Project Details

Description

We propose a set of studies focused on the association of suicide with neuroinflammation andcompromise of the blood-brain barrier, with the goal of identifying a pattern of quantifiable abnormalities thatcould serve as a biomarker for imminent suicidal risk in our Veterans. Autopsy studies are uniquely suited to dothis, because they capture the state of the brain at the time of the suicidal act. Findings from our laboratories and others indicate that susceptibility to suicide includes inflammatoryactivation in the brain and systemically, accompanied by compromised integrity of the blood-brain barrier: (1)Most directly, we reported increased densities of microglia or other phagocytic cells associated with bloodvessels in dorsal prefrontal white matter of people who died by suicide, Similar results are reported in cingulatewhite matter. (2) Studies of brains from individuals who died by suicide and studies of blood and CSF from liveindividuals who had previously attempted suicide found elevations of inflammatory cytokines. (3) Variousinfectious diseases are associated with increased risk of suicide, as is a history of hospitalization for anyinfection. (4) Laboratory animals exposed to stress show elevated levels of inflammatory cytokines, increasedpermeability of the blood-brain barrier, behavioral abnormalities, and activation of microglia. (5) We havereported an association of suicide with a polymorphism and decreased frontal and cingulate transcripts forCD44, which is involved in the normal function of the BBB. (6) Biochemical measures suggesting BBBimpairment are reportedly associated with attempted suicide and with suicidal ideation. (7) In MDD subjectswho died by suicide, compared with nonpsychiatric non-suicide cases, we found differential methylation ofgenes associated with cell death, both in whole cortical homogenates and in purified neuronal fractions. Wealso found significantly lower methylation in the promoter of the gene for CCL3, a powerful inflammatorycytokine synthesized by microglia and astrocytes and an attractant for microglia and white blood cells, but thisdifference was not present in the purified neuronal fraction. Taken together, these findings lead us to hypothesize a suicidal state characterized by impaired BBBfunction, elevation of pro-inflammatory cytokines, and abnormalities in DNA methylation of genes stimulatinginflammation, all of which can be assessed in live individuals. To confirm this phenotype, we propose threespecific aims, each employing the same set of 90 autopsy brains, already collected. In order to distinguishfeatures of suicide from those of psychiatric illness, we employ a 3-group design with 30 cases of psychiatricdisease and suicide, 30 cases of psychiatric disease without suicide, and 30 cases with neither psychiatricdisease nor suicide, all from a well-characterized collection with a single collection protocol at a single autopsyservice. To optimize our ability to distinguish features of suicide from those of psychiatric disease, in addition tofinding the best matches between groups by age and sex, we sought to limit all of the psychiatric cases to asingle clinical group, which was best achieved with schizophrenia spectrum disorders. Our specific aims, foreach of which we will assay cerebral cortex and white matter from dorsal and ventral prefrontal regions, are:(1) To evaluate functional BBB impairment by stereological assessment of perivascular deposits of fibronectin.(2) To quantify a panel of cytokines, and to look for structural evidence of BBB impairment by assaying isolatedmicrovessel fractions for vascular tight junction proteins and matrix metalloproteases.(3) To identifytranscriptional correlates of BBB alterations with a genome-wide methylation survey on microvessel fractions ofcortex and white matter from each region, using the Illumina Infinium MethylationEPIC microarray .These datawill allow us to establish the underlying abnormalities for development of a suicidal profile to better, identify andtreat veterans at risk of suicide. Knowledge and application of this profile will save Veterans’ lives by identifyingpotential targets for novel clinical interventions.

StatusFinished
Effective start/end date1/01/1831/12/21

Funding

  • U.S. Department of Veterans Affairs: $247,334.00

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