bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Myocardium Hypertrophy And Dementia: A Population Based Autopsy Study
Authors: Silva Heberti Eliakim , Paradela Regina Silva , Leite Renata Elaine Paraizo , Pasquallucci Carlos Augusto , Grinberg Lea T. , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: January 2025

Background

Hypertension is a midlife modifiable risk factor for dementia. Uncontrolled hypertension is related to brain damage that could result in cognitive impairment, and one way of evaluating uncontrolled hypertension through life is assessing left ventricular hypertrophy (LVH). Previous imaging studies have shown a relationship between LVH and cognitive impairment. However, no previous study has evaluated this association using direct measurements obtained through autopsy. Furthermore, little is known about this relationship in diverse populations in low and middle‐income countries like Brazil, where the prevalence of dementia is expected to be higher than in high‐income countries. This study aimed to evaluate the association between LVH and dementia using data from an autopsy study in an admixed sample.

Method

We used data from the Biobank for Aging Studies of the University of São Paulo Medical School. The diagnosis of hypertension was obtained through a structured interview with an informant close to the deceased. The LVH was defined based on anatomical analysis and the left ventricular free wall measurement. Cognitive abilities were evaluated by the Clinical Dementia Rating Scale sum of boxes. The analyses were performed using regression models adjusted for sociodemographic and clinical confounders.

Result

In 1067 participants (mean age 70.6±11.9 years old, mean education 4.6±3.8 years, 46.2% women, 66.4% White), LVH was not associated with cognitive abilities in multivariate analyses adjusted for aged, education, sex, race, diabetes, heart disease, body mass index, smoking, alcohol use, and physical inactivity. Age, sex, education, and race did not modify this relationship.

Conclusion

We did not find an association between LVH and cognitive impairment in our sample. Further analyses will be important to investigate the possibility of attrition bias.
Canada’s Enhanced Dementia Surveillance Initiative: Improving national dementia measures to inform public health actions
Authors: Shaver Larry C , Marion Danielle , Pelletier Catherine
Published: January 2025

Background

The Enhanced Dementia Surveillance Initiative (EDSI), led by the Public Health Agency of Canada (PHAC), supports the implementation of Canada’s first national dementia strategy. To improve the national monitoring of dementia and its health impacts, the EDSI projects focused on priority data gaps: dementia by cause, progression stages and impacts; socio‐demographic characteristics, risk and protective factors; and caregivers.

Method

PHAC collaborated on 15 projects with multiple stakeholders (universities/research institutions, health organizations, and federal/provincial government departments). Each employed novel methods and data sources in the Canadian public health surveillance context. Existing and linked health administrative data, electronic medical records (EMR), various primary data collections, and longitudinal cohorts were leveraged to apply new approaches addressing the listed data gaps.

Result

Projects enabled various surveillance advancements in dementia health measures; examples are presented under four categories.

1. By leveraging existing databases with new linkages, algorithm validation and data visualization techniques, projects were able to better identify and characterize (clinical and sociodemographic characteristics) people living with dementia and their caregivers.

2. By enhancing linked health administrative data for national surveillance, new methods to report on dementia in long term care and dementia comorbidities were developed, and health care costs across dementia progression stages were calculated.

3. By developing new conceptual and data models, it was possible to enhance the understanding of the dementia national data landscape. The impact of selected factors on dementia risk in the population was also estimated, and dementia patients’ trajectories across care settings were described.

4. By applying a health equity lens, progress was made towards an improved monitoring of dementia in diverse populations, such as Indigenous communities and individuals experiencing homelessness.

Conclusion

Through a knowledge synthesis of the results and findings from the EDSI projects, PHAC aims to identify and integrate best practices for national dementia surveillance. The expected long‐term outcome of this initiative is to contribute to more robust evidence on dementia in Canada to help inform related public health actions.
Modeling Early Detection and Geographic Variation in Health System Capacity for Alzheimer’s Disease‐Modifying Therapies
Authors: Liu Jodi L. , Baker Lawrence , Chen Annie , Wang Jessie , Girosi Federico
Published: January 2025

Background

The widespread availability of effective disease‐modifying therapies would be a breakthrough in slowing the progression of early Alzheimer’s disease (AD) to later stages of dementia. The purpose of this study is to explore how primary care capacity, variation in patient care‐seeking, and geographic variation in capacity can affect the delivery of AD‐modifying therapies.

Method

We used a county‐level simulation model to assess patient demand and provider supply for the delivery of AD‐modifying therapies. The model simulates the progression of people aged 50 and older through a clinical pathway and through disease states (normal cognitive, mild cognitive impairment, and Alzheimer’s dementia), and compares patient demand to the health care system capacity for detection, diagnosis, and treatment. We developed an interactive, web‐based tool that allows users to adjust key parameters and explore their effects on results.

Result

Care models that enable primary care practitioners to diagnose and evaluate patients for treatment eligibility would make the biggest impact on reducing wait times for dementia specialists and increasing the number of people treated from 2025 through 2044. Improved triage of patients using blood‐based biomarker tests in primary care settings could further reduce caseloads for specialists. The estimated wait times and number of patients treated are sensitive to patient uptake of brief cognitive assessments. There is substantial geographic variation in health care system capacity across the US to detect, diagnose, and treat early AD. Estimated average wait times can be three times longer in rural areas compared to urban areas. States with long wait times include Alaska, Arkansas, Idaho, Mississippi, Montana, Nevada, Oklahoma, and Wyoming.

