Brain Health Research Articles

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N=299), mild cognitive impairment (MCI; N=192), or dementia (DEM; N=65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Plasma biomarkers differed across diagnostic groups (DEM>MCI>CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Plasma biomarkers differ across diagnostic groups (DEM>MCI>CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Reader Response: The Brain Health Imperative in the 21st Century—A Call to Action: The AAN Brain Health Platform and Position Statement

Reader Response: The Brain Health Imperative in the 21st Century—A Call to Action: The AAN Brain Health Platform and Position Statement

Author Response: The Brain Health Imperative in the 21st Century—A Call to Action: The AAN Brain Health Platform and Position Statement

Author Response: The Brain Health Imperative in the 21st Century—A Call to Action: The AAN Brain Health Platform and Position Statement

Deep learning with diffusion MRI as in vivo microscope reveals sex-related differences in human white matter microstructure

Biological sex is a crucial variable in neuroscience studies where sex differences have been documented across cognitive functions and neuropsychiatric disorders. While gross statistical differences have been previously documented in macroscopic brain structure such as cortical thickness or region size, less is understood about sex-related cellular-level microstructural differences which could provide insight into brain health and disease. Studying these microstructural differences between men and women paves the way for understanding brain disorders and diseases that manifest differently in different sexes. Diffusion MRI is an important in vivo, non-invasive methodology that provides a window into brain tissue microstructure. Our study develops multiple end-to-end classification models that accurately estimates the sex of a subject using volumetric diffusion MRI data and uses these models to identify white matter regions that differ the most between men and women. 471 male and 560 female healthy subjects (age range, 22–37 years) from the Human Connectome Project are included. Fractional anisotropy, mean diffusivity and mean kurtosis are used to capture brain tissue microstructure characteristics. Diffusion parametric maps are registered to a standard template to reduce bias that can arise from macroscopic anatomical differences like brain size and contour. This study employ three major model architectures: 2D convolutional neural networks, 3D convolutional neural networks and Vision Transformer (with self-supervised pretraining). Our results show that all 3 models achieve high sex classification performance (test AUC 0.92–0.98) across all diffusion metrics indicating definitive differences in white matter tissue microstructure between males and females. We further use complementary model architectures to inform about the pattern of detected microstructural differences and the influence of short-range versus long-range interactions. Occlusion analysis together with Wilcoxon signed-rank test is used to determine which white matter regions contribute most to sex classification. The results indicate that sex-related differences manifest in both local features as well as global features / longer-distance interactions of tissue microstructure. Our highly consistent findings across models provides new insight supporting differences between male and female brain cellular-level tissue organization particularly in the central white matter.

Editors' Note: The Brain Health Imperative in the 21st Century—A Call to Action: The AAN Brain Health Platform and Position Statement

Editors' Note: The Brain Health Imperative in the 21st Century—A Call to Action: The AAN Brain Health Platform and Position Statement

The Real-World Usability, Feasibility, and Performance Distributions of Deploying a Digital Toolbox of Computerized Assessments to Remotely Evaluate Brain Health: Development and Usability Study.

An ongoing global challenge is managing brain health and understanding how performance changes across the lifespan. We developed and deployed a set of self-administrable, computerized assessments designed to measure key indexes of brain health across the visual and auditory sensory modalities. In this pilot study, we evaluated the usability, feasibility, and performance distributions of the assessments in a home-based, real-world setting without supervision. Potential participants were untrained users who self-registered on an existing brain training app called BrainHQ. Participants were contacted via a recruitment email and registered remotely to complete a demographics questionnaire and 29 unique assessments on their personal devices. We examined participant engagement, descriptive and psychometric properties of the assessments, associations between performance and self-reported demographic variables, cognitive profiles, and factor loadings. Of the 365,782 potential participants contacted via a recruitment email, 414 (0.11%) registered, of whom 367 (88.6%) completed at least one assessment and 104 (25.1%) completed all 29 assessments. Registered participants were, on average, aged 63.6 (SD 14.8; range 13-107) years, mostly female (265/414, 64%), educated (329/414, 79.5% with a degree), and White (349/414, 84.3% White and 48/414, 11.6% people of color). A total of 72% (21/29) of the assessments showed no ceiling or floor effects or had easily modifiable score bounds to eliminate these effects. When correlating performance with self-reported demographic variables, 72% (21/29) of the assessments were sensitive to age, 72% (21/29) of the assessments were insensitive to gender, 93% (27/29) of the assessments were insensitive to race and ethnicity, and 93% (27/29) of the assessments were insensitive to education-based differences. Assessments were brief, with a mean duration of 3 (SD 1.0) minutes per task. The pattern of performance across the assessments revealed distinctive cognitive profiles and loaded onto 4 independent factors. The assessments were both usable and feasible and warrant a full normative study. A digital toolbox of scalable and self-administrable assessments that can evaluate brain health at a glance (and longitudinally) may lead to novel future applications across clinical trials, diagnostics, and performance optimization.

