PET Imaging of the Dopaminergic and Serotonergic Systems in Treated HIV Positive Subjects
Condition: Depression; HIV Infections; HIV-Associated Cognitive Motor Complex
MeSH terms: AIDS Dementia Complex; Depression
Intervention: 18F-FDOPA; 11C-DASB
Intervention description: High resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) system.; High resolution positron emission tomography (PET) of the brain and radioligands targeted against the serotonergic (11C-DASB) system.
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 46.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: 11C-DASB; 18F-Fluoro-L-dopa; HIV; Depression; Positron Emission Tomography (PET)

Summary:

      Background:

      Human immunodeficiency virus (HIV) infection is a serious disease with no cure. Some people
      with HIV have depression and other mood problems. They can have problems with thinking and
      memory. Researchers think 2 chemicals in the brain may cause those problems. The chemicals
      are serotonin and dopamine. The researchers want to take images to learn more about those
      chemicals in HIV patients.

      Objective:

      To learn how HIV affects serotonin and dopamine in the brain.

      Eligibility:

      Adults ages 18-70 with HIV who have been on antiretroviral treatment for at least 1 year

      Healthy adults ages 18-70

      All participants must be already enrolled in protocol 13-N-0149.

      Design:

        -  Participants will be screened with a urine drug test. The results could be shared with
           insurance companies.

        -  Participants who could be pregnant will have a pregnancy test.

        -  Participants may have a physical exam and blood tests.

        -  Participants will have 1 or 2 positron emission tomography (PET) scans. A needle will
           guide a thin plastic tube (catheter) into an arm vein. A radioactive drug will be
           injected into the plastic tube. This is a tracer that helps researchers understand the
           PET images.

        -  Participants who have the dopamine scan will have to fast for 4-6 hours before the scan.
           They will take a pill to help direct the tracer to the brain one hour before the scan.

        -  Each scan will last about 1.5 hours.

        -  Participants will be asked to drink a lot of fluids and empty their bladder frequently
           for the rest of the day after each scan.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Subject groups:

          -  Dopaminergic arm:

               -  Group A: HIV-positive subjects with or without co-morbidities

               -  Group B: HIV-negative subjects with co-morbidities

               -  Group C: HIV-negative subjects without co-morbidities

          -  Serotonergic arm:

               -  Group D: HIV-positive subjects with or without co-morbidities

               -  Group E: HIV-negative subjects with or without co-morbidities

        All Subjects (Groups A-E):

          1. Men and women, 18-70 years of age

          2. Ability to sign informed consent by the subject

          3. Subjects may be enrolled in or have been discharged from IRB approved NIH protocols OR
             subjects may be referred from outside providers/institutions.

          4. Has the ability to be seen by an outside medical doctor who provides care.

        All HIV-positive Subjects with or without co- morbidities (Groups A [dopaminergic arm,
        n=25)] and Group D [serotonergic arm, n=20])

          1. Known and documented HIV-1 infection

          2. Plasma HIV-RNA BLD (<100 copies/mm3) for greater than one year since the last
             available documented viral load measurement..

          3. At least one year of continuous ART prior to last documented suppressed viral load
             measurement and no history of ART modification or interruption since then.

        HIV-negative Subjects WITH Co-morbidities (Group B, n=25)

          1. HIV-antibody negative

          2. At least one or more of the following criteria:

               1. Hypertension, as defined by treatment with medications for hypertension or with a
                  systolic blood pressure at screening greater than or equal to 140mm Hg.

               2. Diabetes mellitus, as defined by HgbA1C greater than or equal to 6.5% or known
                  treatment for diabetes.

               3. Hepatitis C infection as documented by lab results of a positive Hepatitis C
                  antibody and/or detectable Hepatitis C viral load. Subjects who responded to HCV
                  treatment (SVR) will be included.

               4. History of previous but not current drug abuse.

               5. History of previous but not current alcoholism (defined as alcohol intake that
                  affect/affected the subject s work or home life).

