bluuebunny/crossref_metadata_2025 huggingface dataset:
A single nucleotide polymorphism from a differentially‐expressed gene shared across four neurodegenerative diseases increases tau accumulation independently of amyloid
Authors: Ramos Vanessa G. , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Siebert Marina , Cristino Alexandre Santos , Bastiani Marco De , Zimmer Eduardo R.
Published: January 2025

Background

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Parkinson's disease (PD) are characterized by the accumulation of misfolded proteins and progressive loss of neurons. However, whether a neurodegeneration transcriptomic signature exists remains uncertain. Thus, we aimed to explore differentially expressed genes (DEGs) in common to AD, HD, MS, and PD. We also seek to evaluate the effect of single nucleotide polymorphisms (SNPs) derived from the NDs‐shared DEGs on AD pathophysiology.

Methods

We obtained RNA‐sequencing and microarray datasets of vulnerable brain regions of AD, HD, MS, and PD individuals from the Gene Expression Omnibus. Differential gene expression analysis (adjusted p‐value < 0.05) was conducted to identify DEGs in common among these four NDs. Then, we examined the impact of shared DEG‐related SNPs on amyloid and tau burden in AD through a linear regression model adjusted for the covariates of age, sex, and ApoEε4 status. We obtained DEG‐related SNPs and amyloid‐ and tau‐PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results

We identified 467 DEGs in common among AD, HD, MS, and PD vulnerable brain regions (Figure 1, p‐value < 0.05). From these DEGs, 15,574 SNPs were available in ADNI. Linear regression analysis revealed that IQGAP2 rs79679327 carriers had higher tau accumulation independently of amyloid burden (Figure 2, p‐value = 0.001; carriers: n = 21, mean age ± standard deviation (SD) = 72.76 ± 4.54; non‐carriers: n = 176, mean age ± SD = 71.64 ± 6.85).

Conclusion

Here, we show transcriptional similarities across four NDs. In AD, individuals carrying the IQGAP2 rs79679327 variant exhibited greater tau accumulation, regardless of amyloid. Our findings may provide insights into neurodegenerative traits, through a common signature of neurodegeneration.
Structural desegregation of salience network is associated with executive functioning deficits in behavioral variant frontotemporal dementia
Authors: Matyi Melanie A , Radhakrishnan Hamsi , Phillips Jeffrey S , Cook Philip A. , Rhodes Emma , Gee James C. , Irwin David J , McMillan Corey T , Massimo Lauren
Published: January 2025

Background

The human brain is organized in dense and distinct intrinsic networks that are topographically arranged and mediate particular cognitive functions. The characteristic of intrinsic network organization that supports this functional specialization of cognitive domains is known as modular segregation. Neurodegeneration is associated with changes in brain network organization that contribute to cognitive decline among healthy older adults but network segregation has rarely been studied in behavioral variant frontotemporal dementia (bvFTD). Examining segregation may provide insights into network organization and its contribution to cognition in bvFTD. We hypothesize that desegregation of structural networks will differ between bvFTD and healthy controls (HC) and will be associated with deficits in high‐executive demand cognitive tasks in bvFTD patients.

Methods

86 bvFTD and 37 HC (see Table 1) underwent diffusion MRI. Patients also completed tests of letter‐guided fluency, category‐naming fluency, and the Boston Naming Test (BNT). Structural connectivity was derived from deterministic tracking among 100 cortical regions mapped to 7 intrinsic networks, defined by the Schaefer atlas, using the DSI‐Studio generalized q‐sampling imaging pipeline as implemented in QSIPrep. Network segregation was characterized by high within‐network connectivity but low between‐network connectivity. To identify patterns of desegregation in structural networks, one‐way ANOVAs were conducted between bvFTD and HC groups for each network, controlling for age and motion. Linear regression was then performed to assess whether desegregation was associated with executive performance, controlling for disease duration and education.

Results

Desegregation of the salience network was observed in bvFTD, relative to HC (see Figure 1) and was associated with deficits in tasks with high executive demand (letter‐guided and category‐naming fluency), but not with performance on the BNT, a task with lower executive demand (see Figure 2).

Conclusions

Results indicate that structural desegregation of salience network is characteristic of bvFTD, reflecting a reduced capacity for specialized processing. Salience network desegregation was also uniquely associated with performance on cognitive tasks requiring high demand on executive resources. Overall, findings underscore the importance of salience network in bvFTD pathology. Critically, results demonstrate the executive consequences of network desegregation.
Establish Stronger Correlation between Surrogate Endpoint and Clinical Endpoint Using All Post‐baseline Data
Authors: Li Yan , Wang Guoqiao
Published: January 2025

Background

A traditional method for validating a surrogate endpoint typically involves assessing the correlation between changes in biomarkers and changes in clinical endpoints using Pearson’s and/or Spearman’s correlation. However, this approach may not provide an accurate representation of the true correlation due to several reasons: (i) it only considers the change from baseline to the last visit and does not use all post‐baseline longitudinal data; (ii) the raw change has large variability; (iii) it does remove the within‐subject variability. The objective of this presentation is to propose two alternative approaches that overcome these limitations and allow for a more accurate estimation of the true correlation using all available longitudinal data.

