bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo 18F‐MK6240 tau PET imaging in relation to peripheral inflammation and episodic memory in late middle‐aged adults
Authors: Malarte Mona‐Lisa , Chiotis Konstantinos , Ioannou Konstantinos , Rodriguez‐Vieitez Elena 
Published: January 2025

AbstractBackgroundDetecting early stages of Alzheimer's disease (AD) remains a crucial yet complex challenge. While recent interest has surged in detecting biomarkers linked with the disease preclinical phase, a comprehensive understanding of the concomitant peripheral biological pathways before the potential disease onset is necessary. We aim to explore the associations between the 18F‐MK6240 tau PET tracer with plasma inflammatory markers, other AT(X)N biomarkers and episodic memory.MethodThe cross‐sectional sample consisted of n=132 cognitively unimpaired late middle‐aged Hispanic individuals (64.5 ± 3.4 years old, 34.1% APOE4 carriers, 69.7% female, 10.7 ± 4.0 years of education) from Northern Manhattan (AD Knowledge Center database). All individuals underwent multi‐modal imaging with T1‐weighted MRI, T2‐weighted FLAIR MRI, Aß PET (18F‐florbetaben), tau PET (18F‐MK6240), plasma measures of inflammation (OLINK panel of 92 markers), plasma neuronal injury (NfL), and neuropsychological assessments. Data on demographics: age, sex, education, APOE, body mass index (BMI), and diabetes mellitus, were also included. Using the median split to dichotomize global Aß and NfL measures, the study sample was stratified into four groups: “Aß‐low, NfL‐low” (Group 0); “Aß‐high, NfL‐low” (Group 1); “Aß‐high, NfL‐high” (Group 2); and “Aß‐low, NfL‐high” (Group 3).ResultOur results revealed that 18F‐MK6240 tau PET is sensitive in detecting early neocortical tau pathology, even without evident neuronal injury (Fig. 1). Plasma inflammation was not directly linked with Aß or tau pathologies but strongly associated with NfL (Fig. 2). Markers of neuronal injury (NfL), cerebrovascular injury (WMH) and specific inflammatory markers were associated with lower episodic memory (Fig. 1). High NfL correlated with factors such as high inflammation, BMI, diabetes and older age.ConclusionThe study emphasizes the complex nature of early AD markers suggesting that, aside from Aß and tau, peripheral markers of NfL and inflammation are also central. Our findings call for a broader perspective in identifying early AD markers, underscoring the interplay between neuronal damage, inflammation, comorbidities and early cognitive changes.
Cognitive impairment due to ischemic stroke in female rats is associated with secondary neurodegeneration, and attenuated with microRNA‐20a‐3p as assessed by diffusion tensor MR imaging and histological analysis
Authors: Sampath Dayalan , Singer Jacob , Gopalakrishnan Balaji , Akbari Zara , Villarreal Monserrat , Hurst David A , Noarbe Brenda P , Obenaus Andre , Sohrabji Farida 
Published: January 2025

AbstractBackgroundOur studies show that the small non‐coding RNA, mir20a‐3p, is neuroprotective for stroke in the acute phase and also attenuates long term cognitive decline in middle‐aged female rats. Cognitive decline due to vascular diseases, such as stroke, is associated with secondary neurodegeneration in cortex and limbic structures. In this study, we assessed the volume of white matter, ventricles and regional diffusion‐weighted MR imaging measures to delineate pathological tissue characteristics from the postmortem brain of stroke rats.MethodMiddle‐aged females were subjected to ischemic stroke using the vasoconstrictor endothelin 1, injected adjacent to the left middle cerebral artery (MCA). Mir‐20a‐3p mimic (n=10) or scrambled oligo (n=8) was administered i.v. 4h, 24h and 70d post stroke. Animals were assessed periodically for cognitive performance up to 100d after stroke using both the cued fear conditioning test and the novel object recognition test (NORT). After perfusion fixation, T2 and diffusion tensor imaging (DTI) magnetic resonance imaging were performed on postmortem tissue. Subsequently, brains were processed for histology, including the Weil myelin stain.ResultStroke resulted in impairment in both the cued fear conditioning test and the NORT, which was attenuated by mir‐20a‐3p treatment (Sampath et al., 2023). Weil myelin‐stained sections showed that both the corpus callosum and internal capsule had a reduction in volume in the ischemic hemisphere as compared to non‐ischemic hemisphere in vehicle treated (scrambled oligo) MCAo animals. In contrast, sham and MCAo+Mir‐20a‐3p animals displayed no hemispheric differences in the volume in either tract. A similar volume asymmetry was also observed in the ventricles in the MCA0+ Scrambled group. Entorhinal cortex volume (diffusion tensor MR images) was also asymmetric in the MCAo+scrambled oligo group.ConclusionCognitive changes measured with remote fear memory retrieval and NORT were associated with reduced density of major forebrain white matter tracts due to stroke and enlarged ventricular volume indicative of cell loss. This was observed in the entorhinal cortex, a region involved with contextual memory processing. These stroke‐induced deficits were attenuated in Mir‐20‐3p treated animals, indicating that microRNA treatment attenuated secondary neurodegeneration.