               6. Clinical atherosclerotic cardiovascular disease (ASCVD) (e.g. history of acute
                  coronary syndromes, or myocardial infarction, stable or unstable angina, coronary
                  or other arterial revascularization or peripheral arterial disease of
                  atherosclerotic origin) and/or 10-year heart disease risk score (ASCVD risk
                  score) >7.5% (7.5 % score is the threshold for starting statin therapy as per the
                  2013 American College of Cardiology [ACC] / American Heart Association [AHA]
                  guidelines).

        HIV-negative Subjects WITHOUT co-morbidities (Group C, n=25)

          1. HIV-antibody negative

          2. No history of any of the following:

               1. Hypertension, as defined by treatment with medications for hypertension or with a
                  systolic blood pressure at screening greater than or equal to 140mm Hg.

               2. Diabetes mellitus, as defined HgbA1C greater than or equal to 6.5% or treatment
                  for diabetes.

               3. Hepatitis C infection as documented by lab results of positive Hepatitis C
                  antibody and/or detectable Hepatitis C viral load. Subjects who responded to HCV
                  treatment (SVR) will not be included.

               4. History of previous drug abuse.

               5. History of previous alcoholism. Alcoholism is based on alcohol having affected
                  the subject s work or home life.

               6. Clinical ASCVD (e.g. history of acute coronary syndromes, or myocardial
                  infarction, stable or unstable angina, coronary or other arterial
                  revascularization or peripheral arterial disease of atherosclerotic origin)
                  and/or 10-year heart disease risk score (ASCVD risk score) >7.5% (7.5 % score is
                  the threshold for starting statin therapy as per the 2013 ACC/AHA guidelines 35).

               7. Any other disease entities including chronic infections (e.g. Hepatitis B, Lyme
                  disease), neurological diseases (e.g. Multiple sclerosis, vasculitis) or systemic
                  diseases (e.g. Sjogren s diseases, sarcoidosis, systemic lupus erythematosus
                  [SLE]) that in the opinion of the investigator would be considered a significant
                  co-morbidity.

        HIV-negative Subjects with or without co- morbidities (Group E, n=20)

        1. HIV-antibody negative

        EXCLUSION CRITERIA:

        All Subjects (Groups A-E):

          1. Illness or other condition that, in the opinion of the PI, may interfere with study
             participation at the time of enrollment, including known history of significant
             intracranial structural damage such as previous stroke(s) or history of intracranial
             benign or malignant tumors.

          2. Conditions other than HAND associated with cognitive impairment or dementia such as
             Alzheimer s, Parkinson s disease, head injury with loss of consciousness >30 minutes,
             or seizure disorders.

          3. A positive screening result for psychiatric diseases that are known to affect the
             dopaminergic or serotonergic systems.

          4. Current substance abuse that would interfere with PET scan results at the
             investigators discretion.

          5. Medications: use of any drug with known dopaminergic or serotonergic activity within 6
             months prior to planned imaging date(s).

          6. Pregnant or Lactating women: Women of childbearing potential must have a negative
             serum or urine pregnancy test within 1 week prior to study entry. Pregnancy testing
             will also be performed in enrolled female participants prior to any radiation
             exposure.

          7. Prior or planned/anticipated exposure to radiation due to clinical care or
             participation in other research protocols, which would exceed the recommended
             acceptable annual limit of radiation exposure once accounting for the requirements of
             the current study.

        Additional Exclusion Criteria for the Dopaminergic Arm (Groups A, B and C):

          1. Use of any of the following drugs within 6 months from planned imaging date(s):

               1. Haloperidol (increased intracerebral dopamine turnover caused by haloperidol may
                  result in increased accumulation of 18F-DOPA)

               2. Monoamine oxidase (MAO) inhibitors (may result in increased accumulation of
                  18F-DOPA in the brain)

               3. Reserpine (reserpine-induced depletion of the contents of intraneuronal vesicles
                  may prevent retention of 18F-DOPA in the brain)

               4. Carbidopa/LDOPA (LDOPA competes with 18F-DOPA for DOPA decarboxylase activity)

          2. Allergy to carbidopa

        Note that HBV is not an exclusion criterion for groups A, B, D or E since it s not known to
        have direct CNS pathology in the absence of advanced liver disease and cirrhosis.