[The possibilities of differential diagnosis of primary progressive aphasia]. / Differentsial'naya diagnostika pervichnoi progressiruyushchei afazii.

The authors describe a clinical case demonstrating the difficulties of diagnosing primary progressive aphasia, the need for a differential diagnosis with a logopenic variant of Alzheimer's disease. The data of a clinical, neuropsychological study with a detailed instrumental and diagnostic search, including data from cerebrospinal fluid, positron emission tomography-CT, MRI, electroencephalography with cognitive loads, are presented. The article focuses on the widespread use of various diagnostic scales based on the international diagnostic criteria.

[A case of neurolymphomatosis]. / Sluchai neirolimfomatoza.

OBJECTIVE: To demonstrate the potential of positron emission tomography with 18F-fluorodeoxyglucose in the diagnosis of a rare manifestation of lymphoma - peripheral nerve plexus lesions. MATERIAL AND METHODS: A 73-year-old female patient with B-cell small cell lymphoma, stage II B complained of progressive weakness in the lower and upper extremities. The patient was referred for 18F-FDG PET/CT to rule out disease progression and evaluate the effectiveness of the treatment. RESULTS: The diagnosis of neurolymphomatosis was verified. Neurolymphomatosis differs from paraneoplastic, inflammatory, or drug-induced neuropathies both in terms of clinical manifestations and in terms of prognosis. Difficulties in diagnosis lie in the extreme variety of symptoms and the extensive differential diagnosis. CONCLUSION: 18F-FDG PET/CT is a sensitive method for the diagnosis of neurolymphomatosis.

Parent-of-origin effects on nuclear chromatin organization and behavior in a Drosophila model for Williams-Beuren Syndrome.

Prognosis of neuropsychiatric disorders in progeny requires consideration of individual (1) parent-of-origin effects (POEs) relying on (2) the nerve cell nuclear 3D chromatin architecture and (3) impact of parent-specific miRNAs. Additionally, the shaping of cognitive phenotypes in parents depends on both learning acquisition and forgetting, or memory erasure. These processes are independent and controlled by different signal cascades: the first is cAMPdependent, the second relies on actin remodeling by small GTPase Rac1 - LIMK1 (LIM-kinase 1). Simple experimental model systems such as Drosophila help probe the causes and consequences leading to human neurocognitive pathologies. Recently, we have developed a Drosophila model for Williams-Beuren Syndrome (WBS): a mutant agnts3 of the agnostic locus (X:11AB) harboring the dlimk1 gene. The agnts3 mutation drastically increases the frequency of ectopic contacts (FEC) in specific regions of intercalary heterochromatin, suppresses learning/memory and affects locomotion. As is shown in this study, the polytene X chromosome bands in reciprocal hybrids between agnts3 and the wild type strain Berlin are heterogeneous in modes of FEC regulation depending either on maternal or paternal gene origin. Bioinformatic analysis reveals that FEC between X:11AB and the other X chromosome bands correlates with the occurrence of short (~30 bp) identical DNA fragments partly homologous to Drosophila 372-bp satellite DNA repeat. Although learning acquisition in a conditioned courtship suppression paradigm is similar in hybrids, the middle-term memory formation shows patroclinic inheritance. Seemingly, this depends on changes in miR-974 expression. Several parameters of locomotion demonstrate heterosis. Our data indicate that the agnts3 locus is capable of trans-regulating gene activity via POEs on the chromatin nuclear organization, thereby affecting behavior.

[Daytime sleepiness and cognitive disorders in elderly patients]. / Dnevnaia sonlivost' i kognitivnye rasstroistva v pozhilom vozraste.

Data on the contribution of daytime sleepiness to cognitive impairment in elderly patients are presented. Currently, diagnostic methods of daytime sleepiness, which include diaries, neurological, clinical and instrumental tools, are used. It has been shown that daytime sleepiness correlates with different types of dementia that suggests the involvement of common neurochemical mechanisms. Multiple studies report that daytime sleepiness increases the risk of dementia in elderly people. Future research of daytime sleepiness could be focused on its clinical and paraclinical presentations to facilitate the prognosis of dementia.

[Autoimmune mechanisms and new opportunities for treatment narcolepsy]. / Autoimmunnye mekhanizmy i novye vozmozhnosti lecheniia narkolepsii.

Narcolepsy is a disease related to hypersomnia type-sleep disorders and characterized by the following manifestations: excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night sleep. There are several models of the disease pathogenesis each of them assumes the autoimmune nature of the disease. In this regard, it is necessary to develop etiological approaches to the treatment of the disease.

[Morphological characteristics of fetal testes in chronic intrauterine hypoxia in different gestation periods]. / Morfologicheskie osobennosti iaichek ploda pri khronicheskoi vnutriutrobnoi gipoksii na raznykh srokakh gestatsii.

