Brain volume, energy balance, and cardiovascular health in two nonindustrial South American populations.

Little is known about brain aging or dementia in nonindustrialized environments that are similar to how humans lived throughout evolutionary history. This paper examines brain volume (BV) in middle and old age among two indigenous South American populations, the Tsimane and Moseten, whose lifestyles and environments diverge from those in high-income nations. With a sample of 1,165 individuals aged 40 to 94, we analyze population differences in cross-sectional rates of decline in BV with age. We also assess the relationships of BV with energy biomarkers and arterial disease and compare them against findings in industrialized contexts. The analyses test three hypotheses derived from an evolutionary model of brain health, which we call the embarrassment of riches (EOR). The model hypothesizes that food energy was positively associated with late life BV in the physically active, food-limited past, but excess body mass and adiposity are now associated with reduced BV in industrialized societies in middle and older ages. We find that the relationship of BV with both non-HDL cholesterol and body mass index is curvilinear, positive from the lowest values to 1.4 to 1.6 SDs above the mean, and negative from that value to the highest values. The more acculturated Moseten exhibit a steeper decrease in BV with age than Tsimane, but still shallower than US and European populations. Lastly, aortic arteriosclerosis is associated with lower BV. Complemented by findings from the United States and Europe, our results are consistent with the EOR model, with implications for interventions to improve brain health.

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Natural selection of immune and metabolic genes associated with health in two lowland Bolivian populations.

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population.

In post-industrial settings, apolipoprotein E4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population.

Genes contain the instructions needed for a cell to make molecules called proteins, which perform various roles in the body. Different variants of a gene can affect how the protein works, and in some cases, can increase a person's risk to develop certain diseases. For example, people who carry a version of the apolipoprotein E gene called APOE4 have a greater risk of developing Alzheimer's disease or heart disease. Individuals with two copies of this genetic variant have a 45% higher risk of heart disease and 12 times higher risk of Alzheimer's disease. Studies in industrialized countries suggest this increased risk may be the result of higher cholesterol and inflammation in people with APOE4. But if APOE4 is harmful, why does it continue to be so common worldwide? One potential explanation is that APOE4, which has been around since before modern humans, may be beneficial in some contexts. Cholesterol is essential for many vital tasks in the body. In physically demanding environments where parasitic infections are common ­ conditions similar to those experienced by early humans ­ APOE4 might be beneficial. Under those circumstances, having more cholesterol might help fuel metabolic activities, fight infections, or reduce inflammation caused by infections. Garcia et al. investigated the link between the APOE4 genetic variant, cholesterol and inflammation in 1,266 Indigenous Tsimane people from 80 villages in Bolivia. Tsimane people live an active lifestyle foraging and farming for food. Parasite infections are a common problem in their communities, but obesity rates are very low. Garcia et al. found that Tsimane people with at least one copy of the APOE4 have lower levels of inflammation and higher levels of cholesterol than those who have two copies of the APOE3 version of the gene. Very lean people with APOE4 had especially high levels of the so called "bad" low density lipoprotein (LDL) cholesterol compared to people with APOE3 only. However, in this situation, storing a little extra cholesterol may not be so bad. The findings contradict other studies that have linked obesity to higher LDL levels and APOE4 to higher levels of inflammation. For the majority of human history, humans lived in more physically strenuous and calorically restrictive environments, with less access to clean water. Garcia et al. suggest that the harmful effects of APOE4 seen in studies in more industrialized societies ­ where people tend to be more sedentary and have less exposure to pathogens ­ may reflect a mismatch between a person's environment and their genes. More studies that capture the diversity of environmental conditions under which people live will help clarify the role of APOE4 health and disease.

El tratamiento intralesional de Leishmaniasis cutánea es seguro frente al riesgo de complicaciones mucosas? / Is the intralesional treatment of cutaneous Leishmaniasis safe against the risk of mucosal complications?

OBJETIVO: evaluar la seguridad a largo plazo frente al riesgo de complicaciones mucosas del uso intralesional de antimoniales pentavalentes en pacientes con leishmaniasis cutánea comparado con el uso sistémico de los mismos. MÉTODOS: estudio observacional, cuantitativo de tipo longitudinal retrospectivo. Se analizó un total de 66 registros clínicos de pacientes, con diagnóstico de Leishmaniasis cutánea del parque Isiboro Secure durante el periodo 2012 a 2016. Se evaluó un total de 46 tratamientos sistémicos y 20 intralesionales. RESULTADOS: la evaluación clínica realizada entre 4 y 7 años posteriores a la cicatrización de las lesiones cutáneas de Leishmaniasis mostró la ausencia de desarrollo de lesiones mucosas. Así mismo no se reportó fallas terapéuticas, recidivas ni efectos adversos a corto plazo. CONCLUSIONES: el tratamiento intralesional fue seguro y eficaz a largo plazo y es una opción confiable para el tratamiento de leishmaniasis cutánea evitando las complicaciones futuras de la enfermedad.

