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.

Frontotemporal dementia presentation in patients with heterozygous p.H157Y variant of TREM2.

BACKGROUND: The triggering receptor expressed on myeloid cell 2 (TREM2) is a major regulator of neuroinflammatory processes in neurodegeneration. To date, the p.H157Y variant of TREM2 has been reported only in patients with Alzheimer's disease. Here, we report three patients with frontotemporal dementia (FTD) from three unrelated families with heterozygous p.H157Y variant of TREM2: two patients from Colombian families (study 1) and a third Mexican origin case from the USA (study 2). METHODS: To determine if the p.H157Y variant might be associated with a specific FTD presentation, we compared in each study the cases with age-matched, sex-matched and education-matched groups-a healthy control group (HC) and a group with FTD with neither TREM2 mutations nor family antecedents (Ng-FTD and Ng-FTD-MND). RESULTS: The two Colombian cases presented with early behavioural changes, greater impairments in general cognition and executive function compared with both HC and Ng-FTD groups. These patients also exhibited brain atrophy in areas characteristic of FTD. Furthermore, TREM2 cases showed increased atrophy compared with Ng-FTD in frontal, temporal, parietal, precuneus, basal ganglia, parahippocampal/hippocampal and cerebellar regions. The Mexican case presented with FTD and motor neuron disease (MND), showing grey matter reduction in basal ganglia and thalamus, and extensive TDP-43 type B pathology. CONCLUSION: In all TREM2 cases, multiple atrophy peaks overlapped with the maximum peaks of TREM2 gene expression in crucial brain regions including frontal, temporal, thalamic and basal ganglia areas. These results provide the first report of an FTD presentation potentially associated with the p.H157Y variant with exacerbated neurocognitive impairments.

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.

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.

Social and non-social working memory in neurodegeneration.

Although social functioning relies on working memory, whether a social-specific mechanism exists remains unclear. This undermines the characterization of neurodegenerative conditions with both working memory and social deficits. We assessed working memory domain-specificity across behavioral, electrophysiological, and neuroimaging dimensions in 245 participants. A novel working memory task involving social and non-social stimuli with three load levels was assessed across controls and different neurodegenerative conditions with recognized impairments in: working memory and social cognition (behavioral-variant frontotemporal dementia); general cognition (Alzheimer's disease); and unspecific patterns (Parkinson's disease). We also examined resting-state theta oscillations and functional connectivity correlates of working memory domain-specificity. Results in controls and all groups together evidenced increased working memory demands for social stimuli associated with frontocinguloparietal theta oscillations and salience network connectivity. Canonical frontal theta oscillations and executive-default mode network anticorrelation indexed non-social stimuli. Behavioral-variant frontotemporal dementia presented generalized working memory deficits related to posterior theta oscillations, with social stimuli linked to salience network connectivity. In Alzheimer's disease, generalized working memory impairments were related to temporoparietal theta oscillations, with non-social stimuli linked to the executive network. Parkinson's disease showed spared working memory performance and canonical brain correlates. Findings support a social-specific working memory and related disease-selective pathophysiological mechanisms.

Source space connectomics of neurodegeneration: One-metric approach does not fit all.

Brain functional connectivity in dementia has been assessed with dissimilar EEG connectivity metrics and estimation procedures, thereby increasing results' heterogeneity. In this scenario, joint analyses integrating information from different metrics may allow for a more comprehensive characterization of brain functional interactions in different dementia subtypes. To test this hypothesis, resting-state electroencephalogram (rsEEG) was recorded in individuals with Alzheimer's Disease (AD), behavioral variant frontotemporal dementia (bvFTD), and healthy controls (HCs). Whole-brain functional connectivity was estimated in the EEG source space using 101 different types of functional connectivity, capturing linear and nonlinear interactions in both time and frequency-domains. Multivariate machine learning and progressive feature elimination was run to discriminate AD from HCs, and bvFTD from HCs, based on joint analyses of i) EEG frequency bands, ii) complementary frequency-domain metrics (e.g., instantaneous, lagged, and total connectivity), and iii) time-domain metrics with different linearity assumption (e.g., Pearson correlation coefficient and mutual information). <10% of all possible connections were responsible for the differences between patients and controls, and atypical connectivity was never captured by >1/4 of all possible connectivity measures. Joint analyses revealed patterns of hypoconnectivity (patientsHCs) in both groups was mainly identified in frontotemporal regions. These atypicalities were differently captured by frequency- and time-domain connectivity metrics, in a bandwidth-specific fashion. The multi-metric representation of source space whole-brain functional connectivity evidenced the inadequacy of single-metric approaches, and resulted in a valid alternative for the selection problem in EEG connectivity. These joint analyses reveal patterns of brain functional interdependence that are overlooked with single metrics approaches, contributing to a more reliable and interpretable description of atypical functional connectivity in neurodegeneration.