Conclusion

Widespread delivery of AD‐modifying therapies will require a combination of strategies to communicate the value of detection and treatment to patients, integrate PCPs into the detection and diagnosis pathway, and address capacity disparities across the United States. Further work is needed to evaluate how primary care‐led models of care can widely and effectively evaluate and manage treatment for people with early AD, as well as how technological advancements, such as improved biomarkers and computerized testing, can be integrated into workflows to better serve people living with AD.
Estimating preclinical amyloid positivity in the community: a case study transporting estimates from ADNI to ARIC
Authors: Stapp Emma K , Mayeda Elizabeth Rose , Stuart Elizabeth A , Gottesman Rebecca F. , Wong Dean F. , Mosley Thomas H. , Griswold Michael E. , Glymour M. Maria , Zimmerman Scott C , Power Melinda C
Published: January 2025

Background

Estimates of the prevalence of preclinical amyloid positivity in the US general population are of great interest to the field, but difficult to measure and thus unavailable in representative studies. A statistical approach from causal inference, ‘transport’, may allow for improved generalizability of findings from a sample of persons from one population to another. We aimed to explore the feasibility and validity of extending results from a deeply‐phenotyped convenience sample, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), to a representative target sample, the Atherosclerosis Risk in Communities Study PET Amyloid Imaging Study (ARIC‐PET) — with “proof of concept” defined by the performance of the transport estimator in recovering the observed prevalence of amyloid positivity in ARIC‐PET.

Method

Eligible ARIC‐PET and ADNI participants were either white or Black and had normal cognition or mild cognitive impairment. Amyloid positivity was defined using study‐specific cutoffs for standardized uptake value ratio (SUVR). Probability of selection into ADNI (vs. into ARIC‐PET), given harmonized sociodemographic and clinical covariates, was estimated using gradient boosted trees (GBM). The resulting study participation probability scores were used to transport the prevalence of amyloid positivity from ADNI to ARIC using inverse odds of sampling weights. Estimates of amyloid positivity prevalence derived from ADNI and from transporting from ADNI to ARIC‐PET were compared to the observed prevalence in ARIC‐PET, overall and by age, sex, race, education, and APOE e4 status.

Result

Transported prevalences substantially underestimated observed prevalences of amyloid positivity in most groups, with the exception of white, non‐Hispanic individuals and persons with at least one APOE e4 allele, where prevalence was slightly overestimated. Prevalence of preclinical amyloid positivity based on transporting ADNI was further from the prevalence in ARIC‐PET than the raw prevalence of amyloid positivity in ADNI except for white, non‐Hispanic individuals and those with mild cognitive impairment.

Conclusion

Transport estimators rely on adequately modeling the selection process. Available data may be insufficient to capture selection biases into deeply‐phenotyped convenience samples, particularly for groups who are under‐represented in research. Transport estimators will have greatest utility when applied to samples derived from known sampling strategies, and with increased diversity in dementia research.
Housing characteristics by living arrangement of older adults with cognitive impairment in the United States
Authors: Okoye Safiyyah , Gitlin Laura N.
Published: January 2025

Background

The home environment is where daily activities are performed and older adults with and without cognitive impairment spend most of their time. While home safety is a priority for healthcare providers, there is limited understanding of housing characteristics of older adults with cognitive impairment in the United States and whether they differ for those who live alone or with others.

Methods

We draw on data collected from N = 968 community‐living older adults with cognitive impairment who responded to the 2022 National Health and Aging Trends Study, a population‐based national survey that comprehensively assesses characteristics of older adults (≥65 years) and their households in a two‐hour in‐home interview. Housing characteristics reported by self/proxy response were: building type, own or rent, home modifications, and whether living in subsidized housing. Housing characteristics directly observed by interviewers were: home disorder (e.g., flooring problems, pests); home disrepair (e.g., missing siding, broken steps); and street disorder (e.g., litter, graffiti, vacant houses). Cognitive status was measured by a composite measure.

Results

We found that 26.0% (n = 261) of our sample lived alone, 46.4% (n = 373) lived with a spouse, and 27.6% (n = 334) lived with others (non‐spouse). The prevalence of some housing characteristics differed between the three groups. For example, renting was most prevalent among those who lived with others (non‐spouses); 67.1% vs 48.4% if lived alone and 20.9% if lived with a spouse. Living in an apartment or mobile home (vs house) was more prevalent for those who lived alone (27.1% vs. 15.4% if lived with others (non‐spouse) and 13.5% if lived with a spouse). Other characteristics were similar across groups: approximately 45% (n = 437) of the overall sample lived in a home with internal disorder, 24% (n = 187) in a home with external disrepair, and 20% (n = 202) on a street where disorder was noted (rates did not statistically significantly differ between groups).

