bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ch4p volumes mediate the relationship between plasma p‐tau and spatial navigation
Authors: Chen Qian 
Published: January 2025

AbstractBackgroundTo investigate the relationships among plasma biomarkers, basal forebrain, and spatial navigation.MethodA total of 78 participants were enrolled, including 23 normal controls (NC), 38 subjective cognitive decline (SCD), and 17 mild cognitive impairment (MCI) patients. According to the spatial navigation distance errors in the human version of the Morris Water Maze, the whole cohort was divided into the good spatial navigation performance (gSN) group and the bad spatial navigation performance (bSN) group, with 39 cases in each group. The plasma biomarkers of p‐tau217, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), β‐amyloid (Aβ) 42/40, and p‐tau181 were measured by single molecule array (SimoA). Basal forebrain (BF) volumes were calculated, as well as the subfields of Ch4p, Ch4a‐i, Ch3, NSP, and Ch1/2. Correlation and mediation analyses were performed to assess the relationships among plasma biomarkers, basal forebrain, and spatial navigation.ResultThe gSN and bSN groups did not differ significantly in sex, age, and education years. Compared to the gSN group, the bSN group showed increased p‐tau217 and p‐tau181. The differences in NfL, GFAP, and Aβ42/40 levels were not significant. The bSN group showed significant volume reduction in the basal forebrain, especially the Ch4p subfield. The plasma p‐tau217 and p‐tau181 levels were positively correlated with navigation errors (r = 0.340, p = 0.003; r = 0.344, p = 0.003; respectively), while negatively correlated with basal forebrain (r = ‐0.250, p = 0.032; r = ‐0.254, p = 0.029; respectively) and Ch4p volumes (r = ‐0.415, p <0.001; r = ‐0.319, p = 0.006; respectively). Mediation analysis showed that the Ch4p volumes mediated the relationships between plasma p‐tau217/181 and navigation errors.ConclusionThese findings suggest that spatial navigation may serve as sensitive markers for the early identification of Alzheimer’s disease p‐tau pathology. The results may also indicate the relationships among “plasma p‐tau → basal forebrain atrophy → spatial navigation dysfunction”.
Recruitment for ADRD Clinical Trials Optimized through Academic and Community Partnership in Appalachia
Authors: Rhodus Elizabeth K. , Gross David , Fairchild Vickie , Henley Laura , Roberts Celeste , Jicha Gregory A , Kryscio Richard J , Gibson Allison 
Published: January 2025

AbstractIntroductionThe United States is undergoing a demographic shift with increasing proportions of older adults. Currently, one in three older adults pass away with a form of Alzheimer’s disease or related dementias (ADRD). This figure is higher in underrepresented and underserved groups including older adults in rural Appalachian communities. Programs that promote inclusion in clinical services and research are needed in rural, medically underserved regions. To establish and evaluate mechanisms for outreach and recruitment in clinical research for caregivers of persons with ADRD living in rural Kentucky counties.MethodsThe University of Kentucky (UK) Sanders‐Brown Center on Aging partnered with St. Claire Healthcare and the Northeast Kentucky Area Health Education Center to promote rural‐tailored clinical trial recruitment of caregivers of older adults with ADRD. Successful approaches and methods were tracked and documented.ResultsA model for rural recruitment and outreach for older adult engagement emerged. Over the course of seven months, 106 rural Kentucky caregivers of persons with ADRD were screened for clinical trial enrollment. This model identified successful outlets for recruitment dissemination through multiple strategies, including community agencies, healthcare providers, social media, emailing, word of mouth, and in‐person promotion of the study (health fairs, self‐initiated conversation at community events, etc.). Flexible engagement efforts were effective, such as calling at convenient times for participants and adapting to schedule changes (i.e., changes during and following historic flooding in recruitment regions).ConclusionsAcademic‐community partnerships extend the enterprise of university‐based clinical research to offer innovative programming directly in underserved and underrepresented rural communities. Recommendations from this program include 1) involving community representatives in recruitment and outreach efforts, 2) targeting communication with local organizations, and 3) including a variety in modes of contact with potential participants. This program illustrates a model that optimizes inclusion of underrepresented populations in clinical research and may have applicability to improve clinical care options in underserved areas.
Alzheimer’s and Related disorders Multicenter Archive (ARMA): a collaborative platform to advance ADRD diagnosis and treatment in Spain
Authors: Illán‐Gala Ignacio 
Published: January 2025

