Microglial Activation in Inflammatory Bowel Disease

Naturalistic Monitoring of Microglial Activation in Inflammatory Bowel Disease

The purpose of this study is to monitor microglial activation in participants with inflammatory bowel disease (IBD) and investigate the relationship that exists between these patients and their risk of acquiring major depressive episodes (MDE). Patients with both IBD and MDE will be subsequently approached to participate in the study.

Study Overview

• Status: Active, not recruiting
• Conditions: Inflammatory Bowel Diseases; Major Depressive Episode
• Intervention / Treatment: Radiation: [18F]FEPPA

Detailed Description

Detailed Description:

Participants may undergo up to 3 PET Scans : [18F]FEPPA PET (for TSPO) before and 3 to 6 months later and [11C]SL25.1188 PET (for MAO-B) as well as 1 MRI scan.

The primary hypothesis is that :

1. The neuroinflammation (TSPO VT) will be increased in PFC, ACC, and insula regions in those with inflammatory bowel disease (IBD) patients compared to healthy people.
2. The neuroinflammation (TSPO VT) in PFC, ACC, and insula regions will be reduced after treatment for IBD.

The Secondary Hypothesis:

1. Elevations in neuroinflammation (TSPO VT) will be similar in those with ulcerative colitis and Crohn's disease.
2. Neuroinflammation (TSPO VT) will be greater in IBD with depression than in depression without IBD.
3. Biologics (TNFalpha antibody treatments), and fecal transplantation will be associated with greater reduction in neuroinflammation in brain than Sulfasalazine/5-Aminosalicylates.
4. MAO-B VT will be elevated in in the PFC, ACC, and insula in IBD compared to healthy controls.

There will be no alterations to standard care of patients due to participation in the study.

• Study Type: Observational
• Enrollment (Estimated): 135

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 1R8
      • Centre for Addiction and Mental Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Community and tertiary care clinic

Description

Inclusion Criteria:

• Age 18 to 65
• aside from IBD groups and common comorbidities of IBD, otherwise good physical health with no current active medical conditions.
• a lifetime diagnosis of IBD verified by medical record, which can include prescription for IBD treatment

Exclusion Criteria:

• no history of neurological illness, excluding migraine
• no use of glucocorticoid antagonists or lithium or medications that bind with affinity higher than 500nM to peripheral benzodiazepine receptors (or TSPO) in the previous two months
• no use of herbal remedies in the previous month that would be expected to influence neuroinflammation
• non-cigarette smoking
• no history of abuse of substances that affect mood and negative urine drug screens for substances of abuse including cotinine (urine drug screen is done at screening and on each PET scan day)
• no history of psychotic symptoms
• not pregnant based on a negative pregnancy test (for women)
• not breastfeeding (for women)
• no recent treatment with electroconvulsive therapy or magnetic seizure therapy in the previous 6 months
• no coagulation disorders, or anticoagulant medication use
• no presence of metal objects or implanted electrical devices in the body that would preclude MRI scanning
• no claustrophobia
• no self-reported history of fainting from blood withdrawals
• size and weight does not exceed capacity of scanner, for which size may vary and weight is 350 lbs
• no history of undergoing a number of PET scans that, including the number of PET scans under this protocol, will bring the total to more than 8 PET scans/lifetime, exceeding permissible limit for subjects participating in research set by our centre's guidelines

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group 1 (IBD primary diagnosis); Participants have active IBD	Radiation: [18F]FEPPA; up to 3 PET Scans ([18F]FEPPA PET scans done 3 to 6 months apart, and one [11C]SL2511.88 PET scan) and 1 MRI
Group 2( IBD + comorbid MDE); 1 [18F]FEPPA PET scan in those with IBD symptoms in the past 2 years as well present with MDE	Radiation: [18F]FEPPA; up to 3 PET Scans ([18F]FEPPA PET scans done 3 to 6 months apart, and one [11C]SL2511.88 PET scan) and 1 MRI
Group 3-Controls; Matched for Level of Depressive Symptoms and Otherwise Healthy -Subjects in an otherwise healthy state with major depressive episodes, obsessive compulsive disorder, or generalized anxiety disorder will provide psychiatric diagnosis matched controls to those with IBD. Data for group three will be largely obtained from previous recent studies (it is anticipated that 95% of this data is already available).	Radiation: [18F]FEPPA; up to 3 PET Scans ([18F]FEPPA PET scans done 3 to 6 months apart, and one [11C]SL2511.88 PET scan) and 1 MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TSPO VT in prefrontal cortex, anterior cingulate cortex, and insula	Between group comparison for 3 regions in IBD compared to controls (analysis done concurrently for group effect across 3 regions)	within 3 to 4 weeks after initiation of screening
change in TSPO VT in prefrontal cortex, anterior cingulate cortex, and insula before and after 3 to 6 months	Change in TSPO VT for three regions (same units for each region)	3 to 6 months
MAO-B VT in prefrontal cortex, anterior cingulate cortex, insula in IBD compared to controls	Between group comparison for 3 regions in IBD compared to controls	within 3 to 4 weeks after initiation of screening

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TSPO VT in prefrontal cortex, anterior cingulate cortex, insula compared between Crohns disease and ulcerative colitis	comparison of TSPO VT in 3 regions between two types of inflammatory bowel disease	within 3 to 4 weeks of initiating screening of subjects
TSPO VT in prefrontal cortex, anterior cingulate cortex, insula compared between IBD with MDE compared to MDE controls	Between group comparison for 3 regions in IBD compared to controls	within 3 to 4 weeks after initiation of screening
change in TSPO VT in prefrontal cortex, anterior cingulate cortex, insula compared between naturalistic treatment with sulfasalazine/5-aminosalicylates versus other interventions like biologics or fecal transplantation	differential change in TSPO VT across 3 regions before and after 6 months in those receiving naturalistic treatment with sulfasalazine/5-aminosalicylates versus other naturalistic treatments of fecal transplantation or biologics	3 to 6 months

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: McMaster University
• Investigators: Principal Investigator: Jeffrey H Meyer, M.D.,PhD, Research Imaging Centre, Centre for Addiction and Mental Health

Publications and helpful links

General Publications

• Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, Suridjan I, Kennedy JL, Rekkas PV, Houle S, Meyer JH. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015 Mar;72(3):268-75. doi: 10.1001/jamapsychiatry.2014.2427.
• Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, Xu C, Richter MA, Kahn A, Kish SJ, Houle S, Ravindran L, Meyer JH. Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder. JAMA Psychiatry. 2017 Aug 1;74(8):833-840. doi: 10.1001/jamapsychiatry.2017.1567.
• Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, Gerhard A, Talbot PS. Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study. Biol Psychiatry. 2018 Jan 1;83(1):61-69. doi: 10.1016/j.biopsych.2017.08.005. Epub 2017 Aug 12.
• Li H, Sagar AP, Keri S. Translocator protein (18kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Apr 20;83:1-7. doi: 10.1016/j.pnpbp.2017.12.011. Epub 2017 Dec 19.

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 18, 2018
• First Submitted That Met QC Criteria: April 3, 2018
• First Posted (Actual): April 4, 2018

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Intestinal Diseases
• Other Study ID Numbers: 102-2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO