Polina S. Shlapakova

Introduction. Cerebral small vessel disease (SVD) is an early but nonspecific manifestation of Fabry disease. We describe a middle-aged patient with severe SVD in whom recognition of long-standing systemic disease ultimately led to the detection of a likely pathogenic GLA variant and enabled initiation of enzyme replacement therapy before advanced renal involvement developed. Methods. The patient underwent clinical evaluation, brain MRI, whole-genome sequencing, biochemical analysis of dried blood spots, and Sanger sequencing. Results. A 41-year-old man presented with recurrent lacunar strokes, progressive gait impairment, pseudobulbar syndrome, cognitive decline, and bladder dysfunction. Brain MRI revealed severe SVD with confluent white matter hyperintensities, multiple lacunes, and microbleeds. From early adulthood, he had arterial hypertension, hypohidrosis, acroparesthesias, and mild proteinuria. Later, he developed a cataract and an acute dissection of the ascending aorta. Whole-genome sequencing identified a hemizygous GLA frameshift variant (c.1095dup), predicted to truncate alpha-galactosidase A (p.Thr366TyrfsTer9) and classified as likely pathogenic. The diagnosis was confirmed by Sanger sequencing, markedly reduced alpha-galactosidase A activity, and elevated lyso-Gb3 in dried blood spots. Discussion. This case expands the neurologic phenotype of Fabry disease and supports its inclusion in the differential diagnosis of severe early-onset SVD, even when the classic systemic phenotype is incomplete.

Age-dependent cerebral microangiopathy (also known as cerebral small vessel disease) is a common heterogeneous condition that ranks high as a cause of disability and mortality of elderly patients due to strokes and intracerebral hemorrhages, vascular cognitive disorders, walking disorders, and the induction of neurodegeneration. In this review, we 1) describe the achievements of neuroimaging in the diagnosis of the age-dependent cerebral microangiopathy forms and the standardization of clinical and experimental studies; 2) analyze the possibilities and prospects of using a lifetime MRI assessment of the brain microstructure and pathophysiological mechanisms of its damage associated with neurovascular unit dysfunction; 3) provide evidence of pathomorphosis of the disease, due to, among other things, the control of vascular risk factors, and indicate the need to search for new risk factors with the determination of individual susceptibility to them; 4) indicate the need to use experimental models of CMA that consider its pathomorphosis, and pay attention to the prospects of endothelial dysfunction models; 5) assess the prospects for the development of pathogenetic treatment in terms of finding molecular targets using omics technologies. The complexity of the condition and the limited approaches to its prevention indicate the need for consortium discussion and collaboration of various specialists in the field of neuroscience for advancements in the management of this disease.

Age-dependent cerebral small vessel disease (CSVD) is a common disease with a high social burden characterized by heterogeneity of forms and frequent comorbidity with Alzheimer’s disease (AD). Previously, we identified two MRI types of CSVD with specific clinical presentation and, probably, different mechanisms. The present study included 34 patients with CSVD and white matter hyperintensity (WMH) of stage Fazekas (F) 3 (mean age 61.7 ± 8.9) and 11 volunteers (mean age 57.3 ± 9.7). Total RNA was isolated from peripheral blood leukocytes. The expression of 58 protein-coding genes associated with CSVD and/or AD and 4 reference genes were assessed as part of the original panel for the NanoString nCounter analyzer. Testing results were validated by real-time PCR. There was a significant decrease in the expression levels of the ACOX1, CD33, CD2AP, TNFR1, and VEGFC genes in MRI type 2 relative to the control group as well as a decrease in the expression level of the CD33 gene in MRI type 2 compared to MRI type 1. Processes associated with inflammatory pathways with decreased expression of the identified genes are important in the development of MRI type 2 of CSVD. Given the direct connection of the established genes with AD, the importance of this form of CSVD in comorbidity with AD has been assumed.

