Publications by authors named "Alireza Minagar"

208 Publications

Nanoparticle-Encapsulated Bryostatin-1 Activates α-Secretase and PKC Isoforms In vitro and Facilitates Acquisition and Retention of Spatial Learning in an Alzheimer's Disease Mouse Model.

Curr Alzheimer Res 2020 ;17(14):1302-1310

LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA, United States.

Background: Alzheimer's disease (AD) animal models have revealed neuroprotective actions of Bryostatin-1 mediated by activation of novel PKC isoforms, suppression of beta-amyloid and downregulation of inflammatory and angiogenic events, making Bryostatin-1 an attractive candidate for attenuating AD-associated neural, vascular, and cognitive disturbances.

Objective: To further enhance Bryostatin-1 efficacy, nanoparticle-encapsulated Bryostatin-1 formulations were prepared.

Methods: We compared nano-encapsulated and unmodified Bryostatin-1 in in vitro models of neuronal PKC-d, PKC-e isoforms, α-secretase and studied nano-encapsulated Bryostatin-1 in an AD mouse model of spatial memory (BC3-Tg (APPswe, PSEN1 dE9) 85Dbo/J mice).

Results: We found that nanoencapsulated Bryostatin-1 formulations displayed activity greater or equal to that of unmodified Bryostatin-1 in PKC-δ and -ε and α-secretase activation assays. We next evaluated how treatment with a nanoencapsulated Bryostatin-1 formulation facilitated spatial learning in the Morris water maze. AD transgenic mice (6.5 to 8 months of age) were treated with nanoparticle encapsulated Bryostatin-1 formulation (1, 2.5, or 5 μg/mouse) three times the week before testing and then daily for each of the 5 days of testing. Across the acquisition phase, mice treated with nanoencapsulated Bryostatin-1 had shorter latencies, increased % time in the target zone and decreased % time in the opposite quadrant. The mice were given retention testing after a 2-week period without drug treatment. Mice treated with nanoencapsulated Bryostatin-1 had shorter latencies to find the escape platform, indicating retention of spatial memory.

Conclusion: These data suggest that cognitive deficits associated with AD could be treated using highly potent nanoparticle-encapsulated formulations of Bryostatin-1.
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http://dx.doi.org/10.2174/1567205018666210218155835DOI Listing
January 2020

Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow.

EBioMedicine 2021 Jan 19;63:103161. Epub 2020 Dec 19.

Molecular and Cellular Physiology, Medicine and Neurology, Ochsner-LSU Health Sciences Center-1501 Kings Highway, Shreveport, LA 71130-3932, USA; Neurology, Ochsner-LSU Health Sciences Center-Shreveport, LA 71130, USA. Electronic address:

Background: Besides long-term trans-differentiation into neural cells, benefits of stem cell therapy (SCT) in ischemic stroke may include secretion of protective factors, which partly reflects extracellular vesicle (EVs) released by stem cell. However, the mechanism(s) by which stem cells/EVs limit stroke injury have yet to be fully defined.

Methods: We evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke 'transient middle cerebral artery occusion (MCAO)/reperfusion' mice model.

Findings: We found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSC-derived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the post-MCAO brain. More importantly, EVs derived from hPMSC promote paracrine-based protection of SCT in the MCAO model in a cholesterol/lipid-dependent manner.

Interpretation: Together, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid "translation" of these cells into clinical trials in the near-term.
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http://dx.doi.org/10.1016/j.ebiom.2020.103161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753936PMC
January 2021

SC411 treatment can enhance survival in a mouse model of sickle cell disease.

Prostaglandins Leukot Essent Fatty Acids 2020 07 3;158:102110. Epub 2020 May 3.

Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Hwy Shreveport, LA, USA; Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA. Electronic address:

Sickle cell disease (SCD) is one of the most common inherited blood disorder among African Americans affecting 70,000-100,000 individuals in the United States. It is characterized by abnormal hemoglobin (HbS) which develops into severe hemolytic anemia and vaso-occlusive crisis. Therefore, patients with SCD suffer from a chronic state of inflammation, which is responsible for multiple organ damage, ischemic attacks, and premature death. Another major hallmark of SCD patients is the abnormally low levels of omega-3 fatty acids, especially docosahexaenoic acid (DHA) in their red blood cell membranes. Treatment with DHA can reduce red blood cell adhesion and enhance cerebral blood flow, thus, our main goal is to investigate the effect of SC411, which is a novel, highly purified DHA ethyl ester formulation with a proprietary delivery platform in SCD. Utilizing a transgenic mouse model of SCD (HbSS-Townes) and recurrent hypoxic challenges (10%O, 0.5% CO and balance N for 3 h) to mimic ischemic-like conditions, our data suggest that SC411 can elevate blood DHA and eicosapentaenoic acid (EPA) levels after 8 weeks of treatment. SC411 can also decrease arachidonic acid (AA) and sickling of red blood cells. In addition, SC411-treated SCD mice showed presented with cerebral blood flow, alleviated neuroinflammation, and revived working memory which ultimately enhanced overall survival. In summary, this study suggests that treatment with SC411 improves cellular and functional outcomes in SCD mice. This finding may provide novel therapeutic opportunities in the treatment against ischemic injury elicited by SCD.
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http://dx.doi.org/10.1016/j.plefa.2020.102110DOI Listing
July 2020

Obstructive sleep apnea intensifies stroke severity following middle cerebral artery occlusion.

Sleep Med 2020 03 29;67:278-285. Epub 2020 Jan 29.

Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, 71130, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.sleep.2020.01.014DOI Listing
March 2020

The Relationship Between Obstructive Sleep Apnea and Ruptured Intracranial Aneurysms.

J Clin Sleep Med 2019 12;15(12):1839-1848

Department of Neurosurgery, LSU Health-Shreveport, Shreveport, Louisiana.

Study Objectives: The role of obstructive sleep apnea (OSA) in the overall outcome of ruptured intracranial aneurysms (RIAs) is unknown. We have investigated the role of OSA in overall outcome of RIAs.

Methods: Data from 159 consecutive patients were retrospectively reviewed. A chi-square test and regression analysis were performed to determine the significant difference. A value of P < .05 was considered significant.

Results: The prevalence of OSA in RIAs was fivefold higher in the nonaneurysm patient group, P = .002. The number of patients with hypertension (P < .0001), body mass index ≥ 30 (P < .0001), hyperlipidemia (P = .018), chronic heart disease (P = .002) or prior ischemic stroke (P = .001) was significantly higher in the OSA group. Similarly, the number of wide-neck aneurysms (P < .0001) and aneurysm > 7 mm (P = .004), poor Hunt and Hess grade IV-V (P = .005), vasospasms, (P = .03), and patients with poor Modified Rankin Scale scores (3-6) was significantly higher in the OSA group (P < .0001). Interestingly, for the first time in univariate (P = .01) and multivariate (P = .003) regression analysis, OSA was identified as an individual predictor of unfavorable outcome of RIAs. In addition, hypertension (P = .04), smoking (P = .049), chronic heart disease (P = .01), and Hunt and Hess grade IV-V (P = .04) were revealed as predictors of poor outcome of RIAs.

Conclusions: This is a novel study to determine the association between OSA and ruptured cerebral aneurysm in terms of comorbidities, size of aneurysm, severity of symptoms, and outcomes after treatment. In addition, for the first time, OSA is identified as a positive predictor of unfavorable outcome of RIAs.
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http://dx.doi.org/10.5664/jcsm.8096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099178PMC
December 2019

Protein Arginine Methyltransferases in Cardiovascular and Neuronal Function.

Mol Neurobiol 2020 Mar 10;57(3):1716-1732. Epub 2019 Dec 10.

Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a type of post-translational modification which is important for numerous cellular processes, including mRNA splicing, DNA repair, signal transduction, protein interaction, and transport. PRMTs have been extensively associated with various pathologies, including cancer, inflammation, and immunity response. However, the role of PRMTs has not been well described in vascular and neurological function. Aberrant expression of PRMTs can alter its metabolic products, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). Increased ADMA levels are recognized as an independent risk factor for cardiovascular disease and mortality. Recent studies have provided considerable advances in the development of small-molecule inhibitors of PRMTs to study their function under normal and pathological states. In this review, we aim to elucidate the particular roles of PRMTs in vascular and neuronal function as a potential target for cardiovascular and neurological diseases.
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http://dx.doi.org/10.1007/s12035-019-01850-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062579PMC
March 2020

Brain Endothelial Cells Release Apical and Basolateral Microparticles in Response to Inflammatory Cytokine Stimulation: Relevance to Neuroinflammatory Stress?

Front Immunol 2019 27;10:1455. Epub 2019 Jun 27.

Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, United States.

Microparticles (MP) are regarded both as biomarkers and mediators of many forms of pathology, including neurovascular inflammation. Here, we characterized vectorial release of apical and basolateral MPs (AMPs and BMPs) from control and TNF-α/IFN-γ treated human brain endothelial monolayers, studied molecular composition of AMPs and BMPs and characterized molecular pathways regulating AMP and BMP release. The effects of AMPs and BMPs on blood-brain barrier properties and human brain microvascular smooth muscle tonic contractility were also evaluated. We report that human brain microvascular endothelial cells release MPs both apically and basolaterally with both AMP and BMP release significantly increased following inflammatory cytokine challenge (3.5-fold and 3.9-fold vs. control, respectively). AMPs and BMPs both carry proteins derived from parent cells including those in BBB junctions (Claudin-1, -3, -5, occludin, VE-cadherin). AMPs and BMPs represent distinct populations whose release appears to be regulated by distinctly separate molecular pathways, which depend on signaling from Rho-associated, coiled-coil containing protein kinase (ROCK), calpain as well as cholesterol depletion. AMPs and BMPs modulate functions of neighboring cells including BBB endothelial solute permeability and brain vascular smooth muscle contractility. While control AMPs enhanced brain endothelial barrier, cytokine-induced AMPs impaired BBB. Cytokine-induced but not control BMPs significantly impaired human brain smooth muscle contractility as early as day 1. Taken together these results indicate that AMPs and BMPs may contribute to neurovascular inflammatory disease progression both within the circulation (AMP) and in the brain parenchyma (BMP).
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http://dx.doi.org/10.3389/fimmu.2019.01455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610500PMC
October 2020

Cervical spinal cord atrophy impact on quality of life in MS: A neuroimaging study.

J Neurol Sci 2019 06 17;401:101-102. Epub 2019 Apr 17.

Departments of Neurology, LSU Health Sciences Center, Shreveport, LA 71130, USA; Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA 71130, USA.

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http://dx.doi.org/10.1016/j.jns.2019.04.022DOI Listing
June 2019

Bioinformatics Analyses Determined the Distinct CNS and Peripheral Surrogate Biomarker Candidates Between Two Mouse Models for Progressive Multiple Sclerosis.

Front Immunol 2019 19;10:516. Epub 2019 Mar 19.

Department of Microbiology, Kindai University Faculty of Medicine, Osakasayama, Japan.

Previously, we have established two distinct progressive multiple sclerosis (MS) models by induction of experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein (MOG) in two mouse strains. A.SW mice develop ataxia with antibody deposition, but no T cell infiltration, in the central nervous system (CNS), while SJL/J mice develop paralysis with CNS T cell infiltration. In this study, we determined biomarkers contributing to the homogeneity and heterogeneity of two models. Using the CNS and spleen microarray transcriptome and cytokine data, we conducted computational analyses. We identified up-regulation of immune-related genes, including immunoglobulins, in the CNS of both models. Pro-inflammatory cytokines, interferon (IFN)-γ and interleukin (IL)-17, were associated with the disease progression in SJL/J mice, while the expression of both cytokines was detected only at the EAE onset in A.SW mice. Principal component analysis (PCA) of CNS transcriptome data demonstrated that down-regulation of prolactin may reflect disease progression. Pattern matching analysis of spleen transcriptome with CNS PCA identified 333 splenic surrogate markers, including , which reflected the changes in the CNS. Among them, we found that two genes (/ and ) and one gene () were also significantly up-regulated and down-regulated, respectively, in human MS peripheral blood, using data mining.
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http://dx.doi.org/10.3389/fimmu.2019.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434997PMC
September 2020