qEEG as Biomarker for Alzheimer’s Disease:Investigating Relative PSD Difference and CoherenceAnalysis
Authors: Simfukwe Chanda , Youn Young Chul , An Seong Soo 
Published: January 2025

AbstractBackgroundElectroencephalography (EEG) is a non‐intrusive technique that provides comprehensive insights into the electrical activities of the brain’s cerebral cortex. The brain signals obtained from EEGs can be used as a neuropsychological biomarker to detect different stages of Alzheimer’s disease (AD) through quantitative EEG (qEEG) analysis. This paper investigates the difference in the abnormalities of resting state EEG (rEEG) signals between eyes‐open (EOR) and eyes‐closed (ECR) in AD by analyzing 19‐ scalp electrode EEG signals and making a comparison with healthy controls (HC).MethodThe rEEG data from 534 subjects (ages 40‐90) consisting of 269 HC and 265 AD subjects in South Korea were used in this study. The qEEG for EOR and ECR states were performed separately for HC and AD subjects to measure the relative power spectrum density (PSD) and coherence with functional connectivity to evaluate abnormalities. The rEEG data were preprocessed and analyzed using EEGlab and Brainstorm toolboxes in MATLAB R2021a software, and statistical analyses were carried out using ANOVA.ResultBased on the Welch method, the relative PSD of the EEG EOR and ECR states difference in the AD group showed a significant increase in the delta frequency band of 19 EEG channels, particularly in the frontal, parietal, and temporal, than the HC groups. The delta power band on the source level was increased for the AD group and decreased for the HC group. In contrast, the source activities of alpha, beta, and gamma frequency bands were significantly reduced in the AD group, with a high decrease in the beta frequency band in all brain areas. Furthermore, the coherence of rEEG among different EEG electrodes was analyzed in the beta frequency band. It showed that pair‐wise coherence between different brain areas in the AD group is remarkably increased in the ECR state and decreased after subtracting out the EOR state.ConclusionThe findings suggest that examining PSD and functional connectivity through coherence analysis could serve as a promising and comprehensive approach to differentiate individuals with AD from normal, which may benefit our understanding of the disease.
