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Principal Investigator: FATEMEH G HAGHIGHI
Organization: JAMES J PETERS VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
We propose a set of studies focused on the association of suicide with neuroinflammation and
compromise of the blood-brain barrier, with the goal of identifying a pattern of quantifiable abnormalities that
could serve as a biomarker for imminent suicidal risk in our Veterans. Autopsy studies are uniquely suited to do
this, 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 inflammatory
activation 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 blood
vessels in dorsal prefrontal white matter of people who died by suicide, Similar results are reported in cingulate
white matter. (2) Studies of brains from individuals who died by suicide and studies of blood and CSF from live
individuals who had previously attempted suicide found elevations of inflammatory cytokines. (3) Various
infectious diseases are associated with increased risk of suicide, as is a history of hospitalization for any
infection. (4) Laboratory animals exposed to stress show elevated levels of inflammatory cytokines, increased
permeability of the blood-brain barrier, behavioral abnormalities, and activation of microglia. (5) We have
reported an association of suicide with a polymorphism and decreased frontal and cingulate transcripts for
CD44, which is involved in the normal function of the BBB. (6) Biochemical measures suggesting BBB
impairment are reportedly associated with attempted suicide and with suicidal ideation. (7) In MDD subjects
who died by suicide, compared with nonpsychiatric non-suicide cases, we found differential methylation of
genes associated with cell death, both in whole cortical homogenates and in purified neuronal fractions. We
also found significantly lower methylation in the promoter of the gene for CCL3, a powerful inflammatory
cytokine synthesized by microglia and astrocytes and an attractant for microglia and white blood cells, but this
difference was not present in the purified neuronal fraction.
Taken together, these findings lead us to hypothesize a suicidal state characterized by impaired BBB
function, elevation of pro-inflammatory cytokines, and abnormalities in DNA methylation of genes stimulating
inflammation, all of which can be assessed in live individuals. To confirm this phenotype, we propose three
specific aims, each employing the same set of 90 autopsy brains, already collected. In order to distinguish
features of suicide from those of psychiatric illness, we employ a 3-group design with 30 cases of psychiatric
disease and suicide, 30 cases of psychiatric disease without suicide, and 30 cases with neither psychiatric
disease nor suicide, all from a well-characterized collection with a single collection protocol at a single autopsy
service. To optimize our ability to distinguish features of suicide from those of psychiatric disease, in addition to
finding the best matches between groups by age and sex, we sought to limit all of the psychiatric cases to a
single clinical group, which was best achieved with schizophrenia spectrum disorders. Our specific aims, for
each 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 isolated
microvessel fractions for vascular tight junction proteins and matrix metalloproteases.(3) To identify
transcriptional correlates of BBB alterations with a genome-wide methylation survey on microvessel fractions of
cortex and white matter from each region, using the Illumina Infinium MethylationEPIC microarray .These data
will allow us to establish the underlying abnormalities for development of a suicidal profile to better, identify and
treat veterans at risk of suicide. Knowledge and application of this profile will save Veterans’ lives by identifying
potential targets for novel clinical interventions.
