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Neurovascular and gliovascular interactions significantly affect endothelial phenotype. Physiologically, brain endothelium attains several of its properties by its intimate association with neurons and astrocytes. However, during cerebrovascular pathologies such as cerebral ischemia, the uncoupling of neurovascular and gliovascular units can result in several phenotypical changes in brain endothelium. The role of neurovascular and gliovascular uncoupling in modulating brain endothelial properties during cerebral ischemia is not clear. Specifically, the roles of metabolic stresses involved in cerebral ischemia, including aglycemia, hypoxia and combined aglycemia and hypoxia (oxygen glucose deprivation and re-oxygenation, OGDR) in modulating neurovascular and gliovascular interactions are not known. The complex intimate interactions in neurovascular and gliovascular units are highly difficult to recapitulate in vitro. However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo. While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D coculture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is pathologically characterized by inflammatory demyelination and neurodegeneration. Axonal damage, along with neuronal loss, occurs from disease onset and may lead to progressive and permanent disability. In contrast with the inflammatory pathways, the molecular mechanisms leading to MS neurodegeneration remain largely elusive. With improved understanding of these mechanisms, new potential therapeutic targets for neuroprotection have emerged. We review the current understanding of neurodegenerative processes at play in MS and discuss potential outcome measures and targets for neuroprotection trials. [ABSTRACT FROM AUTHOR]

With the introduction of interferon-β1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and its natural course was permanently changed. Currently, seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon- β1a intramuscular (Avonex), interferonβ1a subcutaneous (Rebif), interferon-β1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone (Novantrone). In addition, a large number of clinical trials are being conducted to assess the safety and efficacy of various experimental agents in patients with multiple sclerosis, including alemtuzumab, dimethyl fumarate, laquinimod, rituximab, daclizumab, and cladribine. In this paper, the author presents a concise and comprehensive review of present and potential treatments for this incurable disease. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this special issue is to synthesize current concepts about the pathogenesis, MRI measurements and clinical relevance of gray matter (GM) pathology in patients with multiple sclerosis (MS). Progressive GM pathology in MS has been recognized for a long time, however, only in recent years has detection of cortical GM lesions by specific pathology techniques uncovered the full extent of GM damage in MS. This issue reviews current knowledge about GM pathology, as assessed by neuroimaging techniques in early and chronic MS. Some new concepts are discussed with respect to how venous hemodynamic alterations may play an important role in the pathophysiology of MS. The issue emphasizes the critical need for development of better neuroimaging tools that can be used for in vivo visualization of GM pathology in patients with MS. Measures described include specific regional atrophy, diffusion tensor imaging, magnetic resonance spectroscopy, and magnetization transfer imaging, as well as optic nerve imaging techniques. Under development are promising new MRI sequences and analyses that will better identify and characterize cortical lesions. GM pathology imaging correlates are related to disability progression, as measured both by motor and cognitive functional outcomes. [Copyright &y& Elsevier]

The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-associated dementia (HAD; also known as AIDS dementia and HIV encephalopathy). HAD is the most significant and devastating central nervous system (CNS) complications associated with HIV infection. Despite recent advances in our knowledge of the clinical features, pathogenesis, and neurobiological aspects of HAD, it remains a formidable scientific and therapeutic challenge. An understanding of the mechanisms of HIV neuroinvasion, CNS proliferation, and HAD pathogenesis provide a basis for the interpretation of the diagnostic features of HAD and its milder form, HIV-associated minor cognitive/motor disorder (MCMD). Current diagnostic strategies are associated with significant limitations, but it is hoped that the use of biomarkers may assist researchers and clinicians in predicting the onset of the disease process and in evaluating the effects of new therapies. [ABSTRACT FROM AUTHOR]

