bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcranial electric field stimulation on iron deposition cures multiple pathologies of Aß, tau, microglial inflammation and improves cognitive impairment in Alzheimer’s mouse model
Authors: Kim Jong‐Ki 
Published: January 2025

AbstractBackgroundThe interplaying neuropathology of amyloid plaque, tau tangles, and microglia‐driven inflammation (tri‐pathology) are related to neuronal and synaptic loss damage in Alzheimer’s damages. Interventions that target Aβ or tau individually have not yielded substantial breakthroughs. Iron plays a pivotal role in tri‐pathology by protein‐bound iron‐oxide deposition in amyloid plaque, tau tangle, and microglia, resulting in redox‐active toxicity or microglial response induction, such as proinflammatory activation, autophagy dysfunction, and ferroptosis.MethodsUsing a single transcranial treatment, we stimulated the iron deposition in the tri‐pathologic iron inclusions. This treatment involved the use of a noncontact capacitive‐electrode alternating electric field (1 Mhz, < 1.5 V/cm) (TEFS) to induce the electro‐Fenton effect from the iron oxide surface of pathologic iron‐inclusion bodies in the brain of an Alzheimer’s disease (AD) mouse model (3xTg). We assessed the therapeutic effect of this phenomenon one month after treatment using histology, western blot analysis, and behavioral tests and compared the results with an untreated control.ResultsOur study revealed that TEFS‐mediated depletion of iron deposition and Aβ plaque prevented tau expression in early‐stage AD. In late‐stage AD, TEFS depleted Aβ plaque and tau tangle and downregulated ferroptosis and microglial‐driven neuroinflammation. Furthermore, TEFS improved impaired cognitive function, restored hippocampal neurogenesis, and altered microglial phenotype in both stages of AD brain.ConclusionOur results suggest that TEFS‐driven degradation of insoluble iron deposition cures multiple tri‐pathologies, promotes disease‐modifying properties, and offers a potential molecular‐targeting nonpharmacological treatment option for AD.
Effort‐based decision making and white matter tracts associated with dimensions of apathy in Alzheimer’s and Parkinson’s disease
Authors: Gazes Yunglin , Lee Seonjoo , Jin Zekai , Chen Bryan , Huey Edward D. , Heibronner Sarah , Heron Campbell Le , Vanegas Nora 
Published: January 2025

AbstractBackgroundApathy is marked by diminished motivation and goal‐directed behavior, prevalent in neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). Effort‐based decision‐making paradigms (EBDM), which require choices between tasks of varying effort levels for varying rewards, are effective assessments of goal‐directed behavior. Using a transdiagnostic approach, we are examining the neurodegeneration of networks on apathy and EBDM.MethodWe present preliminary results of a novel transdiagnostic study consisting of AD/amnestic Mild Cognitive Impairment (aMCI) and PD patients: 1) apathy is measured with Dimensional Apathy Scale (DAS), 2) an EBDM paradigm (Apple Gathering Task‐AGt) is used to estimate sensitivity to effort and reward, and microstructural integrity of relevant white matter tracts is estimated using fractional anisotropy [FA] from multi‐shell diffusion MRI. Probabilistic tractography in MRtrix toolbox was used to extract tracts connecting frontal‐subcortical regions. Using hierarchical Bayesian modeling and Drift Diffusion Model, we examined the associations among the apathy scale, behavioral performance, and brain health, covaried for age, MMSE, and UPDRS (PDs only).ResultTable 1 shows participant characteristics and group differences in study measures. Overall, AD/aMCI patients showed greater apathy and worse clinical scores for cognition (MMSE and MoCA) than PD patients. On AGt, AD/aMCI patients demonstrated longer latency and lower effort sensitivity. AD/aMCI patients showed lower baseline drift rate with higher scores for the behavioral‐cognitive dimension of DAS (95% credible interval [CrI]: ‐1.6 to ‐0.16, Figure 1). PDs showed less effort sensitivity with higher executive dimension of DAS (95% CrI: ‐2.8 to ‐0.23). In AD/aMCI, higher FA for the tract connecting right dorsal lateral prefrontal cortex to the striatum was associated with lower emotional apathy (95% CrI: ‐0.774, ‐0.048, Figure 2). In PDs, higher FA of Striatum‐Anterior Insula Cortex tract was associated with lower apathy in the executive dimension (95% CrI: ‐0.83, ‐0.161, Figure 2 upper left).ConclusionOur results demonstrate distinctions in apathetic symptoms and behavioral performance for AD/aMCI and PD patients, and also in the role of different fronto‐subcortical white matter tracts in dimensions of apathetic symptoms. Future analysis in a larger cohort will directly test the suggested mediation effects of regional white matter quality on apathy measures.
