Ezsa Berg - Academia.edu (original) (raw)

Papers by Ezsa Berg

Journal of Clinical Neuroscience, Jun 1, 2022

Journal of Endovascular Therapy, Jun 19, 2015

Chronic cerebrospinal venous insufficiency (CCSVI), the new vascular theory of multiple sclerosis... more Chronic cerebrospinal venous insufficiency (CCSVI), the new vascular theory of multiple sclerosis (MS) set forward by Zamboni, has raised a wave of controversy, leading to numerous publications aiming to define the pathology and its causes, as well as offering strategies to correct it. Zamboni’s vascular hypothesis states that MS is caused by the obstruction at different vein levels, namely the internal jugular veins (IJVs), azygos vein (AV), and vertebral veins. In a recent review article, our group presented strong evidence that the route of CCSVI might stem from cardiovascular autonomic system (ANS) dysfunction in general and sympathetic dysfunction in particular. ANS dysfunction could lead to dysregulation in the arterial blood pressure and cerebral perfusion pressure, reducing cerebral blood flow. The dysfunction of this system can also impair cerebral autoregulation, reducing transmural pressure and increasing the critical closure pressure (CrCP). Alterations in the CrCP have the potential to contribute to the compression or the collapse of the cerebral venous system, especially that of the IJVs because of their cytoarchitectural construction. Furthermore, the low sympathetic outflow leads also to suboptimal central venous pressure, hindering the reopening of the IJVs after their collapse due to orthostatic challenge. The relationship between CCSVI and ANS dysfunction is further strengthened by the coexistence of CCSVI with clinical symptoms, such as cognitive impairment, fatigue, sleeping disorders, headache on awakening, and thermal intolerance. Cardiovascular ANS dysfunction is known to contribute to these clinical entities. Furthermore, the coexistence of CCSVI and cardiovascular ANS dysfunction has been reported in other autoimmune and neurological diseases. We propose that ANS dysfunction–derived hemodynamic impairment can lead to morphological and metabolic changes, recently observed in the IJVs. A series of studies by Zamboni and colleagues report morphological changes involving IJV calcification, often observed in the adventitia microvessels. The calcification patterns resemble those observed in the arterial system using similar analytical techniques. In addition, changes in the structure of the IJVs’ endothelial cells and alterations in the patterns of their deposition were observed. Endothelial cells were often absent in the intraluminal obstacles and replaced by fibrous lamina; the latter was encapsulated with microreticulate-containing spheric lipid particles. The same group also reported an increase in the proportions of type III to type I collagen within the adventitia, with possible adverse effects on the vessel wall elastic properties and vessel wall thickness. These venous-related pathological changes have close similarity to hemodynamic impairment–induced arterial remodeling, arterial hardening, and stenosis, a process known as atherosclerosis. The involvement of ANS dysfunction in venous remodeling is supported by a study involving a porcine model of progressive central pulmonary venous (PV) obstruction. PV banding is known to be associated with pulmonary venous remodeling, involving alterations in elastin and collagen structure and an increase in their synthesis. In addition, a surgically created arteriovenous (AV) fistula, used to treat kidney failure patients, is a common example where hemodynamic alterations can lead to vessel remodeling and AV graft stenosis. We propose that ANS dysfunction–induced hemodynamic impairment is a trigger for the venous remodeling, leading ultimately to “venosclerosis.” However, the comparison between IJVs from patients with MS and control subjects did not uncover significantly higher T cell infiltrates in the diseased veins compared with the control veins. 592204 JETXXX10.1177/1526602815592204Journal of Endovascular TherapySternberg research-article2015

Molecular Neurobiology, Jan 7, 2016

Multiple sclerosis (MS) is an inflammatory demyelinating central nervous system (CNS) disease wit... more Multiple sclerosis (MS) is an inflammatory demyelinating central nervous system (CNS) disease with an uncertain etiology. MS is heterogeneous, involving multiple clinical pathologies, including neurodegeneration, depression, fatigue and sleep disorders, migraine, osteoporosis and cerebral hemodynamic impairments. The underlying causes of these pathologies remain mostly unknown. Based on the accumulating evidence derived from our studies and those of other investigators, we propose that the dysregulation in the neurovisceral integration of cardiovascular modulation can lead to many MS-related clinical symptoms. We show that MS inflammatory and neurodegenerative processes are intertwined with the aforementioned clinical morbidities and are collectively the manifestations of cardiovascular autonomic nervous system (ANS) dysfunction. The strategies for improving sympathovagal balance would likely prevent and minimize many MSrelated clinical symptoms, improving patients' quality of life. Similar strategies could be applied to other autoimmune and neurodegenerative diseases where autonomic imbalance plays a role.

