bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivariate analysis of white matter crossing fibers reveals correlations with aMCI and dementia diagnoses
Authors: Bender Andrew R. , Weissman Caleb , Scheel Norman , Jung Youjin , Damoiseaux Jessica S. , Peltier Scott J , Hampstead Benjamin M. 
Published: January 2025

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) permits characterizing differences in white matter microstructure associated with amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD). However, most dMRI measures aggregate signals across multiple axonal fiber populations with varying spatial orientations, which limits the sensitivity and specificity of clinical diagnosis. To overcome this shortcoming, we estimated fiber density (FD) measures, independently from crossing fiber populations, and extracellular cerebral spinal fluid (CSF). We hypothesized that aMCI and AD diagnoses are associated with differential patterns of FD changes in larger and smaller diameter fiber populations.MethodWe evaluated cross‐sectional dMRI data from 179 clinically characterized participants enrolled in the University of Michigan Memory and Aging Project. Image processing leveraged the MRtrix3 multi‐shell multi‐tissue fixel‐based analysis framework to estimate FD, separately for three fiber orientations, and CSF. Data analysis used multi‐block partial least squares correlation (PLS‐C) to estimate factors from multidirectional FD and CSF images correlated with differences between cognitively unimpaired (CU; n=98) and those diagnosed with aMCI (n=52) or AD (n=29).ResultThe PLS‐C model yielded three significant latent variables (LVs; Figure 1), reflecting patterns of both significant positive and negative associations between diagnosis and FD in crossing fibers. LV1 explained 80% of the differences from CU to aMCI to AD, demonstrating a stepwise reduction of FD and increased CSF with greater disease severity. However, LV2 and LV3 showed FD differences in smaller crossing fibers, distinguishing clinical diagnoses. Intriguingly, participants in the aMCI and AD groups showed different regions with increased or decreased FD in smaller crossing fibers, relative to CU participants. Pairwise PLS‐C models showed aMCI and AD diagnoses were associated with similar patterns of FD changes in smaller crossing fibers in overlapping regions.ConclusionThe present study found distinctive patterns of white matter alterations that systematically differ across diagnostic severity in MCI and Alzheimer’s dementia. These results highlight the value of decomposing signals from crossing fibers as a sensitive neuroimaging correlate to clinical diagnosis. These findings challenge the common perspective that MCI and Alzheimer’s dementia are associated with monotonic declines in white matter integrity.
Visual‐Somatosensory Integration: A novel behavioral marker of preclinical Alzheimer’s disease?
Authors: Mahoney Jeannette R , Ayers Emmeline , Verghese Joe 
Published: January 2025

AbstractBackgroundGrowing evidence suggests that Alzheimer’s pathology manifests in sensory association areas well before appearing in neural regions involved in higher‐order cognitive functions, such as memory. The ability to successfully integrate sensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual‐somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging.Method243 older adults (77 ± 6.5yrs; 52% female) with and without cognitive impairments that provided blood (plasma) specimens for amyloid‐beta (Aβ) testing were included in this cross‐sectional observational study. Participants completed a multisensory simple reaction time test in response to visual, somatosensory, and combined visual‐somatosensory stimulation. Magnitude of VSI was computed and served as the independent variable, while Aβ probability scores served as the dependent variable.ResultLinear regression revealed a significant association between magnitude of VSI and Aβ probability scores, even after controlling for several key covariates (β = ‐.17; p <.01). Results indicate an inverse association of Aβ probability with magnitude of VSI, where increased Aβ probability scores were associated with worse multisensory integration performance.ConclusionThese findings provide support for VSI as a potential novel non‐cognitive, non‐invasive biomarker of preclinical Alzheimer’s disease.
Community Psychiatry Clinic’s Impact on Dementia Care: Insight from Rythm Community Mental Healthcare Program
Authors: Vaseel M , Uvais Nalakath A. 
Published: January 2025