Project ECHO Brain Health: Assessing the Impact of a Pilot Program to Promote Self-Efficacy Among Community Health Workers.

This mixed-methods study sought to examine the impact of the Project ECHO Brain Health program on participating community health workers' (CHWs') self-efficacy to address dementia, promote brain health, and advocate for research among Latinx South Texas communities. Using an explanatory sequential design, quantitative data collected from pre- and post-program surveys were analyzed to inform the collection of qualitative data, followed by an interpretation of all findings to better understand the impact of the program on self-efficacy. Pre- and post-surveys were collected from 25 CHWs, 13 of whom later participated in individual interviews. There was a statistically significant increase in mean self-efficacy scores between the pre- and post-surveys among participants. Three categories reflecting the experiences of participants were identified from the qualitative data: addressing training needs; impact on CHWs and their practice; and community of learning. The findings suggest that Project ECHO Brain Health program is a timely intervention that may facilitate increased self-efficacy among CHWs as they navigate the impacts of dementia in their communities.

Sleep Quality Moderates the Associations between Cardiorespiratory Fitness and Hippocampal and Entorhinal Volume in Middle-Aged and Older Adults.

As individuals age, the entorhinal cortex (ERC) and hippocampus-crucial structures for memory-tend to atrophy, with related cognitive decline. Simultaneously, lifestyle factors that can be modified, such as exercise and sleep, have been separately linked to slowing of brain atrophy and functional decline. Yet, the synergistic impact of fitness and sleep on susceptible brain structures in aging adults remains uncertain. We examined both independent and interactive associations of fitness and subjective sleep quality with regard to ERC thickness and hippocampal volume in 598 middle-aged and older adults from the Human Connectome Lifespan Aging Project. Cardiorespiratory fitness was assessed using the 2-minute walk test (2MWT), while subjective sleep quality was measured with the continuous Pittsburgh Sleep Quality Index (PSQI) global score. High-resolution structural magnetic resonance imaging was used to examine mean ERC thickness and bilateral hippocampal volume. Through multiple linear regression analyses, we investigated the moderating effects of subjective sleep quality on the association between fitness and brain structure, accounting for age, sex, education, body mass index, gait speed, and subjective physical activity. We found that greater cardiorespiratory fitness, but not subjective sleep quality, was positively associated with bilateral hippocampal volume and ERC thickness. Notably, significant interaction effects suggest poor subjective sleep quality was associated with a weaker association between fitness and both hippocampal volume and ERC thickness. Findings suggest the potential importance of both cardiorespiratory fitness and subjective sleep quality in preserving critical, age-vulnerable brain structures. Interventions targeting brain health should consider potential combined effects of sleep and fitness on brain health.

Adverse Skeletal Muscle Adaptations in Individuals Born Preterm—A Comprehensive Review

Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and obesity later in life, leading to an increased risk of all-cause mortality in young adults born prematurely. While these preterm-birth-related conditions have been well characterized, less is known about the long-term effects of preterm birth on skeletal muscle health and, specifically, an individual’s skeletal muscle hypertrophic potential later in life. In this review, we discuss how a confluence of potentially interrelated and self-perpetuating elements associated with preterm birth might converge on anabolic and catabolic pathways to ultimately blunt skeletal muscle hypertrophy, identifying critical areas for future research.

