bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocyte reactivity and cerebral glucose hypermetabolism in early Alzheimer's: insights from a longitudinal study in the TgF344‐AD rat model
Authors: de Lima Amanda Muliterno Domingues Lourenço , da Rocha Andreia Silva , Machado Luiza Santos , Soares Carolina , Ferreira Pamela C.L. , Bellaver Bruna , da Silva Patrícia Eduarda Carvalho , Venturin Gianina Teribele , Greggio Samuel , Lazzarotto Gabriela , Vidor Pedro , Kunach Peter , Green Kim N. , da Costa Jaderson Costa , Souza Diogo O. , Rosa‐Neto Pedro , Zimmer Eduardo R. , AD MODEL 
Published: January 2025

AbstractBackgroundRecent studies have suggested a transient glucose hypermetabolism in early phases of Alzheimer's Disease (AD), which is followed by a characteristic glucose hypometabolism in dementia stages. This phenomenon desveres further investigation and it is suggested to be associated to glial/inflammatory or compensatory neuronal responses. Here, we aimed to longitudinally investigate brain glucose metabolism in an AD animal model and explore associated cellular and inflammatory changes.MethodLongitudinal assessments, including cerebral glucose metabolism (18F]FDG‐PET), behavioral tasks and cerebrospinal fluid (CSF) sample collection were performed at 3, 6, 9, and 12 months of age (mo) in wild type (WT) and TgF344‐AD rats (Tg). Glial and inflammatory markers were evaluated in the CSF via ELISA multiplex. A cross‐sectional cohort was used to follow the spatial distribution of Aß plaques (IHC), to assess the brain content of glial and neuronal proteins (western blot), and to analyze the cortical glutamate uptake (ex‐vivo slices) at the same time points.ResultAt 9mo, three months after the initial appearance of Aß plaque deposits, Tg animals exhibited cortical glucose hypermetabolism (Figure 1A‐C). At the same age, astrocytic glutamate uptake was increased in the cortex and hippocampus (Figure 2). Declines in performance on the Y‐maze and Novel Object Recognition tasks were observed at 9 and 12mo (Figure 1D). CSF analysis revealed elevated GFAP levels at 6, 9 and 12mo, and reduced S100B at 9mo (Figure 1E e F). Tissue GFAP immunocontent increased in the temporoparietal cortex at 6 and 9mo, in the hippocampus at 9mo, and was reduced in the frontal and temporoparietal cortices at 12mo (Figure 3).ConclusionOur findings suggest the presence of an early, transient phase of brain glucose hypermetabolism in TgF344‐AD rats, consistent with observations in recent animal and human studies. This phenomenon seems to be closely linked to the astrocyte response, reflected in variations of crucial astrocyte proteins such as GFAP and S100B, along with an increase in the glutamate uptake by these cells. In contrast, neuronal, microglial and inflammatory markers did not exhibit changes during this timeframe.
Estimating age at Aβ onset in the 1946 British birth cohort: exploring the influence of APOE ɛ4 carriership and sex
Authors: Coath William , Betthauser Tobey J. , Teague Jordan P , Scott Catherine J , Thomas David L , Dickson John , Markiewicz Pawel J , Barkhof Frederik , Schöll Michael , Richards Marcus , Fox Nick C , Cash David M , Schott Jonathan M 
Published: January 2025

AbstractBackgroundCerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals from the longest‐running British birth cohort.MethodParticipants in Insight 46 were drawn from the 1946 British birth cohort and underwent combined PET/MR scanning with [18F]florbetapir at two timepoints. Centiloid (CL) values were calculated using a whole cerebellum reference region and partial volume correction. We used Gaussian mixture modelling (99th percentile of lower distribution) to define an Aβ+ threshold of 12 CL. We constructed a CL vs Aβ time curve with SILA from available longitudinal Aβ‐PET scans (n = 324, interval = 2.4±0.2yrs), which was applied to the whole sample (n = 463) to calculate EAAβ. Some scans were below the CL range that could be modelled, and the estimated EAAβ was truncated to the furthest time before onset on the CL vs time curve. Kaplan‐Meyer plots and Cox regression were used to investigate EAAβ and risk of estimated Aβ+ by APOE‐ɛ4 and sex, right censoring participants where EAAβ was truncated.ResultMean (SD) chronological age was 70.6±0.7yrs at baseline and 73.0±0.6yrs at follow‐up scan and 30.5% were Aβ+ve by follow‐up (n = 141, 55.3% APOE‐ɛ4, 51.8% female). SILA results and distribution of EAAβ are shown in figures 1 and 2. EAAβ were truncated due to low Aβ binding in 35.7% (n = 166, 15.7% APOE‐ɛ4, 50% female). APOE ɛ4 carriers reached median EAAβ 8.6 years earlier than non‐carriers (figure 3A). Median EAAβ for females was marginally earlier than males with overlapping CIs (figure 3B). APOE‐ɛ4 was strongly associated with risk of estimated Aβ+ (HR[95%CI] = 2.4[1.9,3.0]), adjusted for sex. Female sex (1.1[0.8,1.3]) and the interaction between APOE‐ɛ4 and sex (1.2[0.8,1.9]) were non‐significant.ConclusionEstimated Aβ positivity was reached on average 8.6 years earlier for APOE ɛ4 carriers. Consistent with results from other cohorts, APOE‐ɛ4, not sex, significantly heightened the risk of estimated Aβ positivity. Future research will explore life course and downstream events related to Aβ timing.
MCI Diagnosis and Neighborhood Disadvantage Predict Differences in White Matter Microstructure in a Rural Aging Cohort
Authors: Bender Andrew R. , Giriprakash Pavithran Pattiam , Cordes Dietmar , Zhuang Xiaowei , Caldwell Jessica ZK , Miller Justin B 
Published: January 2025