Method

We propose two models that have the capability to eliminate within‐subject variability and utilize all available post‐baseline longitudinal data for estimating the correlation: (i) bivariate linear mixed effects (bivariate‐LME) model utilizing time as a continuous variable, and (ii) bivariate MMRM with random effects (bivariate‐MMRM‐RE) utilizing time as a categorical variable. Through simulations that mimicking treatments with disease modifying effects, we will compare the estimated correlations using these two models to the Pearson’s and/or Spearman’s correlations.

Result

Our preliminary simulations showed that the Pearson’s and/or Spearman’s correlation tends to significantly underestimate the true correlation. And the magnitude of underestimation increases with shorter trial durations. On the other hand, correlations estimated from both the bivariate‐LME model and bivariate‐MMRM‐RE model demonstrate higher accuracy compared to the true correlation estimation, and they are also less influenced by the trial duration.

Conclusion

The Pearson’s and/or Spearman’s correlations estimated from clinical trial data are usually small (eg, 0.19 between the change in amyloid PET and CDR SB in EMERGE). Our simulations suggest that the Pearson’s or Spearman’s correlation is smaller than the true correlation. Therefore, it is advisable to estimate the true correlation using either the bivariate‐LME model or the bivariate‐MMRM‐RE model. These models provide more accurate estimations of the true correlation compared to the traditional Pearson’s and/or Spearman’s correlation.
The landscape of dementia research in Brazil (2010‐2021): A Scopus‐based bibliometric study
Authors: Ramos Ari Alex , Bertola Laiss , da Mata Fabiana A F , Miguel Andrew Christopher , Júnior Haliton Alves de Oliveira , Ferri Cleusa P
Published: January 2025

Background

In the last two decades, several studies have sought to investigate the trajectory of scholarly publications on dementia. Yet, there has been limited attention to contributions from Latin America. This bibliometric review aimed to partially address this gap by providing a comprehensive overview of the literature output on dementia in Brazil. Moreover, we were particularly interested in categorizing each included publication according to the research areas in dementia recently defined by the World Health Organization.

Method

We conducted a Scopus‐based literature search for publications indexed between 2010 and 2021 and developed syntaxes into R software for data analysis.

Result

Among the 5,534 documents found in Scopus, 2,528 met the inclusion criteria. The annual growth rate of publications on dementia (9.9%, SD = 15.5) closely paralleled that of general health‐related literature (6.7%, SD = 4.9), with no statistically significant differences between the two rates. Over 65% of the publications were categorized into the areas of dementia diagnosis (33.4%) and disease mechanisms, origins, and models (32.7%), followed by dementia care (14.9%), drug development (7.2%), risk reduction (6.5%), and epidemiology (4%). There were notably low percentages of publications related to clinical trials (1%) and economic cost (0.3%). Based on the first affiliation of Brazil‐affiliated authors with leading authorship roles (first, second, second‐to‐last, and/or last authors), approximately 90% of the analyzed affiliations stemmed from the Southeast (68.4%) and South (20.9%). However, the State of São Paulo accounted for 41.1%, contributing to 60.1% of the Southeast. Interestingly, 55% of authors holding leading authorship roles were women. Furthermore, first and second authorships were predominantly held by female researchers, whereas male researchers occupied most of the second‐to‐last and last authorships. Overall, 71.7% of the included reports were published in 346 foreign journals and 28.3% in 43 Brazilian journals. The National Council for Scientific and Technological Development (CNPq, 19.5%) and the Coordination for the Improvement of Higher Education Personnel (CAPES, 11.8%) were the leading research funding agencies acknowledged in the analyzed publications.

Conclusion

There is a pressing need for more studies across all Brazilian regions and all areas of dementia research, especially in epidemiology and economic cost.
24‐hour activity cycle movement behaviours and brain volume in people with mild cognitive impairment: A compositional and isotemporal substitution analysis
Authors: Balbim Guilherme Moraes , Silva Nárlon Cássio Boa Sorte , Falck Ryan S , Liu‐Ambrose Teresa
Published: January 2025

Background

People with mild cognitive impairment are at greater risk of Alzheimer’s disease. Physical activity (PA), sedentary behaviour, and sleep are movement behaviours constituting the 24‐hour activity cycle (24‐HAC) and are interactively associated with cognitive and brain health. However, the relationship between 24‐HAC compositions (i.e., time in one behaviour relative to remaining) and brain volume in this population remains underexplored. We aimed to investigate the associations between 24‐HAC compositions and time reallocation of 24‐HAC movement behaviours with brain volume.

Method

A cross‐sectional study in 110 community‐dwelling adults (55+ years) with mild cognitive impairment (Montreal Cognitive Assessment <26/30). MotionWatch8© assessed 24‐HAC movement behaviours (5‐7 days). Compositional data analysis determined 24‐HAC compositions (four isometric log‐ratio pivot coordinates). FreeSurfer quantified gray matter volume using T1‐weighted magnetic resonance imaging. Linear regressions adjusted for age, sex, intracranial volume, and education determined 24‐HAC compositions and brain volume associations. Compositional isotemporal substitution analysis estimated the difference in brain volume associated with reallocating time between pairs of 24‐HAC movement behaviours. The Benjamini‐Hochberg false‐discovery rate (FDR) adjusted p‐values for multiple comparisons.