Objective: Potential surrogate markers of disease activity, including response to therapy, are particularly important in a neurological disorder such as multiple sclerosis (MS) which often has a fluctuating course. Based upon previous studies in our laboratory, we hypothesized that measurement of soluble HLA (sHLA) molecules class II in saliva of MS patients can serve as marker of therapeutic response to high dose interferon beta-1a. Methods: We measured the expression patterns of sHLA-II in saliva in 17 patients with relapsing/remitting MS and compared the results to clinical course and brain MRI. For comparison purposes we also assayed the saliva sHLA-II levels in 53 normal control subjects. Solid phase ELISA was used for measurement of sHLA-I and sHLA-II concentrations at baseline and after three and six months of treatment with high dose interferon beta-1a (IFN β-1a). Results: The mean saliva sHLA-ll levels in MS patients was significantly higher than normal controls (354 ± 42 unit/mL vs. 222 ± 18 unit/mL, t= 8.16, p < 0.003). Comparison of saliva sHLA-II values before and after treatment with IFN β-1a revealed a consistent increase in mean concentration. The increase in saliva sHLA-II values (354 ± 42 unit/mL at baseline versus 821 ± 86 unit/mL at 3 months and 776 ± 63 unit/mL at 6 months, in unit/mL, p < 0.001 for both comparisons) was associated with a stable clinical course and a decline of the number of contrast-enhancing lesions on brain MRI. Comparison of the volume of T2-weighted lesions and the number of black holes on T1-weighted images did not reveal any significant changes (during pre-treatment versus posttreatment month 6) or any correlations with saliva sHLA-II levels. Saliva sHLA-I levels were not detectable. Conclusion: Serial measurement of saliva sHLA-II may serve as a potential marker of therapeutic response to IFN β-1a. Larger clinical studies involving more RRMS patients over longer periods of time are needed to further test the significance and value of saliva sHLA-II as an accurate marker of therapeutic response to beta-interferons. [ABSTRACT FROM AUTHOR]

Objective: Potential surrogate markers of disease activity, including response to therapy, are particularly important in a neurological disorder such as multiple sclerosis (MS) which often has a fluctuating course. Based upon previous studies in our laboratory, we hypothesized that measurement of soluble HLA (sHLA) molecules class II in saliva of MS patients can serve as marker of therapeutic response to high dose interferon beta-1a. Methods: We measured the expression patterns of sHLA-II in saliva in 17 patients with relapsing/remitting MS and compared the results to clinical course and brain MRI. For comparison purposes we also assayed the saliva sHLA-II levels in 53 normal control subjects. Solid phase ELISA was used for measurement of sHLA-I and sHLA-II concentrations at baseline and after three and six months of treatment with high dose interferon beta-1a (IFN β-1a). Results: The mean saliva sHLA-ll levels in MS patients was significantly higher than normal controls (354 ± 42 unit/mL vs. 222 ± 18 unit/mL, t= 8.16, p < 0.003). Comparison of saliva sHLA-II values before and after treatment with IFN β-1a revealed a consistent increase in mean concentration. The increase in saliva sHLA-II values (354 ± 42 unit/mL at baseline versus 821 ± 86 unit/mL at 3 months and 776 ± 63 unit/mL at 6 months, in unit/mL, p < 0.001 for both comparisons) was associated with a stable clinical course and a decline of the number of contrast-enhancing lesions on brain MRI. Comparison of the volume of T2-weighted lesions and the number of black holes on T1-weighted images did not reveal any significant changes (during pre-treatment versus posttreatment month 6) or any correlations with saliva sHLA-II levels. Saliva sHLA-I levels were not detectable. Conclusion: Serial measurement of saliva sHLA-II may serve as a potential marker of therapeutic response to IFN β-1a. Larger clinical studies involving more RRMS patients over longer periods of time are needed to further test the significance and value of saliva sHLA-II as an accurate marker of therapeutic response to beta-interferons. [ABSTRACT FROM AUTHOR]

