bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel small molecule agonist improves behavior deficits and synaptic plasticity in a model of Alzheimer’s disease
Authors: Amin Raj , Steinke Ian , Wibowo Fajar , Yoo Sieun , Suppiramaniam Vishnu , Singh Meenakshi , Arnold Robert Rusty
Published: January 2025

Background

The increased incidence of Alzheimer’s disease (AD) rate represent an unmet medical need and thus critical for the development of novel molecular therapeutics. Recent work focusing on patients with apoE4 alleles has highlighted the association of brain cholesterol dysregulation with elevated pathological burden and neurodegeneration. These studies have highlighted the importance of the nuclear receptor Liver X receptor (LXR) for developing AD therapies. Unfortunately many current LXR agonists have failed at the clinical levels due to hepatotoxicity and neutropenia in humans. Our newest LXR agonist, AU403, was developed in silico as a novel Liver X Receptor‐β (LXRβ) with partial PPARδ/α activity. Thus our design serves as a dual LXRβ/ PPARα agonist. This strategy seeks to avoid the unwanted side effects of traditional LXRα agonists. Lastly our studies in 3xTgAD mice have observed an increase in gene and protein expression of ABCB1, the lipid efflux protein.

Method

Our library of compounds and lead compound AU403 was designed computationally using Schrodinger software and molecular dynamics to model enzymatic activity using crystal structures of LXR beta and alpha. Further AU403, drug design was optimized by modeling ADME properties using both QikProp and GastroPlus to enhance distribution to the CNS. 11 month aged 3xTgAD mice were given orally 10mg/Kg/day for 1 month. Animal behavior for working declarative memory was observed, using Y‐maze and Novel object recognition studies Electrophysiological studies (LTP) and analysis of pathological markers (Amyloid beta and pTau) were measured.

Result

Our in silico design led to the development of our lead compound, AU403, which avoids Trp443 and Leu439, which are deep in the LXRα‐AF2 ligand binding pocket. Furthermore, we observed significant improvement in working declarative memory and long‐term potentiation in 12‐month‐old 3xTgAD mice treated with our lead compound AU403. Mechanistically, we observed enhanced microglia interaction with dendritic spine density and reduced amyloid‐beta plaque levels as well as reduced pay levels.

Conclusion

We have observed that AU403 can serve as a highly novel potential therapeutic agent for AD.
Heart rate variability during routine cognitive testing: preliminary analyses of time and frequency domain metrics
Authors: Bateman James R. , Schaich Christopher L. , Shaltout Hossam A , Alphin Kathryn H , Lockhart Samuel N. , Hughes Timothy M. , Lindquist Kristen A , Craft Suzanne
Published: January 2025

Background

Early autonomic function changes in Alzheimer’s disease (AD) may represent a biomarker for early affective changes in prodromal disease. We report preliminary differences in metrics of heart rate variability (HRV) before and during routine cognitive testing.

Method

We enrolled 50 participants from the Wake Forest Alzheimer’s Disease Research Center to wear continuous ECG devices during their visit to assess time and frequency domain based metrics of HRV over 5 minutes at rest and during cognitive testing. We used linear mixed effects models adjusted for age, sex, race, education, and APOE genotype to estimate the effect of condition (rest vs. cognitive testing) on HRV by cognitive status.

Result

The sample (n=50) included 39 (78%) individuals adjudicated as having normal cognition (NC), 11 (22%) had MCI, 72% women, 12% Black, 86% White, and 2% Asian. The average age was 73±7 years old, and average education was 15.5±2.6 years. There were no significant differences in time‐ or frequency‐based metrics of HRV between rest and cognitive testing in the total sample (Figure 1). MCI tended towards lower root mean square of successive differences (RMSSD; p=0.11) and higher low‐frequency/high‐frequency (LF/HF) ratio (p=0.062) at rest. RMSSD (p=0.05) but not LF/HF (p=0.99) remained lower during cognitive testing (Table 1, Figure 2).

Conclusion

Preliminary findings from our ongoing study using gold‐standard continuous ECG‐tracing during routine cognitive testing suggest no differences in HRV during the rest and cognitive testing conditions among the total sample, but may preliminarily suggest a shift to higher sympathetic and lower parasympathetic tone in participants with MCI.
Association of brain MRI signatures with Alzheimer Disease CSF biomarkers
Authors: Cheng You , Gopinath Karthik , Billot Benjamin , Iglesias Juan Eugenio , Touroutoglou Alexandra , Kivisäkk Pia , Wu Chao‐Yi , Dodge Hiroko H , Hyman Bradley T. T , Arnold Steven E , Das Sudeshna
Published: January 2025

Background

The relationship between CSF measures of Alzheimer disease (AD) pathologies and their neurodegenerative signatures is not fully understood. This study seeks to employ machine learning approaches on clinical MRI data to identify patterns associated with amyloid and tau, aiming to guide diagnosis and therapeutic interventions.

Method

We selected brain volumes that differed significantly between AD pathology and control groups. Then we utilized logistic LASSO regression to identify and compare neurodegenerative signatures associated with amyloid and tau burdens using selected brain volumes. Our methods were applied to a dataset that included clinical MRI scans from patients who also had cerebrospinal fluid (CSF) biomarkers assessed within a year of the MRI scan (Figure 1). Model performance was measured using the cross‐validation area under the receiver operating characteristic curve (AUROC), as well as the accuracy, sensitivity, and specificity in a 25% held‐out test set.

