Nearly 30 years after the end of the 1991 Persian Gulf War (GW), an estimated 25-32% of GW veterans still suffer from Gulf War illness (GWI),1 the term used to describe the symptoms that have plagued many GW veterans since their return from deployment. Although symptoms may vary from veteran to veteran, GWI typically includes some combination of fatigue, pain, cognitive/mood dysfunction, sleep disturbances, and autonomic disturbances such as gastrointestinal (GI), urinary, and sexual dysfunction. Epidemiological data suggest a possible link between chemical exposures and Parkinson?s disease (PD).4 Although GW military personnel were exposed to multiple, potentially hazardous chemicals in the Persian Gulf theater, to date there has been no reliable data on the incidence or prevalence of PD among GW veterans.1 However, it is noteworthy that many of the symptoms of GWI are similar to non-motor symptoms (NMS) in PD,7 which can predominate years to decades prior to clinical diagnosis.9 For example, some common NMS in PD include fatigue, pain, autonomic disturbances, such as GI, urinary, and sexual dysfunction, sleep disturbances, anxiety, depression, and cognitive dysfunction such as difficulties with memory, concentration, and word finding. We have preliminary evidence of positive associations between GW veterans? self-reported frequency of exposures to deployment-related chemicals and GWI symptoms similar to PD?s NMS. We have also found an inverse relationship between GW veterans? self-reported frequency of wearing pesticide-treated uniforms and measures of manual dexterity. Finally, we have preliminary evidence of negative associations between the veterans? self-reported frequency of exposures to GW-related chemicals and basal ganglia volume and basal ganglia N-acetylaspartate (NAA), a marker of neuronal integrity.11 Because NMS and significant neuronal loss in the substantia nigra are two characteristics that have been repeatedly noted in individuals who eventually develop clinical PD,9 based on these preliminary findings, we hypothesize that GW veterans with excessive exposures to deployment-related chemicals have prodromal PD. While there is presently no cure or disease- modifying treatment that halts or slows the progression PD, the precocious diagnosis of PD in GW veterans with high exposures to GW-related toxicants would facilitate the targeted delivery of neuroprotective therapies when they eventually do become available. Furthermore, these GW veterans may be counseled to adopt lifestyle changes, such as increasing physical activity, which have been associated with lowering the risk of PD.13 The proposed four-year study will enroll 140 GW veterans with high levels of exposure to deployment- related chemicals (e.g., GW pesticide applicators). We will obtain clinical and behavioral measures and in vivo ultra-high field (7 Tesla) and 3 Tesla magnetic resonance imaging (MRI) measures of iron, neuromelanin, and free water in the substantia nigra. We propose three specific aims that will: (1) evaluate GW veterans using the International Parkinson and Movement Disorder Society (MDS) research criteria for prodromal PD;14 (2) examine the association between the veterans? self-reported frequency of exposures to GW deployment- related chemicals and 7 Tesla measures of iron and neuromelanin and the veterans? probability of prodromal PD according to the MDS research criteria; and (3) compare 3 Tesla measures of free water in the substantia nigra and scores from various NMS scales from the Parkinson's Progression Markers Initiative (PPMI)15 dataset in GW veterans with age- and gender-matched healthy controls, PD patients, and subjects with prodromal PD from the PPMI cohort. The proposed experiments are timely and important because it is expected to provide much needed information on the long-term consequences of GWI in the context of aging and neurodegenerative diseases, particularly PD.

Public Health Relevance

The Department of Defense (DOD) estimates that more than 41,000 veterans were likely overexposed to pesticides during the Gulf War (GW).17 In addition to pesticides, GW veterans were exposed to a myriad of other chemicals/toxicants during deployment.1 Despite the epidemiological link between environmental exposures, particularly pesticides, and Parkinson?s disease (PD),4 there is no reliable data on incidence or prevalence of PD among GW veterans.1 PD?s symptomatology is heterogenous. There are motor and non- motor symptoms (NMS),7 which are similar to many symptoms of Gulf War Illness (GWI) and can precede clinical diagnosis by decades.9 The proposed study will examine the long-term consequences of GWI in the context of aging and PD. The precocious diagnosis of PD in GW veterans with high-levels of deployment- related exposures could facilitate the targeted delivery of neuroprotective therapies when they become available. At-risk veterans may also be counseled to adopt lifestyle changes that may lower their risk of PD.13

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01CX000798-05
Application #
9665178
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2013-10-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Veterans Affairs Medical Center San Francisco
Department
Type
DUNS #
078763885
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Chao, Linda L; Abadjian, Linda R; Esparza, Iva L et al. (2016) Insomnia Severity, Subjective Sleep Quality, and Risk for Obstructive Sleep Apnea in Veterans With Gulf War Illness. Mil Med 181:1127-34
Chao, Linda L; Reeb, Rosemary; Esparza, Iva L et al. (2016) Associations between the self-reported frequency of hearing chemical alarms in theater and regional brain volume in Gulf War Veterans. Neurotoxicology 53:246-256
Araque Caballero, Miguel Ángel; Brendel, Matthias; Delker, Andreas et al. (2015) Mapping 3-year changes in gray matter and metabolism in A?-positive nondemented subjects. Neurobiol Aging 36:2913-2924
Chao, Linda L; Zhang, Yu; Buckley, Shannon (2015) Effects of low-level sarin and cyclosarin exposure on white matter integrity in Gulf War Veterans. Neurotoxicology 48:239-48
Chao, Linda L; Kriger, Stephen; Buckley, Shannon et al. (2014) Effects of low-level sarin and cyclosarin exposure on hippocampal subfields in Gulf War Veterans. Neurotoxicology 44:263-9