OBJECTIVE: To study the morphological characteristics and expression of vascular endothelial growth factor (VEGF) in the fetal testes exposed to chronic intrauterine hypoxia during pathological pregnancy in different gestation periods. MATERIAL AND METHODS: The testes from 48 male fetuses that had died in the antenatal or early neonatal period in mothers with pathological pregnancy were morphologically evaluated. RESULTS: Chronic intrauterine hypoxia was shown to be a powerful damaging factor and leads to delayed gonadal development. Histological examination of testicular tissue showed a significant reduction in the number of tubular cells per vision field, a decrease in tubular diameter and area, with the simultaneously increased area of the stroma and a larger number of vessels. Immunohistochemical study revealed the pronounced cytoplasmic expression of VEGF in testicular tissue in different gestation periods in the spermatogenic epitheliocytes, vessels, Leydig interstitial cells, while the maximal expression of this receptor was observed at 19-25 weeks' gestation, the degree of expression decreased at 26-29 weeks' gestation. CONCLUSION: Intrauterine hypoxia has a destabilizing effect on the processes of proliferation and differentiation of the spermatogenic epithelium, interstitial endocrinocytes, activates the processes of angiogenesis and the growth of connective tissue. All this can involve not only gonadal dysgenesis, but also future reproductive dysfunction. Hypoxia stimulates the expression of VEGF, whose receptors are present in almost all testicular cell populations. It can be assumed that VEGF can act as a paracrine regulator of Leydig cell activity, also as an inducer of angiogenesis, and thus play a certain role in the development of male fertility.

[Influence of limk1 Gene Polymorphism on Learning Acquisition and Memory Formation with pCREB Distribution and Aggregate Formation in Neuromuscular Junctions in Drosophila melanogaster].

We have shown previously that the polymorphic structure of the limk1 gene in drosophila leads to changes in LIMK1 content and to defects in courtship behavior, sound production, and learning/memory. The results of the present study of three wild-type strains and mutant agn(ts3) with altered limk1 structure demonstrate that long-term memory is normal in Canton-S and Oregon-R but is impaired in Berlin and drastically suppressed in agn(ts3). This temperature-sensitive mutant carries the S-element from the Tc1/mariner family insertion near the dlimk1 3'-UTR and, compared to Canton-S, has a reverse pCREB distribution in adult neuromuscular junctions (NMJ) of the second dorsal imago nerve before and after learning. Moreover, only agn(ts3) demonstrates amyloid-like aggregate formation in NMJ. This suggests that this impedes pCREb transport and thereby impairs the formation of short- and long-term memory.

[Neurogenetics and Neuroepigenetics].

"Genetics of behavior," or "Neurogenetics," is based on the evolutionary ideas of T. Dobzhansky on brain development and behavior. It continues with the "experimental genetics of higher nervous activity" of I. Pavlov and uses a comparative approach in the study of heredity and variation in behavioral manifestations, from Protozoa to humans. The study of the classical Pavlovian conditioned reflex in mutant Drosophila helped to identify the main types of memory and their evolutionary conservatism. Long-term memory defects are caused by mutations of the same genes as in mental, retardation in humans, when signaling cascades intersecting with the cAMP-dependent pathway are damaged. The cascade of actin remodeling is also among these. The key enzyme, LIM-kinase 1, controls cognitive manifestations of the "genomic disease" Williams deletion syndrome. Its study resulted in the recognition of neuroepigenetics as an interface between the genome and environmental influences. Epigenetic factors of "variability"--DNA methylation, histone acetylation, and microRNA regulation--do not change the structure of the gene but its manifestations. Certain miRNAs have already been considered to be both biomarkers for neurodegenerative diseases and factors of the intergenerational transmission of the behaviorial properties of ancestors who experienced stress from adverse environmental influences.

The Drosophila agnostic Locus: Involvement in the Formation of Cognitive Defects in Williams Syndrome.

The molecular basis of the pathological processes that lead to genome disorders is similar both in invertebrates and mammals. Since cognitive impairments in Williams syndrome are caused by LIMK1 hemizygosity, could the spontaneous and mutant variants of the Drosophila limk1 gene serve as a model for studying two diagnostic features from three distinct cognitive defects of the syndrome? These two symptoms are the disturbance of visuospatial orientation and an unusualy strong fixation on the faces of other people during pairwise interaction with a stranger. An experimental approach to the first cognitive manifestation might be an analysis of the locomotor behavior of Drosophila larvae involving visuospatial orientation during the exploration of the surrounding environment. An approach to tackle the second manifestation might be an analysis of the most natural ways of contact between a male and a female during courtship (the first stage of this ritual is the orientation of a male towards a female and following the female with constant fixation on the female's image). The present study of locomotor activity and cognitive repertoire in spontaneous and mutant variants of the Drosophila agnostic locus allows one to bridge alterations in the structure of the limk1 gene and behavior.