Result

Higher moderate‐to‐vigorous PA composition was associated with greater cortical volume in the inferior temporal gyrus TE2a region (ß = 0.30, 95% CI = 0.15; 0.44, FDR‐adjusted‐p = 0.030). Higher light PA composition was associated with lower cortical volume in the TE2a region (ß = ‐0.45, 95% CI = ‐0.65; ‐0.24, FDR‐adjusted‐p = 0.015). Sedentary behaviour and sleep were not associated with brain volume (FDR‐adjusted‐p>0.05). Reallocating 30 minutes from sedentary behaviour to moderate‐to‐vigorous PA was associated with 2.1% greater volume in the TE2a region (ß = 0.06, 95% CI = 0.02; 0.10, p<0.001). Reallocating 30 minutes from moderate‐to‐vigorous PA to sedentary behaviour was associated with 2.8% lower volume in the TE2a region (ß = ‐0.08, 95% CI = ‐0.14; ‐0.02, p<0.001).

Conclusion

Greater light PA composition may happen at the expense of lower moderate‐to‐vigorous PA composition, which could explain its associations with lower cortical volume. Greater moderate‐to‐vigorous PA composition and reallocating time from sedentary behaviour to moderate‐to‐vigorous PA may counteract cortical atrophy in an Alzheimer’s disease signature region in people with mild cognitive impairment.
Population Attributable Fractions for Risk Factors for Dementia in Latin America
Authors: Paradela Regina Silva , Calandri Ismael Luis , Pozo Natalia , Garat Emanuel , Delgado Carolina , Crivelli Lucia , Yaffe Kristine , Ferri Cleusa P , Mukadam Naaheed , Livingston Gill , Suemoto Claudia Kimie
Published: January 2025

Background

Approximately 40% of global dementia cases are associated with 12 modifiable risk factors (less education, hearing loss, hypertension, obesity, smoking, depression, social isolation, physical inactivity, diabetes, alcohol excess, air pollution, and traumatic brain injury). However, the number of people with these risk factors differs between populations. Latin American countries differ in socioeconomic and geographic aspects and, therefore, risk factors prevalence. Our goal was to determine the population‐attributable fraction (PAF) of these risk factors (combined and individually) for dementia by analyzing population‐based samples from seven countries in Latin America (LA).

Method

We used data from Argentinian, Brazilian, Bolivian, Chilean, Honduran, Mexican, and Peruvian cross‐sectional, nationally representative surveys with harmonized measurements of the 12 modifiable risk factors for dementia. Data were collected between 2015 and 2021, and the survey sample size varied from 5,995 to 107,907 participants aged 18 years or older across the seven countries. We calculated the risk factor prevalence and their communalities in each country and used these with relative risks for dementia from previous meta‐analyses to calculate the PAFs. Pooled PAFs for LA were then obtained using random effect meta‐analyses.

Result

The overall proportion of dementia cases attributed to 12 modifiable risk factors varied across LA countries (62% in Chile, 60% in Argentina, 56% in Bolivia, 56% in Mexico, 54% in Honduras, 48% in Brazil, and 45% in Peru), with an overall PAF of 54% for LA (95% CI 48.8‐59.6). Obesity (weighted PAF = 7%), physical inactivity (weighted PAF = 6%), and depression (weighted PAF = 5%) had the highest PAFs in LA.

Conclusion

There is potential for prevention of a higher proportion of dementia in LA than worldwide. Obesity, physical inactivity, and depression are the major contributors to dementia variance across the seven LA countries. These findings have implications for dementia prevention strategies in LA.
Determinants of loneliness and depressive symptomatology among LGBTQ older adults living with cognitive impairment
Authors: Kim Hyun‐Jun , Fredriksen‐Goldsen Karen I , Jung Hailey H. , Lee Chaejeong
Published: January 2025

Background

Loneliness and depression among older adults are linked to a higher likelihood of chronic diseases, deterioration of physical function, and compromised quality of life. LGBTQ older adults are known to experience social isolation and mental distress at higher rates than their heterosexual counterparts, and those with cognitive impairment may be particularly susceptible to loneliness and depression. However, there is limited knowledge regarding the risk and protective factors for loneliness and depression among LGBTQ older adults living with cognitive impairment. This study fills this critical research gap and provides insights to improve the well‐being of this historically marginalized and underserved population.

Method

A sub‐sample (N = 160) of the Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS), the first longitudinal study of LGBTQ adults aged 50 and older in the U.S., was used. Those who were identified as experiencing cognitive impairment based on their Montreal Cognitive Assessment (MOCA) scores were included in this study. The MOCA scores ranged from 14 to 25 with a mean score of 22.1 (SD = 2.7). Mixed models were tested to identify factors predicting the overall levels and slopes of loneliness and depressive symptomatology over 6 years (2014 – 2020).

Result

The mean age was 68 (range: 50 – 97) with 69% men, 44% people of color, 55% with income below 200% federal poverty guideline, and 22% with high school or less education. Half reported feeling lonely, and about 30% had clinical‐level depressive symptoms. After controlling for background characteristics, loneliness and depressive symptomatology were positively associated with everyday discrimination, sub‐optimal sleep, and limited social resources. Loneliness was also positively associated with being single and limited outdoor activity, and depressive symptomatology with identity stigma and malnutrition. Loneliness increased over time if being single.

