Infection with the human immunodeficiency virus (HIV) results in serious deficits in the functioning of the immune system, but a lesser-known result of infection is the development of a dementia with cognitive and motor components known as the AIDS Dementia Complex (ADC). This name in itself provides a great deal of information about the disorder. The term “AIDS” reveals that it is a consequence of HIV infection and emphasizes its poor prognosis, the term “dementia” represents the continual cognitive decline, and the term “complex” stresses the idea that the disorder impairs not only cognitive abilities, but also motor performance and behavior. A variety of mechanisms are understood to play a role in the pathogenesis of ADC, including HIV neuroninvasion, cellular protein secretion, and HIV protein secretion, but a mechanism that is of particular interest is that of altered neurotransmitter systems, specifically involving dopamine. The dopamine system, which is located primarily in the basal ganglia, has been determined to be particularly sensitive to HIV infection, which has been demonstrated by an array of evidence such as increased HIV protein levels and increased sensitivity to dopamine antagonists. A thorough understanding of this alteration will ultimately allow for more effective treatments of ADC.
The incidence of AIDS Dementia Complex after progression to AIDS was about 7% before the implementation of HAART (highly active antiretroviral therapy), and the overall risk of a person infected with HIV developing ADC over their lifetime was 5 – 20% (McArthur, 2004). Since the introduction of this treatment, though, the incidence of ADC has dropped significantly, with the percentage of HIV-infected adults falling to about 10%, and it typically only develops when an individual’s CD4+ cell count drops to a level of 200 cells/mm3. Although HAART has proven to be an effective treatment for HIV infection, and has postponed the onset of ADC, it has also increased the rate of minor cognitive motor disorder, a milder form of dementia (Gonzalez-Scarano, 2005). The symptoms of this dementia are not as extreme as those in ADC, which include mental and physical slowing, forgetfulness, changes in behavior, difficulty carrying out daily activities, memory loss, apathy, depression, abnormal gait, tremors, bradykinesia, and language disorders. These symptoms provide the basis for the five stage system of classifying ADC, which evaluates patients based on the intensity of three classes of symptoms: cognition, motor performance, and behavior (Price, 1998).
A variety of mechanisms have been identified by which HIV infection leads to the development of ADC. The first of these is HIV neuroinvasion, or the mechanism by which HIV infiltrates the brain, and it is believed that this occurs when infected CD4+ cells enter the central nervous system (Singh, 2007). From there, they can proceed to infect other cells, such as microglia and astrocytes. A second mechanism, and a more indirect one, is that of cellular proteins, in which HIV infection can cause the secretion of proinflammatory cytokines, chemokines, nitrous oxide, and other neurotoxic factors. The secretion of these products can occur both from infected cells of the immune system and activated, but non-infected, cells (Gonzalez-Scarano, 2004). A third mechanism is damage to neurons by secreted HIV proteins, including gp120 and Tat (Silvers, 2007). Although neurons themselves cannot become infected with the HIV virus, infected cells in the brain can secrete proteins into the extracellular environment that may be taken up by neurons. These viral proteins can harm the cells by activating astrocytes, microglia, and macrophages to release cytokines, chemokines, or neurotoxic substances. A fourth mechanism by which HIV infection can lead to the development of ADC is by altering neurotransmitter systems in the brain, and while there are multiple neurotransmitters affected, including amino acids and acetylcholine, dopamine appears to be the most significantly affected (Koutsilieri, 2001).
The first indication that dopamine systems are altered in patients with ADC is the fact that many similarities exist between ADC and Parkinson’s disease, such as apathy, bradykinesia, impaired manual dexterity, gait abnormalities, rigidity, and poorly articulated speech (Koutsilieri, 2001). Because of these commonalities, and the fact that medicinal treatments for Parkinson’s often target the dopamine system, it was inferred that ADC likely involves some sort of dopamine system dysfunction as well. To test this theory, patients with ADC were given levodopa, the single most effective drug used to treat Parksinon’s and metabolizes to dopamine in the brain. It was observed that they were responsive to the drug, suggesting upregulation of dopamine receptors. This same study found that they were also very sensitive to dopamine-blocking agents (Kieburtz, 1991). However, just as Parkinson’s patients can often have adverse reactions to such medications and develop other symptoms, patients with ADC can also develop severe Parkinsonism, and this result has been seen with a variety of drugs, including levodopa, prochlorperazine, thiothixine, and metoclopramide (Nath, 2000).
