Designing in vitro Blood-Brain Barrier Models Reproducing Alterations in Brain Aging

Blood-brain barrier (BBB) modeling in vitro is a huge area of research covering study of intercellular communications and development of BBB, establishment of specific properties that provide controlled permeability of the barrier. Current approaches in designing new BBB models include development of new (bio) scaffolds supporting barriergenesis/angiogenesis and BBB integrity; use of methods enabling modulation of BBB permeability; application of modern analytical techniques for screening the transfer of metabolites, bio-macromolecules, selected drug candidates and drug delivery systems; establishment of 3D models; application of microfluidic technologies; reconstruction of microphysiological systems with the barrier constituents. Acceptance of idea that BBB in vitro models should resemble real functional activity of the barrier in different periods of ontogenesis and in different (patho) physiological conditions leads to proposal that establishment of BBB in vitro model with alterations specific for aging brain is one of current challenges in neurosciences and bioengineering. Vascular dysfunction in the aging brain often associates with leaky BBB, alterations in perivascular microenvironment, neuroinflammation, perturbed neuronal and astroglial activity within the neurovascular unit, impairments in neurogenic niches where microvascular scaffold plays a key regulatory role. The review article is focused on aging-related alterations in BBB and current approaches to development of “aging” BBB models in vitro

Аберрантный ангиогенез в ткани головного мозга при экспериментальной болезни Альцгеймера

The aim was to study the molecular mechanisms of the violation of the structural and functional integrity ofthe blood-brain barrier in chronic neurodegeneration of the Alzheimer’s type associated with the development of cerebral angiopathy.Materials and methods. The transgenic model of Alzheimer’s disease is the B6SLJ-Tg line mice (APPSwFlLon,PSEN1 * M146L * L286V) 6799Vas group which includes 9 months aged males. The control group included C57BL / 6 x SJL mice, males aged 9 months.Results. The total length of the vessels in the area of the dentate gyrus is 2.5 times greater in transgenic animal models of Alzheimer’s disease than in animals of the control group (p < 0.01). The average diameter of blood vessels in all areas of the hippocampus is smaller compared with the control (p < 0.05). Transgenic modeling of neurodegeneration in the CA2 zone of the hippocampus increases the relative area of tissue with increased permeability of blood-brain barrier (BBB) (17.80 [9.15; 36.75]) compared to control (1.38 [0.04; 7.60]) at p < 0.05. A similar difference (p < 0.05) is also observed in the hippocampal area CA1. A tendency (p > 0.05) to decrease the number of CD31+ endothelial cells in the dentate gyrus of the hippocampus (21.52 [17.56; 24.50]) in animals of the experimental group compared with the control group (23.08[21.18; 29.84]) was detected. A similar situation is observed in the CA2 and CA3 areas of the hippocampus.Conclusion. Neurodegenerative changes in the hippocampus of animals with a transgenic AD model are associated with impaired microcirculation in the brain tissue as a result of a reduction in the diameter and branching of blood vessels, and damage and increased permeability of BBB.Цель – изучение молекулярных механизмов нарушения структурно-функциональной целостности гематоэнцефалического барьера (ГЭБ) при хронической нейродегенерации  альцгеймеровского типа, ассоциированной с развитием церебральной ангипопатии. Материалы и методы. Опытная группа – генетическая модель болезни Альцгеймера (БА) – мыши линии B6SLJ -Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas, самцы в возрасте 9 мес. Контрольная группа – мыши линии C57BL/6 x SJL, самцы в возрасте 9 мес.Результаты. У животных с генетической моделью БА в зубчатой извилине гиппокампа  общая длина сосудов в 2,5 раза больше, чем у контрольной группы (p < 0,01), при этом  средний диаметр сосудов во всех областях гиппокампа меньше по сравнению с контролем (p < 0,05). Выявлено, что при генетическом моделировании  нейродегенерации в СА2 зоне гиппокампа наблюдается увеличение относительной  площади ткани с повышенной проницаемостью ГЭБ (17,80 [9,15;36,75]) по сравнению с контролем (1,38 [0,04;7,60]) при p < 0,05. Подобное различие (p < 0,05) наблюдается и в зоне СА1 гиппокампа. У животных опытной группы выявлена тенденция (p > 0,05) к снижению количества CD31+ эндотелиальных клеток в зубчатой извилине гиппокампа (21,52 [17,56; 24,50]) по сравнению с контролем (23,08 [21,18; 29,84]). Аналогичная ситуация наблюдается в зонах СА2 и СА3 гиппокампа.Заключение. Нейродегенеративные изменения в гиппокампе животных с генетической  моделью БА ассоциированы с нарушением микроциркуляции в ткани головного мозга в  результате сокращения диаметра и разветвленности сосудов, повреждения и повышения проницаемости ГЭБ

