bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of Alzheimer’s and Neurodegeneration Blood Biomarkers with Prevalent and Incident Mobility and Cognitive Impairment
Authors: Windham B Gwen , Blackshear Chad T , Ali Farwa , Knopman David S. , Walker Keenan A. , Pike James Russell , Lu Yifei , Mosley Thomas H. , Palta Priya , Griswold Michael E. 
Published: January 2025

AbstractBackgroundOlder adults with dual cognitive and mobility impairments have higher financial costs and poorer quality of life than adults with either impairment alone. Blood biomarkers of Alzheimer Disease (AD) pathology (Aβ42, Aβ40 and p‐tau181) and neurodegeneration (neurofilament light (NFL) and glial fibrillary acidic protein (GFAP)) may identify individuals at risk for both mobility and cognitive impairment and provide novel insights into mechanistic underpinnings.MethodBlood biomarkers (SiMoA Quanterix N4PE, p‐tau181 single‐plex) were available in a subsample of 1751 ARIC study participants at Visit 5 (V5, 2011‐13, mean age 76.2 years (5.3), 41% men, 28% Black); Aβ42 was reversed and adjusted for Aβ40 (‐Aβ42|40) for consistent directions of associations (higher=worse). Usual gait speed and cognitive status were assessed over 8 years at V5, V6 (2016‐17), and V7 (2017‐18). Participants were categorized by V5 impairment: mobility‐only (gait speed <0.8m/s, n=430), cognitive‐only (expert‐adjudicated dementia, n=38), dual (n=54), or neither (referent, n=1229). Multinomial regression models examined relative risk ratios (RRR) of V5 log‐transformed biomarkers with prevalent impairments and, among those with neither impairment at V5, incident impairments through V7. All models adjusted for V5 age, sex, self‐reported race (Black or White), renal function, and body mass index.ResultHigher levels of all biomarkers were associated with greater risk of prevalent impairment in mobility, cognitive, or dual domains (Figure A). Over 8‐years of follow‐up, incident impairments included 471 participants with only mobility impairments, 39 with only cognitive impairments, 55 with dual impairments, and 168 died without developing any impairment. All biomarkers were associated with incident dual impairment per IQR higher biomarker: p‐tau181 (RRR=2.54; 95% CI: 1.45, 4.44), ‐Aβ42|40 (RRR=1.66; 1.31, 2.09), NfL (RRR=2.69; 1.22, 5.91) and GFAP (RRR=2.13; 1.07, 4.25). P‐tau181, ‐Aβ42|40, and GFAP were also associated with incident cognitive‐only impairment, while P‐tau181, NFL and GFAP were associated with incident mobility‐only impairment. (Figure B).ConclusionBlood biomarkers of brain health may be useful tools for earlier identification of those at risk for cognitive, mobility, or dual declines, facilitating earlier targeted interventions. Potential differences in AD‐pathology versus neurodegeneration blood biomarker relationships with outcomes of mobility and cognition may help to identify more targeted interventions for both.
Risk Factors For Insomnia Among Care Partners Recruited From An Outpatient Memory Care Clinic
Authors: Gallagher Virginia , Mattos Meghan K , Patterson Ashleigh , Thompson Ryan C , Reilly Shannon , Williams Ishan Canty , Shaffer Kelly M , Manning Carol A 
Published: January 2025

AbstractBackgroundPrior research on factors associated with sleep problems among care partners (CPs) of persons with cognitive decline (PwCD) are often limited by imprecise (i.e., single yes/no questions) measures of insomnia, burden, and CP mental health. This study aimed to: 1) determine the prevalence of insomnia disorder using DSM‐5 criteria among PwCD CPs in an outpatient memory care clinic, and 2) identify risk factors for CP insomnia symptoms using rigorous measures. We hypothesized that caregiver burden, depression, and role overload would be the strongest predictors of PwCD CP insomnia symptoms.MethodsIn this cross‐sectional survey study, PwCD CPs completed a demographic and caregiving questionnaire; a modified Insomnia Severity Index (ISI) that included assessment of frequency, duration, and impact of insomnia symptoms per DSM‐5 insomnia disorder criteria A‐D; Short Form Zarit Burden Interview; and the Hospital Anxiety and Depression Scale. Multiple linear regressions using forward elimination were used to determine the most robust predictive model of PwCD CP insomnia symptoms (ISI).ResultsAmong all CPs (n = 80), 10.00% met DSM‐5 insomnia criteria A‐D. Regarding ISI score classification, 26.00% CPs had clinically significant symptoms of insomnia (ISI≥10). The most robust risk factor model [R2 = .423, F(3,76) = 18.605, p<.001] for CP insomnia symptoms included CP anxiety (β = .374, p = .004), CP‐PwCD co‐dwelling status (β = ‐.229, p = .012), and burden (β = .255, p = .042), and did not include factors such as demographics and PwCD nighttime needs and behaviors. Among CPs who co‐dwelled with the PwCD (n = 65), the most robust risk factor model [R2 = .412, F(2,62) = 21.764, p<.001] for CP insomnia symptoms included CP burden (β = .392, p = .004) and CP anxiety (β = .309, p = .022), and did not include other factors.ConclusionsCP mental health symptoms and caregiving burden appear to be notable risk factors for PwCD CP insomnia symptoms, which has implications for intervention approaches for CPs.
