Genetic Predisposition to Disease, Healthy Volunteers
Conditions
Brief summary
This study consists of two study parts (Part I and Part II) conducted under a single IRB approval. Individuals that participated in Part I of the study were invited to participate in Part II of the study. Alzheimer's disease is a devastating neurodegenerative disease characterized by accumulation of clumps (also called plaques) and bundles of fibers (also called tangles) in the brain, for which there is currently no cure. Sirolimus is an FDA-approved medication which may improve the blood flow to the brain. Part I: This study is designed to see if sirolimus treatment improves MRI blood flow to the brain in individuals with and without a genetic predisposition to Alzheimer's disease. Part I of this study is complete and no longer enrolling participants. Part II: Ongoing research will expand the genetic predisposition cohort and further explore the drug's impact on the lung perfusion via hyperpolarized xenon-129 gas MRI and the brain-vascular connection. Only subjects who are APOE4 carriers will be enrolled in Part II. Hyperpolarized xenon-129 gas MRI is a non-invasive technique in which a subject inhales a bolus of hyperpolarized xenon-129 gas which can be directly imaged by the MRI as it physiologically distributes itself throughout the lung interior and within tissue and red blood cells. It thus allows for direct imaging and quantification of regional lung function: ventilation, gas-exchange, and perfusion. The relationship between pulmonary vascular function and brain perfusion is largely unstudied. We hope to investigate the relationship between pulmonary vascular function and cerebral blood flow by quantifying both lung and brain perfusion before and after the administration of Sirolimus.
Interventions
DRUGSirolimus
This study consisted of two separate study parts conducted under the same IRB approval. Part I and Part II were operationally distinct but administratively linked. During Part I and Part II of the study, 1 mg of Sirolimus was taken orally once a day for 4 weeks.
Sponsors
University of Missouri-Columbia
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
This study consisted of two separate study parts conducted under the same IRB approval. Part I and Part II were operationally distinct but administratively linked. Part I: Inclusion Criteria: * 1\. Age 45-65 y/o * 2\. Male or female, all ethnic groups * 3\. Montreal Cognitive Assessment (MoCA) score greater than or equal to 26 * 4\. Clinical Dementia Rating (CDR) Staging Instrument = 0 * 5\. Carrier Cohort: APOE4 homozygous or heterozygous * 6\. Non-Carrier cohort: no APOE4 gene identified
Exclusion criteria
* 1\. Diagnosis of mild cognitive impairment (MCI) or dementia, including Alzheimer's disease * 2\. BMI ≥35 (based on MRI feasibility) * 3\. Diabetes (HBA1c≥6.5% or antidiabetic medications) * 4\. History of skin ulcers or poor wound healing * 5\. Current tobacco or illicit drug use or alcohol abuse (defined as ≥4 per day or ≥14 per week for men and ≥3 per day or ≥7 per week for women) (Per NIAAA guidelines) * 6\. Use of anti-platelet or anti-coagulant medications other than aspirin * 7\. Current medications that affect cytochrome P450 3A4 (CYP3A4) * 8\. Immunosuppressant therapy within the last year * 9\. Chemotherapy or radiation treatment within the last year * 10\. Current or chronic history of liver or kidney disease or known hepatic or biliary abnormalities * 11\. Untreated hypertriglyceridemia (fasting triglycerides \< 300 mg/dl) * 12\. Current or chronic significant history of pulmonary disease * 13\. Chronic heart failure * 14\. Pregnancy or lactation * 15\. Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack * 16\. Poorly controlled blood pressure (systolic BP\>160 or diastolic BP\>100 mmHg) * 17.Active inflammatory, Coronavirus (COVID-19), autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or severe mental illness * 18\. History of, or MRI, or CT positive for, any space occupying brain lesion, including mass effect or abnormal intracranial pressure * 19\. Organ transplant recipients * 20\. History of Stroke * 21\. History of ruptured intracranial aneurysm * 22\. Any condition for which a MRI procedure is contraindicated. Some examples include: metallic material in the body, such as pacemakers, metallic clips, etc. * 23\. Likelihood of claustrophobia Part II: The inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebral Blood Flow as measured on MRI | Baseline to 4 weeks | Rate of blood perfusion expressed as mL/100g/min globally and regionally |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part I: Plasma and Microbiome Biomarkers | Part I: Baseline to 4 weeks | Part I: To assess baseline-to-post-treatment changes in plasma metabolomics and short-chain-fatty-acids (SCFA) profiles |
| Part I: Plasma and Microbiome Markers | Part I: Baseline to 4 weeks | Part I: To assess baseline-to-post-treatment changes in plasma markers associated with AD pathology |
| Part II: RBC/Membrane Ratio | Part II: Baseline to 4 weeks | Part II: In addition to the outcome measures listed for Part I of this study, the secondary outcome measures for Part II are as follows: ratio of xenon signal dissolved in RBCs to xenon signal dissolved in membrane tissues |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAi-Ling Lin, PhD
University of Missouri-Columbia
Outcome results
None listed