Result

For amyloid status, among 30 amyloid‐positive, tau‐negative (A+T‐) patients and 24 cognitively unimpaired A‐T‐ controls, we identified 25 significant features associated with amyloid status, including subcortical areas (e.g., amygdala, thalamus, hippocampus), cortical areas (e.g., inferior temporal cortex, inferior parietal cortex, precuneus), ventricles (lateral ventricle, inferior lateral ventricle, and the 3rd ventricle), cerebellum (cerebellum white matter and cerebellum cortex), and brain stem (Figure 2A). Our model with these features yielded an AUROC of 0.792 (95% CI: [0.783, 0.801]), and a sensitivity of 0.857 at specificity of 1 (Figure 2B). In the assessment of tau status, where the amyloid‐negative, tau‐positive group (A‐T+) included 14 patients and the control group comprised 24. The volumes showed significant difference associated with tau status, including subcortical areas (amygdala, ventral diencephalon, hippocampus), the 4th ventricle, and cerebellum white matter (Figure 3A). The model achieved an AUROC of 0.858 (95% C.I. [0.85, 0.866]), with a sensitivity of 1 at specificity of 1 (Figure 3B and C).

Conclusion

The study underscores the potential of using widely available clinical MRI images to measure AD and associated pathologies in the brain, which hold significant promise for guiding treatment interventions.
Methodology of INDICATE: Investigating Neuromarkers for Decline & Impairment of Cognition After Thrombectomy for ELVO
Authors: Harp Jordan P. , Fraser Justin F , McLouth Christopher J , Frank Jacqueline A , Isaacs Jennifer , Dahlke Elise , Pennypacker Keith R
Published: January 2025

Background

Vascular cognitive impairment and dementia (VCID) is present in 25‐30% of stroke patients, and a need exists to develop predictive biomarkers to identify patients that will incur chronic cognitive impairment. The National Plan to Address Alzheimer’s Disease and the NHLBI‐NINDS VCID Workshop called for increased research on VCID prediction, especially in underserved populations. Our stroke patient population is comprised of 70% from Appalachian areas, part of US Stroke Belt, so we are uniquely situated to perform this study. We present the design, rationale, and early implementation considerations of the INDICATE study (Investigating Neuromarkers for Decline & Impairment of Cognition After Thrombectomy for ELVO), an expansion of our novel blood and clot registry (Blood And Clot Thrombectomy Registry and Collaboration; BACTRAC).

Method

The study is prospectively enrolling 225 patients, collecting systemic arterial blood at the time of thrombectomy and venous blood thereafter to analyze protein expression. Blood collections start at time of thrombectomy followed by from 3 months to 2 years post‐thrombectomy. At these time points, measures of cognition, functional status, and social determinants of health (SDoH) are also surveyed. The plasma will be analyzed for biomarkers for Alzheimer disease and related disorders (ADRD), and inflammatory proteomic biomarkers. Advanced statistical modeling will be utilized to identify biomarkers that predict functional and cognitive impairment after stroke.

Result

Our group has previously identified inflammatory proteins expressed at time of thrombectomy that were predictive of functional and cognitive impairment. The study aims to validate these predictors in a broader sample with more rigorous procedures. These predictors will enable clinicians to target patients that would benefit from intensive rehabilitation.

Conclusion

Capitalizing on an already existing translational model for studying stroke, we were able to design a large scale study to evaluate the relationship between ischemic stroke and cognitive outcome in human patients. The addition of ADRD biomarkers, additional time points, and more sensitive cognitive measures will strengthen our predictive model for function and cognition after stroke. We will discuss preliminary experiences with recruitment, retention, and implementation, as well as future directions.
BDNF Val66Met polymorphism moderates the neuroprotective effects of physical activity in older adults
Authors: Cadwallader Claire J. , Fischer David Luke , VandeBunte Anna M. , Chen Coty , Diaz Valentina E. , Lee Shannon Y. , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Kramer Joel H. , Paolillo Emily W. , Saloner Rowan , Casaletto Kaitlin B.
Published: January 2025

Background

Physical activity (PA) is associated with increased release of brain derived neurotrophic factor (BDNF), a mechanism that may underlie protective effects of PA on cognitive and brain aging. The Met allele of the BDNF Val66Met single‐nucleotide polymorphism reduces activity‐dependent BDNF release and is associated with increased phosphorylated tau (p‐tau181) in dementia populations. We sought to determine whether BDNF Val66Met influences the effects of PA on plasma p‐tau181 and cognition in older adults without dementia.

Method

123 older adults from the UCSF Memory and Aging Center completed blood draw assayed for p‐tau181 (Quanterix Simoa), BDNF Val66Met (rs6265) genotyping (Sequenom), 30‐days of FitbitTM actigraphy monitoring, and comprehensive neuropsychological evaluation (Mage = 73.93; SDage = 8.88, 59% female, 42% Met‐allele carriers). Habitual PA levels were operationalized via average daily step count. Composite z‐scores were calculated for cognitive domains of memory and executive functioning. Linear regression was used to determine the moderating effect of BDNF genotype on the relationship between PA and plasma p‐tau181. Moderated mediation analyses subsequently examined the consequences of this moderation effect on cognitive outcomes.