AbstractBackgroundDementia, a major concern in India (1‐10% prevalence), is challenging, particularly in rural areas with a significant treatment gap. Community psychiatry offers a promising solution, aiming to provide essential dementia care in underserved rural India, reflecting innovative approaches to extend mental health services equitably.MethodsThis study, employing a descriptive approach, examines the impact of Rythm community psychiatry clinics, an initiative by IQRAA International Hospital and Research Centre, on dementia care. The analysis focuses on key community activities, volunteer roles, provided services, and the engagement of Community‐Based Organizations (CBOs).ResultsSince August 2022, among the 8 Rythm community clinics with a total of 298 psychiatry patients, 4 clinics specifically address dementia cases. In these 4 clinics, 29 dementia cases were identified in the community, ranging in age from 68 to 95 years, with an average age of 77.5 years. Of the 29 cases, 25 were females, and 4 were males, resulting in a male‐to‐female ratio of 1:6. A post‐retirement group in Kodencherry, a CBO, alone identified 17 out of the total 29 cases, constituting 58% of the total. Nearly 90% of patients are under homecare follow‐up due to mobility restrictions, while the rest utilize clinic‐based consultations. Two rural community clinics also serve tribal patients with dementia. Dementia causes vary, including Alzheimer’s, vascular dementia, and Parkinson’s disease. Targeted case‐finding approaches effectively identify dementia cases early in the community through trained community volunteers, leading to referrals to community clinics and home‐based consultations. Caregiver education, behavioral management, symptomatic relief, psychological services, and specialist referrals contribute to comprehensive community‐level dementia care. Medications such as Donepezil, Memantine, Quetiapine, and Melatonin are employed based on symptom profiles, with Quetiapine being a commonly used antipsychotic. The results indicate a reduction in caregiver burden, fewer hospital admissions, increased access to primary and behavioral care, early case detection, referrals, and improved community awareness, subsequently reducing stigma surrounding dementia.ConclusionCommunity psychiatry clinics significantly impact dementia care by offering targeted case identification, caregiver education, and comprehensive services, ultimately contributing to improved community‐level dementia care and awareness.
Inhibition of Lyn kinase: A novel approach to treatment of Alzheimer’s disease
Authors: Benitah Avi L , Richardson Timothy I. , Weerawarna Pathum M , Robo Michael T , Mason Emily R 
Published: January 2025

AbstractBackgroundThe TREAT‐AD centers aim to improve Alzheimer’s Disease (AD) research by offering free, high‐quality tools and technologies.Lyn is a tyrosine kinase that belongs to the Src family kinases. The expression of Lyn and its activity have been implicated in AD. This class of proteins is involved in TREM2 mediated microglial activation and phagocytosis, a process which is beneficial for clearing neurotoxins such as Aβ oligomers in the brain. Lyn inhibition may activate microglia. Given the relationship between accumulation of Aβ and its exacerbation of neurodegenerative diseases such as AD, selective inhibition of Lyn has been proposed as a novel therapeutic approach to treating early‐onset AD. However, potent, selective, and brain penetrant Lyn inhibitors are unavailable to test this hypothesis.MethodWe screened a variety of known kinase inhibitors to determine their activity towards inhibition of Lyn using the biochemical HotSpot kinase assay. With this data in hand, we identified imatinib as a starting point for the design of novel Lyn inhibitors. Structure‐based design and computational docking models were used to propose more active and selective Lyn inhibitors, which were synthesized. The activities were determined, and multiple parameter optimization (MPO) informed iterative Structure Activity Relationship (SAR) studies. The best compounds were evaluated in assays of microglia activation, and their drug metabolism and pharmacokinetic (DMPK) properties were determined.ResultA series of novel type II inhibitors are now available for testing. The results demonstrate a unique tail group provides the novel scaffold with potent activity and selectivity towards inhibition of Lyn, exceeding that of imatinib.ConclusionComputational models, SAR, and MPO provided potent and selective Lyn inhibitors with good DMPK properties. Further studies are under way to determine the impact of these compounds on TREM2 mediated activation of microglia both in vitro and in vivo.Author List:Avi Benitah PhD,Pathum M Weerawarna PhD,Michael Robo, PhD,Shaoyou Chu, PhDEmily R Mason, PhDTimothy I Richardson, PhD
Impact of Study Partner Type on Participant Retention Across Global Regions in the Tauriel and Lauriet Trials for Alzheimer’s Disease
Authors: Ritchie Marina , Datta Seema , Monteiro Cecilia , Toth Balazs , Teng Edmond 
Published: January 2025