The Effective Strategies Program for Dementia Care Partners (ESP‐C): A Pilot Study
Authors: Reilly Shannon , Gallagher Virginia , Thompson Ryan C , Williams Ishan Canty , Manning Carol A 
Published: January 2025

AbstractBackgroundFor care of persons with dementia (PWDs), the healthcare system relies on informal care partners (CPs), who are disproportionately at risk of detrimental health outcomes. Psychosocial interventions, including via telehealth, have been shown to buffer against negative outcomes and improve CPs’ ability to provide care. We aimed to develop and pilot an evidence‐informed CP intervention using in‐person and telehealth modalities. We hypothesized that the group’s psychoeducation and socioemotional support would result in increased CP self‐efficacy and decreased burden and depression. This study examined the protocol development and initial feasibility and acceptability of ESP‐C.MethodsESP‐C is an 8‐session supportive, psychoeducational group intervention for PWD CPs. Ninety‐minute sessions occurred weekly; see Table 1 for session topics. Groups (two in person, two via telehealth) were intended to comprise 7‐10 CPs each. Supervised care was provided for PWDs for the in‐person groups. For this pilot, we collected information about personal characteristics (Table 2), uptake, and satisfaction (e.g., “today’s session was beneficial,” “I learned something today,” “I recommend keeping this session for future groups”).ResultsTwenty‐four CPs participated across 4 groups; group sizes ranged from 5‐7. Preliminary results indicate feasibility and acceptability of this program. Both session attendance (93.26%) and session satisfaction (M = 4.51 on a 5‐point scale) were high. Uptake of supervised care for the PWD was low (range = 0 – 2 across all sessions). Qualitative lessons learned included the benefit of adding 2 sessions (total of 8 sessions) to allow for more introduction time and discussion of advance care planning; the importance of providing resources after sessions; and that the program is not appropriate for CPs of individuals with mild cognitive impairment. The program was easily adapted for telehealth.ConclusionsThis study shows initial feasibility and acceptability of ESP‐C to support PWD CPs. Importantly, the sample was relatively privileged (e.g., in terms of race, education level), underscoring the need to expand recruitment to reach underserved CPs. Next steps will include examining CP outcomes of this pilot study, as well as expanding access to the virtual ESP‐C to rural CPs without reliable internet/device access via a novel telehealth approach.