The parallels between the characteristic symptoms and response to drugs of AIDS Dementia Complex and Parkinson’s disease are consistent with the idea that ADC is a subcoritcal dementia. The basal ganglia, one of the structures located in the subcortical region of the brain, has been identified as the primary site of HIV infection within the brain, and because this region is also rich in dopamine neurons, it further supports the theory that dopamine plays a major role in the HIV-related dementia. This involvement of the basal ganglia has been supported by a wide array of studies, some of which involve autopsies. These have found that the basal ganglia is rich not only in immune system cells such as multinucleated giant cells, microglial nodules, and HIV-infected microglial cells, but also in toxic HIV proteins, giving them opportunity to damage and destroy dopamine neurons (Nath, 2000). Neuroimaging studies have aided in the detection of more physical abnormalities of the basal ganglia.
Studies using MRI and PET with fluorodeoxyglucose have demonstrated that the basal ganglia is particularly susceptible to HIV infection, confirming that there are specific dopamine system alternations and decreased levels of tyrosine hydroxylase, an enzyme responsible for the conversion of L-tyrosine into a precursor of dopamine called DOPA, immunoreactivity (Berger, 2000). Variations in the physical size of the basal ganglia region have also been identified in patients with HAD, and this includes a reduction of gray matter volume in the basal ganglia and atrophy in the caudate, a specific region of the basal ganglia involved in motor activity (Berger, 2000). The cerebral atrophy that has been identified has preferential central rather than cortical involvement, putting it at the level of the basal ganglia.
The metabolic, electrophysiological, and radiological characteristics of dopamine systems in the basal ganglia of patients with ADC have not been as thoroughly studied as other aspects of the disorder, but such analysis still provides useful information. Metabolic studies using [18F]2-fluroro-2-deoxy-D-glucose have consistently found that there is a hypermetabolism of the basal ganglia in early ADC, and that the metabolism continues to increase as ADAC worsens (Berger, 2000). Studies of motor performance using electrophysiological measures have found that such performance rapidly deteriorates in the presence of ADC, and that these problems are often associated with clinical basal ganglia deficits (Berger, 2000). Radiological studies have been involved in investigating tissue loss in various regions of the brain in patients with ADC, and it was found that basal ganglia volumes were smaller, as well as detection of central and caudate atrophy that correlate with decreased performance on neuropsychological tests (Berger, 2000).
As previously mentioned, toxic HIV proteins, namely gp120 and Tat, have been found in high concentrations in the basal ganglia of patients with ADC and, because of this location and the fact that dopaminergic systems lie within the region, it is likely that they play a significant role in the destruction of neurons involved with dopamine. The idea of this toxicity is complicated by the inability of the HIV virus to actually infect neuronal cells, meaning that neuronal loss in patients with ADC must occur without neuronal infection (Silvers, 2007). There are two proposed methods to explain this: that HIV proteins are secreted into the extracellular environment and affect those neurons, or that these same secreted proteins are then taken up by neurons and attack from within. (Silvers, 2007) In addition to studies investigating the concentrations of HIV proteins in the basal ganglia, many studies have examined the effects these proteins have on neurons. In a study investigating the hypersensitivity of patients with ADC to dopamine receptor blockade, it was found that the HIV viral envelope protein gp120 is capable of blocking dopamine uptake in vitro, and this results in the loss of neuronal processes of dopaminergic neurons. (Koutsilier, 2002) This was further demonstrated in a study that used purified gp120 and observed neuronal death in the hippocampus of mice, and a more recent study replicated this finding and also found death of retinal ganglion cells, a type of neuron. The toxic effects of gp120 have also been shown to be dependent on the N-methyl-D-aspartate (NMDA) receptor, for the addition of NMDA receptor antagonists and/or enzymes that degrade glutamate was shown to prevent neuronal cell death induced by gp120. (Kieburtz, 1991) This hypothesis of NMDA abnormalities suggests that these receptors likely play a role in the overactivation of channels permeable to calcium ions, and this excessive influx of calcium ions will lead to neuronal damage (Lopez, 1999).