Ageing, Cognitive Decline, and Effects of Physical Exercise: Complexities, and Considerations from Animal Models

In our ageing global population, the cognitive decline associated with dementia and neurodegenerative diseases represents a major healthcare problem. To date, there are no effective treatments for age-related cognitive impairment, thus preventative strategies are urgently required. Physical exercise is gaining traction as a non-pharmacological approach to promote brain health. Adult hippocampal neurogenesis (AHN), a unique form of brain plasticity which is necessary for certain cognitive functions declines with age and is enhanced in response to exercise. Accumulating evidence from research in rodents suggests that physical exercise has beneficial effects on cognition through its proneurogenic capabilities. Given ethical and technical limitations in human studies, preclinical research in rodents is crucial for a better understanding of such exercise-induced brain and behavioural changes. In this review, exercise paradigms used in preclinical research are compared. We provide an overview of the effects of different exercise paradigms on age-related cognitive decline from middle-age until older-age. We discuss the relationship between the age-related decrease in AHN and the potential impact of exercise on mitigating this decline. We highlight the emerging literature on the impact of exercise on gut microbiota during ageing and consider the role of the gut-brain axis as a future possible strategy to optimize exercise-enhanced cognitive function. Finally, we propose a guideline for designing optimal exercise protocols in rodent studies, which would inform clinical research and contribute to developing preventative strategies for age-related cognitive decline.

Unsupervised multimodal modeling of cognitive and brain health trajectories for early dementia prediction

Predicting the course of neurodegenerative disorders early has potential to greatly improve clinical management and patient outcomes. A key challenge for early prediction in real-world clinical settings is the lack of labeled data (i.e., clinical diagnosis). In contrast to supervised classification approaches that require labeled data, we propose an unsupervised multimodal trajectory modeling (MTM) approach based on a mixture of state space models that captures changes in longitudinal data (i.e., trajectories) and stratifies individuals without using clinical diagnosis for model training. MTM learns the relationship between states comprising expensive, invasive biomarkers (β-amyloid, grey matter density) and readily obtainable cognitive observations. MTM training on trajectories stratifies individuals into clinically meaningful clusters more reliably than MTM training on baseline data alone and is robust to missing data (i.e., cognitive data alone or single assessments). Extracting an individualized cognitive health index (i.e., MTM-derived cluster membership index) allows us to predict progression to AD more precisely than standard clinical assessments (i.e., cognitive tests or MRI scans alone). Importantly, MTM generalizes successfully from research cohort to real-world clinical data from memory clinic patients with missing data, enhancing the clinical utility of our approach. Thus, our multimodal trajectory modeling approach provides a cost-effective and non-invasive tool for early dementia prediction without labeled data (i.e., clinical diagnosis) with strong potential for translation to clinical practice.

A pathway linking pulse pressure to dementia in adults with Down syndrome

Abstract Individuals with Down syndrome (DS) are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with DS via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with DS from the Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome study (ADDS; n=195, age=50.6+7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal, and occipital white matter hyperintensity (WMH) volume but not to enlarged perivascular spaces (PVS), microbleeds, or infarcts. Through a structural equation model, we found that pulse pressure was associated with greater WMH volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with DS despite the low likelihood of frank hypertension.

Brain organoids engineered to give rise to glia and neural networks after 90 days in culture exhibit human-specific proteoforms

Human brain organoids are emerging as translationally relevant models for the study of human brain health and disease. However, it remains to be shown whether human-specific protein processing is conserved in human brain organoids. Herein, we demonstrate that cell fate and composition of unguided brain organoids are dictated by culture conditions during embryoid body formation, and that culture conditions at this stage can be optimized to result in the presence of glia-associated proteins and neural network activity as early as three-months in vitro. Under these optimized conditions, unguided brain organoids generated from induced pluripotent stem cells (iPSCs) derived from male–female siblings are similar in growth rate, size, and total protein content, and exhibit minimal batch-to-batch variability in cell composition and metabolism. A comparison of neuronal, microglial, and macroglial (astrocyte and oligodendrocyte) markers reveals that profiles in these brain organoids are more similar to autopsied human cortical and cerebellar profiles than to those in mouse cortical samples, providing the first demonstration that human-specific protein processing is largely conserved in unguided brain organoids. Thus, our organoid protocol provides four major cell types that appear to process proteins in a manner very similar to the human brain, and they do so in half the time required by other protocols. This unique copy of the human brain and basic characteristics lay the foundation for future studies aiming to investigate human brain-specific protein patterning (e.g., isoforms, splice variants) as well as modulate glial and neuronal processes in an in situ-like environment.

Brain, behavior, cognition, and physical health in first-onset adolescent anorexia nervosa: The BRAVE Study design and cohort profile

Background Anorexia nervosa is a severe psychiatric disorder with a heterogeneous course with one of the highest rates of morbidity and mortality of all psychiatric disorders. Little is known about factors that predict both course and treatment outcomes of this disorder. The BRAVE Study is a longitudinal first-onset anorexia nervosa cohort study focusing on four topics of interest in girls only: (1) behavior, (2) neurobiology, (3) cognitive functions, and (4) physical health. Objective The goal of this paper is to introduce the BRAVE Study. The primary aim of the BRAVE Study is to identify predictors of treatment response in a large sample of 12-to-22-year-old females with first-onset typical or atypical anorexia nervosa. The second aim is to longitudinally investigate the association between clinically significant changes in eating disorder symptoms with the underlying behavioral, neurobiological, cognitive and physical health changes. The results of this study will allow us to develop more precise treatment strategies in order to provide more optimal treatment. Methods and analysis The BRAVE Study implements a longitudinal case-control design. Study recruitment was designed within a collaborative network of 16 Dutch mental health organizations, each with expertise in the diagnosis and treatment of patients with anorexia nervosa. After obtaining informed consent, assessments were performed at baseline and one-year follow-up. Patients with anorexia nervosa received treatment as usual. The primary outcome measures at one year are restoration of weight and a reduction of eating disorder symptomatology. Predictive measures include neurobiological, cognitive, behavioral and physical health measures. Sample description In the BRAVE Study 79 girls with anorexia nervosa and 75 typically developing girls were included between May 2017 and October 2021. This period of time partially overlapped with the COVID-19 pandemic. 72% of the girls with anorexia nervosa and 88% of the typically developing girls also completed measurements at follow-up. The mean time between data collections points was 13 months. The groups were comparable in education level of their mothers, neurodevelopmental disorders, and ethnical background. The girls with anorexia nervosa were slightly younger than the typically developing girls. Conclusion The BRAVE Study aligns with one of the most important study priorities in the field of anorexia nervosa by examining (i) predictors of treatment response and (ii) investigating how symptoms with eating disorder symptoms track with changes in neurobiological, cognitive, behavorial and physical health functioning. Moreover, the study is innovative by its longitunal case control design, relatively large study sample and broad selection of measures.

In sickness and in health—Type I interferon and the brain

Type I interferons (IFN-I) represent a group of pleiotropic cytokines renowned for their antiviral activity and immune regulatory functions. A multitude of studies have unveiled a critical role of IFN-I in the brain, influencing various neurological processes and diseases. In this mini-review, I highlight recent findings on IFN-I’s effects on brain aging, Alzheimer’s disease (AD) progression, and central nervous system (CNS) homeostasis. The multifaceted influence of IFN-I on brain health and disease sheds light on the complex interplay between immune responses and neurological processes. Of particular interest is the cGAS-STING-IFN-I axis, which extensively participates in brain aging and various forms of neurodegeneration. Understanding the intricate role of IFN-I and its associated pathways in the CNS not only advances our comprehension of brain health and disease but also presents opportunities for developing interventions to modify the process of neurodegeneration and prevent age-related cognitive decline.

Initiating PeriCBD to probe perinatal influences on neurodevelopment during 3–10 years in China

Adverse perinatal factors can interfere with the normal development of the brain, potentially resulting in long-term effects on the comprehensive development of children. Presently, the understanding of cognitive and neurodevelopmental processes under conditions of adverse perinatal factors is substantially limited. There is a critical need for an open resource that integrates various perinatal factors with the development of the brain and mental health to facilitate a deeper understanding of these developmental trajectories. In this Data Descriptor, we introduce a multicenter database containing information on perinatal factors that can potentially influence children’s brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development associated with perinatal factors among children aged 3–10 years. Ultimately, our goal is to help understand how different adverse perinatal factors specifically impact cognitive development and neurodevelopment. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD.

Understanding engagement in diet and dementia prevention research among British South Asians: a short report of findings from a patient and public involvement group.