Conclusion

Findings identify modifiable factors that may provide protection against loneliness and depressive symptomatology. Individuals living with cognitive impairment and no care partner had loneliness increase over time, which is of particular concern. This study provides evidence‐based information for the development of tailored interventions, addressing LGBTQ‐specific needs as well as enhancing independence in daily living and overall quality of life.
Neuroimaging Markers of Microstructural Neurodegeneration are More Sensitive to Cognitive Dysfunction than Hippocampal Volume in Early Alzheimer’s Disease: A Mixed‐Longitudinal Study
Authors: Moody Jason F , Jonaitis Erin M. , Langhough Rebecca E. , Dean Douglas C , Alexander Andrew L , Johnson Sterling C. , Bendlin Barbara B.
Published: January 2025

Background

While magnetic resonance imaging (MRI) markers of neurodegeneration are nonspecific to Alzheimer’s disease (AD) pathology, they have been correlated with cognitive dysfunction, and therefore, provide important information pertaining to disease staging. Neurodegeneration in AD is commonly assessed with macrostructural measures of brain atrophy, such as hippocampal volume. However, recent investigations have shown that markers of neural microstructure derived from diffusion MRI (DWI) may provide supplementary insight into the progression of AD pathophysiology. Furthermore, DWI measures of neurite density index (NDI), isotropic volume fraction (ISO), return to origin probability (RTOP), and mean squared displacement (MSD) have recently been associated with cerebrospinal fluid markers of senile plaques, neurofibrillary tangles, and AD‐related neurodegeneration.

In this study, we used linear mixed‐effects (LME) modeling to compare the utility of different MRI markers for predicting performance on a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC3) in 268 late‐middle‐aged participants.

Methods

268 participants from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center (216 unimpaired, 37 MCI, 15 AD) were imaged between 1 and 2 times with T1‐weighted MRI and multi‐shell DWI (Table 1). For each scan, hippocampal volume was estimated and average NDI, ISO, RTOP, and MSD values were extracted from the hippocampus and anterior parahippocampal gyrus. PACC3 scores were calculated from comprehensive neuropsychological testing within 6 months of imaging. Neuroimaging metrics were used as predictors in separate LME models of the following form:

PACC3 = b0 + b1*(metric) + b2 *(age) + b3*(sex) + b4*(metric*clinical status) + b5*(years of education) + ui

Results

DWI metrics consistently outperformed hippocampal volume in predicting PACC3 scores across both brain regions (Table 2). Anterior parahippocampal MSD exhibited the lowest AIC/BIC values, while hippocampal NDI had the strongest association with PACC3 scores among unimpaired participants. Meanwhile, hippocampal volume had the largest AIC/BIC values and the weakest correlation with PACC3 scores (Table 2, Figure 1).

Conclusion

Our study provides evidence that neuroimaging markers of brain microstructure may be particularly sensitive to subtle alterations predictive of cognitive performance, especially early in AD. Future work will translate these analyses to larger cohorts and incorporate fluid markers of amyloid and tau.
Green, Blue, Brown, Gray? Nature exposure and cognitive function among aging Mexican Americans
Authors: Darwish Hala J , Hokett Emily , Tureson Kayla N , Allan Alexa C , Finlay Jessica M , Webster Noah J
Published: January 2025

Background

Studies link nature exposure to better cognitive health outcomes. However, little is known about which types or ‘how much’ of nature is needed for health benefits. Studies often lack diverse aging populations and have small sample sizes.

Method

Our study investigated the relationship between land cover types (e.g., water, green, developed, or barren) and cognitive function (Mini Mental Status Exam) in 2,069 participants from the Wave 5 Hispanic Established Population for the Epidemiological Study of the Elderly. Linear mixed‐effect models adjusted for individual (e.g., age) and area‐level (e.g., poverty) covariates were used.

Result

The mean age was 81.9±5.2, 61.5% women, and the mean years of education was 4.9±4.0. The median MMSE score was 22, range of 0‐30. Latent Profile Analysis of land cover types revealed four distinct classes. Individuals living in less developed, green‐mix areas had higher cognitive scores, particularly among women.

Conclusion

Environments with a mix of nature and access to services, amenities, and other people positively impact cognition in aging Mexican American women.
Using TAS Test online hand‐tapping tests to detect cognitive decline in a large community cohort of older Australians
Authors: Alty Jane E , Wang Xinyi , Bindoff Aidan , George Rebecca J St , Roccati Eddy , Bartlett Larissa , Lawler Katherine , Noyce Alastair J , Tran Son , King Anna E , Bai Quan , Vickers James C
Published: January 2025

Background

Finding low‐cost, accessible methods to detect people with early‐stage Alzheimer’s disease is a research priority for neuroprotective drug development. Subtle motor impairment of gait occurs years before episodic memory decline but there has been little investigation of whether self‐administered hand motor tests can detect this pre‐symptomatic period. This study evaluated how home‐based unsupervised keyboard tapping tests from the TAS Test protocol predict episodic memory performance in a sample of older adults without overt cognitive impairment, as a potential indicative measure of early Alzheimer’s disease.

