[Hypothalamic hamartoma dissection using focused ultrasound under MRI control. The first successful experience in Russia]. / Pervyi uspeshnyi opyt dissektsii gamartomy gipotalamusa metodom fokusirovannogo ul'trazvuka pod kontrolem MRT v Rossii.

Treatment of motor disorders by MRI-guided focused ultrasound is an alternative to neuro- and radiosurgery such as stereotactic radiofrequency ablation and thalamotomy with a gamma knife. However, safety, efficacy and feasibility of this technology for intracranial neoplasms are still unclear. The authors report successful hypothalamic hamartoma dissection by MRI-guided focused ultrasound in a 32-year-old woman with drug-resistant gelastic epilepsy and violent laughter and crying attacks. Magnetic resonance imaging revealed type II hypothalamic hamartoma. The last one was detached from surrounding brain tissue by MRI-guided focused ultrasound without side effects. Symptoms regressed immediately after surgery. No laughter and crying attacks were observed throughout 6-month follow-up.

[Oral disease-modifying therapy for adult patients with spinal muscular atrophy type 2]. / Peroral'naya patogeneticheskaya terapiya vzroslykh patsientov so spinal'noi myshechnoi atrofiei tipa 2.

Disease modifying therapy for adult patients with SMA still raises certain questions regarding its effectiveness, given the long-term chronic process with often significant neurological deficits at the time of initiation of therapy. This paper presents three clinical cases of adult sitter patients with SMA type 2, who began risdiplam therapy 16.5-41 years after the disease onset. All patients have been receiving therapy since 2020, at the time of observation for 2.5-3 years. All patients showed subjective and objective (using specialized scales) improvement during long-term therapy with risdiplam. In addition to an increase in muscle strength, mainly in the proximal and distal parts of the arms, several non-motor effects were also noted (including improved swallowing and breathing), which cannot be recorded using scales. No adverse events were recorded during therapy.

[Neurological manifestations of hypoparathyroidism: diagnostic difficulties. Case report].

Hypoparathyroidism is a rare condition characterized by reduced production of parathyroid hormone or tissue resistance which leads to hypocalcemia and hyperphosphatemia. Neurological manifestations often occur as the first symptoms of hypoparathyroidism and are characterized by a wide variety of symptoms of both the central and peripheral nervous systems dysfunction, which requires a differential diagnosis with a wide range of neurological diseases. Two clinical cases illustrating the features of subacute and chronic hypoparathyroidism are presented. In the case of subacute hypoparathyroidism, a young woman presented with severe tetany involving the oculomotor muscles (paroxysmal strabismus), laryngeal muscles (respiratory stridor), body muscles (opisthotonus, «obstetrician's hand¼) and the development of secondary myopathy. In another case with a long-term chronic course of postoperative hypoparathyroidism, the patient's adaptation to severe hypocalcemia was noted; the clinical features were dominated by cerebral syndromes due to brain structures calcification (Fahr's syndrome). Possible reasons for late diagnosis of hypoparathyroidism, the importance of active detection of symptoms of neuromuscular hyperexcitability and laboratory testing of phosphorus and calcium metabolism are discussed.

[Cognitive impairment and tactics of using the drug Cerebrolysin. Resolution of the International Council of Experts (May 12, 2023)]. / Kognitivnye narusheniya i taktika primeneniya preparata Tserebrolizin. Rezolyutsiya mezhdunarodnogo soveta ekspertov (12 maya 2023 g.).

The aging of the population and the associated increase in the share of cognitive impairments in the structure of a wide range of diseases are a serious challenge for modern healthcare. Difficulties in the treatment of cognitive disorders are determined by many factors, including the age of patients, comorbidity, forced polypragmasia and the adequacy of the dosage of drugs that restore cognitive activity. The experts discussed information about the therapeutic potential of the drug Cerebrolysin in the treatment of cognitive disorders of various origins, stated significant experience of its effective and safe use in many clinical studies in mild and moderate forms of dementia. At the same time, there was a lack of consistent and systematic data on the dosage regimen, frequency, and duration of use of the drug in different forms of cognitive impairment and the degree of their severity. The aim of the international council of experts was to determine the optimal dosage regimens of the drug Cerebrolysin in patients with various etiologies and severity of cognitive impairment. The result of the work was the approval of a unified scheme for the use of the drug Cerebrolysin, considering the severity of the disease and its duration.

