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Multiple Sclerosis: HELP
Articles by Robert Zivadinov
Based on 200 articles published since 2008

Between 2008 and 2019, R. Zivadinov wrote the following 200 articles about Multiple Sclerosis.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8
1 Editorial Vascular pathology of multiple sclerosis. 2012

Zivadinov, Robert / Alexander, Steven J / Minagar, Alireza. · ·Neurol Res · Pubmed #22971464.

ABSTRACT: -- No abstract --

2 Editorial Advances in understanding gray matter pathology in multiple sclerosis: are we ready to redefine disease pathogenesis? 2012

Zivadinov, Robert / Pirko, Istvan. · ·BMC Neurol · Pubmed #22394621.

ABSTRACT: The purpose of this special issue in BMC Neurology is to summarize advances in our understanding of the pathological, immunological, imaging and clinical concepts of gray matter (GM) pathology in patients with multiple sclerosis (MS). Review articles by Lucchinetti and Popescu, Walker and colleagues, Hulst and colleagues and Horakova and colleagues summarize important recent advances in understanding GM damage and its implications to MS pathogenesis. They also raise a number of important new questions and outline comprehensive approaches to addressing those questions in years to come. In the last decade, the use of immunohistochemistry staining methods and more advanced imaging techniques to detect GM lesions, like double inversion recovery, contributed to a surge of studies related to cortical and subcortical GM pathology in MS. It is becoming more apparent from recent biopsy studies that subpial cortical lesions in early MS are highly inflammatory. The mechanisms responsible for triggering meningeal inflammation in MS patients are not yet elucidated, and they should be further investigated in relation to their role in initiating and perpetuating the disease process. Determining the role of antigens, environmental and genetic factors in the pathogenesis of GM involvement in MS is critical. The early involvement of cortical and subcortical GM damage in MS is very intriguing and needs to be further studied. As established in numerous cross-sectional and longitudinal studies, GM damage is a better predictor of physical disability and cognitive impairment than WM damage. Monitoring the evolution of GM damage is becoming an important marker in predicting future disease course and response to therapy in MS patients.

3 Editorial Iron deposition and inflammation in multiple sclerosis. Which one comes first? 2011

Zivadinov, Robert / Weinstock-Guttman, Bianca / Pirko, Istvan. ·Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA. rzivadinov@bnac.net ·BMC Neurosci · Pubmed #21699686.

ABSTRACT: Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor.

4 Editorial Transcranial sonography of deep gray nuclei: a new outcome measure in multiple sclerosis? 2009

Pirko, Istvan / Zivadinov, Robert. · ·Neurology · Pubmed #19710403.

ABSTRACT: -- No abstract --

5 Editorial Is functional MRI feasible for multi-center studies on multiple sclerosis? 2008

Zivadinov, R / Cox, J L. · ·Eur J Neurol · Pubmed #18217879.

ABSTRACT: -- No abstract --

6 Review Extracranial Veins in Multiple Sclerosis: Is There a Role for Vascular Surgery? 2018

Zamboni, Paolo / Zivadinov, Robert. ·Vascular Diseases Centre and Post Graduated School in Vascular Surgery, Azienda Ospedaliera Universitaria di Ferrara, S. Anna Hospital, University of Ferrara, Ferrara, Italy. Electronic address: paolozamboni@icloud.com. · Buffalo Neuroimaging Analysis Centre, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, NY, USA; Centre for Biomedical Imaging at the Clinical Translational Science Institute, State University of New York at Buffalo, NY, USA. ·Eur J Vasc Endovasc Surg · Pubmed #30049571.

ABSTRACT: -- No abstract --

7 Review Ocrelizumab: a B-cell depleting therapy for multiple sclerosis. 2017

Jakimovski, Dejan / Weinstock-Guttman, Bianca / Ramanathan, Murali / Kolb, Channa / Hojnacki, David / Minagar, Alireza / Zivadinov, Robert. ·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. · b Jacobs MS Center, Department of Neurology , Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo , NY , USA. · c Department of Pharmaceutical Sciences , Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo , NY , USA. · d Department of Neurology , Louisiana State University Health Sciences Center , Shreveport , LA , USA. · e Translational Imaging Center at Clinical Translational Science Institute , Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo , NY , USA. ·Expert Opin Biol Ther · Pubmed #28658986.

