Dysfunction of Astrocytic Syncytium in Neurological Disorders

The current population is living longer than ever before as a result of improved health care services; therefore, the size of the ageing population is increasing [1]. Dementia is emerging as one of the main conditions affecting the elderly population. According to the WHO report, in 2010, there were approximately 35.6 million people suffering from dementia worldwide. This figure continues to rise, doubling approximately every 20 years and it is estimated that this will soon rise to 65.7 million by 2030, and further to 115.4 million by 2050. Current incidence shows an individual is diagnosed with dementia every four seconds. This has substantial socioeconomic and financial implications on people globally and the societal costs associated with disease were estimated at US$ 605 billion in 2010 [2].

Varicella is a high infectious disease with a worldwide distribution. According to a WHO position paper, global annual disease burden of Varicella is estimated to be 140 million cases [1]. Even if it is often considered a harmless disease, it may have a serious course and may require hospitalization. Among complications, neurological ones have been reported in previous studies. They may be caused by a primary infection or may be associated with a virus reactivation. Generally, children present with neurological complications associated to a primary infection. Those associated with recurrences are often due to the direct effect of viral replication in the central nervous system. Varicella zoster virus reaches the nervous system either through the bloodstream or by direct spread from sensory ganglia where it remains latent. The neurological consequences of Varicella reactivation are more frequent detached among elderly individuals and immunodeficient patients. Neurological involvement in immunocompetent children following Varicella reactivation is exceptionally rare. Varicella-zoster virus can infect a wide variety of cells in the central and peripheral nervous system, including neurons, oligodendrocytes, meningeal cells, ependymal cells, and cells of the blood vessel wall. The wide range of susceptible cells explains the diversity of the clinical and pathologic nervous system manifestations of VZV. The spectrum of VZV infection can range from mild symptomatic infection to meningoencephalitis.

The neurological disorders and stroke represent the last century’s medical challenge. Despite increasing number of elderly people and the subsequent increase of neurological diseases, in socalled industrialized countries, we have no efficacious strategy to fight this plague.

Probably, the more effective method to take on this challenge may be a rigorous prevention and principle risk factors (e.g. high-pressure, stress, obesity, smoke of tobacco and alcohol) elimination. On the other hand, further scientific research in this field could be very useful. This kind of research should be based on the use of animal models to improve current understanding of the pathophysiological features of these diseases and may yield important information on how to improve analysis of the “efficacy” of some possible molecules.

As the expansion of global aging population with improved lifespan and loaded social burden, the incidence of neurological disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) presents a continuous climbing trend [1]. All of these neurological disorders afflicting health status and quality of life for elderly and increasing medical burden to their family and society are highly associated with protein quality control, because damaged, mis-folded or aggregated proteins can cause the proteotoxic stress for cell functional impairment and the intracytoplasmic deposition of aggregate-prone proteins or dysfunctional mitochondria in neurons with limited treatment strategies [2].

Autophagy is a cellular self-consumption process characterized by sequestration of bulk cytoplasm, long-lived proteins and damaged cellular organelles in double membrane vesicles called autophagosomes, which are delivered to lysosomes for the degradation [3,4]. Protein quality control via autophagy is particularly important for the timely removal of aggregated forms of pathogenic proteins in neurodegenerative diseases, including tau in AD, α-synuclein in PD and polyQ-Htt in HD [5,6]. It is also a powerful and selective degradation process for dysfunctional mitochondria in neurons for maintaining mitochondrial homeostasis. A decline in autophagic function is a common trait of the aging process

The neonatal astrocytes used to be considered a population of stage specific, proliferating immature astrocytes. Over the course of brain maturation, the newly generated astrocytesundergo extensive changes in gene expression, form spatially exclusive domains, connect through gap junctions into a syncytial network, and interact with and envelop blood vessels as part of the blood brain barrier [1-8]. Over the past two decades, increasing evidence shows that the very same “immature” astrocytes are the sculptors of synaptogenesisand facilitators of myelination in the CNS [8-10].

Background: Osteogenesis Imperfecta (OI) is a rare inherited collagen disease of variable severity. Our patient was diagnosed with OI prior to aneurysmal Subarachnoid Hemorrhage (aSAH) occurrence. To our knowledge, this is the first case report of an OI patient with SAH associated vasospasm treated with milrinone.

Case Presentation: A 35 year old female - known for OI - was brought to the Neuro-critical care unit after being intubated for generalized tonic-clonic seizure. A CT/CTA of the brain revealed acute aSAH due to basilar artery aneurysmal rupture, with early hydrocephalus. An External Ventricular Drain (EVD) was installed and the aneurysm was coiled the next day. Two days later her Glasgow Comma Scale (GCS) was back to 15/15. Ten Days post aSAH she became obtunded, with right arm weakness. Transcranial Doppler confirmed the diagnosis of vasospasm. She received IV Mi-lrinone and regained her level of consciousness and power. Her modified Rankin Score (mRS) was 1 at time of discharge and 0 three months later. To our knowledge, this is the first case report of OI treated (successfully) using IV milrinone for cerebral vasospasm after aSAH.

