bluuebunny/crossref_metadata_2025 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

Background

Older 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.

Method

Blood 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.

Result

Higher 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).

Conclusion

Blood 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

Background

Prior 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.

Methods

In 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).

Results

Among 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.

Conclusions

CP 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

Background

For 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.

Methods

ESP‐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”).

Results

Twenty‐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.

Conclusions

This 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

Background

Limbic‐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.

Method

We 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.

Result

Plasma 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).

Conclusion

Plasma 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

Background

In 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.

Methods

We 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+).

Results

In 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).

Conclusion

We 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

Background

The 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.

Method

The 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.

Result

One 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.

Conclusion

IMPACT’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

Background

Abnormal 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.

Method

Serum 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.

Result

A 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.

Conclusion

Benfotiamine 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

Background

(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.

Methods

Desk review, bibliometric study, cross sectional data and secondary analysis of existing data.

Results

There 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.

Conclusion

Although 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

Background

Neurofibrillary 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.

Method

In 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.

Result

We 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.

Conclusion

Our 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.
Novel approach to optimization of Alzheimer’s vaccine configuration for maximal targeting of toxic amyloid‐beta oligomers
Authors: Kaplan Johanne , Gibbs Ebrima , Napper Scott , Scruten Erin , Coutts Juliane , Cashman Neil R
Published: January 2025

Background

A large body of evidence now indicates that the most pathogenic species of Aß in Alzheimer’s disease (AD) consist of soluble toxic oligomers (AßO) as opposed to insoluble fibrils and monomers. Using our computational platform, we identified 4 different AßO‐restricted conformational B cell epitopes (300, 301, 303, 305) that were tested as vaccines for their ability to induce an antibody response that selectively targets toxic AßO, without inducing potentially detrimental B or T cell responses against plaque or normal Aß. A novel ex vivo approach was then used to select an optimal vaccine configuration amongst the 15 possible combinations of the 4 epitopes to provide maximal binding to a toxic oligomer‐enriched low molecular weight (LMW) fraction of soluble AD brain extracts.

Method

Mice were vaccinated with four different AßO‐restricted conformational B cell epitopes conjugated to KLH to provide T cell help and formulated with QS‐21 adjuvant. Serum IgG titers against the peptide epitopes were measured by ELISA and T helper cell responses by ELISPOT. The reactivity of serum antibodies with AßO versus monomers was evaluated by SPR, and plaque binding by immunohistochemistry.

Result

All 4 epitopes elicited robust antibody responses when administered either individually or together as part of a quadrivalent vaccine. ELISPOT analysis showed a T cell response to KLH and not the AßO B cell epitopes. Serum antibodies elicited by the monovalent and quadrivalent vaccines all showed the desired selectivity and reacted with AßO only, not monomers nor plaque. Comparison of the SPR binding responses to the toxic AßO‐enriched LMW fraction of AD brain extract by equivalent amounts of IgG from immune serum of monovalent vaccines vs mixtures of 2, 3 or 4 sera was used to rank vaccine configurations. Interestingly, maximal reactivity was observed with immune IgG against the monovalent vaccine containing epitope 301, the target of PMN310, our clinical‐stage monoclonal antibody. There was no advantage of additional epitopes beyond 301 alone.

Conclusion

Vaccination with AßO‐restricted conformational B cell epitopes conjugated to KLH produced strong antibody responses with no measurable pro‐inflammatory T cell responses against Aß. Immunization with epitope 301 alone was sufficient to produce maximal reactivity against brain AßO.
Implementation of the meaningful activity for managing behavioral symptoms of distress (MAC‐4‐BSD) intervention in assisted living
Authors: Scherr Susan
Published: January 2025

Background

Most assisted living (AL) settings organize and provide opportunities for residents to participate in activities (e.g., exercise, music, arts and craft, cognitive activities, religious services, community outings). Despite the known benefits of activity participation, it is widely reported that there is a lack of activities that are considered meaningful for residents and thus many residents spend much of their time during the day disengaged. Further, there are numerous challenges to engaging assisted living (AL) residents with dementia in meaningful activity at the resident and community level. Resident challenges include acute medical events, advanced age, comorbidities, physical and cognitive abilities, lack of motivation, cultural expectations, pain, and behavioral symptoms of distress (BSD). Community level challenges include environments and policies that limit opportunities for meaningful activities and limited resources.

Method

To overcome these challenges and optimize engagement in meaningful activity for residents with dementia, the Meaningful Activity for Managing Behavioral Symptoms of Distress (MAC‐4‐BSD) intervention was developed. MAC‐4‐BSD is theoretically based using the Social Ecological Model and Social Cognitive Theory and includes four components: 1. Assessment of the environment and policies; 2. Education of staff; 3. Assessment of resident preferences and goals for meaningful activity; 4. Mentoring and motivating staff and residents. The overall aim of MAC‐4‐BSD is to reduce BSD, increase engagement in meaningful activity, and improve quality of life for residents by modifying the environment and empowering staff to facilitate and engage residents with dementia in AL settings. The MAC‐4‐BSD intervention is implemented by a Research Facilitator working with a facility champion and monthly meetings take place with a facility stakeholder team to provide updates on successful strategies and brainstorm challenges encountered.

Results

To date, a total of 5 AL settings and 71 residents with dementia have participated in the study. Based on content analysis of field notes we will describe stakeholder goals established, barriers to implementation, and facilitators to meet goals in the participating settings.

Conclusions

Key findings include the influence of administrative or leadership support, level of engagement among direct care staff, interdisciplinary collaboration, and access to resources and supplies in the environment to facilitate meaningful activity for residents with dementia.
Cross‐sectional evaluation of early childhood experiences and AD biomarkers in older adults
Authors: Streitz Marissa L , Bui Quoc , Xiong Chengjie , Moulder Krista L. , Morris John C.
Published: January 2025

Background

Calculating an individual’s risk for preclinical and symptomatic Alzheimer disease (AD) involves considering their experiences across the lifespan. This includes assessment of childhood experiences as risk factors for dementing disorders in later life.

Method

The Knight Alzheimer Disease Research Center (ADRC) examined the relationship of well‐established AD biomarkers with childhood experiences as reported by research participants. ANCOVA was used to model biomarker outcomes as a function of childhood events, adjusting for covariates such as age, education, cognitive status, presence of APOE e4, race, sex, and fasting status (for plasma only). Amyloid‐β (Aβ) and tau biomarkers (Aβ42, Aβ40, p‐tau181, p‐tau217) were measured in the cerebrospinal fluid (CSF) and plasma, cerebral amyloid and tau uptakes with positron emission tomography (PET) scans, and MRI scans assessed hippocampal and cortical volumes.

Result

There were 656 participants; 314 were female (56%) and 80 (14%) self‐identified as Black. The mean age was 75.2 ± 8.9 years, and 90% of the participants were cognitively unimpaired (CDR® 0). Those who reported attending a segregated school during childhood demonstrated lower hippocampal volume (p = 0.0005) and cortical thickness (p = 0.0028), as well as higher plasma tau181 (p = 0.037). Participants who attended a private school had lower levels of tauopathy as measured by tau PET compared to those who attended public school (p = 0.036). Frequently experiencing food insecurity throughout early life was related to higher levels of CSF p‐tau181 (p< 0.0001), total tau (p<0.0001), and PET tauopathy (p = 0.03) as well as lower levels of CSF Aβ42/Aβ40 (p = 0.002). Higher levels of CSF total tau (p = 0.0003) and p‐tau181 (p = 0.0015) were found for those who experienced an intensely frightening event as a child. Participants who reported frequent physical punishments showed a trend toward lower hippocampal volumes (p = 0.077). Lower levels of CSF p‐tau181 (p = 0.037) and plasma tau217 (p = 0.029) were found among those who frequently felt special, loved, supported, protected, and close to their families during adolescence. All findings remained significant after adjustment for covariates except for the biomarkers for segregated school attendance.