Objective: Potential surrogate markers of disease activity, including response to therapy, are particularly important in a neurological disorder such as multiple sclerosis (MS) which often has a fluctuating course. Based upon previous studies in our laboratory, we hypothesized that measurement of soluble HLA (sHLA) molecules class II in saliva of MS patients can serve as marker of therapeutic response to high dose interferon beta-1a. Methods: We measured the expression patterns of sHLA-II in saliva in 17 patients with relapsing/remitting MS and compared the results to clinical course and brain MRI. For comparison purposes we also assayed the saliva sHLA-II levels in 53 normal control subjects. Solid phase ELISA was used for measurement of sHLA-I and sHLA-II concentrations at baseline and after three and six months of treatment with high dose interferon beta-1a (IFN β-1a). Results: The mean saliva sHLA-ll levels in MS patients was significantly higher than normal controls (354 ± 42 unit/mL vs. 222 ± 18 unit/mL, t= 8.16, p < 0.003). Comparison of saliva sHLA-II values before and after treatment with IFN β-1a revealed a consistent increase in mean concentration. The increase in saliva sHLA-II values (354 ± 42 unit/mL at baseline versus 821 ± 86 unit/mL at 3 months and 776 ± 63 unit/mL at 6 months, in unit/mL, p < 0.001 for both comparisons) was associated with a stable clinical course and a decline of the number of contrast-enhancing lesions on brain MRI. Comparison of the volume of T2-weighted lesions and the number of black holes on T1-weighted images did not reveal any significant changes (during pre-treatment versus posttreatment month 6) or any correlations with saliva sHLA-II levels. Saliva sHLA-I levels were not detectable. Conclusion: Serial measurement of saliva sHLA-II may serve as a potential marker of therapeutic response to IFN β-1a. Larger clinical studies involving more RRMS patients over longer periods of time are needed to further test the significance and value of saliva sHLA-II as an accurate marker of therapeutic response to beta-interferons. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule α4β1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy. [ABSTRACT FROM AUTHOR]

Background: Measurement of soluble HLA in body fluids has a potential role in assessing disease activity in autoimmune disorders. Methods: We applied a solid phase, enzyme-linked immunoassay to measure soluble HLA class I (sHLA-I) and class II (sHLA-II) molecules in the saliva and cerebrospinal fluid (CSF) in 13 untreated patients with relapsing-remitting form of multiple sclerosis (MS). For comparison purposes, we also studied saliva from 53 healthy subjects. Results: Saliva from normal controls had detectable sHLA-I levels in 41 of 53 individuals studied, with values ranging from 9-100 ng/ml (mean = 41 ± 2.8 ng/ml). sHLA-I was undetectable in the saliva in 11 of 13 MS patients, and in none of the CSF specimens. In contrast, mean sHLA-II concentration in the saliva of MS patients was significantly increased compared to controls (386 ± 52 unit/ml vs. 222 ± 18.4 unit/ml, t = 8.68, P < 0.005). The mean CSF sHLA-II level (369 ± 16 unit/ ml) was equivalent to the mean sHLA-II concentration measured in saliva (mean = 386 ± 52 unit/ml) (P = 0.7). In patients with brain magnetic resonance imaging (MRI) enhancing lesions (n = 5), reflective of more active disease, CSF sHLA-II averaged 356 ± 26 unit/ml compared to 380 ± 51 in saliva. Similarly, in patients with non-enhancing lesions (n = 8), CSF sHLA-II averaged 377 ± 18 unit/ ml compared to 390 ± 77 unit/ml in saliva. Thus, the mean sHLA-II concentration in saliva and CSF was essentially equivalent for MS patients with or without enhancing plaques. Conclusion: Our data suggest that the measurement of soluble HLA in saliva, specifically sHLAII, correlates with the level found in the CSF. Therefore, if sHLA correlates with disease activity in MS, as has been proposed, saliva measurements provide a noninvasive correlate of CSF measurement. [ABSTRACT FROM AUTHOR]

RNA and protein gene expression technologies are revolutionizing our view and understanding of human diseases and enable us to analyze the concurrent expression patterns of large numbers of genes. These new technologies allow simultaneous study of thousands of genes and their changes in regulation and modulation patterns in relation to disease state, time, and tissue specificity. This review summarizes the application of this modern technology to four common neurological and psychiatric disorders: HIV-1-associated dementia, Alzheimer''s disease, multiple sclerosis, and schizophrenia and is a first comparison of these diseases using this approach. [Copyright &y& Elsevier]

The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (CEC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. Collectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the 'interior milieu' of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal CNS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury. Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in CEC. Exposure of endothelium to proinflammatory cytokines (IFN-γ, TNF-α and IL-1β) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial 'microparticles' (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated CEC in the pathogenesis of BBB failure in MS. [ABSTRACT FROM AUTHOR]