Theiler's Virus-Mediated Immunopathology in the CNS and Heart: Roles of Organ-Specific Cytokine and Lymphatic Responses.

Front Immunol 2018 10;9:2870. Epub 2018 Dec 10.

Department of Microbiology, Kindai University Faculty of Medicine, Osaka, Japan.

Theiler's murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, with cytokines playing key roles for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord about 1 month post-inoculation (p.i.). Unlike other immunopathology models, both pro- and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play beneficial roles in viral clearance while they are also detrimental in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. Conversely, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three distinctive phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the exact mechanism(s) by which a single virus, TMEV, induces these different diseases in different organs is unclear, our bioinformatics approaches, especially principal component analysis (PCA) of transcriptome data, allow us to identify the key factors contributing to organ-specific immunopathology. The PCA demonstrated that infection of a cardiomyocyte cell line reproduced the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in TMEV-infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of the CNS transcriptome data showed that decreased lymphatic marker expressions were weakly associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels is shown to potentially contribute to immunopathology by delaying the clearance of cytokines and immune cells from the inflammatory site, although this can also confine the virus at these sites, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility provoked by pro-inflammatory cytokines. Therefore, TMEV infection may induce different patterns of cytokine expressions as well as lymphatic vessel dysfunction by rather different mechanisms between the CNS and heart, which might explain observed patterns of organ-specific immunopathology.
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http://dx.doi.org/10.3389/fimmu.2018.02870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295469PMC
October 2019

Evaluation of the risk of cervical cancer in patients with Multiple Sclerosis treated with cytotoxic agents: A cohort study.

Iran J Neurol 2018 Apr;17(2):64-70

Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

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. 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. 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 (CI): 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. 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131331PMC
April 2018

Multiple sclerosis pathogenesis: missing pieces of an old puzzle.

Rev Neurosci 2018 12;30(1):67-83

MS Research Center, Neuroscience Institute, Tehran University of Medical Science, Department of Neurology, Sina Hospital, 1136746911 Tehran, Iran.

Traditionally, multiple sclerosis (MS) was considered to be a CD4 T cell-mediated CNS autoimmunity, compatible with experimental autoimmune encephalitis model, which can be characterized by focal lesions in the white matter. However, studies of recent decades revealed several missing pieces of MS puzzle and showed that MS pathogenesis is more complex than the traditional view and may include the following: a primary degenerative process (e.g. oligodendroglial pathology), generalized abnormality of normal-appearing brain tissue, pronounced gray matter pathology, involvement of innate immunity, and CD8 T cells and B cells. Here, we review these findings and discuss their implications in MS pathogenesis.
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http://dx.doi.org/10.1515/revneuro-2018-0002DOI Listing
December 2018

Medical students and brain death: An educational initiative.

Clin Neurol Neurosurg 2018 07 30;170:116. Epub 2018 Apr 30.

Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clineuro.2018.04.031DOI Listing
July 2018

Cerebral ischemia and neuroregeneration.

Neural Regen Res 2018 Mar;13(3):373-385

Department of Neurology, Louisiana State University Health Science Center; Center for Brain Health, Louisiana State University Health Science Center; Department of Cellular Biology and Anatomy, Louisiana State University Health Science Center, Shreveport, LA, USA; Cardiovascular and Metabolomics Research Center, Hualien Tzu Chi Hospital, Hualien, Taiwan, China.

