Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE)

Columbia University

Status: Completed

Conditions: Mitochondrial Diseases

Treatments: Behavioral: Trier social stress test

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04831424

NYSPI 7424

5R01MH122706 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 110 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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)

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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110 participants in 4 patient groups

Healthy controls

Experimental group

Description:

No diagnosis of mitochondrial disease

Treatment:

Behavioral: Trier social stress test

Mutation

Experimental group

Description:

Participants carrying the m.3243A\>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)

Treatment:

Behavioral: Trier social stress test

Mutation with MELAS

Experimental group

Description:

Participants carrying the m.3243A\>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)

Treatment:

Behavioral: Trier social stress test

Deletion

Experimental group

Description:

Participants carrying a single, large-scale mtDNA deletion

Treatment:

Behavioral: Trier social stress test