Mild Neurocognitive Disorder in HIV Infection of the Brain

Objective:

To determine the relationship among neuroinflammation, Permeability-glycoprotein (P-gp)
function and mild neurocognitive disorder (MND), a cognitive disorder associated with HIV
infection.

Study Population:

HIV seropositive subjects with MND, HIV seropositive subjects with normal cognitive function,
and HIV seronegative control subjects.

Design:

Subjects will undergo history and physical exam, screening laboratory tests, EKG, brain MRI
and neuropsychological evaluation. HIV-seropositive subjects will be stratified based on
results of neuropsychological evaluation into HIV-seropositive controls (i.e., cognitively
normal) and HIV-seropositive with MND. All subjects will receive brain PET imaging with
[11C]dLop after P-gp blockade to measure the function of P-gp at the blood-brain barrier.
P-gp will be blocked prior to the PET scan with tariquidar. HIV-seropositive subjects will
receive one lumbar puncture at baseline and one lumbar puncture after P-gp blockade with
tariquidar to measure CSF concentrations of anti-retroviral medications and to measure
biomarkers of blood-brain barrier integrity and inflammation in the CSF. HIV-seronegative
subjects will receive one lumbar puncture at baseline to measure biomarkers of blood-brain
barrier integrity and inflammation in the CSF.

Outcome Measures:

The main outcome measures of the study is brain uptake of [11C]dLop in response to P-gp
blockade with tariquidar. We will correct for individual metabolism of tariquidar by
measuring the plasma concentration of tariquidar during the P-gp blocked scan.

As a secondary outcome measure, concentrations of anti-retroviral medications in CSF will be
measured in HIV seropositive subjects with and without MND. CSF concentrations will be used
as a surrogate marker for CNS delivery of anti-retroviral drugs.

- INCLUSION CRITERIA:

1. Subjects must be between 18 and 60 years of age.

2. Capable of providing informed consent.

3. Ambulatory at initial visit.

4. Speak English fluently

5. For HIV seropositive subjects:

1. Confirmation of HIV antibody status by ELISA and Western Blot

2. Documented HIV-infection for at least one year

3. On a stable antiretroviral regimen that includes a protease inhibitor for at
least 3 months and have a viral load < 400 copies/mL.

4. Have a primary care physician.

Specific inclusion criteria for mild neurocognitive disorder are as follows:

1. Subject has an acquired mild-to-moderate impairment in cognitive function documented
by a score of at least 1 SD below demographically corrected norms on testing of at
least two different cognitive domains.

2. The cognitive impairment interferes, at least mildly, with activities of daily living,
as determined by neuropsychological interview.

3. The impairment does not meet DSM-IV criteria for delirium or dementia.

4. The impairment is not fully explained by co-morbid conditions.

EXCLUSION CRITERIA:

1. Current Axis I psychiatric illness or severe systemic disease (other than HIV and MND)
based on history and physical exam that would make study participation unsafe in the
opinion of the investigators.

2. Current alcohol use greater than 14 drinks per week for men and 7 drinks per week for
women.

3. Laboratory tests with clinically significant abnormalities. Normal organ and marrow
function are defined as: total leukocyte count greater than or equal to 3000 cells/ul,
ANC greater than or equal to 1500 cells/ul, platelet count greater than or equal to
100,000 cells/ul, serum creatinine less than or equal to 2.0 times upper limit of
normal, hemoglobin greater than or equal to 9.0 g/dL, serum calcium <12.0 mg/dL,
AST/ALT less than or equal to 1.5 times the upper limit of normal, PT 1.5 upper limit
of normal.

4. EKG finding consistent with ischemic heart disease unless there is documentation of
normal cardiac function (e.g., normal stress test or echocardiogram results).

5. Previous research radiation exposure (X-rays, PET scans etc.) that, with the study PET
scans, would exceed annual research limits.

6. Pregnancy or breast feeding.

7. Evidence of brain disease such as stroke, tumor, epilepsy, traumatic brain injury, or
any neurodegenerative disease on history or on screening MRI.

8. Inability to lay on his/her back for long periods, severe claustrophobia, pacemaker,
or other contraindication for MRI.

9. More than moderate hypertension, defined as blood pressure greater than or equal to
160/95 at the time of screening.

10. Current use of illicit drugs based on positive result on urine screen for illicit
drugs at the time of screening.

11. Subjects taking medications, other than anti-retroviral drugs, that are known
substrates of P-gp that cannot be safely discontinued for this study. Anti-retroviral
drugs, particularly protease inhibitors such as ritonavir, that are P-gp substrates
are allowed.

Note: The rationale for the exclusion criteria for alcohol use is to avoid alcohol-related
cognitive impairment as a confounding factor.