bluuebunny/crossref_metadata_2025 huggingface dataset:
Human iPSC derived organoid models to study tau pathology
Authors: Bertucci Taylor , Bowles Kathryn , Lotz Steven , Qi Le , Stevens Katherine , Goderie Susan K , Borden Susan , Oja Laura M , Lane Keith , Lotz Ryan , Lotz Hailey , Chowdhury Rebecca , Joy Shona , Arduini Brigitte , Butler David , Miller Michael , Baron Heide , Sandhof Carl Alexander , Silva M. Catarina , Haggarty Stephen , Geschwind Daniel H. , Goate Alison M. , Temple Sally
Published: January 2025

Background

Human pluripotent stem cell (hPSC)‐derived brain organoids patterned towards the cerebral cortex are valuable models of interactions occurring in vivo in cortical tissue. We and others have used these cortical organoids to model dominantly inherited FTD‐tau. While these studies have provided essential insights, cortical organoid models have yet to reach their full potential. Studies are hindered by well‐recognized hurdles: low production efficiency and high variability between individual organoids, across lines, and experiments. A protocol that consistently generates well‐patterned cerebral cortical organoids is needed.

Methods

Two key stages of the protocol were optimized: the initial growth of hPSCs and the first 6 days of differentiation. Analysis of hPSC pluripotency and organoid quality control (QC) measures at 20 day and 2 months was assessed by bulk RNAseq, qPCR and IHC for ± QC and single‐cell RNA sequencing (scRNAseq). The optimized protocol was tested across 63 lines to examine robustness.

Results

We established a 96 Slit‐well plate method for efficient (approaching 100%), scalable, reproducible cortical organoid production. When hPSCs were cultured with controlled‐release FGF2 (FGF2Discs) and an SB431542 concentration appropriate for their TGFBR1/ALK5 expression level, organoid cortical patterning and reproducibility were significantly improved. Well‐patterned organoids included 16 neural subtypes identified by scRNA‐seq, abundant rosettes, and robust BCL11B+/TBR1+ cortical neurons at 2 months. In contrast, poorly patterned organoids contained mesendoderm‐related cells, identifiable by negative QC marker COL1A2 and/or few cortical neurons. Using this improved protocol, we demonstrate increased sensitivity to study the impact of MAPT mutations associated with FTD, and across different MAPT‐mutants, neurons exhibited common early changes in key metabolic pathways, including upregulation of oxidative phosphorylation and dampening of ceramide synthesis and sphingolipid signaling.

Conclusions

Variability between different hPSC lines in the expression of key ligands and receptors contributes to the variability of success of cortical organoid production. Hence, small adjustments in the culture of hPSCs and the concentration of patterning molecules during the first 6 days of differentiation are essential to enable efficient and reproducible organoid production. This allows rigorous comparisons of disease phenotypes using many different lines from different donors and across heritable and sporadic diseases affecting the cerebral cortex.
Deployment of Tablet‐based Cognitive Assessment Tool (TabCAT) for detecting cognitive impairment in elderly Primary Health Care Population in Southeast Nigeria
Authors: OGBUAGU CHUKWUANUGO , Uwakwe Richard , Kahn James G , OGBUAGU Ekenechukwu , Emelumadu Obiageli , Okereke Uzoma , Okeke Irene , Chisom Chigbo , Javandel Shireen , Possin Katherine L , Miller Bruce L. , Valcour Victor , Allen Isabel Elaine , Goode Collette A
Published: January 2025

Background

Cognitive assessment should be actively incorporated into the clinical evaluation of patients in Primary Health Care (PHC) settings. This is because of the imminent demand with the changing demographics especially in low‐ and middle‐income countries (LMICs) concerning dementia and Alzheimer’s disease.

Method

A cross‐sectional mixed‐method descriptive study was conducted to evaluate the useability and performance of a tablet‐based cognitive assessment tool (TabCAT) for use in geriatric primary healthcare settings in southeast Nigeria.

Result

In our study involving 207 participants, with an average age of 64.69 years, educational levels varied, with 51.8% having primary education, 41.2% secondary, and 6.6% tertiary. The research found that education had a significant positive impact on associative memory, processing speed, executive function, language skills, and visuospatial skills (p<0.001). Rural residents exhibited higher scores in associative memory, processing speed, executive function, language, and visuospatial skills (p<0.000). However, gender and location did not show significant contributions to cognitive performance across the examined domains.

Conclusion

There is an urgent need to deploy and routinely conduct cognitive assessments in primary healthcare clinics for elderly patients for early detection of cognitive changes to improve healthy living.
Multispecialty Interprofessional Team (MINT) Memory Clinic Overview and Data From Spread Across Canada
Authors: Lee Linda , Hillier Loretta M , Lee Michael
Published: January 2025

Background

Multispecialty Interprofessional Team (MINT) Memory Clinics build capacity for dementia care within primary care. This presentation will provide an overview of the MINT care model and results of a process evaluation of the implementation of the model in three provinces in Canada using the Research Medical Council framework for evaluating complex interventions.