Hippocampus volume and plasma‐derived extracellular vesicle TDP‐43 levels as biomarkers for LATE‐NC
Authors: Grothe Michel J. , Silva‐Rodríguez Jesús , Ortega‐Cruz Diana , López‐González Francisco J. , Martinez‐Castillo Minerva , Oezdemir Selçuk , Rabano Alberto , Sanchez‐Juan Pascual , Schneider Anja 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is a common neuropathologic finding at advanced age that associates with hippocampal sclerosis (HS) and is often comorbid with AD pathology. Neuroimaging measurements of LATE‐NC‐associated limbic degeneration have been proposed as indirect biomarkers, but molecular‐specific biomarkers for LATE‐NC are still lacking. Here we used combined ante‐mortem blood and MRI data to study TDP‐43 levels in plasma‐derived small extracellular vesicles (sEV‐TDP‐43) and hippocampal volume (HV) in relation to LATE‐NC and HS at autopsy.MethodWe studied 56 autopsied dementia patients from the Reina Sofia Alzheimer Center (Madrid) who had ante‐mortem blood samples and quality‐controlled 3T‐MRI available. Plasma sEVs were isolated by size exclusion chromatography and TDP‐43 was quantified by SIMOA. HV was derived from structural MRI using Freesurfer. Neuropathological examination included assessment of AD neuropathologic change (ADNC), LATE‐NC, and presence of HS. Differences in plasma sEV‐TDP‐43 levels and HV between individuals with (+) and without (‐) LATE‐NC were assessed using t‐tests and ROC curve analysis. Additional analyses stratified cases by presence/absence of HS and limited the sample to those with high ADNC.ResultPlasma sEV‐TDP‐43 levels were significantly higher (p=0.02) and HV (p=0.03) was significantly lower in LATE‐NC(+)(n=35) vs LATE‐NC(‐)(n=21), although group separation in ROC analysis was relatively weak (AUCsEV‐TDP‐43 = 0.65; AUCHV = 0.68). Combining both biomarkers increased group separation to AUCsEV‐TDP‐43+HV = 0.76. HV was highly sensitive to HS status (p=0.001), whereas sEV‐TDP‐43 was not (p=0.45). As a consequence, sEV‐TDP‐43 also distinguished between LATE‐NC(‐) and LATE‐NC(+) without HS (p=0.02, AUC=0.72), whereas HV did not (p=0.17). When limited to cases with high ADNC, sEV‐TDP‐43 distinguished between those with and without comorbid LATE‐NC (p=0.03, AUC=0.64), but HV did not (p=0.37).ConclusionPlasma sEV‐TDP‐43 levels and hippocampal volume provide complementary information as biomarkers of LATE‐NC. While hippocampal volume is a sensitive biomarker of LATE‐NC‐associated neurodegeneration, plasma sEV‐TDP‐43 levels appear to be more directly linked to the pathology. The relatively low group separation could be partly due to the characteristics of the study sample focused on end‐of‐life dementia patients with late stage disease and multiple comorbidities.
The atrophy of specific amygdala subnuclei is associated with temporal tauopathy in preclinical AD individuals
Authors: Salman Yasmine , Gérard Thomas , Huyghe Lara , Colmant Lise , Quenon Lisa , Malotaux Vincent , Boyer Emilien , Ivanoiu Adrian , Lhommel Renaud , Dricot Laurence , Hanseeuw Bernard J 
Published: January 2025

AbstractBackgroundIn AD, tauopathy and atrophy start in the mesiotemporal lobe, including the amygdala‐hippocampal complex. Until recently, subnuclei and subfields within these structures were indistinguishable in‐vivo. FreeSurfer 7.0 now enables their segmentation. Our goal was to study hippocampal and amygdala subregions’ atrophy in preclinical AD to assess whether specific subregion atrophy could indicate early tauopathy at the preclinical stage.MethodsWe conducted an exploratory study in the ADNI3 cohort including 144 amyloid‐positive cognitively‐normal adults (Aβ+CN) with 3DT1‐MRI and [18F]AV‐1451 Tau‐PET data. We identified hippocampal and amygdala subregions explaining at least 1% of the variance of the Tau‐PET signal from the temporal meta‐ROI defined by Jack (2017). We validated these results with our in‐house data, including 112 individuals with 3DT1‐MRI and [18F]MK6240 Tau‐PET scans. Groups were categorized by visual Braak‐stage or bioclinical classification based on cognition (CN/MCI) and amyloid status (Aβ‐/Aβ+).ResultsIn ADNI3, amygdala and hippocampal volumes were not associated with temporal tauopathy in Aβ+CN (R²<0.001). However, four amygdala subnuclei (cortical, central, medial, and accessory‐basal nuclei) out of nine and the hippocampal tail (out of twelve subfields) each explained over 1% of the variance in temporal tauopathy in Aβ+CN (one‐tail p<0.10). These tau‐associated subnuclei were pooled into an amygdala aggregate whose volume was significantly associated with temporal tauopathy in Aβ+CN, even after adjusting for amygdala volume. In Aβ+MCI (n=132), global structure volumes were significantly associated with temporal tauopathy, with subnuclei atrophy adding no explanatory power (Figure 1).Within our in‐house data, individuals with early Tau‐PET signal (Braak I‐II) had similar global amygdala and hippocampal volumes than Braak 0 individuals. However, the tau‐associated amygdala aggregate generated in ADNI3 was significantly smaller in Braak I‐II individuals. Similarly, only the aggregate was significantly smaller in Aβ+CN compared to Aβ‐CN (Figure 2). These results remained significant after adjusting for global structures (Figure 3).ConclusionWe identified four amygdalae subnuclei whose atrophy is earlier than global amygdala. Atrophy in these subnuclei is associated with temporal tauopathy in preclinical AD, distinguishing visual Braak‐stage I‐II from Braak‐stage 0 individuals. Measuring amygdala subnuclei volumes in older adults is a promising approach to identify individuals at‐risk of progression to clinical AD.