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) studies show cerebral white matter alterations are associated with both mild cognitive impairment (MCI) and contextual psychosocial factors. However, these reports are almost exclusively based on older adults residing in metropolitan areas. Individuals living in rural communities face increased risk for Alzheimer’s disease and related dementias, but little is known regarding the sensitivity of dMRI markers to incident MCI or psychosocial stressors in this population. In a rural‐dwelling community cohort of older adults, this study evaluated associations between dMRI measures of white matter microstructure and both clinical MCI diagnosis and neighborhood disadvantage.MethodThe study sample included rural‐dwelling older adults (n = 69) from the Nevada Exploratory Alzheimer’s Disease Research Center. Participants were characterized as cognitively unimpaired (CU; n = 42) or diagnosed with MCI (n = 27) based on clinical expert consensus, and all had dMRI data and Area Deprivation Index (ADI) measures of neighborhood disadvantage. dMRI data processing leveraged the MRtrix3 fixel‐based analysis framework and free water mapping to estimate voxel‐based measures of white matter organization, transformed to a sample template. Data analysis utilized voxel‐based analysis (VBA) to model differences in clinical diagnosis and ADI scores as predictors of fiber density, crossing fiber entropy, and extracellular free water, and free water‐corrected diffusion tensor parameters, accounting for differences in age, sex, and handedness.ResultsThe VBA models showed both MCI diagnosis and elevated neighborhood disadvantage predicted significantly greater (familywise error corrected p<.05) free water and reduced crossing fiber entropy in centrum semiovale and internal capsule (Figure 1). Uncorrected models for both diagnosis and higher ADI level revealed widespread associations with dMRI measures of free water, tensor parameters, and fiber density that were nonsignificant following permutation‐based corrections.ConclusionThese preliminary findings reveal white matter alterations associated with consensus MCI diagnosis and to socioeconomic differences in a clinical cohort of rural‐dwelling older adults. The present results highlight the value of modeling extracellular cerebral spinal fluid or ‘free water’ as a marker of microstructural changes associated with both cognitive impairment and contextual psychosocial factors. Future efforts are needed to compare these effects between rural‐ and metropolitan‐dwelling older adults at risk for dementia.
Voxel‐wise Florzolotau (APN‐1607) Tau PET Covariance Patterns in Alzheimer’s Disease and Progressive Supranuclear Palsy
Authors: Blazhenets Ganna , Brumberg Joachim , Endo Hironobu , Hsu Jung‐Lung , Frings Lars , Schroeter Nils , Hellwig Sabine , Chang Chiung‐Chih , Higuchi Makoto , Meyer Philipp Tobias 
Published: January 2025