ABSTRACT: 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.

8 Review The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. 2016

Sati, Pascal / Oh, Jiwon / Constable, R Todd / Evangelou, Nikos / Guttmann, Charles R G / Henry, Roland G / Klawiter, Eric C / Mainero, Caterina / Massacesi, Luca / McFarland, Henry / Nelson, Flavia / Ontaneda, Daniel / Rauscher, Alexander / Rooney, William D / Samaraweera, Amal P R / Shinohara, Russell T / Sobel, Raymond A / Solomon, Andrew J / Treaba, Constantina A / Wuerfel, Jens / Zivadinov, Robert / Sicotte, Nancy L / Pelletier, Daniel / Reich, Daniel S / Anonymous1630887. ·Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive MSC 1400, Building 10 Room 5C103, Bethesda, Maryland, USA. · St. Michael's Hospital, University of Toronto, Ontario, Canada. · Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Diagnostic Radiology, Yale University, New Haven, Connecticut, USA. · Division of Clinical Neuroscience, University of Nottingham, UK. · Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA. · Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy. · Multiple Sclerosis Research Group, Department of Neurology, University of Texas Health Science Center at Houston, Texas, USA. · Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio, USA. · Department of Pediatrics, Division of Neurology, UBC MRI Research Centre, University of British Columbia, Vancouver, Canada. · Advanced Imaging Research Center, Oregon Health &Science University, Portland, Oregon, USA. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Pathology, Stanford University School of Medicine, Stanford, California, USA. · Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, USA. · Medical Image Analysis Center, University Hospital Basel, Switzerland. · Buffalo Neuroimaging Analysis Center, Department of Neurology, State University of New York at Buffalo, New York, USA. · Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Multiple Sclerosis Center, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA. ·Nat Rev Neurol · Pubmed #27834394.

ABSTRACT: Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.

9 Review MRI in the evaluation of pediatric multiple sclerosis. 2016

Banwell, Brenda / Arnold, Douglas L / Tillema, Jan-Mendelt / Rocca, Maria A / Filippi, Massimo / Weinstock-Guttman, Bianca / Zivadinov, Robert / Sormani, Maria Pia. ·From The Children's Hospital of Philadelphia (B.B.) Perelman School of Medicine, University of Pennsylvania · McConnell Imaging Center (D.L.A.), McGill University, Montreal, Quebec, Canada · Mayo Clinic (J.-M.T.), Rochester, MN · Neuroimaging Research Unit (M.A.R., M.F.), Institute of Experimental Neurology, San Raffaele Scientific Institute, "Vita-Salute" San Raffaele University, Milan, Italy · State University of New York at Buffalo (B.W.-G., R.Z.) · and Department of Health Sciences (M.P.S.), University of Genoa, Italy. ·Neurology · Pubmed #27572868.

ABSTRACT: MRI plays a pivotal role in the diagnosis of multiple sclerosis (MS) in children, as it does in adults. The presence of multiple lesions in CNS locations commonly affected by MS, along with the presence of both enhancing and nonenhancing lesions, can facilitate a diagnosis of MS at the time of a first attack, whereas the accrual of serial lesions or new clinical attacks over time confirms the diagnosis in patients not meeting such criteria at onset. T2 and enhancing lesion accrual could serve as a primary outcome metric for pediatric MS clinical trials of selected therapies with anti-inflammatory activity in order to facilitate feasible trial size numbers. More-advanced MRI techniques reveal the impact of MS on tissue integrity within both T2-bright and T1-hypointense lesions and regions of normal-appearing tissue. Volumetric MRI analyses quantify the impact of MS on age-expected brain growth, and fMRI reveals activation and resting-state functional connectivity patterns in patients with pediatric MS that differ from those seen in healthy age-matched youth. Such studies are of critical importance because MS onset during childhood may profoundly influence maturing and actively myelinating neural networks. High-field MRI visualizes MS pathology at a near-microscopic level and has the potential to more fully explain mechanisms for cognitive impairment, fatigue, and disability in patients with pediatric MS.