Method

1,140 community participants (65.7 ± 7.4 years old; 73% female) without cognitive impairment from the ISLAND cohort study completed a 40‐second single key tapping test, a 60‐second alternate key tapping test, and a 40‐second sequence tapping test from TAS Test. Participants also completed validated CANTAB cognitive tests of episodic memory, working memory and executive function. Frequency, variability, key press duration and accuracy scores were calculated for each tapping test. Generalized linear models examined associations between keyboard tapping and cognitive performance, adjusted for confounders including age, sex, depression, anxiety and education.

Result

Combination of motor features of the single key (R2
adj = 8.0%, ΔAIC = 3.7), alternate key (R2
adj = 7.9%, ΔAIC = 2.8), and sequence tapping tests (R2
adj = 8.2%, ΔAIC = 8.4) improved estimation of episodic memory performance relative to models with demographic and mood confounders only (R2
adj = 7.3%). Only tapping features of tests involving sequence tapping (R2
adj = 6.3%, ΔAIC = 2.5) improved estimation of working memory. Tapping features of single key tapping tests (R2
adj = 15.8%, ΔAIC = 8.3) and sequence tapping tests (R2
adj =16.5%, ΔAIC = 13.7) improved the estimation of executive function performance.

Conclusion

Brief unsupervised and self‐administered online keyboard tapping tests predict asymptomatic episodic memory decline in a sample of older adults. This provides a potential low‐cost and brief home‐based method for risk stratification of enriched cohorts for further assessment.
Gender difference in cognitive functioning varies by level of purpose in life – Results of the New Zealand Health, Work and Retirement (NZHWR) study
Authors: Röhr Susanne , Gibson Rosemary , Alpass Fiona
Published: January 2025

Background

High purpose in life – the extent of engagement in activities that are personally valued and give a sense of direction and meaning to life – has been associated with higher cognitive functioning and may protect against dementia. Less is known about gender differences in cognitive functioning regarding purpose in life. Understanding gender‐specific links can inform tailored interventions aimed at promoting cognitive health.

Method

A subsample (n = 875, aged 50‐85 years) of the NZHWR study completed face‐to‐face cognitive assessments and postal surveys in 2012. Cognitive functioning was assessed with Addenbrooke’s Cognitive Examination–Revised (ACE‐R), adapted for culturally acceptable use in New Zealand. Purpose in life was measured with the Life Engagement Test. Linear regression analysis assessed associations of gender, purpose in life and their interaction with cognitive functioning, controlling for socioeconomic factors (age, age², education, ethnicity [Māori, Indigenous people of New Zealand, and Non‐Māori, mostly of European descent], marital status, employment, individual‐level economic hardship, area‐based socioeconomic deprivation), lifestyle and health factors (smoking, alcohol consumption, physical activity, SF‐12 physical and mental health, social engagement, social loneliness).

Result

The analytical sample (n = 643) was M = 65.3 (SD = 7.4) years old; 53.3% women, 21.2% Māori. The ACE‐R score was M = 92.9 (SD = 5.3). N = 55 (8.5%) scored ≥1.5SD below the mean, indicating cognitive impairment. Women had higher cognitive functioning (M = 93.7, SD = 4.6 vs. M = 92.0, SD = 5.8; Z = ‐3.88, p<.001) and purpose in life (M = 26.2, SD = 3.8 vs. M = 25.8, SD = 3.4; Z = ‐2.19, p = .029) than men. In the adjusted regression analysis (R² = 27.6%), higher purpose in life (B = 0.29, 95%CI = 0.12;0.46; p = .001) and female gender (B = 9.97, 95%CI = 4.71;15.24, p<.001) were associated with higher cognitive functioning. The association of purpose in life with cognitive functioning was less pronounced for women than men (B = ‐0.31, 95%CI = ‐0.51;‐0.11; p = .003) (Fig. 1). Significant covariates included age², education, deprivation, and social loneliness.

Conclusion

In this sample of older New Zealanders, a gender difference in cognitive functioning varied by level of purpose in life. Women had higher cognitive functioning than men, particularly at lower purpose in life, with the difference decreasing as purpose in life increases. Interventions to enhance purpose in life might particularly benefit men. Notably, cognitive functioning may also impact purpose in life, emphasising the need for longitudinal studies.
Influence of in vivo Hsp90α inhibition on irisin signaling to the brain
Authors: White Zachary J , Sudasinghe Keshari , Weber Ramona , Hall Stephanie E
Published: January 2025

Background

Irisin is an exercise‐induced myokine that elicits beneficial effects of exercise in fat, bone, and the brain. Previous work suggests that extracellular heat shock protein 90a (Hsp90a) mediates irisin‐receptor interaction in bone and fat. Despite this, it remains unclear if Hsp90a is necessary for irisin signaling in the brain.

