Application of Clinical Aging Indicators for the Assessment of Neurological Health via Screening Among Residents of the Almaty Region

Introduction. Life expectancy at birth is considered to be a primary indicator of public health success. However, an increase in life expectancy is meaningless if it is not accompanied by an equivalent increase in the number of life years without disability such as physical, cognitive, and psychological abilities. The main consequences of disease leading to neurological dysfunction are directly related to issues such as the inability to walk, talk, learn, live in society, or take care of oneself. The objective of the study was to conduct a medical examination of elderly people as a part of the scientific program "Development of a model (program) of anti-aging to provide active longevity of elderly people of Kazakhstan.”Methods. As part of a pilot study, we assessed the presence of the following clinical indicators of aging: cognitive impairment (MMSE test), pyramidal symptoms,and  ataxia. We conducted medical examination (screening) among 150 elderly persons in Almaty City Polyclinic #8 and 287 elderly persons in Central Regional Clinic of Rayimbek Area, Almaty region aged 45 and above.Results. The results show that the intensity of changes is directly dependent on the age of the study groups. The cognitive function is the most affected and depends on the age of examinees. The changes are more expressed among residents of Almaty region. The average MMSE score in Almaty was 28.2 (age group of 45-49 years) and 25.8 (age group of 80 and above), and 27.3 and 24.0 respectively  in Almaty region. The various symptoms among residents of Almaty tend to stabilize after 65 years, however, the frequency of ataxia continues to grow and increases significantly after 75 years.Conclusions. Considering that important risk factors of neurological disorders are cerebrovascular diseases of various origins (primarily hypertension, atherosclerosis, and diabetes), an adequate treatment of these diseases will increase a healthy lifespan. Furthermore, it is necessary to conduct additional research for possible methods of reducing existing morbidities so that healthy aging can be achieved

Application of Clinical Aging Indicators for the Assessment of Neurological Health via Screening Among Residents of the Almaty Region

Introduction. Life expectancy at birth is considered to be a primary indicator of public health success. However, an increase in life expectancy is meaningless if it is not accompanied by an equivalent increase in the number of life years without disability such as physical, cognitive, and psychological abilities. The main consequences of disease leading to neurological dysfunction are directly related to issues such as the inability to walk, talk, learn, live in society, or take care of oneself. The objective of the study was to conduct a medical examination of elderly people as a part of the scientific program "Development of a model (program) of anti-aging to provide active longevity of elderly people of Kazakhstan.” Methods. As part of a pilot study, we assessed the presence of the following clinical indicators of aging: cognitive impairment (MMSE test), pyramidal symptoms,and  ataxia. We conducted medical examination (screening) among 150 elderly persons in Almaty City Polyclinic #8 and 287 elderly persons in Central Regional Clinic of Rayimbek Area, Almaty region aged 45 and above. Results. The results show that the intensity of changes is directly dependent on the age of the study groups. The cognitive function is the most affected and depends on the age of examinees. The changes are more expressed among residents of Almaty region. The average MMSE score in Almaty was 28.2 (age group of 45-49 years) and 25.8 (age group of 80 and above), and 27.3 and 24.0 respectively  in Almaty region. The various symptoms among residents of Almaty tend to stabilize after 65 years, however, the frequency of ataxia continues to grow and increases significantly after 75 years. Conclusions. Considering that important risk factors of neurological disorders are cerebrovascular diseases of various origins (primarily hypertension, atherosclerosis, and diabetes), an adequate treatment of these diseases will increase a healthy lifespan. Furthermore, it is necessary to conduct additional research for possible methods of reducing existing morbidities so that healthy aging can be achieved

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

LRRK2 Mutations and Asian Disease-Associated Variants in the First Parkinson’s Disease Cohort from Kazakhstan

Background. LRRK2 mutations have emerged as the most prevalent and potentially treatable determinants of Parkinson’s disease (PD). Peculiar geographic distribution of these mutations has triggered an interest in genotyping PD cohorts of different ethnic backgrounds for LRRK. Objective. Here, we report on the results of LRRK2 screening in the first Central Asian PD cohort. Methods. 246 PD patients were consecutively recruited by movement disorder specialists from four medical centers in Kazakhstan, and clinicodemographic data and genomic DNA from blood were systematically obtained and shipped to the Institute of Neurology University College London together with DNAs from 200 healthy controls. The cohort was genotyped for five LRRK2 mutations (p.Gly2019Ser, p.Arg1441His, p.Tyr1699Cys, p.Ile2020Thr, and p.Asn1437His) and three East Asian disease-associated variants (p.Gly2385Arg, p.Ala419Val, and p.Arg1628Pro) via Kompetitive allele-specific polymerase chain reaction assay analysis. Results. None of the study subjects carried LRRK2 mutations, whereas the following Asian variants were found with insignificant odds ratios (OR): p.Gly2385Arg (1.2%, minor allele frequency (MAF) 0.007, OR 1.25, p=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5, p=0.4), and p.Arg1628Pro was found only in 1% of controls. p.Gly2385Arg was positive in a big family with PD and tremor, although with incomplete segregation. One early-onset PD subject was homozygous for p.Ala419Val who developed fast progression and severe dyskinesias. p.Ala419Val was associated with early-onset PD. Conclusions. We showed that East Asian LRRK variants could be found in Central Asian populations but their pathogenicity remains to be elucidated in larger PD cohorts

Abstracts of the First Eurasian Conference; The Coronavirus Pandemic and Critical ICT Infrastructure

While the world is struggling with COVID-19, the ICT industry seeks to play a constructive role in combating the spread of the virus. This book contains the abstracts of the papers presented at The First Eurasian Conference; The Coronavirus Pandemic and Critical ICT Infrastructure (PANDEMIC-ICT-2020) organized by AMIR Technical Services LLC, Tbilisi, Georgia held on November 28-30, 2020. Conference Title: The Coronavirus Pandemic and Critical ICT InfrastructureConference Acronym: PANDEMIC-ICT-2020Conference Date: 28-30 November 2020Conference Location: Online (Virtual Mode)Conference Organizer: AMIR Technical Services LLC, Tbilisi, Georgi

Identification of sixteen novel candidate genes for late onset Parkinson's disease

Altres ajuts: Italian Ministry of Health grant (RF 2019-12370224, GR2016-02362247); Italian Ministry of Economic Development (F/0009/00X26); Fondazione Umberto Veronesi.Background: Parkinson's disease (PD) is a neurodegenerative movement disorder affecting 1-5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods: The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results: Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions: Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia