Educational disparities in brain health and dementia across Latin America and the United States.

BACKGROUND: Education influences brain health and dementia. However, its impact across regions, specifically Latin America (LA) and the United States (US), is unknown. METHODS: A total of 1412 participants comprising controls, patients with Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) from LA and the US were included. We studied the association of education with brain volume and functional connectivity while controlling for imaging quality and variability, age, sex, total intracranial volume (TIV), and recording type. RESULTS: Education influenced brain measures, explaining 24%-98% of the geographical differences. The educational disparities between LA and the US were associated with gray matter volume and connectivity variations, especially in LA and AD patients. Education emerged as a critical factor in classifying aging and dementia across regions. DISCUSSION: The results underscore the impact of education on brain structure and function in LA, highlighting the importance of incorporating educational factors into diagnosing, care, and prevention, and emphasizing the need for global diversity in research. HIGHLIGHTS: Lower education was linked to reduced brain volume and connectivity in healthy controls (HCs), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Latin American cohorts have lower educational levels compared to the those in the United States. Educational disparities majorly drive brain health differences between regions. Educational differences were significant in both conditions, but more in AD than FTLD. Education stands as a critical factor in classifying aging and dementia across regions.

High-order brain interactions in ketamine during rest and task: a double-blinded cross-over design using portable EEG on male participants.

Ketamine is a dissociative anesthetic that induces a shift in global consciousness states and related brain dynamics. Portable low-density EEG systems could be used to monitor these effects. However, previous evidence is almost null and lacks adequate methods to address global dynamics with a small number of electrodes. This study delves into brain high-order interactions (HOI) to explore the effects of ketamine using portable EEG. In a double-blinded cross-over design, 30 male adults (mean age = 25.57, SD = 3.74) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Ketamine induced an increase in redundancy in brain dynamics (copies of the same information that can be retrieved from 3 or more electrodes), most significantly in the alpha frequency band. Redundancy was more evident during resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine's HOI and experiences of derealization. Ketamine appears to increase redundancy and HOI across psychometric measures, suggesting these effects are correlated with alterations in consciousness towards dissociation. In comparisons with event-related potential (ERP) or standard functional connectivity metrics, HOI represent an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations between electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

Allostatic Interoceptive Overload Across Psychiatric and Neurological Conditions.

Emerging theories emphasize the crucial role of allostasis (anticipatory and adaptive regulation of the body's biological processes) and interoception (integration, anticipation, and regulation of internal bodily states) in adjusting physiological responses to environmental and bodily demands. In this review, we explore the disruptions in integrated allostatic interoceptive mechanisms in psychiatric and neurological disorders, including anxiety, depression, Alzheimer's disease, and frontotemporal dementia. We assess the biological mechanisms associated with allostatic interoception, including whole-body cascades, brain structure and function of the allostatic interoceptive network, heart-brain interactions, respiratory-brain interactions, the gut-brain-microbiota axis, peripheral biological processes (inflammatory, immune), and epigenetic pathways. These processes span psychiatric and neurological conditions and call for developing dimensional and transnosological frameworks. We synthesize new pathways to understand how allostatic interoceptive processes modulate interactions between environmental demands and biological functions in brain disorders. We discuss current limitations of the framework and future transdisciplinary developments. This review opens a new research agenda for understanding how allostatic interoception involves brain predictive coding in psychiatry and neurology, allowing for better clinical application and the development of new therapeutic interventions.

The impact of COVID-19 post-infection on the cognition of adults from Peru.

Introduction: The COVID-19 pandemic, with over 83 million confirmed cases and 1.8 million deaths, has raised concerns about long-term cognitive issues, especially in populations facing disparities. Despite a few years since Peru's first COVID-19 wave, the cognitive effects on adults remain unclear. This study is the first in Peru to explore COVID-19's impact on general cognition and executive function. Methods: A retrospective cross-sectional study compared individuals with COVID-19 history to controls, assessing general cognition, verbal fluency, attention, and executive function. Among 240 assessed, 154 met the study inclusion criteria, with about 60% female and an average age of 38.89 ± 16.001 years. Groups included controls (n = 42), acute phase (AP, n = 74) (1-14 days of symptoms), and hyperinflammatory phase (HP, n = 38) (>14 days of symptoms). Results: Significant cognitive differences were observed. The HP group exhibited lower general cognitive performance (p = 0.02), working memory (p = 0.01), and executive function (planning; p < 0.001; flexibility; p = 0.03) than controls. Those with <14 days of illness (AP vs. HP) had deficits in general cognitive performance (p = 0.02), working memory (p = 0.02), and planning (p < 0.001), mainly during the hyperinflammatory phase, showing differences in working memory (p = 0.003) and planning (p = 0.01). Gender differences emerged, with males in the HP phase having poorer working memory (p = 0.003) and planning (p = 0.01). Discussion: This study underscores COVID-19's negative impact on cognitive function, even in mild cases, with potential heightened effects in men during acute or hyperinflammatory phases. The findings provide Peru's first evidence, highlighting the vulnerability of populations facing socioeconomic disparities.