Neuromolecular Medicine, Feb 10, 2018

The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attri... more The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attributed to reduced mobility and or the use of disease-modifying drugs. However, MS-impaired cardiovascular autonomic nervous system (ANS) function has the potential of reducing bone mass density (BMD) by altering the expression and/or function of the neuronal, systemic, and local mediators of bone remodeling. This review describes the complex regulation of bone homeostasis with a focus on MS, providing evidence that ANS dysfunction and low BMD are intertwined with MS inflammatory and neurodegenerative processes, and with other MS-related morbidities, including depression, fatigue, and migraine. Strategies for improving ANS function could reduce the prevalence of MS osteoporosis and slow the rate of MS progression, with a significant positive impact on patients' quality of life.

Inflammopharmacology, Jan 25, 2012

Future Neurology, Nov 1, 2019

The photic sneeze reflex (PSR) is a condition of uncontrollable sneezing episodes in response to ... more The photic sneeze reflex (PSR) is a condition of uncontrollable sneezing episodes in response to bright light. This reflex often manifests as a mild phenomenon but may cause devastating consequences in some situations (aeroplane pilots, car drivers, etc.). Its exact mechanism is poorly understood. Interestingly, the roles of the fifth and tenth cranial nerves, brainstem nuclei and inciting patterns closely mimic a wellknown brainstem reflex, known as the trigeminocardiac reflex (TCR). In this critical review, we hypothesize that the PSR can be a variant of the TCR. This concept will lead to a better understanding of the PSR and sharpens the TCR characteristics and open the doors for new research possibilities.

Inflammopharmacology, Nov 17, 2011

Journal of stroke and cerebrovascular diseases, Feb 1, 2016

Objective: We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, m... more Objective: We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). Methods: Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 ± 5 hours and 64 ± 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. Results: P-selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. Conclusion: Clopidogrel exerts both platelet-dependent and plateletindependent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration.

Atherosclerosis, Aug 1, 2013

Objectives: The relative contribution of the local vs. peripheral inflammation to the atherothrom... more Objectives: The relative contribution of the local vs. peripheral inflammation to the atherothrombotic processes is unknown. We compared the inflammatory status of the immune cells of the carotid plaque with similar cells in peripheral circulation of patients with advanced carotid disease (PCDs). Methods: Mononuclear cells (MNCs) were extracted from carotid endarterectomy (CEA) samples by enzymatic digestion and subsequent magnetic cell sorting. The cell surface antigenic expressions, and mRNA expression levels were compared between CEA MNCs and peripheral MNCs, using flow cytometry and RT-PCR techniques. Results: The percentages of resting MNCs were lower, and activated MNCs, particularly monocytes, were higher in the CEAMNCs, as compared to the peripheral MNCs. The percentages of activated T cells and B cells were higher in the peripheral MNCs of PCDs, than in healthy controls (HCs), but the percentages of activated monocytes did not differ between the two groups. The expression levels of both proinflammatory/pro-thrombotic (P 38 , JNKB-1, Egr-1 PAI-1, MCP-1, TF, MMP-9, HMGB-1, TNF-a, mTOR) and anti-inflammatory (PPAR-g, TGF-b) mediators were significantly higher in the CEA MNCs as compared to the peripheral MNCs. Furthermore, MMP-9 and PPAR-g expression levels were higher in the peripheral MNCs of PCDs than HCs. Conclusion: The inflammatory status is higher in the immune cells of the carotid plaque, as compared to those cells in the peripheral blood. The altered expression levels of both pro-inflammatory/prothrombotic and anti-inflammatory mediators in the milieu of the plaque suggest that the balance between these various mediators may play a key role in carotid disease progression.

Multiple Sclerosis Journal, Jul 1, 2008

The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RA... more The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O 2)-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentrationeresponse curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.

Alzheimers disease & dementia, May 5, 2021

• We measured serum levels of one of the polyamines, spermidine, in AD, MCI, and controls • Sperm... more • We measured serum levels of one of the polyamines, spermidine, in AD, MCI, and controls • Spermidine serum levels were significantly higher in MCI as compared to controls • Spermidine serum levels correlated with MMSE, CDR, and CDR-SOB Introduction Alzheimer's disease (AD) is a chronic progressive neurological disease, where amyloid-beta (Aβ) and tau protein aggregates are among common brain pathologies [1]. The current AD diagnosis depends on the combination of clinical,