[Diagnosis and treatment of early forms of cognitive impairment: possibilities of influencing neuronal energy metabolism. Resolution of the Council of Experts]. / Diagnostika i lechenie rannikh form kognitivnykh narushenii. Vozmozhnosti vozdeistviya na energeticheskii metabolizm neironov. Rezolyutsiya Soveta ekspertov.

Diagnosis and treatment of early forms of cognitive impairment: possibilities of influencing neuronal energy metabolism. Resolution of the Council of Experts.

[Experience of staged and simultaneous bilateral thalamotomy using MR-guided focused ultrasound in the treatment of essential tremor]. / Opyt poetapnoi i odnomomentnoi dvustoronnei talamotomii metodom fokusirovannogo ul'trazvuka pod kontrolem magnitno-rezonansnoi tomografii v lechenii essentsial'nogo tremora.

OBJECTIVE: To show that effective and safe bilateral MR-guided focused ultrasound (MRgFUS) treatment of essential tremor (ET) is achievable. MATERIAL AND METHODS: Four male patients underwent bilateral thalamotomy. Two patients underwent staged thalamotomy, with the ≥12 month interval between operations. Two patients underwent simultaneous bilateral thalamotomy. RESULTS: After six months, all patients noted a significant reduction in symptoms on both sides: when assessing tremors with the Clinical Rating Scale for Tremor, the severity of hyperkinesis decreased by 57.5-69.7%. We did not observe any complications in any of the cases. CONCLUSION: Our experience indicates that simultaneous bilateral MRI-guided focused ultrasound treatment of ET can be performed safely and effectively. Further research is necessary to estimate the effectiveness and adverse effect rates.

[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.

[Gerstmann-Sträussler disease: a familial case with common PRNP mutation and atypical features]. / Bolezn' Gerstmana­Shtrosslera: semeinyi sluchai s chastoi mutatsiei gena PRNP i atipichnymi proyavleniyami.

Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP. Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.

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.

[Roadmap for ecosystem-based approach for patients with Alzheimer disease in Russia: current needs, barriers, and possible solutions (resolution of the scientific and practical experts meeting)]. / Dorozhnaya karta po okazaniyu pomoshchi patsientu s bolezn'yu Al'tsgeimera v Rossii v formate ekosistemy: tekushchie potrebnosti, bar'ery i vozmozhnye resheniya (rezolyutsiya nauchno-prakticheskoi vstrechi ekspertov).

The care of a patient with Alzheimer's disease (AD) is considered from the perspective of an ecosystem, that is, a systemic approach describing effective partnership, collaboration and research aimed at creating value, involving all participants in the AD patient journey. The effectiveness of this ecosystem is only possible with the involvement of all stakeholders in its development, including patients, healthcare professionals at all levels, government agencies, private companies, and patient organizations. The unmet health care and information needs of patients with AD are a consequence of barriers in the AD ecosystem. Key barriers for the patient include low awareness and stigmatization of the disease in society, lack of quality epidemiological data, difficulties in timely diagnosis, lack of prevention programs, unpreparedness of most physicians to conduct AD patient rehabilitation, and other factors. Based on the analysis of the ecosystem of AD and the patient pathway, 10 main directions (strategies) necessary for the formation of the ecosystem were identified: conducting research in the diagnosis and epidemiology of AD, creating and implementing a cognitive health program, forming a legal framework, raising public awareness, optimizing patient routing for timely diagnosis, organizing a network of memory clinics/laboratories, creating a register of patients with dementia, developing digital solutions and supporting social projects.

Multiple Sclerosis Is Associated with Immunoglobulin Germline Gene Variation of Transitional B Cells.

The regulatory functions of the B-cell compartment play an important role in the development and suppression of the immune response. Disruption of their anti-inflammatory functions may lead to the acceleration of immunopathological processes, and to autoimmune diseases, in particular. Unfortunately, the exact mechanism underlying the functioning and development of regulatory B cells (Breg) has not yet been fully elucidated. Almost nothing is known about their specificity and the structure of their B-cell receptors (BCRs). In this research, we analyzed the BCR repertoire of the transitional Breg (tBreg) subpopulation with the CD19+CD24highCD38high phenotype in patients with multiple sclerosis (MS), using next-generation sequencing (NGS). We show, for the first time, that the immunoglobulin germline distribution in the tBreg subpopulation is different between MS patients and healthy donors. The registered variation was more significant in patients with a more severe form of the disease, highly active MS (HAMS), compared to those with benign MS (BMS). Our data suggest that during MS development, deviations in the immunoglobulin Breg repertoire occur already at the early stage of B-cell maturation, namely at the stage of tBregs: between immature B cells in the bone marrow and mature peripheral B cells.