Informing the design of embedded pragmatic trials of dementia care interventions: perspectives from a Lived Experience Panel
Authors: Romero‐Ramos Yaideliz M , Malone Carolyn , Moreno Monica , Brandt Katherine , Epstein‐Lubow Gary 
Published: January 2025

AbstractBackgroundThe National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer’s Disease and Alzheimer’s Related Dementia (AD/ADRD) Clinical Trials (IMPACT) Collaboratory, in partnership with the Alzheimer’s Association, convened a Lived Experience Panel (LEP), a group of 9‐12 individuals, including people living with cognitive symptoms, proxies representing people with an advanced cognitive disorder or who are deceased, and care partners of a person living with dementia. The aim was for the LEP members to share their experiences with research, inform the development of research priorities, and provide input on conducting embedded pragmatic clinical trials (ePCTs) of dementia care interventions. Given the importance of providing a space for people with lived experiences to share their thoughts and recommendations, we continue to report on the final stage of LEP in its original design.MethodThe recruitment and selection process, as well as the initial convening of the LEP have been reported in the Journal of the American Geriatrics Society. Since that publication, two additional panel series have concluded. In the recent series, the LEP addressed the intersections of dementia care interventions on the topics of health equity and goal‐concordant care. Summary reports of the LEP meetings are available on the IMPACT website. Currently the LEP is convening for a series to assess LEP members’ changes in perspectives about research as a result of participating in the LEP activities. In addition, the current series will gather their recommendations for improvement on the LEP as a model to improve ePCTs.ResultOne summary report was released, titled, “Voices of the Lived Experience Panel: Health Equity in Dementia Care and Research” and one summary report related to goal‐concordant care is in progress. Panelists identified the importance of recognizing diversity of diagnoses within AD/ADRD, as well as discussing opportunities and limitations of evaluating goal‐concordant care for people living with cognitive symptoms and their care partners.ConclusionIMPACT’s LEP provides a model for the collaborative engagement of people with lived experiences related to dementia. Results from the LEP reports should be widely shared with the dementia research community to promote further work of including people with lived experiences as research partners.
Pharmacological thiamine (Vitamin B1) as a treatment for alzheimer’s disease
Authors: Gibson Gary E. , Flowers Sarah A , Feldman Howard H. , Luchsinger Jose A , Zhang Sheng 
Published: January 2025

AbstractBackgroundAbnormal glucose metabolism in AD brains correlates with cognitive deficits. The glucose changes are consistent with brain thiamine (vitamin B1) deficiency. In animals, thiamine deficiency causes multiple AD‐like changes including memory loss, neuron loss, brain inflammation, enhanced phosphorylation of tau, exaggerated plaque formation and elevated advanced glycation end products (AGE). Increasing thiamine as much as 100 times with the thiamine prodrug benfotiamine diminishes all these changes.These results plus an outstanding safety profile stimulated a double‐blind placebo‐controlled pilot trial for 12 months with benfotiamine in mild AD patients (MMSE >20). Blood thiamine increased >100 fold compared to placebo. The decline in ADAS cog was diminished by 43% (p<0.125). Worsening of the CDR was 77% lower (p<0.034). Considerable data suggests that the thiamine dependent transketolase regulates AGE, which are elevated in AD. In the pilot trial, the benfotiamine reduced AGE (p<0.044).The following experiments sought to determine if other metabolites/lipids in serum can serve as biomarkers of the effects of benfotiamine.MethodSerum from a subset of patients on placebo and benfotiamine groups in the pilot trial was analyzed by LC‐MS/MS in parallel for comparative metabolome and lipidome.ResultA total of 315 unique metabolites and 417 lipids species were confidently identified and quantified. Differences to benfotiamine treatment were found in 25 metabolites, including thiamine, tyrosine, tryptophan, lysine, and 22 lipid species, especially phosphatidylcholines and triglycerides. Ten of 11 metabolites and 14 of 15 lipid species reported in previous literature to reflect AD progression changed in the opposite direction after benfotiamine treatment. Enrichment pathway analyses show that significantly altered metabolites are involved in glucose metabolism and biosynthesis of aromatic amino acids.ConclusionBenfotiamine reverses the changes of metabolites/lipids reflecting AD progression. Our ongoing NIH funded multicenter trial includes blood biomarkers of thiamine, amyloid, tau, inflammation, neurodegeneration, AGE, and extensive cognitive testing. A larger sample size is necessary to test whether metabolic biomarkers are useful for disease diagnosis, prognosis, and monitoring therapeutic efficacy.This research was partially funded by National Institute of Aging R01AG043679 (G.E.G), AG014930 (G.E.G, S.Z) and R01 AG076634 (GEG, HF, JAL)