Digital assessment of turning behaviours in Alzheimer’s disease and Lewy body disease and their association with cognitive function
Authors: Ardle Ríona Mc , Din Silvia Del , Rehman Rana Zia , Galna Brook , Thomas Alan J , Rochester Lynn , Alcock Lisa 
Published: January 2025

AbstractBackgroundDigital mobility outcomes (DMOs) can be captured using body‐worn inertial measurement units (IMUs) in lab‐based and real‐world environments. DMOs may support differential diagnosis of dementia; for example, Alzheimer’s disease (AD) and Lewy body disease (LBD) show unique signatures of gait impairment. Growing evidence suggests that turning impairments are related to cognitive decline. Turning outcomes can be captured via IMUs and may complement use of existing DMOs. This study aims to assess differences in turning outcomes between AD, LBD and older adult controls, and explore their clinical and cognitive correlations.MethodParticipants completed six intermittent 10‐metre walks while wearing a IMU (APDM, Opal 128Hz) attached to their lower back. Following each walk, they made a 180degree turn. Two spatiotemporal (turn duration, angular velocity) and two acceleration‐based (combined direction [anterior‐posterior/medio‐lateral/vertical] Root Mean Square (RMS) and Jerk RMS) turning outcomes were extracted using validated algorithms. Analysis of covariance assessed between‐group differences in turning outcomes, controlling for age and sex. Tukey HSD tests for multiple comparisons determined where differences occurred. Correlations (Spearman’s rho) between significant turning outcomes and age, motor disease severity (MDS Unified Parkinson’s Disease Rating Scale III), global cognition (standardised Mini Mental State Examination; sMMSE), information processing (Trail Making Task A), and executive function (FAS Verbal Fluency Test) were assessed.Results98 eligible participants from the GaitDem study were included: 28 controls (Age (mean±SD):74±9 years, sMMSE:29±1), 35 AD (Age:77±6, sMMSE:23±4), and 35 LBD (Age:76±6, sMMSE:24±3). Both dementia disease subtypes demonstrated lower jerk RMS compared to controls (p<.05), while people with LBD also showed lower angular velocity, RMS and Jerk RMS (p<.05; Fig.1). For AD, turning impairments were associated with greater motor disease severity (Fig.2). For LBD, slower angular velocity was associated with greater motor disease severity, slower information processing and worse executive function (Fig.3).ConclusionsResults suggest that dementia disease subtypes have significant turning impairments compared to normal ageing, but not compared to each other. However, turning impairments were related to discrete motor‐cognitive profiles in dementia disease subtypes. Further work should explore other turning characteristics (i.e. related to turn phase, signal direction, turn strategy) as differential markers of dementia.
Amyloid‐associated hyperconnectivity drives tau spreading across connected brain regions in Alzheimer’s disease
Authors: Roemer Sebastian Niclas , Wagner Fabian , Evangelista Lisa , Rauchmann Boris‐Stephan , Dehsarvi Amir , Steward Anna , Dewenter Anna , Biel Davina , Zhu Zeyu , Pescoller Julia , Gross Mattes , Perneczky Robert , Malpetti Maura , Ewers Michael , Schöll Michael , Dichgans Martin , Höglinger Günter , Brendel Matthias , Jäkel Sarah , Franzmeier Nicolai 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease, Aß triggers tau spreading which drives neurodegeneration and cognitive decline. However, the mechanistic link between Aß and tau remains unclear, which hinders therapeutic efforts to attenuate Aß‐related tau accumulation. Preclinical research could show that tau spreads across connected neurons in an activity‐dependent manner, and Aß was shown to trigger neuronal hyperactivity and hyperconnectivity. Therefore, we hypothesized that Aß induces neuronal hyperactivity and hyperconnectivity, thereby promoting tau spreading from initial epicenters across connected brain regions.MethodsFrom ADNI, we included 140 Aß‐positive subjects across the AD spectrum plus 69 Aß‐negative controls, all with baseline amyloid‐PET, 3T resting‐state fMRI and longitudinal Flortaucipir tau‐PET data. For validation, we included cross‐sectional tau‐PET, amyloid‐PET and resting‐state fMRI data of 345 preclinical AD patients from A4. PET and fMRI data were parceled into 200 cortical ROIs, ROI‐wise longitudinal tau‐PET change rates were computed using linear mixed models. Resting‐state fMRI connectivity was computed across the 200 ROIs. Subject‐specific tau epicenters were defined as 5% of ROIs with highest baseline tau‐PET. Further, we included post‐mortem brain tissue from 5 AD patients vs. 4 controls stained for Aß and c‐Fos, i.e. a marker of ante‐mortem neuronal activity.ResultsIn the AD spectrum cohort, we confirmed that Aß induces hyperconnectivity of temporal lobe tau epicenters (Fig.1) to posterior brain regions that are highly vulnerable to tau accumulation in AD (Fig.2A‐C). This was fully replicated in the validation cohort of preclinical AD patients with low cortical tau‐PET, suggesting that the emergence of Aß‐related hyperconnectivity precedes neocortical tau spreading (Fig.2D). Supporting that Aß‐associated fMRI‐based hyperconnectivity may mirror neuronal hyperactivity, we found that neurons in AD post‐mortem tissue expressed higher levels of c‐Fos compared to controls, i.e. a Calcium‐sensitive marker of ante‐mortem neuronal activity (Fig.3). Lastly, using longitudinal tau‐PET, we confirmed that Aß‐related connectivity increases of the tau epicenters to posterior brain regions mediated the effect of Aß on tau accumulation and triggered faster tau spreading (Fig.4).ConclusionsOur translational results suggest that Aß promotes tau spreading via increasing neuronal activity and connectivity. Therefore, Aß‐associated neuronal hyperexcitability may be a promising target for attenuating tau spreading in AD.
