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 determinants of health but not global genetic ancestry predict dementia prevalence in Latin America.

INTRODUCTION: Leveraging the nonmonolithic structure of Latin America, which represents a large variability in social determinants of health (SDoH) and high levels of genetic admixture, we aim to evaluate the relative contributions of SDoH and genetic ancestry in predicting dementia prevalence in Latin American populations. METHODS: Community-dwelling participants aged 65 and older (N = 3808) from Cuba, Dominican Republic, Mexico, and Peru completed the 10/66 protocol assessments. Dementia was diagnosed using the cross-culturally validated 10/66 algorithm. Multivariate linear regression models adjusted for SDoH were used in the main analysis. This study used cross-sectional data from the 1066 population-based study. RESULTS: Individuals with higher proportions of Native American (>70%) and African American (>70%) ancestry were more likely to exhibit factors contributing to worse SDoH, such as lower educational levels (p < 0.001), lower socioeconomic status (p < 0.001), and higher frequency of vascular risk factors (p < 0.001). After adjusting for measures of SDoH, there was no association between ancestry proportion and dementia probability, and ancestry proportions no longer significantly accounted for the variance in cognitive performance (African predominant p = 0.31 [-0.19, 0.59] and Native predominant p = 0.74 [-0.24, 0.33]). DISCUSSION: The findings suggest that social and environmental factors play a more crucial role than genetic ancestry in predicting dementia prevalence in Latin American populations. This underscores the need for public health strategies and policies that address these social determinants to effectively reduce dementia risk in these communities. HIGHLIGHTS: Countries in Latin America express a large variability in social determinants of health and levels of admixture. After adjustment for downstream societal factors linked to SDoH, genetic ancestry shows no link to dementia. Population ancestry profiles alone do not influence cognitive performance. SDoH are key drivers of racial disparities in dementia and cognitive performance.

The impacts of social determinants of health and cardiometabolic factors on cognitive and functional aging in Colombian underserved populations.

Global initiatives call for further understanding of the impact of inequity on aging across underserved populations. Previous research in low- and middle-income countries (LMICs) presents limitations in assessing combined sources of inequity and outcomes (i.e., cognition and functionality). In this study, we assessed how social determinants of health (SDH), cardiometabolic factors (CMFs), and other medical/social factors predict cognition and functionality in an aging Colombian population. We ran a cross-sectional study that combined theory- (structural equation models) and data-driven (machine learning) approaches in a population-based study (N = 23,694; M = 69.8 years) to assess the best predictors of cognition and functionality. We found that a combination of SDH and CMF accurately predicted cognition and functionality, although SDH was the stronger predictor. Cognition was predicted with the highest accuracy by SDH, followed by demographics, CMF, and other factors. A combination of SDH, age, CMF, and additional physical/psychological factors were the best predictors of functional status. Results highlight the role of inequity in predicting brain health and advancing solutions to reduce the cognitive and functional decline in LMICs.

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.

Classification of Alzheimer's disease and frontotemporal dementia using routine clinical and cognitive measures across multicentric underrepresented samples: A cross sectional observational study.

Background: Global brain health initiatives call for improving methods for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, diagnostic procedures in upper-middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers. Methods: This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants [904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs)] collected in 11 clinical centres across five LAC (ReDLat cohort). Findings: A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex. Interpretation: Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region. Funding: This work was supported by the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat), funded by NIA/NIH (R01AG057234), Alzheimer's Association (SG-20-725707-ReDLat), Rainwater Foundation, Takeda (CW2680521), Global Brain Health Institute; as well as CONICET; FONCYT-PICT (2017-1818, 2017-1820); PIIECC, Facultad de Humanidades, Usach; Sistema General de Regalías de Colombia (BPIN2018000100059), Universidad del Valle (CI 5316); ANID/FONDECYT Regular (1210195, 1210176, 1210176); ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and Alzheimer's Association GBHI ALZ UK-22-865742.

Race, Genetic Admixture, and Cognitive Performance in the Cuban Population.

BACKGROUND: Population aging will lead to a dramatic increase in dementia prevalence, which will disproportionally affect racial minorities. The presence of racial differences in dementia prevalence has been widely reported in United States, but there are no relevant studies on this topic in low- and middle-income countries. METHODS: In a cross-sectional survey, 2944 older Cubans were recruited at a community-based level aimed to identify the effects of self-identified race and genetic admixture on cognitive performance. Dementia diagnosis was established using 10/66 Dementia and DSM-IV criteria. APOE-ε4 genotype was determined in 2511 (85%) and genetic admixture was completed for all dementia cases and in a randomly selected sample of cognitive healthy participants (218 dementia cases and 367 participants without dementia). RESULTS: The overall prevalence of dementia was 8.7%, without large or statistically significant differences on dementia prevalence (p = .12) by self-identified race. Mean cognitive scores were similar across racial groups (p = .46). After controlling for age, sex, and education, greater proportion of African ancestry was not associated with cognitive performance (p = .17). CONCLUSIONS: We found no evidence of an independent effect of self-identified race and/or population ancestry on dementia prevalence or cognitive performance. This suggests that observed differences in dementia prevalence among diverse populations may be driven primarily by social determinants of health.

Systematic Review: Genetic, Neuroimaging, and Fluids Biomarkers for Frontotemporal Dementia Across Latin America Countries.

Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.

Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).

INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. METHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. RESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). DISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Frontotemporal dementia in a Brazilian kindred with the c9orf72 mutation.

OBJECTIVES: To describe the clinical features of a Brazilian kindred with C9orf72 frontotemporal dementia-amyotrophic lateral sclerosis and compare them with other described families with C9orf72 and frontotemporal dementia-amyotrophic lateral sclerosis-causing mutations. DESIGN: Report of a kindred. SETTING: Dementia center at a university hospital. PATIENTS: One kindred encompassing 3 generations. RESULTS: The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed polymerase chain reaction and Southern blot. The observed phenotypes were behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis with dementia, with significant variability in age at onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations, and more posterior atrophy on neuroimaging than is typical for frontotemporal dementia were seen. CONCLUSIONS: Behavioral variant frontotemporal dementia due to C9orf72 expansion displays some phenotypic heterogeneity and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede the diagnosis of dementia by many years and may be a distinguishing feature of this mutation.