Methods

Female F344 rats (3‐4 mo, n = 32) were randomized into four treatment groups: irisin + Hsp90a inhibition (IX, n = 10); irisin + vehicle o.g. (IC, n = 10); vehicle i.p. + Hsp90a inhibition (CX, n = 6) and; vehicle i.p. + vehicle o.g. (CC, n = 6). Due to the impact of irisin on memory, a novel object recognition test was conducted over 4 days. Days 1‐2 were habituation, day 3 was familiarization, and day 4 was testing. Directly following NOR day 2, animals received single administrations of irisin (100 mg/kg, i.p.) or vehicle control and selective Hsp90a inhibitor SNX‐5422 (10 mg/kg, o.g.) or vehicle control. Day 4 NOR testing and tissue collection occurred 48 hours following drug administrations. Blood was collected via LV puncture, centrifuged to isolate serum, and stored at ‐80°C. Brains were sectioned, weighed, and snap‐frozen in liquid nitrogen. The downstream target of irisin signaling, hippocampal cyclic‐AMP Response Element Binding Protein (CREB) was quantified via Jess Simple Western automated western blot analysis. Hippocampal BDNF and serum irisin were quantified via ELISA. Values are mean ± standard deviation.

Results

In the NOR task, the IC group displayed a preference for the novel object (68.77 ± 17.93% of exploration time with novel object; p<0.01, one‐sample t‐test vs 50%). Novel object preference was not displayed in other groups. Hippocampal total CREB was greater in the IC than in the CC group (11.0 ± 0.85 vs 9.4 ± 0.80 a.u.; p<0.05, one‐way ANOVA). No differences in tissue masses, levels of hippocampal phosphorylated CREB, p/t CREB, and BDNF or serum irisin were present between groups 48 hours following dosing.

Conclusions

This investigation supports irisin signaling to promote memory function and indicates a mediating role of Hsp90a in the brain. Further analysis of hippocampal mRNA is needed to understand the influence of Hsp90a inhibition on irisin‐mediated transcriptional changes.
Media Contribution to Dementia Awareness in Recruitment and Retention of Alzheimer’s Disease Diversity Genetic Cohorts‐ Alzheimer’s disease Sequencing Project in Africa
Authors: Farombi Temitope Hannah , Arulogun Oyedunni , Nichols Michelle , Olorunsogbon Olorunyomi F , Kumolu Timilehin , Ogunronbi Mayowa , Sanni Taofeek Adedayo , Mutiso Victoria , Uthman Muhammed , Sule Abdullateef , Assey Emmanuel , Mwombeki Innocent , Onoria Joy , Onunka Godspower Chibuke , Tagoe Benedict , Melkamu Selem K , Adigwe Ifeoma , Ogunyemi Adedoyin O , Gyabaah Solomon , Byrd Goldie S. , Ogunniyi Adesola , Pericak‐Vance Margaret A , Akinyemi Rufus O. , Consortium Africa Dementia
Published: January 2025

Background

The escalating prevalence of dementia in Africa, propelled by rapidly ageing population, necessitates innovative approaches to raise awareness and address associated challenges. The prevalent misconception of dementia as a result of witchcraft or wizardry is a challenge, and the media acts as a key agent in dispelling such myths. By reaching divers audiences, the media reinforces the notion that dementia is not confined to Africa alone but it is a global concern. It also aids in overcoming the shame and stigma associated with dementia, encouraging individuals to seek consultation.

Method

A comprehensive analysis of media initiatives used by the African Dementia Consortium (AfDC) during the World Alzheimer’s Month and subsequently was conducted. Digital Platforms (Instagram, LinkedIn, Facebook), print and traditional media (publications, journals, newspaper, radio and television stations) were examined for their effectiveness in achieving recruitment objectives, destigmatizing and promoting early diagnosis. Quality tools, such as cameras and recorders, were utilized to capture relevant information, while the outcome was evaluated based on their impact on target audience assessed by greater participation.

Result

Media Platforms have proven instrumental in recruitment efforts by disseminating information that reaches diverse demographic groups in Africa. Through compelling visual and textual content, the media has played a key role in destigmatizing dementia, challenging prevalent misconceptions, and fostering a more inclusive understanding of the condition. In addition, media initiatives have contributed significantly to the promotion of early diagnosis by disseminating educational content that empowers individuals to recognize early signs and seek timely medical intervention.

Conclusion

Both the digital and traditional media play vital roles in visually and textually representing dementia, correcting misconceptions, and fostering understanding. Allocating increased resources to media initiatives hold immense benefit for Africa, contributing to a more positive perspective on dementia and dispelling negative attitudes.
How Does the Latest Clinical Pharmacology Data & Modeling Support Continued Lecanemab Dosing?
Authors: Reyderman Larisa , Willis Brian A. , Penner Natasha , Charil Arnaud , Dhadda Shobha , Hersch Steven , Irizarry Michael C. , Kramer Lynn D
Published: January 2025

Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid‐beta (Aβ) protein. In 18‐month clinical studies, lecanemab has been shown to reduce a complex group of protein interactions associated with early symptomatic Alzheimer’s disease (AD) and slow decline on clinical endpoints of cognition and function for up to 30 months to date. In prior research, results from the phase 2 study gap period (no study drug treatment) between the end of the study core and the beginning of retreatment in the open‐label extension (OLE) provides evidence regarding the need for continued maintenance therapy beyond 18 months. Clinical pharmacology data can help supplement the clinical and mechanistic data to establish the rationale for ongoing treatment. Herein, we will present how the latest clinical pharmacology data and modeling support continued long‐term maintenance lecanemab dosing. Data from the lecanemab phase 2 study (Study 201) and Clarity‐AD (Study 301) were pooled, and biomarker, amyloid PET, and CDR‐SB scores were used to develop models describing the change in amyloid PET and plasma biomarkers with lecanemab treatment. A model was also developed to show how change in amyloid PET predicts slowing of disease progression. These models were used to explore the change in plasma biomarkers, amyloid PET, and CDR‐SB over 4 years, and to evaluate the effect of transitioning to less frequent dosing of lecanemab following 18 to 24 months of initial treatment. Simulations projected that CDR‐SB difference between lecanemab and placebo subjects continued increasing over the 4‐year simulation period. Low amyloid and less severe disease at baseline were associated with slower disease progression. Continued treatment with lecanemab at less frequent dosing intervals following an initial treatment period was demonstrated to effectively maintain the benefit associated with lecanemab treatment on plasma biomarkers, amyloid PET, and clinical outcomes as compared to the initial dosing regimen. We will offer learnings from these recent analyses into the ability of amyloid reduction to be predictive of slowing Alzheimer’s disease progress, the importance of early initiation of treatment, and the utility of continued lecanemab maintenance treatment.
Specific Neuroimaging Signatures of Superagers in an Urban Indian Ageing Cohort
Authors:   Sandhya G ,   Monisha S , Singh Sadhana , Lingegodwa Abhishek Mensegere , Issac Thomas Gregor
Published: January 2025

Background

Decline in cognitive functioning is one significant change that occurs as people age. But, certain individuals in the community have their cognitive functioning on par with people 20‐30 years younger than them. Such individuals above the age of 80 are referred to as superagers. Previous studies identified higher brain volumes in superagers compared to typical agers. The present study aims to identify superagers in an urban Indian cohort and compare their imaging parameters with those of typical agers.

Method

The study used baseline data from Tata Longitudinal Study of Ageing (CBR‐TLSA). The 65 octogenarians of the cohort were screened based on the Northwestern criteria for superagers. The criteria includes one memory test score being equal to or greater than the mean of 50‐65‐year‐old gender and education‐matched controls, and scores in three tests of other cognitive domains not being less than 1 standard deviation of the octogenarian group. Neuroimaging was performed for a subset of the octogenarians using a 3 Telsa MR scanner. Generalised linear models were used to identify associations of brain region volumes with cognition after adjusting for total intracranial volumes.

Result

A total of 14 superagers were identified in the TLSA cohort based on the criteria mentioned. Superagers were found to have significantly larger right (p = 0.01) and left hippocampus (p<0.001) owing to better memory scores in them. The total volumes of cortex (p<0.001), cerebral white matter (p = 0.02), brain stem (p = 0.037) and subcortical grey matter (p = 0.01) were greater in superagers. The right (p = 0.024) and left thalamus (p = 0.014), right cerebellum cortex (p = 0.048) and left cerebellum white matter (p = 0.025) volumes were also found to be significantly higher in superagers when compared with typical agers.

Conclusion

The results identified higher volumes of specific brain regions across both hemispheres among superagers as compared to typical agers. Further, studies on superaging from healthy ageing cohorts are necessary to identify factors contributing to cognitive reserve.
Intervening paths: A dual networks approach to modifiable dementia risk in healthy older adults
Authors: Brady James J R , Bartlett Larissa , Bindoff Aidan , Norris Kimberley , Roccati Eddy , Vickers James C , Sinclair Duncan
Published: January 2025

Background

Multi‐domain initiatives which target modifiable, lifestyle‐associated, dementia risk factors are promising tools for dementia prevention. However, those at greatest risk of preventable dementia likely have the least capacity to enact change. Interventions may improve outcomes for those most vulnerable by looking up‐stream. Doing so may identify targets of intervention which influence modifiable dementia risks. Applying an emerging method, we reveal candidates for targeted intervention using partial correlation and direct‐path machine‐learned networks.

Method

Observations from the Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Resilience Initiative (n = 1225) were sourced from the longitudinal ISLAND Study of adults over 50. Regularized partial correlation network (RPCN) was plotted with demographic and dementia risk factors using glasso and extended Bayesian Information Criteria. Removing missingness, we systematically selected nonparanormal data transformation and a H2PN algorithm to bootstrap 10,000 Bayesian networks. Our directed acyclic graph (DAG) comprised connections averaged across at least 85 per‐cent of the bootstraps. DAG network stability was tested by incrementally diminishing number of observations. Common, highly connected, and intervenable variables which led to most‐influenced modifiable dementia risks were identified by contrasting the DAG and RPCN.

Result

RPCN showed modifiable risk domains of depression, cognitive activity, and MIND diet adherence were most influenced by partially correlated factors. As revealed by the DAG, pathways leading to depression included a direct link from social support availability, and indirect links from age through anxiety and the stress variables, excepting PSS’s unable to cope subscale. Gender and social subscales, except interaction frequency, led to cognitive activity, and dietary adherence (through cognitive activity and BMI). Of the up‐stream variables, identified links between stress, anxiety, and depression were the strongest, visible as thicker connections in the RPCN.