Egas Moniz is generally remembered for having discovered cerebral angiography in 1927, and having introduced lobotomy as a form of treatment for mental illness in 1935. Less well known is his pioneering research on occlusive cerebrovascular disease, namely internal carotid artery (ICA) occlusion, as documented by cerebral angiography. It is our contention that the medical community has, until recently, largely overlooked his research. His neglected observations on ICA occlusion and the important diagnostic role played by angiography are reviewed. We propose to show how our paper differs from previous publications regarding Moniz's ICA occlusion contributions. Whereas most previous reviews have focused on either the role played by cerebral angiography in the diagnosis of ICA occlusion, or on the importance of Moniz's internal carotid occlusion observations, our review attempts to integrate both topics. We will tie Moniz's ICA occlusion research to his documented use of angiography. Keywords: Cerebral angiography; angiographic technique; internal carotid artery (ICA) occlusion; internal carotid occlusion; occlusive cerebrovascular disease; carotid thrombosis; Moniz; Lima [ABSTRACT FROM AUTHOR]

Disruption of the blood-brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). Occludin and vascular endothelial-cadherin (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition. [ABSTRACT FROM AUTHOR]

Abstract: Cardioembolic stroke accounts for approximately 15% of all strokes and is thought to be one of the more preventable types of strokes. Features that have been reported to support cardioembolism as a mechanism for ischemic stroke have included documented cardiac source of embolism, maximal neurologic deficit at onset, multiple cerebrovascular territories involved, enhanced tendency toward hemorrhagic transformation, enhanced risk of syncope or seizure associated with presentation, and lower likelihood of premonitory transient ischemic attacks. Features that tend to make cardioembolic stroke less likely include significant cerebral atherosclerosis, stepwise progression of the neurologic deficit within a finite period of time, vascular distribution such as entire internal carotid artery territory with combined middle cerebral artery and anterior cerebral artery involvement or watershed distribution, and premonitory transient ischemic attacks. A number of cardiac conditions can promote thromboembolism, and there is risk stratification reflective of the specific condition or coexistent conditions. Anticoagulant therapy generally has been found to be the most effective means of preventing cardiogenic brain embolism, but the intensity of anticoagulation needs to be optimized to reflect the risk-to-benefit ratio for the particular patient. [ABSTRACT FROM AUTHOR]

Macrophage/microglia (M∅) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood–brain barrier, behave as one of the immune effecter cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M∅, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS). HAD primarily involves subcortical gray matter, and both HAD and MS affect sub-cortical white matter. AD is a cortical disease. The process of M∅ and astrocytes activation leading to neurotoxicity share similarities among the three diseases. Human Immunodeficiency Virus (HIV)-1-infected M∅ are involved in the pathogenesis of HAD and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). In AD, M∅s produce these molecules and are activated by β-amyloid proteins and related oligopeptides. Demyelination in MS involves M∅ that become lipid laden, spurred by several possible antigens. In these three diseases, cytokine/chemokine communications between M∅ and astrocytes occur and are involved in the balance of protective and destructive actions by these cells. This review describes the role of M∅ and astrocytes in the pathogenesis of these three progressive neurological diseases, examining both beneficent and deleterious effects in each disease. [Copyright &y& Elsevier]

Devic disease is characterized by an attack or attacks of optic neuritis and necrotizing myelitis without clinical or magnetic resonance imaging (MRI) evidence of brain involvement or presence of oligoclonal bands in the cerebrospinal fluid (CSF). More than a century after its first systematic study by the French physician, Eugene Devic, its cause as well as its pathogenesis, remains unknown. Devic disease is both a diagnostic and therapeutic challenge to clinicians. The authors present the latest review on the nature, course, possible mechanisms, and therapeutic options of Devic disease. [Copyright &y& Elsevier]

Presents a case report of an AIDS patient having one-and-a-half syndrome and pontine tuberculosis. Magnetic resonance imaging of the brain; Etiology of the brainstem lesion; Complete recovery after anti-tuberculosis treatment.

Movement disorders associated with multiple sclerosis (MS) are uncommon, except for tremor. We report two patients with relapsing-remitting MS, who developed either dystonia or chorea during clinical exacerbation of their MS. The movement disorders resolved during treatment with adrenocorticotropin hormone (ACTH). Acute exacerbations of MS may be associated with transient movement disorders, which are responsive to ACTH. [Copyright &y& Elsevier]

The article focuses on the late-age onset polyneuropathy with gait ataxia. It presents a case of an elderly female patient who initially presented with gait ataxia associated with sensory complaints, weakness of the distal lower extremities, and diffuse hyporeflexia. Electrophysiologic examination showed abnormalities supporting a diagnosis of sensory motor polyneuropathy with primary axonal loss. Neuropathologic examination of the sural nerve disclosed a loss of myclinated nerve fibers with segmental demyelination of teased nerve fibres and mild axonal loss.