Differential diagnosis of myopathy and multiple epiphysal dysplasia caused by mutations in the <i>COMP</i> gene in children

Background. Multiple epiphysal dysplasia (MED) type 1 (OMIM: 132400) is one of 7 genetic variants of this group of skeletal dysplasias described to date. The disease is caused by mutations in the COMP gene located on chromosome 19p13.1. The presence of muscle hypotonia and ligamentous laxity, as well as a moderate increase in the level of creatinephosphokinase activity, can lead to misdiagnosis of myopathy.Objective: to analyze the clinical and genetic characteristics of type 1 MED caused by mutations in the COMP gene in a series of Russian patients. Differential diagnosis was focused on the distinctive features of the disorder and hereditary myopathies.Materials and methods. We observed 8 patients from 7 families aged 7 to 15 years with MED type 1 caused by heterozygous mutations in the COMP gene. To confirm the diagnosis, the following methods were used: genealogical analysis, clinical examination, neurological examination with psycho-emotional testing, radiography and targeted sequencing of a panel consisting of 166 genes responsible for the development of inherited skeletal pathology.Results. Case history, clinical, radiological and genetic characteristics of 8 patients with MED type 1 caused by mutations in the COMP gene were analyzed. The first clinical manifestations of the disease were recorded from the age of 2–3 years and were characterized by gait disturbances, muscle weakness, difficulties with climbing stairs, frequent falls when walking, the inability to get up from the floor and from a squatting position and hypermobility of the joints. Electroneuromyographic study did not reveal the signs of miopathy. In two patients, a moderate increase in the creatinekinase level of up to 250–360 u / l was found. All patients were surveyed by neurologists for several years with a clinical diagnosis of congenital myopathy. At the age of 5–6 years patients COMPlained knee and ankle pain, which was assumed as rheumatic arthropathy. X-ray examination revealed typical signs of deficient ossification of the epiphyses. The next-generation sequencing analysis revealed seven single nucleotide variants in the COMP gene that lead to MED type 1. Three of the found variants here identified for the first time. As previously described, the majority of nucleotide variants (six out of seven) were localized in the 8–14 exons of the COMP gene and led to amino acid substitutions in calmodulin-like protein domain repeats, and only one substitution was localized in the C-terminal region of the protein molecule.Conclusion. In most patients with MED caused by mutations in the COMP gene, the first symptoms of the disease are gait disturbance, muscle weakness, and Gowers» maneuvers. The presence of these symptoms, along with a moderate increase in the level of creatinephosphokinase activity, often precedes the onset of clinical manifestations of skeletal dysplasia, leading to a misdiagnosis with myopathies. Accession of expressive arthralgias to these symptoms was mistakenly identified as reactive arthritis. X-ray examination of patients’ long bones helps to suspect the presence of MED. This X-ray imaging shows specific signs of epiphyses damage. A molecular-genetic analysis needs to be done to diagnose the genetic variant, caused by mutations in gene COMP

MEG resting state functional connectivity in Parkinson's disease related dementia

Parkinson's disease (PD) related dementia (PDD) develops in up to 60% of patients, but the pathophysiology is far from being elucidated. Abnormalities of resting state functional connectivity have been reported in Alzheimer's disease (AD). The present study was performed to determine whether PDD is likewise characterized by changes in resting state functional connectivity. MEG recordings were obtained in 13 demented and 13 non-demented PD patients. The synchronization likelihood (SL) was calculated within and between cortical areas in six frequency bands. Compared to non-demented PD, PDD was characterized by lower fronto-temporal SL in the alpha range, lower intertemporal SL in delta, theta and alpha1 bands as well as decreased centro-parietal gamma band synchronization. In addition, higher parieto-occipital synchronization in the alpha2 and beta bands was found in PDD. The observed changes in functional connectivity are reminiscent of changes in AD, and may reflect reduced cholinergic activity and/or loss of cortico-cortical anatomical connections in PDD. © 2008 The Author(s)

Дифференциальная диагностика миопатии и множественной эпифизарной дисплазии, обусловленной мутациями в гене COMP, в детском возрасте

