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.

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.

Advances in Treatment of Frontotemporal Dementia.

In this review, the authors explored the clinical features of frontotemporal dementia (FTD), focusing on treatment. The clinical features of FTD are unique, with disinhibition, apathy, loss of empathy, and compulsions common. Motor changes occur later in the illness. The two major proteins that aggregate in the brain with FTD are tau and TDP-43, whereas a minority of patients aggregate FET proteins, primarily the FUS protein. Genetic causes include mutations in MAPT, GRN, and C9orf72. There are no medications that can slow FTD progression, although new therapies for the genetic forms of FTD are moving into clinical trials. Once a diagnosis is made, therapies should begin, focusing on the family and the patient. In the setting of FTD, families experience a severe burden associated with caregiving, and the clinician should focus on alleviating this burden. Advice around legal and financial issues is usually helpful. Careful consideration of environmental changes to cope with abnormal behaviors is essential. Most compounds that have been used to treat dementia of the Alzheimer's disease type are not effective in FTD, and cholinesterase inhibitors and memantine should be avoided. Although the data are scant, there is some evidence that antidepressants and second-generation antipsychotics may help individual patients.

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.

The Psychiatric Misdiagnosis of Behavioral Variant Frontotemporal Dementia in a Colombian Sample.

Objective: To describe the demographic characteristics, initial psychiatric diagnoses, and the time to reach a diagnosis of probable behavioral variant frontotemporal dementia (bvFTD) in a public psychiatric hospital in Cali, Colombia. Methods: We retrospectively reviewed the medical records of 28 patients who were diagnosed with probable bvFTD based on a multidisciplinary evaluation that included a structural MRI, neuropsychological testing, functional assessment, and neurological exam. Prior to this evaluation, all patients were evaluated by a psychiatrist as part of their initial consultation at the hospital. The initial consultation included the Neuropsychiatric Inventory and diagnoses based on the DSM-V. Demographics, clinical features, and initial psychiatric misdiagnoses were extracted from clinical records and summarized in the full sample and by gender. Results: The study sample had a mean education of 10.0 years (SD = 4.9) and 68.0% were female. In the full sample, 28.6% were initially diagnosed with dementia, and 71.4% with a psychiatric disorder. The psychiatric diagnosis at initial consultation differed by gender. Women were most likely to be diagnosed with depression (26.3%) or bipolar disorder (26.3%), while the men were most likely to be diagnosed with anxiety (33.3%) or a psychotic disorder (22.2%). Psychotic symptoms were common (delusions, 60.7% and hallucinations, 39.3%), and the pattern of neuropsychiatric symptoms did not differ by gender. Conclusions: This is one of few case series of bvFTD in a Colombian population, where bvFTD is a recognizable and prevalent disorder. In this psychiatric hospital, the majority of patients with bvFTD were initially diagnosed with a primary psychiatric condition. There was a gender difference in psychiatric diagnosis, but not in neuropsychiatric symptoms. In this sample, the rate of psychiatric misdiagnosis, as well as the psychotic symptoms, were higher compared to rates described in other countries. These results highlight the need for interventions to improve bvFTD diagnosis in under-represented populations.

A Brief Digital Cognitive Assessment for Detection of Cognitive Impairment in Cuban Older Adults.

BACKGROUND: Rapid technological advances offer a possibility to develop cost-effective digital cognitive assessment tools. However, it is unclear whether these measures are suitable for application in populations from Low and middle-income countries (LMIC). OBJECTIVE: To examine the accuracy and validity of the Brain Health Assessment (BHA) in detecting cognitive impairment in a Cuban population. METHODS: In this cross-sectional study, 146 participants (cognitively healthy = 53, mild cognitive impairment (MCI) = 46, dementia = 47) were recruited at primary care and tertiary clinics. The main outcomes included: accuracy of the BHA and the Montreal Cognitive Assessment (MoCA) in discriminating between controls and cognitively impaired groups (MCI and dementia) and correlations between the BHA subtests of memory, executive functions, and visuospatial skills and criterion-standard paper-and-pencil tests in the same domains. RESULTS: The BHA had an AUC of 0.95 (95% CI: 0.91-0.98) in discriminating between controls and cognitively impaired groups (MCI and dementia, combined) with 0.91 sensitivity at 0.85 specificity. In discriminating between control and MCI groups only, the BHA tests had an AUC of 0.94 (95% CI: 0.90-0.99) with 0.71 sensitivity at 0.85 specificity. Performance was superior to the MoCA across all diagnostic groups. Concurrent and discriminant validity analyses showed moderate to strong correlations between the BHA tests and standard paper-and-pencil measures in the same domain and weak correlations with standard measures in unrelated domains. CONCLUSION: The BHA has excellent performance characteristics in detecting cognitive impairment including dementia and MCI in a Hispanic population in Cuba and outperformed the MoCA. These results support potential application of digital cognitive assessment for older adults in LMIC.

Deep clinical and neuropathological phenotyping of Pick disease.

OBJECTIVE: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease. METHODS: Detailed neuropathological examination using 70µm and traditional 6µm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity. RESULTS: Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. INTERPRETATION: Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.

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.