Result

Average PA, plasma p‐tau181, and cognitive z‐scores did not differ between Met‐allele carriers and Val/Val participants. BDNF genotype moderated the relationship between PA and plasma p‐tau181 (b = 0.18, p = 0.036), whereby higher PA was associated with lower plasma p‐tau181 concentrations in Val/Val participants only (Figure 1). In moderated mediation analyses examining cognitive outcomes, plasma p‐tau181 concentration mediated the relationship between PA and executive function for Val/Val participants only (index of mod‐med = ‐0.037, p = 0.031; Figure 2). Models examining memory did not reach statistical significance.

Conclusion

Findings converge with prior studies highlighting BDNF release as a potential mechanism underlying the neuroprotective effects of physical activity, including lower AD pathological burden and better cognition. These results further elucidate sources of individual variation observed in the effects of PA on the brain in older adults. Future work should further examine the molecular pathways bridging the effects of the BDNF Val66Met polymorphism on PA‐related benefits for brain aging to guide personalized neurotrophic treatments in older adults.
Decreased levels of CSF CXCL8 in clinical and biological profiles of Alzheimer's disease: results of a cohort of Brazilian older adults
Authors: Burgos Ivonne Carolina Bolaños , Barreto Júlia de Almeida , Ribeiro Caio Mendes , Aquino Pedro Henrique Oliveira , Real Ana Paula Bernardes , de Souza Aline Siqueira , Ribeiro Aloisio Joaquim Freitas , Montenegro Lourdes Coral Contreras , Engelmann Gabriela Tomé Oliveira , Hansen Erika de Oliveira , Dias Natália Silva , Carvalho Andréa Teixeira , de Miranda Debora Marques , Romano‐Silva Marco Aurélio , de Marco Luiz Armando Cunha , Viana Bernardo M , Bicalho Maria Aparecida Camargos
Published: January 2025

Background

Inflammation plays a key role in Alzheimer's disease (AD) progression. Interleukin 8 (CXCL8) has emerged as an important cytokine involved in neuroinflammation. It is known as an inflammatory factor that induces a chemotactic response to sites of injury, involving the infiltration of neutrophils. In AD, interactions between CXCL8, Aβ42, and Tau suggest that CXCL8 amplifies inflammatory reactivity induced by Aβ42 and increases Tau phosphorylation and subsequent NFT formation. Our main objective was to determine the CXCL8 profile and its relationship with AD biomarkers in clinical and biological groups in a cohort of Brazilian older adults.

Method

seventy‐four older adults were recruited and grouped based on different cognitive profile: Alzheimer’s dementia (n=33), Mild Cognitive Impairment (MCI) (n= 22) and normal cognition (NC) (n=19). CSF samples were collected by lumbar puncture and levels of Aβ42, p‐Tau, t‐Tau and, CXCL8 were assessed by the Luminex xMAP technique. Subsequently, based on biological criteria, the participants were classified in accordance with the AT(N) system into two groups AD continuum and non‐AD. Spearman correlation test and comparison between groups using the Mann‐Whitney U‐test and Kruskal‐Wallis's test were performed. Significant associations between CSF levels of Aβ42, p‐Tau, and p‐Tau/Aβ42 and CXCL8 were further explored in multiple linear regression analyses adjusted for age, sex, education, and APOE allele ε4 carrier status.

Result

A significant correlation was found between CSF IL‐8 levels and the pTau/Aβ42 ratio (r=‐.456; p=.009) only in individuals with AD. We observed decreased CSF CXCL8 levels in the AD continuum compared to the non‐AD group [U=450.0; p=.022]. Considering clinical groups, we also observed decreased CXCL8 levels in AD group compared to the MCI group [X2 (2): 8.2; p=.016]. A significant positive association adjusted by sex, age, formal education and allele Ɛ4 was found between CXCL8 and Aβ42 (ß=.316; p=.016) and a negative association with pTau/Aß42 ratio (ß=. ‐257; p=.036).

Conclusion

a decrease in CXCL8 levels was observed in the AD‐related groups and there was an increase in the MCI group, suggesting that IL‐8 may be more active in the prodromal stage of the disease and then its activity decreases as the disease progresses.
Days, rather than hours of care, mediate the effect of older adults’ cognitive performance on the burden of informal caregivers
Authors: de Carvalho Pelegrini Lucas Nogueira , Palma Leticia Fernanda , Rebecchi Laís , Pulgatti Karen Letícia , Victoriano Pedro Henrique Moreira , de Sousa Danilo Barroso , Grigoli Marina Mantellatto , Popolin Cecilia Patricia , da Silva Vanessa Alexandre , de Oliveira Sabrina Dorta , Manzine Patricia Regina , Cominetti Marcia Regina
Published: January 2025

Background

Informal care of older adults impacts the lives of millions worldwide. Critically, low‐ and middle‐income countries have the highest proportion of dementia costs related to informal care. Research suggests that older adults’ cognitive decline is associated with burden among caregivers, which corroborates the worsening in caregivers’ quality of life and mental health. Understanding factors related to this relationship may contribute to creating strategies to reduce the caregiver’s burden. This study analyzes whether hours and days dedicated to care mediate the relationship between older adults’ cognitive performance and caregiver burden.

