Recent Developments in Engineering Non-Paralytic Botulinum Molecules for Therapeutic Applications.

This review discusses the expanding application of botulinum neurotoxin in treating neurological conditions. The article specifically explores novel approaches to using non-paralytic botulinum molecules. These new molecules, such as BiTox or el-iBoNT, offer an alternative for patients who face limitations in using paralytic forms of botulinum neurotoxin due to concerns about muscle function loss. We highlight the research findings that confirm not only the effectiveness of these molecules but also their reduced paralytic effect. We also discuss a potential cause for the diminished paralytic action of these molecules, specifically changes in the spatial parameters of the new botulinum molecules. In summary, this article reviews the current research that enhances our understanding of the application of new botulinum neurotoxins in the context of common conditions and suggests new avenues for developing more efficient molecules.

Validation of the Kazakh version of the movement disorder Society-Unified Parkinson's disease rating scale.

Background and Purpose: The International Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is widely used in the assessment of the severity of Parkinson's disease (PD). This study aimed to validate the Kazakh version of the MDS-UPDRS, explore its dimensionality, and compare it to the original English version. Methods: The validation was conducted in three phases: first, the English version of the MDS-UPDRS was translated into Kazakh and thereafter back-translated into English by two independent teams; second, the Kazakh version underwent a cognitive pretesting; third, the Kazakh version was tested in 360 native Kazakh-speaking PD patients. Both confirmatory and exploratory factor analyses were performed to validate the scale. We calculated the comparative fit index (CFI) for confirmatory factor analysis and used unweighted least squares for exploratory factor analysis. Results: The CFI was higher than 0.90 for all parts of the scale, thereby meeting the pre-set threshold for the official designation of a validated translation. Exploratory factor analysis also showed that the Kazakh MDS-UPDRS has the analogous factors structure in each part as the English version. Conclusions: The Kazakh MDS-UPDRS had a consistent overall structure as the English MDS-UPDRS, and it was designated as the official Kazakh MDS-UPDRS, which can reliably be used in the Kazakh-speaking populations. Presently, Kazakhstan stands as the sole country in both Central Asia and Transcaucasia with an MDS-approved translated version of the MDS-UPDRS. We expect that other Central Asian and Transcaucasian countries will embark on the MDS Translation Program for MDS-UPDRS in the near future.

A glimpse of the genetics of young-onset Parkinson's disease in Central Asia.

BACKGROUND: Knowledge of the genetic background of many human diseases is currently lacking from genetically undiscovered regions, including Central Asia. Kazakhstan is the first Central Asian country where the genetic studies of Parkinson's disease (PD) have been emerging since it had become a member of the International Parkinson Disease Genomics Consortium. Here we report on the results of whole-exome sequencing (WES) in 50 young-onset PD (YOPD) cases from Kazakhstan. METHODOLOGY: WES was performed on 50 unrelated individuals with YOPD from Kazakhstan. Exome data were screened for novel/ultra-rare deleterious variants in known and candidate PD genes. Copy number variants and small indels were also called. RESULTS: Only three cases (6%) were found to be positive for known PD genes including two unrelated familial PD cases with LRRK2 p.(Arg1441Cys) and one case with a homozygous pathogenic PRKN p.(Arg84Trp) variant. Four cases had novel and ultra-rare variants of uncertain significance in LRRK2, DNAJC13, and VPS35. Novel deleterious variants were found in candidate Mendelian PD genes including CSMD1, TNR, EIF4G1, and ATP13A3. Eight cases harbored the East Asian-specific LRRK2 p.(Ala419Val) variant. CONCLUSIONS: The low diagnostic yield in our study might imply that a significant proportion of YOPD cases in Central Asia remains unresolved. Therefore, a better understanding of the genetic architecture of PD among populations of Central Asian ancestry and the pathogenicity of numerous rare variants should be further investigated. WES is a valuable technique for large-scale YOPD genetic studies in Central Asia.

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=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5. 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.

Parkinson's Disease in Central Asian and Transcaucasian Countries: A Review of Epidemiology, Genetics, Clinical Characteristics, and Access to Care.

Our understanding of Parkinson's disease (PD) has significantly accelerated over the last few years, but predominant advances have been made in developed, Western countries. Little is known about PD in the Central Asian (CA) and Transcaucasian (TC) countries. Here, we review the clinical characteristics, treatments used, epidemiology, and genetics of PD in CA and TC countries via a methodological search in MEDLINE, EMBASE, Scopus, Web of Science, and Google Scholar databases. For the acquisition of PD care-related data, the search was extended to the local web resources. Our findings showed that PD prevalence in the region is averaging 62 per 100,000 population. The mean age of onset is 56.4 ± 2.8 in females and 63.3 ± 3.5 in males. Large-scale national studies on PD prevalence from the region are currently lacking. A limited number of genetic studies with small cohorts and inconclusive results were identified. The G2019S LRRK2 mutation, the commonest mutation in PD worldwide, was found in 5.7% of patients with idiopathic PD and 17.6% of familial cases in 153 Uzbek patients. Our review highlighted systematic deficiencies in PD health care in the region including lacks of neurologists specializing in PD, delays in PD diagnosis, absence of specialized PD nurses and PD rehab services, limited access to PD medications and surgery, and the unavailability of PD infusion therapies. Overall, this article demonstrated the paucity of data on this common neurological disorder in CA and TC countries and identified a number of healthcare areas that require an urgent consideration. We conclude that well-designed large-scale epidemiological, genetic, and clinical studies are desperately needed in this region. Healthcare professionals, local and national institutions, and stakeholders must come together to address deficiencies in PD healthcare systems in CA and TC countries.

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.