Combat PTSD, Cellular Aging, and Atrophy of the Hippocampus

Investigator: Thomas Neylan, MD
Sponsor: Lightfighter Trust

Location(s): United States


Accumulating evidence indicates that Post Traumatic Stress Disorder (PTSD) substantially increases risk for age-related diseases, including cardiovascular, autoimmune, neurodegenerative diseases, and early mortality. Although the biological mechanisms mediating these associations remain unclear, PTSD is associated with dysregulation of bodily systems that have been linked with biological aging. Accelerated biological aging is a possible mechanism of increased disease risk in PTSD. The hippocampus is a brain area essential for learning and memory, and known to be responsive to stress. Advanced age is associated with a reduction in the size of the hippocampus. Magnetic resonance imaging (MRI) studies have shown that PTSD is also associated with a reduced size of the hippocampus. However, the nature of the relationship between PTSD and hippocampal size is poorly understood. Two fundamentally different ideas about the relationship are currently considered. According to one, a small hippocampus is considered a sequel of chronic stress reactivity in PTSD and hippocampal damage is attributed to the toxic effects of glucocorticoids and glutamate, or alternatively, related to decreased brain trophic factors such as brain derived neurotrophic factor. This model implies hippocampal plasticity in humans. The second model of hippocampal atrophy in PTSD is that it represents a pre-existing hereditary risk factor that increases the vulnerability to develop PTSD. Telomeres are DNA-protein complexes that cap the ends of chromosomes and protect against DNA damage. Telomeres shorten with each cycle of cell division and with oxidative stress. Leukocyte telomere length (LTL) is a marker of biological age that predicts incidence of age-related diseases as well as mortality. Telomere shortening is not just an index of biological age, but also a mechanism of biological aging because critically short telomere length can lead to DNA damage and cell death. Preliminary data indicates that short LTL is associated with smaller hippocampal volume, a risk factor for neurodegenerative disease. Inflammation is a widely accepted mechanism of biological aging in general, and of telomere shortening in particular. There is accumulating evidence that PTSD is associated with elevated inflammation. However, it is not known if elevated inflammation is a vulnerability factor for PTSD or a consequence of PTSD, and little is known about the association of inflammation with brain abnormalities such as hippocampal abnormalities in PTSD. This project will analyze levels of the inflammatory proteins C-reactive protein, interleukin-6 and tumor necrosis factor-alpha in a large sample of almost 300 veterans who served in the Persian Gulf War and participated in a prior neuroimaging project which obtained detailed measures of both childhood and combat trauma exposure. The project aims to shed light on the nature of inflammatory abnormalities in PTSD and also examine if elevated inflammation is associated with reduced hippocampal volume in PTSD.