Conclusion

Early life experiences, both positive and negative, may be associated with the development and presence of AD biomarkers in later life.
Evaluation of the therapeutic potential of nucerin, an oral TGR5 agonist HY209, in a murine model of alzheimer’s disease
Authors: Kim Siwon , Islam Jahirul , Kim Juyong , Koh Youngjae , Hwang Jungjoong , Kim Hyoung Tae , Seong Seung‐Yong
Published: January 2025

Background

Previously, we demonstrated therapeutic benefits following intraperitoneal delivery of the TGR5 agonist HY209 in 5xFAD, a transgenic mouse model of Alzheimer’s Disease (AD). Given the desirability of a more acceptable administration route for prolonged AD treatment, we assessed the efficacy of HY209 via oral delivery. This study aims to elucidate the therapeutic potential of NuCerin, an oral formulation of HY209, in the aforementioned AD model, while simultaneously identifying potential blood biomarkers indicative of NuCerin’s therapeutic action.

Method

In both non‐Tg and 5xFAD mouse models, NuCerin (or its vehicle control) was orally administered for a duration of 12 weeks (30 mg/kg, b.i.d.). Subsequent cognitive assessment was undertaken using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Amyloid plaque deposition in the cortical regions was measured after Thioflavin‐S staining. NeuN immunostaining was conducted to quantify mature neuronal population. LC‐MS/MS was employed on serum samples to identify potential protein biomarkers indicative of NuCerin’s efficacy.

Result

The MWM and NOR tests indicated that oral delivery of NuCerin ameliorated cognitive impairment observed in 5xFAD murine models. Furthermore, a marked reduction in amyloid plaque deposition was observed in the NuCerin‐treated 5xFAD group. There was also an attenuation in the decline of NeuN‐positive neuronal populations in the NuCerin‐treated 5xFAD group as compared to the vehicle‐treated counterparts. Proteomic assessment highlighted an elevation in biomarker H levels in 5xFAD mice relative to non‐Tg mice; this increase, however, was mitigated in the NuCerin‐treated 5xFAD group.

Conclusion

Our findings indicate that oral delivery of NuCerin attenuates the progression of Alzheimer’s disease, positioning NuCerin as a potential oral therapeutic for AD. Concurrently, we identified biomarker H as a potential biomarker to gauge NuCerin’s efficacy
Specialized infrastructure in a tertiary hospital to administer disease modifying treatments in Alzheimer’s disease
Authors: Nathan Talya , Ash Elissa , Shir Dror , Trabulus Noa , Bar‐David Aya , Wolpe Galia , Shiner Tamara , Bregman Noa
Published: January 2025

Introduction

Lecanemab (LEQEMBI®), a humanized monoclonal antibody targeting Amyloid‐beta (Aβ) protofibrils, received full FDA approval in July 2023 for treating early‐stage Alzheimer’s disease (AD). This abstract highlights Tel Aviv Medical Center’s (TLVMC) specialized infrastructure for early AD diagnosis and treatment and includes presenting baseline characteristics of initial patients opting for LEQEMBI®.

Methods

Outlining our clinics' operational experience in establishing the Center for advanced treatments for AD, treatment protocol, and a descriptive analysis of baseline assessment data including demographics, baseline Magnetic‐Resonance‐Imaging (MRI), Cerebrospinal‐fluid (CSF)/PET biomarkers, pre‐treatment cognitive evaluations (Mini‐Mental‐State‐Examination (MMSE)/Montreal‐Cognitive‐Assessment (MoCA)), and Apolipoprotein‐E (APOE) status.

Results

Rigorous screening and specialist approval were prerequisites for candidate selection, adhering with published appropriate use recommendations. All patients, diagnosed with Mild‐Cognitive‐Impairment (MCI)/mild dementia due to AD confirmed by biomarkers, underwent APOE testing.

Lecanemab Administration commenced in Israel in November 2023, with 31 patients (F = 15, mean age = 72) initiating treatment by year‐end. 22 underwent neurological evaluation within a year of symptom onset. Mean MMSE = 24 (n = 27, SD = 3) mean MoCA = 23 (n = 4, SD = 2). CSF testing (27 patients), showed mean levels (pg/ml) of total‐Tau = 585 (SD = 251), phosphorylated‐Tau = 121 (SD = 38) and Aβ = 261 (SD = 172). APOE Ɛ4 polymorphism was present in 55%, with 18% showing 1‐2 micro‐hemorrhages on baseline MRI, compared to 8% of non‐carriers.