Methods

178 healthcare providers (HCP) were trained to establish 10 MINT clinics across three Canadian provinces. We collected data on clinic referrals and service provision over a nine‐month period to describe fidelity (assessment adherence; management; timely access), dose (number of assessments, follow‐up appointments), and reach (patients served). We conducted individual interviews with 20 key informants (HCP, system leaders) to learn about the contextual factors that affected implementation and clinic impacts.

Results

Across 10 clinic sites, 521 patients were referred; 368 (71%) completed assessments. All clinics implemented the assessment protocol as fully intended with the exception of two clinics which did not administer depression and caregiver burden screening. The majority of patients (73%) were assessed within a month of referral; 87% of patients were managed in primary care, with 13% referred for specialist consultation. Follow‐up appointments were recommended for 83% of patients assessed (305/368); 33% (N = 123) completed follow‐up appointments. Key themes related to context were: MINT model fits an existing care gap; Multi‐disciplinary collaborative approach; Systematic approach to diagnosis and management; and, the need for easily accessible care close to home. Facilitating factors included: Senior leadership and physician champion support; Access to and support from various disciplines; and Access to resources (funding, space). Identified challenges varied by province and included: Lack of resources (staff, funding, space) and HCP new to dementia care required time to assimilate new knowledge to practice. The clinics were seen as impacting dementia care with: Provision of better dementia care than usually available in primary care; More comprehensive assessment and care plans; Interprofessional collaboration; Increased care partner support, and Quicker access to assessment and diagnosis.

Conclusions

The implementation of the MINT model in three provinces with different health systems demonstrates its scalability and its potential to improve dementia care in differing jurisdictions.
Current epidemiological and experimental evidence relating the chemical exposome to Alzheimer’s disease
Authors: Lefèvre‐Arbogast Sophie , Chaker Jade , Mercier Fabien , Barouki Robert , Coumoul Xavier , Miller Gary W , David Arthur , Samieri Cécilia
Published: January 2025

This critical overview aims to provide one of the most comprehensive synthesis of epidemiological and experimental evidence relating the chemical exposome to Alzheimer’s Disease (AD). We have focused on chemical pollutants that mostly result from anthropic activities and involved in toxicology pathways, including pesticides, organic solvents, metals, combustion air pollutants, dioxins, flame retardants, fluorosurfactants, plastic components and food/cosmetic additives. In total, we have reviewed over 120 epidemiological studies examining the link between chemical exposures and the risk of AD or cognitive impairment in older adults, along with more than 250 experimental studies assessing the impact of chemical exposures on neurodegeneration‐related pathways.

The predominant emphasis in epidemiological research has been on pesticides, metals, solvents and combustion air pollutants. The most consistently observed associations with AD/cognitive impairment involve occupational exposure to pesticides and exposure to fine particulate matter. Less is known about the impact of lower levels of pesticide exposure in the general population, with emerging evidence supported by a few studies. Conversely, in the general population, there is growing evidence of the role of air pollution, especially increased exposure to fine particulate matters, in AD. Regarding metals and solvents, associations with AD have been suggested in several case‐control or cross‐sectional studies but the overall weight of evidence remains low. In experimental studies, pesticides and metals have also been the most extensively investigated and predominantly implicated in the disruption of neurotransmission, oxidative stress and mitochondrial dysfunction; some pesticides might also specifically target amyloid‐β aggregation.

Finally, our comprehensive literature review highlights a gap in knowledge concerning the influence of many chemical exposures on AD, especially the most recent pesticide families as well as synthetic additive chemicals considered as ubiquitous. Yet, some of these chemicals have been incriminated in neurodevelopmental defects, and there exists suggestive, albeit still limited, evidence of their involvement in neurodegeneration‐related pathways, such as neurotransmission disruption, supporting the need for further research efforts.
Toxicological evaluation of environmental chemicals associated with AD identified using an exposomic framework
Authors: Kalia Vrinda
Published: January 2025

Exposure to environmental chemicals has been associated with Alzheimer’s disease (AD); however, most studies have used a targeted approach to study this relationship. While targeted approaches have been critical to understand mechanisms, they do not reflect real world exposures where an individual is exposed to multiple chemicals at the same time. Exposomics provides the opportunity to use an ‐omics level approach to understand the environmental drivers of disease by measuring the burden of multiple chemicals at the same time. Using an exposomic approach, we found a metabolite of the legacy pesticide DDT to be associated with AD in an observational study. We then investigated whether DDT can exacerbate AD‐related pathology using a transgenic strain of the nematode model Caenorhabditis elegans (worm) that expresses a mutant tau protein fragment that is prone to aggregation.

Exposure to 3µM DDT resulted in internal levels of 0.5 pg (SD: 0.01) p, p’‐DDT per worm and 0.1 pg (SD: 0.01) of its metabolite p, p’‐DDE. We found that exposure DDT significantly restricted growth in the transgenic strain more than it does in wildtype worms. Further, DDT significantly lowered mitochondrial respiration rates in both strains. High‐resolution mass spectrometry‐based metabolomics (HRMS) analysis using the whole worm showed reduced levels of several amino acids and an increase in adenosylselenohomocysteine in DDT exposed worms. DDT exposure in the transgenic strain significantly increased the amount of time spent curling. The curling phenotype has been previously associated with mitochondrial dysfunction. Our data suggest that low level exposure to DDT likely exacerbates the mitochondrial inhibitory effects of aggregating tau protein in C. elegans.