10 Review Use of natalizumab in multiple sclerosis: current perspectives. 2016

Gandhi, Sirin / Jakimovski, Dejan / Ahmed, Rahil / Hojnacki, David / Kolb, Channa / Weinstock-Guttman, Bianca / Zivadinov, Robert. ·a Buffalo Neuroimaging Analysis Center, Department of Neurology , University at Buffalo, State University of New York , Buffalo , NY , USA. · b Jacobs MS Center, Department of Neurology , University at Buffalo, State University of New York , Buffalo , NY , USA. · c MR Imaging Clinical Translational Research Center, School of Medicine and Biomedical Sciences , University at Buffalo, State University of New York , Buffalo , NY , USA. ·Expert Opin Biol Ther · Pubmed #27413840.

ABSTRACT: INTRODUCTION: Natalizumab is an efficacious monoclonal antibody approved for use in relapsing-remitting multiple sclerosis (RRMS). Multiple studies have demonstrated reduced relapse rate, decreased disability progression and prolonged disease-free intervals with natalizumab use. However, natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), thus restricting its widespread use with populations at high risk for developing PML. Recently, the effect of natalizumab in secondary-progressive (SPMS) population has been explored. AREAS COVERED: This review highlights the pathophysiology behind disease progression in MS and summarizes various attributes of natalizumab including: its pharmacological properties and global economic impact, results of clinical efficacy studies, its role in SPMS, pregnancy and its adverse events profile including PML and discontinuation protocols. EXPERT OPINION: Despite an established role in reducing RRMS disease activity, natalizumab has found limited use in SPMS due to insufficient evidence of efficacy. Current disease-modifying therapies exert modest overall benefit in SPMS owing to its complex pathophysiology, higher prevalence of comorbidities and increased PML risk with age and lack of reliable outcome measures. Finding more appropriate MRI and clinical outcome measures is quintessential for designing future randomized trials and possibly exploring primary neuroprotective agents for treating SPMS.

11 Review Optical coherence tomography and neurodegeneration: are eyes the windows to the brain? 2016

Gupta, Sahil / Zivadinov, Robert / Ramanathan, Murali / Weinstock-Guttman, Bianca. ·a Department of Neurology , University of Alabama , Birmingham , Alabama 35294-2172 , United States. · b Buffalo Neuroimaging analyisis Center, Jacobs School of Medicine and Biomedical Sciences , University at Buffalo , Buffalo , New York , USA. · c Department of Pharmaceutical Sciences and Neurology , State University of New York , Buffalo , NY , USA. · d Jacobs MS Center for Treatment and Research, Jacobs School of Medicine and Biomedical Sciences , University at Buffalo , Buffalo , NY , USA. ·Expert Rev Neurother · Pubmed #27138997.

ABSTRACT: INTRODUCTION: Central nervous system (CNS) pathologies have ocular manifestations due to direct and/or retrograde degeneration of the visual pathways, most often related to a direct injury to the optic nerve, retinal ganglion cells and/or its surrounding cells. These ocular manifestations can be recognized and monitored by a non-invasive technique called Optical Coherence Tomography (OCT). AREAS COVERED: This review article describes the OCT technique and its application in various neurological pathologies. OCT helps in the measurement of retinal nerve fiber layer thickness (RNFLT) and macular thickness which consists of retinal ganglion cells. OCT provides a near-histological level of image resolution up to 5┬Ám by using principles of interferometry that can detect CNS inflammatory, as well as degenerative, pathologies (i.e Multiple Sclerosis, Parkinson's disease and Alzheimer's Disease etc.) at initial clinical and possibly subclinical stages. Expert Commentary: RNFLT and macular volumes measured by OCT can serve as biomarkers for early recognition and progression of a variety of neurological disease, although the specificity of these findings in clinical diagnosis requires further refinement. An early biomarker can help in an earlier therapeutic intervention and thus preventing further progression and provide the opportunity for possible regenerative interventions of the underlying disease process. With the advent of "next-generation" OCT technology an increase in use is foreseen in research as well as in clinical practice.