AbstractBackgroundFlorzolotau (APN‐1607) tau‐PET has shown distinct patterns of binding in patients with AD and 4‐repeat tauopathies. We aimed to establish disease‐specific tau covariance patterns in AD and PSP/CBS and validate them as user‐independent quantitative biomarkers for reference‐region‐free evaluation of tau‐PET in an independent clinical cohort.MethodWe analyzed Florzolotau PET data from four different cohorts. The derivation dataset included 30 Aß‐ healthy controls (HC) and 30 patients each with Aß+ AD and PSP with Richardson’s syndrome (PSP‐RS). The validation dataset included 44, 51, 6, 15, and 17 patients with AD, PSP/CBS, MSA, LBD, and FTD, respectively. First, we applied scaled sub‐profile modelling principal components analysis to the derivation dataset to define the AD‐ and PSP‐RS‐related covariance patterns. Second, the topographic profile rating algorithm was applied to each scan to calculate AD‐ and PSP‐RS‐related pattern scores.ResultThe AD‐ and PSP‐RS‐related patterns are described in Figures 1 and 2. In the derivation dataset, the AD‐ and PSP‐RS‐scores showed strong increases compared to HC (both p<0.001,AUC‐ROC = 0.994 and 0.898, respectively). AD‐scores showed a significant negative association with age (r = ‐0.66,p<0.001) and MMSE (r = ‐0.64,p<0.001) in AD, while PSP‐RS‐scores correlated with the PSP rating scale (r = 0.43,p = 0.018) in PSP‐RS. In the validation dataset (Figure 3), AD‐scores were highest in AD (p<0.001 vs. all other, AUC‐ROC[AD vs. all other] = 0.946) and were negatively associated with age and MMSE in AD (r = ‐0.62,p<0.001 and r = ‐0.49,p = 0.002, respectively). PSP‐RS‐scores were highest in the PSP/CBS (p<0.001 vs. all other [at least p<0.05 vs. each group], AUC‐ROC[PSP/CBS vs. all other] = 0.734), though also relatively increased in FTD and MSA. UPDRS‐III scores (off‐state) were available in 23 PSP/CBS patients and significantly associated with PSP‐RS‐scores (r = 0.60,p = 0.002).ConclusionModelling with principal components analysis allows for reference‐region‐free quantification of tau imaging data by constructing disease‐specific covariance patterns. When applied to Florzolotau, AD‐ and PSP‐RS‐related patterns showed high discrimination power in both the derivation and the clinically heterogeneous validation cohorts. PSP‐RS‐related pattern expression in FTD and MSA may be related to PSP pathology and known striatal off‐target binding, respectively. Strong association with respective disease severity scores further advocates for use of AD‐ and PSP‐RS‐related patterns as potential quantitative biomarkers of tau pathology.
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 (Fig. 1; PMID37767219) and analyzed the effects of (trans)entorhinal tau accumulation on the AT/PM FC as a function of distance to the MTL (Fig. 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; Fig. 2a). Associations with tau were not present in other MTL‐AT connections (Figs. 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 (Fig. 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.
Older adults at‐risk for type 2 diabetes exhibit decreased performance on spatial and working memory tasks using classic and novel cognitive testing
Authors: Ghosh‐Swaby Olivia R , Al‐Shaikh Jennifer Hanna , Palmer Daniel , Khan Ali R. , Thornton Jane , Bussey Timothy J , Saksida Lisa M , Liu‐Ambrose Teresa , Nagamatsu Lindsay 
Published: January 2025

AbstractBackgroundType 2 diabetes (T2D) and older age are well‐known risk factors for dementia. Indeed, there is evidence that older adults not diagnosed, but at‐risk for T2D can show early signs of cognitive decline, further exacerbated by excessive body weight or high blood glucose levels. Such a finding would have implications for early treatment strategies; however, the evidence is still sparse. We examined the correlation of risk factors for diabetes with cognitive function in older adults at‐risk for T2D using a battery of touchscreen tasks translated from their rodent versions, as well as traditional pen‐to‐paper cognitive tests.MethodSixty‐five older adults (69.39 ± 10.31 years old, 68% female) at‐risk for T2D (BMI = 25 kg/m2, hemoglobin A1c = 6.0%, CANRISK score = 21) completed 3 novel touchscreen tasks: paired associative learning (PAL) (learning and object‐in‐location memory), progressive ratio (motivation), and trial unique, non‐matching to location (TUNL) (spatial pattern separation and working memory). They were also tested on pen‐to‐paper cognitive tests: trail‐making (task switching), Stroop (selective inhibition), and digit span (working memory). A correlation analysis was performed between BMI or HbA1c and cognitive performance. Performance on touchscreen tasks was analyzed using a repeated measures one‐way ANOVA.ResultHigher HbA1c levels were correlated with lower digit span scores (r2 = 0.12, p = 0.011). There was no correlation between breakpoint (motivation level) and BMI or HbA1c during the progressive ratio task (r2 = 0.0, p = 0.38). Interestingly, this population performed at chance level (59.7 ± 5.3% accuracy) on the PAL task, indicating they were unable to learn object‐location paired associates. When manipulating the spatial similarity in distance between stimuli during the TUNL task, older adults at risk for diabetes were 10% lower in accuracy when stimuli were close together compared to further apart (p<0001). Participants also responded more slowly to stimuli at choice during the TUNL task during the heaviest working memory load condition (p = 0.003).ConclusionOlder adults at‐risk for T2D exhibit decreased performance on tasks with higher demands on spatial and working memory. Future research will compare performance on all tasks to healthy age‐matched controls and reassess performance after a six‐month exercise intervention.
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.
Task fMRI networks predict memory in cognitively unimpaired older adults
Authors: Ziontz Jacob , Chen Xi , Jagust William J. 
Published: January 2025