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke (a form of cerebral ischemia)-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics (i.e., tissue plasminogen activator) and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies against stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism(s) underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies (i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells) as it relates to cerebral ischemia.
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http://dx.doi.org/10.4103/1673-5374.228711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900490PMC
March 2018

Neuromyelitis optica spectrum disorder in the very young: An in depth review of the present data.

J Neurol Sci 2018 05 17;388:232. Epub 2018 Feb 17.

Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport 71130, LA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2018.02.027DOI Listing
May 2018

Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest.

J Vis Exp 2018 01 5(131). Epub 2018 Jan 5.

Department of Neurology, Louisiana State University Health Science Center; Center for Brain Health, Louisiana State University Health Science Center;

Background: Evaluating mild to moderate cognitive impairment in a global cerebral ischemia (i.e. cardiac arrest) model can be difficult due to poor locomotion after surgery. For example, rats who undergo surgical procedures and are subjected to the Morris water maze may not be able to swim, thus voiding the experiment. New Method: We established a modified behavioral spontaneous alternation T-maze test. The major advantage of the modified T-maze protocol is its relatively simple design that is powerful enough to assess functional learning/memory after ischemia. Additionally, the data analysis is simple and straightforward. We used the T-maze to determine the rats' learning/memory deficits both in the presence or absence of mild to moderate (6 min) asphyxial cardiac arrest (ACA). Rats have a natural tendency for exploration and will explore the alternate arms in the T-maze, whereas hippocampal-lesioned rats tend to adopt a side-preference resulting in decreased spontaneous alternation ratios, revealing the hippocampal-related functional learning/memory in the presence or absence of ACA.

Results: ACA groups have higher side-preference ratios and lower alternations as compared to control. Comparison with Existing Method(s): The Morris water and Barnes maze are more prominent for assessing learning/memory function. However, the Morris water maze is more stressful than other mazes. The Barnes maze is widely used to measure reference (long-term) memory, while ACA-induced neurocognitive deficits are more closely related to working (short-term) memory.

Conclusions: We have developed a simple, yet effective strategy to delineate working (short-term) memory via the T-maze in our global cerebral ischemia model (ACA).
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http://dx.doi.org/10.3791/56694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908446PMC
January 2018

Immunoregulation of Theiler's virus-induced demyelinating disease by glatiramer acetate without suppression of antiviral immune responses.

Arch Virol 2018 May 23;163(5):1279-1284. Epub 2018 Jan 23.

Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA, 71130, USA.

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.
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http://dx.doi.org/10.1007/s00705-018-3729-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276114PMC
May 2018

Management of a complex intracranial arteriovenous malformation with gamma knife radiosurgery: A case report with review of literature.

J Clin Neurosci 2018 Mar 14;49:26-31. Epub 2017 Dec 14.

Department of Neurosurgery, LSU Health-Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932, USA. Electronic address:

The risks and benefits of arteriovenous malformation (AVM) treatment should be considered cautiously in each patient since management strategy of it depends on various factors including age of the patient, location and volume of AVM and presence of other vascular abnormalities. Current management options of AVM include observation, endovascular embolization, radiosurgery and microsurgical resection or in combination of any two of the above procedures. Here, we have discussed a case of intracranial AVM with radiation induced early cyst formation, and performed a literature review to determine the optimum treatment of complex intracranial AVM. Standard search strategies were performed in PubMed/Medline using appropriate terms such as "intracranial arteriovenous malformation" radiosurgery, embolization and microsurgical resection as well as medical subject headings. The particular case in this study was retrospectively reviewed. Literature review revealed that the mean marginal radiation dose used by the different authors was 19 Gy, cysts were developed in 3.6% patients, the average time to form cyst was 6.6 years, average volume of cyst was 6.7 ml and maximum cysts were removed by resection. In our case, the cyst was developed 2.5 years after radiosurgery. Radiation induced cyst formation is a delayed complication of AVM management. However, cyst formation in this case was comparatively earlier in our case. Therefore, continuous follow-up after radiosurgery is required for early detection of cyst formation. In addition, the review revealed that embolization before radiosurgery was a poor strategy.
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http://dx.doi.org/10.1016/j.jocn.2017.10.056DOI Listing
March 2018

A case of neuromyelitis optica spectrum disorder presenting with undiagnosed Sjogren's syndrome and a single, atypical tumefactive lesion: A diagnostic challenge.