AbstractBackgroundParticipant retention is a key determinant for a successful clinical trial. In Alzheimer’s disease (AD) trials, participants are typically required to enroll with a study partner, which adds barriers to retention. Previous analyses of North American trial data found that most study partners were spouses and that such dyads had higher study completion rates than other study partner types. We sought to determine whether these findings could be confirmed in additional trials conducted across broader geographic regions.MethodOur post‐hoc analyses used data from two phase II trials of semorinemab, Tauriel (prodromal‐to‐mild AD; NCT03289143) and Lauriet (mild‐to‐moderate AD; NCT03828747), we examined the proportion of participants completing the trials by study partner type (Domestic Partner vs. Other) and geographical region (North America and Europe). We fit logistic regression models to assess whether participant retention differed by study partner type in the two trials (separately and combined) and adjusted the models for region, study partner type, participant age, sex, education, APOE4 status, and study partner sex. We considered potential effect modification by region by including an interaction term between study partner type and region. We conducted sensitivity analyses excluding participants who discontinued based on adverse events or death.ResultWe observed effect modification by region in the association between study partner type and retention (Tauriel: p = 0.011, Lauriet: p = 0.015; combined: p = 0.003). In Europe, Other study partner types had significantly lower odds of trial completion compared to domestic partners in Tauriel (OR: 0.21; CI: 0.06, 0.74) and in the combined analysis (OR: 0.28; CI: 0.11, 0.65). While not statistically significant, we observed similar trends in Lauriet (OR: 0.36; CI: 0.10, 1.22). No clear differences in retention were observed across study partner types in North America for either trial.ConclusionData from the two semorinemab trials suggest that there may be regional differences in the impact of study partner type on retention. Further studies are needed to assess the generalizability of these findings, with an emphasis on cohorts with more representative samples of non‐spousal dyads.
IUSM‐Purdue TREAT‐AD Center Capabilities and Strategy to Enable and Advance Novel Therapeutic Targets for the Treatment of Alzheimer’s Disease
Authors: Mowery Stephanie A. , Huang Kun , Mesecar Andrew D. , Dage Jeffrey L. , Clayton Brent , Lamb Bruce T. , Palkowitz Alan D. , Richardson Timothy I. 
Published: January 2025

AbstractBackgroundThe TaRget Enablement to Accelerate Therapy Development of Alzheimer’s Disease (TREAT‐AD) Centers are dedicated to identifying and validating targets from the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD). The centers develop Target Enabling Packages (TEPs) to explore new therapeutic target hypotheses, moving beyond the traditional focus on amyloid or tau pathologies. In accordance with open science principles, data, methods, and tools are freely shared with the research community via an open‐access platform, the AD Knowledge Portal. The Indiana University School of Medicine and Purdue University TREAT‐AD (IUSM Purdue TREAT‐AD) Center comprises four technical cores: Bioinformatics and Computational Biology (BCB), Structural Biology and Biophysics Core (SBB), Assay Development and High Throughput Screening (ADHTS), and Medicinal Chemistry and Chemical Biology (MCCB). These cores collaborate to develop research tools that are used to validate biological targets and assess their druggability with an initial focus on understanding the role of neuroinflammation in AD.MethodThe BCB Core supports target selection and validation with data and analysis. The SBB Core provides proteins for assay development, biophysical assays, and structural studies to aid in mode of action and Structure Activity Relationship (SAR) studies. The ADHTS Core develops in vitro and in vivo assays for SAR studies and translational PD biomarker strategies to assist in determining early phase clinical dosing regimens. The MCCB Core selects therapeutic modalities (small molecules, antibodies, siRNA) and discovers pharmacological tools, employing strategies for SAR studies to balance pharmacological and drug‐like properties.ResultTarget Enabling Packages (TEPs) are now available via the AD Knowledge Portal for microglia targets that were prioritized for early drug discovery studies. TEPs include bioinformatics analysis, biological reagents and protocols, protein production methods, and recommended chemical probes with detailed information (Figure 1). Novel small molecule hits and leads were identified for SHIP1, PLCG2, SHP1 and LYN/HCK.ConclusionA pipeline of prioritized microglia targets were selected and enabled for early drug discovery. The IUSM Purdue TREAT‐AD Center is now working with AMP‐AD researchers to explore biological hypothesis in addition to the role of neuroinflammation in AD.
The role of Community Health Workers in supporting caregivers of Hispanic/Latino older adults with dementia and the need for workforce expansion
Authors: Turner Wesli H , Patrick Shannon , Aguilar Saúl Juárez , Pinzon Maria C Mora 
Published: January 2025