Similar studies have been conducted analyzing the effects the HIV trans-activator protein Tat has on dopaminergic neurons. Initial interest in this protein was generated by its increased concentrations in the basal ganglia, both in humans and in HIV infected primates, as well as the fact that it has been proven to have a negative affect on the cognitive processes of neonatal and adult rats. (Silver, 2007) The ability of this protein to be secreted and taken up by neighboring cells gives it the ability to affect both infected and uninfected cells, and once it has been taken in, it can causes oxidative stress-dependent apoptotic cascades in neurons. This has been displayed both in vivo and in vitro. (Silvers, 2007) This neurotoxicity, like that of gp120, is thought to depend upon activation of NMDA receptors. Tat has also been shown, again like gp120, to inhibit dopamine uptake, and through such changes it is able to modulate the activity of dopamine receptors and dopaminergic neurons. A recent study explored the role that D1 dopamine receptors played in the neurotoxicity of Tat and found that, in primary rat neuronal cell cultures, addition of the D1 antagonist SCH 23390 greatly reduced the cell death that is caused by Tat. This provides even more evidence that dopamine systems are intimately involved in the dementia caused by HIV infection (Silvers, 2007).
The role of dopamine receptors in the brain, especially in the basal ganglia, has proven to be a very compelling aspect of ADC analysis. A study conducted by Wang and his colleagues examined the affect HIV infection has on dopamine D2 receptors in the basal ganglia, and it was observed that patients with HIV-associated dementia had lower availability of dopamine transporter (DAT), which is a protein that binds to dopamine and is responsible for the reuptake of the neurotransmitter into the neuron. Further, higher plasma viral load of HIV correlated with lower DAT in the caudate (Wang, 2004). These results provide evidence of dopamine terminal injury in patients with ADC, and suggest that decreased DAT levels play a role in dementia progression.
Another measure of dopamine levels that has proven to be indicative of AIDS dementia complex are those that are found in fluids within the body, specifically the level of homovanillic acid (HVA), the primary metabolite of dopamine, and 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of L-DOPA, within the cerebral spinal fluid (CSF) (Koutsilieri, 2001). Although studies of CSF fluid provide a limited amount of information since they cannot localize the dopamine to any specific region within the brain, the mere fact that dopamine levels in (CSF) are indicative of dopaminergic neurons within the brain make studies of this nature useful (Nath, 2000). Once patients are infected with the HIV virus, even before the initial progression to ADC, levels of dopamine in the CSF were found to be decreased while levels of HVA were found to be slightly increased, suggesting an increased turnover rate of dopamine and, consequently, oxidative stress on dopaminergic neurons (Nath, 2000). In later stages, the level of HVA is severely decreased, suggesting a loss of neurons involved with dopamine. This level continues to drop as ADC progresses (Lopez, 1999).
Because of the obvious association of HIV infection with intravenous drug use and the fact that several drugs act through the dopamine pathway, studies of ADC have often looked at the effect drug use has on the progression of the disorder. Addictive drugs, such as cocaine, amphetamines, and opiates, act through the mesocortical and mesolimbic dopaminergic pathways, giving such substances their rewarding properties. Stimulants, particularly cocaine and amphetamines, act directly on the synapses of dopaminergic neurons by increasing the concentration of dopamine released into the synaptic cleft, and prolonged use of such drugs result in decreased availability of dopamine, but an increased level of postsynaptic D1 and D2 dopamine receptor responsiveness (Koutsilieri, 2002). Statistical reports have provided a great deal of evidence suggesting that such drug use may contribute to or even accelerate the development of AIDS dementia complex, namely that patients who used drugs were two to four times more likely to develop the Parkinsonian symptoms of ADC than patients who did not use drugs and that symptoms were often more severe in drug users (Nath, 2000). Additionally, SPECT studies comparing patients with ADC to HIV-negative cocaine users found that similar changes developed in the basal ganglia of both sets of subjects, despite the absence of HIV infection in the second group (Koutsilieri, 2002).
