, p = 0.0479; distant connections: r = ‐0.324, p = 0.047] but not the AT network.ConclusionsTogether, the current results implicate functional abnormalities in the AT network during the preclinical stage, while those in the PM network are closely related to disease severity. This dissociation likely represents distinct pathophysiology in AD and has potential implications for FC‐based metrics as a surrogate measure for assessing functional response to disease‐modifying immunotherapies.
Differential whole‐brain patterns of cardiometabolic risk and blood biomarker using multi‐modal neuroimaging and explainable deep learning
Authors: Ma Da , Lockhart Samuel N. , Hughes Timothy M. , Bateman James R. , Register Thomas C. , Mielke Michelle M. , Gurcan Metin Nafi , Craft Suzanne 
Published: January 2025

AbstractBackgroundCardiometabolic disorders are emerging risk factors for Alzheimer's disease (AD) and AD‐related dementia (ADRD). There is currently insufficient understanding of how different cardiometabolic profiles and blood biomarkers impact different AD‐related brain pathology regionally. This project uses data‐driven approaches and explainable artificial intelligence methods to determine the cardiometabolic and fluid contributions toward AD‐related pathophysiologic patterns in the brain.MethodA total of 504 participants from the Wake Forest Alzheimer's Disease Research Center (Mean age=70.1, female/male=327/177, cognitive‐comal/mild‐cognitive‐impairment/dementia/other=217/172/45/7, White/Black/Asian/Native=416/81/4/3) had 3T MRI and cardiovascular risk factors (pulse pressure = systolic ‐ diastolic blood pressure), fasting metabolic risk factors (hemoglobin A1c, fasting glucose, insulin, and lipid levels), obesity measures (hip‐to‐waist ratio, and body mass index [BMI]) and plasma biomarker (pTau181, Glial‐fibrillary‐acidic‐protein [GFAP], A Multi‐modal neuroimaging‐based regional brain phenotypes were extracted from T1, T2FLAIR, and ASL imaging sequences to derive structural volume and thickness (FreeSurfer parcellated regions), white matter hyperintensity (WMH) volume, and blood flow information. Regional cerebral blood flow phenotypes were derived from parcellated ASL images registered to the MNI template space using the AAL atlas. Whole‐brain linear association analysis was conducted, followed by a multi‐layer‐perceptron (MLP) deep‐learning‐based non‐linear regression model along with feature importance analysis (Shapley‐Additive‐exPlainations [SHAP]).ResultFigure 1 shows the heatmap of multi‐modal whole‐brain linear association patterns. Blood biomarkers (pTau181, GFAP) showed an overall strong association with structural data (T1, T2FLAIR), while metabolic factors (esp. fasting insulin and BMI) showed a strong association with ASL (esp. in white matter). The deep‐learning‐based neuroimaging feature importance (SHAP value, Figure 2) further revealed a relatively higher impact of ASL data on various cardiometabolic risk and blood biomarkers than the linear association pattern, indicating potential whole‐brain non‐linear association of cerebral blood flow.ConclusionThe current study demonstrated differential whole‐brain association patterns across multi‐domain cardiometabolic risk factors. Furthermore, the explainable deep learning approach revealed additional localized brain regions compared to whole‐brain association analysis, especially in gray matter regions from the regional AAL signal. Future studies will incorporate additional neuroimage modalities and derive individual domain‐specific CMR‐associated whole‐brain patterns.