Healthy aging meta-analyses and scoping review of risk factors across Latin America reveal large heterogeneity and weak predictive models.

Models of healthy aging are typically based on the United States and Europe and may not apply to diverse and heterogeneous populations. In this study, our objectives were to conduct a meta-analysis to assess risk factors of cognition and functional ability across aging populations in Latin America and a scoping review focusing on methodological procedures. Our study design included randomized controlled trials and cohort, case-control and cross-sectional studies using multiple databases, including MEDLINE, the Virtual Health Library and Web of Science. From an initial pool of 455 studies, our meta-analysis included 38 final studies (28 assessing cognition and 10 assessing functional ability, n = 146,000 participants). Our results revealed significant but heterogeneous effects for cognition (odds ratio (OR) = 1.20, P = 0.03, confidence interval (CI) = (1.0127, 1.42); heterogeneity: I2 = 92.1%, CI = (89.8%, 94%)) and functional ability (OR = 1.20, P = 0.01, CI = (1.04, 1.39); I2 = 93.1%, CI = (89.3%, 95.5%)). Specific risk factors had limited effects, especially on functional ability, with moderate impacts for demographics and mental health and marginal effects for health status and social determinants of health. Methodological issues, such as outliers, inter-country differences and publication bias, influenced the results. Overall, we highlight the specific profile of risk factors associated with healthy aging in Latin America. The heterogeneity in results and methodological approaches in studying healthy aging call for greater harmonization and further regional research to understand healthy aging in Latin America.

Automated free speech analysis reveals distinct markers of Alzheimer's and frontotemporal dementia.

Dementia can disrupt how people experience and describe events as well as their own role in them. Alzheimer's disease (AD) compromises the processing of entities expressed by nouns, while behavioral variant frontotemporal dementia (bvFTD) entails a depersonalized perspective with increased third-person references. Yet, no study has examined whether these patterns can be captured in connected speech via natural language processing tools. To tackle such gaps, we asked 96 participants (32 AD patients, 32 bvFTD patients, 32 healthy controls) to narrate a typical day of their lives and calculated the proportion of nouns, verbs, and first- or third-person markers (via part-of-speech and morphological tagging). We also extracted objective properties (frequency, phonological neighborhood, length, semantic variability) from each content word. In our main study (with 21 AD patients, 21 bvFTD patients, and 21 healthy controls), we used inferential statistics and machine learning for group-level and subject-level discrimination. The above linguistic features were correlated with patients' scores in tests of general cognitive status and executive functions. We found that, compared with HCs, (i) AD (but not bvFTD) patients produced significantly fewer nouns, (ii) bvFTD (but not AD) patients used significantly more third-person markers, and (iii) both patient groups produced more frequent words. Machine learning analyses showed that these features identified individuals with AD and bvFTD (AUC = 0.71). A generalizability test, with a model trained on the entire main study sample and tested on hold-out samples (11 AD patients, 11 bvFTD patients, 11 healthy controls), showed even better performance, with AUCs of 0.76 and 0.83 for AD and bvFTD, respectively. No linguistic feature was significantly correlated with cognitive test scores in either patient group. These results suggest that specific cognitive traits of each disorder can be captured automatically in connected speech, favoring interpretability for enhanced syndrome characterization, diagnosis, and monitoring.

Advancements in dementia research, diagnostics, and care in Latin America: Highlights from the 2023 Alzheimer's Association International conference satellite symposium in Mexico City.

INTRODUCTION: While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care. METHODS: In 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm. RESULTS: Significant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted. DISCUSSION: The myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

Brain health in diverse settings: How age, demographics and cognition shape brain function.

Diversity in brain health is influenced by individual differences in demographics and cognition. However, most studies on brain health and diseases have typically controlled for these factors rather than explored their potential to predict brain signals. Here, we assessed the role of individual differences in demographics (age, sex, and education; n = 1298) and cognition (n = 725) as predictors of different metrics usually used in case-control studies. These included power spectrum and aperiodic (1/f slope, knee, offset) metrics, as well as complexity (fractal dimension estimation, permutation entropy, Wiener entropy, spectral structure variability) and connectivity (graph-theoretic mutual information, conditional mutual information, organizational information) from the source space resting-state EEG activity in a diverse sample from the global south and north populations. Brain-phenotype models were computed using EEG metrics reflecting local activity (power spectrum and aperiodic components) and brain dynamics and interactions (complexity and graph-theoretic measures). Electrophysiological brain dynamics were modulated by individual differences despite the varied methods of data acquisition and assessments across multiple centers, indicating that results were unlikely to be accounted for by methodological discrepancies. Variations in brain signals were mainly influenced by age and cognition, while education and sex exhibited less importance. Power spectrum activity and graph-theoretic measures were the most sensitive in capturing individual differences. Older age, poorer cognition, and being male were associated with reduced alpha power, whereas older age and less education were associated with reduced network integration and segregation. Findings suggest that basic individual differences impact core metrics of brain function that are used in standard case-control studies. Considering individual variability and diversity in global settings would contribute to a more tailored understanding of brain function.