Method

Participants were informal caregivers (n = 92) of healthy older adults (n = 74) and persons living with Alzheimer’s Disease (PLwAD, n = 18) from a middle‐income country (Brazil). The assessment comprised the following instruments: a sociodemographic questionnaire, Zarit burden scale, Memory Complaint Scale‐caregiver’s version (MCS), Pfeffer Functional Activities Questionnaire (FAQ), and IQCODE. ACE‐R was used to assess older adults’ cognitive performance.

Result

Caregivers were mostly female (72.8%), daughters (42.4%), or wives (43.5%), who were dedicated to caring, on average, 7.6 (±9.1) hours per day and 5 (±2) days per week. PLwAD caregivers had higher scores on the Zarit Scale (t = ‐5.35; p<0.001), MCS (t = ‐11.54; p<0.001), FAQ (t = ‐14.31; p<0.001), IQCODE (t = ‐6.36; p<0.00). They also provided more hours of care (t = ‐3.97; p<0.001; 95%CI [‐15.89 to ‐4.93]), for more days per week (t = ‐2.30; p = 0.028; 95%CI [‐2.65 to ‐0.16]). Mediation analysis indicated that cognitive performance had a total effect of ‐0.374 (p<0.001; 95%CI [‐0.52 to ‐0.23]) on caregivers’ burden. When controlling for days of care, the direct effect of cognitive performance on the burden was ‐0.3251 (p<0.001; 95%CI [‐47 to ‐0.18]), and there was an indirect effect of ‐0.0698 (95%BCaCI [‐0.14 to ‐0.01]) through the mediation of days of care. Considering hours of care per day, the indirect effect of cognitive performance on the burden was not significant (95%BCaCI [‐0.21 to 0.005]), which suggests it does not mediate this relationship.

Conclusion

Our findings suggest that days dedicated to care mediate the effect of older adults’ cognitive performance on caregivers' burden. These findings underscore the importance of considering the temporal aspects of caregiving in developing strategies to alleviate caregiver burden.
Metabolic PET brain networks predict clinical conversion prior to amyloid positivity in cognitively unimpaired individuals
Authors: Limberger Christian , Martins Gabriel Colissi , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Peixoto Guilherme G. Schu , de Bastiani Marco Antônio , Machado Luiza Santos , Povala Guilherme , Pascoal Tharick A. , Rosa‐Neto Pedro , de Souza Débora Guerini , Zimmer Eduardo R.
Published: January 2025

Background

The default‐mode network (DMN) consists of brain regions with higher resting activity levels. Amyloid‐β (Aβ) deposition in Alzheimer’s disease (AD) occurs predominantly throughout the DMN, suggesting that activity within the network may facilitate disease processes. Indeed, increased neural activity is positively associated with Aβ production. In this context, variations in DMN activity and associated metabolic networks may be linked to the risk of developing AD. However, how patterns of metabolic disruption relate to the progression of AD pathology remains unknown. Here, we investigated whether the metabolic brain networks (MBNs) architecture predicts clinical conversion in cognitively unimpaired (CU) individuals.

Method

We selected CU individuals negative to amyloid and tau (A‐T‐) from the ADNI cohort with [18F]FDG‐PET imaging data at baseline. These patients were divided in stable (non‐converters, n = 18) and clinical progressors (converters, n = 22). Individuals were age‐ and APOEε4‐matched (Table 1). The mean [18F]FDG standard uptake value ratio (SUVR, pons as reference) of brain regions of interest (ROIs) was extracted based on the DKT atlas. MBNs were assembled with a multiple sampling bootstrap scheme and corrected for group imbalance with the Adaptive Synthetic Sampling Approach for Imbalance (ADASYN) and for multiple comparisons using FDR (p < 0.05).

Result

[18F]FDG regional SUVRs presented no differences between groups (Figure 1). However, converters had a prominent brain PET metabolic hyperconnectivity compared to non‐converters, with a 1.5 fold‐change in connection density (p < 0.001, Figure 2A). Notably, this hyperactivation was not limited to the ROIs comprising the DMN; MBNs constructed with all brain regions reveal that the brains of converters typically display metabolic hyperactivity before the onset of CI (Figure 2B).

Conclusion

Our findings suggest the existence of early metabolic alterations at the network level in amyloid negative converters. This corroborates the notion that early soluble forms of amyloid, considered synaptoxins, may trigger brain metabolic hyperconnectivity. MBNs hold promise as biomarkers for detecting individuals at risk of clinical progression, even before amyloid positivity status.
Longitudinal changes in amyloid, glucose, and glial reactivity imaging biomarkers in a transgenic rat model of amyloidosis
Authors: Lazzarotto Gabriela , Spelta Lidia Emmanuela Wiazowski , Vera Cleinando Clemente da Silva , da Rocha Andreia Silva , de Souza Débora Guerini , de Paula Faria Daniele de Paula , Zimmer Eduardo R.
Published: January 2025

Background

Imaging biomarkers have helped to reconceptualize Alzheimer's disease pathophysiology. More specifically, positron emission tomography (PET) radiopharmaceuticals for non‐invasively assessing amyloid‐beta (Aβ) plaques, glucose metabolism, and glial reactivity allow for tracking disease progression in a temporally ordered manner. However, whether transgenic models recapitulate biomarker‐related changes remains elusive. Here, we longitudinally evaluated Aβ, glucose metabolism, and glial reactivity using PET in a transgenic amyloid rat model.

