An investigation of the relationship between toxicant exposures during Gulf War deployment and prodromal Parkinson's disease.

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.

Grant Number: 5I01CX000798-11
NIH Institute/Center: VA
Principal Investigator: Linda Chao