Dementia is a global public health challenge. Evidence suggests that individuals from South Asian communities are an at-risk group for dementia, partly as a result of early and cumulative exposure to known dementia risk factors, such as obesity and type 2 diabetes. There needs to be more culturally appropriate community engagement to increase awareness of dementia and identify better strategies to encourage participation in dementia-related research. We aimed to better understand the barriers and facilitators towards engaging with, and participating in, diet and dementia related research among British South Asians. This was achieved using a public and patient involvement (PPI) approach. A community-based, engagement event involving information sharing from experts and roundtable discussions with South Asian communities (n = 26 contributors) was held in June 2023 in Newcastle-upon-Tyne, UK. Collaboration from preidentified PPI representatives (n = 3) informed the content and structure of PPI activities, as well as recruitment. Data were synthesised using template analysis, a form of codebook thematic analysis. This involved deductively analysing data using relevant a priori themes, which were expanded upon, or modified, via inductive analysis. The findings highlighted the importance of trust, representation and appreciation of cultural barriers as facilitators to engagement in diet and dementia risk reduction research. Consideration of language barriers, time constraints, social influences and how to embed community outreach activities were reported as driving factors to maximise participation. This PPI work will inform the design and co-creation of a culturally adapted dietary intervention for brain health in accordance with the Medical Research Council and National Institute for Health and Care Research guidance for developing complex interventions.

Exploring the link between tooth loss, cognitive function, andbrain wellness in the context of healthy aging.

The aim of this study was to evaluate the utility of using MRI-derived tooth count, an indirect and nonspecific indicator of oral/periodontal health, and brain age gap (BAG), an MRI-based measure of premature brain aging, in predicting cognition in a population of otherwise healthy adults. This retrospective study utilized data from 329 participants from the University of South Carolina's Aging Brain Cohort Repository. Participants underwent neuropsychological testing including the Montreal Cognitive Assessment (MoCA), completed an oral/periodontal health questionnaire, and submitted to high-resolution structural MRI imaging. The study compared variability on cognitive scores (MoCA) accounted for by MRI-derived BAG, MRI-derived total tooth count, and self-reported oral/periodontal health. We report a significant positive correlation between the total number of teeth and MoCA total scores after controlling for age, sex, and race, indicating a robust relationship between tooth count and cognition, r(208) = .233, p < .001. In a subsample of participants identified as being at risk for MCI (MoCA <= 25, N = 36) inclusion of MRI-based tooth count resulted in an R2 change of .192 (H0 = 0.138 → H1 = 0.330), F(1,31) = 8.86, p = .006. Notably, inclusion of BAG, a valid and reliable measure of overall brain health, did not significantly improve prediction of MoCA scores in similar linear regression models. Our data support the idea that inclusion of MRI-based total tooth count may enhance the ability to predict clinically meaningful differences in cognitive abilities in healthy adults. This study contributes to the growing body of evidence linking oral/periodontal health with cognitive function.

Can micronutrients intake really impact brain health ?

Can micronutrients intake really impact brain health ?

Acupuncture in the treatment of cocaine addiction: how does it work?

Cocaine is a frequently abused and highly addictive drug that damages brain health and imposes substantial social and economic costs. Acupuncture has been used in the treatment of cocaine addiction and has been shown to improve abnormal mental and motor states. This article mainly focuses on the neurobiological mechanisms involving the central nervous system (CNS) and peripheral nervous system (PNS) that underlie the effects of acupuncture in the treatment of cocaine addiction. The central dopamine system is a key player in acupuncture treatment of cocaine addiction; the ventral tegmental area (VTA)-nucleus accumbens (NAc) signaling pathway, which has a modulatory influence on behavior and psychology after chronic use of cocaine, is a significant target of acupuncture action. Moreover, acupuncture alleviates cocaine-induced seizures or acute psychomotor responses through the paraventricular thalamus and the lateral habenula (LHb)-rostromedial tegmental (RMTg) nucleus circuits. The data suggest that acupuncture can impact various cocaine-induced issues via stimulation of diverse brain areas; nevertheless, the interconnection of these brain regions and the PNS mechanisms involved remain unknown. In this review, we also discuss the effects of specific acupuncture protocols on cocaine addiction and note that variations in needling modalities, current intensities and traditional acupuncture point locations have led to different experimental results. Therefore, standardized acupuncture protocols (with respect to stimulation methods, point locations and number of sessions) may become particularly important in future studies.