OBJECTIVE: to assess the long-term safety against the risk of mucosal complications of intralesional pentavalent antimonials (PA) in patients with cutaneous Leishmaniasis compared to the systemic use of PA. METHODS: retrospective longitudinal quantitative observational study. A total of 66 clinical records of patients diagnosed with cutaneous Leishmaniasis in Isiboro Secure Park were analyzed between 2012 and 2016. A total of 46 systemic and 20 intralesional treatments were evaluated. RESULTS: clinical evaluation 4-7 years after healing of Leishmaniasis skin lesions showed no development of mucosal lesions. Likewise, no therapeutic failures, relapses or short-term adverse effects were reported. CONCLUSIONS: intralesional treatment was safe and effective in the long term and is a reliable option for the treatment of cutaneous Leishmaniasis avoiding the future complications of the disease.

"Cheaper and better": Societal cost savings and budget impact of changing from systemic to intralesional pentavalent antimonials as the first-line treatment for cutaneous leishmaniasis in Bolivia.

INTRODUCTION: Cutaneous leishmaniasis (CL), endemic in Bolivia, mostly affects poor people in rainforest areas. The current first-line treatment consists of systemic pentavalent antimonials (SPA) for 20 days and is paid for by the Ministry of Health (MoH). Long periods of drug shortages and a lack of safe conditions to deliver treatment are challenges to implementation. Intralesional pentavalent antimonials (ILPA) are an alternative to SPA. This study aims to compare the cost of ILPA and SPA, and to estimate the health and economic impacts of changing the first-line treatment for CL in a Bolivian endemic area. METHODS: The cost-per-patient treated was estimated for SPA and ILPA from the perspectives of the MoH and society. The quantity and unit costs of medications, staff time, transportation and loss of production were obtained through a health facility survey (N = 12), official documents and key informants. A one-way sensitivity analysis was conducted on key parameters to evaluate the robustness of the results. The annual number of patients treated and the budget impact of switching to ILPA as the first-line treatment were estimated under different scenarios of increasing treatment utilization. Costs were reported in 2017 international dollars (1 INT$ = 3.10 BOB). RESULTS: Treating CL using ILPA was associated with a cost-saving of $248 per-patient-treated from the MoH perspective, and $688 per-patient-treated from the societal perspective. Switching first-line treatment to ILPA while maintaining the current budget would allow two-and-a-half times the current number of patients to be treated. ILPA remained cost-saving compared to SPA in the sensitivity analysis. CONCLUSIONS: The results of this study support a shift to ILPA as the first-line treatment for CL in Bolivia and possibly in other South American countries.

Challenging the Inevitability of Prostate Enlargement: Low Levels of Benign Prostatic Hyperplasia Among Tsimane Forager-Horticulturalists.

BACKGROUND: Often considered an inevitable part of male aging, benign prostatic hyperplasia (BPH) is the most common non-life threatening disease to affect men in Western populations. We examine age-related change in prostate size and BPH risk and related serum biomarkers among the Tsimane Amerindians of the Bolivian Amazon who live a traditional lifestyle of hunting and small-scale horticulture. The Tsimane are a critical case study for understanding the etiology of BPH as they have low levels of obesity and metabolic syndrome, as well as lower levels of testosterone than age matched U.S. males, factors associated with BPH in previous research. METHODS: Ultrasounds were conducted on 348 men aged 28-89 years (median age 56 years). Testosterone, prostate specific antigen, sex hormone binding globulin, and glycosylated hemoglobin were examined in relationship to prostate size and BPH. RESULTS: Tsimane have less than half of the BPH prevalence experienced by U.S. men, and prostate volumes 62.6% smaller. While Tsimane have low levels of testosterone and subclinical levels of metabolic syndrome compared to U.S. men, Tsimane with high testosterone were more likely to experience BPH, as were those with higher glycosylated hemoglobin, suggesting targets for clinical interventions to reduce BPH. CONCLUSIONS: These results have clinical significance for the growing number of men taking testosterone supplementation; even at low levels the additional testosterone exposure could be placing these men at higher risk of BPH. Overall, these data suggest that BPH may not have been an inevitable part of male aging throughout human evolutionary history.