Method

TGF344‐AD (APP/PS1) and wild‐type rats were scanned at 6, 9, and 12 months with [18F]FDG, [11C]PK11195 and [11C]PIB. Images were manually co‐registered in a rat magnetic resonance template. Standardized uptake values (SUV) were calculated for [18F]FDG and [11C]PK11195, and SUV ratio (SUVR) was calculated for [11C]PIB using the pons as the reference region. The results were normalized using Z‐Score and statistical significance was determined at Z>2 (p < 0.05).

Result

At 6 months, no differences between groups were observed. At 9 months, however, we detected significant amyloid load, glucose hypermetabolism, and increased glial reactivity. At 12 months, animals presented increased Aβ load while still presenting signs of brain glucose hypermetabolism. By contrast, glial reactivity did not present alterations compared to 9‐month‐old rats.

Conclusion

Our findings indicate that in the early phases of detectable Aβ deposition, there is a joint increase in brain glucose metabolism and glial reactivity. These findings suggest that amyloid deposition triggers early neuroinflammatory response. We and others have provided evidence that early FDG‐PET hypermetabolism is an indicator of glial reactivity.
Amyloid‐PET in patients with a clinical diagnosis of sporadic early‐ versus late‐onset AD: comparison of the LEADS and ADNI cohorts
Authors: Lagarde Julien , Maiti Piyush , Schonhaut Daniel R. , Zhang Jiaxiuxiu , soleimani‐meigooni David N. , Zeltzer Ehud , Windon Charles , Raya Maison Abu , Vrillon Agathe , Hammers Dustin B. , Dage Jeffrey L. , Nudelman Kelly N. , Eloyan Ani , Koeppe Robert A. , Landau Susan M. , Carrillo Maria C. , Touroutoglou Alexandra , Vemuri Prashanthi , Dickerson Bradford C. , Apostolova Liana G. , Rabinovici Gil D. , Joie Renaud La ,   LEADS Consortium, Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age≥65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).

Method

731 patients meeting the 2011 NIA‐AA criteria for AD dementia or MCI were included (505 early‐onset from LEADS, 226 late‐onset from ADNI3, Table 1). All participants underwent amyloid‐PET with [18F]Florbetaben or [18F]Florbetapir. Amyloid positivity was centrally determined by a process involving a visual read by a trained expert and PET‐only quantification; in case of a discrepancy, a read from an independent physician acted as a tiebreaker. Logistic regressions in each cohort examined relations between amyloid positivity and age, sex, MMSE and APOE4 genotype. Amyloid burden was independently quantified in Centiloids using an MRI‐based pipeline. Mean Centiloids in LEADS and ADNI were compared with two‐way ANOVA, for visually positive and visually negative scans.

Result

Amyloid positivity rate was higher in LEADS (76%) than ADNI (64%, p<0.001, Figure 1A). Lower MMSE and APOE4 genotype increased odds of amyloid positivity in both cohorts, although the APOE4 effect was stronger in ADNI than LEADS (OR=10.1 versus 2.4, p=0.007, Table 2). Amyloid positivity was more common in females across cohorts, but this effect was only statistically significant in LEADS (Table 2). Centiloids were bimodally distributed in both cohorts, although the separation between positive and negative scans was more prominent in LEADS (Figure 1B). Visually positive scans had significantly higher Centiloids in LEADS than in ADNI, whereas no cohort difference was observed for visually negative scans (Figure 1C). Sensitivity analyses showed that this effect was driven by patients with MCI (CDR≤0.5; Figure 1D‐E).

Conclusion

The lower amyloid positivity rate in ADNI might be due to AD‐mimicking pathologies being more common at an older age. The higher amyloid burden in early‐onset, amyloid‐positive patients could reflect younger patients being diagnosed later in the disease course compared to typical, late‐onset patients. Alternatively, younger patients might tolerate higher neuropathology burden due to higher brain reserve or fewer co‐pathologies.
Process evaluation of a community advisory board for a multi‐site clinical trial addressing dementia literacy and linkage to dementia care
Authors: Han Hae‐Ra
Published: January 2025

Background

Community engagement is a key strategy to promoting health equity. While community advisory boards (CABs) are used as a popular tool for community engagement, the process of forming CABs and maintaining them is mostly missing in the literature. The purpose of this study is to showcase a set of processes our collaborative team went through to form and implement a CAB in the context of dementia literacy and linkage to dementia care research.

Method

PLAN—Preparing for healthy aging through dementia Literacy education And Navigation—is an ongoing, multi‐site clinical trial involving community‐dwelling Korean American older adults (65+ years) with probable dementia and their care partners in the US. Data for the current analysis came from multiple sources: monthly CAB meeting minutes, study team meeting minutes, and notes taken during individual discussions with CAB members. We used content analysis to identify common themes across these data sources.

