DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS


Posted October 9, 2020

Dr. Mohamed Abou Donia, Duke University
Dr. Kimberly Sullivan, Boston University

Dr. Mohamed Abou Donia, Duke University
Dr. Mohamed Abou Donia
Dr. Kimberly Sullivan, Boston University
Dr. Kimberly Sullivan

Gulf War illness (GWI) is a chronic multi-symptom illness unique to Veterans who served in the 1990-91 Persian Gulf War. Though the associated symptoms are heterogeneous, they typically include chronic widespread pain, headaches, debilitating fatigue, cognitive and mood impairment, gastrointestinal issues, respiratory symptoms, sleep problems, and other abnormalities that cannot be explained by established medical diagnoses or standard laboratory tests. Studies indicate that approximately 25-32% of Gulf War Veterans continue to experience symptoms associated with their deployment.

Over the 30 years since the Gulf War (GW), the etiology of GWI has remained elusive despite continued research into the effects of service-related exposures. This includes identifying objective biomarkers for diagnosing the disease. Drs. Mohamed Abou Donia of Duke University and Kimberly Sullivan of Boston University, and their study teams, used a GWIRP FY14 Investigator-Initiated Research Award Expansion Award to identify autoantibodies that might be diagnostic for GWI. The team initially screened the serum of 20 GW veterans with GWI and 10 non-veteran symptomatic (low back pain) controls for the presence of autoantibodies against a panel of central nervous system (CNS) proteins. They found that veterans with GWI had statistically significantly higher levels of autoantibody reactivity in all proteins examined except one (S100-B). 

These early findings led to a confirmatory study to see if the newly developed biomarker panel could differentiate GWI from other chronic conditions and healthy controls and validate the earlier preliminary findings. The larger study consisted of 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (50 with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 35 with irritable bowel syndrome (IBS)). Cases and controls were determined by Kansas GWI criteria, which requires GW veterans to self-report symptoms in 3 out of 6 symptom domains (neurologic/mood/cognitive, fatigue, pain, gastrointestinal, respiratory, and skin). Veteran controls were those deployed to the GW but that did not meet the Kansas GWI or exclusionary criteria. The tested antibodies were against neuronal tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII) and glial proteins Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP) and S100B. Plasma antibody levels were determined by measurement of chemi-luminescent optical density. The results showed statistically increased levels of nine of ten CNS autoantibodies tested in the plasma of veterans with GWI. The increased levels of CNS autoantibodies were found to be consistent across ill GW veterans with chronic neurological complaints. Low levels of autoantibodies were found in the plasma of GW healthy controls, consistent with previous findings, suggesting that GW healthy controls had no lasting CNS effects from their deployment. Drs. Abou Donia and Sullivan therefore propose, increased levels of CNS autoantibodies may provide an objective biomarker of the illness. 

The researchers took the analyses a step further by developing a new index designed to determine the overall neurodegenerative condition of an individual based on the level of plasma autoantibodies. The Neurodegenerative Disease Index (NDI) is calculated by adding all of the values of autoantibodies for each neural protein tested in the panel and dividing the sum by the number of autoantibodies used. This value is then multiplied by 10 to produce the NDI. The NDI is imagined as a simple, blood-based proxy to determine the extent of neurodegeneration of an individual. 

The research team acknowledges there were limitations with this study, including GWI diagnosis using the Kansas definition was based on veterans’ self-reported symptoms, which could have introduced some classification errors. However, the study benefited from a large sample size and comparison of both healthy and symptomatic veteran control groups. Overall, this study confirmed the utility of a panel of plasma CNS autoantibodies to distinguish among veterans with GWI versus other healthy and symptomatic control groups, which is a much needed development for the ill Gulf War veteran community. Additionally, the new NDI summary score can be further utilized to compare pre- and post-treatment trial efficacy. 

Reference:

Abou-Donia MB, Lapadula ES, Krengel MH, Quinn E, LeClair J, Massaro J, Conboy LA, Kokkotou E, Abreu M, Klimas NG, Nguyen DD, Sullivan K. Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls. Brain Sci. 2020 Sep 5;10(9):E610. doi: 10.3390/brainsci10090610. PMID: 32899468. 

Link:

Public and Technical Abstracts: Novel Autoantibody Serum and Cerebrospinal Fluid Biomarkers in Veterans with Gulf War Illness

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Last updated Thursday, October 8, 2020