Cervical artery dissection (CeAD) is the primary cause of ischemic stroke in young adults. Monogenic heritable connective tissue diseases account for fewer than 5% of cases of CeAD. The remaining sporadic cases have known risk factors. The clinical, radiological, and histological characteristics of systemic vasculopathy and undifferentiated connective tissue dysplasia are present in up to 70% of individuals with sporadic CeAD. Genome-wide association studies identified CeAD-associated genetic variants in the non-coding genomic regions that may impact the gene transcription and RNA processing. However, global gene expression profile analysis has not yet been carried out for CeAD patients. We conducted bulk RNA sequencing and differential gene expression analysis to investigate the expression profile of protein-coding genes in the peripheral blood of 19 CeAD patients and 18 healthy volunteers. This was followed by functional annotation, heatmap clustering, reports on gene–disease associations and protein–protein interactions, as well as gene set enrichment analysis. We found potential correlations between CeAD and the dysregulation of genes linked to nucleolar stress, senescence-associated secretory phenotype, mitochondrial malfunction, and epithelial–mesenchymal plasticity.

Clarification of the aetiology of ischemic stroke (IS) in young adults (aged between 18 and 45 years) is an extremely difficult task, as rare causes that are hardly known to neurologists are very common. One of these causes is paradoxical embolism due to pulmonary arteriovenous malformation (AVM), one of the manifestations of hereditary hemorrhagic telangiectasia (HHT). The diagnosis of HHT-associated pulmonary AVMs and IS is a multistep task that requires a personalized multidisciplinary approach using high-tech ultrasound, tomographic and genetic examination methods. This article discusses the clinical case of a young patient with HHT and recurrent IS through the mechanism of paradoxical embolism from pulmonary AVMs; issues of diagnosis, treatment and prevention of both the underlying disease and recurrent vascular events are discussed.

ЦЕЛЬ ИССЛЕДОВАНИЯ Уточнить роль изменения экспрессии генов, ассоциированных с воспалением, при церебральной микроангиопатии (ЦМА). МАТЕРИАЛ И МЕТОДЫ Обследованы 44 пациента с ЦМА (средний возраст 61,4±9,2 года) и 11 добровольцев (средний возраст 57,3±9,7 года). Экспрессия генов оценивалась на индивидуальной панели NanoString nCounter из 58 генов, ассоциированных с воспалением, и 4 эталонных генов. Набор генов сформирован на основе конвергирующих результатов полногеномных исследований ассоциаций (GWAS) при ЦМА и болезни Альцгеймера и циркулирующих маркеров, ассоциированных с поражением сосудистой стенки и мозга при ЦМА. РНК выделяли из лейкоцитов крови и анализировали с помощью nCounter Analysis System, последующий анализ проводили в nSolver 4.0. Результаты проверяли методом ПЦР в режиме реального времени. РЕЗУЛЬТАТЫ Пациенты с ЦМА по сравнению с контролем имели значимое снижение экспрессии BIN1 (log2FC=–1,272; p=0,039) и VEGFA (log2FC=–1,441; p=0,038), которые показали предиктивную способность в отношении ЦМА. Пороговое значение экспрессии BIN1 5,76 у.е. (чувствительность 73%, специфичность 75%), VEGFA 9,27 у.е. (чувствительность 64%, специфичность 86%). Снижение экспрессии VEGFA (p=0,011), VEGFC (p=0,017), CD2AP (p=0,044) было связано с клинически выраженными когнитивными расстройствами. Выявлена значимая прямая корреляционная связь результата тестирования по Монреальской шкале оценки когнитивных функций с экспрессией VEGFC; теста отсроченного запоминания — с экспрессией BIN1 и VEGFC. ЗАКЛЮЧЕНИЕ Возможность предикции развития ЦМА по сниженному уровню экспрессии BIN1, VEGFA и связь клинически значимых когнитивных расстройств со снижением VEGFA и VEGFC указывают на их значение в развитии и прогрессировании заболевания. Установленная значимость данных генов в патогенезе болезни Альцгеймера указывает на то, что сходные изменения профиля их экспрессии при ЦМА могут быть одним из условий коморбидности двух патологий.