Age‐Related Declines in Cerebral Blood Flow are Moderated by Sex, but not APOE ε4, in Mild Cognitive Impairment
Authors: Sanchez Danielle L , Sabbah Maria G , Bennett Ilana J 
Published: January 2025

AbstractBackgroundAge‐related disruptions in cerebral blood flow have been linked to increased Alzheimer’s disease risk. At least one study in cognitively unimpaired (CU) older adults found that cerebral blood flow varies with interactive effects of age, sex, and Apolipoprotein (APOE) ε4 status. However, it remains unknown whether these effects are stronger in older adults diagnosed with mild cognitive impairment (MCI). Therefore, the current study examined the moderating effects of sex and APOE ε4 status on age‐related differences in cerebral blood flow separately in CU and MCI groups.MethodPerfusion‐ and T1‐weighted magnetic resonance imaging data and APOE ε4 status (ε4+, ε4‐) were obtained from 111 CU and 49 MCI Alzheimer’s Disease Neuroimaging Initiative (ADNI3) participants at their baseline visit. Cerebral blood flow was measured as the average perfusion within anatomical masks of bilateral cortical lobes (frontal, temporal, parietal, occipital) and the hippocampus. Multiple linear regressions tested the effect of each moderator (sex, APOE ε4 status) on the relationship between age and cerebral blood flow separately in each region of interest and each cognitive status group.ResultFor the MCI group, results revealed both independent and interactive effects of Age and Sex on cerebral blood flow in the frontal, parietal, and occipital lobes, with the age‐related decline in cerebral blood flow being stronger in males than females. There were no significant effects of Age, Sex, or their interaction on cerebral blood flow in the hippocampus. Moreover, there were no significant effects of APOE ε4 status on cerebral blood flow nor moderation of Age on cerebral blood flow in any region. For the CU group, there were no significant effects of Age, Sex, APOE ε4 status, or their interactions on cerebral blood flow.ConclusionThe age‐related decline in cortical lobe cerebral blood flow was stronger in males with clinically diagnosed MCI. This finding indicates that sex and cognitive status, but not APOE ε4 status, are important moderators of cerebrovascular health.
Association of APOE genotype and ELOVL2 methylation with brain function in non‐demented adults during aging
Authors: Ponomareva Natalya V , Andreeva Tatiana V , Kuznetsova Irina L , Protasova Maria , Kunizheva Svetlana , Kupryanova Daria , Konovalov Rodion , Krotenkova Marina V. , Kolesnikova Ekaterina P , Malina Daria , Kanavets Elena V. , Fokin Vitaly , Illarioshkin Sergey N , Rogaev Evgeny I 
Published: January 2025

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE4+) genotype and aging synergistically contribute to the risk of Alzheimer's disease (AD), but the mechanisms underlying their influence are not completely understood. The methylation of ELOVL2 DNA accounts for 70% of the variance in the aging epigenetic clock. The ELOVL2 gene is essential for synthesizing long polyunsaturated fatty acids, crucial for cell membrane integrity, inflammation modulation, and energy maintenance. This study investigated the impact of APOE genotype and ELOVL2 methylation on EEG alpha rhythm and functional MRI (fMRI) resting‐state functional connectivity (rsFC) of brain networks in non‐demented adults during aging.MethodWe examined EEG alpha sub‐bands power and individual alpha peak frequency (IAPF) and the fMRI rsFC in 151 non‐demented volunteers, age range 20‐84 years, stratified by APOE genotype. APOE ε3/ε3 subgroup (APOE4‐) included 104 subjects, APOE ε4/ε3 (APOE4+) subgroup – 47 subjects. ELOVL2 cg16867657 methylation was examined in the blood in subgroup of 56 individuals (35 APOE4‐ and 21 APOE4+). The individuals underwent fMRI tsFC of the brain using the CONN Matlab/SPM‐based toolbox (Whitfield‐Gabrieli and Nieto‐Castanon, 2012). Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening.ResultThe presence of the APOE4+ genotype was associated with more pronounced alpha rhythm slowing and more pronounced decrease of fMRI rsFC during aging. Age‐related increase of ELOVL2 methylation was observed. The partial correlation analysis, with age as a covariate, revealed a significant correlation between ELOVL2 methylation and IAPF.ConclusionMore pronounced alpha rhythm slowing and fMRI rsFC reduction in APOE4+ carriers during aging can be linked to synaptic dysfunction and deterioration of white matter integrity. Impaired lipid metabolism, driven by age‐dependent ELOVL2 methylation, may accelerate the impact of the APOE4+ genotype on neurophysiological alterations during aging. These changes increase the risk of AD developed.Funding:This study was supported by Russian Science Foundation (Project No. 19‐75‐30039 to TA genotyping; Project No. 22‐15‐00448 to NP, RK, VF, EK EEG and fMRI analysis and MP for genotyping) and by Ministry of Science and Higher Education of the Russian Federation (Agreement 075‐10‐2021‐093 project GEN‐RND‐2017).