AbstractCommunity Health Workers (CHWs), also known as Promotores de Salud expand health equity to underserved and hard‐to‐reach communities by providing increased access to healthcare and support services for caregivers and persons living with dementia (PLWD). CHWs have been particularly useful in supporting Hispanic/Latino communities, who are 1.5 times more likely to develop Alzheimer’s Disease and related dementias than non‐Hispanic whites and are less likely to access support services due to language and cultural barriers. CHWs offer support in culturally appropriate ways, linking families to much needed services and assistance acting as a crucial support system for many who lack the knowledge of where to access services or face cultural or linguistic barriers to accessing those services. When CHWs are integrated into care teams, they can reduce the burden on other health professionals by focusing on addressing the social determinants of health, allowing health professionals to focus on their area of expertise with patients. CHWs can increase awareness of the disease, promote activities that reduce the risk factors for ADRD, provide navigation services, and facilitate caregiver support groups.This presentation will highlight the value of CHWs in providing culturally and linguistically appropriate dementia caregiver support within Hispanic/Latino communities. Presenters will discuss outcomes from a CHW‐led caregiver support program that showed a 22% increase in knowledge of ADRD (p <0.001), 56% increase in caregiver preparedness skills (p <0.001) and showed a 33% reduction in depression symptoms among participants (p <0.001). To date, 82 caregivers have been served through this program, supporting the development of the CHW workforce in assisting caregivers and PLWD.Presenters will also detail a novel HRSA‐funded CHW training program that creates a workforce pipeline from the community to the healthcare system providing paid training through a federal grant. From March 2023 to January 2024, 105 CHWs have been trained across 17 counties in Florida, of which 58% identify as Hispanic/Latino. By demonstrating the possibilities of a workforce pipeline, this presentation will provide the “How” and “What” of bridging the growing labor gap in supportive services for Hispanic/Latino persons living with dementia and their caregivers using CHWs.
CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly
Authors: Shue Francis , White Launia J , Hendrix Rachel , Ulrich Jason D , Henson Rachel L. , Knight William C. , Martens Yuka A , Wang Ni , Roy Bhaskar , Starling Skylar C , Ren Yingxue , Xiong Chengjie , Asmann Yan W. , Syrjanen Jeremy A. , Vassilaki Maria , Mielke Michelle M. , Cruchaga Carlos , Holtzman David M. , Bu Guojun , Petersen Ronald C. , Heckman Michael G. , Kanekiyo Takahisa 
Published: January 2025

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aβ42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aβ42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aβ42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.
Elevated plasma neurofilament light and glial fibrillary acidic protein are associated with impaired cerebrovascular reactivity in older adults
Authors: Kapoor Arunima , Dutt Shubir , Nguyen Amy , Gaubert Aimée , Alitin John Paul M , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Engstrom Allison C , Shao Xingfeng , Martini Alessandra Cadete , Head Elizabeth , Wang Danny JJ , Nation Daniel A. 
Published: January 2025

AbstractBackgroundPlasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are markers of axonal and astroglial injury, respectively. Both markers have been proposed as predictive biomarkers of cerebral small vessel disease, with elevated levels indicating higher burden of white matter hyperintensities, lacunar infarcts and cerebral microbleeds. However, to date, no study has examined whether NfL and GFAP levels are associated with dynamic markers of small vessel damage such as cerebrovascular reactivity (CVR)—the ability of cerebral blood vessels to regulate cerebral blood flow (CBF) in response to vasodilatory or vasoconstrictive stimuli. In this study, we examined whether levels of NfL and GFAP are associated with CVR to hypercapnia and hypocapnia.MethodIndependently living older adults (N = 78; mean age = 69.5 years; SD = 8.1; age range 55‐89 years; 35.9% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma levels of NfL, and GFAP were determined using a digital immunoassay. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction) and hypercapnia (15s breath holds, vasodilation).ResultA significant negative association was observed between circulating levels of NfL and global CVR to hypocapnia (r = ‐.26, p = .027) and hypercapnia (r = ‐.23, p = 0.049) as well as GFAP and CVR to hypercapnia (‐.26, p = .025).ConclusionThis study demonstrates that elevated levels of NfL and GFAP are associated with diminished CVR to hypercapnia and levels of NfL are associated with impaired CVR to hypocapnia. These findings are consistent with prior studies suggesting that plasma NfL and GFAP may serve as biomarkers of cerebral small vessel disease. Given that these markers signify axonal and astroglial injury, these findings also provide insight into the pathophysiological processes underlying cerebrovascular dysfunction, which may contribute to the development of neurodegenerative conditions.