Conclusion

The evolving landscape of AD treatments necessitates complex screening and comprehensive clinical‐radiological follow‐up. Establishing specialized medical infrastructures is crucial to enable the wide and safe administration of new treatments, reflecting the ongoing paradigm shift in AD management.
Investigating remote assessments and interventions for multilingual people living with dementia and their caregivers
Authors: Taiebine Mohamed , Keegan Louise
Published: January 2025

Background

Given the widespread of tele‐assessment and tele‐rehabilitation in speech language pathology and clinical neuropsychology for monolingual English‐speaking patients with acquired neurogenic language and cognitive disorders, there is an urgent need to implement a culturally and linguistically tailored telepractice for multilingual people living with dementia (MPLWD), for whom there is no consensus on a standard model. This study aims to investigate the delivery model of remote assessment and intervention for this population.

Method

A systematic scoping review was conducted in December 2023 following frameworks described by Arksey and O’Malley (2007). A literature search was conducted for articles published in English that addressed telepractice services MPLWD in the field of speech language pathology and clinical neuropsychology. Factors that contributed to the successful delivery of telepractice sessions were described in terms of technological medium, modality of intervention (assessment vs rehabilitation), as well as target population (patients, caregivers or both).

Result

A total of 53 articles were identified through search engines and 12 duplicates were excluded. After title and abstract screening, another 32 studies were removed. Finally, a total of 9 full‐text studies were selected. This review has demonstrated a need for setting up tele‐rehabilitation for the benefit of MPLWDs. Despite the paucity of studies addressing multilingual considerations and needs of patients with dementia and their caregivers, the focus on caregivers was reported in 7 studies using different remote services (web‐based intervention, mobile, draw‐care), while 2 studies reflected on gender and health disparities stemming from Latino, Korean, American and Australian contexts. MPLWDs may experience a mild or severe loss of one or more of their acquired languages as a result of the neurodegenerative trajectory of their disease. They may also present cognitive, communicative, and socio‐professional impairments impeding their daily life functioning.

Conclusion

The scarcity of studies reflects a need for future research of MPLWD. More inclusive model of telepractice is the leitmotiv for cross‐linguistic studies in ethnically diverse population with dementia. The underrepresentation of multilingual telepractice should be taken into consideration and technological advances should be made accessible to diverse MPLWDs in different cultures and languages through equity and digital inclusion.
Semi‐passive monitoring of game play detects learning curves distinctive to subjective cognitive decline (SCD) and mild cognitive impairment (MCI)/mild‐stage dementia
Authors: Wu Chao‐Yi , Galler Jake A , Schwab Nadine A , Rashid Barnaly , Young Cathrine , Yang Liuqing , Gerber Jessica A. , Dodge Hiroko H , Arnold Steven E.
Published: January 2025

Background

The ability to monitor cognitive trajectories over the course of trials can provide valuable insights into treatment efficacy. However, existing trial methods are limited in monitoring cognition in real‐time and at high frequencies. Gameplay‐based assessments hold promise as complementary cognitive tools. In this study, we investigated the learning curves of gameplay features linked to cognitive impairment.

Method

MIND GamePack is an iOS‐based system that includes a set of four games: Memory Match (Card matching), Word Scramble (Boggle), FreeCell (Solitaire), and Block Drop (Tetris). Sixty participants included 26 older adults with intact cognition, 11 with subjective cognitive decline (SCD) and 23 with mild cognitive impairment (MCI)/mild‐stage dementia. Participants were asked to play each game for at least five minutes/day and five days/week for four months. Latent trajectory models were used to detect learning curves distinctive to persons with SCD and MCI/mild‐stage dementia as compared with normal.