12 Review Clinical relevance of brain atrophy assessment in multiple sclerosis. Implications for its use in a clinical routine. 2016

Zivadinov, Robert / Jakimovski, Dejan / Gandhi, Sirin / Ahmed, Rahil / Dwyer, Michael G / Horakova, Dana / Weinstock-Guttman, Bianca / Benedict, Ralph R H / Vaneckova, Manuela / Barnett, Michael / Bergsland, Niels. ·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. · b MR Imaging Clinical Translational Research Center, Jacobs School of Medicine and Biomedical Sciences , University at Buffalo, State University of New York , Buffalo , NY , USA. · c Department of Neurology and Center of Clinical Neuroscience , Charles University in Prague, First Faculty of Medicine and General University Hospital , Prague , Czech Republic. · d Jacobs Multiple Sclerosis Center, Department of Neurology, School of Medicine and Biomedical Sciences , University at Buffalo, State University of New York , Buffalo , NY , USA. · e Department of Radiology, First Faculty of Medicine and General University Hospital , Charles University , Prague , Czech Republic. · f Sydney Neuroimaging Analysis Centre; Brain & Mind Centre , University of Sydney , Sydney , Australia. · g IRCCS 'S.Maria Nascente' , Don Gnocchi Foundation , Milan , Italy. ·Expert Rev Neurother · Pubmed #27105209.

ABSTRACT: INTRODUCTION: Brain atrophy measurement in multiple sclerosis (MS) has become an important outcome for determining patients at risk for developing physical and cognitive disability. AREAS COVERED: In this article, we discuss the methodological issues related to using this MRI metric routinely, in a clinical setting. Understanding trajectories of annualized whole brain, gray and white matter, thalamic volume loss, and enlargement of ventricular space in specific MS phenotypes is becoming increasingly important. Evidence is mounting that disease-modifying treatments exert a positive effect on slowing brain atrophy progression in MS. Expert Commentary: While there is a need to translate measurement of brain atrophy to clinical routine at the individual patient level, there are still a number of challenges to be met before this can actually happen, including how to account for biological confounding factors and pseudoatrophy, standardize acquisition and analyses parameters, which can influence the accuracy of the assessments.

13 Review Aging and multiple sclerosis. 2016

Sanai, Shaik Ahmed / Saini, Vasu / Benedict, Ralph Hb / Zivadinov, Robert / Teter, Barbara E / Ramanathan, Murali / Weinstock-Guttman, Bianca. ·Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, The State University of New York, Buffalo, NY, USA. · Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, The State University of New York, Buffalo, NY, USA/New York State MS Consortium, University at Buffalo, The State University of New York, Buffalo, NY, USA/Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA. · Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, The State University of New York, Buffalo, NY, USA/New York State MS Consortium, University at Buffalo, The State University of New York, Buffalo, NY, USA/Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA. · Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, The State University of New York, Buffalo, NY, USA/New York State MS Consortium, University at Buffalo, The State University of New York, Buffalo, NY, USA/Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA bweinstock-guttman@kaleidahealth.org. ·Mult Scler · Pubmed #26895718.

ABSTRACT: The life expectancy and average age of persons with multiple sclerosis (MS) have increased significantly during the last two decades. The introduction of disease-modifying therapies and a better delineation and understanding of the superimposed comorbidities often diagnosed in MS patients are probably the most important factors accountable for the increase in aging MS population worldwide. Healthcare teams must therefore address the problems arising due to advancing age superimposed on this chronic neurologic disease. In this review, we focus on the physiology of aging, its effects on MS disease course, and the pathological and immunological changes associated with aging and disease progression. Additionally, we discuss the common comorbidities that occur in aging persons with MS that may arise either as a result of the aging process or from relentless chronic MS disease progression as well as the challenges on differentiating the two processes for a more appropriate therapeutic approach.

14 Review The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants. 2013

Dolic, Kresimir / Siddiqui, Adnan H / Karmon, Yuval / Marr, Karen / Zivadinov, Robert. ·Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, 100 High St, Buffalo, NY 14203, USA. ·BMC Med · Pubmed #23806142.