We are investigating the relationship between persistent organic pollutants and age‐related cognitive decline in the Reference Ability Neural Network study. This study, conducted in healthy volunteers, allows us to consider the relationship between exposure and poor cognitive function without confounding by underlying disease. We plan to investigate the potential mechanism through which these chemicals affect neuronal health while considering them as a mixture using C. elegans. Recent advancements in predictive toxicology provide a starting point to consider the appropriate health and functional end points that should be investigated.
Research gaps and unmet challenges to study the impact of chemicals on neurodegenerative diseases
Authors: Samieri Cécilia , Lefèvre‐Arbogast Sophie , Chaker Jade , Mercier Fabien , Barouki Robert , Coumoul Xavier , Miller Gary W , David Arthur
Published: January 2025

Chemicals are ubiquitous in modern life. More than 100,000 chemicals are currently used worldwide, and the production continues to increase. Measuring with accuracy all the components of the chemical exposome represents a tremendous challenge which has been only very partly met so far, and gaps in science remain multiple. For example, there is a need for a comprehensive understanding of the chemical exposome’s impact on the brain, emphasizing the integration of various exposure routes and an expanded list of emerging concern chemicals. Biomonitoring, a relatively recent approach, has begun linking internal exposure to neurological impacts, shedding light on the potential neurotoxicity of non‐persistent pesticides like neonicotinoids and pyrethroids. Research should explore overlooked ubiquitous chemicals, such as flame retardants, fluorosurfactants, plasticizers, and food additives, and overlooked pathways such as neurovascular dysfunction or the impact on non‐neuronal cells.

Furthermore, analytical challenges posed by exposomic studies are specifically important, since the chemical space is highly variable, dynamic and diverse in concentration levels (with ultra‐trace substances). Chemical exposures are multiple and potential additive or synergistic effects of chemicals, within mixtures, likely underlie the impact of the chemical exposome on the brain. Capturing the depth and breadth of that chemical exposome necessitates cutting‐edge molecular markers. The development of high throughput omics‐based molecular approaches has allowed simultaneous analysis of thousands of individual biological entities at a large scale – a technological revolution which has enabled the development of exposomics. High‐resolution mass spectrometry (HRMS)‐based methods applied to various matrices, allows to uncover unknown elements of the internal chemical exposome associated with neurodegenerative diseases.

This presentation will discuss all the promises that new technologies combined with omics‐based methodologies could provide to uncover unknown chemical signatures associated to neurodegenerative diseases.
Sleep health, cognitive function, and self‐management skills in middle‐aged adults
Authors: Kim Minjee , Yeh Fangyu , Zheng Pauline , Kwasny Mary , Yoshino‐Benavente Julia , Curtis Laura M , Bailey Stacy C , Bonham Morgan , Sun Britney , Luu Han Q , Cecil Patrick , Agyare Prophecy , Zee Phyllis C , Wolf Michael S
Published: January 2025

Background

Poor sleep health has been associated with worse cognitive and health outcomes in older adults. Less is known about this relationship in midlife. Thus, we aimed to investigate the relationship between self‐reported sleep health, cognitive function, and performance on common health tasks among middle‐aged adults, as sleep may be a modifiable target to address later life risk of cognitive decline.

Method

English‐speaking adults aged 35‐64 were recruited from an academic general internal medicine practice and federally qualified health centers in the greater Chicagoland area. Multidimensional sleep health (regularity, satisfaction, alertness, timing, efficiency, and duration) was measured by the RU‐SATED questionnaire. Global cognitive function was measured using the Montreal Cognitive Assessment (MoCA); age‐ and education‐adjusted Z‐scores were calculated. Cognitive impairment was defined as MoCA Z‐score lower than one standard deviation below population mean. Performance on common health tasks (e.g. comprehension of print health material, recall of spoken instructions, dosing medications, recall of multimedia education) were assessed using the Comprehensive Health Activities Scale (CHAS). We examined the association between sleep health, cognitive impairment, and health task performance using univariate and multivariable logistic regression. Covariates, selected a priori, included age, sex, number of chronic conditions, and depressive symptoms.

Result

A total of 310 participants (mean age 51.2 ± 8.1; 66% female; 39% non‐Hispanic Black, 32% non‐Hispanic White, 21% Hispanic; 54% with 2+ chronic conditions) were included in analyses. The median sleep health score was 8 (interquartile range: 6‐10) and cognitive impairment was found in 11.3%. Poorer sleep health was significantly associated with cognitive impairment after adjusting for a priori covariates (adjusted odds ratio, 0.98; 95% CI, 0.96‐0.99; P = 0.007). Both poorer sleep health (ß, 1.11; 95% CI, 0.22‐1.99; P = 0.014) and cognitive impairment (ß, ‐27.7; CI, (‐34.3)‐(‐21.1); P<0.001) were independently associated with poorer performance on health tasks, after adjusting for a priori covariates.