Williams syndrome as a model for elucidation of the pathway genes - the brain - cognitive functions: genetics and epigenetics.

Genomic diseases or syndromes with multiple manifestations arise spontaneously and unpredictably as a result of contiguous deletions and duplications generated by unequal recombination in chromosomal regions with a specific architecture. The Williams syndrome is believed to be one of the most attractive models for linking genes, the brain, behavior and cognitive functions. It is a neurogenetic disorder resulting from a 1.5 Mb deletion at 7q11.23 which covers more than 20 genes; the hemizigosity of these genes leads to multiple manifestations, with the behavioral ones comprising three distinct domains: 1) visuo-spatial orientation; 2) verbal and linguistic defect; and 3) hypersocialisation. The shortest observed deletion leads to hemizigosity in only two genes: eln and limk1. Therefore, the first gene is supposed to be responsible for cardiovascular pathology; and the second one, for cognitive pathology. Since cognitive pathology diminishes with a patient's age, the original idea of the crucial role of genes straightforwardly determining the brain's morphology and behavior was substituted by ideas of the brain's plasticity and the necessity of finding epigenetic factors that affect brain development and the functions manifested as behavioral changes. Recently, non-coding microRNAs (miRs) began to be considered as the main players in these epigenetic events. This review tackles the following problems: is it possible to develop relatively simple model systems to analyze the contribution of both a single gene and the consequences of its epigenetic regulation in the formation of the Williams syndrome's cognitive phenotype? Is it possible to use Drosophila as a simple model system?

[Participation of GDNF, LIMK1 signal pathways and heat shock proteins in processes of Drosophila learning and memory formation].

Molecular mechanisms of the synapse and dendrite maintenance and their disturbance in psychiatric and neurodegenerative diseases (ND) are intensively studied in searching for target genes of therapeutic actions. It is suggested that glia, alongside with well-studied pre- and postsynaptic neurons, is the third, poorly studied partner in synaptic transmission (the tripartite synapse) that is involved in the positive feedback between the first two partners. This bidirectional coupling between presynaptic neurons and their postsynaptic targets involve neurotrophins (NTF), such as glial cell-derived neurotrophic factor (GDNF) that is produced LIM kinase 1 (LIMK1, the key enzyme of actin remodeling). The cytoplasmic domain of neuregulins interacts with LIMK1. Since neurons and axons that do not receive a sufficient NTF amount are at risk of degeneration and synapse elimination, GDNF seems to be the best studied factor of the ND therapy. The delivery of GDNF stem cells to the neurodegeneration locus is very efficient. There has been proposed a new approach based on use of Drosophila heat shock (hs) promoter. This promoter responds to the mammalian body temperature as to the shock factor resulting in the constant expression of the GDNF gene. The Drosophila models allow studying any given component of the bidirectional communication between pre- and postsynaptic neurons in development of the main diagnostic ND symptom, such as defective memory resulted from synaptic atrophy. In the present study we used the Drosophila stocks imitating different disturbances of the nervous system: Canton-S (wild type), GDNF (transgenic flies that carry human glial-cell-line derived nerve factor (GDNF) gene under hs promoter), l(1)ts403 with dusturbance of HSPs mRNA extranuclear transport, a defect of intracellular stress report, and agn(ts3) mutation in LIMK1 gene. We have revealed functional connections at the behavioral level (learning/memory) depending on the GDNF and LIMK1 brain expression and HSPs transduction that might provide targets for complex approaches for the ND treatment.

[Systemic regulation of genetic and cytogenetic processes by a signal cascade of actin remodeling: locus agnostic in Drosophila].

The concept on systemic regulation of genetic and cytogenetic processes has acquired a new perspective after the completion of the Human Genome project, when the view on systemic realization of genetic activity in the dynamic spatial organization of the genome is the nucleus was generally accepted. This organization underlies plasticity of complex biological systems. Chromosome position within the nucleus determined both processes of normal development and the development of genomic diseases, i.e., changes according to the environmental requirements, current needs of the organism, and its individual experience. Nuclear actin has been envisioned as a main factor bridging three levels of the genome organization (nucleotide, structural, and spatial), due to its capability of (1) regulating transcription by activating all three classes of RNA polymerase; (2) participating in chromatin remodeling by interacting with numerous proteins; and (3) lining the nuclear membrane, determining the chromosome attachment points and regulating export from the nucleus. In view of this, the role of actin remodeling factors (LIMK1, cofilin, actin) in the development of neurodegenerative diseases, including prionic ones, and in the mechanisms of generation of genomic diseases, syndromes resulting from unequal recombination, has been intensely studied. Drosophila is a helpful model organism to determine the sequence of events in this system of hierarchical relationships. Using spontaneous and mutant variants of the agnostic locus, we have designed a model of the Williams syndrome, which also reproduces main diagnostic traits of neurodegenerative diseases.