ABSTRACT: The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the "gold standard" for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.

15 Review The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. 2013

Minagar, Alireza / Barnett, Michael H / Benedict, Ralph H B / Pelletier, Daniel / Pirko, Istvan / Sahraian, Mohamad Ali / Frohman, Elliott / Zivadinov, Robert. ·Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA. ·Neurology · Pubmed #23296131.

ABSTRACT: The paired thalamic nuclei are gray matter (GM) structures on both sides of the third ventricle that play major roles in cortical activation, relaying sensory information to the higher cortical centers that influence cognition. Multiple sclerosis (MS) is an immune-mediated disease of the human CNS that affects both the white matter (WM) and GM. A number of clinical observations as well as recent neuropathologic and neuroimaging studies have clearly demonstrated extensive involvement of the thalamus, basal ganglia, and neocortex in patients with MS. Modern MRI techniques permit visualization of GM lesions and measurement of atrophy. These contemporary methods have fundamentally altered our understanding of the pathophysiologic nature of MS. Evidence confirms the contention that GM injury can be detected in the earliest phases of MS, and that iron deposition and atrophy of deep gray nuclei are closely related to the magnitude of inflammation. Extensive involvement of GM, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in patients with MS. In this review, we characterize the neuropathologic, neuroimaging, and clinical features of thalamic involvement in MS. Further, we underscore the contention that neuropathologic and neuroimaging correlative investigations of thalamic derangements in MS may elucidate not heretofore considered pathobiological underpinnings germane to understanding the ontogeny, magnitude, and progression of the disease process.

16 Review Arterial, venous and other vascular risk factors in multiple sclerosis. 2012

Karmon, Yuval / Ramanathan, Murali / Minagar, Alireza / Zivadinov, Robert / Weinstock-Guttman, Bianca. ·The Jacobs Neurological Institute, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA. ·Neurol Res · Pubmed #22971465.

ABSTRACT: PURPOSE OF REVIEW: This article reviews vascular risk factors with specific emphasis on lipid abnormalities reported to be associated with multiple sclerosis (MS). RECENT FINDINGS: The current paradigm of MS, supported only partially by MS lesion histopathology and its animal model (experimental allergic encephalomyelitis) considers MS to be a predominantly autoimmune disease. Until recently, most of the known risk factors for MS were interpreted in the context of the autoimmune theory, which still fails to explain why genetically close populations exposed to similar pathogens and/or environmental risk factors have different incidences of MS. Therapies which partially modulate the inflammatory arm of MS pathogenesis, fail to achieve similar benefits in later disease stages, when less inflammatory lesions and more neurodegeneration are present. Several studies have reported an increased cardiovascular morbidity in MS patients and that vascular comorbidity at any time during the disease course also increased the risk of progressive disability. A condition named chronic cerebrospinal venous insufficiency provided a different perspective, on the possible association of MS with the abnormalities of the venous system. Our recent findings revealed increased prevalence of chronic cerebrospinal venous insufficiency associated with MS disease progression as well as with other neurologic disorders. On the other hand, recently emerging evidence indicates that there is an association between lipoproteins and cholesterol metabolism and MS disease progression. Expanded disability status scale worsening was associated with higher baseline low-density lipoprotein and total cholesterol, and higher serum high-density lipoprotein levels were associated with lower contrast-enhancing T1-weigthed lesion volume. It is thought that apolipoprotein A-1 and paraoxonase anti-oxidant enzyme are associated with high-density lipoprotein and contribute to its anti-oxidant and anti-inflammatory properties. A significant inter-dependence was also recently demonstrated between vitamin D, one of the best known environmental risk factors for MS and MS disease progression and the serum lipid profile. Future work in this direction is required in order to better elucidate the role of lipid metabolism and vascular pathology in pathogenesis of MS.