Conclusion

Poorer self‐reported sleep health in midlife was associated with a greater likelihood of cognitive impairment, whereas both poorer sleep health and cognitive impairment were associated with lower self‐management abilities to navigate healthcare. Future studies should examine whether sleep‐targeted intervention in midlife can mitigate cognitive later‐life decline and poorer health outcomes.
Dietary intervention, biomarkers of brain pathology and neurodegeneration, and cognition: The MIND Trial Study
Authors: Dhana Klodian , Rajan Kumar B , Aggarwal Neelum T. , Arfanakis Konstantions , Carey Vince J , Sacks Frank , Barnes Lisa L.
Published: January 2025

Background

Plasma levels of phosphorylated tau (pTau‐181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) as biomarkers of brain pathology and neurodegeneration have been associated with cognition and Alzheimer’s dementia. Whether a dietary intervention modifies these relationships by potentially promoting cognitive reserve is unknown. We conducted a posthoc analysis of the MIND trial to investigate whether dietary intervention modifies the association of longitudinal changes in pTau‐181, NfL, and GFAP with cognition during 3 years of follow‐up.

Method

MIND trial was a 3‐year, two‐site, randomized controlled clinical trial comparing the MIND diet with a usual diet on cognitive changes among 604 older participants (65 to 85 years) with a family history of dementia but without cognitive impairment, overweight, and with suboptimal diets at enrollment. pTau‐181, NfL, and GFAP were measured in plasma from blood collected after an overnight fast. Relative change in biomarkers (i.e., %change) from baseline to Year 3 were computed [(year 3 ‐ baseline)/baseline)*100]. Global cognition was derived from a standardized 12‐test cognitive battery. We included 508 individuals with biomarkers and cognitive assessments at the baseline and year 3.

Result

Changes in pTau‐181 and NfL were associated with global cognition. One SD increase in %change of pTau‐181 was associated with 0.049 SD units lower in cognition at year 3 ($∖beta$ ‐0.049; 95%CI ‐0.081 to ‐0.016). For NfL, cognition was 0.044 SD units lower at year 3 (β ‐0.044; 95%CI 0.076 to ‐0.012). The strength of these associations differed by the dietary arm (p for interaction = 0.063), such that effects were attenuated in the MIND diet arm and more robust in the control arm. Specifically, pTau‐181 in the MIND diet group was ‐0.027 (p = 0.264), and in the control group, ‐0.076 (p = 0.001). For NfL, these estimates were ‐0.022 (p = 0.263) and ‐0.087 (p = 0.002) in the MIND and control diet arms, respectively.

Conclusion

Levels of biomarkers reflecting neurodegeneration increase with age, and we showed that the greater increase was associated with lower cognitive scores. Among individuals with greater changes in biomarkers, MIND diet intervention attenuated the association with cognition, suggesting that the MIND diet may promote cognitive reserve in older adults.
Expanding Clinical Services to Hispanic/Latinx Dementia and Caregiver Populations in Central Virginia
Authors: Tlatenchi Antonio A Martinez , Sabino Yenifer A Valera , Rossetti M. Agustina
Published: January 2025

Background

Hispanic/Latinx older adults have increased risk of developing Alzheimer’s disease, poor access to timely and quality dementia care, as well as limited access to caregiver support and interventions. We addressed these structural barriers at a local level in central Virginia in order to improve disparities in risk, early detection, and care.

Method

Systematic expansion of services was undertaken by establishing a Spanish neuropsychological clinic, providing personalized scheduling services by providers to ensure appropriate follow‐up after referral is received, engaging in dementia specific community talks through a broader health system initiative (UVA Latinx Health Initiative), and facilitating dementia care coordination services for caregivers.

Result

The expansion of services has resulted in increased care to the Spanish‐speaking population with minimal wait‐time from time of referral to neuropsychological services and assignment of a care coordinator. Additionally, community talks resulted in increased awareness of services in the local area.

Conclusion

These efforts have addressed well documented barriers of the Latinx community including timely and adequate access to dementia specific care for patients and their caregivers.
Creating Inclusive Research Through a Culturally Aware Data Collection Site
Authors: Salazar Hector , Lingler Jennifer H , Simó Carola A. Ferrer , Carter Fabu P. , Bester James , Floyd Lytonia , SmithBA Tracy , Dupaty Annik , Gleason Carey E.
Published: January 2025

Background

Ethnic and racial diversity in clinical research is critical for developing generalizable treatments and caregiving strategies. Barriers to participation among persons from underrepresented groups (URG) are systemic in clinical research. To increase URG research participation, we designed a community‐based data collection site where study participants complete full research visits.

Method

For an Alzheimer’s disease study, we established the first community‐based data collection site in Madison, WI, forging connections with Black community leaders and campus outreach staff. The site is proximal to diverse neighborhoods, public transportation, and is a hub for multi‐ethnic businesses. We rent space in the South Madison Partnership Office, an established community outreach center. This has allowed us to cultivate a consistent presence in the Black community, which evolved into a full data‐collection site. Staff include research specialists, community liaisons, nurse practitioners, and clinicians who are culturally‐aware and members of the Black community. The site is decorated with art from local Black and Indigenous artists, and food served is from a local Black‐owned business.

Result

We established proof of concept by successfully launching a fully‐equipped research site in the community, used for memory testing, biometric readings, blood draws, and one‐on‐one conversations with clinicians. Initial comments suggest participants prefer this comfortable, familiar setting over that of a hospital setting.

