HIV-associated neurocognitive disorder

1. Marked acquired impairment of at least two ability domains of cognitive function (e.g. memory, attention): typically, the impairment is in multiple domains, especially in learning, information processing and concentration/attention. The cognitive impairment is ascertained by medical history, mental status examination or neuropsychological testing.
2. Cognitive impairments identified in 1 interfere markedly with day-to-day functioning.
3. Cognitive impairments identified in 1 are present for at least one month.
4. Cognitive impairments identified in 1 do not meet the criteria for delirium, or if delirium is present, dementia was diagnosed when delirium was not present.
5. No evidence of another, pre-existing cause that could explain the dementia (e.g. another CNS infection, CNS neoplasm, cerebrovascular disease, pre-existing neurological disease, severe substance abuse compatible with CNS disorder.[8]

While the progression of dysfunction is variable, it is regarded as a serious complication and untreated can progress to a fatal outcome. Diagnosis is made by neurologists who carefully rule out alternative diagnoses. This routinely requires a careful neurological examination, brain scans (MRI or CT scan) and a lumbar puncture to evaluate the cerebrospinal fluid. No single test is available to confirm the diagnosis, but the constellation of history, laboratory findings and examination can reliably establish the diagnosis when performed by experienced clinicians. The amount of virus in the brain does not correlate well with the degree of dementia, suggesting that secondary mechanisms are also important in the manifestation of ADC.

AIDS dementia complex (ADC) is not a true opportunistic infection; it is one of the few conditions caused directly by HIV itself. However, the cause of ADC can be difficult to discern because the central nervous system can be damaged by a number of other causes related to HIV infection:

• opportunistic infections
• Primary cerebral lymphoma or metastasis of other AIDS-related cancers
• direct effects of HIV in the brain
• toxic effects of drug treatments
• malnutrition

Many researchers believe that HIV damages the vital brain cells, neurons, indirectly. According to one theory, HIV either infects or activates cells that protect the brain, known as macrophages and microglia. These cells then produce toxins that can set off a series of reactions that instruct neurons to kill themselves. The infected macrophages and microglia also appear to produce additional factors such as chemokines and cytokines that can affect neurons as well as other brain cells known as astrocytes. The affected astrocytes, which normally nurture and protect neurons, also may now end up harming neurons. Astrocytes produce neurotoxic protein such as HIV Tat, Nef and Rev. Tat is secreted and induces reactivity in astrocytes through increased GFAP expression.[9] HIV protein gp120 inhibits the stem cells in the brain from producing new nerve cells.[10] In the neuronal cells, the HIV gp120 induces mitochondrial-death proteins like caspases, which may influence the upregulation of the death receptor Fas leading to apoptosis.[11]

• Stage 0 (Normal) Normal Mental and Motor Function
• Stage 0.5 (Subclinical) Minimal symptoms of cognitive or motor dysfunction characteristic of ADC, or mild signs (snout response, slowed extremity movements), but without impairment of work or capacity to perform activities of daily living (ADL). Gait and strength are normal.
• Stage 1 (Mild) Evidence of functional intellectual or motor impairment characteristic of ADC, but able to perform all but the more demanding aspects of work or ADL. Can walk without assistance.
• Stage 2 (Moderate) Cannot work or maintain the more demanding aspects of daily life, but able to perform basic activities of self care. Ambulatory, but may require a single prop.
• Stage 3 (Severe) Major intellectual incapacity - cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all output. And/or motor disability - cannot walk unassisted, requiring walker or personal support, usually with slowing and clumsiness of arms as well.
• Stage 4 (End Stage) Nearly vegetative. Intellectual and social comprehension and responses are at a rudimentary level. Nearly or absolutely mute. Paraparetic or paraplegic with urinary incontinence and fecal incontinence.

Cognitive impairments associated with HIV occur in the domains of attention, memory, verbal fluency, and visuospatial construction. Specifically for memory, the lowered activity of the hippocampus changes the basis for memory encoding and affects mechanisms such as long-term potentiation.[22] Severity of impairment in different domains varies depending on whether or not a patient is being treated with HAART or monotherapy.[23] Studies have shown that patients exhibit cognitive deficits consistent with dysfunction of fronto-striatal circuits including associated parietal areas, the latter of which may account for observed deficits in visuospatial function.[24][25] In addition to cognitive impairments, psychological dysfunction is also noted. For example, patients with HIV have higher rates of clinical depression and alexithymia, i.e., difficulty processing or recognizing one’s own emotions.[24] Patients also have more difficulty recognizing facial emotions.[26]

Without combination antiretroviral therapy, cognitive impairments increase with successive stages of HIV.[27] HIV patients in early stages show mild difficulties in concentration and attention.[28] In advanced cases of HIV-associated dementia, speech delay, motor dysfunction, and impaired thought and behavior are observed.[28] Specifically, lower motor speeds were found to correlate with hypertrophy of the right putamen.[16]

