Mitochondrial Diseases
Conditions
Keywords
Mitochondria, Brain Imaging, Psychophysiology, Epigenetics, Stress, Metabolic rate, Mitochondrial function
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.
Interventions
BEHAVIORALTrier 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.
Sponsors
Dartmouth College
Centre National de la Recherche Scientifique, France
Massachusetts General Hospital
Technische Universität Dresden
National Institute of Mental Health (NIMH)
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls No diagnosis of mitochondrial disease | 70 |
| Mutation Participants carrying the m.3243A\>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) | 20 |
| Deletion Participants carrying a single, large-scale mtDNA deletion | 15 |
| Mutation With MELAS Participants carrying the m.3243A\>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) | 5 |
| Total | 110 |
Baseline characteristics
| Characteristic | Healthy Controls | Total | Mutation With MELAS | Deletion | Mutation |
|---|---|---|---|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 10.6 | 37.5 years STANDARD_DEVIATION 10.7 | 39.2 years STANDARD_DEVIATION 7.6 | 43.1 years STANDARD_DEVIATION 9.8 | 34.4 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 10 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 100 Participants | 5 Participants | 14 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 6 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 11 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 7 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 82 Participants | 5 Participants | 12 Participants | 18 Participants |
| Region of Enrollment United States | 70 participants | 110 participants | 5 participants | 15 participants | 20 participants |
| Sex: Female, Male Female | 48 Participants | 76 Participants | 2 Participants | 11 Participants | 15 Participants |
| Sex: Female, Male Male | 22 Participants | 34 Participants | 3 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 20 | 0 / 15 | 0 / 5 |
| other Total, other adverse events | 0 / 70 | 0 / 20 | 0 / 15 | 0 / 5 |
| serious Total, serious adverse events | 0 / 70 | 0 / 20 | 0 / 15 | 0 / 5 |
Outcome results
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. 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.
Time frame: Blood collected on Day 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Average Allostatic Load Index | 9.10 allostatic load score | Standard Deviation 3.81 |
| Mutation | Average Allostatic Load Index | 10.74 allostatic load score | Standard Deviation 4.05 |
| Deletion | Average Allostatic Load Index | 11.31 allostatic load score | Standard Deviation 3.61 |
| Mutation With MELAS | Average Allostatic Load Index | 12.00 allostatic load score | Standard Deviation 4.08 |
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.
Time frame: Day 1 post challenge (approximately 2 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Average TSST-induced Elevation in Cortisol | 37.44 ng*min/mL | Standard Deviation 114.6 |
| Mutation | Average TSST-induced Elevation in Cortisol | 33.86 ng*min/mL | Standard Deviation 54.46 |
| Deletion | Average TSST-induced Elevation in Cortisol | 42.83 ng*min/mL | Standard Deviation 35.83 |
| Mutation With MELAS | Average TSST-induced Elevation in Cortisol | 45.42 ng*min/mL | Standard Deviation 43.65 |
Secondary
Average Neuropsychological Function
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.
Time frame: Day 2 neuropsychological session
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Average Neuropsychological Function | 0.00 Z-score | Standard Deviation 1 |
| Mutation | Average Neuropsychological Function | -0.14 Z-score | Standard Deviation 0.96 |
| Deletion | Average Neuropsychological Function | -0.58 Z-score | Standard Deviation 1.35 |
| Mutation With MELAS | Average Neuropsychological Function | -0.26 Z-score | Standard Deviation 1.52 |
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.
Time frame: Baseline and 2 hours post challenge on Day 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Average TSST-induced Elevation in Heart Rate | 14.8 beats per minute | Standard Deviation 12.4 |
| Mutation | Average TSST-induced Elevation in Heart Rate | 12.4 beats per minute | Standard Deviation 10.7 |
| Deletion | Average TSST-induced Elevation in Heart Rate | 10.9 beats per minute | Standard Deviation 6.41 |
| Mutation With MELAS | Average TSST-induced Elevation in Heart Rate | 12.7 beats per minute | Standard Deviation 10.1 |
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.
Time frame: Day 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Healthy Controls | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and state anxiety | 0.10 coefficient of determination (R^2) |
| Healthy Controls | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and trait anxiety | 0.04 coefficient of determination (R^2) |
| Mutation | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and trait anxiety | 0.003 coefficient of determination (R^2) |
| Mutation | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and state anxiety | 0.04 coefficient of determination (R^2) |
| Deletion | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and state anxiety | 0.01 coefficient of determination (R^2) |
| Deletion | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and trait anxiety | 0.334 coefficient of determination (R^2) |
| Mutation With MELAS | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and state anxiety | 0.22 coefficient of determination (R^2) |
| Mutation With MELAS | Correlation Between Anxiety and Mitochondrial Respiration | Correlation between mitochondrial respiration and trait anxiety | 0.02 coefficient of determination (R^2) |