The lymphatic system maintains tissue homeostasis by transporting interstitial fluid, lipids and debris from tissues to the main circulation, and delivers antigen and antigen presenting cells to local lymph nodes where they elicit immune responses. During inflammation, lymph flow increases to limit edema and prevents tissue antigen-presenting cell transport. Lymphatics also adjust their contractile activity to increase fluid transfer during acute inflammation. Conversely, chronic inflammation can provoke lymphostasis, which might limit pathogen spread within the circulation; however, decreased lymph flow leads to the persistence of immune cells and mediators in tissues to intensifying injury. Here, we review lymphatic structure function within the gut, heart and central nervous system, discussing potential roles of these lymphatics in the etiology of inflammatory bowel disease, myocarditis and neurovascular disease, and as novel targets for therapeutic management of several disease states. [ABSTRACT FROM AUTHOR]

Background Frequency of sleep-disordered breathing (SDB) among stroke and transient ischemic attack (TIA) patients ranges from 30–80% and is associated with poor neurological outcomes. Per current stroke prevention guidelines from American Heart Association/American Stroke Association (AHA/ASA), SDB is included in the list of modifiable risk factors for stroke and TIA prevention. Goal of our study is to determine screening practices for SDB in stroke medical community. Methods A web-based survey was sent to physicians taking care of stroke patients across North America and Europe. Results Among 112 total responses, 91 (81%) were stroke physicians, nine (8%) were general neurologists, nine (8%) were from other specialties and three (3%) were sleep medicine physicians. Majority of physicians (72%, n = 81) do not use SDB screening questionnaires in their stroke patients. Epworth sleepiness scale is the most used among SDB questionnaires (24%, n = 25/105), followed by Berlin sleep questionnaire (10%) and STOP-BANG questionnaire (7%). Only 13% of physicians use screening questionnaires in both in-patients and outpatients, whereas 21% use only in outpatients and 5% use only in acute stroke setting. Only 50% (n = 56/111) of physicians would refer their stroke patients to a sleep medicine specialist when patients screen positive for SDB on questionnaires. Conclusion Despite being an independent risk factor for stroke and TIA, majority of physicians in the pilot targeted cohort of medical professionals, who are involved in the management of stroke and TIA, do not screen these patients for SDB. Further work involving systematic, more detailed standardized surveys are needed to be developed to objectively evaluate and improve screening practices for SDB in national and international stroke medical communities. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) typically affects young adults; however, the first symptoms can occur after age 50 and is classified as late-onset MS (LOMS). Methods: In this retrospective study, we extracted the records of 3522 MS patients (2716 females and 806 males) registered in the Isfahan MS Society (IMSS) from 2003 to 2010. Next, we searched for LOMS cases. We aimed to compare these cases with 1698 non-LOMS subjects also extracted from the IMSS database. Results: We found 48 LOMS patients (28 females and 20 males), which gave a crude frequency of 1.36%. The frequency by sex of LOMS in males (2.4%) was significantly greater than in females (1.0%, P = 0.002). The mean age at onset was 55.1 ± 4.3 years. The female to male ratio of 1.4:1 in these patients was significantly lower than in non-LOMS subjects (3.37:1, P= 0.003). The leading pattern of MS was relapsing-remitting (RR) in 62.5%, followed by primary progressive (PP) in 27.1%, and secondary progressive (SP) in 10.4%. Predominant presenting symptoms and signs were motor disturbances (35.4%), followed by brainstem (25%), optic neuritis (22.9%), and sensory related deficits (18.7%). The mean progression index (PI) in LOMS patients (0.88 ± 0.48) was significantly higher than in non-LOMS cases, 0.37 ± 0.17 (P< 0.0001). Discussion: In comparing LOMS patients with the non-LOMS cohort, there was a higher frequency of the PP pattern and a higher PI in the LOMS group. In comparing other high-risk populations with the Isfahan cohort, LOMS formed a lower percentage of the total Isfahan MS population. [ABSTRACT FROM AUTHOR]