Result

We identified three main stages in relation to CAB: Formation, Implementation, and Sustainability. Formation stage was mainly to build genuine connections as a team while clarifying the research purpose and establishing the mission and goals of the CAB. Key activities for the Implementation stage included: Strategizing for community outreach to build trust with the local community; advocating for the rights of vulnerable research participants such as those with limited English proficiency and/or with probable dementia with/without care partners; ensuring that the language of research materials and message is culturally relevant, friendly, and easy to understand; increasing awareness and building bridges between science, patients, caregivers, and families; strategizing how to make clinical research accessible to everyone; and creating a CAB‐led community engagement project to share experiences and perspectives. In the current, Sustainability stage, we are actively evaluating our partnership processes, while determining next steps to scale and adapt the PLAN program.

Conclusion

When implemented effectively, CABs can help center the perspectives and experiences of marginalized groups such as those with limited English proficiency. It would be important for future research to evaluate in greater depth what components make a CAB partnership successful so that more resources related to CAB formation, implementation, and sustainability can be utilized for research.
Adverse Events in a Multicenter Randomized Controlled Trial for Dementia Prevention (rrAD study)
Authors: Hall Tristyn , Kerwin Diana R. , Vongpatanasin Wanpen , Gahan William , Keller Jeffrey N. , Stowe Ann M , Zhu David C , Hynan Linda , Cullum Munro , Vidoni Eric D , Burns Jeffrey M , Zhang Rong , Binder Ellen F.
Published: January 2025

Background

The Exercise and Intensive Vascular Risk Reduction in Preventing Dementia (rrAD study) was a multicenter randomized, controlled trial to determine the effects of moderate to vigorous aerobic exercise training and intensive pharmacological treatment of cardiovascular risk factors on dementia prevention in older adults (NCT02913664). The trial duration was 2 years. We present herein the adverse events (AEs) reported in the rrAD trial. Our objective is to determine whether the trial interventions were associated with higher reports of AEs in older adults aged 60 to 85 who had hypertension, family history of dementia, and/or subjective memory complaints.

Method

513 subjects were randomized to one of four intervention treatment arms: Aerobic Exercise (Ex), Intensive Reduction of Vascular Risk Factors (IRVR), Combined Arm (IRVR+Ex), and Usual Care. The IRVR groups received intensive pharmacological treatment of blood pressure (BP) (SBP<130mmHg) and cholesterol management (atorvastatin, 80mg daily). AEs were categorized by the abnormal lab results and body systems which are likely affected by the trial interventions.

Result

The IRVR arms had slightly higher abnormal lab results of electrolytes (potassium) and creatinine (Table 1) relative to the non‐IRVR arms, which were expected with BP treatment using angiotensin receptor blockers (ARBs) such as, losartan. The IRVR arms also had higher AEs of leg cramps, edema, dizziness, lightheadedness, and fatigue likely reflecting side effects of antihypertensives and/or statin use. The exercise arms had higher AEs in the musculoskeletal system relative to the non‐exercise arms. Overall, the rates of injuries, serious adverse events (SAEs), or death were low, and no noticeable differences were observed among the intervention arms.

Conclusion

Participants in the IRVR arms may report higher AEs related to the side effects of antihypertensives and/or statin use, and in the exercise arms higher AEs related to musculoskeletal events such as muscle pain. The rrAD study showed that it is safe to implement moderate to vigorous aerobic exercise training and intensive cardiovascular risk factor reduction in older adults for dementia prevention.
Investigation of the correlation between negative communication by caregivers and neuropsychiatric symptoms in people with dementia: Preliminary Results
Authors: Gheno Lucimara Lehmen , da Silva Amanda Gorziza , Fernandez Liana Lisboa , Rieder Carlos Roberto Mello , Beber Bárbara Costa
Published: January 2025

Background

Caregivers of people with dementia (PwD) often experience the burden of caregiving and depressive symptoms that may be associated. PwD who experience a higher occurrence of neuropsychiatric symptoms often cause a greater burden on their caregivers due to the difficulty in managing these symptoms. Caregivers may transfer their feelings of frustration and exhaustion with caregiving through the way they communicate with the PwD. On the other hand, it is also possible that inadequate communication triggers the occurrence of challenging behaviors in PwD, demonstrating the importance of communication between caregivers and care recipients. The objective of this study was to verify the correlation between the negative communication scale (NCS) answered by caregivers and PwD and the neuropsychiatric inventory (NPI).

Method

This is a segment of a descriptive observational study with a quantitative approach, involving a sample of 11 dyads. The NPI and NCS were administered to the caregivers of PwD, and the NCS was also answered by the PwD themselves (to observe the perception of negative communication by the caregivers from the perspective of the PwD).

Result

Characteristics of the sample are shown in Table 1. Correlations of NCS and NPI domains are described in Table 2 and show that the greater the disinhibition, the lower the perception of negative communication use by caregivers, as perceived by individuals with dementia. Also, the greater the aberrant motor changes, the lower the perception of negative communication use by caregivers, according to individuals with dementia.

Conclusion

The results suggest a possible relationship between caregivers' communication and neuropsychiatric symptoms of PwD. Despite the presented correlations, it is necessary to increase the sample size to highlight/confirm these correlations.
Online‐based Recruitment Methods for Community‐Dwelling Older Adults: Challenges and Strategies
Authors: Han Hae‐Ra , Min Deborah
Published: January 2025

Background

Despite technology adoption and increased dependence on digital technologies, the digital divide persists among older adults. The purpose of this study was to understand barriers and facilitators of recruiting non‐English speaking older individuals who are cognitively impaired along with their caregivers for PLAN, an ongoing RCT designed to promote the transition of Korean American older adults with probable dementia and their caregivers into the healthcare system for adequate diagnostic follow‐up and care. We also examined online‐based recruitment strategies focused on older adults reported in relevant published studies to compare with our experiences.