Repeat Testing Reliability of Plasma pTau217 in Preclinical AD
Authors: Rissman Robert A. , Langford Oliver , Raman Rema , Donohue Michael C. , Molina‐Henry Doris P. , Abdel‐Latif Sara , Sims John R. , Yaari Roy , Holdridge Karen Chilcott , Johnson Keith A , Aisen Paul S. S. , Sperling Reisa A 
Published: January 2025

AbstractBackgroundData from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial (NCT02008357), including cognitively unimpaired participants with brain amyloid pathology on florbetapir F 18, demonstrates that levels of plasma P‐tau217, as detected by an electrochemiluminescence (ECL) immunoassay, is strong predictor of elevated cerebral amyloid on florbetapir PET in cognitively unimpaired individuals. Here we compare plasma P‐tau217 measures over 12 weeks using a P‐tau217 ECL immunoassay.MethodA4 trial placebo‐group participants who had their first baseline and first post‐baseline plasma P‐tau217 samples collected within 175 days of each other were included in these analyses. This time was chosen to maximize the number of available samples while minimizing the likelihood of significant change. The coefficient of variation (CV) was used to measure relative variability between samples computed as the difference in plasma P‐tau217 values, and the “test‐retest” performance of the plasma P‐tau217 assay was evaluated using an intraclass correlation coefficient (ICC) from a two‐way mixed‐effects model. A Box‐Cox data transform was performed due to significant observed heteroscedasticity in the P‐tau217 values.ResultAnalysis sample included 573 A4 study participants (mean age: 71.9 +/‐ 5 years, mean florbetapir SUVr: 1.33 +/‐ 0.18; days between assays: 86.5 +/‐ 6.5 days; 59.9% female sex). Low levels of variability were observed between the samples with a coefficient of variation of 7% and the test‐retest reliability was ICC=0.90 (ICC: 0.90; 95% CI: 0.89, 0.92).ConclusionA P‐tau217 ECL immunoassay showed low levels of variability between samples and excellent test‐retest reliability over 12 weeks in cognitively unimpaired individuals with elevated cerebral amyloid.
Exploring the effects of using multiple different cerebellar reference regions to improve tau‐PET harmonization ‐ The HEAD Study
Authors: Bauer‐Negrini Guilherme , Povala Guilherme , Bellaver Bruna , Lussier Firoza Z , Tissot Cécile , Tsai Hsin‐Yeh , Amaral Livia , Ferreira Pamela C.L. , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundTau‐PET tracers have been used to diagnose and stage Alzheimer’s disease. However, different tau tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their results. We hypothesize that the choice of a reference region can impact the harmonization of the tau‐PET standardized uptake value ratio (SUVR). In this context, we aimed to explore how different cerebellar reference regions impact the association between [18F]Flortaucipir and [18F]MK‐6240 SUVR values.MethodWe studied 185 individuals across the aging and AD spectrum with head‐to‐head Flortaucipir and MK‐6240 tau PET (HEAD Study). SUVRs were processed to a common 8mm FWHM using 15 different reference regions defined in the spatially unbiased atlas template of the cerebellum (SUIT) (Diedrichsen, 2009). Regression models investigated the association between Flortaucipir and MK‐6240 using multiple combinations of reference regions. R2 statistic was used to estimate goodness‐of‐fitting.Result225 combinations of associations Flortaucipir and MK‐6240 SUVR were tested, where the SUVRs are not necessarily quantified using the same reference region. Figure 1 presents the top 25 strongest and 25 weakest associations, ordered based on the coefficient of determination (R²). Flortaucipir and MK‐6240 exhibited the most robust associations when the inferior cerebellar gray matter or Crus I were employed for SUVR determination (R2=0.89, Figure 1‐2). Conversely, combinations incorporating the fastigial region consistently yielded weaker associations between the two tracers (R2<0.70, Figure 1‐2).ConclusionInterestingly, we showed that the inferior cerebellum, when used for both tracers, serves as a robust reference region for determining the most similar SUVRs for Flortaucipir and MK‐6240. Notably, these two regions have been commonly utilized in previous studies involving these tau tracers. Our results imply that the inferior cerebellum could be the optimal reference region for research aimed at harmonizing tau PET tracers using statistical scales.