Allostasis, health, and development in Latin America.

The lifespan is influenced by adverse childhood experiences that create predispositions to poor health outcomes. Here we propose an allostatic framework of childhood experiences and their impact on health across the lifespan, focusing on Latin American and Caribbean countries. This region is marked by significant social and health inequalities nested in environmental and social stressors, such as exposure to pollution, violence, and nutritional deficiencies, which critically influence current and later-life health outcomes. We review several manifestations across cognition, behavior, and the body, observed at the psychological (e.g., cognitive, socioemotional, and behavioral dysfunctions), brain (e.g., alteration of the development, structure, and function of the brain), and physiological levels (e.g., dysregulation of the body systems and damage to organs). To address the complexity of the interactions between environmental and health-related factors, we present an allostatic framework regarding the cumulative burden of environmental stressors on physiological systems (e.g., cardiovascular, metabolic, immune, and neuroendocrine) related to health across the life course. Lastly, we explore the relevance of this allostatic integrative approach in informing regional interventions and public policy recommendations. We also propose a research agenda, potentially providing detailed profiling and personalized care by assessing the social and environmental conditions. This framework could facilitate the delivery of evidence-based interventions and informed childhood-centered policy-making.

Biophysical models applied to dementia patients reveal links between geographical origin, gender, disease duration, and loss of neural inhibition.

BACKGROUND: The hypothesis of decreased neural inhibition in dementia has been sparsely studied in functional magnetic resonance imaging (fMRI) data across patients with different dementia subtypes, and the role of social and demographic heterogeneities on this hypothesis remains to be addressed. METHODS: We inferred regional inhibition by fitting a biophysical whole-brain model (dynamic mean field model with realistic inter-areal connectivity) to fMRI data from 414 participants, including patients with Alzheimer's disease, behavioral variant frontotemporal dementia, and controls. We then investigated the effect of disease condition, and demographic and clinical variables on the local inhibitory feedback, a variable related to the maintenance of balanced neural excitation/inhibition. RESULTS: Decreased local inhibitory feedback was inferred from the biophysical modeling results in dementia patients, specific to brain areas presenting neurodegeneration. This loss of local inhibition correlated positively with years with disease, and showed differences regarding the gender and geographical origin of the patients. The model correctly reproduced known disease-related changes in functional connectivity. CONCLUSIONS: Results suggest a critical link between abnormal neural and circuit-level excitability levels, the loss of grey matter observed in dementia, and the reorganization of functional connectivity, while highlighting the sensitivity of the underlying biophysical mechanism to demographic and clinical heterogeneities in the patient population.

Emerging Theories of Allostatic-Interoceptive Overload in Neurodegeneration.

Recent integrative multilevel models offer novel insights into the etiology and course of neurodegenerative conditions. The predictive coding of allostatic-interoception theory posits that the brain adapts to environmental demands by modulating internal bodily signals through the allostatic-interoceptive system. Specifically, a domain-general allostatic-interoceptive network exerts adaptive physiological control by fine-tuning initial top-down predictions and bottom-up peripheral signaling. In this context, adequate adaptation implies the minimization of prediction errors thereby optimizing energy expenditure. Abnormalities in top-down interoceptive predictions or peripheral signaling can trigger allostatic overload states, ultimately leading to dysregulated interoceptive and bodily systems (endocrine, immunological, circulatory, etc.). In this context, environmental stress, social determinants of health, and harmful exposomes (i.e., the cumulative life-course exposition to different environmental stressors) may interact with physiological and genetic factors, dysregulating allostatic interoception and precipitating neurodegenerative processes. We review the allostatic-interoceptive overload framework across different neurodegenerative diseases, particularly in the behavioral variant frontotemporal dementia (bvFTD). We describe how concepts of allostasis and interoception could be integrated with principles of predictive coding to explain how the brain optimizes adaptive responses, while maintaining physiological stability through feedback loops with multiple organismic systems. Then, we introduce the model of allostatic-interoceptive overload of bvFTD and discuss its implications for the understanding of pathophysiological and neurocognitive abnormalities in multiple neurodegenerative conditions.

Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole-brain modeling.

INTRODUCTION: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) lack mechanistic biophysical modeling in diverse, underrepresented populations. Electroencephalography (EEG) is a high temporal resolution, cost-effective technique for studying dementia globally, but lacks mechanistic models and produces non-replicable results. METHODS: We developed a generative whole-brain model that combines EEG source-level metaconnectivity, anatomical priors, and a perturbational approach. This model was applied to Global South participants (AD, bvFTD, and healthy controls). RESULTS: Metaconnectivity outperformed pairwise connectivity and revealed more viscous dynamics in patients, with altered metaconnectivity patterns associated with multimodal disease presentation. The biophysical model showed that connectome disintegration and hypoexcitability triggered altered metaconnectivity dynamics and identified critical regions for brain stimulation. We replicated the main results in a second subset of participants for validation with unharmonized, heterogeneous recording settings. DISCUSSION: The results provide a novel agenda for developing mechanistic model-inspired characterization and therapies in clinical, translational, and computational neuroscience settings.

Associations of the 'weekend warrior' physical activity pattern with all-cause, cardiovascular disease and cancer mortality: the Mexico City Prospective Study.

OBJECTIVES: The objective was to investigate the benefits of the 'weekend warrior' physical activity pattern in Latin America, where many people take part in high levels of non-exercise physical activity. METHODS: Participants in the Mexico City Prospective Study were surveyed from 1998 to 2004 and resurveyed from 2015 to 2019. Those who exercised up to once or twice per week were termed weekend warriors. Those who exercised more often were termed regularly active. Analyses were adjusted for potential confounders. RESULTS: The main analysis included 26 006 deaths in 154 882 adults (67% female) aged 52±13 years followed for 18±4 years (mean±SD). Compared with those who reported no exercise, the HR (95% CI) was 0.88 (0.83 to 0.93) in the weekend warriors and 0.88 (0.84 to 0.91) in the regularly active. Similar results were observed for cardiovascular disease and cancer mortality, but associations were weaker. Stratified analyses showed that substantial reductions in all-cause mortality risk only occurred when the duration of exercise sessions was at least 30-60 min. The repeated-measures analysis included 843 deaths in 10 023 adults followed for 20±2 years. Compared with being inactive or becoming inactive, the HR was 0.86 (95% CI 0.65 to 1.12) when being a weekend warrior or becoming a weekend warrior and 0.85 (95% CI 0.70 to 1.03) when being regularly active or becoming regularly active. CONCLUSIONS: This is the first prospective study to investigate the benefits of the weekend warrior physical activity pattern in Latin America. The results suggest that even busy adults could benefit from taking part in one or two sessions of exercise per week.

Neurocognitive correlates of semantic memory navigation in Parkinson's disease.

Cognitive studies on Parkinson's disease (PD) reveal abnormal semantic processing. Most research, however, fails to indicate which conceptual properties are most affected and capture patients' neurocognitive profiles. Here, we asked persons with PD, healthy controls, and individuals with behavioral variant frontotemporal dementia (bvFTD, as a disease control group) to read concepts (e.g., 'sun') and list their features (e.g., hot). Responses were analyzed in terms of ten word properties (including concreteness, imageability, and semantic variability), used for group-level comparisons, subject-level classification, and brain-behavior correlations. PD (but not bvFTD) patients produced more concrete and imageable words than controls, both patterns being associated with overall cognitive status. PD and bvFTD patients showed reduced semantic variability, an anomaly which predicted semantic inhibition outcomes. Word-property patterns robustly classified PD (but not bvFTD) patients and correlated with disease-specific hypoconnectivity along the sensorimotor and salience networks. Fine-grained semantic assessments, then, can reveal distinct neurocognitive signatures of PD.

Multivariate word properties in fluency tasks reveal markers of Alzheimer's dementia.

INTRODUCTION: Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease-specific semantic memory patterns. Here, we leveraged automated word-property analysis to capture neurocognitive markers of AD vis-à-vis behavioral variant frontotemporal dementia (bvFTD). METHODS: Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group-level discrimination, patient-level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns. RESULTS: Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group- and subject-level discrimination only in AD, also predicting executive outcomes. Disease-specific cortical thickness patterns were predicted by frequency in both disorders. Default-mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD. DISCUSSION: Word-property analysis of fluency can boost AD characterization and diagnosis. HIGHLIGHTS: We report novel word-property analyses of verbal fluency in AD and bvFTD. Standard valid response counts captured deficits and brain patterns in both groups. Specific word properties (e.g., frequency, granularity) were altered only in AD. Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD. Word-property analysis of fluency can boost AD characterization and diagnosis.