Method

Data sources included recruitment tracking files, study team meeting minutes, and interviews with community staff and consultants. We also conducted a review of published studies that used online‐based recruit of community‐dwelling older adults.

Result

Five themes emerged: unfamiliarity with technology—limited digital literacy; differences in internet access and use across older age groups; providing technological support to promote recruitment; successful and unsuccessful recruitment using social media; and other diverse online‐based methods. Direct quotes from multiple sources for the PLAN trial revealed technological challenges that were common among immigrant older adults. While the studies included in the review indicated similar internet accessibility and use between young‐old and older‐old adults, actual online recruitment was least successful in the older‐old group. Most studies included in the review used social media but the success varied across these studies with slightly more than half of the studies reporting little to no success. Similarly, other online‐based methods such as e‐newsletters, emails, or postings on professional organizational websites yielded varying successes.

Conclusion

Our analysis revealed the digital divide along with the issue of limited digital literacy in the recruitment of older adults, particularly non‐English speaking immigrants. The usefulness of online‐based recruitment of older adults is uncertain due, in large part, to limited sociodemographic diversity noted in the samples included in the review. Future research needs to explore the role of race/ethnicity and other characteristics such as socioeconomic status, gender, education, access to technology, and digital literacy in relation to online‐based recruitment for adequate representation of diverse older adults in research.
Quebec Eastern Township Regional Dementia Care Update after COVID. Reorganisation for the Quebec Ministerial Alzheimer program
Authors: Lacombe Guy , Legresley Marie‐Pier , Stiffel Michael , Gosselin Suzanne
Published: January 2025

Background

In the province of Quebec, Canada, primary care management of Alzheimer’s disease is provided by the Family Medicine Group with the support of the Ministerial Initiative on Alzheimer’s Disease and the collaboration of specialized memory clinics. The COVID years have severely strained health resources in all areas, including cognitive intervention resources. We describe the reorganization of regional support in the Eastern Townships.

Method

The results of a survey on the situation of care are shared with each of the family medicine groups involved in the Eastern Townships Alzheimer Plan, comparing the processes and results of each team to the provincial average. The difficulties and improvements proposed by each of the groups are noted and discussed with a view to continuous improvement.

Result

A regional tour was necessary to re‐establish contact between the regional support resources (nurse and doctors of the memory clinic) and the Family Medicine Group. Nursing, medical, and pharmaceutical staff and social workers were met at each FMG. Interdisciplinary care models, local resources, leaderchip and development opportunities were discussed. Training needs have been identified. Demands to involve social workers and pharmacists are growing. The evolution of the clientele is striking, with a significant increase in the number of evaluations for patients with mild neurocognitive disorders.

Conclusion

The presence of at least one experienced person at each FMG made it possible to reorganize the clinics after the staff changes related to the COVID period. The tour allows us to recreate the links that are essential to the development of expertise and to provide specialized support to the family medicine groups involved in the Alzheimer’s plan.
Associations of hearing loss with subjective cognitive decline among American Indians and Alaska Natives and other race/ethnic groups: results from the BRFSS
Authors: Li Lingling , Yang Manxi , Manson Spero , O'Connell Joan , Jiang Luohua
Published: January 2025

Background

Prior research has established a relationship between hearing loss (HL) and cognitive decline. However, this association remains unclear in the American Indian/Alaska Native (AI/AN) population. Given the high prevalence of subjective cognitive decline (SCD) and HL in the AI/AN population, exploring this relationship is crucial. This study investigated the HL‐SCD association among AI/AN and other racial/ethnic participants of the Behavioral Risk Factor Surveillance System (BRFSS).

Method

This study analyzed data from 170,048 participants aged 45+ in the 2019‐2020 BRFSS, encompassing AI/AN (n = 2,942), non‐Hispanic White (NHW, n = 143,172), non‐Hispanic Black (NHB, n = 13,377), and Hispanic (n = 10,557) adults. Sociodemographic characteristics, health behaviors, and comorbidities were reported across the four groups. HL was defined as self‐reported deaf or having serious difficulty hearing, and SCD was defined as self‐repoted worsening confusion or memory loss in the past 12 months. Logistic regressions were employed to assess the HL‐SCD association, adjusting for demographic, behavioral, and clinical variables. Additionally, age‐specific analyses were conducted for the 45‐64 and 65+ age cohorts.

Result

AI/ANs exhibited higher prevalence of HL, at 18.92% (95% CI: 14.3% ‐ 23.53%), and SCD, at 16.9% (95% CI: 14.13% ‐ 19.66%), compared to other groups (Table 1). A consistent and significant positive association between HL and SCD was observed across all groups. For AI/AN participants, the fully adjusted odds ratio (OR) for SCD associated with HL was 2.35 (95% CI: 1.4 ‐ 3.95). The ORs for NHW, NHB, and Hispanic participants were 2.02 (95% CI: 1.81 ‐ 2.25), 2.2 (95% CI: 1.61 ‐ 3.01), 2.7 (95% CI: 1.8 ‐ 4.06) respectively (Table 2). The study also revealed that the HL‐SCD association varies by age. Among AI/ANs, NHWs, and NHBs, this association is more pronounced in the 45‐64 age group. Conversely, for Hispanics, it is stronger in the 65+ age group (Figure 1).