[The influence of parasomnia on clinical and functional characteristics of extrapyramidal disorders]. / Vliyanie parasomnii na klinicheskie i funktsional'nye kharakteristiki ekstrapiramidnykh rasstroistv.

OBJECTIVE: To compare clinical and functional features of the essential tremor (ET) and Parkinson's disease (PD) with- or without rapid eye movement (REM) sleep behavior disorder (RBD). MATERIAL AND METHODS: Sixty patients with PD and 52 patients with ET were examined. Cognitive functions, anxiety, asthenia and depression, autonomic disorders and sleep disorders were assessed with scales and questionnaires. All patients underwent polysomnography (PSG). Based on the results of PSG, patients were divided by the presence or absence of parasomnia, known as REM sleep behavior disorder. RESULTS: Patients with PD and ET suffering from RBD were more likely to be overweight, more likely to develop cognitive impairment, obstructive sleep apnea, and emotional disorders. In addition, presence of RBD has adverse effects on the sleep structure. The profile of memory, attention, psychoemotional and sleep disorders in patients with PD and ET had common features, which suggests that it is RPBDH that affects the change in the clinical picture. CONCLUSION: Presence of RBD aggravates non-motor manifestations of such extrapyramidal diseases as PD and ET. On the one hand it helps to predict the course of the disease, on the other hand let us suspect RBD when we see non-motor symptoms worsening.

Generation of induced pluripotent stem cell line RCPCMi008-A derived from patient with spinocerebellar ataxia 17.

IPSC line RCPCMi004-8 was generated from skin fibroblasts collected from a male patient with spinocerebellar ataxia 17. The patient has expanded trinucleotide CAG repeats in the TBP (TATA-binding protein) gene on chromosome 6q27. The reprogramming of fibroblasts was performed with Sendai viruses containing Oct-4, Sox-2, Klf-4, and c-Myc. Pluripotency was confirmed by immunofluorescence, RT-PCR, and the formation of embryoid bodies. The RCPCMi008-A cell line carries the same trinucleotide CAG repeats in the TBP gene. The RCPCMi008-A cell line can be used to model Spinocerebellar ataxia in vitro.

Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes.

Currently, pathogenic variants in more than 25 nuclear genes, involved in mtDNA maintenance, are associated with human disorders. mtDNA maintenance disorders manifest with a wide range of phenotypes, from severe infantile-onset forms of myocerebrohepatopathy to late-onset forms of myopathies, chronic progressive external ophthalmoplegia, and parkinsonism. This study represents the results of molecular genetic analysis and phenotypes of 102 probands with mtDNA maintenance disorders. So far, this is the largest Russian cohort for this group of diseases. Mutations were identified in 10 mtDNA maintenance genes: POLG (n = 59), DGUOK (n = 14), TWNK (n = 14), TK2 (n = 8), MPV17 (n = 2), OPA3 (n = 1), FBXL4 (n = 1), RRM2B (n = 1), SUCLG1 (n = 1) and TYMP (n = 1). We review a mutation spectrum for the DGUOK and TWNK genes, that can be specific for the Russian population. In 34 patients we measured the blood mtDNA copy number and showed its significant reduction. Novel variants were found in 41 cases, which significantly expands the mutational landscape of mtDNA maintenance disorders.

[Spinocerebellar ataxia 17: full phenotype in a 42 CAG/CAA-repeats carrier]. / Spinotserebellyarnaya ataksiya 17-go tipa: polnyi fenotip u nositelya 42 CAG/CAA-povtorov.

Spinocerebellar ataxia 17 (SCA17) is one of the most heterogeneous forms of autosomal dominant cerebellar ataxia with a wide clinical spectrum, which can imitate other motor disorders. The article presents an observation of a 51-year-old woman with slowly progressive coordination disorders and changes in handwriting manifested at the age of 39 years. Neurologic examination reveals severe cerebellar ataxia, choreiform hyperkinesis, polyneuropathy, cognitive and mental disorders; magnetic resonance imaging (MRI) of the brain shows moderate diffuse atrophy of the cerebral cortex, severe atrophy of the cerebellum hemispheres. Molecular analysis of the TBP demonstrates an allele with 42 CAG/CAG-repeats suggesting that an allele of this size could be an allele associated with the full clinical spectrum of SCA17.

[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.