J Neurol Sci 2017 12 1;383:219-220. Epub 2017 Nov 1.

Dept. Neurology, LSU Health Sciences Center, Shreveport, LA 71130, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2017.10.042DOI Listing
December 2017

Assessing the cerebral gray matter volume in response to fingolimod therapy in multiple sclerosis: A more analytic view.

J Neurol Sci 2017 12 13;383:230-231. Epub 2017 Oct 13.

Dept. Neurology, LSU Health Sciences Center, Shreveport, LA 71130, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2017.10.018DOI Listing
December 2017

Ocrelizumab: a B-cell depleting therapy for multiple sclerosis.

Expert Opin Biol Ther 2017 09 3;17(9):1163-1172. Epub 2017 Jul 3.

a Buffalo Neuroimaging Analysis Center, Department of Neurology , Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo , NY , USA.

Introduction: Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.
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http://dx.doi.org/10.1080/14712598.2017.1347632DOI Listing
September 2017

Changing paradigm in the management of elderly patients with intracranial aneurysms: An institutional review.

J Clin Neurosci 2017 Sep 7;43:94-102. Epub 2017 Jun 7.

Department of Neurosurgery, LSU Health-Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932, USA. Electronic address:

Optimal treatment of intracranial aneurysms (IAs) in elderly patients has not yet been well established. We have investigated the clinical and radiological outcomes and predictors of unfavorable outcome of IAs in elderly patients. Radiological and clinical data of 85 elderly patients from 2010 through 2015 were retrospectively reviewed. Significant differences between the groups were determined by a chi-square test. Regression analysis was performed to identify the predictors of unfavorable outcome. Among the 85 patients with IAs, the number of patients with >7mm size aneurysm (p=0.01), diabetes mellitus (DM) (p=0.02), smoking (0.009) and Hunt and Hess grade 4-5 (p=0.003) was significantly higher in the ruptured group compared to the unruptured group. Similarly, the number of patients who underwent clipping was higher in the ruptured aneurysm group (p=0.01). The overall clinical outcome was comparatively better in the unruptured group (p=0.03); however, microsurgical clipping of aneurysms provides a significantly higher rate of complete aneurysmal occlusion (p=0.008). Overall, there was no significant difference in outcome in respect to treatment approach. In regression analysis, hypertension (HTN), obstructive sleep apnea (OSA), prior stroke, ruptured aneurysms and partial occlusion of aneurysms were identified as predictors of unfavorable outcome of IAs. Intracranial aneurysms in elderly patients reveals that endovascular treatment provides better clinical outcome; however, microsurgical clipping yields higher complete occlusion. Retreatment of residual aneurysms was comparatively more in the coiling group. Practice pattern has shifted from clipping to coiling for aneurysms in posterior circulation but not for aneurysms in anterior circulation.
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http://dx.doi.org/10.1016/j.jocn.2017.05.015DOI Listing
September 2017

Liver Disease and Neurology.

Continuum (Minneap Minn) 2017 Jun;23(3, Neurology of Systemic Disease):762-777

Purpose Of Review: Neurologists often encounter patients with acute and chronic liver disease and must be aware of how these diseases can affect the nervous system. This is particularly true when evaluating patients with alterations in cognition and level of consciousness. Wilson disease, while uncommon, is a treatable condition with many neurologic and psychiatric symptoms. Neurologic disorders associated with liver disease may affect not only the brain, but also the spinal cord and peripheral nervous system. This article reviews the association of liver disease and the nervous system and provides new information regarding diagnostic and therapeutic approaches to evaluating patients with liver diseases.

