Mitochondrial Stress, Brain Imaging, and Epigenetics

Mitochondrial Diseases Clinical Trial

— MiSBIE  

Official title:

The Mitochondrial Stress, Brain Imaging, and Epigenetics Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04831424
• Other study ID #: NYSPI 7424
• Secondary ID: 5R01MH122706
• Status: Completed
• Phase: N/A
• Start date: June 12, 2018
• Est. completion date: May 3, 2024

Study information

• Verified date: May 2024
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: May 3, 2024
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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)

Related Conditions & MeSH terms

• Mitochondrial Diseases

Intervention

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.

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center	New York	New York

Sponsors (6)

Lead Sponsor	Collaborator
Columbia University	Centre National de la Recherche Scientifique, France, Dartmouth College, Massachusetts General Hospital, National Institute of Mental Health (NIMH), Technische Universität Dresden

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Average TSST-induced elevation in cortisol	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.	Day 1 post challenge (approximately 2 hours)
Primary	Average allostatic load index	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.	Blood collected on Day 1
Secondary	Average TSST-induced elevation in heart rate	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.	Day 1 post challenge (approximately 2 hours)
Secondary	Correlation between anxiety and mitochondrial respiration	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.	Day 1
Secondary	Average neuropsychological function	Groups will be compared on the fluency/initiation domain of executive functioning assessed using the Delis-Kaplan Executive Function System (D-KEFS) test.	Day 2 neuropsychological session

External Links

•   Study Brochure