The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

An Exploratory Study of Sleep-Wake Differences of Autonomic Activity in Patients with Mild Cognitive Impairment: The Role of Melatonin as a Modulating Factor.

Purpose: The objective of the present study was to assess sleep-wake differences of autonomic activity in patients with mild cognitive impairment (MCI) compared to control subjects. As a post-hoc objective, we sought to evaluate the mediating effect of melatonin on this association. Patients and Methods: A total of 22 MCI patients (13 under melatonin treatment) and 12 control subjects were included in this study. Sleep-wake periods were identified by actigraphy and 24hr-heart rate variability measures were obtained to study sleep-wake autonomic activity. Results: MCI patients did not show any significant differences in sleep-wake autonomic activity when compared to control subjects. Post-hoc analyses revealed that MCI patients not taking melatonin displayed lower parasympathetic sleep-wake amplitude than controls not taking melatonin (RMSSD -7 ± 1 vs 4 ± 4, p = 0.004). In addition, we observed that melatonin treatment was associated with greater parasympathetic activity during sleep (VLF 15.5 ± 0.1 vs 15.1 ± 0.1, p = 0.010) and in sleep-wake differences in MCI patients (VLF 0.5 ± 0.1 vs 0.2 ± 0.0, p = 0.004). Conclusion: These preliminary findings hint at a possible sleep-related parasympathetic vulnerability in patients at prodromal stages of dementia as well as a potential protective effect of exogenous melatonin in this population.

Identifying resources used by young people to overcome mental distress in three Latin American cities: a qualitative study.

OBJECTIVE: To explore which resources and activities help young people living in deprived urban environments in Latin America to recover from depression and/or anxiety. DESIGN: A multimethod, qualitative study with 18 online focus groups and 12 online structured group conversations embedded into arts workshops. SETTING: This study was conducted in Bogotá (Colombia), Buenos Aires (Argentina) and Lima (Peru). PARTICIPANTS: Adolescents (15-16 years old) and young adults (20-24 years old) with capacity to provide assent/consent and professionals (older than 18 years of age) that had experience of professionally working with young people were willing to share personal experience within a group, and had capacity to provide consent. RESULTS: A total of 185 participants took part in this study: 111 participants (36 adolescents, 35 young adults and 40 professionals) attended the 18 focus groups and 74 young people (29 adolescents and 45 young adults) took part in the 12 arts workshops. Eight categories captured the resources and activities that were reported by young people as helpful to overcome mental distress: (1) personal resources, (2) personal development, (3) spirituality and religion, (4) social resources, (5) social media, (6) community resources, (7) activities (subcategorised into artistic, leisure, sports and outdoor activities) and (8) mental health professionals. Personal and social resources as well as artistic activities and sports were the most common resources identified that help adolescents and young adults to overcome depression and anxiety. CONCLUSION: Despite the different contexts of the three cities, young people appear to use similar resources to overcome mental distress. Policies to improve the mental health of young people in deprived urban settings should address the need of community spaces, where young people can play sports, meet and engage in groups, and support community organisations that can enable and facilitate a range of social activities.

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

Worsening of memory deficit induced by energy-dense diet in a rat model of early-Alzheimer's disease is associated to neurotoxic Aß species and independent of neuroinflammation.

Diet is a modifiable risk factor for Alzheimer's disease (AD), but the mechanisms linking alterations in peripheral metabolism and cognition remain unclear. Since it is especially difficult to study long-term effects of high-energy diet in individuals at risk for AD, we addressed this question by using the McGill-R-Thy1-APP transgenic rat model (Tg(+/-)) that mimics presymptomatic AD. Wild-type and Tg(+/-) rats were exposed during 6months to a standard diet or a Western diet (WD), high in saturated fat and sugar. Results from peripheral and hippocampal biochemical analysis and in situ respirometry showed that WD induced a metabolic syndrome and decreased presynaptic bioenergetic parameters without alterations in hippocampal insulin signaling or lipid composition. Cognitive tests, ELISA multiplex, Western blot, immunohistochemistry and RT-qPCR indicated that WD worsened cognition in Tg(+/-) rats, increased hippocampal levels of monomeric Aß isoforms and oligomeric species, promoted deposits of N-Terminal pyroglutamate-Aß (AßN3(pE)) in CA1 pyramidal neurons and interneurons, decreased transcript levels of genes involved in neuroprotective pathways such as Sirtuin-1 and increased nitrated proteins. Our results support the concept that in the presence of early Aß pathology, diet-induced metabolic dysfunctions may contribute as a "second hit" to impair cognition. Noteworthy, such effect is not mediated by higher microglia activation or disruption of blood brain barrier. However, it may be attributed to increased amyloidogenic processing of amyloid precursor protein, generation of AßN3(pE) and dysregulation of pathways governed by Sirtuin-1. This evidence reinforces the implementation of prophylactic interventions in individuals at risk for AD.

Identification of PSEN2 mutation p.N141I in Argentine pedigrees with early-onset familial Alzheimer's disease.

Presenilin 2 gene (PSEN2) mutations account for <5% of all early-onset familial Alzheimer's disease (EOFAD) cases and only 13 have strong evidence for pathogenicity. We aimed to investigate the presence of PSEN2 mutation p.N141I and characterize the clinical phenotypes in 2 Argentine pedigrees (AR2 and AR3) with clinical symptoms of EOFAD. Detailed clinical assessments and genetic screening for PSEN2 and APOE genes were carried out in 19 individuals of AR2 and AR3 families. The p.N141I mutation was identified in all affected subjects and was associated with prominent early onset, rapidly progressive dementia, neurologic, and behavioral symptoms. AR2 and AR3 families share the same Volga German ancestry as all the families reported presenting this mutation. To our knowledge, this is the first report of PSEN2 mutation p.N141I in Argentina and even more, in South America. Our contribution increases the total number of described families carrying this mutation and help to improve the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations.

Melatonin Therapy in Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is a major health problem and a growing recognition exists that efforts to prevent it must be undertaken by both governmental and non-governmental organizations. In this context, the pineal product, melatonin, has a promising significance because of its chronobiotic/cytoprotective properties potentially useful for a number of aspects of AD. One of the features of advancing age is the gradual decrease in circulating melatonin levels. A limited number of therapeutic trials have indicated that melatonin has a therapeutic value as a neuroprotective drug in the treatment of AD and minimal cognitive impairment (which may evolve to AD). Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects, which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100 mg/day are urgently needed to assess its therapeutic validity in neurodegenerative disorders such as AD.

Therapeutic application of melatonin in mild cognitive impairment.

Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome defined by cognitive impairment in advance of dementia. We previously reported in a retrospective analysis that daily 3 - 9 mg of a fast-release melatonin preparation given p. o. at bedtime for up to 3 years significantly improved cognitive and emotional performance and daily sleep/wake cycle in MCI patients. In a follow up of that study we now report data from another series of 96 MCI outpatients, 61 of who had received daily 3 - 24 mg of a fast-release melatonin preparation p. o. at bedtime for 15 to 60 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin exhibited significantly better performance in Mini-Mental State Examination and the cognitive subscale of the Alzheimer's disease Assessment Scale. After application of a neuropsychological battery comprising a Mattis´ test, Digit-symbol test, Trail A and B tasks and the Rey´s verbal test, better performance was found in melatonin-treated patients for every parameter tested. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with the improvement in the quality of sleep and wakefulness. The comparison of the medication profile in both groups of MCI patients indicated that 9.8% in the melatonin group received benzodiazepines vs. 62.8% in the non-melatonin group. The results further support that melatonin can be a useful add-on drug for treating MCI in a clinic environment.