17 Review Chronic cerebrospinal venous insufficiency in multiple sclerosis: diagnostic, pathogenetic, clinical and treatment perspectives. 2011

Zivadinov, Robert / Ramanathan, Murali / Dolic, Kresimir / Marr, Karen / Karmon, Yuval / Siddiqui, Adnan H / Benedict, Ralph Hb / Weinstock-Guttman, Bianca. ·Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, NY, USA. rzivadinov@bnac.net ·Expert Rev Neurother · Pubmed #21864074.

ABSTRACT: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in multiple sclerosis patients. CCSVI is characterized by impaired brain venous drainage due to outflow obstruction in the extracranial venous system, mostly related to anomalies in the internal jugular and azygos veins. The current CCSVI diagnosis is based on Doppler sonography of extracranial and transcranial venous hemodynamics criteria. To date, prevalence estimates of CCSVI, provided by different groups using various imaging methods of assessment, vary widely from none to 100%. There is an urgent need to define and validate the spectrum of cranial/extracranial venous anomalies and to establish reliable, diagnostic gold-standard test(s). The potential usefulness of endovascular treatment for CCSVI in multiple sclerosis patients is still unknown.

18 Review Recent developments in imaging of multiple sclerosis. 2011

Poloni, Guy / Minagar, Alireza / Haacke, E Mark / Zivadinov, Robert. ·Department of Neurology, Buffalo Neuroimaging Analysis Center, Buffalo, NY, USA. ·Neurologist · Pubmed #21712664.

ABSTRACT: BACKGROUND: Magnetic resonance imaging (MRI) has revolutionized the diagnosis and management of patients with multiple sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations. Conventional MRI measures have insufficient sensitivity and specificity to reveal the true degree of pathologic changes occurring in MS. T2-weighted and T1-weighted imaging cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. Nonconventional MRI techniques are now emerging and proving to be more related with the most disabling features of MS. REVIEW SUMMARY: The large variety of MRI metrics presently available are summarized, including measurement of T1-weighted hypointense lesions, central nervous system atrophy, magnetization transfer imaging, myelin water fraction, diffusion tensor imaging, magnetic resonance spectroscopy, and susceptibility-weighted imaging. The most up-to-date MRI techniques and their relationship with central nervous system pathology are described, and a comprehensive overview of the use of MRI in patients with MS is offered. CONCLUSIONS: Advanced MRI techniques provide a better understanding of the pathologic processes that most likely are related to disease activity and clinical progression. Such metrics are able to reveal a range of tissue changes that include demyelination, axonal loss, iron deposition, and neurodegeneration and they provide the evidence that important occult pathology is occurring in the normal appearing white and gray matter. Despite these promising results none of these techniques have been adopted in the MRI consensus guidelines for imaging of the brain and spinal cord in patients with MS due to lack of standardization.

19 Review Risk factors for and management of cognitive dysfunction in multiple sclerosis. 2011

Benedict, Ralph H B / Zivadinov, Robert. ·Department of Neurology, Suite D6, Buffalo General Hospital, State University of New York at Buffalo, 100 High Street, Buffalo, NY 14203, USA. benedict@buffalo.edu ·Nat Rev Neurol · Pubmed #21556031.

ABSTRACT: Cognitive impairment is common in multiple sclerosis (MS), especially when assessed by neuropsychological tests that emphasize mental processing speed, episodic memory, and some aspects of executive function. In this Review, we question why some MS patients develop severe impairment in cognitive abilities, while cognitive ability remains intact in others. We find that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors. Neuropsychological deficits are also robustly correlated with brain MRI metrics. Male patients with early evidence of cerebral gray matter atrophy are most prone to impairment, whereas high premorbid intelligence improves the neuropsychological prognosis. Routine evaluation of cognition is useful for helping patients to navigate problems related to activities of daily living and work disability and, if reliable methods are employed, cognitive decline can be detected and included among the many clinical signs of disease progression or treatment failure. Pharmacological treatments for neuropsychological impairment are on the horizon, although presently no firm medical indications exist for the condition.

20 Review Role of platelets in neuroinflammation: a wide-angle perspective. 2010

Horstman, Lawrence L / Jy, Wenche / Ahn, Yeon S / Zivadinov, Robert / Maghzi, Amir H / Etemadifar, Masoud / Steven Alexander, J / Minagar, Alireza. ·Wallace Coulter Platelet Laboratory, Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA. ·J Neuroinflammation · Pubmed #20128908.