Conclusion

Researchers can use culturally‐aware and convenient data collection sites. Our site prioritizes the needs of participants toward the goal of achieving representation of racialized groups in research. This model has potential for broad implementation across aging and biomedical research.
Community Involvement: From Presentations to Participation
Authors: Tang Tara , Lavoie Athena , Brunson Gregory A
Published: January 2025

Background

Building a foundation of trust is the first step to establishing a relationship with the community that transcends any enrollment period. The Memory and Aging Program (MAP) Outreach Team formed in 2016 and has grown to a core of four team members in 2022, all focused on educating the public about Alzheimer’s Disease and Related Disorders (ADRD) and sharing opportunities to participate in research. This team explores different approaches to improve the access underrepresented populations (URPs) have to research and share some of their takeaways from community events.

Method

The team specializes in building trust and two‐way communication with community partners. In 2023 MAP held ∼ 200 outreach events and presentations, 115 in underrepresented communities, where individuals were invited to join our prevention registry, and offered opportunities to learn about pathways to research participation. Health fairs held at community centers focused on the overall health of the BIPOC community and partnered with other organizations for health screenings, food and music. ApoE “swab parties” provided education and a low burden pathway to participate in research at cultural venues, alumni events and conferences. They offered time to meet MAP people in a warm environment to facilitate genuine conversations.

Result

In combination with events and social media campaigns, the prevention registry has grown to over 5,300 enrollees, 16% of which are representative of URPs. Our swab parties generated 335 biospecimens, 7% enrolled in studies. The 2023 health fairs were attended by approximately 230 individuals with approximately 11% enrolling in our prevention registry. We established 20 new community connections and saw a 76% increase in URP events since 2022.

Conclusion

It’s imperative researchers continue to refine best practices in diversity recruitment and enrollment to foster trust between URPs and investigators. Authentic connections are best made by hosting frequent events that focus on the community’s overall health and located in settings where people feel comfortable. We’re optimistic in 2024 with plans to translate our registry into Spanish, acquire a sprinter van to bring memory screens and blood draws to community events, and offer more studies in Spanish with an increase in bilingual staff.
Non‐traditional Dementia Caregivers: Does a more distant relation diminish burden?
Authors: Leggett Amanda N. , Troost Jonathan , Tsuker Sophia , Miner Jennifer A. , Carlozzi Noelle E.
Published: January 2025

Background

Examination of family caregiving and the stress process has focused on a “primary” caregiver (e.g., spouse, adult child) at the exclusion of other members of the caregiving network. Yet “non‐traditional” (e.g., grandchild, friend) caregivers are increasingly providing substantial caregiving support. This study explores whether non‐traditional dementia caregivers vary from traditional caregivers in terms of caregiving approaches and outcomes.

Method

Participants included 200 family caregivers (n = 156 traditional and n = 54 non‐traditional) for a person living with dementia from the Style Measure Study. Descriptive statistics and t‐tests were run to examine differences between traditional and non‐traditional caregivers. Linear regressions were run adjusting for caregiver demographics and the care context with caregiver type predicting use of dementia management strategies (criticism, encouragement, active management), Neuro‐QOL measures of caregiver strain, caregiver‐specific anxiety, feeling trapped, and positive affect, PROMIS measures of sleep‐related impairment, fatigue and pain intensity, and caregiver readiness.

Result

Non‐traditional caregivers were significantly younger, more likely to be Black, had higher levels of financial difficulty, had provided care for less time, and reported significantly greater pain intensity and significantly lower levels of caregiver readiness. In adjusted linear regressions however, caregiver type only predicted use of active management care strategies; traditional caregivers used more active management than non‐traditional caregivers (B = ‐2.24, p<.05).

Conclusion

Non‐traditional caregivers are notably distinct from their traditional counterparts demographically, yet non‐traditional status generally did not predict differences in caregiving outcomes. Future research should prioritize inclusion of diverse caregivers to represent the broader caregiver population and recognize that their care needs are just as extensive as traditional caregivers.
External Validation of Dementia Prediction Models in Black or African American and White Older Adults: A Population‐Based Study in the United States
Authors: Dhana Klodian , Beck Todd , Liu Xiaoran , Dhana Anisa , Ng Ted K.S. , Desai Pankaja , Evans Denis A , Rajan Kumar B
Published: January 2025

Background

Identifying people at high risk of dementia allows for timely intervention, potentially slowing cognitive decline and delaying the onset of dementia. We externally validated commonly used risk predictions model for Alzheimer’s dementia in Black American and white older adults.

Method

The study included 2,130 participants with 1,159 Black American and 971 white participants without dementia at baseline from the Chicago Health and Aging Project (CHAP). Based on a recent systematic review and a comparative analysis, four prediction models were selected, including Cardiovascular Risk Factors, Ageing and Dementia (CAIDE), Dementia Risk Score (DRS), Brief Dementia Screening Indicator (BDSI), and Australian National University AD Risk Index (ANU‐ADRI). Using reported scores (i.e., points or beta estimates) from each model, we computed the predicted risk of dementia. The clinical diagnosis of dementia was based on the criteria of the joint working group of NINCDS and ADRDA for probable Alzheimer’s disease. The performance of each prediction model was assessed by the C‐statistic (discrimination ability) and calibration plots (comparing observed vs. expected dementia probabilities).