Study Objectives: Obstructive sleep apnea (OSA) is a sleep disorder caused by transient obstruction of the upper airway and results in intermittent hypoxia, sleep fragmentation, sympathetic nervous system activation, and arousal which can have an adverse effect on cardiovascular disease. It is theorized that OSA might intensify stroke injury. Our goal here was to develop a new model of experimental OSA and test its ability to aggravate behavioral and morphological outcomes following transient brain ischemia/reperfusion.Methods: We used a 3D printed OSA device to expose C57BL6 mice to 3 h of OSA (obstructive apnea index of 20 events per hour) for three days. These mice were then subjected to ischemia/reperfusion using the middle cerebral artery occlusion model (MCAO) stroke and examined for overall survival, infarct size and neurological scoring.Results: We found that OSA transiently decreased respiration and reduced oxygen saturation with bradycardia and tachycardia typical of human responses during apneic events. Brain injury from MCAO was significantly increased by OSA as measured by infarct size and location as well as by intensification of neurological deficits; mortality following MCAO was also increased in OSA animals.Conclusions: Our findings suggest that our new model of OSA alters respiratory and cardiovascular physiological functions and is associated with enhanced ischemia/reperfusion mediated injury in our non-invasive, OSA intensified model of stroke. [ABSTRACT FROM AUTHOR]

While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler’s murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with GA neither enhanced viral loads nor suppressed antiviral immune responses, while it resulted in an increase in the Foxp3/Il17a ratio and IL-4/IL-10 production. This is the first study to suggest that GA could be safe for MS patients with a proven viral infection. [ABSTRACT FROM AUTHOR]

Background: Since most patients with relapsing-remitting multiple sclerosis (RRMS) are women, the present study aimed to determine whether treatment of patients with MS by cytotoxic agents is associated with an increased risk of cervical dysplasia. Cancer screening is often neglected in the chronic diseases such as MS, so more attention in this field was needed. Decreasing morbidity and mortality due to cervical cancer is the most important goal of screening in female MS patients especially in child bearing age. Thus, it can be said that this is the first study which investigated this important issue. Methods: A total of 129 individuals participated in this cohort study. They were assigned into 3 groups including 43 patients with MS who were treated with cytotoxic drugs, 43 patients with MS on immunomodulators, and 43 normal healthy controls. Pap smears were performed following standard methods and the results obtained from the three groups were compared by statistical analysis. Demographic data, Expanded Disability Status Scale (EDSS), and Pap smear changes were analyzed by SPSS software. Results: The most commonly detected abnormality in all examined patients and healthy controls was inflammation. Five patients with MS who were treated with cytotoxic agents revealed benign cellular changes (BCC) in their Pap smear that were statistically significant in comparison with other groups (P = 0.03). Patients who took Mitoxantrone presented BCC more than other groups [Odds ratio (OR) = 9.44, 95% confidence interval (Cl): 1.46-60.70]. There was no significant difference between mean duration of MS diagnosis (P = 0.12), mean duration of previous MS treatments (P = 0.25), and mean duration of current MS treatments (P = 0.21) in patients with BCC compared to normal healthy controls or inflammatory change. Conclusion: According to the results of present study, BCC is more frequently observed in patients with MS who were treated with cytotoxic agents with immunosuppressive effect. Since BCC is a 'premalignant condition', the authors suggest that mandatory annual Pap smear should be performed for patients with MS who are treated with cytotoxic agents irrespective of their age in order to detect early signs of malignancy. [ABSTRACT FROM AUTHOR]

Background Proteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1–13] . Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state. Methods Patients presenting to the Neurosurgery service at the Louisiana State University Hospital-Shreveport with an admitting diagnosis of TBI or SAH were prospectively enrolled. Patients undergoing CSF sampling for diagnostic procedures were also enrolled as controls. CSF aliquots were subjected to 2-dimensional gel electrophoresis (2D GE) and spot percentage densities analyzed. Increased or decreased spot expression (compared to controls) was defined in terms of in spot percentages, with spots showing consistent expression change across TBI or SAH specimens being followed up by Matrix-Assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS). Polypeptide masses generated were matched to known standards using a search of the NCBI and/or GenPept databases for protein matches. Eight hundred fifteen separately identifiable polypeptide migration spots were identified on 2D GE gels. MALDI-MS successfully identified 13 of 22 selected 2D GE spots as recognizable polypeptides. Results Statistically significant changes were noted in the expression of fibrinogen, carbonic anhydrase-I (CA-I), peroxiredoxin-2 (Prx-2), both α and β chains of hemoglobin, serotransferrin (Tf) and N-terminal haptoglobin (Hp) in TBI and SAH specimens, as compared to controls. The greatest mean fold change among all specimens was seen in CA-I and Hp at 30.7 and −25.7, respectively. TBI specimens trended toward greater mean increases in CA-I and Prx-2 and greater mean decreases in Hp and Tf. Conclusions Consistent CSF elevation of CA-I and Prx-2 with concurrent depletion of Hp and Tf may represent a useful combination of biomarkers for the prediction of severity and prognosis following brain injury. [ABSTRACT FROM AUTHOR]

