Gulf War (GW) veterans are a unique cohort of individuals who were exposed to numerous neurotoxicants in theater. These exposures include pyridostigmine bromide pills, pesticides, chemical warfare agents, vaccines, combustion byproducts from oil well fires, and solvent fumes from chemical agent resistant coating paint. After returning home from deployment, GW veterans began reporting a constellation of symptoms that encompassed multiple body systems and has since been collectively termed Gulf War Illness (GWI). Research immediately following the war has linked several of the neurotoxicant exposures to adverse health outcomes including cardiovascular, neuropsychological, and neuroanatomical effects. Over the years, GW research has transitioned to focusing on the illness as a whole and to investigating its potential biomarkers and mechanisms. Much of this research has compared veterans with and without GWI, however this grouping may be problematic given that veterans without GWI may have been exposed to the same neurotoxicants but present without symptoms or health effects or with symptoms below the threshold for current GWI diagnostic criteria. Additionally, some neurotoxicant exposures, without initially producing overt signs of toxicity, may produce delayed and persistent effects. As GW veterans begin to age, neurotoxicant exposures may exert delayed effects that may be different from symptoms initially experienced after the war. Therefore, it is of utmost importance to continue to characterize health effects from neurotoxicant exposures in GW veterans. This dissertation aims to investigate the effects of individual neurotoxicant exposures on cardiac risk, neuropsychological functioning, and brain morphology in GW veterans, nearly 30 years post-war. The first study examines the impact of these exposures on cardiac risk using the Framingham 10-year cardiovascular disease risk score, as well as the prevalence of cardiovascular and cerebrovascular medical conditions. The second study examines the impact of these exposures on neuropsychological and mood functioning, using an extensive battery of neuropsychological tests as well as the Profile of Mood States questionnaire. In the third study, the effects of these exposures on brain volumes of the Yeo functional networks are examined. The results of this dissertation will serve as a comprehensive update on GW veteran health regarding specific neurotoxicant exposures.

Gulf War Illness (GWI) is a medically unexplained illness that is classified by two common case criteria including the CDC chronic multisymptom illness definition and Kansas GWI criteria. It occurred among veterans who served in the Persian Gulf War from August, 1990 to February, 1991. Because of its complex chronic symptoms and multiple potential causes the neuropathological mechanisms and/or successfully clinical treatments for it remain elusive. Those in the theater of this war experienced exposures to many neurotoxicants, suggesting an association between GWI and neurologic dysfunction. In order to better understand the underlying cause of GWI, we have chosen to explore cerebral blood flow. Our hypothesis is that abnormal cerebral blood flow is associated with GWI and ultimately neurological dysfunction. By conducting a comprehensive evaluation of cerebral blood flow we will be able to determine if it has a role in Gulf War Illness. Historically, several techniques have been used to measure cerebral blood flow. Arterial spin labeling (ASL) has been widely used in research as a non-invasive and non-ionizing technique, which has the least adverse effects on the participants. An ASL subtype called pseudo-continuous arterial spin labeling (PCASL) has become a favorable technique in ASL research because it combines the advantages of continuous arterial spin labeling (CASL) and pulsed arterial spin labeling (PASL). PCASL can quantify the absolute cerebral blood flow without the exogenous contrast agents. The cost of PCASL is relatively low as most scanner can run this sequence without additional hardware. It provides higher label efficiency (to CASL) and greater signal-to-noise ratio (to PASL). We utilized the data from an ongoing study with 114 GW veterans study participants aged from 42 to 80. Their regional cerebral blood flow was scanned using a 3T Philips Achieva MRI scanner. Asltoolbox (Wang et al., 2016) was used to calculate the cerebral blood flow, and Freesurfer v6.0 was used to do the co-registration and quantification. The analysis of demographic data suggested that the presence of hypertension was the only variables that made differences between control and GWI case groups (p = 0.02). General linear models indicated that alternations of cerebral blood flow were not a component of GWI at least using CMI definition. Whether cerebral blood flow associates with GWI is still pending on further studies with utilizing a more refined case definition.

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