Mortality Trends in Alzheimer’s Disease in Mississippi, 2011‐2021
Authors: Jones Elizabeth A.K. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is the sixth most common cause of death in the United States (U.S.), with one in three adults 65 years of age and older dying of the disease each year. Deaths from Alzheimer’s have more than doubled between 2000 and 2019, killing more adults than both breast cancer and prostate cancer. In 2021, Alzheimer’s disease resulted in 36 deaths per 100,000 in the U.S. In Mississippi, deaths from Alzheimer’s have almost doubled between 2011 and 2021, resulting in 52.9 deaths per 100,000. Women have a higher mortality rate from Alzheimer’s than men. Alzheimer’s is a progressive disease that develops through seven stages. There are effective strategies to prevent the onset of Alzheimer’s.MethodThis paper reviews the risk factors, mortality trends, etiology, and prognosis of Alzheimer’s in Mississippi with a focus on prevention.ResultThe southern diet with foods high in sugar and sodium, along with sedentary and poor lifestyle choices, increases mortality risk from Alzheimer’s disease for women in Mississippi, specifically due to women over 65 having higher rates of obesity and hypertension.ConclusionUnderstanding the epidemiology and risk factors of Alzheimer’s in Mississippi will help inform communities, policies, and programs to prevent disease occurrence.
Structural and functional frontal‐executive dysfunction in patients with isolated REM sleep behaviour disorder
Authors: Mitolo Micaela , Baldelli Luca , Sighinolfi Giovanni , Sambati Luisa , Manners David Neil , Lodi Raffaele , Provini Federica , Tonon Caterina 
Published: January 2025

AbstractBackgroundIsolated REM Sleep Behavior Disorder (iRBD) is a well‐recognized prodromal state of an underlying α‐synucleinopathy, occurring several years before an overt neurodegenerative disorder becomes fully manifest. iRBD has been related to poorer cognitive performance and higher frequency of mild cognitive impairment (MCI). The aim of this study was to explore in detail, with structural and functional MRI, frontal‐executive dysfunction in iRBD patients and to evaluate its association with cognitive performance.MethodThirty‐two iRBD patients (24 males; age, mean±SD = 67.9±7.1 years) and thirty age‐matched healthy controls were recruited and underwent an extensive neuropsychological assessment and multiparametric MR acquisition. The MR protocol (3T) included T1‐w volumetric (isotropic 1mm3), diffusion weighted imaging (b = 2000 s/mm2, 64 directions) and resting‐state (TR = 0.735s, 10 minutes) acquisitions. Brain volumetry analysis was conducted using FreeSurfer. TBSS was applied to evaluate white matter microstructural alterations. Resting state networks were investigated with ICA. Correlations between MR parameters and neuropsychological variables were explored with Spearman’s test.ResultiRBD patients, when compared with healthy controls, showed worse performance on tests related to attentive‐executive, memory, and visuospatial functions (i.e., cancellation test p = 0.041, similarities p = 0.015, 15‐words recall p = 0.004, and simple drawing copy p = 0.007); they also showed volume reduction in left rostral anterior cingulate (p = 0.005). TBSS highlighted increased anterior corpus callosum and forceps minor Radial Diffusivity in iRBD patients (p <0.05). Significant correlations were found between this alteration and executive dysfunctions (i.e. Stroop test, r = 0.46, p = 0.009). Moreover, fMRI data showed ‘Executive control’ network alteration in iRBD patients within cortical (i.e. superior and middle frontal gyrus, opercular cortex, paracingulate and precentral gyrus) and subcortical structures (i.e. putamen and caudate); these data correlated with worse performance in executive‐attentive tests (i.e., cancellation time, r = ‐0.45, p = 0.018 and frontal assessment battery, r = 0.44, p = 0.023).ConclusionThis study showed that structural and functional frontal‐executive alterations in iRBD patients are associated with attentive‐executive functioning, findings that are similar to those observed in some synucleinopathies. Further studies with bigger samples and follow‐ups are needed to confirm these results, and to monitor the trajectory of these alterations longitudinally.Acknowledgement: This study was supported by the Italian Ministry of Health (#GR‐2019‐12369242).