Conclusions

Although the distribution of some housing characteristics differed by living arrangement, 25‐50% in all groups were observed to have housing challenges such as disrepair and disorder. As housing conditions can have significant health consequences and prompt relocation, attention to housing should be part of routine dementia care.
Lifespan cardiometabolic exposures are associated with midlife white matter microstructure: The Bogalusa Heart Study
Authors: Dugan Reagan T , Ramakrishnapillai Sreekrishna , Amant Julia St , Murray Kori , McKlveen Kevin , Naseri Maryam , Madden Kaitlyn , Bazzano Lydia , Carmichael Owen T.
Published: January 2025

Background

Compartment model analysis of diffusion MRI data provides unique information on the microstructural properties of white matter in the brain. However, studies relating compartment model microstructural measures to longitudinal cardiometabolic health data are rare.

Method

In this study, 130 cognitively healthy participants in the Bogalusa Heart Study (age 55.4 ± 4.5) completed high angular resolution diffusion MRI scans. Neurite orientation dispersion and density imaging (NODDI) and diffusion tensor analysis were performed, and values of neurite density, orientation dispersion, free water fraction, fractional anisotropy, and mean diffusivity were measured in ROIs of highly organized and diffuse white matter. Multiple linear regression models were used to relate the white matter microstructure metrics to demographics and cardiometabolic risk factors.

Result

Organized tracts showed significantly greater NDI, and FWF, and significantly lower ODI, than the diffuse white matter. In organized white matter greater age was associated with greater FWF and lesser NDI, women had lower FWF than men, and African Americans had greater ODI than whites. Worse cardiometabolic measures and brain health were generally associated with lesser NDI. Greater blood pressure in pre‐adulthood was associated with lesser NDI. Within the diffuse white matter, greater age was associated with greater FWF, women had lesser FWF than men, and African Americans had lesser NDI and greater ODI than whites. Worse cardiometabolic measures and brain health were generally associated with greater FWF.

Conclusion

In a racially diverse, cognitively healthy, middle‐aged community cohort sample, summary measures from diffusion tensor and compartment model analyses of multi‐shell diffusion MRI data were associated cardiometabolic risk factors from youth to midlife as well as demographic factors.
Incretin receptor agonists rapidly and markedly attenuate multi‐cause insulin resistance in the hippocampal formation from MCI and AD dementia cases
Authors: Talbot Konrad
Published: January 2025

Background

Only about 50% of the variance in cognitive decline occurring during Alzheimer’s pathogenesis is attributable to standard AD biomarkers (cerebrocortical Aβ, pathological tau, and atrophy) (Tosun et al., Alzheimer’s Dement. 18: 1370, 2022). Other factors contributing to such decline include brain insulin resistance (BIR). Levels of its biomarker, pathological IRS‐1 pS616 (insulin receptor substrate‐1 phosphorylated at S616), accounts for as much as 47% of the variance in episodic memory scores in an elderly population we studied (Talbot et al., JCI 122: 1316, 2012). To better understand BIR in Alzheimer’s disease (AD), its proximal causes, and if incretin receptor agonists (IRAs) can reduce BIR, we extended our earlier ex vivo work on the hippocampal formation (HF) of non‐cognitively impaired (NCI) and AD dementia (ADd) cases to non‐amnestic MCI (naMCI) and amnestic MCI (aMCI) cases

Method

Diverse brain banks donated fresh frozen HF tissue from NCI, naMCI, aMCI, and ADd cases (n = 10 per diagnostic group) who were age‐ and ‐sex matched whites with no history of diabetes and low postmortem intervals (m ± SD = 6.75 ± 2.2 h). Using our ex vivo stimulation protocol (Talbot et al., 2012), tissue sections were tested for insulin‐induced phosphorylation of insulin signaling and regulating enzymes after 30 min incubations in 0, 1, or 10 nM insulin with or without 30 min preincubation in 100 nM of liraglutide activating GLP‐1 (glucagon‐like peptide‐1) receptors, [D‐Ala2]‐GIP activating GIP (gastric inhibitory peptide) receptors, or Peptide 19, a dual IRA activating both GLP‐1 and GIP receptors. Statistical significance was defined as p < 0.05.

Result

HF responsiveness to 1 and 10 nM insulin was significantly reduced in both the MCI and ADd samples. Pretreatment with each of the IRAs tested virtually restored normal insulin responsiveness in both MCI groups even though the proximal cause of insulin resistance in naMCI differed from aMCI and ADd. Only the dual IRA, however, significantly increased insulin responsiveness in ADd samples.

Conclusion

IRAs reaching brain neurons can virtually eliminate hippocampal insulin resistance in naMCI and aMCI cases, but significantly reducing such resistance in ADd cases appears to require a dual IRA.
Usefulness of Safinamide in Lewy Body Dementia
Authors: Oliveros‐Cid Antonio , Moreno Lisbed Rondon , Martinez Esther Sierrra , Beltran Pablo Navarro , Miguel Nicolas Fayed , Lopez Maria Angeles Cid , Salvador Fernando Jarauta , Oliveros‐Juste Antonio
Published: January 2025

Background

The therapeutic management of dementia with Lewy bodies (LBD) is a challenge given the high sensitivity to drugs in this disease. This is particularly sensitive with regard to the management of parkinsonism. In particular, treatment of motor symptoms with levodopa or dopaminergic agonists poses a risk of worsening cognitive and behavioral symptoms. Safinamide is a drug with several mechanisms of action (dopaminergic and non‐dopaminergic), authorized to treat idiopathic Parkinson’s disease, complementary to levodopa alone or in combination with other antiparkinsonian drugs, in patients with fluctuations. The scarce literature on the use of safinamide in MCI shows benefits with few side effects.

