Friday, September 19, 2008

AIDS-related dementia

I’m Bevin English

Since the early stages of the AIDS pandemic, doctors have known about an important neurological complication of HIV infection. This condition, known as AIDS-related dementia, AIDS dementia complex (ADC), or HIV-associated dementia (HAD), is a complex and poorly understood disease, and has the potential to greatly impact many people’s lives, including HIV-positive individuals and their families and close friends. In the United States, HIV-1 is the most common cause of dementia in adults under the age of 40. Also, neurological impairment affects roughly 60% of HIV-positive patients throughout the world. The major causes of neurological impairment include opportunistic infections, such the parasite toxoplasmosis, and AIDS-related dementia.

The primary symptoms of AIDS-related dementia include cognitive impairment, such as the inability to concentrate and impaired short-term memory; motor dysfunction, including leg weakness, affected gait, and slow hand movements; and behavioral changes, such as depression, apathy, and social withdrawal. In rare cases, the dementia progresses so that the patient is in a nearly vegetative and mute state. Before the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, AIDS-related dementia affected up to 30% of HIV-positive individuals, but the current prevalence has dropped to approximately 10% in areas with high HAART availability. However, a less-severe form of the disease, called minor cognitive motor disorder (MCMD), has become more prevalent in regions where HAART is widely available, with estimates ranging up to a 30% prevalence rate. This high prevalence rate shows that HAART is not sufficient in reducing neurological impairment in HIV-positive individuals.

Despite years of research and progress, much remains unknown about HIV’s interaction with central nervous system (abbreviated CNS; this includes the brain and spinal cord), and this lack of knowledge has serious implications for treatment. HIV is found in the CNS of all AIDS-related dementia patients, but there is still controversy regarding how HIV enters the CNS. The brain is protected by the blood-brain barrier, which is a selectively permeable layer of tightly-linked endothelial cells that carefully regulate what enters and exits the CNS. While many things are excluded from the brain by the blood-brain barrier, some immune system cells are allowed to cross the barrier. The most widely accepted theory to explain HIV’s entry into the brain is the “Trojan horse hypothesis,” which states that infected monocytes (cells that later mature into macrophages) cross the barrier and carry HIV into the CNS. However, there are other possible explanations for the presence of HIV in the brain. For example, infected CD4+ T-cells may also carry the virus into the brain. It is also possible that the virus may be able to directly cross the blood brain barrier, especially if the barrier’s integrity is compromised, or that the cells that make up the barrier ingest the virus and expel it in the brain in a process called transcytosis. Because the virus may enter the CNS through many pathways, most of which are not fully understood, it will be difficult for scientists to come up with treatments to prevent the entry of HIV into the brain in the near future.

Once in the CNS, HIV’s most devastating effect is the sheer loss of neurons. For example, 20-40% of neurons are lost in the frontal cortex, a region of the brain that is involved in planning, coordinating, controlling, and executing behavior (or more specifically, impulse control, judgement, language production, working memory, motor function, and socialization). This large loss in neurons can be seen in the CT scans below (image courtesy of AIDS Images Library )

However, HIV cannot infect neurons because they do not express CD4, but instead HIV persists in the CNS by infecting other cells; thus, neurodegeneration is not a result of active infection of neurons. There are two major pathways for neuropathogenesis in AIDS-related dementia: direct and indirect. The direct pathway includes the effects of different viral proteins on neurons. For example, three HIV proteins, gp120, Tat, and Vpr, have been shown to cause neuronal cell death through many different pathways. Further, Tat has been shown to increase the permeability of the blood-brain barrier, thus increasing the amount of HIV that can enter the CNS. The indirect pathway of neuropathogenesis involves infected cells’ secretion of chemicals that harm neurons. For example, when activated by infected macrophages, astrocytes, which normally provide support for neurons, actually secrete neurotoxins. Thus, HIV causes neuronal cell death through many different mechanisms, making AIDS dementia extremely difficult to treat.

Despite these difficulties, many scientists have been investigating treatments to prevent or slow the progession of AIDS-dementia. Many antiretroviral treatments currently in use cannot penetrate the blood brain barrier, and the few that can enter the CNS do so very inefficiently. For example, protease inhibitors, an entire class of drugs, are actively pumped out of the CNS. The ineffectiveness of current antiretroviral treatments in penetrating the blood-brain barrier has led scientists to investigate other means of preventing neuronal cell death. Many different compounds that block different steps in the pathways that cause neuronal death have been tested in AIDS-related dementia patients, but so far none have shown any significant therapeutic benefits. However, progress is being made in understanding the processes involved in HIV’s interaction with the CNS, and these new discoveries may open the door for new treatments for AIDS-related dementia.


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Health said...

The early stages of Alzheimer's and other causes of dementia can be difficult to spot, but there are some signs that are useful in spotting the disease.