Plasma proteome profile of Lewy body pathology‐positive individuals
Authors: Gomes Bárbara Fernandes , Benedet Andrea L. , Padovani Alessandro , Tolassi Chiara , Zanusso Gianluigi , Bongianni Matilde , Moda Fabio , Blennow Kaj , Zetterberg Henrik , Pilotto Andrea , Rosa‐Neto Pedro , Ashton Nicholas J. 
Published: January 2025

AbstractBackgroundLewy bodies (LB), the main hallmark of Parkinson’s disease (PD), are a frequent co‐pathology in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The varying extents of LB pathology in these disorders can influence disease progression and severity. Consequently, understanding LB impact on the proteomic profile of these diseases is crucial, potentially leading to identifyng novel blood biomarkers related to this pathology which are urgently needed. The aim of this project was to assess novel NULISAseq™ α‐synuclein (αSyn) biomarkers in blood. Considering the prevalence of monomeric αSyn in blood, we investigated whether other plasma proteins identified via NULISAseq™ or protein models could serve as surrogates for LB pathology determined by real‐time quake‐inducing conversion seed amplification assay (SAA).MethodThe proteomic profile of two independent cohorts was assessed using the NULISAseq™ CNS Disease Panel (Alamar Biosciences). A pilot cohort included amyloid‐β (Aβ)‐positive and SAA‐negative AD patients (n = 30) and Aβ‐negative SAA‐positive patients (DLB, n = 22; PD, n = 2). The TRIAD cohort included young (n = 32), cognitively unimpaired Aβ‐positive and Aβ‐negative (CU+, n = 111; CU‐, n = 26) individuals, Aβ‐positive and Aβ‐negative mild cognitive impairment (MCI+, n = 40; MCI‐, n = 39), as well as AD dementia (ADD, n = 38) and non‐AD (n = 27) patients. LB pathology was confirmed in both cohorts by the same SAA method.ResultIn the pilot cohort, no differences in plasma αSyn (SNCA, pSyn129, Oligo‐Syn) levels were observed. However, plasma phosphorylated tau‐217 (pTau‐217, logFoldChange (FC) = ‐1.00, p.adj<0.001), enolase‐2 (ENO2, logFC = ‐2.03, p.adj = 0.02), Fms Related Receptor Tyrosine Kinase 1 (FLT1, logFC = 0.54, p.adj = 0.04), and amyloid‐β42 (Aβ42, logFC = 1.09, p.adj = 0.04) were differentially expressed in SAA‐negative vs SAA‐positive patients. Furthermore, the ratio of pTau‐217/FLT1 exhibited the best separation between the SAA‐positive and SAA‐negative groups (AUC = 0.90, 95% CI 0.82‐0.98). The TRIAD cohort was used to validate these results, from which data is to be shown.ConclusionThe proteomic profile of LB‐positive is distinct from LB‐negative individuals, with four biomarkers differentially expressed in plasma. We also determined that a combination of these biomarkers may be useful to discriminate SAA‐positive from SAA‐negative individuals. Plasma αSyn levels did not reflect CSF SAA outcome, possibly due to peripheral αSyn expression not reflecting brain pathology.
Heart rate variability and cardiorespiratory fitness associated with biological brain aging in a healthy adult lifespan sample
Authors: Gazes Yunglin , Mackay‐Brandt Anna , Colcombe Stan 
Published: January 2025

AbstractBackgroundMeasures of cardiovascular health have long been associated with brain health. For example, aerobic capacity (VO2max) is associated with preservation of functional and structural brain integrity in later life. Recent work has highlighted the utility of relative brain age (RBA; the age‐corrected difference between a brain’s chronological and estimated biological ages) to examine the rate of biological brain aging. However, the impact of cardiovascular factors on RBA remains underexplored. Here, we examine estimates of biological brain aging (via RBA) in the context of two key measures of cardiovascular health: aerobic fitness (VO2max), and heart rate variability (HRV) ‐ a measure of autonomic regulation associated with cognitive control, emotional regulation, and risk of neurological conditions, including dementia.MethodData were obtained from ‘Mapping Interindividual Variation in the Aging Connectome’, an open‐science, community‐ascertained neuroimaging study with deep health and behavioral phenotyping. We examined a subset of 164 participants aged 38‐71 with imaging and heart rate data. HRV (std of beat‐to‐beat intervals) was computed from photoplethysmography collected during the neuroimaging procedure. RBA was derived from a machine learning method (Joint and Individual Variation Explained; JIVE) trained using structural features extracted from T1‐weighted MRI data. VO2max was estimated using a modified Balke submaximal testing procedure. RBA, HRV, and VO2max associations were examined using ordinary least squares, controlling for age and sex.ResultAs expected, higher VO2max was associated with younger RBA (Figure 1: t(77) = ‐2.11, p = 0.038) and lower mean HR (t(58) = ‐2.49, p = 0.015). Interestingly, higher HRV (Figure 2: t(161) = ‐1.98, p = 0.049) also predicted younger RBA.ConclusionOur findings were conceptually consistent with previous work demonstrating that higher VO2max is associated with greater brain integrity, extending these findings to biological brain aging (RBA). Interestingly, the HRV findings suggest that autonomic integrity may also play a role in slowing apparent brain aging. In combination, these findings suggest that HRV may provide a similar but more accessible window into the physiological factors that influence brain health than VO2max testing. Future work examining the association between autonomic integrity metrics and brain health longitudinally or during interventions may prove fruitful.