Background. Multiple epiphysal dysplasia (MED) type 1 (OMIM: 132400) is one of 7 genetic variants of this group of skeletal dysplasias described to date. The disease is caused by mutations in the COMP gene located on chromosome 19p13.1. The presence of muscle hypotonia and ligamentous laxity, as well as a moderate increase in the level of creatinephosphokinase activity, can lead to misdiagnosis of myopathy.Objective: to analyze the clinical and genetic characteristics of type 1 MED caused by mutations in the COMP gene in a series of Russian patients. Differential diagnosis was focused on the distinctive features of the disorder and hereditary myopathies.Materials and methods. We observed 8 patients from 7 families aged 7 to 15 years with MED type 1 caused by heterozygous mutations in the COMP gene. To confirm the diagnosis, the following methods were used: genealogical analysis, clinical examination, neurological examination with psycho-emotional testing, radiography and targeted sequencing of a panel consisting of 166 genes responsible for the development of inherited skeletal pathology.Results. Case history, clinical, radiological and genetic characteristics of 8 patients with MED type 1 caused by mutations in the COMP gene were analyzed. The first clinical manifestations of the disease were recorded from the age of 2–3 years and were characterized by gait disturbances, muscle weakness, difficulties with climbing stairs, frequent falls when walking, the inability to get up from the floor and from a squatting position and hypermobility of the joints. Electroneuromyographic study did not reveal the signs of miopathy. In two patients, a moderate increase in the creatinekinase level of up to 250–360 u / l was found. All patients were surveyed by neurologists for several years with a clinical diagnosis of congenital myopathy. At the age of 5–6 years patients COMPlained knee and ankle pain, which was assumed as rheumatic arthropathy. X-ray examination revealed typical signs of deficient ossification of the epiphyses. The next-generation sequencing analysis revealed seven single nucleotide variants in the COMP gene that lead to MED type 1. Three of the found variants here identified for the first time. As previously described, the majority of nucleotide variants (six out of seven) were localized in the 8–14 exons of the COMP gene and led to amino acid substitutions in calmodulin-like protein domain repeats, and only one substitution was localized in the C-terminal region of the protein molecule.Conclusion. In most patients with MED caused by mutations in the COMP gene, the first symptoms of the disease are gait disturbance, muscle weakness, and Gowers» maneuvers. The presence of these symptoms, along with a moderate increase in the level of creatinephosphokinase activity, often precedes the onset of clinical manifestations of skeletal dysplasia, leading to a misdiagnosis with myopathies. Accession of expressive arthralgias to these symptoms was mistakenly identified as reactive arthritis. X-ray examination of patients’ long bones helps to suspect the presence of MED. This X-ray imaging shows specific signs of epiphyses damage. A molecular-genetic analysis needs to be done to diagnose the genetic variant, caused by mutations in gene COMP.Введение. Множественная эпифизарная дисплазия (МЭД) 1‑го типа (OMIM: 132400) – один из семи описанных к настоящему времени генетических вариантов этой группы скелетных дисплазий. Заболевание обусловлено мутациями в гене COMP, локализованном на хромосоме 19р13.1. Наличие мышечной гипотонии и слабости связочного аппарата суставов, а также умеренное повышение уровня активности креатинфосфокиназы часто приводят к ошибочной диагностике миопатии.Цель исследования – анализ клинико‑генетических характеристик МЭД 1‑го типа, обусловленной мутациями в гене COMP, в выборке российских пациентов и формирование принципов дифференциальной диагностики заболевания с наследственными миопатиями.Материалы и методы. Под нашим наблюдением находилось 8 пациентов из 7 семей в возрасте от 7 до 15 лет с МЭД 1‑го типа, обусловленной гетерозиготными мутациями в гене COMP. Для уточнения диагноза использовались генеалогический анализ, клиническое обследование, неврологический осмотр по стандартной методике с оценкой психоэмоциональной сферы, рентгенография и таргетное секвенирование панели, состоящей из 166 генов, ответственных за развитие наследственной скелетной патологии.Результаты. Проведен анализ анамнестических данных, клинико‑рентгенологических и молекулярно‑генетических характеристик 8 пациентов с МЭД 1‑го типа, обусловленной мутациями в гене COMP. Первые клинические проявления заболевания регистрировались с 2–3‑летнего возраста и характеризовались изменением походки, быстрой утомляемостью, трудностью подъема по лестнице, частыми падениями при ходьбе, отсутствием возможности самостоятельно встать с пола и из положения на корточках, выраженной гипермобильностью в суставах. В результате проведения электронейромиографического исследования не отмечалось признаков первично‑мышечного поражения. У 2 пациентов обнаружено умеренное повышение уровня активности креатинфосфокиназы в плазме крови до 250–360 Ед/л. Все пациенты в течение нескольких лет наблюдались у неврологов с диагнозом врожденной миопатии. В возрасте 5–6 лет у пациентов возникали боли в коленных и голеностопных суставах, которые расценивались как реактивные, чаще всего ревматические, артропатии. При проведении рентгенологического обследования выявлены типичные признаки поражения эпифизов длинных трубчатых костей, что позволило диагностировать МЭД. В результате анализа секвенирования нового поколения выявлено 7 нуклеотидных вариантов в гене COMP, ответственном за возникновение 1‑го типа этой группы заболеваний. Три из выявленных вариантов зарегистрированы впервые. Как и в ранее описанных выборках, в анализируемой выборке пациентов большинство нуклеотидных вариантов (6 из 7) локализовались в области 8–14‑го экзонов гена COMP и приводили к аминокислотным заменам в повторах кальмодулиноподобного домена белка, и лишь 1 замена была локализована в С‑концевом участке белковой молекулы.Заключение. МЭД 1‑го типа – генетический вариант скелетных дисплазий, не сопровождающийся значимым снижением роста. У большинства пациентов первыми симптомами заболевания, отмеченными в возрасте 2–3 лет, были нарушение походки, повышенная мышечная утомляемость и приемы Говерса. Наличие этих симптомов наряду с умеренным повышением уровня активности креатинфосфокиназы предшествовало возникновению клинических проявлений скелетной дисплазии, приводя к ошибочной диагностике у пациентов нервно‑мышечного заболевания из группы миопатий. Присоединение к этим симптомам выраженных артралгий приводило к ошибочному диагнозу реактивных артритов. Заподозрить наличие МЭД у пациентов позволяет рентгенологическое исследование длинных трубчатых костей, в результате которого выявляются специфические признаки поражения эпифизов. Для диагностики генетического варианта, обусловленного мутациями в гене COMP, необходимо проведение молекулярно‑генетического анализа