Longitudinal changes in neuroimaging markers of small vessel disease: Implications for clinical trials
Authors: Lao Patrick J. , Edwards Natalie C. , Flores‐Aguilar Lisi , Rizvi Batool , Smith Anna C. , Tudorascu Dana , Rosas H. Diana , Yassa Michael A. , Handen Benjamin L , Christian Bradley T. , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M. 
Published: January 2025

AbstractBackgroundAdults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown.MethodAdults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 78; age = 50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.2±0.6 years apart) quantified as white matter hyperintensity volume (WMH), which represents ischemic small vessel disease. Participants underwent consensus diagnosis at both timepoints (59% Cognitively‐Stable at both timepoints, 9% Cognitively‐Stable to MCI‐DS, 8% MCI‐DS at both timepoints, 14% MCI‐DS to AD, 10% AD at both timepoints). The annual rate of change in frontal, temporal, parietal, and occipital WMH volume was assessed, adjusting for baseline WMH volume.ResultThe annual rate of change in frontal WMH was not significantly different by diagnosis. The annual rate of change in temporal (0.7 [0.4, 1.1], p<0.001) and in occipital WMH (1.6 [0.7, 2.5], p = 0.0008) was faster in the group that remained AD at both timepoints compared to the group that remained Cognitively‐Stable at both timepoints. The annual rate of change in parietal WMH was greater in the group that progressed from MCI‐DS to AD (0.6 [0.1, 1.0], p = 0.02) and in the group that remained AD at both timepoints (1.1 [0.6, 1.7], p = 0.0002) compared to the group that remained Cognitively‐Stable at both timepoints.ConclusionIn adults with DS, parietal WMH accumulates fastest in those that progress to or have a diagnosis of AD, while temporal and occipital WMH accumulate fastest in those with a diagnosis of AD. Posteriorly distributed WMH may have specificity for AD progression in adults with DS with implications for anti‐amyloid therapeutics that have cerebrovascular side effects.
Microglial activation impacts amyloid‐β effects on reactive astrogliosis
Authors: Ferrari‐Souza João Pedro , Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Lussier Firoza Z , Leffa Douglas Teixeira , Aguzzoli Cristiano Schaffer , Soares Carolina , Carello‐Collar Giovanna , Borelli Wyllians Vendramini , Therriault Joseph , Rahmouni Nesrine , Macedo Arthur C. , Servaes Stijn , Stevenson Jenna , Gauthier Serge , Souza Diogo O. , Schilling Lucas Porcello , Lourenco Mychael V , Tudorascu Dana , Rosa‐Neto Pedro , Pascoal Tharick A. , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundGlial reactivity is a key phenomenon in Alzheimer’s disease (AD) and is closely associated with amyloid‐ß (Aß) pathology. Although compelling experimental data suggest that microglial activation modulates reactive astrogliosis, it remains to be elucidated whether microglial activation influences the association of Aß pathology with reactive astrogliosis in the living AD human brain. Here, we tested the association of microglial activation and Aß pathology with reactive astrogliosis in individuals across the aging and AD clinical spectrum.MethodWe studied 101 participants (62 cognitively unimpaired [CU], 26 with mild cognitive impairment [MCI], and 13 with AD dementia) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aß ([18F]AZD4694) and microglial activation ([11C]PBR28), as well as magnetic resonance imaging. We further assessed reactive astrogliosis with plasma glial fibrillary acidic protein (GFAP). Linear regression analyses were used to investigate the associations between Aß, microglial activation and GFAP.ResultDemographic characteristics of the study population are reported in Table 1. Regression analyses revealed a significant positive association between Aß PET burden and plasma GFAP levels in microglial activation‐positive but not in microglial activation‐negative individuals (Fig. 1A). A significant interaction between continuous values of Aß PET burden and [11C]PBR28 PET uptake on plasma GFAP levels (Fig. 1B) supported that microglial activation affects the association of Aß pathology with reactive astrogliosis. Analysis of variance further confirmed that the model with the interaction term was the most adequate to describe the association of Aß PET and microglial activation PET with plasma GFAP (P = 0.007). In additional analyses investigating the topography of the observed findings, we found that higher Aß PET burden was associated with higher plasma GFAP levels only in the presence of microglial activation positivity across Aß‐vulnerable cortical brain regions (Fig. 1C).ConclusionOur results suggest that microglial activation impacts Aß‐dependent reactive astrogliosis in the living AD brain. This can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development of novel therapeutic strategies for AD targeting the interplay between Aß and glial reactivity.
Impact of regional MAPT, APOE, and Aβ on tau propagation in Alzheimer’s disease: Insights from a connectome‐based simulation model
Authors: Xiao Yu , Strandberg Olof , Bazinet Vincent , Shafiei Golia , Behjat Hamid , Spotorno Nicola , Smith Ruben , van Westen Danielle , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Stomrud Erik , Misic Bratislav , Dagher Alain , Hansson Oskar , Vogel Jacob W. 
Published: January 2025

AbstractBackgroundTau pathology, a hallmark of Alzheimer’s disease (AD), is thought to spread cell‐to‐cell via axonal connections, beginning focally before expanding throughout the brain. This study uses computational models to investigate the interplay between network spread and regional vulnerability in influencing tau spread, focusing specifically on MAPT and APOE genes, and Aβ plaques.Method66 regional (Desikan‐Killiany atlas) tau‐PET standardized uptake value ratio (SUVR) values were extracted from participants in the Swedish BioFINDER‐2 study: 429 cognitively normal (CN), 91 subjective cognitive decline (SCD), 168 mild cognitive impairment (MCI), and 182 AD. Values were adjusted for mean choroid plexus signal and converted to tau‐positive probabilities using two‐component Gaussian mixture models. The Susceptible‐Infectious‐Recovered (SIR) model (Fig. 1A) was employed to simulate tau spread through brain networks measured using structural connectivity from young individuals. We examined the roles of MAPT, APOE, and Aβ in tau propagation by parameterizing them regionally to influence tau synthesis, clearance, spreading, or misfolding. Regional MAPT and APOE were extracted from Allen Brain Atlas, and Aβ from Aβ‐PET. Performance of both baseline models (connectivity‐only) and models incorporating regional biological information were evaluated based on their ability to reconstruct observed regional tau levels. Performance was evaluated across the whole sample and groups based on diagnosis, APOE e4 carriage and Aβ positivity.ResultThe SIR model recapitulates observed tau patterns, suggesting connectivity‐based propagation in early‐stage regions (Fig. 1B, C). Allowing regional MAPT to moderate normal tau synthesis improved the model fit overall, and for all groups except CN or Aβ‐ participants (Fig. 2,3). Regional APOE or Aβ information did not enhance the model performance overall (Fig. 2B, C). However, allowing regional APOE to moderate tau clearance showed better performance in APOE e4 carriers vs. non‐carriers, and allowing regional Aβ to moderate tau spread improved performance compared to baseline model among Aβ+ individuals (Fig. 3).ConclusionOur results suggest that brain connectivity explains early temporal lobe tau spread patterns, while regional intrinsic (MAPT) and disease‐related (Aβ) susceptibility may influence spread of tau into other regions at later stages. Future work will test other hypotheses of tau spread by refining this model with additional biological information.