[Cerebellar degeneration associated with HIV infection]. / Mozzhechkovye degeneratsii, assotsiirovannye s VICh-infektsiei.

OBJECTIVE: To describe the features of the clinical presentation and evaluate the incidence of HIV-associated cerebellar degeneration in patients with progressive cerebellar ataxia. MATERIAL AND METHODS: Three hundred and seventy-seven patients with progressive cerebellar ataxia were studied. Brain MRI study, assessment by the Scale for the Assessment and Rating of Ataxia (SARA), screening for cognitive impairment by the Montreal Cognitive Assessment Scale (MoCA) were performed. In patients with HIV infection, autoimmune, deficient and other causes of ataxia, as well as opportunistic infections, multiple system atrophy and frequent forms of hereditary spinocerebellar ataxias were excluded. RESULTS: Five patients (1.3%) were identified with a combination of cerebellar ataxia and HIV infection (2 men, 3 women, aged 31 to 52 years). The median duration of HIV infection was 5 years, the duration of ataxia was 1 year. In the clinical findings, in addition to progressive ataxia, pyramidal signs, dysphagia, less often ophthalmoparesis, dystonia, postural hand tremor, affective and mild cognitive impairment were observed. In three patients, brain MRI revealed signs of olivopontocerebellar atrophy, two patients had isolated cerebellar degeneration (mainly of the vermis). All patients received combination of antiretroviral therapy in various regimens, but despite this, ataxia was progressive. CONCLUSION: HIV infection is a rare cause of cerebellar degeneration. This diagnosis remains a diagnosis of exclusion to this day. Cerebellar degeneration can occur and progress even after achieving a stable remission of HIV infection while taking highly active antiretroviral therapy.

MicroRNA Expression Profile Changes in the Leukocytes of Parkinson's Disease Patients.

Parkinson's disease (PD) is one of the most common movement disorders. It is primarily diagnosed clinically. A correct diagnosis of PD in its early stages is important for the development of a pathogenic treatment, which necessitates a search for potential biomarkers of the disease. We evaluated the diagnostic value of several microRNAs and their relationship with the clinical characteristics of PD. The study included 70 PD patients and 40 healthy volunteers. We analyzed the expression of 15 microRNAs in blood leukocytes, which were selected based on literature data and modern concepts of molecular PD pathogenesis. All patients were evaluated using the Hoehn and Yahr scale, UPDRS, NMSQ, and PDQ-39. The data analysis revealed a statistically significant increase in the expression of miR-7-5p, miR-29c-3p, and miR-185-5p and a statistically significant decrease in the expression of miR-29a-3p and miR-30c-1-5p in leukocytes in PD. However, the altered microRNA profile was shown to have a moderate diagnostic value for PD diagnosis. MicroRNA expression changes were associated with the motor and non-motor phenotypic features of PD and administration of anti-Parkinson's drugs. Also, a relationship between some of the microRNAs studied and the duration and severity of PD was found, which may potentially be used to monitor disease progression.

[Spinocerebellar ataxia type 8 in Russian patients]. / Spinotserebellyarnaya ataksiya 8-go tipa u rossiiskikh bol'nykh.

OBJECTIVE: To assess the incidence of spinocerebellar ataxia type 8 (SCA8) in patients with progressive cerebellar ataxia and describe the clinical features of the SCA8 phenotype in Russian patients. MATERIAL AND METHODS: Genotyping of CTA/CTG repeats in ATXN8OS gene was carried out in 411 patients with degenerative ataxias using fragment analysis. SCA types 1, 2, 3 and 6 as well as Friedreich's ataxia were preliminarily excluded. All patients underwent brain MRI study. Scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) to screen for cognitive impairment were used. RESULTS: Six patients with SCA8 (1.5%) were identified as carriers of the expansion in the ATXN8OS gene (91-152 CTA/CTG repeats). All cases were sporadic. Age of onset ranged from 14 to 42 years. All patients had slowly progressive cerebellar ataxia, oculomotor disturbances, dysarthria, pyramidal signs, and two patients had cognitive impairment. In one patient the clinical presentation corresponded to multiple system atrophy cerebellar type (ataxia, orthostatic hypotension, cerebellum and brainstem atrophy). Brain MRI study in all patients revealed cerebellar atrophy. CONCLUSION: SCA8 is a rare form of autosomal dominant ataxia with a predominance of the classical phenotype. All identified cases of SCA8 were sporadic, which should be taken into account when planning genetic testing in patients with spinocerebellar ataxia.