Result

During 18 years of follow‐up, 275 (23.7%) Black and 167 (17.2%) white older adults developed incident dementia. Of the prediction models evaluated, BDSI had the highest discriminant value for dementia risk with c‐statistics of 0.79 (95%CI 0.74‐0.84) in Black and 0.77 (95%CI 0.70‐0.85) in white individuals. The c‐statistics for ANU‐ADRI were 0.78 (95%CI 0.74‐0.83) in Black and 0.75 (95%CI 0.70‐0.81) in white participants. CAIDE had a lower discriminating power, 0.55 (95%CI 0.51‐0.58) and 0.53 (95%CI 0.48‐0.57), respectively, in Black and white individuals. DRS performed better among individuals aged 65‐79 (c‐statistics: 0.75 in black and 0.66 in white individuals) than 80‐95 (c‐statistics: 0.61 in black and 0.55 in white individuals). The calibration plots showed that prediction models (i.e., DRS and CAIDE) significantly underestimated (i.e., 10 times lower) the risk of Alzheimer’s in both Black and white study participants.

Conclusion

The prediction model assessed in this study underestimated the risk of Alzheimer’s in both Black and white individuals. This underscores the necessity for developing models specific to race to predict the risk of Alzheimer’s dementia more accurately in the population.
S‐Cysteinylated Transthyretin in Cerebrospinal Fluid as a Biomarker of Specimen Integrity
Authors: Kremer Schuyler Phillip , Borges Chad
Published: January 2025

Background

Currently there is no way to determine if archived cerebrospinal fluid (CSF) specimens have been properly handled and can be considered suitable for research purposes. Transthyretin (TTR) is abundant in CSF and undergoes a redox reaction that shifts its native proteoform into an S‐cysteinylated form. This reaction proceeds spontaneously ex vivo when CSF is thawed, but ceases at storage temperatures of ‐80°C. The relative abundance of these TTR proteoforms can be measured using dilute‐and‐shoot, intact protein liquid chromatography/mass spectrometry (LC/MS). Here we report that the spontaneous ex vivo changes in TTR S‐cysteinylation that occur when CSF is in the thawed state are systematic and substantial enough to potentially qualify the relative abundance of S‐cysteinylated TTR as an endogenous marker capable of tracking specimen integrity.

Method

Twelve CSF samples that were recovered postmortem were provided by Banner Sun Health Research Institute. The specimens were from patients diagnosed with Alzheimer’s or Parkinson’s disease or deemed by a pathologist as neurologically normal. A 1:2 dilution of 10 µL of CSF with 0.1% trifluoroacetic acid was directly injected onto a capillary LC system through a protein captrap (via a 10‐minute run), then into a time‐of‐flight mass spectrometer. Raw mass spectra were averaged over the TTR elution period. Following charge state deconvolution, the peak heights representing S‐cysteinylated TTR and native TTR were determined. Specimens were then incubated at 37°C for 24 hours to drive the ex vivo oxidation process to its conclusion and the LC/MS measurement process was repeated.

Result

The mean relative percentage of all initially measured CSF specimens was 23.1% (± 20% SD). Following 24 hours of incubation at 37°C, the mean relative percentage of S‐cysteinylated TTR increased to 86.0% (± 5.3% SD); paired t‐test p<0.0001 and ROC c‐statistic=0.99.

Conclusion

The dynamic range observed in the relative percentage of S‐cysteinylated TTR between nominally fresh and fully ex vivo‐oxidized CSF specimens was substantially greater than that observed in our previously developed ΔS‐Cys‐Albumin assay, which is used to forensically track the exposure of blood plasma and serum to thawed conditions. This suggests that a ΔS‐Cys‐TTR assay could find similar utility for archived CSF specimens.
Is the US infusion capacity sufficient for the expected demand with the emergence of disease‐modifying Alzheimer’s treatments?
Authors: Mattke Soeren , Chen Jiahe , Hanson Mark
Published: January 2025

Background

Disease‐modifying treatments for Alzheimer’s disease (AD) are becoming available. To date, all current treatments require intravenous infusion, and concerns have emerged that lack of infusion capacity may limit access to treatment. We predict supply and demand for infusions for AD treatment in the US under different assumptions over a 10‐year period.

Method

We use a Markov model to predict the number of individuals identified as eligible for AD treatment from 2023 to 2032, taking into account constrained capacity for AD specialist visits and confirmatory biomarker testing. We analyze chronic treatment starting at mild cognitive impairment (70% of patients) and mild dementia (30%) until transition to moderate dementia with infusions every two and four weeks for an estimated duration of 5.7 years, and time‐limited treatment every four weeks for 52 weeks as a lower bound estimate. National historic trends of infusion capacity were obtained from the CDC’s Ambulatory Health Care Data surveys and projected forward. Estimates for excess capacity and future growth of capacity for AD treatment were obtained from a survey covering 404 US infusion centers.