Biological studies of the effects of drug abuse in HIV-infected individuals further support the theory that dopamine is an important factor in ADC. Preliminary post-mortem studies have suggested that drug abusers with AIDS had more severe neuronal loss and shrunken neuronal cells in the substantia nigra, a component of the basal ganglia containing a great deal of dopaminergic neurons, than AIDS patients without a history of drug abuse (Nath, 2000). A particularly interesting in vitro experiment has shown that cocaine and methamphetamine have synergistic neurotoxic properties with HIV viral proteins gp120 and Tat, with the toxicity of any combination of Tat or gp120 with cocaine or methamphetamine resulting in a highly increased percentage of neuronal cell death. It has also been found that when neuronal cell lines are exposed to dopamine, cocaine, or morphine, along with supernatants from HIV infected cells, neuronal cell death and oxidative stress occur (Nath, 2000). Further, cocaine abuse has been found to increase the rate of HIV replication throughout the body, as well as to stimulate HIV replication in peripheral blood mononuclear cells in vitro. This is likely due to cocaine’s ability to increase the permeability of the blood-brain barrier, thereby increasing the susceptibility of the brain to HIV infection (Koutsilieri, 2002).
Understanding the specific pathogenesis of AIDS Dementia Complex, specifically concerning the dopamine systems, will ultimately allow for more effective treatment options in the future. Although the antiretroviral therapies used today have proven to be somewhat effective in slowing the progression from HIV infection to AIDS as well as postponing the onset of ADC, they ultimately fail to adequately address the clinical symptoms of HIV-associated dementia that develop. Evidence indicates that in order to effectively treat the Parkinson’s symptoms that develop, drugs and therapies must be created which target the dysfunctional dopamine systems, for antiretroviral therapies offer no protection to dopaminergic neurons. A variety of treatment options have been presented in light of the findings on altered dopamine systems, the first of which are dopaminergic therapies. Because of the responsiveness of ADC patients to drugs typically used to treat Parkinson’s disease, it is logical to consider these drugs as potential treatments, especially in terms of battling motor difficulties (Kieburtz, 1991). Use of direct dopamine agonists, such as bromocriptine, will also likely be beneficial, with preliminary studies finding improvements in the motor functions of pediatric ADC patients (Berger, 2000). Excitatory amino acid receptor antagonists, such NMDA blockers, have also been suggested due to their role in modulating the neurotoxic effects of HIV proteins Tat and gp120 (Nath, 2000). Additional factors that must be taken into account in developing new drug treatments include the medications’ ability to cross the blood brain barrier, and that they must not stimulate HIV replication. The drug Valproate has become popular due to the fact that it does not cause extrapyramidal side effects that are common to many drugs used to treat those with HIV dementia. A great deal of additional research regarding drugs targeting the dopamine system is necessary before the knowledge of the dysfunction of this system can be used in any sort of beneficial way.
Although the pathogenesis of AIDS dementia complex is not entirely understood, studies involving dopamine system abnormalities, particularly concerning the effect of toxic HIV proteins, have provided a great deal of information on the disorder. These studies have revealed that it is, in fact, a direct result of HIV infection. Additional research is necessary not only to investigate possible treatments for the disorder, but also to further clarify the role of the basal ganglia in such dopaminergic dysfunction. The understanding of dopaminergic dysfunction gained through the studies discussed, however, has provided a great deal of information on the cause of HIV-associate dementia.
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