Method

We present 4 cases of patients with Dementia with Lewy Bodies (DLB) evaluated in our clinics, where safinamide improved motor symptoms without worsening cognitive or behavioral symptoms. MDS‐UPDRS (I, II, III, IV), RBDSQ, CGI‐S, CGI‐C, SEADL, PGI‐S, PGI‐C, MDS‐NMS, MoCA, CDT, RBANS were performed before and after at least 3 months of Safinamide therapy.

Result

The study included 3 males and 1 female aged between 63 and 78 years, diagnosed with DLB 1 to 4 years before starting Safinamide treatment. The most evident parkinsonian symptoms were axial rigidity, antecollis, camptocormia, simple and complex motor fluctuations, and freezing of gait. All of them exhibited fluctuations in both motor and cognitive evolution, with characteristic cognitive decline and visual hallucinations. All had previously received treatment with L‐dopa and were on acetylcholinesterase inhibitor therapy. UPDRS‐III scores ranged from 24 to 43 points. Initial safinamide dose: 50 mg/24 h. Final safinamide dose: 100 mg/24 h. Mean improvement in UPDRS: 17%.

Conclusion

In these 4 isolated cases, we observe that safinamide treatment improved axial and appendicular rigidity without worsening cognitive or behavioral symptoms. It could be considered as a safe and effective option in DLB, even in patients with insufficient improvement with L‐dopa, and without clinically significant interactions with acetylcholinesterase inhibitors. Further extensive studies would be necessary to confirm this preliminary observation.
Social vulnerability and cognitive functioning among older adults in the United States National Health and Nutrition Examination Survey
Authors: Arboleda‐Merino Laura C , Walker Erika , Fansler Samuel D , Park Sung Kyun , Bakulski Kelly M.
Published: January 2025

Background

Numerous social factors, including socioeconomic status, education, and healthcare access, influence health outcomes in older adults. Despite the potential clinical utility of assessing social vulnerability, it is not routinely evaluated in clinical assessments of older adults. This study aims to investigate the association between cognitive decline and a comprehensive social vulnerability index, defined as an index comprising many social factors such as income, education, and housing tenure.

Method

The study used data from the US National Health and Nutrition Examination Survey (NHANES) 1999‐2002 and 2011‐2014 cross‐sectional cycles. Cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0‐117) among participants 60+ years of age. Social vulnerability was assessed using a modified Social Vulnerability Index (SVI) based on components such as race/ethnicity, household income, education, health insurance, employment, housing tenure, and food security, with scores indicating the degree of social vulnerability ranging from 0 (least vulnerable) to 7 (most vulnerable). Associations of social vulnerability with cognitive function (adjusted for sex, age, and NHANES cycle) were analyzed by generalized linear models.

Result

Participants with complete cognition and demographic measures (n = 5,272) were of mean age 70.5 years, 51.1% female, 68.0% had completed high school or above, and 55.0% were non‐Hispanic White. The mean DSST score was 43.3 (SD = 18.1), and 24.8% had low cognitive performance (lowest 25th percentile; DSST<31). The mean SVI was 2.55 (SD = 1.67). In adjusted analyses, each additional social deficit—a one unit increase in the Social Vulnerability Index—was associated with almost 6 points lower DSST score (β: ‐5.97; 95% Confidence interval (CI): ‐6.20, ‐5.74; p <0.0001).

Conclusion

Our results suggest that increasing social vulnerability, defined by using a social vulnerability index incorporating many social factors, is associated with lower cognitive functioning among older adults. The results suggest the need for further investigation into the relationship between social vulnerability and cognition, with a focus on exploring potential interventions to mitigate its impact.
The Multiple Neurovascular Pathologies in Older Adults Living with and without Peripheral Insulin Resistance
Authors: Mehta Rupal I. , Capuano Ana W. , Biswas Roshni , Bennett David A. , Arvanitakis Zoe
Published: January 2025

Background

The overall odds and permutations of neurovascular pathologies (NVP) in older adults living with diabetes or peripheral insulin resistance (PIR) have not been comprehensively investigated. Moreover, specific biological mechanisms linking apolipoprotein E (ApoE) genotype, NVP, and Alzheimer’s disease (AD) remain unclear. Here, we examine the odds and permutations of NVP in older adults with PIR in relation to those without.

Materials and Method

This study evaluated older adults who were followed in longitudinal studies of aging and underwent autopsy. Annual clinical evaluations included data to classify PIR status by history, direct medication inspection, and/or blood hemoglobin A1C level (≥6.5%). Neuropathological examinations were systematically performed upon death and included evaluation for NVP and AD pathology. Logistic regression models were used to analyze the association of PIR with the presence of moderate to severe NVP as well as NVP permutations, respectively, in persons with or without ApoE ε2 or ε4 allele and/or AD.