[C9orf72-associated frontotemporal dementia in the Russian population]. / C9orf72-assotsiirovannaya forma lobno-visochnoi dementsii v rossiiskoi populyatsii.

OBJECTIVE: To evaluate the frequency of C9orf72-associated frontotemporal dementia (FTD) in the Russian population and to study clinical features of GGGGCC-repeat expansion carriers. MATERIAL AND METHODS: Twenty-eight patients with FTD are included in the study: 15 with a behavioral variant of FTD (bvFTD) and 13 with a agrammatic/non-fluent variant of primary progressive aphasia (avPPA). The mean age was 62 years (34-80), the mean disease duration was 4 years (1-10). The positive family history was noted in 46% of cases. DNA diagnosis was performed using repeat-primed polymerase chain reaction. RESULTS: The frequency of the C9orf72 repeat expansion in patients with FTD was 14%, in patients with bvFTD 20%, in patients with avPPA 8%. The mean age of disease onset in the expansion carriers was 63 (55-75) years. The frequency of the C9orf72 repeats expansion in familial FTD cases was 31%, in sporadic cases 7%. bvFTD with parkinsonian syndrome was noted in two out of four cases, bvFTD with amyotrophic lateral sclerosis (ALS) was shown in one case, avPPA with ALS was shown in one case. One female patient with bvFTD with parkinsonian syndrome presented with cognitive fluctuations that required a differential diagnosis with Lewy body disease. CONCLUSION: This is the first study of the genetic structure of FTD in the Russian population. The prevalence and clinical characteristics of C9orf72-associated FTD were defined, in particular, the spectrum of motor symptoms was shown along with behavioral and aphasic disturbances. DNA diagnosis plays an important role in confirming the diagnosis and selection of patients for potential disease-modifying treatment.

C9orf72 Gene Expression in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We studied the expression of C9orf72 gene in pathologies associated with hexanucleotide repeats expansion in this gene: frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The study included 7 patients with hexanucleotide repeats expansion in the C9orf72 gene and 9 patients of the control group. The expression of C9orf72 mRNA was evaluated in blood leukocytes by real-time PCR. Methylation of CpG-sites in C9orf72 promotor region was evaluated by DNA sequencing after bisulfite conversion. A 2-fold decrease in the C9orf72 gene expression was found in patients with hexanucleotide repeats expansion in comparison with controls, though the difference did not reach statistical significance due to small sample size. The highest expression was shown for ALS in comparison with FTD and FTD-ALS phenotype. A trend to inverse correlation between C9orf72 mRNA level and promoter methylation of this gene as well as between mRNA level and age of disease onset was demonstrated.

The SNCA-Rep1 Polymorphic Locus: Association with the Risk of Parkinson's Disease and SNCA Gene Methylation.

Neurodegeneration in Parkinson's disease is characterized by the accumulation of alpha-synuclein, a protein encoded by the SNCA gene, in neurons. In addition to mutations, many polymorphisms have been identified in this gene, and one of these is a dinucleotide microsatellite: SNCA-Rep1. The mechanisms by which specific configurations of SNCA-Rep1 may contribute to the development of this disease have yet to be clarified. In our study, a relationship between long SNCA-Rep1 alleles and Parkinson's was confirmed in the Russian population. Long allelic variants of SNCA-Rep1 were shown to be associated with the hypomethylation of the CpG-sites in intron 1 of the SNCA gene. Long variants of SNCA-Rep1 are supposed to exert their effect through the hypomethylation of a transcriptionally significant region of this gene. Hypomethylation is usually associated with increased expression, which, in turn, contributes to alpha-synuclein accumulation in neuronal cytoplasm, with the latter being the main molecular marker of Parkinson's disease. Further studies are needed to establish a relationship between our finding and SNCA gene expression.

[Clinical and morphological analysis of a caseof Parkinson's disease]. / Kliniko-morfologicheskii analiz sluchaia bolezni Parkinsona.

Parkinson's disease (PD) is a neurodegenerative disease that belongs to a group of cerebral proteinopathies. The main pathomorphological signs of PD are neuronal degeneration in the midbrain substantia nigra and detection of pathological forms of the synaptic protein α-synuclein in the nigral neurons. At the same time, the pathological forms of α-synuclein in this disease have been recently shown to accumulate in the cells of not only the central, but also peripheral autonomic nervous system. The paper provides a clinical and morphological description of a PD case in a 70-year-old patient, which demonstrates that there are typical α-synuclein-positive inclusions in the brain regions (substantia nigra, caudate nucleus, and frontal cortex), salivary glands and colon. The systemic nature of α-synucleinopathy in PD is important in both clarifying the pathogenesis of the disease and elaborating new approaches to its diagnosis and, in the future, to targeted therapy.