Result

For Memory Match, the latent trajectory model identified two learning curves for card matching accuracy. Participants with MCI/mild‐stage dementia were more likely to belong to a group where their accuracy exhibited a slight improvement but remained consistently below‐average throughout the monitoring period (odds ratio [OR] = 3.17, p<.001). Two learning curves were identified for the self‐chosen game level. Participants with MCI/mild‐stage dementia were more likely to belong to the flat curve group that chose the same game level throughout the monitoring period (OR = 1.98, p = .01). For Word Scramble, two learning curves were identified for word discovery rate and word repetition rate, respectively. Participants with MCI/mild‐stage dementia were more likely to belong to the group that demonstrated a decrease in the word discovery rate and an increase in word repetition rate throughout the monitoring period (OR = 2.91, p = .001; OR = 3.17, p<.001). For FreeCell, two learning curves were identified for the percentage of incorrect moves. Those with SCD and MCI/mild‐stage dementia were more likely to belong to the group that showed a higher percentage of incorrect moves at the beginning but gradually decreased throughout the monitoring period (OR = 2.01‐2.62, p = 0.03‐0.003).

Conclusion

Learning curves of game features associated with memory and language can distinguish cognitive severities. Changes in gameplay learning patterns could serve as additional evidence of potential treatment effects.
An automated method for quantifying syntactic complexity of spontaneous speech in Primary Progressive Aphasia
Authors: Agmon Galit , Cho Sunghye , Ash Sharon , Cousins Katheryn A Q , Pradhan Sameer , Kim Yoon Duk , Liberman Mark Y , Irwin David J , Nevler Naomi
Published: January 2025

Background

Reduced syntactic complexity is the predominant linguistic impairment unique to the nonfluent agrammatic variant of PPA (naPPA).

Reliable, objective and automatic methods for assessing syntactic complexity are currently lacking. Here, we introduce an automatic method for quantifying syntactic complexity in speech. We show that this method differentiates naPPA from other subtypes and monitors disease progression and severity.

Method

We analyzed speech samples of picture descriptions that were collected from PPA patients and healthy controls (HC) at the University of Pennsylvania during 2000‐2021, including a subset of patients with longitudinal data. Ten syntactic features were automatically extracted from the speech samples and combined into a composite score, using principal component analysis, to represent syntactic complexity. Regression models compared syntactic complexity between PPA phenotypes, covarying for age, sex, education and MMSE. Linear mixed‐effects models tested change in syntactic complexity over time. The correlation of syntactic complexity with neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) was tested in naPPA and svPPA patients.

Result

We examined a total of 136 participants: HC (n=36, 31% males, age 69±8y, MMSE 29±1), naPPA (n=31, 51% males, age 71±8y, MMSE 24±5), lvPPA (n=32, 50% males, age 68±9y, MMSE 22±6) and svPPA (n=37, 49% males, age 64±7y, MMSE 22±7). Z‐scored syntactic complexity scores showed significant group differences, with naPPA scoring lower than HC (β=1.08, p=.004), lvPPA (β=1.19, p=.001) and svPPA (β=.93, p=.008) [Fig‐1]. Sensitivity to disease progression and severity was found only within the naPPA group. The syntactic score of naPPA significantly decreased over time (‐.5 per year, p=.005), significantly different from the 0 decrease in lvPPA (p=.001) or the .1 decrease in svPPA (p=.001) [Fig‐2]. naPPA patients had a significant inverse correlation of syntactic complexity score and CSF NfL levels (r=‐.58, p=.03), while svPPA patients did not (r=.39, p=.9) [Fig‐3].

Conclusion

We introduce a novel measure of syntactic complexity which can be extracted automatically from brief naturalistic speech samples. We validated this measure by relating it to naPPA and its biological underpinning. We provided objective evaluation of syntax, which has great potential as a non‐invasive biomarker in the dementia research and clinic.
Prevalence of Subjective Cognitive Decline by Social Determinants of Health and Health‐Related Social Needs — 15 States, 2022
Authors: Eugene DaJuandra Y
Published: January 2025

Background

Dementia is a critical public health issue with known health disparities. Social determinants of health (SDOH) and health‐related social needs (HRSN) may influence differences across various health outcomes, including cognitive functioning. We describe the association between subjective cognitive decline (SCD), an early indicator of possible future dementia, and select adverse SDOH‐HRSN.

