- Treatment of Memory Impairment and Sensorimotor Deficits in an Animal Model for the Gulf War Veterans' Illnesses
- Biomarkers of Gulf War Veterans' Illnesses: Tissue Factor, Chronic Coagulopathy, and Inflammation
- Identification of Biological Pathways Implicated in Hippocampal Dysfunction and Cognitive Impairment in Gulf War Illness
Roughly one-fourth of the almost 700,000 veterans of the 1990-91 Persian Gulf War report health issues including widespread pain, chronic fatigue, and memory and cognitive deficits, now characterized as Gulf War Illness (GWI). Research has shown that these health issues may have been caused by exposures to pesticides and insect repellents, as well as anti-nerve gas medication, experienced during Gulf War deployment. Dr. Mohamed Abou Donia at Duke University developed a rat model of Gulf War (GW) exposures that uses topical treatment of permethrin (insecticide) and DEET (insect repellent) to simulate chronic GWI symptoms. Dr. Abou Donia is using a Fiscal Year 2008 Gulf War Illness Research Program Investigator-Initiated Research Award to systematically study the potential benefits of the analgesic Flupirtine to treat GWI using this rat model. Flupirtine has been used to treat pain and memory deficits associated with other disorders and has been shown to be safe and non-addictive, though it is not approved by the U.S. Food and Drug Administration (FDA).
In the study, rats in the GW model, either Flupirtine-treated or untreated, are compared with Flupirtine-treated and untreated normal controls for performance in a water maze test. Rats are timed as they try to find a hidden platform in a water tank from different starting points. Reduced swimming times indicate spatial learning and memory. The water maze test also gauges sensorimotor parameters such as reflexes, motor strength, and coordination. In addition, researchers learn about cognition from observing the rats' probing activity during these tests. The study is currently underway, and data will be collected over the next 3 years. Dr. Abou Donia's GW exposures model has effectively reproduced GWI symptoms, as the rats developed alterations in memory and neuropathology. The effects of Flupirtine will be analyzed after all water maze and histopathological tests have been completed. If successful, this research would provide proof of concept that could ultimately lead to FDA approval of Flupirtine for the treatment of GWI.
Many veterans of the 1990-1991 Persian Gulf War suffer from unexplained chronic and often debilitating health issues. It is estimated that 25% to 32% of the nearly 700,000 Gulf War veterans currently experience widespread pain, headaches, fatigue, cognitive deficits, and other symptoms. Preliminary evidence has indicated that a high percentage of ill Gulf War veterans may be in a hypercoagulable state, i.e., an abnormally increased tendency toward blood clotting, the basis of which is unknown. Dr. Ronald Bach of the VA Medical Center in Minneapolis is using funds from an FY08 GWIRP Investigator-Initiated Research Award to further investigate this concept. Dr. Bach will examine the level of tissue factor (TF), the biological initiator of blood coagulation, in blood samples from ill Gulf War veterans and healthy controls. Overexpression of TF in the bloodstream can lead to disseminated intravascular coagulation (DIC) and impaired blood flow in the smallest of blood vessels. This restriction of microcirculation applied chronically can produce symptoms commonly associated with Gulf War Illness (GWI), including fatigue, somatic pain, and cognitive difficulties.1
Dr. Bach will initially try to find more evidence of clotting system abnormalities in ill veterans' blood by measuring an expanded panel of coagulation markers, including D-Dimer, which indicates fibrin clot formation, thrombin-antithrombin III complex (TAT), to indicate ongoing coagulation activity, prothrombin fragment 1.2 (F1.2), a measure of ongoing thrombin generation, and TF-procoagulant activity (TF PCA), which can initiate DIC. Serial samples taken over 24 months will be assayed to establish the chronic nature of the abnormalities. This analysis may also uncover new biomarkers for GWI. Dr. Bach will also assess immune function by measuring levels of inflammatory markers in the blood samples. This may indicate a possible state of chronic inflammation in ill veterans and may support a connection between chronic coagulation and immune function.
This study seeks to contribute to the understanding of GWI etiology. The results generated could identify a novel biomarker for the diagnosis of GWI, lead to clinical trials of therapies, and improve the health of veterans with GWI.
1 Hannan KL, Berg DE, Baumzweiger W, Harrison HH, Berg LH, Ramirez R, and Nichols D. 2000. Activation of the coagulation system in Gulf War Illness: A potential pathophysiologic link with chronic fatigue syndrome, a laboratory approach to diagnosis. Blood Coagulation and Fibrinolysis 11(7):673-678.
Identification of Biological Pathways Implicated in Hippocampal Dysfunction and Cognitive Impairment in Gulf War Illness
Posted February 24, 2011
Fiona Crawford, Ph.D., Roskamp Institute, Sarasota, Florida
Gulf War Illness (GWI), a multisymptom condition associated with service in the 1990-1991 Persian Gulf War, is thought to affect approximately 200,000 to 250,000 veterans. Among the complex and chronic symptoms experienced by these veterans, persistent cognitive impairment has been widely reported and largely attributed to combined exposure to pyridostigmine bromide (PB) and overuse of pesticides and insect repellants (referred to as Gulf War agents). Evidence of structural and metabolic abnormalities of the hippocampus provided from imaging studies, and memory impairment from neuropsychological testing both suggest that hippocampal damage may be the main culprit. Hippocampal damage has also been cited as an important clinical feature associated with neurocognitive disorders such as Alzheimer's disease. With funds from a Fiscal Year 2008 GWI Research Program Investigator-Initiated Research Award, Dr. Crawford is developing a mouse model of cognitive dysfunction following exposure to Gulf War agents; she will characterize the accompanying hippocampal-related cognitive and neuropathological changes and apply state-of-the-art proteomic technology to identify molecular pathways of interest. Pilot studies have generated a mouse model of delayed and persistent cognitive dysfunction and increased astrogliosis presenting at 4 months after combined exposure to PB and permethrin. Proteomic analyses of these mice reveal distinct brain and plasma protein profiles unique to the Gulf War agent-exposed mice compared to controls.
Replication of these findings in additional cohorts of mice is underway. These studies include analysis of APOE-E4-expressing transgenic mice, to determine whether the APOE genotype influences outcome after GW agent exposure; the E4 allele of APOE is a known risk factor for Alzheimer's disease and is also associated with worse outcome after brain injury. Neurobehavioral, neuropathological, and proteomic analyses will all be applied to identify brain molecular profiles corresponding with exposure and response to GW agents. Collectively, these experiments will significantly increase our understanding of the molecular basis of Gulf War agent-induced cognitive dysfunction.