Posttraumatic stress disorder (PTSD) is a condition of critical importance to the Veterans Health Administration that affects up to 15% of Vietnam combat veterans.1 Studies in animals demonstrated that stress is associated with alterations in the morphology of the hippocampus, a brain structure involved in learning and memory, as well as memory deficits. Patients with PTSD have smaller hippocampal volume on magnetic resonance imaging (MRI) and deficits in memory on neuropsychological testing. Animal models also show a progressive diminution of hippocampal volume with normal aging that is associated with a loss of memory function. In humans, in very old age in some individuals the hippocampus becomes smaller, with associated declines in memory function. Clinically, PTSD patients appear to have a more rapid rate of memory decline with age, which has led to their being characterized as having an "accelerated aging"; however there is little empiric data related to the interaction between normal aging and PTSD and its effect on memory. In the prior period of VA Merit funding the PI has studied memory and the hippocampus in twin pairs discordant for PTSD as well as normal twin pairs. We have studied 42 MZ and DZ twin pairs discordant for Vietnam theater exposure and discordant for PTSD and 28 MZ and DZ twin pairs concordant for Vietnam theater exposure and discordant for PTSD. All twins underwent measures of hippocampal volume, neuropsychological testing, and cortisol. A subset of 10 pairs of MZ pairs discordant for PTSD and combat exposure underwent positron emission tomography (PET) imaging of neural correlates of declarative memory function. Preliminary analyses are consistent with smaller hippocampal volume and deficits in verbal declarative memory in PTSD affected twins compared to their non-PTSD brothers who were not exposed to Vietnam combat.

We now propose to measure hippocampal volume, memory function, and neural correlates of declarative memory, in MZ and DZ twins previously studied, who are discordant for combat and PTSD. We will study 42 twin pairs who were studied during 1999-2003, of whom 34 were discordant for PTSD at the Atlanta based assessment and had all study data including MRI, neuropsychological testing, and cortisol (with PET in a subsample of 10 pairs), with repeat measurements performed 8 years after the initial assessment, a time of life when they become vulnerable to memory decline associated with aging (subjects not discordant for PTSD at the Atlanta based assessment will also be studied as a comparison). These assessments will allow a comprehensive assessment of the relative impact of shared environment (e.g. family life), unique environment (Vietnam theater service), and genetics on the outcomes of interest. We hypothesize that there will be an interaction between PTSD diagnosis and aging, i.e. PTSD patients relative to non-PTSD will show smaller hippocampal volume as measured with MRI, deficits in verbal declarative memory as measured with neuropsychological testing, lower cortisol, and a failure of hippocampal function during memory tasks as measured with PET, and that the rate of decline will be greater in PTSD v non PTSD. We further hypothesize that analysis of all twin pair combinations will show a combined impact of genetics and PTSD diagnosis on the hippocampal outcomes of interest.