Journal of vascular surgery. Venous and lymphatic disorders, 2014

directed thrombosis (CDT). Our goal is to evaluate the efficacy of the RAPID thrombectomy techniq... more directed thrombosis (CDT). Our goal is to evaluate the efficacy of the RAPID thrombectomy technique for the treatment of acute deep venous thrombosis (DVT). Methods: A single-center registry of 313 lower extremities in 301 patients treated for acute DVT between 1999 and 2012 was reviewed. Patients underwent pharmacomechanical thrombectomy (PMT) using the RAPID thrombectomy technique, which involves a 6F rheolytic thrombectomy catheter placed coaxially through a directional 8F guiding catheter used in a spiraling fashion, allowing for wall-to-wall thrombectomy. Extent of clot removal and the need for adjunctive CDT, percutaneous transluminal angioplasty, and stenting were evaluated venographically. Follow-up with ultrasound was performed. Results: A total of 92 limbs demonstrated femoropopliteal DVT, while 221 had iliofemoral DVT, with IVC involvement in 57. Thrombectomy by venography was complete (>90% removal + flow) in 203 (65%), substantial (50% to 90% removal + flow) in 75 (24%), partial (<50%) in 31 (10%), and minimal in 4 (1%) limbs following initial PMT. Flow was successfully restored in 90%. A total of 166 (53%) patients underwent additional CDT with an average infusion time of 17.7 hours; 47% of cases were completed in one session. Eighty-six percent were completed in <24 hours. Stenting was performed in 106 (34%) limbs. Binary patency by ultrasound was 94%, 90%, and 77% at 3, 6, and 12 months. Conclusions: The RAPID thrombectomy technique is effective for rapid removal of thrombus in patients with acute DVT with significant reduction, in the need for, and length of, CDT.

Journal of the Neurological Sciences, 2019

Background/aims: Prostate specific antigen (PSA) is regulated by steroid hormones, such as testos... more Background/aims: Prostate specific antigen (PSA) is regulated by steroid hormones, such as testosterone, the serum levels of which are altered in patients with Alzheimer's disease (AD).This pilot study compared serum levels of the free (f) PSA between AD, mild cognitive impairment (MCI), and control subjects, and evaluated the relationship between fPSA serum levels and cognitive assessment tests and neuroimaging data. In addition, in a subgroup of AD patients, we correlated fPSA serum levels with the existing data on serum levels of amyloid-beta (Aβ), and iron-related proteins, including hepcidin and ferritin. Methods: Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of fPSA using enzyme-linked immunosorbent assay. Results: fPSA serum levels calculated as median ± SD were higher in AD males (663.6 ± 821.0 pg/ml) compared to control males (152.0 ± 207.0 pg/ml), p = 0.003. A similar Pattern emerged when comparing MCI males (310.7 ± 367.0 pg/ml) to control males (P = 0.02). Correlation studies showed a significant association between fPSA and CDR (r = 0.56, P = 0.006) and CDR-SOB (r = 0.54, P = 0.009) in AD males. Conclusion: Additional studies in a larger cohort are required for determining whether fPSA can be used as biomarker of AD disease progression and whether it has the potential to identify male subjects at risk of AD dementia.

Neuropharmacology, 2018

We investigated Fingolimod treatment effects on the RAGE (receptor for advanced glycation endprod... more We investigated Fingolimod treatment effects on the RAGE (receptor for advanced glycation endproducts) axis in multiple sclerosis (MS) patients. The primary outcome of the study was whether Fingolimod treatment increases serum levels of the soluble RAGE isoforms, sRAGE and esRAGE - both being considered putative endogenous inhibitors of RAGE signaling. Additional variables were serum levels of RAGE ligands, the high mobility group box (HMGB)1 and pentosidine. Serum levels of the study variables were measured by ELISA, and compared between baseline (before Fingolimod treatment) and 6 and 12 months post-drug treatment in 17 relapsing MS patients. Fingolimod treatment effects on MS disease progression were assessed by comparing pre- and post-Fingolimod values of the EDSS and rate of clinical relapse, and changes in the T1-and T2-enahncing lesions on the MRI scan.methods RESULTS: Twelve months treatment with Fingolimod increased serum levels of sRAGE and esRAGE by 32.4% (P = 0.004) and ...

