Early and Accurate Identification of Parkinson Disease Among US Veterans
Radiologic and fluid biomarkers for the atypical syndromes are under active investigation; at present the most accessible study is magnetic resonance imaging (MRI), which may show characteristic features such as degeneration of the pontocerebellar fibers in MSA or midbrain atrophy in PSP.45,46 By contrast, standard MRI sequences in idiopathic PD are usually normal, although high-resolution (7 tesla) imaging can reveal loss of neuromelanin in the substantia nigra.47 MRI also can be useful in the workup of suspected normal pressure hydrocephalus or vascular parkinsonism, which would show disproportionate ventriculomegaly with transependymal flow, or white matter lesions in the basal ganglia, respectively.
Data-Based Identification of Preclinical PD
The integration of clinical motor or prodromal features with biomarker data has led to the development of several large-scale clinical and administrative databases to identify PD. The Parkinson Progression Markers Initiative initially enrolled only de novo clinically identified people with PD, but it expanded to include a prodromal cohort who are being assessed for rates of conversion to PD.48 Similarly, metabolic imaging can be combined with prodromal symptoms, such as hyposmia or RBD, to predict risk for phenoconversion into manifest motor PD.49
The PREDICT-PD study synthesizes mood symptoms, RBD, smell testing, genotyping, and keyboard-tapping tasks to divide individuals into high-, middle-, and low-risk groups; interim analysis at 3 years of follow-up (N = 842) demonstrated a hazard ratio of 4.39 (95% CI, 1.03-18.68) for the diagnosis of PD in the highrisk group compared with the low-risk group.50 Lastly, administrative claims data for prodromal features, such as constipation, RBD, and mood symptoms, is highly predictive of eventual PD diagnosis.51 VA databases accessed through the Corporate Data Warehouse are complementary sources of information to nonveteranspecific Medicare databases; to our knowledge there has not yet been a comprehensive search of VA databases to identify veterans with preclinical PD.
Risk Factors Associated With Military Service
A number of potential environmental risk factors may increase the risk of developing Parkinson disease for veterans. Perhaps the most commonly recognized is pesticide exposure, particularly given the presumptive service connections established by the VA for Parkinson disease and exposure to Agent Orange or contaminated water at Camp Lejeune.52,53 Both dioxin, the toxic ingredient in Agent Orange, and the solvents trichloroethylene and perchloroethylene, found in the water supply at Camp Lejeune, interfere with mitochondrial function leading to oxidative stress and apoptosis of nigrostriatal neurons.54,55 Other potential exposures, which are not necessarily limited to the veteran population, include rotenone, a phytochemical used to kill fish in reservoirs, and paraquat, an herbicide that may directly promote synuclein aggregation.56,57 Veterans who have reported exposure to these or other environmental chemicals in civilian life should be carefully assessed for the presence of motor PD or prodromal features.
Traumatic brain injury (TBI) also may be a risk factor for PD, which may be particularly relevant for veterans who had served in Iraq or Afghanistan. Retrospective claims data suggest a strong association between PD and recent TBI in the 5 to 10 years prior to motor PD diagnosis.58,59 A recent assessment of combat veterans with TBI found that even mild TBI was associated with a 56% increased risk of PD, while moderate-to-severe TBI was associated with an 83% higher risk of PD.60 The pathologic mechanism for this link is unclear, but post-TBI inflammatory processes may lead to the formation of reactive oxygen species and/or glutamatergic excitotoxicity, thus leading to secondary injury in the nigrostriatal pathway.61 As with prodromal symptoms, the risk of PD related to environmental risk factors may be synergistic; repetitive TBI may be more damaging than a single injury, and a combination of TBI and pesticide exposure markedly increases PD risk beyond the risk of TBI or the risk of pesticides alone.62 Recently, parkinsonism, including Parkinson disease, was recognized as a service connected condition for veterans with a servicerelated moderate or severe TBI.63
Conclusion
Because of the substantial impact on quality of life and disability-adjusted life years, early and accurate identification and management of veterans at risk for PD is an important priority area for the VA. The 10-year cost of PD-related benefits through the VA was estimated at $3.5 billion in fiscal year 2010, and that number is likely to rise in coming years, due to the aging population as well as synergistic effects of independent risk factors described above.64 In response, the VA has created a network of specialty care sites, known as Parkinson Disease Research, Education, and Clinical Centers (PADRECCs) located in Philadelphia, Pennsylvania; Richmond, Virginia; Houston, Texas; West Los Angeles and San Francisco, California; and Seattle, Washington/ Portland, Oregon (www.parkinsons.va.gov).
The PADRECCs are supplemented by a National VA PD Consortium network of VA physicians trained in PD management (Figure 2). Studies, including one investigating care of veterans with PD, have demonstrated that involvement of specialty care services early in the course of PD leads to improved patient outcomes.65,66 In addition to patient-facing resources such as support groups and specialized physical/occupational/speech therapy, PADRECCs and the consortium sites are national leaders in PD education and clinical trials and provide high-quality, multidisciplinary care for veterans with PD.67 Thus, veterans with significant risk factors or prodromal symptoms of PD should be referred into the PADRECC/Consortium network in order to maximize their quality of care and quality of life.