Wnt/pathway, APP processing and telomere shortening in Down syndrome adults
Authors: Cordeiro Augusto Magno Tranquezi , Bram Jessyka Maria de França , Talib Leda Leme , Forlenza Orestes Vicente , Fernandes Lillian 
Published: January 2025

AbstractBackgroundThe Down Syndrome (DS), also referred to as trisomy of chromosome 21, is a prevalent cause of intellectual disability and also contributes to the acceleration of aging, among other developmental and health concerns. Certain pathological characteristics shared by DS and Alzheimer’s Disease (AD) indicate similar commonalities.This study aims to unravel the relationship between the canonical Wnt/pathway, the amyloid precursor protein processing, the telomere shortening in DS individuals. The telomere is a structure found at the end of the chromosomes that protects against degradation during cell division. The shortening of the telomere length is associated with the risk of AD. β‐catenin is an important factor in the canonical Wnt pathway. The activation of this pathway can protect against neurotoxic effects caused by accumulation of β‐amyloid peptide and the phosphorylation of Tau protein. The canonical Wnt activation is related with the activation of subunit Tert, also known as telomerase. Telomerase is an enzyme responsible for the maintenance of telomere length.MethodsThe biomarkers were quantified in the plasma and platelets of adults and elderly with DS (n = 55) and adults and elderly without DS (n = 80). We utilized western blot, for APP fragments (110 kDa and 130 kDa), Luminex xMAP, for AB40 fragment. The DNA was extracted from leukocytes and measured using qPCR method using 36B4 as single copy gene. Telomere length was calculated using the delta Ct value.ResultsWe found increased levels of Aβ40 and in 110 kDa, 130 kDa APP fragments of Down syndrome individuals. β‐catenin was also increased in DS group when compared with non DS group. The telomere length was decrease in DS group when compared with non DS group.ConclusionThe increase in Aβ40 and 110 kDa, 130 kDa fragments, demonstrated an imbalance in the APP processing, that could lead to the Aβ aggregation observed in DS individuals. The increase in the β‐catenin expression could be a compensatory mechanism for the telomere shortening in DS group.