Brain, cognitive, and physical disability correlates of decreased quality of life in patients with Huntington's disease.

PURPOSE: Following a case-control design, as a primary objective, this study aimed to explore the relationship between quality of life (QoL) scores and gray matter (GM) volumes in patients with Huntington's disease (HD). As a secondary objective, we assessed the relationship between QoL scores and other important behavioral, clinical and demographical variables in patients with HD and HD patients' caregivers. METHODS: We recruited 75 participants (25 HD patients, 25 caregivers, and 25 controls) and assessed their QoL using the World Health Organization Quality of Life scale-Brief Version (WHOQOL-BREF). Participants were also assessed with general cognitive functioning tests and clinical scales. In addition, we acquired MRI scans from all participants. RESULTS: Our results showed that patients exhibited significantly lower scores in all four QoL domains (physical health, psychological wellbeing, social relationships, and relationship with the environment) compared to caregivers and controls. Caregivers showed lower scores than controls in the physical health and the environmental domains. In HD patients, lower scores in QoL domains were associated with lower GM volumes, mainly in the precuneus and the cerebellum. Moreover, in HD patients, physical disability and GM volume reduction were significant predictors of QoL decrease in all domains. For caregivers, years of formal education was the most important predictor of QoL. CONCLUSIONS: HD patients exhibit greater GM volume loss as well as lower QoL scores compared to caregivers and controls. However, caregivers displayed lower scores in QoL scores than controls, with years of education being a significant predictor. Our results reflect a first attempt to investigate the relationships among QoL, GM volumes, and other important factors in an HD and HD caregiver sample.

Genuine high-order interactions in brain networks and neurodegeneration.

Brain functional networks have been traditionally studied considering only interactions between pairs of regions, neglecting the richer information encoded in higher orders of interactions. In consequence, most of the connectivity studies in neurodegeneration and dementia use standard pairwise metrics. Here, we developed a genuine high-order functional connectivity (HOFC) approach that captures interactions between 3 or more regions across spatiotemporal scales, delivering a more biologically plausible characterization of the pathophysiology of neurodegeneration. We applied HOFC to multimodal (electroencephalography [EEG], and functional magnetic resonance imaging [fMRI]) data from patients diagnosed with behavioral variant of frontotemporal dementia (bvFTD), Alzheimer's disease (AD), and healthy controls. HOFC revealed large effect sizes, which, in comparison to standard pairwise metrics, provided a more accurate and parsimonious characterization of neurodegeneration. The multimodal characterization of neurodegeneration revealed hypo and hyperconnectivity on medium to large-scale brain networks, with a larger contribution of the former. Regions as the amygdala, the insula, and frontal gyrus were associated with both effects, suggesting potential compensatory processes in hub regions. fMRI revealed hypoconnectivity in AD between regions of the default mode, salience, visual, and auditory networks, while in bvFTD between regions of the default mode, salience, and somatomotor networks. EEG revealed hypoconnectivity in the γ band between frontal, limbic, and sensory regions in AD, and in the δ band between frontal, temporal, parietal and posterior areas in bvFTD, suggesting additional pathophysiological processes that fMRI alone can not capture. Classification accuracy was comparable with standard biomarkers and robust against confounders such as sample size, age, education, and motor artifacts (from fMRI and EEG). We conclude that high-order interactions provide a detailed, EEG- and fMRI compatible, biologically plausible, and psychopathological-specific characterization of different neurodegenerative conditions.