[Architecture of the X chromosome, expression of LIM kinase 1, and recombination in the agnostic mutants of Drosophila: a model of human Williams syndrome]. / Osobennosti arkhitektury X-khromosomy, ékspressii LIM kinazy 1 i rekombinatsii u mutantov drozofily lokusa agnostic: model' sindroma uil'iamsa cheloveka.

As the Human Genome and Drosophila Genome Projects were completed, it became clear that functions of human disease-associated genes may be elucidated by studying the phenotypic expression of mutations affecting their structural or functional homologs in Drosophila. Genomic diseases were identified as a new class of human disorders. Their cause is recombination, which takes place at gene-flanking duplicons to generate chromosome aberrations such as deletions, duplications, inversions, and translocations. The resulting imbalance of the dosage of developmentally important genes arises at a frequency of 10(-3) (higher than the mutation rate of individual genes) and leads to syndromes with multiple manifestations, including cognitive defects. Genomic DNA fragments were cloned from the Drosophila melanogaster agnostic locus, whose mutations impair learning ability and memory. As a result, the locus was exactly localized in X-chromosome region 11A containing the LIM kinase 1 (LIMK1) gene (CG1848), which is conserved among many species. Hemizygosity for the LIMK1 gene, which is caused by recombination at neighboring extended repeats, underlies cognitive disorders in human Williams syndrome. LIMK1 is a component of the integrin signaling cascade, which regulates the functions of the actin cytoskeleton, synaptogenesis, and morphogenesis in the developing brain. Immunofluorescence analysis revealed LIMK1 in all subdomains of the central complex and the visual system of Drosophila melanogaster. Like in the human genome, the D. melanogaster region is flanked by numerous repeats, which were detected by molecular genetic methods and analysis of ectopic chromosome pairing. The repeats determined a higher rate of spontaneous and induced recombination. including unequal crossing over, in the agnostic gene region. Hence, the agnostic locus was considered as the first D. melanogaster model suitable for studying the genetic defect associated with Williams syndrome in human.

Organization of the Drosophila genome in mutants with changes in second messenger metabolism and learning ability.

Mechanisms modifying the structural-functional organization of polytene chromosomes were studied in a Drosophila line in which the activating properties of calmodulin were altered and learning ability was increased, by treating mutants with homeopathic preparations which affect Ca2+ and F- ion metabolism. The results indicated a dominant role for Ca2+ ions and calmodulin in determining the chromocentric organization of the nucleus. F- ions, which stimulate the adenylate cyclase complex, were found not to have a role.

[The organizational characteristics of the Drosophila genome in mutants with altered second-messenger metabolism and with learning ability]. / Osobennosti organizatsii genoma drozofily u mutantov s izmenennym metabolizmom vtorichnykh posrednikov i sposobnosti k obucheniiu.

The data obtained on homeopathic correction of the Drosophila mutant strains with altered activation properties of calmodulin and increased ability for learning, suggest an important role of Ca ions calmodulin in formation of chromocentral organisation of the nucleus. No significant role of the F ions was revealed.

The influence of serotonin and p-chlorophenylalanine on locomotor activity of Drosophila melanogaster.

Two hours after injection of serotonin into 3-day-old virgin females of Drosophila melanogaster, a significant dose-dependent increase in locomotor activity was observed. Since this stimulating effect can be produced either by serotonin or by some of its derivatives that might have formed during these two hours, the fate of injected [3H]-serotonin in the organism of Drosophila was traced by means of thin layer chromatography. The only metabolite found appeared to be N-acetylserotonin. Its formation was rather intense immediately after injection of [3H]-serotonin, and its excretion was rapid enough to make it undetectable at the end of the second hour, when more than 50% of the injected [3H]-serotonin still remained and was being absorbed by tissues. Thus, the increase in locomotor activity observed two hours after injection should be wholly attributed to serotonin, while the rather long latency might be related to some effect of N-acetylserotonin. p-Chlorophenylalanine, an inhibitor of tryptophan-5-hydroxylase, both injected or administered with food, led to increases in locomotor activity level and to some decreases in serotonin content in the heads of flies. The effect of p-chlorophenylalanine on locomotor activity in Drosophila seems to be non-specific in relation to serotoninergic mechanisms of its regulation.