ABSTRACT: OBJECTIVES: This review summarizes recent developments in platelet biology relevant to neuroinflammatory disorders. Multiple sclerosis (MS) is taken as the "Poster Child" of these disorders but the implications are wide. The role of platelets in inflammation is well appreciated in the cardiovascular and cancer research communities but appears to be relatively neglected in neurological research. ORGANIZATION: After a brief introduction to platelets, topics covered include the matrix metalloproteinases, platelet chemokines, cytokines and growth factors, the recent finding of platelet PPAR receptors and Toll-like receptors, complement, bioactive lipids, and other agents/functions likely to be relevant in neuroinflammatory diseases. Each section cites literature linking the topic to areas of active research in MS or other disorders, including especially Alzheimer's disease. CONCLUSION: The final section summarizes evidence of platelet involvement in MS. The general conclusion is that platelets may be key players in MS and related disorders, and warrant more attention in neurological research.

21 Review Alemtuzumab and multiple sclerosis: therapeutic application. 2010

Minagar, Alireza / Alexander, J Steven / Sahraian, Mohammad Ali / Zivadinov, Robert. ·Louisiana State University Health Sciences Center, Department of Neurology, 1501 Kings Highway, Shreveport, LA 71130, USA. aminag@lsuhsc.edu ·Expert Opin Biol Ther · Pubmed #20095876.

ABSTRACT: IMPORTANCE OF THE FIELD: The cause and cure for multiple sclerosis (MS) remain unknown. Immunomodulatory agents are only partially effective and many patients do not tolerate the side effects or fail them. Immunosuppressive agents act non-specifically and are associated with serious complications. An emerging group of biologic agents with great potential for treatment of immune-mediated disorders such as MS are monoclonal antibodies. A review of alemtuzumab in MS is presented. AREAS COVERED IN THIS REVIEW: Mechanisms of action of alemtuzumab and the results of Phase II clinical trials in MS. WHAT THE READER WILL GAIN: Alemtuzumab is a humanized mAb, which targets the surface molecule CD52 on all T cell populations and other cellular components of the immune system such as thymocytes, B cells, and monocytes. Alemtuzumab, which is administered intravenously, depletes T as well as B lymphocyte populations for extended periods. Adverse effects in MS patients such as thyroid disorders and idiopathic thrombocytopenic purpura are discussed. TAKE HOME MESSAGE: Alemtuzumab may hold great promise for treatment of MS patients and serve as an option for patients refractory to immunomodulatory therapies. Due to its unique mechanism of action and profound effect on MS disease activity it enhances our knowledge about pathogenic mechanisms of MS.

22 Review Advanced magnetic resonance imaging metrics: implications for multiple sclerosis clinical trials. 2009

Zivadinov, Robert. ·University of Buffalo Department of Neurology, School of Medicine and Biomedical Sciences, The Jacobs Neurological Institute, Buffalo, New York 14203, USA. rzivadinov@thejni.org ·Methods Find Exp Clin Pharmacol · Pubmed #19357796.

ABSTRACT: Magnetic resonance imaging (MRI) techniques contribute substantially to the management of multiple sclerosis (MS); however, no specific predictive marker of clinical outcome has been identified. Traditional MRI measures are effective diagnostic tools for MS but do not accurately correlate with the progression of neurological impairment and physical disability. Moreover, in studies that apply traditional MRI techniques to evaluate MS disease-modifying therapies (DMTs), the weak correlation between suppression of inflammation and continued progression of disability has initiated an awareness of a "clinico-radiological paradox". Thus, a need exists for alternative MRI measures that more accurately monitor clinical disease activity and measure the efficacy of DMTs. In this regard, advanced MRI measures allow more sensitive quantification of microscopic neuronal damage present in normal-appearing brain tissue and serve as more reliable surrogate markers for neuronal injury and repair. These advanced MRI metrics allow assessment of neuronal metabolite concentrations; assessment of macromolecular density, geometry and structural integrity of neuronal tissue; noninvasive spatial localization of brain function; and high-intensity scanning of microscopic MS lesions. The objective of this review is to provide a brief description of these advanced MRI measures and to discuss preliminary clinical studies that employ these techniques in order to evaluate the efficacy of DMTs.