Recent Findings: Early recognition of hepatic encephalopathy may be possible using a combination of clinical suspicion and various neuropsychological studies. Management of severe hepatic encephalopathy from acute liver failure is important to neurologists involved in neurocritical care. Next-generation genetic testing may aid in the diagnosis of patients suspected of having Wilson disease. The relationship of numerous neurologic findings from hepatocerebral degeneration and from viral hepatitis is more widely recognized.

Summary: It is important for neurologists to recognize the neurologic symptoms that may occur in patients with acute and chronic liver failure, Wilson disease, and viral hepatitis to inform prompt diagnostic and management decisions.
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http://dx.doi.org/10.1212/CON.0000000000000486DOI Listing
June 2017

Atypical presentation and outcome of cervicogenic headache in patients with cervical degenerative disease: A single-center experience.

Clin Neurol Neurosurg 2017 Aug 13;159:62-69. Epub 2017 May 13.

Department of Neurology and Sleep Medicine, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.

Objective: Cervicogenic headache affects a significant portion of the entire population. This type of headache especially with atypical presentation is often hard to diagnose and manage since its etiopathophysiology is not been yet well understood. We have investigated the prevalence of cervicogenic headache with atypical presentation and discussed the etiology of it, and the outcome of surgical intervention on this type of headache in patients with cervical degenerative disease.

Patients And Methods: Radiological and clinical data of 160 patients (from 2001 through 2016) were retrospectively reviewed. Significant differences between the groups were determined by chi-square test. Logistic regression analysis was performed to identify the predictors of unfavorable outcome.

Results: In this study, 10% of the patients had atypical presentation of cervicogenic headache. In overall cohort, after surgical intervention, there was significant improvement in symptoms and pain control, whether the presentation is typical or atypical. Sixty-one percent of the patients had no complaints, and 90% of the patients were headache-free (p<0.0001). Sixty-nine percent of the patients were free of neck, shoulder and extremity pain, and visual analogue scale pain score was reduced by 7 points (pre-op, 8.4 vs. last follow-up, 1.5, p<0.0001). However, number of patients with reduced headache was significantly higher in the group with typical presentation of headache (90.1%) compared to group with atypical (80%) presentation, p=0.04. In this study, female gender, smoking, obesity and depression were identified as predictors of overall unfavourable outcome. In addition, in a separate analysis, smoking and depression were revealed as risk factors for persistent headache.

Conclusions: A notable portion of patients with cervicogenic headache can have an atypical presentation mimicking a primary type headache. However, cervicogenic headaches with atypical presentation can be difficult to diagnose and manage at the initial visit of the patients. Etiopathophysiology of this type of headache could be explained by the theories including discogenic, convergence and sensitization-desensitization theories. When cervicogenic headache is accompanied with CDD, performing ACDF or laminectomy would be the treatment of choice. Surgical intervention can also relieve the accompanying neck, shoulder and extremity pain with minimal complications. Lastly, outcomes of surgical intervention depend on the patients' morbidities including obesity, smoking and depression.
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http://dx.doi.org/10.1016/j.clineuro.2017.05.016DOI Listing
August 2017

Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

Pathophysiology 2017 Sep 13;24(3):169-183. Epub 2017 May 13.

Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, LA, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pathophys.2017.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303909PMC
September 2017

Coexistence of obstructive sleep apnea worsens the overall outcome of intracranial aneurysm: a pioneer study.

J Neurosurg 2018 03 21;128(3):735-746. Epub 2017 Mar 21.

Departments of1Neurology and Sleep Medicine and.