Conclusion

Our study found a significant association between HL and SCD in the AI/AN population, consistent with other racial/ethnic groups. We also found age was a key effect modifier in this association. These findings suggest the potential value of routine hearing tests in older AI/AN adults for early dementia detection and prevention.
Facilitating Participation of People with Dementia and their Caregivers in Emergency Care Research
Authors: Benson Clark , Block Laura M , Gilmore‐Bykovskyi Andrea L
Published: January 2025

Background

People living with dementia (PLWD) are high utilizers of acute illness and emergency care, with over 50% of the more than 6 million people with Alzheimer’s disease and Alzheimer’s disease related dementia (ADRD) visiting an emergency department (ED) annually. While the ED plays an important role meeting the urgent and acute needs of PLWD and their caregivers, presence of ADRD is often not well recognized and ED visits are associated with significant adverse outcomes for PLWD. Despite these factors, research on the emergency care needs of PLWD is extremely limited. Challenges navigating informed consent and assent in the context of a dynamic environment that often necessitates rapid enrollment is a major barrier to conducting ADRD‐focused emergency care research. This presentation reports on a structured framework developed to facilitate participation of PLWD and/or their caregivers in research during ED visits, with attention to maximizing flexible participation and supported decision‐making.

Method

We developed a scenario guided decision‐tree framework for facilitating rapid, flexible enrollment of PLWD and their caregivers in emergency care research. This framework was trialed and iteratively revised through the conduct of a prospective qualitative study (N = 31 participants; 10 PLWD, 15 caregivers, and 3 dyads). This presentation will summarize challenges in facilitating participation, the refined decision‐tree framework, and highlight strategies for successful implementation of the framework.

Result

Major barriers to facilitating participation included navigating supported participation and enrollment in the context of stringent legal and compliance procedures, supporting participation across disease stages, and monitoring for and responding to fluctuations in attention and capacity. The resultant framework guides early assessments to determine tailored procedures for consent, assent, and flexible participation approaches including supported participation.

Conclusion

A major challenge to engaging PLWD in research about their own care experiences is ensuring that research enrollment procedures are responsive to the broad variation in abilities across the continuum of cognitive challenges, decision‐making needs, and participation preferences. The developed framework supports study team members in navigating this challenge in a manner that is inclusive of flexible participation needs and supported as well as proxy decision‐making.
Rostral locus coeruleus metabolism relates to Alzheimer's disease pathology and cognition in amyloid‐positive symptomatic individuals
Authors: Koops Elouise A. , Dutta Joyita , Becker Alex , Hanseeuw Bernard J , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L.
Published: January 2025

Background

Higher cerebrospinal fluid noradrenergic metabolic turnover has been associated with higher levels of Alzheimer’s disease pathology in cognitively impaired individuals. It remains unclear whether there is a specific anatomic vulnerability to metabolic alterations within the locus coeruleus (LC) and whether this hypermetabolism relates to steeper rates of pathology accumulation. Here, we overcome a spatial limitation of Positron Emission Tomography (PET) imaging in small nuclei with a dedicated Magnetic Resonance Imaging (MRI)‐guided framework to recover PET resolution. This method allowed us to investigate the [18F]Fluorodeoxyglucose (FDG)‐PET signal, reflecting energetic metabolic demand of the LC and its association with serial beta‐amyloid and tau‐PET.

Methods

We included 78 amyloid‐positive, cognitively impaired participants from the ADNI‐3 cohort (Table 1). The LC was identified using a dilated Keren template registered to each T1 (Figure 1A). The LC mask was subdivided into a rostral, middle, and caudal part to investigate region‐specific associations (Figure 1B). We used an MR joint‐entropy‐penalty algorithm to quantify PET signal via deconvolution based on spatially‐variant blur kernels. The deconvolution step was stabilized using an anatomical‐based joint‐entropy prior (Figure 1C). The FDG‐PET signal was referenced to the pons, excluding the LC (Figure 1D). Amyloid positivity was determined as a centiloid score ≥ 21, reflecting moderate neuritic plaques, on florbetaben and florbetapir scans. Linear mixed effects models investigated relationships between LC‐FDG, global beta‐amyloid and meta‐temporal tau burden (flortaucipir) over time. Age and sex were included as covariates.

Results

Higher LC FDG‐PET signal was associated with higher meta‐temporal tau‐PET at baseline (T=2.87, p=0.00463) and accumulation over time (T=2.257, p=0.0273; Figure 2A&C). Higher LC FDG‐PET signal was associated with higher global amyloid at baseline (T=2.066, p=0.041) and faster amyloid accumulation over time in the dementia group (T=‐2.74, p=0.00904; Figure 2B&D), following a rostro‐caudal gradient.

Conclusion

In a cohort with cognitive impairment, we observed steeper accumulation of Alzheimer’s disease pathology in individuals with higher LC FDG‐PET signal, with a specific amyloid‐related vulnerability for the rostral parts of the LC. Future steps will be to include cognitively unimpaired individuals to investigate the relationship between LC FDG‐PET signal and pathology accumulation in early stages of the disease process.