Result

A total of 1997 older adults (404 with PIR) were studied. Participants died at mean age of 89 years (SD = 6.81 years). Overall, persons with PIR had higher odds of chronic macroinfarcts (odds ratio (OR), 1.33 [95% CI, 1.08–1.65]) and chronic microinfarcts (OR, 1.37 [95% CI, 1.10‐1.71]) but exhibited lower odds of CAA (OR, 0.74 [95% CI, 0.59–0.92]). Analysis of NVP permutations revealed that single pathologies (with absence of others) were most common, followed by combined microinfarcts plus macroinfarcts. Persons with PIR had higher odds of microinfarcts alone (OR, 1.56 [95% CI, 1.02–2.37]), macroinfarcts alone (OR, 1.54 [95% CI, 1.01‐2.35]), and combined microinfarcts with macroinfarcts (OR, 2.02 [95% CI, 1.21‐3.35]). However, the odds of microinfarcts were not significantly higher in persons with PIR when controlling for the presence of ApoE ε2 allele, and only the presence of both types of infarcts together was significantly higher in PIR after controlling for the presence of ApoE ε4 allele with or without AD.

Conclusion

This study examined multiple NVP in persons with and without PIR. It shows that older adults living with PIR, relative to those without, have higher odds of microinfarcts and macroinfarcts in the absence of CAA, atherosclerosis and arteriolosclerosis.
Metabolomics Analysis of the MIND Study Informs about Metabolic Benefit and Heterogeneity among Individuals‐ A Precision Medicine Approach for Diet Interventions
Authors: MahmoudianDehkordi Siamak , Voigt‐Zuwala Robin M , Dhana Klodian , Labus Jennifer S , Mohanty Ipsita , Agarwal Puja , Morris Martha Clare , Barnes Lisa L. , Sacks Frank , Batra Richa , Kastenmuller Gabi , Keshavarzian Ali , Kaddurah‐Daouk Rima ,   Alzheimer's Gut Microbiome Project Consortium (AGMP)
Published: January 2025

Background

Metabolomics captures net influences of exposome, diet, gut microbiome, and genome, informing about individuality and how we respond to interventions. Applications of metabolomics in pharmacology are starting to enable a Systems Pharmacology approach, where the outcome of a treatment is considered to evolve from effects on complex molecular networks, enabling insights into response variations. We bring the power of these approaches to the study of the MIND, a Mediterranean DASH diet for prevention of cognitive decline. We evaluate if metabolomics can reveal beneficial metabolic effects linked to improved cognition in all participants or subgroups of individuals.

Methods

Serum samples were collected from participants enrolled in the MIND trial at the Rush University Medical Center site. Participants were randomized to either the MIND diet or control diet group for three years with study visits, cognitive testing, and sample collection occurring at baseline, Years 1, 2, and 3. A total of 746 serum samples from 243 participants were profiled using targeted and non‐targeted metabolomics, lipidomics, metagenomics, and foodomics approaches. The longitudinal effects of the diet on the metabolome were evaluated.

Results

We identified metabolic signatures of participants on the MIND diet that were unique compared to the control diet. Major changes in lipid metabolism including ceramides, sphingomyelins, PUFAs, and plasmalogens were noted along with changes in energy metabolism and one carbon metabolism (Figure 1). Food components and exposome‐related metabolites were changed. For example, tryptophan betaine (lower in cognitive dysfunction) was increased in the MIND diet group with strongest effects in individuals with low levels at baseline. Additionally, glycoprotein acetyls (GlycA, an inflammation marker associated with AD, cognitive decline, reduced brain volume) was decreased in the MIND diet group compared to controls. Detailed mapping of influences on the gut microbiome are being defined and linked to changes in metabolome.

Conclusion

The metabolomics data highlighted alterations in metabolism in response to MIND diet. These alterations suggest metabolic benefit for cognitive function and inflammation based on big metabolomics data in ADNI and other cohorts. The variation among individuals seen in our analysis warrants stratification of people enrolled in the MIND study before final conclusions are made on its outcome.
Optimizing referral pathways to a community based organization for early‐stage Alzheimer’s and dementia Cognitive Stimulation Therapy services
Authors: Shivers Stephani , Tiede Lauren , Ehrhardt Annabess , Cisek Edward , Curbeam Deanna , Lepore Michael
Published: January 2025

Community‐based organizations (CBOs) are an essential part of dementia service delivery to people living with dementia (PLWD) and family caregivers (CG) impacted by Alzheimer’s and other dementias, however use of CBO services particularly by PLWD is limited. Referral of PLWD to CBOs by health systems (HS) and health care providers (HCPs) is a common way that PLWD come to use CBO services, but integration between CBOs and HS/HCPs is inconsistent. For example, referrals to CBOs might come from HS/HCPs or from other CBOs, these referrers might provide referrals for a single program or for multiple different programs, and the referrers might be physicians, social workers, case managers, or other clinicians. Aiming to advance effective integration with the broader constellation of HS/HCPs and CBOs, CaringKind, a CBO providing dementia services, examined the outcomes of referrals from different clinical contexts and different referral sources. This program analysis leverages CaringKind’s referral data and information on enrollment and participation in CaringKind’s Cognitive Stimulation Therapy (CST) program, which receives referrals as one of many programs available in standard operating procedures, and receives referrals in the context of a pragmatic trial with no other program options.

