MiSBIE: Mitochondrial Stress, Brain Imaging, and Epigenetics

Sponsor

Columbia University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04831424

Collaborator

Dartmouth College (Other), Centre National de la Recherche Scientifique, France (Other), Massachusetts General Hospital (Other), Technische Universität Dresden (Other)

120

Enrollment

Location

Arms

82.6

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The MiSBIE study collects biological, behavioral, psychosocial, neuropsychological, and brain imaging data in participants with either: normal mitochondrial function, individuals with the m.3243A>G mitochondrial DNA (mtDNA) mutation, and individuals a single large-scale mtDNA deletion. These defects induce mitochondrial allostatic load (MAL). The 2-day protocol, plus home-based data collection, will provide a comprehensive assessment of the multi-systemic dysregulation associated with MAL or mitochondrial dysfunction, and the link to physical and mental health-related symptoms.

Aim 1: Determine the influence of MAL on systemic AL biomarkers.

Aim 2: Establish the influence of MAL on stress reactivity profiles.

Aim 3. Examine the association between MAL and psychological functioning.

Condition or Disease	Intervention/Treatment	Phase
Mitochondrial Diseases	Behavioral: Trier social stress test	N/A

Detailed Description

Age-related physical and cognitive decline, as well as the risk of neurological diseases, are increased by the effects of psychosocial stress. Psychosocial stress triggers neuroendocrine, metabolic, cardiovascular, and inflammatory changes in the body. These changes vary in nature and magnitude between individuals, and are associated with long-term disease risk. However, the biological determinants of the stress response are not well understood.

This project aims to translate the preclinical findings (how mitochondria regulate the different organ systems and major stress response axes are activated during psychological stress) by studying a population of individuals with varying degree of mitochondrial dysfunction, and to test potential neural mechanism, and why some individuals respond more strongly than others to the same stressor.

Each participant will be studied over two consecutive days. Participants will be housed on campus to standardize study conditions. On Day 1, participants will donate blood and saliva, undergo a neuropsychological assessment, and complete questionnaires to assess psychosocial functioning and psychiatric symptoms. After lunch, the investigator will monitor dynamic changes in mental health-related biological outcomes (positive and negative affect, circulating levels of the inflammatory cytokine IL-6, and salivary cortisol) in response to a standardized laboratory challenge. On Day 2, participants will undergo a medical evaluation to assess clinical symptoms and undergo a whole brain neuroimaging session where both resting and stress elicited activity will be measured. A variant of the same stressor as on Day 1 will be used in the neuroimaging session. Participants will then be debriefed, concluding the individuals participation in the study. Participants also complete a home-based saliva and stool collection to examine diurnal variation in salivary hormones, and to examine microbiome composition. This translational project will generate a unique combination of complimentary molecular, cellular, and neuroimaging data that will advance our understanding of the links between mitochondria, the brain, and mental health-related outcomes.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

All participants will undergo TSST and have samples With DNA collected (blood plasma and serum, purified leukocytes, saliva, urine, buccal epithelial cells, hair are stored).All participants will undergo TSST and have samples With DNA collected (blood plasma and serum, purified leukocytes, saliva, urine, buccal epithelial cells, hair are stored).

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

The Mitochondrial Stress, Brain Imaging, and Epigenetics Study

Actual Study Start Date :

Jun 12, 2018

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Apr 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Healthy controls No diagnosis of mitochondrial disease	Behavioral: Trier social stress test The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study. Other Names: TSST
Experimental: Mutation Participants carrying the m.3243A>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)	Behavioral: Trier social stress test The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study. Other Names: TSST
Experimental: Mutation with MELAS Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)	Behavioral: Trier social stress test The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study. Other Names: TSST
Experimental: Deletion Participants carrying a single, large-scale mtDNA deletion	Behavioral: Trier social stress test The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study. Other Names: TSST

Outcome Measures

Primary Outcome Measures

Average TSST-induced elevation in cortisol [Day 1 post challenge (approximately 2 hours)]
This is designed to measure cortisol reactivity to the trier social stress test (TSST), quantified from salivary cortisol (LC-MS) over an 8-timepoints timecourse. The elevation will be measured as the area under the curve (AUC) for the cortisol time course.
Average allostatic load index [Blood collected on Day 1]
Groups will be compared on a quantitative allostatic load (AL) index integrating baseline fasting measures of neuroendocrine, immune and metabolic systems, urinary catecholamines, hematological measures, and hair/diurnal cortisol levels.

Secondary Outcome Measures

Average TSST-induced elevation in heart rate [Day 1 post challenge (approximately 2 hours)]
Groups will be compared on heart rate (HR) as a measure of cardiovascular reactivity to stress, monitored using a continuous 3-lead ECG. The elevation will be computed from the baseline HR to the peak HR reached during the TSST.
Correlation between anxiety and mitochondrial respiration [Day 1]
The association between mitochondrial respiration using extracellular flux analysis (Seahorse) on blood lymphocytes, and anxiety symptoms measured using the state and trait anxiety inventory (STAI), will be quantified by a linear regression across all study participants.
Average neuropsychological function [Day 2 neuropsychological session]
Groups will be compared on the fluency/initiation domain of executive functioning assessed using the Delis-Kaplan Executive Function System (D-KEFS) test.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Men and women patients between 18 and 55 years of age
Willing to provide saliva samples and have venous catheter installed for blood collection during the hospital visit
Willing to provide informed consent and capacity to consent
Use of effective method of birth control for women of childbearing capacity
English Speaking

Exclusion Criteria:

Individuals with cognitive deficit incapable of providing informed consent will not be included
Symptoms of flu or other seasonal infection four weeks preceding hospital visit
Raynaud's syndrome (Raynaud phenomenon)
Involvement in any therapeutic trials listed on clinicaltrials.gov, including exercise
Metal inside or outside the body or claustrophobia prohibitive to MRI testing
Diagnosed with mitochondrial disease m.3243A>G, or large scale mtDNA deletion (for healthy controls)