Mitochondrial Stress, Brain Imaging, and Epigenetics

Not Applicable

Completed

Conditions: Mitochondrial Diseases

Interventions: Behavioral: Trier social stress test

Registration Number: NCT04831424

Lead Sponsor: Columbia University

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 110

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Healthy controls	Trier social stress test	No diagnosis of mitochondrial disease
Mutation	Trier social stress test	Participants carrying the m.3243A\>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)
Mutation with MELAS	Trier social stress test	Participants carrying the m.3243A\>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)
Deletion	Trier social stress test	Participants carrying a single, large-scale mtDNA deletion

Primary Outcome Measures

Name	Time	Method
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. 32 different biomarkers were analyzed for this outcome. The full range of the allostatic load index score is 0 to 32. A lower score is considered better, and a higher score is considered worse.

Secondary Outcome Measures

Name	Time	Method
Average TSST-induced Elevation in Heart Rate	Baseline and 2 hours post challenge on Day 1	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	The fluency/initiation domain of executive functioning was assessed using the Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Test, specifically Condition 1: Letter Fluency total correct. Raw scores were converted to Z-scores based on the control group. A Z-score of 0 represents the mean of the control group, with positive values indicating better performance and negative values indicating worse performance.