23 Review Gray matter pathology in (chronic) MS: modern views on an early observation. 2009

Geurts, Jeroen J G / Stys, Peter K / Minagar, A / Amor, S / Zivadinov, R. ·Dept. of Pathology, VU University Medical Center, Amsterdam, The Netherlands. j.geurts@vumc.nl ·J Neurol Sci · Pubmed #19249061.

ABSTRACT: Involvement of the gray matter (GM) in the pathology of multiple sclerosis (MS) was already recognized in the early days of MS research, but the detection of (cortical) GM lesions under the microscope and with magnetic resonance imaging (MRI) techniques was initially suboptimal and could only recently be enhanced. The visualization of GM lesions in vivo opens new doors for studies focusing on clinical, especially cognitive, effects of GM pathology, as well as for monitoring of neuroprotective treatment. However, so far little is known about what causes GM pathology. In this review, several pathogenetic mechanisms will be discussed, affecting the MS brain both from the 'outside-in' and from the 'inside-out'. Also, the use and reliability of MRI atrophy measures as a monitoring tool for GM damage in the therapeutic setting will be reviewed.

24 Review Antiphospholipid antibodies: paradigm in transition. 2009

Horstman, Lawrence L / Jy, Wenche / Bidot, Carlos J / Ahn, Yeon S / Kelley, Roger E / Zivadinov, Robert / Maghzi, Amir H / Etemadifar, Masoud / Mousavi, Seyed Ali / Minagar, Alireza. ·Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. lhorstman@med.miami.edu ·J Neuroinflammation · Pubmed #19154576.

ABSTRACT: OBJECTIVES: This is a critical review of anti-phospholipid antibodies (aPL). Most prior reviews focus on the aPL syndrome (APS), a thrombotic condition often marked by neurological disturbance. We bring to attention recent evidence that aPL may be equally relevant to non-thrombotic autoimmune conditions, notably, multiple sclerosis and ITP. ORGANIZATION: After a brief history, the recent proliferation of aPL target antigens is reviewed. The implication is that many more exist. Theories of aPL in thrombosis are then reviewed, concluding that all have merit but that aPL may have more diverse pathological consequences than now recognized. Next, conflicting results are explained by methodological differences. The lupus anticoagulant (LA) is then discussed. LA is the best predictor of thrombosis, but why this is true is not settled. Finally, aPL in non-thrombotic disorders is reviewed. CONCLUSION: The current paradigm of aPL holds that they are important in thrombosis, but they may have much wider clinical significance, possibly of special interest in neurology.

25 Review Clinical efficacy, effects on MRI and tolerability of weekly intramuscular interferon-beta-1a in patients with MS and CIS. 2008

Zivadinov, Robert / Munschauer, Frederick E / Ramanathan, Murali / Benedict, Ralph H B / Weinstock-Guttman, Bianca. ·Buffalo Neuroimaging Analysis Center, Department of Neurology, University at Buffalo, State University of New York, Buffalo, New York 14203, USA. rzivadinov@bnac.net ·Drugs Today (Barc) · Pubmed #18846271.

ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Interferon (IFN) beta products are potent antiinflammatory and immunomodulatory agents that interfere with the autoimmune processes in MS and reduce CNS damage. Once-weekly intramuscular IFN beta-1a slows the progression of neurologic and cognitive disability, reduces the frequency of relapses and inflammatory lesion burden, and preserves cognitive function. It has a positive effect on both conventional and nonconventional measures of magnetic resonance imaging (MRI) and reduces the progression of brain atrophy, predominantly due to reduced grey matter atrophy. Early initiation of disease-modifying therapy after the diagnosis of relapsing-remitting MS or after a single demyelinating event (and evidence of lesions on MRI) allows patients the opportunity to obtain maximal long-term benefits.