AbstractBackgroundAlzheimer’s and related disorders (ADRD) represent a range of neurodegenerative conditions characterized by abnormal protein deposits in the brain. Despite advances, there is a need for enhanced diagnostic and treatment approaches that acknowledge the diversity of ADRD. This project introduces the Alzheimer’s and Related Disorders Multicenter Archive (ARMA), a collaborative platform with an advanced Electronic Data Capture (EDC) system linked to Electronic Medical Records (EMR) designed to refine ADRD diagnosis and natural history understanding, thus informing precision medicine.Specific AimsARMA aims to: 1) prove the feasibility of implementing an EDC‐augmented ARMA within two memory units; 2) Establish the clinical utility of biofluid and imaging biomarkers with real world data from diverse ADRD clinical profiles; 3) Develop the ARMA Trial Platform (ARMA‐TP) for clinical trials, hypothesizing enhanced, recruitment and retentionfor of diverse ADRD populations.MethodologyThis four‐year project will recruit key personnel to integrate ARMA into clinical workflows, ensuring data integrity and GDPR compliance. The registry’s feasibility and the clinical utility of biomarkers will be evaluated, and disease progression will be tracked. Its advanced EDC system facilitates decentralized data collection, enhancing patient engagement and providing a scalable model for collaborative research. By its final year, ARMA‐TP will be launched to facilitate personalized treatment options in trials. Clinical‐biological profiles and recuittment data will be analyzed to describe biases in the recruitment process. Debiasing algorithms will be developed to ensure diverse recruitment and targeted recruitment campaigns will be designed to attract underrepresented ADRD profiles. We anticipate that the ARMA echosystem will reduce barriers to participation in both industry sponsored and industry‐independent trials, thereby improving the external validity of research findings.ImpactThe ARMA project is set to transform collaboration within the Alzheimer´s Disease Barcelona Hub, impacting clinical practice and research in Spain. The project will be instrumental in improving the recruitment of a diverse and representative populations in clinical trials.
Echinacoside improves the memory impairment of senescence accelerated mouse‐prone 8 (SAMP8) mice via inhibiting glial activation
Authors: Zhou Rong , Tian Ge , Yu Jing , Wang Rui , Guo Xingzhi , Li Rui 
Published: January 2025

AbstractBackgroundCognitive impairment, a common aging‐related pathology, is a risk factor for dementia. Echinacoside (ECH), derived from the traditional Chinese medicine Cistanche deserticola, shows anti‐aging properties including anti‐inflammation, oxidative stress reduction, and neuronal protection. Despite its benefits, the beneficial impact of ECH on age‐related cognitive decline remains unclear. Senescence accelerated mouse‐prone 8 (SAMP8) mice, known for rapid aging and related pathologies in the brain like glial activation, neuro‐inflammation, neuron loss, and cognitive decline, are ideal for this study. The purpose of this study is to investigate the effect of ECH effects on cognitive functions in SAMP8 mice.MethodsSix‐month‐old male SAMP8 mice (n = 8∼9) were used as the model group, while age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice were used as normal controls. After adaptation in the specific pathogen free (SPF) room for one week, we administered ECH intragastrically to the SAMP8 mice daily for two months, and the control group was administered with saline. Behavioral tests, including open field test and Morris water maze, were performed to assess the mood and memory function of the SAMP8 mice. After that, all mice were sacrificed by intraperitoneal perfusion to extract brain tissues for western blotting and immunofluorescence.ResultsECH‐treated SAMP8 mice showed significantly reduced escape latency in the Morris water maze compared to controls, indicating improved cognitive abilities (P<0.05). ECH also tended to lower beta‐amyloid and phosphorylated Tau levels in the hippocampus of SAMP8 mice, though not statistically significant due to small sample sizes (n = 3). SAMP8 mice had higher microglia and astroglia activation than SAMR1 mice, but ECH notably inhibited this in SAMP8 mice (Figure 1).ConclusionsOur study demonstrates that ECH intervention can markedly enhance the memory function in SAMP8 mice and inhibits microglial and astroglial activation. These findings suggest a beneficial role of ECH in alleviating cognitive decline in SAMP8 mice by reducing glia‐related inflammation.
Automated detection of cognitive symptom severity and mild cognitive impairment in Parkinson’s disease
Authors: Ferrante Franco Javier , Grisales Daniel Escobar , Lopez María Fernanda , da Cunha Pamela Lopes , Sterpin Lucas , Cuevas Pedro Chaná , Muñoz Edinson , Estienne Claudio , Hesse Eugenia , Amoruso Lucía , Arroyave Juan Rafael Orozco , Garcia Adolfo M. 
Published: January 2025