The diagnosis of HIV-associated neurocognitive impairment is made using clinical criteria after considering and ruling out other possible causes.[28] The severity of neurocognitive impairment is associated with nadir CD4, suggesting that earlier treatment to prevent immunosuppression due to HIV may help prevent HIV-associated neurocognitive disorders.[27]

A study by Melrose et al. (2008) examined the integrity of the fronto-striatal circuitry that underlies executive functioning in HIV. Participants in the study were diagnosed with HIV three months to sixteen years before the study. Ten out of eleven patients were on antiretroviral medication and none scored within the demented range on the HIV Dementia Scale. It was found that HIV+ patients showed less activity within the ventral prefrontal cortex (PFC) and left dorsolateral PFC. There was reduced connectivity between the left caudate and ventral PFC and between the left caudate and dorsolateral PFC compared to healthy controls. Additionally, there was hypoactivation of the left caudate in the HIV+ patients. In the control group, there was correlation between caudate activity and executive functioning as shown by performance on neuropsychological testing. Further analysis of the pathways in the HIV+ group involving left caudate showed reduced functional connectivity between the left caudate and globus pallidus (basal ganglia output nucleus). This dysfunction with the basal ganglia and PFC may explain the executive function and semantic event sequencing task impairments noted in HIV+ patients included in this study.[29]

The study by Melrose et al. (2008) also investigated parietal activation. It was found that anterior parietal activation in HIV+ patients was slightly anterior to that in control participants, which follows the idea that HIV causes a reorganization of the attention network leading to cognitive impairments. Additionally, the anterior parietal activity showed a relationship with caudate functioning, which implicates a compensatory mechanism set forth when damage to the fronto-striatal system occurs.[29]

Overall, the study by Melrose et al. (2008) showed that HIV in the brain is associated with cognitive impairments. Damage to the fronto-striatal system may underlie cognitive problems including executive function and sequencing tasks.

Another area of impairment due to fronto-striatal dysfunction is in the area of emotion recognition. In a study of HIV+ patients and control adults by Clark et al. (2010), it was shown that HIV patients demonstrate impairments in the recognition of fearful facial expressions. The authors suggested that fronto-striatal abnormalities related to HIV may underlie these impairments.[26]

In identification tasks, administered by Clark et al. (2010), HIV+ patients and control participants were asked to identify different facial emotions and landscapes, with these picture categories matched for image complexity. HIV+ patients did worse than the control group on the facial recognition task but not on landscape identification. In the facial emotion task, fear recognition was significantly worse in the HIV than in the control group.[26]

Mother-to-child transmission during pregnancy is the dominant mode of acquisition of HIV infection in children and has been associated with an increased risk of mortality and developmental delay. Children with AIDS appear to have neurological diseases as a consequence of HIV-1 infection. In HIV-1 infected newborn and children, central nervous system (CNS) is infected with HIV-1 weeks after primary infection, causing neuronal damage and cell death.[30] Although neurological dysfunctions have been associated to HIV infection of the CNS, it is unclear how the pathogenesis of neurological disorders has been established.

The main cells infected by HIV-1 in the nervous tissue are the microglia, astrocytes and macrophages, whereas infected neurons have been rarely observed. The susceptibility to HIV-1 infection and replication in neuronal and glial cells is a function of cellular differentiation, and it is more likely in immature precursors than with differentiated cells. Several soluble signals, such as cytokines, have been described to modulate susceptibility and can further contribute in supporting virus latency or virus replication during organ development. In fact, within the developing CNS, cells are under the control of environmental factors that provide instructive signals to neural cell targets. By regulating the survival, differentiation and maintenance of specific functions of neuronal and glial precursors, these extracellular signals can influence many steps of the CNS development and concur in controlling virus-cell interactions in the maturing brain.[31]

In addition to the production of cytokines, HIV-1 infected mononuclear cells and astrocytes can produce a number of soluble mediators, including viral proteins such as gp120 and Tat, that can exert damaging effects on both developing and mature neural tissues. Moreover, molecules such as the platelet activating factor (PAF) and prostaglandins, which are produced upon microglia/macrophages and astrocytes functional interactions, have been reported to mediate cell damage in primary neural cell cultures and neural cell lines with immature phenotype.[32]

Taken together, these observations suggest that the mechanism by which the virus can alter CNS development and induce pathology in the immature brain may depend upon the altered production of soluble bioactive compounds. Several potentially neurotoxic mediators have been identified in different model systems, including inflammatory cytokines, viral proteins and neurotoxic metabolites. Thus, it is likely that a complex interaction of several mediators may alter the function and survival of actively developing and maturing cells, responsible for the neurologic disorders.