Conclusion: Cerebral vasospasm after aSAH has been known to occur in OI. Here we present a patient with OI who developed vasospasm related deficit that responded well to IV Milrinone, with good outcome based on mRS

Autosomal Recessive Primary Microcephaly (MCPH) is one of the most common hereditary neurological disorders in Saudi Arabia. Frequent consanguineous unions, due to isolated tribal set ups and large family sizes, is considered the primary reason for this high prevalence. In our study we ascertained a consanguineous family living in the South-Western region of the Kingdom. The patients were characterized by primary microcephaly, moderate intellectual disability and developmental delays. For genetic analysis we performed SNP array Based Comparative Genome Hybridization (aCGH) and analyzed the data for homozygosity mapping alongside Whole Exome Sequencing (WES). Three putative causal variants in regions of extended homozygosity on chromosome 1q31, chromosome 5p13.2 and chromosome 5p13.3 were identified: respectively, a nonsense variant in the ASPM gene (NM_018136; c.8903G>A; p.Trp2968*); a missense variant in SPEF2 (NM_024867; c.1262G>A; p.Arg421His); and a missense variant in PDZD2 (NM_178140; c.2153C>A; p.Thr718Asn) were found potential candidates for the disease phenotype in this family. Sanger sequencing determined that the variants in SPEF2 and PDZD2 did not co-segregate with the disease phenotype. However, the nonsense variant in ASPM does co-segregate with disease in this family. Our study concludes WES as a successful molecular diagnostic tool in this highly inbred population.

A wide variety of disease patterns are found in the practice of neurology, which has led to the development of numerous advanced MR (Magnetic Resonance) imaging techniques. Some techniques such as DWI have found such widespread application that they have been incorporated into nearly all-imaging protocols for a variety of neurological conditions, and yet others are used to answer specific clinical questions. The advent of higher strength MR magnets have allowed for clinical application of exciting new MR techniques like BOLD fMRI imaging, DTI, and ASL perfusion. The subsequent sections briefly highlights various advanced imaging technique and its clinical application.

Microcephaly is an autosomal recessive neuro developmental disorder in which affected individual characterized by microcephaly present at birth and non-progressive mental retardation. In primary microcephaly, head circumference of the affected person shows variation from >3S D in normal population and in very rare cases non progressive mental retardation seen in affected individual [1-2]. Primary microcephaly is due to mutations in at least twelve lociat autosomal chromosome, which result in different phenotypes [3]. Persons with primary microcephaly have reduced skull consequently smaller brain but brain a architecture is quite normal as in normal person, the darker portion of brain (Gray matter)remain greatly preserved due to which no neurological abnormalities had seen such as abnormal muscle reflex, inability in speaking etc., but mild to severe mental retardation had been observed [4]. Recently it is identified that mutation in a new geneisal so involved in causing dominant microcephaly named as kinesine family member 11 (KIF11) which is reported in 16 families worldwide. It is firmly believed that due to mutations in the segenes ultimately lead to following consequences like in term it tent mitotic spindle fibers, transcriptional regulation, premature condensation, DNA aberration and many other problems which are not visible yet [5].

Objectives: P-Glycoprotein (P-gp) an efflux transporter localized in the blood-brain barrier, influences drug concentrations in the brain and thereby their clinical efficacy. P-gp knockout mice differ markedly from wild type animals with respect to pharmacokinetics and -dynamics of P-gp substrates. Using the P-gp substrate risperidone as a model drug, we studied the effects of P-gp induction on drug concentrations in blood and CNS as well as its effects on drug related behavior.

Methods: P-gp inducing drugs dexamethasone and 5-pregnene-3beta-ol-20-on-16alpha-carbonitrile (PCN) were given to FVB/N mice for 11 days. Control mice received vehicle only. On day 12, risperidone was injected i.p. For kinetic investigations, brain and serum levels of risperidone and 9-hydroxyrisperidone were measured by reversed phase-high performance liquid chromatography with spectrophotometric detection. To study pharmacodynamic effects, risperidone induced RotaRod behavior was analysed with Rota Rod.

Results: Risperidone and 9-hydroxyrisperidone concentrations were decreased in the blood serum and brain homogenate of animals treated with dexamethasone or PCN. Baseline Rota Rod behavior was only slightly affected by P-gp inducing drugs. Rota Rod deficits due to risperidone were markedly reduced after induction of P-gp by both drugs.

Conclusion: Induction of P-gp diminishes the CNS effects of drugs characterized as substrates of P-gp. Therefore, it seems likely that induction of P-gp by co-medication has the potential to minimize treatment response and increase potential side effects of CNS drugs in a clinical respect.