Method

We used 2022 data (n = 80,943) from 15 states that administered both the Cognitive Decline and Social Determinants and Health Equity modules in the Behavioral Risk Factor Surveillance System. Prevalence of SCD was estimated among adults aged ≥45 years by 6 adverse SDOH measures (i.e., loss of employment, food stamp use, food insecurity, housing insecurity, inconsistent home utility, lack of transportation) and 3 HRSN measures (i.e., lack of social emotional support, social isolation, stress). Pairwise t‐tests were used to identify significant differences (P <.05).

Result

Overall, prevalence of SCD was 11.1% (95% CI: 10.4‐11.8), and SCD was significantly higher among adults reporting each adverse SDOH‐HRSN (e.g., housing insecurity = 27.4%; 95% CI: 23.6‐31.1 vs no housing insecurity = 9.5%; 95% CI: 8.8‐10.1). For adverse SDOH, prevalence of SCD ranged from 19.3% (95% CI: 15.6‐23.1) among those with loss of employment to 32.6% (95% CI: 27.5‐37.8) among those with lack of transportation. For HRSN, prevalence of SCD ranged from 20.3% (95% CI: 18.2‐22.4) among those with lack of social or emotional support to 33.2% (95% CI: 29.7‐36.7) among those with stress.

Conclusion

In 2022, differences in the prevalence of SCD were identified between adults with and without each adverse SDOH‐HRSN examined. Addressing these key drivers of inequities (e.g., transportation), which may lead to barriers in accessing care and services, is essential to help reduce potential disparities in dementia and to support early detection and cognitive health.
Intersections of sex and racialization on ATV(N) biomarkers
Authors: Shaaban C. Elizabeth , Reese Alexandria C. , Royse Sarah K. , Snitz Beth E. , Karikari Thomas K , Hengenius James , Huppert Theodore , Roush Rebecca E. , Cisneros Geraldine , Potopenko Katey , Becker James T , Cohen Annie
Published: January 2025

Background

Differences in Alzheimer’s disease (AD) amyloid, tau, vascular, and neurodegeneration (ATV(N)) biomarkers by sex and racialized group have been reported, but little is known about the intersections of sex and racialization on these biomarkers.

Methods

Participants in this cross‐sectional analysis are from the Connectomics of Brain Aging study, a Human Connectome Project protocol evaluating brain structure and function in aging and AD. We measured A using global amyloid SUVR from 11C‐PiB PET, T using plasma p‐tau 217, V using lobar unhealthy white matter connectivity (UWMC), a novel measure indicating the proportion of WM connections impacted by white matter hyperintensities (WMH), and N using cortical thickness from an AD‐based meta‐region of interest. We tested for intersectional effects of sex and racialized group on ATV(N) biomarkers in robust regressions by testing models with and without sex*racialized group interaction terms.

Results

The sample included N=202 participants with the following characteristics: age, 62 years; female sex, 67%; Black racialization, 50%; education, 14 years; APOE4+, 31%; cognitively impaired, 27%; Table 1. In robust regression models we found that women had significantly more amyloid and frontal UWMC, and less tau and parietal and occipital UWMC than men; participants racialized as Black had significantly more temporal lobe UWMC and significantly less occipital lobe UWMC, amyloid, tau, and cortical thickness than participants racialized as white (Table 2). Intersectional effects were found only for parietal lobe UWMC (p for interaction=0.03; Table 2), such that men racialized as Black had the greatest parietal UWMC, while men and women racialized as white did not vary in their parietal UWMC (Figure 1). Results with lobar WMH instead of UWMC were similar.

Conclusion

Our results confirm ATV(N) biomarker differences by sex and racialized group. They suggest that men racialized as Black may be uniquely at risk for UWMC in the parietal lobe but found no intersectional effects on other biomarkers. Future work will investigate specific WM tracts involved in the parietal UWMC and associated risk factors such as structural and social determinants of health as well as cardiovascular risk factors and comorbidities.