Background Patients with small (<3 cm) intracranial meningiomas can be either observed or treated. Treatment can be either radiosurgery or microsurgery if and when tumor progression occurs. We compared local tumor growth control and recurrence-free survival (RFS) of microsurgical resection and radiosurgery in small intracranial meningiomas and identified predictors of unfavorable outcome. Methods A retrospective review (2005–2016) was performed of 90 consecutive patients with intracranial meningiomas who underwent either microsurgery ( n = 31) or Gamma Knife radiosurgery (GKRS) ( n = 59). The study population was evaluated clinically and radiographically after treatment. Results GKRS in meningiomas showed a significantly higher percentage of local control of tumor growth compared with microsurgery ( P = 0.02) 5 and 10 years ( P = 0.003) after treatment. The median RFS was also significantly higher in the GKRS group compared with the microsurgery group ( P = 0.04). There was no difference in RFS between Simpson grade I resection and GKRS ( P = 0.69). In univariate analysis, RFS after procedures was significantly affected by tumor involvement of cranial nerves, presence of comorbidities, and preoperative Karnofsky performance scale score ≤70. In multivariate analysis, only preoperative Karnofsky performance scale score ≤70 was a predictor of unfavorable outcome. Conclusions GKRS offers a high rate of tumor control and longer RFS that is comparable to Simpson grade I resection. Subtotal resection is not a good choice for small meningiomas. The treatment procedure should be tailored according to the presence of comorbidities and the maximum benefit for the patient. [ABSTRACT FROM AUTHOR]

Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia. [ABSTRACT FROM AUTHOR]

Discovered in 1947, microparticles (MP) represent a group of sub-micron cell-derived particles isolated by high speed centrifugation. Once regarded as cellular ‘trash', in the past decade MP have gained tremendous attention in both basic sciences and medical research both as biomarkers and mediators of infection, injury and response to therapy. Because MP bear cell surface markers derived from parent cells, accumulate in extracellular fluids (plasma, serum, milk, urine, cerebrospinal fluid) MP based tests are being developed commercially as important components in ‘liquid biopsy’ approaches, providing valuable readouts in cardiovascular disease and cancer, as well as stroke, Alzheimer’s disease and Multiple Sclerosis. Importantly, MP have been reported as mobile transport vectors in the intercellular transfer of mRNAs, microRNAs, lipids and proteins. Here we discuss MP structure, properties and functions with particular relevance to neurological and neurovascular diseases. [ABSTRACT FROM AUTHOR]

Iran has the highest prevalence of multiple sclerosis (MS) in the Middle East and Asia. Rate of emigration has been significantly raised among Iranians and though, multiple studies have been published on prevalence of MS among Iranian emigrants. Here we systematically reviewed these publications. We performed a comprehensive literature search was performed on April 30, 2015 in data bases of MEDLINE, EMBASE, Scopus and Google Scholar for the terms 'multiple sclerosis', 'incidence', 'prevalence', 'epidemiology', 'migration', 'emigrant', 'immigrant', 'Iran', 'Parsis' and 'Persian'. Study location, prevalence day or period, and age of at disease onset were recorded for all the included publications. Nine publications from Sweden, Canada, Norway, UK, and India were included. Only three reported age-adjusted prevalence and six reported age of disease onset. MS prevalence among Iranian emigrants varied from 21 per 100,000 people in Bombay, India in 1985 to 433 per 100,000 people in British Columbia, Canada in 2012. Five studies reported the prevalence in the region of interest, ranging from 1.33 in Bombay, India to 240 in British Columbia, Canada. Five studies also reported the prevalence of MS in the population of the destination country, and in all of them, the prevalence of MS was higher in Iranian immigrants compared to native people. Prevalence studies performed in Iran and also on Iranian emigrants indicate roles for both genetic and environmental factors in MS susceptibility. Data might indicate that living in a high-risk area increases the susceptibility to MS. [ABSTRACT FROM AUTHOR]