Result

The model predicts that 370,527 patients would be eligible to start treatment in 2023, increasing by 1% per year. Based on the CDC data, around 21 million infusions across therapeutic areas would be provided in 2023 with a projected annual growth rate of 3%. The survey of infusion centers suggests that 3% of capacity is currently devoted to AD with that share growing 1% per year, as well as up to 17% average unused capacity. Figure 1 shows the projected supply and demand. The solid lines show demand for the three types of treatment, the green and black dashed lines the projected supply and the maximum projected supply, if all unused capacity were devoted to AD infusions.

Conclusion

Projected US infusion capacity would be insufficient for all three treatment types, and even the maximum projected capacity would only be sufficient for time‐limited treatments. Expansion of capacity and introduction of treatments that do not require intravenous infusions will be necessary to ensure timely access to treatment.
Feasibility of detecting Amyloid burden in preclinical Alzheimer’s disease with quantitative magnetization transfer MRI
Authors: Mao Andrew , Flassbeck Sebastian , Marchetto Elisa , Rusinek Henry , Assländer Jakob
Published: January 2025

Background

Magnetization transfer (MT) MRI is sensitive to the presence of macromolecules, including amyloid‐beta, and previous work suggests that it may be useful for discriminating patients with Alzheimer's disease (AD) from healthy controls. In this study, we investigated if quantitative MT (qMT) is capable of detecting the amyloid concentration in a preclinical cohort.

Method

We recruited 14 subjects with a clinical dementia rating of 0 from NYU's ADRC cohort (7 male, mean age 74, 6 amyloid‐negative). An experimental 12 min qMT technique with an effective 1.24 mm isotropic resolution was used to obtain 6 parameter maps describing an unconstrained 2‐pool qMT model (Figure 1). MPRAGE and FLAIR images were acquired at 1 mm isotropic, rigid‐body registered to the qMT maps and used to perform Freesurfer‐based cortical parcellation. [18F]Florbetaben (FBB) images acquired within the preceding 24 months were rigid‐body registered to the qMT maps and used to compute average measurements across each cortical lobe for each hemisphere at 50% of the cortical thickness. Pearson's correlation coefficients were computed for all 6 qMT parameters with respect to FBB SUVR values. Amyloid‐positive and negative groups were compared using one‐way ANOVA tests. 5 Desikan‐Killiany ROIs containing substantial artifacts in the qMT maps were excluded from all analyses, though some imaging artifacts remain.

Result

The exchange rate between the two spin pools and the macromolecular pool's longitudinal relaxation rate were found to be both negatively correlated with amyloid concentration and significantly decreased in amyloid‐positive subjects most prominently within the temporal lobe (Figures 2–3). The former is consistent with previous reports in more advanced AD stages, but the latter has not previously been reported as its value is fixed in most qMT methods. However, we observed no significant changes in the macromolecular pool size—which encompasses both myelin and amyloid‐beta—with increasing amyloid burden.

Conclusion

MT MRI may be a promising tool for monitoring amyloid accumulation without the need for contrast agents or radiotracers. A larger cohort and a further optimized qMT sequence are needed to validate these preliminary findings.
Leveraging WeChat for Dementia Caregiver Support: Insights from a Process Evaluation
Authors: Hong Y. Alicia , Shen Kang , Chang Wei‐Hsuan
Published: January 2025

Background

The evaluation of mHealth interventions often lacks detailed process evaluation data. This study presents the design and results of a process evaluation for the Wellness Enhancement for Caregivers (WECARE) program, an mHealth intervention designed to improve caregiving skills and psychosocial wellbeing of Chinese American dementia caregivers. This evaluation focused on understanding the acceptance, engagement, and the barriers and facilitators influencing behavioral changes among participants, offering valuable feedback for program refinement and dissemination.

Method

A group of 23 Chinese American family caregivers for persons with dementia participated in the WECARE, delivered via WeChat, a widely used social media platform in Mandarin‐speaking communities. WECHAT sent multimedia materials for psychoeducation and skills enhancement six days per week over a seven‐week period. In addition, weekly surveys were distributed via WeChat to gather participants' experiences and suggestions regarding the program.

Result

Response rates to the weekly assessments ranged from 40% to 80%. The study found a higher level of participant interaction with private messaging as opposed to links to external surveys. WeChat’s text and audio message features enriched the quantitative survey data, yielding deeper qualitative insights. The analysis indicated a positive correlation between the applicability of the content and participants' implementation of the intervention strategies in their daily routines, as well as noticeable behavioral improvements. Suggestions from participants were also collected for future enhancements of the program.

Conclusion

The process evaluation data provided critical insights into the implementation and effectiveness of mHealth initiatives, particularly for minority groups such as Chinese American dementia caregivers. The use of short interactive surveys incorporating open‐ended questions on preferred social media platforms proved to be an efficient method for both process evaluation and increasing participant engagement. This study highlights the importance of continued research into process evaluations to refine and improve mHealth interventions for marginalized groups.
Dementia Mortality in the United States, 2020‐2022
Authors: Kramarow Ellen A. , Tejada‐Vera Betzaida
Published: January 2025

Background

Dementia‐related mortality increased significantly in the first year of the COVID‐19 pandemic in the United States. Explanations for the rise in dementia‐related death rates are complex and multi‐factorial. Older adults with dementia often have other chronic conditions that result in increased risk of death. Residence in institutional settings, more common among older adults and those with dementia, was associated with COVID‐19 mortality, particularly at the beginning of the pandemic. Death rates for both COVID‐19 and dementia among the older population have declined since 2020. However, dementia‐related death rates remain higher than pre‐pandemic levels. This research describes the changing contribution of COVID‐19 deaths to overall dementia mortality.