Functional connectivity changes through Alzheimer’s disease continuum: disease onset, progression, and response to therapy
Authors: Zimmer Aline R. , Bourourou Miled , Lesage Frédéric , Hamel Edith 
Published: January 2025

AbstractBackgroundHemodynamic signals are the basis of functional brain imaging techniques, such as fMRI and NIRS, and are often used to infer changes in resting‐state functional connectivity (RSFC) in Alzheimer’s disease (AD) and other dementias. Increasing evidence suggests that disruption of neuronal circuits has been associated with the AD continuum and may precede changes in Ab and tau biomarkers, neurodegeneration, and cognitive impairment. To better understand the changes in brain RSFC through the AD spectrum, we use hemodynamic signals to detect disease onset, progression, and response to therapy in a mouse model of AD.MethodHemodynamic signals were recorded longitudinally (3‐8 months) in anesthetized (ketamine/xylazine) and awake WT and APP (J20) mice, implanted with full cranial window, using optical imaging of intrinsic signals (OIS), together with cognitive testing. Seed‐based functional connectivity maps were generated for the bilateral connectivity (BC) and RSFC analyses. The effects of simvastatin (SV), a cardiovascular medicine that has shown promise in preventing dementia, were evaluated after 2.5 and 5 months.ResultAlterations in RSFC in brain regions associated with the sensory‐motor (SM) and default‐mode (DMN) networks were detected before the appearance of cognitive impairment. 3‐month‐old APP mice showed consistent decrease in bilateral functional connectivity (BC) in motor (M) and cingulate (C) cortical regions and a severe hypoconnectivity within the SM network in the RSFC analysis. Throughout the course of the disease, RSFC analysis in APP mice uncovered an early hyperconnectivity within the DMN, mainly driven by the frontal (F) cortex, followed by a later hypoconnectivity stage. At late stage of the disease (8‐months‐old), a decreased BC in somatosensory (S) cortex was detected. SV treatment prevented the aberrant increases in DMN FC in midlife APP mice, improved the BC of S cortex, while concurrently sparing cognitive function.ConclusionOur results demonstrated that hemodynamic signals measured by OIS at the cortical level successfully detected RSFC disruptions preceding dementia in APP mice and allowed to capture SV therapeutic benefits. These findings suggest that OIS, or its human equivalent NIRS, could contribute to effectively diagnosing the early stages of AD, leading to promising intervention opportunities.
White matter aging in late midlife women: Validation and association with neurodegenerative biomarkers
Authors: Li Jinghang , Wu Minjie , Chen Chang‐Le , Wang Linghai , Yang Shaolin , Aizenstein Howard J , Chang Yuefang , Karikari Thomas K , Derby Carol A. , Maki Pauline M , Thurston Rebecca C 
Published: January 2025

AbstractBackgroundBrain age (BA) prediction models have emerged as valuable tools for understanding individual differences in trajectories of brain aging. These models aim to estimate overall brain health by predicting BA based on structural MRI data. To enhance the specificity of existing BA models, we introduce a deep learning‐based BA prediction model. The model focuses on the cerebral white matter to assess the prominent cerebrovascular AD risk pathway for women. Here we validate our deep learning‐derived white matter brain age (WMBA) in a sample of late midlife women enrolled in MsBrain. We also examine WMBA in relation to plasma neurodegenerative biomarkers in this sample.MethodWe developed an age‐conditioned variational autoencoder along with a multilayer perceptron (MLP) for brain age prediction (Figure 1). The model was trained on the Human Connectome Project healthy aging (HCP‐A) dataset (female, n=396; male, n=316, 36‐90 yr, mean=60 yr). To achieve white matter specificity, the model was trained only on the myelin ratio map. Adaptability and credibility were assessed by testing the model with MsBrain data, a study for which midlife women with no cardiovascular disease, stroke, or dementia were recruited (n=239, 45‐67 yr, mean=59 yr). Plasma biomarkers included amyloid β (aβ) 42, phosphorylated tau (181, 231), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) via Simoa. All brain age predictions underwent bias correction through fitted linear regression models.ResultFigure 1 shows the overall WMBA model schematics, including myelin ratio map training inputs, brain age predictions, and generated WMBA outputs. Compared with chronological age, the WMBA model was more strongly associated with cerebral white matter volume (Figure 2a). When considering brain age gap (i.e., difference between predicted brain age and chronological age), a greater brain age gap (indicating older brain age) was found with lower cerebral white matter ratio (Figure 2b). Lastly, greater WMBA was associated with higher GFAP and aβ42.ConclusionThis work validates a new approach for measuring WMBA and demonstrates its utility in studies of midlife women. Findings indicate that WMBA varies with plasma markers of neurodegeneration in late midlife women, suggesting a novel neuroimaging marker to detect early neurodegenerative changes.