Right from the early years of the epidemic, researchers have recognized that HIV can affect the brain. Before effective antiretroviral therapy (ART), people with AIDS were susceptible to a variety of opportunistic infections of the brain, as well as HIV-related dementia.
After some time out of the spotlight, neurocognitive problems have again become a pressing concern as the average age of the HIV positive population rises (nearly 25% are now over 50, according to the National Institute on Aging). Recent conferences and journal articles reveal an increased emphasis on the effects of HIV on the brain, part of a larger shift of focus from classic AIDS-related illnesses to long-term progressive conditions in an aging population that are related to HIV and its treatment in ways that are not yet fully understood.
In particular, there is a new appreciation of the detrimental effects of low-level HIV replication and HIV-related immune activation and inflammation, even while the CD4 cell count remains high. And researchers and people with HIV are increasingly questioning whether the virus somehow accelerates the aging process. (See "Aging and HIV: A Conversation with Dr. Malcolm John," for more on getting older with HIV.)
This article discusses the spectrum of neurocognitive manifestations related to HIV/AIDS, looks at their natural history and possible causes, and reviews recent research, including studies presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal in February 2009 and the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town the following July.
Specific neurological manifestations depend on which parts of the brain are affected. Impairment can range from so mild that it is not apparent without specialized testing, to so severe that it prevents independent living.
Before the advent of effective ART, individuals with advanced immunosuppression and low CD4 counts were susceptible to a host of opportunistic infections (OIs) that attack the brain, including cryptococcal meningitis, toxoplasmosis, and progressive multifocal leukoencephalopathy (PML), as well as primary central nervous system (CNS) lymphoma, an AIDS-related malignancy (see sidebar on page 19).
Though less common now, OIs still frequently occur in areas where access to ART is limited and among people who do not begin treatment until HIV disease has already progressed.
Today, most neurocognitive impairment among HIV positive people is not due to opportunistic pathogens, but rather to the effects of HIV itself. As discussed below, neurological disorders are not the result of the virus attacking neurons directly, but instead result from changes in the brain's chemical environment triggered by HIV infection.
People with HIV -- especially those with severe immune suppression -- can develop frank (clearly evident) HIV-associated dementia (HAD), formerly called AIDS dementia complex. HAD is characterized by significant cognitive impairment that affects activities of daily living (for example, taking medications properly, personal care, handling money, or preparing meals). The ability to perform learned complex tasks (e.g., buttoning a shirt) is particularly affected.
A diagnosis of HAD requires significant impairment in at least two separate "domains," or areas of function. HAD is considered to be a subcortical form of dementia, meaning it is more likely to involve executive functions, such as attention, concentration, and processing speed. Cortical dementias, in contrast, are more likely to involve memory loss and deficits in higher-level cognitive functions controlled by the cerebral cortex, such as language comprehension and problemsolving. These categories overlap, however, and patients with HAD may experience the full range of symptoms.
People with HAD typically also develop some degree of motor impairment, including psychomotor slowing, poor coordination, tremors, or impaired fine motor skills (e.g., handwriting). Changes in personality, behavior, and mood are common as well, especially apathy, lack of motivation, or depression.
Individuals with a nadir (lowest ever) CD4 cell count below 200 cells/mm3 remain at higher risk for significant neurocognitive problems even if they subsequently achieve undetectable viral load and good CD4 cell recovery. This has led some researchers to conclude that HIV-related brain injury may in part be irreversible, thus underlining the importance of timely ART to prevent neurocognitive impairment from the outset.
In the ART era, HIV positive individuals with well-preserved immune function generally experience less severe cognitive impairment, known as HIVrelated mild cognitive-motor disorder (MCMD). Overall, the neurocognitive manifestations of MCMD are similar in kind to those of HAD, but of lesser severity. As with HAD, there is no single prototypical pattern of impairment.
A newer classification scheme divides MCMD into asymptomatic neurocognitive impairment (ANI) and HIV-associated mild neurocognitive disorder (MND) or mild cognitive impairment (MCI). People with asymptomatic impairment score below average on standardized neuropsychological tests, but do not have functional deficits apparent either to the individuals themselves or to their families, friends, and coworkers.
Symptoms in people with mild neurocognitive disorder can range from noticeable changes in concentration and short-term memory -- sometimes described as "brain fog" -- to increasing difficulty carrying out daily tasks.
It is not clear whether mild neurocognitive disorder is a precursor to HAD. Some individuals do experience this progression, but many others have stable mild-to-moderate impairment for years without significant worsening. Whereas neurocognitive disorders often appeared suddenly and progressed rapidly in the pre-ART era, today chronic, slowly progressing impairment is a more typical pattern.
The use of varying terminology can make it difficult to compare findings across studies. Because symptoms can wax and wane and there is no clear dividing line between mild and severe impairment, researchers often refer to the entire spectrum as HIVassociated neurocognitive disorder (HAND) or HIV-associated neurocognitive impairment (HNI).
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