Immunologic Research, 2015

This study is one in series determining the potential of RAGE axis (receptor for advanced glycati... more This study is one in series determining the potential of RAGE axis (receptor for advanced glycation end products, isoforms, ligands) as a biomarker in multiple sclerosis (MS). We evaluated serum levels of RAGE ligand, the high-mobility group box (HMGB)1 in MS patients, and assessed the correlation between HMGB1 serum levels and the use of disease-modifying drugs (DMDs), and between HMGB1 serum levels and indicators of MS disease severity. HMGB1 serum levels were compared between 96 (23 males) MS patients and 34 age- and gender-matched healthy controls (HCs) using enzyme-linked immunosorbent assays. DMD-naïve MS patients had significantly higher HMGB1 serum levels compared with DMD-treated (P = 0.04) and compared with HCs (P = 0.01). HMGB1 serum levels were not significantly different between total MS patients (DMD-naïve plus DMD-treated) and HCs (P = 0.09). DMD-naïve MS patients in clinical relapse tended to have lower HMGB1 serum levels than clinically stable RRMS patients (P = 0.07). HMGB1 serum levels showed 0.65 area under the curve (95 % CI 0.55-0.95) sensitivity/specificity for MS clinical relapse. The role of HMGB1 in MS disease pathology and DMD modulation of this protein warrant further investigations.

CNS & Neurological Disorders - Drug Targets, 2013

Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurode... more Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients. We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients. MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001, but lower plasma glucose, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001. The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients.

Hormone and Metabolic Research, 2015

Aging and Disease, 2017

This pilot study examined the status of the master iron regulatory peptide, hepcidin, and periphe... more This pilot study examined the status of the master iron regulatory peptide, hepcidin, and peripheral related iron parameters in Alzheimer's disease (AD) and mild cognitive impairment patients, and evaluated the relationship between iron dyshomeostasis and amyloid-beta (Aβ), cognitive assessment tests, neuroimaging and clinical data. Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of hepcidin, ferritin, Aβ40, Aβ42 using enzyme-linked immunosorbent assay. Serum transferrin levels were determined indirectly as total iron binding capacity, serum iron was measured and the percent saturation of transferrin calculated. The study variables were correlated with the patients' existing cognitive assessment tests, neuroimaging, and clinical data. Hepcidin, and iron-related proteins tended to be higher in AD patients than controls, reaching statistical significance for ferritin, whereas Aβ40, Aβ42 serum levels tended to be lower. Patients with pure AD had three times higher serum hepcidin levels than controls; gender differences in hepcidin and iron-related proteins were observed. Patient stratification based on clinical dementia rating-sum of boxes revealed significantly higher levels of iron and iron-related proteins in AD patients in the upper 50% as compared to controls, suggesting that iron dyshomeostasis worsens as cognitive impairment increases. Unlike Aβ peptides, iron and iron-related proteins showed significant association with cognitive assessment tests, neuroimaging, and clinical data. Hepcidin and iron-related proteins comprise a group of serum biomarkers that relate to AD diagnosis and AD disease progression. Future studies should determine whether strategies targeted to diminishing hepcidin synthesis/secretion and improving iron homeostasis could have a beneficial impact on AD progression.

Multiple Sclerosis, Jul 1, 2008

Immunobiology, 2016

This study is one in series measuring RAGE axis (receptor for advanced glycation end products, it... more This study is one in series measuring RAGE axis (receptor for advanced glycation end products, its isoforms, and ligands) as a biomarker in multiple sclerosis (MS). We identified and quantified membrane-bound RAGE (mRAGE) expression levels on freshly isolated PBMCs and its subpopulation (monocytes and T cells), and determined the relationship between mRAGE expression levels and MS disease severity. mRAGE expression was determined for 28 MS patients and 16HCs, by flow cytometry, using fluorochrome unconjugated primary RAGE monoclonal antibody and a polyclonal secondary antibody conjugated to R-Phycoerythrin (PE). After adjusting for multiple comparisons and correcting for group differences in age and gender, MS patients showed higher percentages of mRAGE-positive on PBMCs (12.4±2.1 vs. 4.08±0.8, P=0.02), monocytes (37.4±5.8 vs. 20.1±5.0, P=0.08) and T cells (4.1±1.2 vs. 2.1±0.3, P=0.05). SPMS patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; showed lower percentages of RAGE-positive monocytes (13.7±5.5 vs. 49.5±6.6, P=0.0006) and RAGE-positive T cells (4.1±1.8 vs. 6.6±1.5, P=0.04) than RRMS patients. We observed a negative relationship between the percentages of mRAGE-positive PBMCs and MS severity scale (MSSS) (r=-0.39, P=0.04), monocytes and EDSS (r=-0.48, P=0.01), monocytes and MSSS (r=-0.58, P=0.001), and T cells and MSSS (r=-0.40, P=0.04). Monocytes expression of mRAGE showed 0.811 area under the curve (95% CI: 0.64-0.98) sensitivity/specificity for MSSS. The reduced mRAGE expression on PBMCs in general, and on monocytes in particular, can be used as biomarker of MS disease severity and progression.