[Genetic Diversity in Frontotemporal Dementia].

Frontotemporal dementia is a progressive neurodegenerative disorder with high clinical, genetic, and pathomorphological diversity It is the third most common cause of dementia in all ages and the most common cause of early onset dementia (below 65). Despite its multifactorial nature, up to 40% of patients have a family history where the autosomal dominant inheritance type is seen in a quarter of cases. In this review, we describe key genes whose mutations can result in the development of frontotemporal dementia, the possible pathogenic mechanisms of the degenerative process, and provide information on the clinical features of the disease for different genetic variants. Special emphasis is placed on the frontotemporal dementia phenotype that is associated with amyotrophic lateral sclerosis.

[Epigenetic regulation of clinical manifestations of Friedreich's disease]. / Épigeneticheskaia reguliatsiia klinicheskikh proiavlenii bolezni Fridreikha.

AIM: To study a methylation profile of FXN gene and its influence on the clinical phenotype of Friedreich's desease (FD). MATERIAL AND METHODS: The methylation pattern was analyzed in 17 patients with FD. Forty-five CpG-sites in the promoter region and the region of intron 1 of FXN: before the GAA-expansion (UP-GAA) and after the GAA-expansion (DOWN-GAA), were studied. RESULTS: Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed. CONCLUSION: The results indicate a significant contribution of epigenetic modifications of FXN to the clinical presentation of FA.

[Diagnostic algorithm for autosomal recessive ataxia]. / Algoritm diagnostiki autosomno-retsessivnykh ataksii.

AIM: To develop a complex algorithm for autosomal recessive ataxia (ARA) diagnosis applicable for Russian patients with degenerative ataxias. MATERIAL AND METHODS: 48 patients with of presumably degenerative ataxias were examined. Clinical evaluation was performed with the use of the SARA and ICARS scales (for ataxia) and MoCA (cognitive functions), and a set of laboratory tests was carried out, including electromyography, brain MRI, and DNA analysis of mutations responsible for Friedreich's disease and spinocerebellar ataxias (SCAs) types 1, 2, 3, 6 and 17. 28 patients underwent mutation screening using a multigenic MPS panel. RESULTS: 8 patients (16.7%) with non-hereditary causes of ataxia were identified: cerebellar alcoholic degeneration (n = 6) and multiple system atrophy of cerebellar type (n = 2); 3 patients (6.3%) with genetic ataxias were identified using routine DNA tests, such as with SCA type 1, 2 and 17, and 9 (18.8%) patients with Friedreich's disease. The MPS panel enabled molecular diagnosis of ARA in 8 patients (28.6%): ataxia-telangiectasia (n = 2), SANDO syndrome (n = 2), ataxia with oculomotor apraxia type 2 (n = 1), SCAR10 (n = 1), SCAR16 (n = 1), and atypical form of neuroaxonal dystrophy (n = 1). The diagnosis was not established in 20 patients. CONCLUSION: We have proposed an appropriate algorithm for degenerative ataxia diagnosis which is recommended to be used when examining patients with sporadic and autosomal recessive cases of the disorders with dyscoordination of movements.

[Unilateral posteroventral pallidotomy in the treatment of drug-induced dyskinesia in Parkinson's disease]. / Odnostoronniaia posteroventral'naia pallidotomiia v lechenii lekarstvennykh diskinezii pri bolezni Parkinsona.

OBJECTIVE: to determine the efficacy of unilateral posteroventral pallidotomy (PVP) in the treatment of drug-induced dyskinesia (DID) in Parkinson's disease (PD). MATERIAL AND METHODS: We analyzed surgical treatment of 14 patients with PD complicated by DID who underwent unilateral PVP at the Research Center of Neurology in the period between 2012 and 2015. The clinical type of DID was mainly represented by peak-dose choreoathetoid dyskinesia, more pronounced in the distal limbs, and predominantly unilateral. The severity of drug-induced dyskinesia was assessed on the UPDRS scale (part IV-A) before surgery and at 1 week and 6 months after surgery. RESULTS: One week after pallidotomy, all of the 14 patients had a regression of contralateral dyskinesia by 68.3±9.7%; 50% of patients had a regression of ipsilateral dyskinesias by 43%, on average. In 50% of cases, the dose of levodopa was reduced by 15%, on average. On examination at 6 months after surgery, regression of contralateral dyskinesia was 55.7±8.8%, and the severity of ipsilateral DID returned to the preoperative level. The use of pallidotomy significantly improved the indicators of daily activity and quality of life of patients. There were no significant postoperative complications. Three patients had mild speech disorders in the form of dysarthria, which regressed 2-3 weeks after surgery.