Hypertension‐Induced Accelerating Brain Oxygen Extraction Fraction Precedes Age‐Related White Matter Dysfunction in Asymptomatic Cognitive Decline
Authors: Yan Yifan , Zhao Xuhao , Zhang Yaping , Li Wanxin , Lin Zhiying , Zhou Yi , Fang Shenghao , Huang Jingkai , Song Peige , Lin Zixuan , Xu Xin 
Published: January 2025

AbstractBackgroundOxygen extraction fraction (OEF) reflects the equilibrium between brain oxygen delivery and consumption, potentially serving as an early Alzheimer’s disease (AD) biomarker. Previous investigations were mainly conducted in cognitive impairment and AD population. However, the potential neuropathway connecting cardiometabolic condition, OEF, and dementia‐related brain structural changes, especially in early cognitive decline, is unclear. This study investigated the associations of OEF with white matter dysfunction (WMD) among cognitively normal older adults and explored OEF’s mediating role between early cardiometabolic conditions and WMD.MethodEligible cognitively intact older participants (aged above 50 years without cognitive impairment on a comprehensive cognitive battery) were recruited from communities in China and completed the demographic, medical investigations and MRI scans. OEF was measured using T2‐relaxation‐under‐spin‐tagging (TRUST). WMD was assessed by two certified neuroradiologists from T2‐flair images to obtain a Fazekas score. Subjective cognitive decline (SCD) was assessed. Cardiometabolic conditions, including hypertension, diabetes mellitus, hyperlipidemia, stroke, and heart disease were assessed through medical history and/or lab measurements. General linear regression models and formal mediation analysis were performed. Sensitivity analysis was performed among participants without any cardiovascular diseases (stroke and/or heart disease).ResultAmong a total of 267 individuals (mean age 68.4±8.8 years, 183(68.5%)female, 118(44.2%) SCD), OEF ranged from 28.6% to 53.5% (IQR = 5.3). After adjustment for demographics (age, sex, education), lifestyle factors (smoke, BMI, and physical inactivity), medical history, and SCD status, increasing OEF was associated with worsen Fazekas scores (β = 0.02, 95%CI = (0.01,0.04)). Both hypertension (β = 1.90, 95%CI = (0.53,3.27)) and stroke (β = ‐2.54, 95%CI = (‐4.42,‐0.67)) were independently associated with OEF. Mediation analysis demonstrated that higher OEF mediated the effects of hypertension on Fazekas scores (mediation effect = 0.04, 95%CI = (0.01,0.09)). The mediation proportion was up to 13.0% (p = 0.02). Robust mediation effect was found among participants without any cardiovascular diseases.ConclusionAbnormal brain oxygen delivery is associated with WMD at the early stage of cognitive impairment. Our study elucidates the potentially casual influence of OEF on the pathway between hypertension and WMD. OEF could be utilizable as a fast and convenient measurement in predicting early brain structural disturbances implicated in cognitive impairment and dementia.