OBJECTIVE Obstructive sleep apnea (OSA) is associated with the progression of abdominal and thoracic aortic aneurysms. However, the role of OSA in the overall outcome of intracranial aneurysms (IAs) has not yet been established. Authors of this report investigated the role of OSA in the overall outcome of IAs. METHODS Radiological and clinical data on patients (from 2010 through 2015) with confirmed IA were retrospectively reviewed. Significant differences between the OSA and non-OSA groups were determined using a chi-square test. Logistic regression analysis was performed to identify the predictors of an unfavorable IA outcome. RESULTS Among the 283 patients with confirmed IAs, 45 patients (16%) were positively screened for OSA, a proportion that was significantly higher than the prevalence of OSA in nonaneurysmal neurosurgical patients (4%, p = 0.008). The percentage of patients with hypertension (p = 0.018), a body mass index ≥ 30 kg/m (p < 0.0001), hyperlipidemia (p = 0.034), diabetes mellitus (p = 0.005), chronic heart disease (CHD; p = 0.024), or prior stroke (p = 0.03) was significantly higher in the OSA group than in the non-OSA group. Similarly, the percentage of wide-necked aneurysms (p = 0.00001) and patients with a poor Hunt and Hess Grade IV-V (p = 0.01) was significantly higher in the OSA group than in the non-OSA group. In addition, the percentage of ruptured aneurysms (p = 0.03) and vasospasms (p = 0.03) was significantly higher in the OSA group. The percentage of patients with poor modified Rankin Scale (mRS) scores (3-6) was significantly higher in the OSA group (p = 0.03). A separate cohort of patients with ruptured IAs showed similar results. In both univariate (p = 0.01) and multivariate (p = 0.04) regression analyses, OSA was identified as an individual predictor of an unfavorable outcome. In addition, hypertension and prior stroke were revealed as predictors of a poor IA outcome. CONCLUSIONS Complications of IA such as rupture and vasospasm are often the consequence of uncontrolled OSA. Overall outcome (mRS) of IAs is also affected by the co-occurrence of OSA. Therefore, the coexistence of OSA with IA affects the outcome of IAs. Obstructive sleep apnea is a risk factor for a poor outcome in IA patients.
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http://dx.doi.org/10.3171/2016.10.JNS162316DOI Listing
March 2018

Study of SOCS gene family expression profile in MS patients: Another step forward.

J Neurol Sci 2017 04 16;375:479-480. Epub 2017 Feb 16.

Dept. Neurology, LSU Health Sciences Center, Shreveport, LA 71130, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2017.02.016DOI Listing
April 2017

Direct Comparison of Gamma Knife Radiosurgery and Microsurgery for Small Size Meningiomas.

World Neurosurg 2017 May 6;101:170-179. Epub 2017 Feb 6.

Department of Neurosurgery, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.wneu.2017.01.105DOI Listing
May 2017

Consanguinity and multiple sclerosis susceptibility: A case control study.

Mult Scler Relat Disord 2016 Nov 30;10:179-180. Epub 2016 Sep 30.

Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Background: Several lines of evidence point towards the importance of genetic risk factors in the susceptibility to multiple sclerosis (MS). We aimed to compare the rates of consanguineous marriages between first cousins among parents of MS patients and a healthy unrelated control group.

Method: This study is a cross-sectional hospital registry based study, which was performed by analyzing the clinical records of patients registered with the Kashani hospital database, and also a control group of randomly selected healthy individuals.

Result: MS patients were significantly less an offspring of a consanguineous union than the control group (MS patients=26.1%, vs Control=32.7%, p=0.03; OR=0.730 95%CI: 0.55-0.97) CONCLUSION: Offspring of consanguineous unions seems to have a lower risk of MS compared to offspring of unrelated parents. This may have implications for inheritance mode of protective alleles in MS.
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http://dx.doi.org/10.1016/j.msard.2016.09.013DOI Listing
November 2016

Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia.

Am J Physiol Heart Circ Physiol 2017 Jan 18;312(1):H182-H188. Epub 2016 Nov 18.

Cerebral Vascular Disease Laboratories, University of Miami Miller School of Medicine, Miami, Florida;

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.

New & Noteworthy: Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory.
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http://dx.doi.org/10.1152/ajpheart.00482.2016DOI Listing
January 2017