Identifying Correlates of Brain Microglial Activation in Neuropsychiatric Syndromes: A Dimensional Approach

Identifying Correlates of Brain Microglial Activation in Neuropsychiatric Syndromes: A Dimensional Approach

Identifying Correlates of Brain Microglial Activation in Neuropsychiatric Syndromes: A Dimensional Approach

The purpose of this research is to determine whether there is more extensive inflammation in the brain of people with clinical evidence of neuropsychiatric syndromes, such as mood disorder, chronic pain syndrome, dementia, traumatic brain injury, or substance abuse. The research will also explore whether there is more inflammation in patients with more neuropsychiatric symptoms. Inflammation in the brain will identified by using Positron Emission Tomography (PET) with the radiotracer [11C]PBR-28 or [11C]ER176.

This study will explore whether brain microglial activation (which leads to an inflammatory response) is more extensive in individuals with clinical evidence of neuropsychiatric syndromes and whether the extent of microglial activation is proportional to the extent of neuropsychiatric symptoms. More specifically, the hypothesis is that: Brain microglial activation is more substantial in the presence of neuropsychiatric illness, and the extent of brain microglial activation is proportional to severity of phenotypic presentation of neuropsychiatric illness (i.e. depression, cognitive impairment, fatigue, etc.) in a given patient. Specific brain regions where enhanced microglial activation is present underlie a portion of phenotypic variance in neuropsychiatric patients Combinations of neuropsychiatric phenotypes rather than specific differences in immune mechanisms underlie the contribution of central immune activation to a specific neuropsychiatric diagnosis. The following measures will be obtained: microglial activation as quantified by PET using the radiotracer [11C]PBR-28 or [11C]ER176. ([11C]PBR-28 and [11C]ER176 specifically bind translocator protein (TSPO), which is associated with microglial activation and can thus serve as an in vivo biomarker of microglial activation and neuroinflammation. TSPO is also called the peripheral benzodiazepine receptor (PBR)) dimension of specific neuropsychiatric symptoms (Hamilton Depression Rating Scale (HDRS), Montreal Cognitive Assessment (MoCA), Positive and Negative Affect Schedule (PANAS)) presence/absence of a specific neuropsychiatric diagnosis (Dementing Illnesses, Traumatic Brain Injury, Major Depression, Bipolar Disorder, Pain Syndromes, Other Affective Disorders, etc.) Using the above measures, correlations (and brain regional correlations) between the extent of microglial activation and the presence of a dimension of neuropsychiatric symptoms will be tested for. Following this, the presence of microglial activation (and brain regional microglial activation) 1) between healthy control volunteers and volunteers with neuropsychiatric syndromes and 2) between the various neuropsychiatric syndromes/diagnoses will be tested for.

PET with radiotracer [11C]PBR-28 or [11C]ER176 will be performed. [11C]PBR-28 or [11C]ER176 will be injected into subjects' veins during PET scanning.

PET with radiotracer [11C]PBR-28 or [11C]ER176 will be performed. [11C]PBR-28 or [11C]ER176 will be injected into subjects' veins during PET scanning. Affective challenge (e.g. induction of mood, affective pain) will be presented to the patient during the PET scanning period.

Level of TSPO expression as quantified by PET imaging to detect binding of the TSPO radiotracer [11C]PBR-28

obtained during PET scanning (between 1:30 PM and 3 PM) at study baseline within a few days of study enrollment

HDRS is a multiple item questionnaire used to provide an indication of depression. A score of 0-7 is considered to be normal. Scores of 20 or higher indicate moderate, severe, or very severe depression.

within 1-2 hours before PETobtained during PET scanning (between 1:30 PM and 3 PM) at study baseline within a few days of study enrollment

The MoCA assesses several cognitive domains. The total possible score is 30 points with a score of 26 or more considered normal.

within 1-2 hours before PETobtained during PET scanning (between 1:30 PM and 3 PM) at study baseline within a few days of study enrollment

Positive Affect Score: Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Score: Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

within 1-2 hours before PETobtained during PET scanning (between 1:30 PM and 3 PM) at study baseline within a few days of study enrollment

Positive Affect Score: Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Score: Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

during PET (between 1:30 PM and 3 PM)obtained during PET scanning (between 1:30 PM and 3 PM) at study baseline within a few days of study enrollment

Positive Affect Score: Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Score: Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

immediately following PET (3PM +/- 30 minutes)obtained during PET scanning (between 1:30 PM and 3 PM) at study baseline within a few days of study enrollment

Inclusion Criteria: Must be between 18-45 years old Males or females Must be right handed Must be able to sit unaccompanied for long periods of time with little body movement Must be illicit drug free at time of scanning as appropriate (UDS negative), Must be either healthy (without medical, neurological, psychiatric illness) or have a diagnosis of a neuropsychiatric syndrome (mood disorder, chronic pain syndrome, dementias, traumatic brain injury, substance/alcohol use disorder). Healthy Control volunteers must be medication free (≥ 14 days) Illicit drug free at time of scanning (verified by negative urine drug screen) Exclusion Criteria: Must not be a smoker. Females must not be pregnant or nursing. Must not suffer from claustrophobia Must not meet exclusion criteria for MRI scanning (i.e. non-fixed magnetisable objects) Must not be PBR-28 low affinity binder (or using the [11C]ER176 study radiotracer) Healthy control volunteers must not have on-going, chronic, or relapsing/remitting medical, psychiatric (absence of both DSM-IV Axis I and/or Axis II disorders), or neurological illness as determined by combination of history, medical record, and/or examination.