Structural MRI‐Based AD Score using Bayesian VAEs
Authors: Nemali Aditya , Moyano Jose Bernal , Yakupov Renat , Schütze Hartmut , Spottke Annika , Ramirez Alfredo , Schneider Anja , Metzger Coraline D. , Laske Christoph , Bittner Daniel , Heneka Michael T. , Peters Oliver , Speck Oliver , Glanz Wenzel , Wagner Michael , Jessen Frank , Düzel Emrah , Ziegler Gabriel 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD), a progressively worsening neurodegenerative disorder, impacts millions globally. Understanding its progression is crucial for developing effective interventions and management strategies. However, high variability in disease progression amongst individuals and the complexity of neuroimaging data pose significant challenges. Current diagnostic methods often fail to capture the nuanced progression, leading to delayed interventions, and lack uncertainty estimates, necessary for reliable decision‐making (Schaar et al., 2022). To address these issues, we here propose a Structural MRI‐Based AD Score (SMAS) using a Bayesian supervised Variational Autoencoder (Bayesian sVAE). The approach captures distinct morphometrical brain patterns associated to cognitive impairment across stages of AD. The score and model has potential to support personalized treatment plans and improve the efficacy of diagnostic tools.MethodWe used 415 and 200 longitudinal MRI scans from DELCODE (Jessen et al., 2018;) and ADNI (Salvatore et al., 2018), respectively. We focused on features computed from T1‐w images using CAT12 longitudinal pipeline (Gaser et al., 2022). The Bayesian sVAE model (Fig. 1) consists of an encoder network that learns to map brain features into a lower‐dimensional embedding space. Moreover, a predictive block predicts memory performance based on the latent mapping, and a decoder block that reconstructs the original input images from the latent space. We trained the sVAE on baseline DELCODE cohort with the expectation that the model will capture brain signatures characterizing aging and progression towards AD. We then assessed its generalization ability on follow‐up data and on ADNI.ResultThe Bayesian sVAE model, trained on sMRI features, shows potential for a parsimonous anatomy‐based characterization of individual disease progression. The model’s capacity to differentiate among various clinical groups using a single score (SMAS), and its correlations with key clinical and demographic variables, suggest its potential for identifying structural brain related to progression (Fig. 2). Using longitudinal test data, the model‐based latent scores indicated expected group differences and changes (Fig. 3).ConclusionThe Bayesian sVAE model has shown promise in continuously monitoring atrophy over stages of AD progression. We provide indications for generalizability to unseen data (ADNI), suggesting robustness across different imaging protocols and scanners, and considerable stability over repeated measures.
Implementation and validation of an electroencephalography dual‐task paradigm for detection of preclinical Alzheimer’s Disease
Authors: Rada Juliana Moreno , Saldarriaga Luisa María Zapata , Guevara Eduardo Montoya , Cuartas Santiago Gonzalez , Ramírez María José Hidalgo , Cano Paula Andrea Cataño , Alvarez Sara Garces , Flores Nicolás Vargas , Lopera Juan Esteban Pineda , Estrada Santiago Rivera , Mosquera Andrés Felipe Asprilla , Mancilla Juan Pablo Restrepo , Niño David Fernando Aguillón , Arroyave Juan Rafael Orozco , Quintero Carlos Andrés Tobón , Gómez John Fredy Ochoa 
Published: January 2025

AbstractBackgroundDementia has a worldwide prevalence of 55 million people, with 60 to 70% of cases attributed to Alzheimer’s Disease (AD). In Antioquia, Colombia, exists a group of families with early‐onset AD associated to PSEN1‐E280A, a genetic variant with an autosomal dominant inheritance pattern and a penetrance over 99%, which enables the study of individuals across different disease stages. Electroencephalography (EEG) is a non‐invasive, portable, and low‐cost technique that allows the study of electrophysiological changes associated with neurodegeneration. When used in conjunction with dual‐task paradigms, EEG could serve as a clinical marker for evaluating brain functional reserve according to three theoretical models: the ability to share cognitive resources between tasks, the cross‐talk dependent on the content of processed information, and the bottleneck model. Therefore, the combined use of EEG and dual‐task represents a potential novel and adaptable alternative in clinical settings for detecting preclinical stages of AD.MethodThe study population comprises cognitively healthy individuals who are carriers of the PSEN1‐E280A variant and control subjects without mobility limitations or impairments in verbal or written communication skills. The experimental protocol involves a motor task (single‐task) of elbow flexion‐extension and a motor‐cognitive task (dual‐task) that integrates the single‐task with six cognitive tasks. Data on upper extremity function (UEF) were collected using a tri‐axial wearable gyroscope and accelerometer sensor, while EEG recordings were obtained with the Open BCI CYTON BIOSENSING BOARD device, using the channels FP1, FP2, C3, C4, P7, P8, O1, O2.Result10 healthy non‐carrier individuals have been evaluated to describe the behavior of the metrics in control subjects. The UEF measured by angular velocity curves illustrates a lower amplitude and flat points during the dual‐task compared to the single‐task, indicating that cognitive activity impacted motor performance. The EEG recordings showed a higher power spectral density during dual‐task compared to single‐task.ConclusionThe obtained results represent the motor performance between single and dual‐task modalities, which possibly represent a change in the dynamics of brain functioning as observed in the EEG signals.