Neurocognitive patterns across genetic levels in behavioral variant frontotemporal dementia: a multiple single cases study.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) has been related to different genetic factors. Identifying multimodal phenotypic heterogeneity triggered by various genetic influences is critical for improving diagnosis, prognosis, and treatments. However, the specific impact of different genetic levels (mutations vs. risk variants vs. sporadic presentations) on clinical and neurocognitive phenotypes is not entirely understood, specially in patites from underrepresented regions such as Colombia. METHODS: Here, in a multiple single cases study, we provide systematic comparisons regarding cognitive, neuropsychiatric, brain atrophy, and gene expression-atrophy overlap in a novel cohort of FTD patients (n = 42) from Colombia with different genetic levels, including patients with known genetic influences (G-FTD) such as those with genetic mutations (GR1) in particular genes (MAPT, TARDBP, and TREM2); patients with risk variants (GR2) in genes associated with FTD (tau Haplotypes H1 and H2 and APOE variants including ε2, ε3, ε4); and sporadic FTD patients (S-FTD (GR3)). RESULTS: We found that patients from GR1 and GR2 exhibited earlier disease onset, pervasive cognitive impairments (cognitive screening, executive functioning, ToM), and increased brain atrophy (prefrontal areas, cingulated cortices, basal ganglia, and inferior temporal gyrus) than S-FTD patients (GR3). No differences in disease duration were observed across groups. Additionally, significant neuropsychiatric symptoms were observed in the GR1. The GR1 also presented more clinical and neurocognitive compromise than GR2 patients; these groups, however, did not display differences in disease onset or duration. APOE and tau patients showed more neuropsychiatric symptoms and primary atrophy in parietal and temporal cortices than GR1 patients. The gene-atrophy overlap analysis revealed atrophy in regions with specific genetic overexpression in all G-FTD patients. A differential family presentation did not explain the results. CONCLUSIONS: Our results support the existence of genetic levels affecting the clinical, neurocognitive, and, to a lesser extent, neuropsychiatric presentation of bvFTD in the present underrepresented sample. These results support tailored assessments characterization based on the parallels of genetic levels and neurocognitive profiles in bvFTD.

Neuroanatomy of complex social emotion dysregulation in adolescent offenders.

Social emotions require the correct integration of emotional, cognitive, and social processes and are critical for complex social interactions. Adolescent criminal offenders (AOs) show abnormalities in the experience of basic emotions. However, most research has focused solely on basic emotions, neglecting complex social emotions that could be critical for social reintegration. The purpose of this study was to investigate the behavioral and neural correlates of social emotions (envy and Schadenfreude) in AOs. We explored the experience of complex social emotions, as well as their anatomical correlates, in AOs (n = 19) and a nonoffenders control group (NOs, n = 20). Additionally, we assessed the relationship between social emotions, executive functions (EFs), and fluid intelligence (FI). Structural brain imaging was obtained in all participants. The results showed that AOs had significantly lower envy and Schadenfreude ratings and exhibited lower performance in EFs compared with NOs. The measurement of EFs relied on the INECO frontal screening (IFS). Experiencing fewer social emotions was associated with diminished EFs but not with FI. Moreover, in AOs, reduced levels of envy and Schadenfreude were linked with reduced gray matter volumes in regions subserving mentalizing abilities (inferior parietal lobe and precuneus) and socioemotional processing (inferior and middle temporal regions), as well as key hubs of the executive frontoparietal network (inferior parietal lobule, orbital and rectus gyri). Additional analysis on the AOs revealed no associations between the type of crime and our variables of interest (EFs, FI and social emotions). Our findings are the first to provide evidence on abnormalities in the experience of social emotions in AOs that are associated with neurocognitive markers of social cognition and EFs. Understanding social emotions and their abnormalities (under-experience) as complex intertwined processes may have important future translational implications, including risk prediction for social adaptation/reintegration, sociocognitive targeted interventions, and skill training for social emotions in vulnerable populations.

Dementia in Latin America: Paving the way toward a regional action plan.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

At the Heart of Neurological Dimensionality: Cross-Nosological and Multimodal Cardiac Interoceptive Deficits.