AbstractBackgroundEpisodic memory decline is a hallmark feature of aging and Alzheimer’s disease, but the mechanisms underlying its earliest stages are unknown.MethodCognitively unimpaired older adults from the Berkeley Aging Cohort Study (n=49) completed an fMRI memory encoding task preceded by 15 minutes rsfMRI and standard neuropsychological testing. Participants viewed object, scene, and object‐in‐scene (pair) stimuli in the scanner for 40 minutes. They then completed a recognition test to distinguish repeated from novel stimuli, and their performance was quantified as d’ (false alarm rate – hit rate; Figure 1). Functional connectivity (FC) was computed between all regions of the Schaefer 400 ROI atlas during presentation of each stimulus type and during rest. An elastic net filter model approach identified a sparse subset of connections highly related to successful performance in each task component. Model weights for these connections were applied to each participant’s rsfMRI connectivity to predict performance on each task component. Network strength was computed by summing FC values for each connection in the network.ResultTask fMRI networks comprised unique sets of connections positively and negatively related to performance in each task component: the object network included 27 positive and 37 negative connections, the scene network included 29 positive and 29 negative connections, and the pair network include 28 positive and 10 negative connections (Figure 2). Applied to rsfMRI data collected prior to task, respective networks predicted object (r2 = 0.28, p < 0.001), scene (r2 = 0.52, p < 0.001), and pair (r2 = 0.29, p < 0.001) recognition performance (Figure 3a). Adjusting for age, sex, and education, strength of object (b = 0.36, p = 0.013) and scene networks (b = 0.33, p = 0.005) were correlated with a composite measure of episodic memory performance generated from a neuropsychological test battery (Figure 3b).ConclusionFunctional networks that support successful memory encoding in older adults can be applied to rsfMRI to predict performance, and the strength of these networks is further associated with independent measures of episodic memory. Future work will investigate the potential for these networks to predict the earliest stages of cognitive decline.
Harmonization of amyloid PET radiotracers using ComBat and its influence on detecting treatment effects in a simulated clinical trial
Authors: Yang Braden , Earnest Tom , Kumar Sayantan , Gordon Brian A. , Sotiras Aristeidis 
Published: January 2025

AbstractBackgroundDifferences in amyloid PET radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid uptake measurements, which may adversely affect the statistical power of clinical trials that utilize multiple tracers to track brain amyloid deposition. To address this, Centiloid was developed for standardizing global amyloid SUVRs across tracers to a common scale. Alternatively, ComBat is a technique for harmonizing batch effects while preserving variations from biologically‐relevant covariates. Unlike Centiloid, ComBat is entirely data‐driven, does not require a calibration process, and can be applied to regional SUVRs. However, it has not been validated for amyloid PET. Here, we evaluate whether ComBat improves detection of treatment effects in a simulated clinical trial.Method365 amyloid‐positive subjects were identified from the OASIS‐3 dataset, from which 322 Pittsburgh compound B (PiB) and 260 18F‐Florbetapir (FBP) PET scans were selected. SUVRs of the global cortical region and 82 FreeSurfer regions were computed from each scan using the PET Unified Pipeline. Linear mixed effects (LME) models were fitted on each tracer separately and used to simulate longitudinal SUVRs of placebo and treatment groups in a hypothetical clinical trial (Figure 1). A negative rate‐of‐change was introduced to the treatment group to mimic a treatment effect. Additionally, tracer mixing proportions were varied within each group. Centiloid and ComBat were applied to simulated data to harmonize across tracers. A separate LME model was fitted to test for significant differences in SUVR rate‐of‐change between groups. Power was estimated as the proportion of significant findings across 1000 simulations.ResultAfter harmonization with either Centiloid or ComBat with no covariates, an increase in power was observed in the presence of a treatment effect, and a decrease in Type‐I error was observed for no treatment effect (Figure 2). These changes were most prominent in cases where groups exhibited differing tracer mixing proportions. Similar patterns were observed for regional SUVRs (Figure 3).ConclusionWe demonstrated that tracer harmonization is important for improving power in the presence of a treatment effect and reducing Type‐I error in its absence. ComBat performs comparably to Centiloid in harmonizing amyloid radiotracers in the context of a clinical trial.