Methods

This analysis uses mortality data from the 2020‐2022 National Center for Health Statistics multiple cause‐of‐death files. Dementia‐related deaths are those with International Classification of Diseases, 10th Revision cause‐of‐death codes F01 (vascular dementia), F03 (unspecified dementia), G30 (Alzheimer disease), or G31 (other degenerative diseases of nervous system) reported anywhere on the death certificate. For adults age 65 and older, we describe the underlying and contributing causes of death associated with dementia mortality by sex, age group, race and Hispanic origin, and place of death.

Results

In 2022, 6.7% of death certificates for adults age 65 and older with dementia recorded anywhere on the death certificate also mentioned COVID‐19, a decline from 7.9% in 2021 and 12.0% in 2020 (Figure 1). Declines in the percentage with COVID‐19 mentioned were similar for older Black non‐Hispanic, White non‐Hispanic, and Hispanic decedents. From 2020 to 2022, the percentage of dementia‐related deaths with COVID‐19 mentioned declined for deaths in nursing homes or hospice facilities (from 13.8% to 6.8%) and increased for deaths at home (from 2.2% to 4.3%). In 2022, for all dementia‐related deaths among adults age 65 and older, the leading causes reported as underlying causes of death were dementia (64.6%), heart disease (9.1%), stroke (4.6%), COVID‐19 (3.9%), cancer (2.9%), and Parkinson disease (2.4%) (Figure 2).

Conclusions

Dementia‐related mortality in the United States increased during the COVID‐19 pandemic. To date, dementia‐related death rates remain above pre‐pandemic levels, but the contribution of COVID‐19 to dementia‐related deaths has declined.
Combined population attributable fractions for dementia are dependent on strong assumptions of the form of interactions between risk factors: an analysis of data from the Canadian Longitudinal Study on Aging
Authors: Jones Aaron , Dolatshahi Yasaman
Published: January 2025

Background

Several recent studies have used communality weights to calculate a combined population attributable fraction (PAF) of modifiable risks factors for dementia. Other research has suggested this method may be underestimating the true PAF. We applied multiple methods to calculate the combined PAF of 12 modifiable risk factors using record‐level, national Canadian data.

Method

We used baseline data (2011‐2015) from the comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA). We measured the 12 risk factors identified in the Lancet Commission on dementia prevention, intervention, and care. We calculated a combined PAF of these risk factors using the independent multiplicative method of Barnes and Yaffe (BY‐M), the additive and multiplicative methods of Welberry (W‐A and W‐M), and communality‐adjusted multiplicative method of Norton (N‐M). We also implemented a novel method (J‐MA) to mix multiplicative and additive interactivity based on the number of risk factors present. All methods incorporated sample weights and used the risk ratios from the Lancet Commission.

Result

There were 30,097 baseline participants in the CLSA ranging in age from 45 to 85 years (median 62). Combined PAFs varied widely: 78.5%(W‐M), 75.9% (BY‐M), 59.8% (J‐MA), 58.2% (W‐A), and 43.3% (N‐M). The BY‐M and W‐M methods resulted in unrealistically high combined risk ratios (RR >90) in individuals with many risk factors. The other methods produced broadly realistic results. Despite a nominally multiplicative form, N‐M produced results consistent with sub‐additive interactivity and makes arbitrary analytic choices. The J‐MA method also uses an arbitrary function to blend multiplicative and additive interactions. The W‐A approach made no assumption other than additive interactivity.

Conclusion

Assumptions regarding how risk factors for dementia interact highly influence combined PAFs. All multiplicative methods produce either unrealistic results or require arbitrary analytic choices. The additive method makes no arbitrary assumptions but may not reflect the actual form of interactions between risk factors. Not enough is known on how modifiable risk factors for dementia interact to estimate combined PAFs with confidence. When reporting PAFs for dementia a range of possible values, including one assuming additive interactions, should be provided and the assumptions behind each value clearly stated.
Care negotiation between people living alone with dementia in the United States and non‐kin caregivers
Authors: Lowers Jane , Smith Colby , Brus Kaitlyn , Perkins Molly , Hepburn Kenneth
Published: January 2025

Background

One in five people with cognitive impairment or dementia lacks family caregivers. People aging alone receive care from non‐family sources, including friends and neighbors, but the dynamics of these relationships are unexplored.

Method

Thematic analysis of qualitative interviews with 15 people with cognitive impairment or early dementia without close family and 14 non‐family caregivers

Result

We identified five themes that shape non‐family dementia caregiving dynamics: 1) establishing a relationship of trust, 2) personal motivations for seeking/providing care, 3) negotiating caregiving etiquette, 4) establishing caregiving boundaries, 5) the role of distant family.

Conclusion

Dementia caregiving by non‐family involves ongoing interpersonal negotiation of trust, roles, and boundaries.