Imaging biomarkers can provide safe, non-invasive tools to directly understand disease onset and progression in MS and other neurological diseases and disorders. The Buffalo Neuroimaging Analysis Center (BNAC) is a dedicated research center that is a world leader in developing and testing the predictivity of clinical, MRI, OCT and PET biomarkers with immunology and genetic correlates in neurodegenerative neurological diseases and aging.
Environmental and genetic factors are associated with the risk of developing multiple sclerosis (MS), but the exact cause still remains unidentified. Epstein-Barr virus (EBV), vitamin D, altered lipid metabolism and smoking are among the most well-established environmental risk factors in multiple sclerosis (MS). In collaboration with Dr. Murali Ramanathan from Department of Pharmacy and Pharmaceutical Sciences, and Dr. Richard W. Browne from Department of Biotechnical and Clinical Laboratory Sciences, at the University at Buffalo, as well as collaborators from Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, Prague, Czech Republic, Dr. Francesco Bernardi from University of Ferrara, Ferrara, Italy and Dr. Jens Kuhle from University at Basel, Switzerland, BNAC has published numerous biomarkers-related articles in MS and other neurological disorders.
Epstein-Barr Virus (EBV)
Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab and ofatumumab, have shown promising clinical and MRI benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. BNAC studied extensively EBV association with MS, in order to better understand MS pathogenesis and help identify additional disease biomarkers that may be responsive to theraputic interventions.
Altered Lipid Metabolism
There is increasing evidence for a critical role of cholesterol metabolism as an underlying factor in the MS disease progression. These findings are not surprising given the important role of cholesterol for myelin homeostasis and neuronal functions. BNAC reported in a number of studies that cholesterol pathway biomarkers measured during a routine clinical chemistry lipid panel are associated with measures of brain injury and disease progression in both established MS and following the first demyelinating event. We showed that in established MS, higher baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels are associated with worsening disability, and that higher high-density lipoprotein cholesterol (HDL-C) was associated with lower contrast-enhancing lesion volume.
Significant progress has been made in understanding the complex interactions between the coagulation system and inflammation and autoimmunity. Increased blood-brain-barrier permeability, a key event in the pathophysiology of MS, leads to the irruption into the central nervous system of blood components that include virtually all coagulation/hemostasis factors. Besides their cytotoxic deposition and role as a possible trigger of the coagulation cascade, hemostasis components cause inflammatory response and immune activation, sustaining neurodegenerative events in MS. BNAC studies showed the contribution of altered hemostasis in the complex pathophysiology of MS. Fibrin(ogen), an abundant protein in plasma, has been identified as a key contributor to neuroinflammation. Perturbed fibrinolysis was found to be a hallmark of progressive MS with abundant cortical fibrin(ogen) deposition. The immune-modulatory function of the intrinsic coagulation pathway still remains to be elucidated in MS. BNAC’s work in elucidating molecular details in key hemostasis components participating in MS pathophysiology, and particularly involved in inflammatory and immune responses, could favor the development of novel therapeutic targets to ameliorate the evolution of MS.
Neurofilament Light Chain
Neurofilament light chain (NfL) is main scaffolding component of the axonal cytoskeleton. Multiple neurodegenerative diseases are highlighted by damage and loss of the neuroaxonal unit, processes which result in abnormally high NfL levels in cerebrospinal fluid and in blood. Despite the relatively low serum concentrations of NfL, recent technological development of single molecule array (Simoa) assays allow for reliable quantification. Such analyses were previously utilized in MS cohorts and showed good predictive ability for concurrent and future MS disability, and of global MRI changes. BNAC’s recent work focused on investigating the associations between NfL and number of conventional and non-conventional MRI and OCT measures of disease activity and disease progression.
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FEATURED RECENT LINKING IMAGING BIOMARKERS WITH IMMUNOLOGY AND GENETIC FACTOR STUDIES
Uher T, McComb M, Galkin S, Srpova B, Oechtering J, Barro C, Tyblova M, Bergsland N, Krasensky J, Dwyer M, Havrdova EK, Posova H, Vaneckova M, Zivadinov R, Horakova D, Kuhle J, Ramanathan M (2021) Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis. Mult Scler 27:220-231 [Open article]
Ziliotto N, Zivadinov R, Jakimovski D, Baroni M, Bergsland N, Ramasamy DP, Weinstock-Guttman B, Ramanathan M, Marchetti G, Bernardi F (2020) Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis. Front Neurol 11:553616 [Open article]
Tavazzi E, Zivadinov R, Dwyer MG, Jakimovski D, Singhal T, Weinstock-Guttman B, Bergsland N (2020) MRI biomarkers of disease progression and conversion to secondary-progressive multiple sclerosis. Expert Rev Neurother 20:821-834 [Open article]
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Part of BNAC’s mission is to help share our tools and experience with our colleagues and other industry partners. If you need help with exploring imaging biomarkers in relation to immunology and genetic factors in your research or clinical trial work, please reach out to discuss how we can assist. Our group brings decades of experience and expertise to every collaborative study and service partnership.