Drawing on referrals to CaringKind for CST over the course of an 18‐month period, we calculated the rates of conversion from CST referral to CST participant to count successful referrals. We then compared the successful referral rates in standard operations with the successful referral rates in the pragmatic trial. Results show the percentage of successful referrals from physicians in the pragmatic trial compared to providers in standard practice. Lessons learned on the referral pathway process including the impact of re‐education to identify the most appropriate patients for CST will be highlighted. Participant outcomes and completion rates gathered for program evaluation will also be shared.
Unveiling Insight: Autopsy findings on Alzheimer’s Disease Clinical Trial Participants and the multifaceted existence of comorbid pathologies
Authors: Coskun Elif PINAR , Barber Justin M , Abner Erin L. , Schmitt Frederick A , Goldstein Larry B , Van Eldik Linda J. J. , Nelson Peter T , Jicha Gregory A
Published: January 2025

Background

The presence of multiple comorbid pathologic features in late‐onset dementia has been well documented across cohort studies that incorporate autopsy evaluation. It is likely that such mixed pathology potentially confounds the results of interventional trials that are designed to target a solitary pathophysiologic mechanism in Alzheimer’s disease and related dementias (ADRD).

Method

The UK ADRC autopsy database was screened for participants who had previously engaged in therapeutic interventional trials for Alzheimer’s disease, vascular cognitive impairment, dementia, and/or ADRD prevention trials from 2005 to the present. Sixty‐five cases (out of a total n = 534) were engaged in clinical trials for the prevention or treatment of ADRD. Pathologic features studied included b‐amyloid, tau, a‐synuclein, TDP‐43, and cerebrovascular disease using conventional rating scales.

Result

Autopsy cases for those who previously engaged in clinical trials did not differ significantly from those that were trial‐naïve for demographic, genetic (ApoE), or clinical characteristics except for CDR global scores that were lower for past trial participants (p<0.05). Comorbid pathologies were common across study types with a mean of 3 pathologic features/participant, 17% with quadruple misfolded proteinopathy (QMP; Ab+tau+synuclein+ TDP43). Yet only 10% of MCI/AD trial participants demonstrated a “pure” disease state that was targeted by the study intervention.

Conclusion

In our study, approximately 2 out of 3 ADRD trial participants had comorbid mixed pathologic features. Understanding the heterogeneity of pathologies seen in clinical trial participants may allow improved inclusion/exclusion criteria based on clinical features and the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathology. In addition, the recognition will allow the usage of combination therapy for future interventional strategies. Such insights may also enable improved power analyses and statistical designs that may be able to adjust for the confounds of such mixed pathologic disease states that are common in ADRD clinical trials.
Latent Representation Learning of Cortical Atrophy using BERT‐based Foundation Model
Authors: An Heeyun , Kim Jiyun , Seong Joon‐Kyung , Lee Wha Jin
Published: January 2025

Background

The assessment of cortical thickness through structural magnetic resonance imaging (MRI) reveals various cortical atrophy patterns, delivering crucial insights into the extent of neurodegeneration. Numerous studies have focused on these thickness values to construct models for diverse neurodegeneration‐related tasks, such as classifying disease groups, staging progression, or predicting progression speed. However, these tasks require substantial training datasets tailored to each specific task, necessitating the development of new task‐specific models. We aimed to establish a foundational model using pre‐trained BERT, integrating context‐aware deep latent representations derived from a large cohort of unlabeled cortical atrophy data, to address these challenges.

Method

We collected 10,450 T1‐weighted MRI images within the ADNI dataset. Cortical thickness was derived using FreeSurfer across 68 regions based on the Desikan‐Killiany atlas. Emplying the BERT model, we applied its self‐attention capabilities to encode deep bidrectional representations of the data. The model is pre‐trained with 8,360 unlabeled cortical thickness data through self‐supervised learning, predicting randomly masked thickness values. Subsequently, we fine‐tuned this pre‐trained model with only one additional output layer using a supervised approach, employing independent data subsets for three challenging downstream classification tasks: (1) mild cognitive impairment (MCI) and Alzheimer’s dementia (AD), (2) MCI converters (C‐MCI) and non‐converters (N‐MCI) within 3 years, and (3) Aβ‐positive and negative cases. During fine‐tuning, demographic information encoded by one layer was also incorporated for classification purposes.

Result

Table 1 provides demographic details of the subset data for fine‐tuning, showing comparable trends in each set of information, except for MMSE in the MCI and AD comparison. Table 2 outlines our model's performance on three downstream classification tasks. Despite training with a relatively limited amount of data, our model demonstrated competitive performance with state‐of‐the‐art methods, achieving 85% accuracy on the classification of MCI and AD, 85% of C‐MCI and N‐MCI, and 69% of Aβ‐positive and negative.

Conclusion

This study introduces the novel cortical atrophy foundation model, demonstrating competitive performance even with a limited dataset across diverse challenging tasks. The model's performance in predictive tasks highlights its potential applicability for various nerodegeneration‐related challenges, paving the way for advanced AI applications within the realm of neurodegenerative diseases.
Accounting for White Matter Uptake Improves Between‐Tracer Agreement in Amyloid PET
Authors: Chen Yinghua , Protas Hillary D. , Luo Ji , Li Shan , Sohankar Javad , Ghisays Valentina , Lee Wendy , Wu Teresa , Reiman Eric M. , Chen Kewei , Su Yi
Published: January 2025

Background

Different PET tracers can be used to measure neuritic amyloid plaque deposition in human brain. While mean cortical‐to‐cerebellar standard uptake value ratios (SUVRs) generated using different radiotracer methods can be transformed into Centiloid measurements to facilitate comparisons among the resulting amyloid plaque measurements, the level of agreement as measured by the strength of the correlation between the measurements does not change. In this study, paired 18F‐labeled (i.e., florbetapir, florbetaben, flutemetamol, and NAV4694) and 11C PiB radiotracers from the same research participants to test the hypothesis that the correlation between amyloid plaque measurements derived using different radiotracers can be improved by accounting for variability in white matter uptake.