Russian linguoculture: the concept “justice” as a neuclear linguistic unit of the conceptual field “guardianship”

To define the internal content of the concept “justice”, that operates in the Russian linguoculture being a nuclear unit of the conceptual field “guardianship”, an interdisciplinary method, incorporating historiographical, ideographic, and introspective methods, has been used. In the Russian linguistic world image, the concept “justice” is the basic component of the concept “guardianship”. This concept reflects the idea of guardianship as a social protection of the disadvantaged part of the population in the linguistic consciousness of the Russian people. The linguocultural core of the linguistic world image consists of the concepts verbalized in the consciousness of an individual, forming in it the conceptual frameworks with the subject-specific content. From the linguoculturological point of view, the concept “guardianship” as a form of manifesting mercy in the Russian conceptosphere “Spirituality”, represents the idea of social and legal protection based on the idea of moral justice. Justice as an absolute virtue coexists in the society in three forms: moral, legal, and political.Para definir o conteúdo interno do conceito “justiça”, que tem funcionado na cultura linguística da Rússia, sendo uma unidade nuclear do campo conceitual “tutela”, foi empregado um método interdisciplinar, que incorpora os métodos historiográficos, ideográficos e introspetivos. O conceito “justiça” é uma componente básica do conceito “tutela” na visão linguística russa de mundo. Este conceito realiza uma ideia de tutela, como uma proteção social das populações empobrecidas, na consciência linguística dos russos. O núcleo linguístico e cultural da imagem linguística do mundo inclui os conceitos verbalizados na consciência de pessoa, que formam nela uns campos conceituais com conteúdos temáticos. Do ponto de observação linguístico e culturológico, o conceito “tutela” como uma forma de manifestação de misericórdia no enquadramento conceptual russo “Espiritualidade” é um reflexo da ideia de proteção social e jurídica, baseada na ideia de justiça moral. Três formas de justiça, como uma virtude absoluta, coexistem na sociedade: moral, jurídica e política.Aquí el contenido interno del concepto de justicia que funciona en la cultura lingüística rusa y es una unidad nuclear del campo conceptual de cúratela se defina por el método interdisciplinar que incluye tales métodos como historiográfico, ideográfico e introspección. En la imagen lingüística del mundo rusa la noción de justicia es un componente básico del concepto de cúratela. En la mentalidad de la gente rusa este concepto realiza la idea de la cúratela como la protección social para la parte desdichada de la población. El núcleo cultural lingüístico de la imagen lingüística del mundo consiste de conceptos verbalizados en la percepción del indivíduo que forman campos conceptuales con relleno temático. En términos de cultorología lingüística en concepto de cúratela como una manifestación de la espiritualidad en la esfera de conceptos rusa refleja la idea de la protección legal social basada en la idea de la justicia ética. La existencia social de la justicia como una virtud absoluta tiene tres formas, es decir, ética, legal y política