Postcovid-19 Asthenic Syndrome.

Objective. To study the characteristics of asthenic syndrome and the potential for treating it in the postcovid period. Materials and methods. A continuous sampling method was used to select 129 patients (mean age 49.8 ± 8.9 years) after COVID-19. Study patients were selected at the clinical out-patient and polyclinic facilities in Samara in the period July-August, 2020. All patients signed informed consent. The envelope method was used to randomize patients into two groups: the study group (n = 64) received ethylmethylhydroxypyridine succinate (Neurox) 1 tablet (125 mg) three times daily for four weeks; medications in the reference group (n = 65) did not include any substances of the pharmacological antihypoxant/antioxidant/nootrope groups. Three visits (V) were made: the first (V1) was before inclusion in the study; the second (V2) was at 14 days; the third (V3) was on day 28 from treatment initiation. The dynamics of overall status (weakness, fatigue, concentration of attention, vertigo, headache, sleep impairment) were evaluated on a visual analog scale (VAS); the subjective perception of the severity of asthenia (tiredness, physical and mental fatigue, decreased motivation and activity) was evaluated using the Multidimensional Fatigue Inventory, MFI-20); cognitive functions were assessed using the Mini Mental State Examination (MMSA); and autonomic tone was assessed using the Kérdö index. Results. At the end of the study (V3), statistically significant changes in measures (VAS, MFI-20) were seen only in patients of the study group; the Kérdö Index showed no statistically significant differences. Analysis of MMSE data revealed a decline in cognitive functions in both groups, which may be linked with pseudocognitive deficit due to asthenia. Conclusions. Our studies yielded evidence of a high incidence of asthenic syndrome after COVID-19. Neurox decreased the severity and extent of the symptoms of asthenia.

[Cerebrovascular disease in patients with type 2 diabetes mellitus]. / Tserebrovaskulyarnye zabolevaniya u patsientov s sakharnym diabetom 2-go tipa.

The article discusses the current trends in the spread of carbohydrate disorders, discusses in more detail the problem of type 2 diabetes mellitus and associated cerebrovascular diseases. The spectrum of the therapeutic effect of the drugs neurox and neupilept is considered in relation to this category of patients.

[Post-COVID-19 asthenic syndrome]. / Astenicheskii sindrom u patsientov, perenesshikh COVID-19.

OBJECTIVE: To study the features of asthenic syndrome and the possibilities of its therapy in patients in the post-covid period. MATERIAL AND METHODS: The study included 129 patients with an average age of 49.8±8.9 years who had undergone COVID-19 using a continuous sample method. Patients for the study were selected at the clinical bases of outpatient clinics in Samara (Russia) in July-August 2020. All patients signed an informed consent form prior to enrollment. Patients were randomized into two groups: in the main group (n=64), ethylmethylhydroxypyridine succinate (Neurox) was prescribed 1 tablet (125 mg) 3 times a day for 4 weeks; in the comparison group (n=65), medical drugs (MD) did not contain substances from the pharmacological group related to antihypoxants/antioxidants/nootropics. Three visits (V) were conducted: the first (V1) - the period of inclusion, the second (V2) - after 14 days, the third (V3) - on the 28th day from the start of therapy. The dynamics of the general state (weakness, fatigue, concentration, dizziness, headache, sleep disorders) were evaluated on a visual-analog scale (VAS), the assessment of the subjective feeling of severity of asthenia (fatigue, physical and mental fatigue, decreased motivation and activity) - on Multidimensional Fatigue Inventory (MFI-20), cognitive functions - on Mini-Mental State Examination (MMSE), vegetative tone - according to the Kerdo index. RESULTS: At the end of the study (V3), statistically significant changes in indicators (VAS, MFI-20) were obtained only in the main group patients; no statistically significant differences were obtained for the Kerdo index. Analysis of the MMSE data revealed a decrease in cognitive functions in both groups, which may be associated with pseudocognitive deficits due to asthenia. CONCLUSIONS: We have obtained evidence of a high incidence of asthenic syndrome after COVID-19. Against the background of taking Neurox, there was a decrease in the severity and expression of asthenia symptoms.

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease.

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease.

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10-4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases.

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.

Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.

Evaluating pathogenic dementia variants in posterior cortical atrophy.

Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ∼ 4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.

Mutation analysis of patients with neurodegenerative disorders using NeuroX array.

Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p.M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.

Variation in PARK10 is not associated with risk and age at onset of Parkinson's disease in large clinical cohorts.

A recent study in autopsy-confirmed Parkinson's disease (PD) patients and controls revived the debate about the role of PARK10 in this disorder. In an attempt to replicate these results and further understand the role of this locus in the risk and age at onset of PD, we decided to explore NeuroX genotyping and whole exome sequencing data from 2 large independent cohorts of clinical patients and controls from the International Parkinson's Disease Genomic Consortium. A series of single-variant and gene-based aggregation (sequence kernel association test and combined multivariate and collapsing test) statistical tests suggested that common and rare genetic variation in this locus do not influence the risk or age at onset of clinical PD.