Method

For all four 18F‐labeled radiotracers, paired 18F‐radiotracer and PiB‐derived PET images were downloaded from the Centiloid project (www.gaain.org/centiloid‐project). An in‐house image‐analysis pipeline was used to generate mean cortical‐to‐cerebellar SUVRs (MC‐SUVRs) from every PET image. Two approaches to account for white matter contributions to MC‐SUVR in the inherently low‐resolution PET images: 1) a linear regression approach to account for white matter contributions using a FreeSurfer‐defined UnsegmentedWhiteMatter SUVR; and 2) a regional spread function (RSF)‐based partial volume correction (PVC) technique. Pearson’s correlation coefficient was used to assess the agreement between F18 tracer‐based measure and PIB. Steiger’s test was used to determine whether accounting for white matter signal significantly improves agreement.

Result

Accounting for white matter signal improved the agreement between each 18F radiotracer‐based MC‐SUVR and the corresponding PiB‐derived MC‐SUVR. Using the regression approach, the correlations with PiB SUVRs were significantly improved for florbetapir (p<0.0001) and flutemetamol (p=0.03) but did not reach significance for florbetaben and NAV4694. For the PVC‐based approach, correlations with PiB SUVRs were significantly greater for all four 18F‐tracers (p<0.05).

Conclusion

The relationship between mean cortical measurement of amyloid plaque burden using different PET tracers can be significantly improved by accounting for differences in white matter uptake. Additional studies are needed to optimize this approach and account for any other potential confounds.
Impact of free later life formal university education on longitudinal modifiable risk factors, cognition and plasma phosphorylated tau 181
Authors: Roccati Eddy , Bindoff Aidan , Kitsos Alex , Alty Jane E , Collins Jessica M , King Anna E , Doherty Kathleen , Vickers James C
Published: January 2025

Background

Previous research has focused on early‐life education to reduce dementia risk, yet there is great potential for enhancing cognitive reserve in later‐life through educational interventions, even for people with low early‐life educational attainment. In 2019, we launched ISLAND (Island Study Linking Ageing and Neurodegenerative Disease) Campus, offering free university study to participants, with flexible in‐person/online learning models removing educational, socioeconomic and geographical barriers. After four years, here we investigate our core hypothesis: that engagement in later life education leads to improvements in modifiable risk factors for dementia, cognition and plasma biomarkers.

Method

ISLAND Campus participants were matched on age and gender to non‐Campus participants via propensity score method, with optimal matching based on logistic regression. Participants completed online surveys on background health, demographics, modifiable dementia risk via customised Dementia Risk Profile (DRP) and provided a blood sample for APOE genotyping and plasma phosphorylated‐tau (p‐tau) 181. Cognition was measured online via the validated Cambridge Neuropsychological Test Automated Battery Paired Associates Learning (PAL) and Spatial Working Memory (SWM) tasks. Impact of the opt‐in educational intervention was tested in R via ANCOVA.

Result

Included were 986 participants (intervention = 493, control = 493), mean age 61.2 years, 71.2% female, 11.7 mean years of education, 23.9% APOE e4+. Intervention and control participants were similar on socioeconomic status, location of residence, p‐tau and APOE e4 presence, however intervention participants had significantly higher history of prior university study completion (76.1%) than controls (59.8%). Intervention participants enrolled in a variety of university degrees, the most common were Diploma of Family History (n = 103, 20.8%), Diploma of Arts (n = 74, 15.0%) and Diploma of Fine Arts (n = 52, 10.6%). Over four years of follow‐up, intervention participants significantly improved episodic memory (PAL) and their risk factor profiles as measured via the DRP (p <0.001), indicating a significant change towards lower dementia risk.

Conclusion

We found free later‐life university education was associated with improvements in modifiable dementia risk factors over time and cognition. Intervention participants displayed significantly higher baseline education than control participants, therefore later life educational interventions should be targeted at individuals with lower baseline education.
causal effects of air pollution on dementia: a mendelian randomized study
Authors: GUO YUNYUN , Sindi Shireen , Wang Rui , Middleton Lefkos T , Kivipelto Miia
Published: January 2025

Background

The 2017 Lancet Commission on Dementia Prevention, Intervention and Care included air pollution in the list of potential risk factors for dementia. Air pollution has been associated with an increased risk of dementia in observational studies, but the causal relationship remains unclear. In this study, we used a two‐sample Mendelian randomisation (MR) analysis to assess the causal relationship between PM2.5, PM10, NO2 and NOX exposure and the occurrence of dementia, including Alzheimer’s disease (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia.

Method

We extracted 5 single nucleotide polymorphisms associated with PM2.5, 22 single nucleotide polymorphisms associated with PM10, 6 single nucleotide polymorphisms associated with NO2 and 8 single nucleotide polymorphisms associated with NOX as instrumental variables from a genome‐wide association study based primarily on European ancestry. Summary‐level statistics were obtained from the Dementia GWAS database and the FinnGen consortium. MR estimation was based on the inverse variance weighting (IVW) method as the primary method, supplemented by the MR‐Egger and weighted median (WM) methods. Finally, multiple validity tests and sensitivity analyses were performed to obtain robust and valid estimates.