Dementia in Brazil and the public health response
Authors: Ferri Cleusa P 
Published: January 2025

AbstractBackground(1) to present the main findings of two National Dementia Reports developed in partnership with the Brazilian Ministry of Health; (2) to summarize and discuss the proposed public health initiatives to respond to the challenges identified in the reports.MethodsDesk review, bibliometric study, cross sectional data and secondary analysis of existing data.ResultsThere is a lack of knowledge in Brazil in most parts of the country about the epidemiology as well as other important dementia‐related factors. The majority of research conducted so far has been undertaken in the Southeast, and mainly in Sao Paulo, the richest state.A Delphi consensus was conducted which indicated that there are about 2.5 million people living with dementia in the country, and the report estimated that 80% are not diagnosed. All those diagnosed and treated in the national health system have care needs that, for the most part, are not being met. The costs associated with treatment and care are high, with 73% of the total costs being informal costs, which are mainly borne by the family. Research into dementia has increased, but only at the same pace as health research in general. Moreover, most of the research is related to the diagnosis of the disease and its causes and mechanisms and little has been on epidemiology, care for people with dementia and support for caregivers.A few states and municipalities have approved, or are in the process of approving, legislation relating to policies, and a national bill has been approved in the Senate, and is in the process of being approved in the Chamber of Deputies. In addition, the Ministry of Health, together with other ministries, such as the Social Development and Education Ministries, has put forward an important initiative regarding long‐term care for chronic conditions.ConclusionAlthough there has been important progress, Brazil does not have yet a national dementia plan and a clear strategy that can increase diagnosis rates and improve care for individuals with dementia, and provide greater support for their carers, while taking into account the geographical, socioeconomic and cultural differences within the country.
Hyperphosphorylated Tau Targeting Human Serum Albumin Fusion Protein as Therapeutics for Alzheimer’s Disease
Authors: Bang Sookhee , Song Jeong Keun , Lee Kwan Hee 
Published: January 2025

AbstractBackgroundNeurofibrillary tangles (NFTs), along with amyloid beta plaque, are neuropathological aggregates of Alzheimer’s Disease (AD). Hyperphosphorylated tau is responsible for the NFTs formation and further neurodegeneration in AD. The hippocampal region and the entorhinal cortex (EC) have been a major focus of AD research because the deposits of hyperphosphorylated tau protein and NFT in these regions are correlated with memory deficits. The AD mouse model of human microtubule‐associated protein tau (MAPT) P301 mutations is a reflective model of tau phosphorylation, a key driver of NFTs seen in human AD. AL04 is a recently developed recombinant fusion protein which consists of Cystatin C, human serum albumin and the novel blood brain barrier (BBB) penetrating peptide. In our previous paper, AL04 was reported to reduce amyloid beta plaques in the Tg2576 mouse which is the amyloid beta AD model.MethodIn this study, we investigated the effect of AL04 on lowering hyperphosphorylated tau in JNPL3 mice carrying pathogenic human tau P301L mutation. We injected AL04 (5mg/kg) or PBS intraperitoneally to 3‐month‐old JNPL3 mice every other week for 24 weeks, respectively. We used confocal microscopy and western blot analysis to visualize the changes in hyperphosphorylated tau Ser202/Thr205 labeled with AT8 antibody in the hippocampus and EC.ResultWe found that the AL04 treatment decreases the hyperphosphorylated tau and NFTs in the hippocampus and EC. We observed the reduction of I2PP2A (inhibitor of Protein Phosphatase 2A, PP2A) and increased the expression levels of autophagy regulating proteins in the brain homogenates of AL04 treated mice.ConclusionOur data suggested that AL04 can be a prophylactic/therapeutic agent for AD because it can reduce the hyperphosphorylated tau and NFTs. In combination of our previous research, AL04 can be a dual action therapy to reduce both amyloid beta aggregate and NFTs.