Brain & Nervous
Nervous System
Project Summary

Title: Multi-disciplinary Pathophysiologic Studies of Neurotoxic Gulf War Related Syndromes Leading to Diagnosis and Treatment
Synopsis: This study looks at specific sites and the nature of the brain damage in a sample of Gulf War Veterans in order to develop a system of testing and confirming neurological impairment in large populations of Gulf War Veterans.
Overall Project Objective: 1. Demonstrate the specific sites and nature of neurologic damage associated with the symptoms comprising the case definition 2. Develop a two-stage system of testing and confirming the diagnosis of neurological impairment in Gulf War veterans for use in cost-effective screening of large populations of Gulf War veterans; 3. Provide insights into the pathophysiology of the neurologic impairment of Gulf War veterans upon which to base approaches to treatment.
Status/Results to Date: A) Completed the analysis of a survey of symptoms in 336 Dallas-area Gulf War veterans to replicate the syndrome factor analysis performed in the original sample from the 24th Reserve Naval Construction Battalion (Seabees). Confirmatory factor analysis replicated the factor model demonstrating that the same Gulf War syndromes 1-3 are present in Dallas-area Gulf War veterans. Analyzed the portions of the clinical database collected in the re-study of the 22 cases and 18 controls from the original nested case-control study selected from the Seabees sample and additional cases drawn from the survey of Dallas-area Gulf War veterans. A strong association between Gulf War symptom complexes correlated with genetically determined levels of the Q allozyme of the paraoxonase/arylesterase (PON1) enzyme, potentially explaining why some veterans exposed to low-level nerve agent developed chronic brain damage and others did not. A strong association between Gulf War symptom complexes and a reduction of N-acetyl-aspartate (NAA), measured by magnetic resonance spectroscopy, suggests a loss of functioning neuron mass in the deep structures of the brain (basal ganglia and brain stem): This finding was replicated in 6 Dallas-area veterans with our factor-analysis-derived symptom complex 2. A strong association between Gulf War symptom complexes is associated with failure of the brain to respond to a pharmacologic challenge by reducing blood flow in brain regions controlled by cholinergic receptors, measured in cases and controls by paired SPECT scans with and without cholinergic stimulation. The investigators are currently verifying the results by analysis with statistical parametric mapping (SPM). The subjective memory problems of veterans in this sample represent case-control differences in neuropsychologic measures of attention rather than memory per se. Completed planning of a national survey to measure the prevalence of our factor-analysis-derived syndromes and genetic and brain imaging indicators of chronic neurologic injury in random samples of the Gulf War veterans and Era non-deployed veterans.
Agency:Department Of Defense
Location:University of Texas Southwestern Medical Center at Dallas
P.I. Name:Robert W Haley, M.D.
Research Type:Clinical
Research Focus:Treatment
Focus Category:Brain & Nervous
Study Start Date:April 01,1994
Estimated Completion Date:December 31,2000
Specific Aims: 1. Extend the battery of tests for detecting neurotoxic brain and nerve damage and apply the new battery to the original 43 cases and controls 2. Plan and conduct a population survey of Gulf War veterans to estimate the prevalence of Haley's factor analysis-derived case definitions of Gulf War-related neurologic syndromes; 3. Apply the tests for neurotoxic brain and nerve damage to a new set of cases and controls selected randomly from the population survey.
Methodology: Tests to be applied to the cases and controls with investigators blinded to case-or control-group status include audiovestibular tests of brainstem function including high speed infrared oculography, scans of regional cerebral blood flow (HMPAO-SPECT) before and after a cholinergic challenge with physostigmine, magnetic resonance spectroscopy of the basal ganglia and brainstem to detect gliosis or Neuronal loss, 24-hour Holter monitor with computer analysis of heart rate variation to assess parasympathetic nervous system function, direct recording of sympathetic nerve firing rate from the peroneal nerve by microneurography, quantitative EEG, sleep studies with polysomnography and measurement of circadian rhythm of tympanic temperature, tests of peripheral blood neurohormone levels, genetic tests for paraoxonase and butyrylcholinesterase genotypes and blood enzyme levels, psychiatric interviews for stress-related and other psychopathology, batteries of neuropsychologic tests particularly focusing on tests of subcortical brain function, and evaluation of joint function with standard roentgenographic, MRI and proprioception studies. Planning of the national survey involves analyzing the characteristics of the deployed and nondeployed Gulf War-era military population, developing methods to avoid selection bias from the "healthy-warrior effect," translating Haleys self-administered survey questionnaires into computer-assisted telephone interview format, pretesting the survey method and designing and selecting an efficient stratified random sample of deployed and nondeployed populations for survey.
Most Recent Publications:

Haley RW, Billecke S, La Du BN. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology, 157(3):227-33, Jun 1999. Abstract

Haley RW. Chronic multisystem illness in Gulf War veterans. Journal of the American Medical Association, 327:328-329, 1999. Article

Haley RW, Kurt TL, Roland PS. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. JAMA, 277(3):223-30, Jan 1997. Abstract

Haley RW. Is Gulf War syndrome due to stress? The evidence reexamined. American Journal of Epidemiology, 146(9):695-703, Nov 1997. Abstract

Haley RW, Kurt TL, Horn J. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA, 15;277(3):215-22, Jan 1997. Abstract

Horn J, Haley RW. Neuropsychological correlates of Gulf War syndrome. Arch Clin Neuropsychol, 12:531-544, 1997. Article

Haley RW. PON1 and low-dose sarin in marmosets. Journal of Psychopharmacol, 14 (1): 87-88, 2000. Article

Haley RW. Point: bias from the "healthy-warrior effect" and unequal follow-up in three government studies of health effects of the Gulf War. American Journal of Epidemiology, 148(4):315-23, Aug 1998. Abstract

Haley RW. Re: Is there a Gulf War syndrome? Lancet, 354: 1645-1646, 1999. Article

Haley RW, Kurt TL. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. JAMA, 15;277(3):231-7, Jan 1997. Abstract

Haley RW. The Gulf War syndrome controversy: Dr. Haley replies. American Journal of Epidemiology, 150: 216-217, 1999. Article