AbstractBackgroundBeyond dementia syndromes, cognitive symptoms are highly prevalent in Parkinson’s disease (PD), often manifesting as mild cognitive impairment (MCI). Yet, their detection and characterization remain suboptimal because standard approaches rely on subjective impressions derived from lengthy, univariate tests. Here we introduce a novel approach to detect cognitive symptom severity and identify MCI in PD using fully automated word property analyses on brief verbal fluency tasks.MethodsA total of 384 Spanish speakers with PD completed taxonomic, thematic, and phonemic fluency tasks, requiring them to name animals, supermarket items, and words starting with /p/, respectively. We automatically quantified six objective properties from each word: semantic variability (SV), granularity, length, frequency, phonological neighborhood, and concreteness. In Study 1, these properties were fed to a support vector regression with hyperparameter tuning to predict Mattis Dementia Rating Scale (MDRS) scores as indices of cognitive severity. Predicted MDRS scores were correlated with actual MDRS scores, adjusting for clinical factors (disease duration, motor symptom severity, medication dose). In Study 2, we used the same properties to compare (via a generalized linear model, adjusting for clinical variables) and classify (via ridge regression) between a carefully matched sample of 70 patients with and 75 patients without MCI. Feature importance analyses were conducted in both studies to identify which properties best captured patients’ cognitive profiles.ResultsIn Study 1, MDRS scores predicted by word properties were strongly correlated with actual MDRS scores (R = 0.53, p = .02). In Study 2, patients with MCI exhibited lower SV in taxonomic and thematic fluency, lower granularity and length in taxonomic fluency, higher phonological neighborhood in taxonomic fluency, and higher concreteness in phonemic fluency (p‐values < .05). Machine learning analysis of all properties showed robust subject‐level discrimination between patients with and without MCI (AUC = 0.79). Across both studies, machine learning results were mainly most consistently driven by SV and granularity, pointing to reduced semantic consistency and precision as key cognitive markers of PD.ConclusionsAutomated word property analysis from brief fluency tasks can predict cognitive symptom severity and distinguish cognitive phenotypes of PD, opening new avenues for scalable neuropsychological screenings.
Wake slow waves and aperiodic activity during resting‐state EEG correlate with amyloid burden and hypometabolism
Authors: Champetier Pierre , Albero Claudia , Pereira Filipa Raposo , Herzog Rubén , Chaumon Maximilien , Houot Marion , George Nathalie , Arnulf Isabelle , Oudiette Delphine , Andrillon Thomas ,   INSIGHT‐preAD group
Published: January 2025