Conclusion

We present candidates for focused intervention, demonstrating utility of an emerging dual‐network technique. We unveil a complex RPCN network, highlighting modifiable dementia risk factors most influenced by correlated variables. Combining the DAG’s machine‐learned pathways with the RPCN, we provide support for targeting symptoms of stress and anxiety, and fostering improved social connectivity and quality, to address dementia risk associated with levels of depression, cognitive activity, and MIND diet adherence.
Methods and Initial Data for A Massive Real‐World Deeply Phenotyped Cohort Study
Authors: Ritchie Craig W , Harrison John E , Welstead Miles , Milne Joseph , Green Alison , Doran Clara , Hussain Zain , Kaminioti‐Dumont Laura , Lan Andrew , Nadeem Ayeda , Noonan Tara , Poon Azin , Rannikmäe Kristiina , van der Westhuizen Tanya , Gregory Sarah
Published: January 2025

Background

Recent therapeutic successes in the treatment of Alzheimer’s disease (AD), and diagnostic tools such as blood‐based biomarkers, have energised the field to develop more specific diagnostics and therapies following the best principles of precision medicine. Large, ‘real‐world’ cohorts are needed to understand whether these, and other future breakthroughs, are valid when employed in the wider AD community.

Methods

Our cohort study will provide a well‐phenotyped (combining data on risk factors for neurodegenerative disease, cognitive assessment results, disease biomarkers and genetics) population aged 50 and above across the spectrum of risk for, and the earliest disease stages of, neurodegeneration (beginning in Scotland). Participants complete an innovative cognitive testing battery (combining elements of the ACE‐R (including MMSE), TICS, RBANS and digital cognitive tests), assessments of global functioning, questionnaires about risk factors for neurodegenerative disease, physical health assessments and collection of blood samples for clinical blood tests and storage for future research. A sub‐set of participants are invited to join the Enhanced Phenotyping cohort and additionally undergo brain MRIs and lumbar punctures. Cerebrospinal fluid will be analysed for amyloid beta‐42, phosphorylated tau‐181 and total tau, with additional aliquots stored for future research use. Participants will be followed up every 6 months to complete questionnaires, with more comprehensive visits annually. A minimum of 3000 participants will be recruited to the Enhanced Phenotype cohort with an estimated 7,000 in the cohort overall.

Results

A total of 11 participants have been recruited to the cohort to date (mean age: 69 years; 6 (55%) female). Mean ACE‐R and MMSE scores are 92 and 28 respectively. Data collection is ongoing with recruitment anticipated to continue throughout 2024 and 2025, with a minimum of 100 participants recruited by July 2024. Baseline data, including AD biomarker status where available, will be presented at AAIC 2024.

Conclusion

This an ambitious project aiming to recruit a deeply phenotyped, real‐world representative cohort of participants across the spectrum of risk for, and in the earliest stages of, neurodegenerative conditions. The data and samples collected as part of this cohort will be invaluable to better understanding disease trajectories, and developing and testing new diagnostics and therapeutics.
Feasibility and acceptability of a continuous remote activity monitoring protocol in older adult dyads: A mixed methods pilot study
Authors: Ardle Ríona Mc , Wales Jenny L , Hamilton Calum Alexander , Ryan Leigh James , McCarthy Louis , Din Silvia Del , Bayat Sayeh , Tangen Gro Gujord , Ireson Neil , Lanfranchi Vita , Farina Nicolas , Hicks Ben
Published: January 2025

Background

Walking is a key facilitator of healthy ageing and may reduce risk of cognitive decline in older adults. To develop suitable, accessible interventions, we must objectively consider the socio‐ecological factors which influence participation in walking activities. For example, walking may be influenced by the volume and type of activities one’s partner participates in (i.e., dyadic interactions), or the walkability of their local area. Wearable technologies can continuously and remotely capture digital walking outcomes, such as volume, pattern, variability and location of activities. This pilot study aimed to explore the feasibility and acceptability of deploying a continuous remote activity monitoring toolkit in older adult dyads (i.e., couples).

Methods

Participants were asked to engage with three forms of remote activity monitoring over a period of seven days: (1). Wearing an inertial measurement unit (IMU; AX6, Axivity) on their lower backs, (2). Carrying a smartphone installed with a GPS app on excursions outside the home, and (3). Completing an activity diary (e.g., daily journeys, motivations/perceptions of journeys) each night. Upon study completion, participants were asked to complete open‐ended questionnaires regarding their experiences of the protocol. Feasibility was assessed by quantitatively calculating completion of each form of activity monitoring, while qualitative content analysis of the questionnaires was employed to understand the acceptability of the protocol.

Results

21 dyads (n = 42) participated in the study (Age (median (range)): 69 (61‐79)). 95% of participants wore the IMU for seven days (5% removed early for holidays). 100% completed their activity diaries. 77% (n = 226) of all data collection days (n = 294) were captured from the GPS app; reasons for data loss (68 days) include possible technical error (69.12%), not leaving the house (29.41%), or forgetting the GPS device (1.47%). Most participants found all forms of activity monitoring acceptable; common themes are reported in Tables 1‐3.

Conclusion

Results suggest that a protocol of continuous remote activity monitoring using digital devices and an activity diary is feasible and acceptable to older dyads. Further work will explore how data acquired can be used to identify socio‐ecological predictors of walking and examine independence/interdependence in walking between members of each dyad.