The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk.

Alzheimer's disease, Parkinson's disease, and motor neuron disease, the most common of the late-life neurodegenerative disorders, are in most cases thought to have complex etiologies. Common features among these disorders include insidious onset, pathological findings of protein aggregates and selected neuronal degeneration, and resulting characteristic clinical syndromes. The number of elders in the United States, including aging veterans, is increasing. Investigation of causes and preventive interventions for neurodegenerative disorders is increasingly relevant. Recent epidemiological and laboratory studies suggest that exposures years or decades before diagnosis can trigger the processes that ultimately result in a neurodegenerative disease. If this is correct, preventive measures may be needed in midlife or earlier. This article will focus on putative risk factors relevant to military service.

Effects of military deployment on cognitive functioning.

Military deployment poses many risks for cognitive functioning. When deployed individuals are compared to a nondeployed control group, there is some evidence that deployment may be associated with declines in cognitive functioning. The current study examined cognitive performance before and following deployment in a large sample of active duty military personnel (N = 8002) who reported no traumatic brain injury (TBI). Cognition was assessed using the Automated Neuropsychological Assessment Metrics version 4 TBI Military (ANAM4 TBI-MIL) battery, a computer-based battery of tests measuring attention, processing speed, and general cognitive efficiency. Pre- and postdeployment scores were compared using repeated measures analyses. Although statistically significant differences were observed for all tests (with 5 of 7 tests demonstrating performance improvement), effect sizes were very small for all but 1 test, indicating that performance differences had minimal clinical significance. Likewise, determination of change for individuals using reliable change indices revealed that a very small percentage (<3%) of this presumed healthy sample showed meaningful decline in cognition following deployment. Analyses indicated that despite risks for cognitive decline while in theater, deployment had minimal to no lasting effect on cognition as measured by ANAM4 TBI-Mil upon return from deployment.

Meeting report: consensus statement-Parkinson's disease and the environment: collaborative on health and the environment and Parkinson's Action Network (CHE PAN) conference 26-28 June 2007.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. METHODS: In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. RESULTS: We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. CONCLUSIONS: PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.

A longitudinal program for biomarker development in Parkinson's disease: a feasibility study.

Long-term follow up is necessary to understand the natural history of treated Parkinson's disease (PD). The Longitudinal and Biomarker Study in PD (LABS-PD) is an observational study designed to prospectively measure the evolution of motor and non-motor features of PD and sample promising biomarkers from early to late stage illness. LABS-PD is organized on the premise that cohorts from completed clinical trials can be re-recruited for long-term follow up. LABS-PD will eventually contain multiple cohorts, but to test the feasibility of the strategy, we examined enrollment and biomarker sampling in the initial cohorts. The first PD cohort (PostCEPT) comes from the de novo clinical trial of a mixed lineage kinase inhibitor (PRECEPT). We assessed the recruitment from PRECEPT to PostCEPT, the ability to link data from the two studies, and sample collection for a variety of biomarkers. A total of 537 of 709 eligible PRECEPT subjects (76%) enrolled in PostCEPT; 509 (95%) had repeat dopamine transporter imaging. PRECEPT clinical and imaging data were successfully linked to PostCEPT, to provide 3 to 4 year follow-up. A biomarker sub-study enrolled over 100 PD cases from PostCEPT and 100 controls to measure olfaction and blood markers of gene expression, alpha-synuclein, and proteomic profiles. We were also successful in linking clinical and biomarker data to DNA samples that have been collected in the publicly accessible Coriell repository. The PostCEPT cohort and associated studies strongly support the feasibility of the LABS-PD approach of retaining and repurposing clinical trial cohorts to collect longitudinal clinical and biomarker data.

Neuropsychological issues in military deployments: lessons observed in the DoD Gulf War Illnesses Research Program.

The U.S. Department of Defense invested $150 M to investigate undiagnosed Gulf War Illnesses (GWI) and twice that amount in post hoc clinical management. No new disease syndrome was identified, but the research produced new understanding and awareness of important psychosocial and neurotoxicological interactions that represented a difficult and relatively untapped frontier in biomedical research, especially concerning chronic multisymptom illnesses. Some specific Gulf War issues such as effects of depleted uranium, Leishmania diagnosis and treatment, and pesticide and prophylactic drug interactions have been intensively investigated; remaining priorities for further investigation include: markers of neurologic change (e.g., neuroimaging, neuropsychological testing), interactions between psychological resilience and neurotoxicity, structure-function relationships of neurotoxins with neurodegenerative disease potential, and predictors of individual susceptibility. The primary conclusions from the program are that no specific neurotoxic chemical has been identified that explains the chronic multisymptom illness observed but wellness of service members in future deployments may be better sustained based on continuing research on preexposure health baselining, fitness and health-damaging behaviors, and stress resilience. The many scientific discoveries and accomplishments of the GWI research effort have advanced military medical science, provided a solid basis on which to build future protections against health and performance risks to the warfighter, and improved the ability to respond to future deployment health issues.

Army research needs for automated neuropsychological tests: monitoring soldier health and performance status.

Information on the mental status of soldiers operating at the limits of human tolerance will be vital to their management in future deployments; it may also allow earlier intervention for conditions such as undiagnosed Gulf War illnesses and Parkinson's Disease. The Army needs a parsimonious set of neuropsychological tests that reliably identify subtle changes for: (1) early detection of individual health and military performance impairments and (2) management of occupational and deployment health risks. Testing must characterize cognitive lapses in healthy individuals faced with relevant operational stressors (i.e., anxiety, information overload, thermal strain, hypoxia, fatigue, head impact, chemical or radiation exposures, metabolic challenges). This effort must also explore the neuropsychological methods in militarily relevant conditions to extend our understanding of relevant functional domains and how well they correspond to modes of testing. The ultimate objective is unobtrusive real-time mental status monitoring.

Cognitive change associated with self-reported mild traumatic brain injury sustained during the OEF/OIF conflicts.

Traumatic brain injury (TBI) has received much attention due to high rates of this injury in Service Members returning from the Iraq/Afghanistan conflicts. This study examined cognitive performance in Service Members tested with ANAM prior to and following deployment. The sample was divided into a control group (n=400) reporting no TBI injury prior to or during most recent deployment, and a group who self-reported a TBI injury (n=502) during most recent deployment. This latter group was divided further based on self-report of post-concussion symptoms at post-deployment testing. All three groups performed similarly at pre-deployment. The group reporting TBI with active symptoms performed worst at post-deployment and included the highest percentage of individuals showing significant decline in cognitive performance over time (30.5%). A small sample of symptomatic individuals with a non-TBI reported injury did not demonstrate similar declines in performance, suggesting that active symptoms alone cannot account for these findings. Of those reporting a TBI injury during deployment, 70% demonstrated no significant change in cognitive performance compared with baseline. Although the exact etiology of observed declines is uncertain, findings indicate that individuals who self-report TBI during deployment with active symptomatology at post-deployment are at greatest risk for declines in cognitive performance. These individuals can be identified using self-report and brief computer-based testing. Importantly, the majority of active-duty individuals reporting TBI during deployment do not present with lasting significant cognitive impairment, a finding consistent with the civilian literature on mild TBI.