Result

According to the IVW method, we found a positive association between PM10 and AD risk (OR: 2.03, 95% CI: 1.06‐ 3.89, p = 0.03); NO2 may increase the risk of AD (OR: 14.41, 95% CI: 10.95‐ 18.97, p = 0.04). However, there is insufficient evidence that PM2.5 and NOX are associated with an increased risk of future dementia.

Conclusion

Our study suggests that PM10 and NO2 are causally associated with AD risk. PM10 and NO2 may increase the risk of AD in people of European origin. More animal experiments or population‐based observational studies with long follow‐up are needed in the future to explore the intrinsic mechanisms of PM10, NO2 and AD.
Adherence to the MIND Diet and Cognition in Older Adults: A Post‐hoc Analysis of the MIND Trial
Authors: Dhana Klodian , Agarwal Puja , Ventrelle Jennifer , Liu Xiaoran , Tangney Christy C , Carey Vincent J , Aggarwal Neelum T. , Arfanakis Konstantinos , Barnes Lisa L.
Published: January 2025

Background

The MIND randomized clinical trial demonstrated that the effect of the 3‐year MIND diet intervention on cognition was no different than the calorie‐restricted usual diet in overweight, non‐demented, older adults. However, compliance with dietary interventions may have differed among the participants within the intervention groups. We assessed the adherence to MIND diet (MIND score) and and evaluated the association with global cognition.

Method

This study include 551 individuals with MIND diet score, covariates, and cognitive assessment at baseline and year 3. The MIND diet score (range 0‐14; a higher score reflects a healthier diet) was computed at baseline and during the follow‐up from responses to the 144‐item validated FFQ, and the average within individuals across the follow‐up was calculated. In addition, we computed the absolute (year 3 ‐ baseline) and relative change [((year 3 ‐ baseline)/baseline)*100]. Global cognition was derived from a standardized 12‐test cognitive battery. Regression models were adjusted by age, sex, race, APOE e4, education, cognitive activities, physical activity, BMI, total energy intake, and diet assignment group.

Result

Higher adherence to the MIND diet across the study period was associated with significant improvements in global cognition scores. In the multivariable‐adjusted model, a 1‐point increase in the MIND diet score was associated with 0.027 (95%CI 0.004, 0.051) SD units higher in a 3‐year change in the global cognitive score. Compared to individuals with lower MIND diet scores (i.e., the first tertile), those in the third tertile had 0.140 (95%CI 0.033, 0.247) SD units higher in a 3‐year change in the global cognitive score. Similar associations were noted when we compared the relative changes of the MIND diet score with a 3‐year change in the global cognitive score. These associations (i.e., average MIND score, absolute, and relative changes) with cognition were not different between dietary interventions (P for interaction > 0.4).

Conclusion

Adherence to the MIND diet varied across individuals in the MIND trial. A higher MIND diet score during 3 years of dietary interventions was associated with better cognitive performance in older adults.
Información de la Enfermedad de Alzheimer para Latinos: A Study Framework for Alzheimer’s Genetic Risk Disclosure in an Urban, Latino Population
Authors: Rodriguez Sophia , Caro Daniela Diaz , Wetmore John Brandon , Godinez Jonathan D , Camarillo Itzel A , Goldman Jill S , Uhlmann Wendy R. , Ferber Rebecca , Blasco Drew , Caban Maria , Leu Cheng‐Shiun , Abraido‐Lanza Ana F , Lantigua Rafael A. , Chung Wendy K , Roberts J. Scott , Siegel Karolynn , Ottman Ruth
Published: January 2025

Background

The IDEAL study is a randomized clinical trial investigating the psychosocial, behavioral, and cognitive impacts of genetic risk disclosure for late‐onset Alzheimer’s disease (LOAD) among Latinos.

Methods

We used address‐based sampling in northern Manhattan to recruit Latinos aged 40‐64 for a community‐based survey and clinical trial. Data collection encompasses demographics, Alzheimer’s disease (AD) family history, knowledge and beliefs about AD and genetics, current mental health status, acculturation, impact of COVID‐19, familism, fatalism, caregiver status, and prior AD genetic testing. Eligible participants are invited to complete an education session and provide informed consent before receiving genetic testing for APOE, a key LOAD predictor. The clinical trial component will include 400 participants, who are randomized to learn their LOAD risk by age 85 based on either Latino ethnicity and family history alone or the same factors plus APOE genotype. Risk information is provided through semi‐structured genetic counseling sessions. Psychological impacts, health‐related behavioral changes, and memory performance are evaluated six weeks, nine months, and fifteen months post‐dislosure via surveys and in‐depth qualitative interviews.

Results

From 91,433 invited households, 5,542 (6.1%) responded, and 2,087 (2.3%) were eligible and completed the Baseline survey. Most were 40‐49 years old (41.2%), women (70.5%), identified as Dominican (53.7%), had some college education (63.2%), and completed the survey in English (74.6%). About half reported a family history of AD (48.6%).

Conclusion

This study addresses gaps in understanding of impacts of AD genetic risk disclosure among Latinos and contributes valuable insights through its mixed‐methods approach.