OBJECTIVE: Neurological nosology, based on categorical systems, has largely ignored dimensional aspects of neurocognitive impairments. Transdiagnostic dimensional approaches of interoception (the sensing of visceral signals) may improve the descriptions of cross-pathological symptoms at behavioral, electrophysiological, and anatomical levels. Alterations of cardiac interoception (encompassing multidimensional variables such as accuracy, learning, sensibility, and awareness) and its neural correlates (electrophysiological markers, imaging-based anatomical and functional connectivity) have been proposed as critical across disparate neurological disorders. However, no study has examined the specific impact of neural (relative to autonomic) disturbances of cardiac interoception or their differential manifestations across neurological conditions. METHODS: Here, we used a computational approach to classify and evaluate which markers of cardiac interoception (behavioral, metacognitive, electrophysiological, volumetric, or functional) offer the best discrimination between neurological conditions and cardiac (hypertensive) disease (model 1), and among neurological conditions (Alzheimer's disease, frontotemporal dementia, multiple sclerosis, and brain stroke; model 2). In total, the study comprised 52 neurological patients (mean [standard deviation] age = 55.1 [17.3] years; 37 women), 25 cardiac patients (age = 66.2 [9.1] years; 13 women), and 72 healthy controls (age = 52.65 [17.1] years; 50 women). RESULTS: Cardiac interoceptive outcomes successfully classified between neurological and cardiac conditions (model 1: >80% accuracy) but not among neurological conditions (model 2: 53% accuracy). Behavioral cardiac interoceptive alterations, although present in all conditions, were powerful in differentiating between neurological and cardiac diseases. However, among neurological conditions, cardiac interoceptive deficits presented more undifferentiated and unspecific disturbances across dimensions. CONCLUSIONS: Our result suggests a diffuse pattern of interoceptive alterations across neurological conditions, highlighting their potential role as dimensional, transdiagnostic markers.

Corticostriatal signatures of schadenfreude: evidence from Huntington's disease.

Schadenfreude-pleasure at others' misfortunes-is a multidetermined social emotion which involves reward processing, mentalising and perspective-taking abilities. Patients with Huntington's disease (HD) exhibit reductions of this experience, suggesting a role of striatal degeneration in such impairment. However, no study has directly assessed the relationship between regional brain atrophy in HD and reduced schadenfreude. Here, we assessed whether grey matter (GM) atrophy in patients with HD correlates with ratings of schadenfreude. First, we compared the performance of 20 patients with HD and 23 controls on an experimental task designed to trigger schadenfreude and envy (another social emotion acting as a control condition). Second, we compared GM volume between groups. Third, we examined brain regions where atrophy might be associated with specific impairments in the patients. While both groups showed similar ratings of envy, patients with HD reported lower schadenfreude. The latter pattern was related to atrophy in regions of the reward system (ventral striatum) and the mentalising network (precuneus and superior parietal lobule). Our results shed light on the intertwining of reward and socioemotional processes in schadenfreude, while offering novel evidence about their neural correlates.

A lesion model of envy and Schadenfreude: legal, deservingness and moral dimensions as revealed by neurodegeneration.

The study of moral emotions (i.e. Schadenfreude and envy) is critical to understand the ecological complexity of everyday interactions between cognitive, affective, and social cognition processes. Most previous studies in this area have used correlational imaging techniques and framed Schadenfreude and envy as unified and monolithic emotional domains. Here, we profit from a relevant neurodegeneration model to disentangle the brain regions engaged in three dimensions of Schadenfreude and envy: deservingness, morality, and legality. We tested a group of patients with behavioural variant frontotemporal dementia (bvFTD), patients with Alzheimer's disease, as a contrastive neurodegeneration model, and healthy controls on a novel task highlighting each of these dimensions in scenarios eliciting Schadenfreude and envy. Compared with the Alzheimer's disease and control groups, patients with bvFTD obtained significantly higher scores on all dimensions for both emotions. Correlational analyses revealed an association between envy and Schadenfreude scores and greater deficits in social cognition, inhibitory control, and behaviour disturbances in bvFTD patients. Brain anatomy findings (restricted to bvFTD and controls) confirmed the partially dissociable nature of the moral emotions' experiences and highlighted the importance of socio-moral brain areas in processing those emotions. In all subjects, an association emerged between Schadenfreude and the ventral striatum, and between envy and the anterior cingulate cortex. In addition, the results supported an association between scores for moral and legal transgression and the morphology of areas implicated in emotional appraisal, including the amygdala and the parahippocampus. By contrast, bvFTD patients exhibited a negative association between increased Schadenfreude and envy across dimensions and critical regions supporting social-value rewards and social-moral processes (dorsolateral prefrontal cortex, angular gyrus and precuneus). Together, this study provides lesion-based evidence for the multidimensional nature of the emotional experiences of envy and Schadenfreude. Our results offer new insights into the mechanisms subsuming complex emotions and moral cognition in neurodegeneration. Moreover, this study presents the exacerbation of envy and Schadenfreude as a new potential hallmark of bvFTD that could impact in diagnosis and progression.