[Characteristics of Parkinson's disease course in the heterozygous carriage of mutations in the glucocerebrosidase A gene]. / Osobennosti techeniya bolezni Parkinsona pri geterozigotnom nositel'stve mutatsii v gene glyukotserebrozidazy A.

Parkinson's disease (PD) is a common neurodegenerative disease. Literature sources indicate the association of PD and mutations in the glucocerebrosidase A (GBA) gene. According to our study, the frequency of the two most common mutations in the GBA gene, N370S and L444P, is 1.85%. Mutation carriers have slower progression of motor symptoms, but are more likely to develop drug-induced motor fluctuations and dyskinesia. In carriers of GBA mutations, the severity of cognitive impairment corresponds to age-matched patients without mutations. Cognitive deficit in PD patients carrying GBA mutations primarily affects visual-spatial functions and often is associated with psychotic disorders and parasomnias syndrome. Other non-motor disorders in patients with GBA mutations do not differ from those in patients without mutations. In patients with PD and GBA mutations, a slower escalation of levodopa dose should be recommended because of the high risk of complications of therapy.

[Identification of people at the latent stage of Parkinson's disease (the PARKINLAR study): first results and an optimization of the algorithm].

AIM: To work out an optimal algorithm to identify people at the latent stage of neurodegenerative process of «parkinsonian¼ type in the Russian population. MATERIAL AND METHODS: Authors launched a two-step study aimed at identifying people at the latent stage of Parkinson's disease (PD) in the Russian population - the PARKINLAR (PARKINsonism, LAtent stage, Russia). As the first step, we formed a group of «primary risk¼ by the identification in neurologically healthy people of at least one of the following confirmed PD risk factors: a) the substantia nigra hyperechogenicity (ultrasound screening was performed in 193 people); b) mutations in «parkinsonian¼ genes (genetic screening was performed in 29 relatives of PD patients from families with LRRK2, PARK2 and GBA mutations). Thereby, 37 people comprised the «primary risk¼ group, of whom 23 agreed to continue further examination (44±10.2 years). A matched group of people without the aforementioned primary biomarkers of PD served as control. As the second step, we undertook in the prescreened groups a complex of investigations assessing the presence of secondary («minor¼) biomarkers of PD: Sniffin' Sticks olfactory testing; color visual evoked potentials; analysis of goal-directed eye-head-hand movements with the use of a special neuro-cybernetic system; assessment of motor and non-motor symptoms with the use of UPDRS and NMSS scales. RESULTS: When comparing the «primary risk¼ group with controls, maximal differences in the occurrence of symptoms were seen for goal-directed eye movements (43.5% vs. 20.0%) and color vision (39.1% vs. 26.7%). Among these individuals, we found two people with 4 secondary biomarkers and one with 3, and no such observations in controls. People with the combination of a primary biomarker with several secondary biomarkers of PD comprised a group of «high risk¼ in our study. CONCLUSION: Optimization of this algorithm of population screening of people predisposed to the development of PD may be done by expanding the spectrum of biomarkers and assessing their validity in a long-term prospective observational study.

Mutations in the Parkinson's Disease-Associated PARK2 Gene Are Accompanied by Imbalance in Programmed Cell Death Systems.

Parkinson's disease is caused by the degeneration of midbrain dopaminergic neurons. A rare recessive form of the disease may be caused by a mutation in the PARK2 gene, whose product, Parkin, controls mitophagy and programmed cell death. The level of pro- and anti-apoptotic factors of the Bcl-2 family was determined in dopaminergic neurons derived from the induced pluripotent stem cells of a healthy donor and a Parkinson's disease patient bearing PARK2 mutations. Western blotting was used to study the ratios of Bax, Bak, Bcl-2, Bcl-XL, and Bcl-W proteins. The pro-apoptotic Bak protein level in PARK2-neurons was shown to be two times lower than that in healthy cells. In contrast, the expression of the anti-apoptotic factors Bcl-XL, Bcl-W, and Bcl-2 was statistically significantly higher in the mutant cells compared to healthy dopaminergic neurons. These results indicate that PARK2 mutations are accompanied by an imbalance in programmed cell death systems in which non-apoptotic molecular mechanisms play the leading role.