Background Psammoma bodies (PBs) are whorled, laminated hyaline spherules containing calcium deposits. Intracranially, the presence of PBs is associated with variants of meningioma and pituitary lesions, as well as aging choroid plexus. Limited information exists on their presence in vascular malformation. Results In this report, we describe a case of an adolescent male with drug-resistant epilepsy that was surgically managed at our regional epilepsy center. The epileptogenic focus was determined to be emanating from an indolent right insular lesion. Histopathologic evaluation showed the abundance of intravascular and perivascular PBs. Immunohistochemical evaluation confirmed the vascular origin using vascular markers. The unusual presence of PBs in a vascular lesion was unanticipated. Conclusions Based on our case, we present the clinicoradiologic characteristics, supplemented with intraoperative findings, for this unusual lesion. In addition, because of the unusual presence of PBs in vascular lesions, we provide the findings of a systematic literature review to show the association of PBs with intracranial vascular lesions. [ABSTRACT FROM AUTHOR]

Introduction: Neuromyelitis optica is a demyelinating disease of the central nervous system with various patterns of brain lesions. Corpus callosum may be involved in both multiple sclerosis and neuromyelitis optica. Previous case reports have demonstrated that callosal lesions in neuromyelitis optica are usually large and edematous and have a heterogeneous intensity showing a "marbled pattern" in the acute phase. Their size and intensity may reduce with time or disappear in the chronic stages. Case presentation: In this report, we describe a case of a 25-year-old Caucasian man with neuromyelitis optica who presented clinically with optic neuritis and myelitis. His brain magnetic resonance imaging demonstrated linear enhancement of the corpus callosum. Brain images with contrast agent added also showed linear ependymal layer enhancement of the lateral ventricles, which has been reported in this disease previously. Conclusions: Linear enhancement of corpus callosum in magnetic resonance imaging with contrast agent could help in diagnosing neuromyelitis optica and differentiating it from other demyelinating disease, especially multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Early-onset Alzheimer's disease (EOAD) represents less than 5% of all AD cases. Autosomal dominant EOAD has been defined as the occurrence of at least three cases in three generations. Mutations in the amyloid precursor protein (APP), presenilin-1 and presenilin-2 genes have been recognized to be the cause of EOAD. Objective: We investigated the genotype of EOAD in two generations of two families with EOAD living in an Iranian village. Methods: The polymerase chain reaction method was used to study the presenilin-1 and APP genes in 25 subjects of these generations. Results: A guanine-to-adenine transition in exon 17 of the APP gene resulting in a valine-to-isoleucine substitution at codon 717 was detected in 14 subjects including 6 patients with EOAD. Conclusion: This mutation demonstrates the importance of γ-secretase, the necessity of early detection of patients with memory decline in the susceptible population and raising public awareness of consanguinity marriages. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Multiple sclerosis ( MS) has been proposed to be an immune-mediated disease in the central nervous system ( CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus ( TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immune-mediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells ( Tregs) can suppress inflammation, and have been suggested to be protective in immune-mediated diseases, including MS. However, in virus-induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immune-mediated pathology, Tregs may also suppress antiviral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV-infected mice with ex vivo generated induced Tregs ( iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin-10 production from B cells, CD4+ T cells and dendritic cells, which may contribute to the decreased CNS inflammation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) has been proposed to be an immune-mediated disease in the central nervous system (CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus (TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immunemediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells (Tregs) can suppress inflammation, and have been suggested to be protective in immune-mediated diseases, including MS. However, in virus-induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immunemediated pathology, Tregs may also suppress antiviral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV-infected mice with ex vivo generated induced Tregs (iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin-10 production from B cells, CD4+ T cells and dendritic cells, which may contribute to the decreased CNS inflammation. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature.Methods: We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature.Results and Conclusions: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation. [ABSTRACT FROM AUTHOR]