Mental Ability Challenge Study in Adults With and Without HIV

This study is intended to evaluate the involvement of the neuronal cholinergic receptor
system in the accelerated cognitive aging profile seen in adults living with chronic HIV-1
infection. It is estimated by the CDC that by the year 2016, nearly 50% of the US'
HIV-positive population will be 50 or older. The HIV-1 virus is known to enter the CNS very
rapidly after initial infection, and cause a pattern of persistent neural inflammation, which
is deleterious to neurons and glia. This damage is believed to be the basis of cognitive
impairment associated with long-term chronic HIV infection, known as HIV-Associated
Neurocognitive Disorders (HAND). Successful introduction of Anti-Retroviral Treatment (ART)
has greatly reduced the likelihood of progressing to the most severe category of HAND
(HIV-Associated Dementia), however the mild and moderate forms (Asymptomatic Neurocognitive
Impairment and Mild Neurocognitive Disorder, respectively) are still fairly common even in
adults declared "virally suppressed", with little to no detectable peripheral viral DNA/RNA.
Prior studies have shown that over the lifetime, more than 50% of adults diagnosed with HIV
will experience some degree of cognitive impairment as they age. Some of these changes may be
due to cholinergic dysfunction. The acetylcholinergic receptor system is necessary for normal
cognitive performance, and is active during working memory, executive functioning, attention,
and learning tasks. It has been shown that as the human brain ages, cognitive ability begins
to decline, and correlates with declining acetylcholinergic activity. The cholinergic theory
of cognitive aging postulates that this loss of activity at cholinergic receptors with age is
at least partly responsible for poorer cognitive performance in aging. I will use this model
to examine the impact of HIV infection on cholinergic system functioning. This study will use
a well-established anti-cholinergic drug challenge model to evaluate cognitive performance in
domains of cognitive functioning relevant to cholinergic functioning. Under conditions of
temporary muscarinic or nicotinic blockade, or a combination of both, I aim to explore the
contribution of putative cholinergic receptor dysfunction to the observed symptoms of HAND. I
also intend to determine whether age and HIV-status interact to produce an accelerated
pattern of cholinergic cognitive aging that would indicate that older adults with HIV are at
higher risk for more rapid cognitive aging than HIV-negative individuals. If successful, the
outcome of this study would support the future exploration of novel pro-cholinergic
medications to treat cognitive symptoms of HAND, which may improve quality of life for adults
living with chronic HIV infection, as they survive into old age.

Inclusion Criteria:

1. 35 years of age or older;

2. HIV-Positive (must be on ART's for at least 6 months, most recent viral load (within 6
months) <50, CD4+ count >200, must be diagnosed HIV-positive at least 5 years) or
HIV-Negative, At-Risk Individuals

3. Able and willing to give written informed consent

4. Negative urine pregnancy test

5. Adequate visual and auditory acuity to allow neuropsychological testing.

Exclusion Criteria:

1. Unmanaged HIV Infection, identified by no current medication regimen or the presence
of one or more AIDS-defining conditions

2. Fagerstrom cigarettes per day (CPD) score of '2' indicating heavy use of nicotine

3. An ART regimen including a Protease Inhibitor Medication

4. A documented history of cardiac disease or abnormal ECG at Screening

5. Current alcohol or substance abuse, particularly intravenously

6. Current use of psychoactive medications (antipsychotics, benzodiazepines, etc.)

7. Current Axis I or Axis II psychiatric disorder

8. History of myocardial infarction in the past year or unstable or severe cardiovascular
disease