AbstractBackgroundSpectral power of slow rhythms in resting‐state EEG increases along Alzheimer's disease (AD) continuum. Besides, recent studies have revealed 1) the importance of analyzing the aperiodic component of an EEG power spectrum and 2) the intrusions of sleep‐like slow waves identifiable in wake EEG of animals and young adults. Importantly, the occurrence of these wake slow waves is known i) to increase after sleep deprivation, ii) to be associated with markers of sleepiness, and iii) to predict behavioral errors at different tasks. Our objective was to investigate the links between AD biomarkers and 1) the aperiodic component of the EEG signal and 2) wake slow waves.Method314 elderly individuals with memory complaints from the INSIGHT‐preAD cohort (76.5 ± 3.5 years, range: 70‐85 years) were recruited. Participants underwent a 5‐year follow‐up, including 1) high‐density EEG recordings (256 electrodes) at rest (2 sessions of 2 min) each year, 2) neuropsychological assessments each year, and 3) Florbetapir and 18F‐FDG PET scans at baseline to quantify amyloid burden and hypometabolism. For each EEG recording, characteristics of aperiodic activity (intercept and slope) and wake slow waves (density, amplitude, slope, and frequency) were determined. For each neuroimaging modality, mean standardized uptake value ratios (SUVRs) were computed in AD relevant brain regions. Associations between AD biomarkers (amyloid and FDG SUVRs) and EEG metrics (characteristics of aperiodic activity and slow waves) were tested using linear regressions controlled for age, sex, and education level, after FDR correction. Longitudinal effects, including neuropsychological metrics, will be tested using linear mixed effect models.ResultAt baseline, high amyloid burden was positively associated with 1) the intercept and slope of aperiodic activity and 2) the density and frequency of slow waves. Besides, hypometabolism was associated with lower slow wave density.ConclusionThese preliminary results suggest that aperiodic activity and wake slow waves could serve as early EEG indicators of certain AD biomarkers. This seems particularly promising as these metrics are quantifiable on a simple resting EEG and at a very early stage, even before the onset of cognitive alterations. Longitudinal and neuropsychological data will be analyzed in the next few months.
Spatial Characterization of White Matter Hyperintensity Pathophysiology Across Disorders
Authors: Parent Olivier , Devenyi Gabriel A. , Bussy Aurelie , Pigeau Grace , Costantino Manuela , Fouquet Jérémie , Rodriguez Daniela Quesada , Dadar Mahsa , Chakravarty Mallar M. 
Published: January 2025

AbstractBackgroundWhite matter hyperintensities (WMHs) are age‐related radiological abnormalities indicative of small vessel disease. It is unclear if WMHs in different regions represent similar pathophysiology and etiology. Here, we developed a framework to estimate WMH pathophysiology in vivo, which allowed us to precisely characterize spatial patterns of WMH tissue alterations associated with four disorders.MethodWe used data from 32,014 UK Biobank (UKB) participants. WMHs and normal‐appearing white matter (NAWM) were automatically segmented. Diffusion‐ and susceptibility‐weighted images were used to derive fluid‐, fiber‐, myelin‐ and iron‐sensitive microstructural markers. We calculated voxel‐wise normative models of NAWM microstructure using Bayesian linear regression with age (4th order B‐spline) and sex predictors in a custom UKB template space derived using multi‐spectral registration of T1w and fractional anisotropy (FA) images (Figure 1A‐B). Within‐subject WMH pathophysiology was estimated as the difference between WMH microstructure and predicted NAWM microstructure (Figure 1C).ResultFirst, from between‐subject averages of WMH microstructural abnormality (Figure 2A), we used spectral clustering to derive spatial patterns of WMHs that share similar pathophysiological properties (Figure 2B). The first cluster (periventricular) has low abnormality. The second (posterior) and third (anterior) cluster both show fluid accumulation, fiber alterations, and myelin and iron loss, while the anterior cluster shows higher abnormality. Second, we assessed the differences between four disorders and age‐ and sex‐matched controls in terms of all WMH features with Cohen’s D. Ischemic heart diseases (n=2320) and hypertensive diseases (n=9852) demonstrated small but significant effects across measures, which were slightly higher in anterior regions. Stroke (n=320) demonstrated larger effects, which were more prominent in anterior regions. On the other hand, dementia (n=46) demonstrated smaller effects compared to stroke, reaching significance mostly in posterior regions despite the smaller sample size. Interestingly, the fractional anisotropy and orientation dispersion markers showed drastically inverted patterns of effects between stroke and dementia.ConclusionOur results separating anterior and posterior WMHs are consistent with accumulating evidence showing that posterior WMHs may be linked to Alzheimer’s pathology, whereas anterior WMHs may be associated with vascular pathologies. MRI pathophysiological markers may further help in distinguishing these etiologies.
The Dementia Care Partner Hub: A novel resource to support people living with dementia, care partners, and care teams
Authors: Gelmon Sherril B , Dawson Walter D , Reed Jenn Hollandsworth 
Published: January 2025