Terms: <5HT transporter><5HTT protein><Affect><Age><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Area><Assay><Astrocytes><Astrocytus><Astroglia><Autopsy><BBB crossing><BBB disruption><BBB function><BBB permeabilization><BBB permeable><Behavioral><Bioassay><Biochemical><Biological><Biological Assay><Biological Markers><Blood><Blood - brain barrier anatomy><Blood Coagulation Factor I><Blood Coagulation Factor One><Blood Factor One><Blood Reticuloendothelial System><Blood Sample><Blood Serum><Blood Vessels><Blood leukocyte><Blood specimen><Blood-Brain Barrier><Brain><Brain Nervous System><Brain imaging><CCL3><CCL3 gene><CD44><CD44 gene><Cause of Death><Cell Communication and Signaling><Cell Death><Cell Signaling><Cerebral cortex><Cerebrospinal Fluid><Cessation of life><Characteristics><Chemokine (C-C motif) Ligand 3><Clinical><Clinical Evaluation><Clinical Testing><Coagulation Factor I><Coagulation Factor One><Cold-Insoluble Globulins><Collection><Communicable Diseases><Confounding Factors (Epidemiology)><Confounding Variables><DNA Methylation><Data><Death><Deposit><Deposition><Detection><Development><Diagnostic><Diathesis><Disease><Disease susceptibility><Disorder><Dorsal><Encephalon><Epidemiologic Confounding Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Exposure to><Extravasation><FN1><Factor I><Factor One><Feeling suicidal><Fibrinogen><Fibronectin 1><Fibronectins><Functional impairment><G0S19-1><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Genes><Genetic Polymorphism><Genetic Transcription><Goals><Health><Hemato-Encephalic Barrier><Histologic><Histologically><History><Hortega cell><Hospital Admission><Hospitalization><Immune response><Immune system><Immunological response><Impairment><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Knowledge><LD78ALPHA><LETS Proteins><Laboratories><Laboratory Animals><Large External Transformation-Sensitive Protein><Leakage><Leukocytes><Leukocytes Reticuloendothelial System><Life Stress><Link><MDU3><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><MMPs><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Marrow leukocyte><Matrix Metalloproteinases><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mental Depression><Mental disorders><Mental health disorders><Metallopeptidases><Metalloproteases><Metalloproteinases><Methods><Methylation><Microglia><Modeling><Molecular><NMR Imaging><NMR Tomography><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurobiology><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Noise><Non-Invasive Detection><Noninvasive Detection><Nuclear Magnetic Resonance Imaging><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Occluding Junctions><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Pattern><Peripheral><Persons><Pgp1><Phagocytes><Phagocytic Cell><Phenotype><Plasma Proteins><Predisposition><Prefrontal Cortex><Preventative treatment><Preventive treatment><Probability><Procedures><Process><Prospective Studies><Proteins><Proteomics><Protocol><Protocols documentation><Psychiatric Disease><Psychiatric Disorder><RNA Expression><Recording of previous events><Regulatory Regions><Reporting><Research><Risk Reduction><SCYA3><Sampling><Schizophrenia><Schizophrenic Disorders><Serum><Serum Proteins><Services><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Inducible Cytokine A3><Spillage><Stem Cell Inhibitor><Stress><Suicidal thoughts><Suicide><Suicide attempt><Surface><Survey Instrument><Surveys><Susceptibility><Testing><Tight Junctions><Time><Tissue Sample><Transcript><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Veterans><White Blood Cells><White Cell><Zeugmatography><Zonula Occludens><age group><ages><alpha 2-Surface Binding Glycoprotein><amebocyte><analyze gene expression><astrocytic glia><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><blood-brain barrier crossing><blood-brain barrier disruption><blood-brain barrier function><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier crossing><bloodbrain barrier disruption><bloodbrain barrier function><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain microvasculature><brain microvessels><brain visualization><cerebral microvasculature><cerebral microvessels><cerebral spinal fluid><clinical test><contrast enhanced><cytokine><dementia praecox><depression><design><designing><developmental><diagnostic tool><epigenetic biomarker><epigenetic marker><epigenetically><fatal attempt><fatal suicide><gene expression analysis><gene expression assay><genetic regulatory element><genome scale><genome wide methylation><genome-wide><genomewide><genomewide methylation><gitter cell><glial activation><glial cell activation><global methylation><gray matter><high risk><histories><host response><immune system response><immunoresponse><in vivo><intent to die><interventional strategy><liability to disease><mental illness><mesoglia><methylation pattern><microglial cell><microgliocyte><military veteran><molecular biomarker><molecular marker><necrocytosis><necropsy><neural inflammation><neurobiological><neuroinflammation><neuroinflammatory><neurological disease><neuronal><non fatal attempt><nonfatal attempt><novel><perivascular glial cell><polymorphism><postmortem><promoter><promotor><psychiatric illness><psychologic><psychological><psychological disorder><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><research clinical testing><response><risk-reducing><schizophrenia spectrum><schizophrenia spectrum disorder><schizophrenic><secondary analysis><serotonin transporter><sex><sodium-dependent serotonin transporter><spinal fluid><substantia alba><substantia grisea><suicidal><suicidal act><suicidal attempt><suicidal behavior><suicidal ideation><suicidal risk><suicidal thinking><suicidality><suicide act><suicide attempter><suicide behavior><suicide ideation><suicide risk><suicide victim><suicides><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thoughts about suicide><transcriptional profiling><transcriptomics><vascular><veteran population><white blood cell><white blood corpuscle><white matter>