The interplay between sharing behavior and beliefs about others in children during dictator games.

Previous studies in adults demonstrated that beliefs and sharing decisions in social scenarios are closely related. However, to date, little is known about the development of this relationship in children. By using a modified dictator game, we assessed sharing behavior and beliefs about others in children between 3 and 12 years old. We performed four studies (N = 376) aimed to assess whether decisions were related to beliefs (Studies 1 and 2) and whether information about the recipient's forced sharing behavior would shape decisions and beliefs (Studies 3 and 4). Results of Studies 1 and 2 showed that beliefs about others' generosity were related to children's sharing behavior. In Studies 3 and 4, we found that only children older than 9 years shared more pieces of candy when they knew that the recipient would be forced to share (cooperative context) than when they knew that the recipient would be forced not to share (noncooperative context). Besides, children older than 6 years did not modify their beliefs about others' generosity according to these social contexts. These results suggest that normative or preconceived beliefs about the functioning of the social world may guide social behavior in children.

Neuroanatomical Markers of Social Hierarchy Recognition in Humans: A Combined ERP/MRI Study.

Social hierarchy is an ubiquitous principle of social organization across animal species. Although some progress has been made in our understanding of how humans infer hierarchical identity, the neuroanatomical basis for perceiving key social dimensions of others remains unexplored. Here, we combined event-related potentials and structural MRI to reveal the neuroanatomical substrates of early status recognition. We designed a covertly simulated hierarchical setting in which participants performed a task either with a superior or with an inferior player. Participants showed higher amplitude in the N170 component when presented with a picture of a superior player compared with an inferior player. Crucially, the magnitude of this effect correlated with brain morphology of the posterior cingulate cortex, superior temporal gyrus, insula, fusiform gyrus, and caudate nucleus. We conclude that early recognition of social hierarchies relies on the structural properties of a network involved in the automatic recognition of social identity. SIGNIFICANCE STATEMENT: Humans can perceive social hierarchies very rapidly, an ability that is key for social interactions. However, some individuals are more sensitive to hierarchical information than others. Currently, it is unknown how brain structure supports such fast-paced processes of social hierarchy perception and their individual differences. Here, we addressed this issue for the first time by combining the high temporal resolution of event-related potentials (ERPs) and the high spatial resolution of structural MRI. This methodological approach allowed us to unveil a novel association between ERP neuromarkers of social hierarchy perception and the morphology of several cortical and subcortical brain regions typically assumed to play a role in automatic processes of social cognition. Our results are a step forward in our understanding of the human social brain.

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.

A Multidimensional, Person-Centered Framework for Functional Assessment in Dementia: Insights from the 'What', 'How', 'To Whom', and 'How Much' Questions.

Dementia is a syndrome characterized by cognitive and neuropsychiatric symptoms associated with progressive functional decline (FD). FD is a core diagnostic criterion for dementia, setting the threshold between its prodromal stages and the full-blown disease. The operationalization of FD continues to generate a great deal of controversy. For instance, the threshold of FD for the diagnosis of dementia varies across diagnostic criteria, supporting the need for standardization of this construct. Moreover, there is a need to reconsider how we are measuring FD to set boundaries between normal aging, mild cognitive impairment, and dementia. In this paper, we propose a multidimensional framework that addresses outstanding issues in the assessment of FD: i) What activities of daily living (ADLs) are necessary to sustain an independent living in aging? ii) How to assess FD in individuals with suspected neurocognitive disorders? iii) To whom is the assessment directed? and iv) How much does FD differentiate healthy aging from mild and major neurocognitive disorders? Importantly, the To Whom Question introduces a person-centered approach that regards patients and caregivers as active agents in the assessment process of FD. Thus, once impaired ADLs have been identified, patients can indicate how significant such impairments are for them in daily life. We envisage that this new framework will guide future strategies to enhance functional assessment and treatment of patients with dementia and their caregivers.

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.

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.