AbstractCare partners of people living with dementia (PLWD) need information and access to many services and programs to support their person and maintain their own wellbeing. We conducted focus groups (n = 5) and interviews (n = 24) with care partners of PLWD and interviews with leaders of organizations serving PLWD in the Portland, Oregon region in 2022‐2023. A comprehensive review of organizational websites and relevant literature identified several US‐based role model programs and existing resources. Data analysis revealed community assets and unmet needs, and articulated resource priorities to inform current and future programs/services.Dementia care partners need multiple supports for their caregiving: information about dementia; navigation and coordination; psychological support; recognition of care partner burden; leisure activities; day services; transportation; legal and financial services; home health; and fiscal support. While care partners were generally satisfied with their clinical care and research participation, feedback revealed deficits in accessing information and social supports which may not be within the scope of clinical sites.We propose the creation of a Dementia Care Partner Hub (the “Hub”) to augment existing services and supports for care partners of PLWD. The Hub would be the central node of a regional network of existing services. Details of structure, scope, partnerships, funding, implementation and evaluation will be described in the presentation. While the original design was for implementation in Oregon, the concept could be implemented in other jurisdictions.The Hub should serve all care partners in its service region, with a design that is responsive to the specific assets and needs of historically and currently underrepresented communities; this will ensure that the Hub supports care partners while attempting to ameliorate past inequities. It should augment and complement current clinical, research, and social programs by connecting care partners to programs and services. Community‐specific information for communities defined both by geography and by identity will ensure that the Hub equitably serves care partners with differing needs. Key elements to achieving this equity goal include language access, culturally appropriate information, and the ability for care partners to access the Hub from anywhere within the service region.
Structure‐activity relationship study of neuroprotective complex I inhibitor CP2
Authors: Petrova Olga , Trushin Sergey A , Nguyen Thi Kim Oanh , Ostroot Mark , Schellenberg Matthew , Johnson Graham , Trushina Eugenia , Sazanov Leonid 
Published: January 2025

AbstractBackgroundWe identified small molecule tricyclic pyrone compound CP2 as a mild mitochondrial complex I (MCI) inhibitor that induces neuroprotection in multiple mouse models of AD. One of the major concerns while targeting mitochondria is the production of reactive oxygen species (ROS). CP2 consists of two diastereoisomers, D1 and D2, with distinct activity and toxicity profiles. This study was designed to understand how structure of D1 and D2 affects their binding to MCI and the consequential impact on ROS production.MethodThe X‐ray crystallography and cryo‐electron microscopy (cryo‐EM) at global resolution of 3.25‐3.27Å were employed to identify the molecular structure of D1 and D2 and the D1 binding to the isolated ovine MCI. The assessment of the MCI inhibition and the extent of ROS generation were done in isolated MCI and human neuroblastoma MC65 cells using flow cytometry, a Seahorse extracellular flux analyzer, and the kinetic studies.ResultIn the closed conformation of MCI, D1 selectively binds to the deep Quinone‐site (Qd) but not to the shallow Q‐site (Qs), sharing the same binding pocket as rotenone. In the open MCI state, D1 exclusively binds to the Qs in contrast to rotenone, which binds Qd and Qs in both closed and open states. At the same concentrations, D1 inhibits respiration to a greater extent compared to D2 (5:1 ratio) and produces higher level of ROS.ConclusionCryo‐EM unambiguously identified binding of D1 to both the Qd and Qs sites, contingent upon the conformational state of MCI. In contrast to rotenone, D1 binds Qd only in the closed conformation during catalytic cycle, leading to mild inhibition. Superimposing X‐ray crystallography data of D1 and D2 onto cryo‐EM data suggests that the orientation of the methyl group in D2 induces a flatter conformation, resulting in lower binding affinity to MCI, which correlates with lower inhibition and toxicity compared to D1. At physiologically relevant concentrations, CP2 (D1:D2 = 1:1) demonstrates low MCI inhibition yielding negligible ROS levels. This observation provides new insight into the absence of toxicity associated with CP2 treatment in vivo, further highlighting feasibility for the development of safe and efficacious MCI inhibitors.