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Detection of cerebrospinal fluid antibodies against myelin basic protein in patients with AIDS dementia complex.

We evaluated cerebrospinal fluid (CSF) antibody levels against a lipid-free, denatured form of myelin basic protein (LF-MBP) in 11 patients with AIDS dementia complex (ADC) by using an enzyme-linked immunosorbent assay (ELISA). In 9 out of 11 patients, anti-LF-MBP antibody levels were significantly higher than those observed both in 15 human immunodeficiency virus (HIV)-infected patients without neurological disorders and in 9 anti-HIV-negative subjects affected by other neurological diseases. Furthermore, we followed up anti-MBP levels in 5 out of the 11 ADC patients and detected a strict relationship with the encephalopathy progression. At the same time, with the aim to detect early demyelinating events we investigated CSF antibody levels against a lipid-bound, native-like form of MBP (LB-MBP). Results did not show any significant difference between LF-MBP and LB-MBP in terms of antibody reactivity. The detection of anti-MBP antibodies in CSF may provide the opportunity to assess a diagnostic tool for discovering demyelinating lesions in ADC patients.

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Proton MR spectroscopy of the brain in AIDS dementia complex.

Proton MR spectroscopy of the brain has been undertaken in 8 healthy volunteers and in 11 patients with human immunodeficiency virus infection and varying stages of AIDS dementia complex (ADC). Spectral appearances in patients with no ADC or early ADC were not significantly different from normal volunteers. Spectra from patients with moderate to severe ADC exhibited significant reductions in levels of N-acetyl aspartate (NAA) relative to creatine (Cr) and also showed elevations in choline containing compounds (relative to Cr). Because NAA is though to be a metabolic marker for normally functioning neurons, these findings suggest the presence of neuronal injury or loss in moderate to severe ADC. The significance of these findings is discussed.

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Cerebral blood flow SPECT with Tc-99m exametazine correlates in AIDS dementia complex stages. A preliminary report.

Human immunodeficiency virus (HIV) infection is frequently complicated by a variety of disease processes affecting the central nervous system (CNS). One of them is AIDS dementia complex (ADC), which, in the absence of opportunistic infection, is believed to be caused by HIV itself. ADC is characterized by a constellation of cognitive, motor, and behavioral symptoms that progressively get worse. This study was coined to recruit AIDS patients without any opportunistic CNS infection but with signs of CNS abnormality as evidenced by behavioral and subtle motor changes, then to categorize them into five stages, and finally to perform the cerebral blood flow scan using Ceretec. The aim of this study was to correlate the abnormalities of the brain scan with the different stages of ADC. Five patients were analyzed, with dementias ranging from mild to severe according to Price's classification. After confirming the absence of CNS opportunistic infections and AIDS associated malignancies by CT of the brain, the patients underwent psychiatric evaluation and brain scans. The SPECT scans were very sensitive in showing uptake defects in the brain, even in the early stages of ADC. The blood flow defects were more pronounced in the later stages, while the CT scans remained negative except in patients with the most severe dementia.

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Cerebrospinal fluid beta-2-microglobulin in multiple sclerosis and AIDS dementia complex.

Cerebrospinal fluid (CSF) and serum concentrations of beta-2-microglobulin (beta-2-m) were evaluated in 19 patients with clinically definite multiple sclerosis (MS), in 21 with AIDS dementia complex (ADC), and in 20 subjects with other neurological diseases (OND). CSF beta-2-m and CSF/serum beta-2-m ratio were significantly higher in the patients with ADC than in the MS and OND patients. The CSF and serum levels of beta-2-m in MS patients were not significantly different from those of OND patients. These findings indicate that CSF beta-2-m and CSF/serum ratio may be a useful marker in the diagnosis of ADC. In MS patients the beta-2-m CSF determinations are of no value.

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Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex.

The aim of this work was to study the role of HIV replication and the role of endogenous secretion of interferon-alpha in the pathogenesis of AIDS Dementia Complex (ADC). To accurately establish the diagnosis of ADC, 39 consecutive HIV-positive patients who presented with immune and intellectual deficiency underwent an extensive neurological evaluation. This included magnetic resonance imaging, neuropsychological testing and a lumbar puncture. The levels of HIV-1 RNA were measured in the cerebrospinal fluid (CSF) and blood by HIV Monitor (Roche Diagnostics) and those of interferon-alpha by an in-house biological assay. The diagnosis of ADC was established in 22 cases, which included nine out of the ten patients who had a high CSF viral load (above 4 log HIV-1 RNA copy per ml). Patients receiving highly active antiretroviral therapy had low viral loads in blood and CSF. In all 22 ADC patients, viral load in the CSF correlated with the staging of ADC (r=0.46, P=0.03), the CSF level of interferon-alpha (r=0.42, P=0.05) and with the bicaudate ratio (r=0.43, P=0.06), a measure of cerebral atrophy in the region of the caudate nucleus. No correlation was observed between CSF and plasma HIV-1 RNA. These results show that HIV may play a role in the neurological impairment of ADC patients possibly in part through the deleterious effect of interferon-alpha on the central nervous system and that highly active combination therapy should reduce or prevent these complications.

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Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex.

OBJECTIVE: Concentrations of quinolinic acid, an N-methyl-D-aspartate agonist, are often elevated for long periods of time in the cerebrospinal fluid (CSF) and brain tissue of patients with AIDS dementia complex (ADC). This study was designed to test the hypothesis that chronic exposure of human neurons to quinolinic acid levels equivalent to those in the CSF of ADC patients is neurotoxic. DESIGN AND METHODS: Human fetal brain 14-16 weeks post-menses was cultured in medium with no detectable levels of quinolinic acid. After 4 weeks, 350 or 1200 nmol/l quinolinic acid was added to the feeding medium for a further 5 weeks. Neurotoxicity was evaluated using immunohistochemistry, transmission and scanning electron microscopy, and image analysis. RESULTS: A total of 1200 nmol/l quinolinic acid caused altered cell associations, a decrease in cell density and decreased microtubule-associated protein (MAP)-2 immunoreactivity compared with cultures exposed to 350 nmol/l quinolinic acid or controls. Image analysis of neurons in randomly selected fields revealed significantly swollen cells (P < 0.0001) compared with those treated with 350 nmol/l quinolinic acid or controls. Dendritic varicosities and discontinuous microtubular arrays were present in neurons exposed to both quinolinic acid concentrations, but not in control cultures. CONCLUSIONS: This study is the first to assess quinolinic acid levels in the experimental medium, and demonstrates that chronic exposure of human neurons to concentrations of quinolinic acid equivalent to those in the CSF of patients with ADC leads to alterations in dendritic ultrastructure and MAP-2 immunoreactivity, which is consistent with ADC pathology.

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Cerebrospinal fluid cytokines in AIDS dementia complex.

We evaluated cerebrospinal fluid (CSF) and serum concentrations of interleukin-1-alpha (IL-1-alpha), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in 30 patients with AIDS dementia complex (ADC), and in 20 HIV-seronegative subjects with other neurological diseases (OND). CSF TNF-alpha, IL-1-alpha and IL-6 were more frequently detectable in ADC patients than in OND subjects. These cytokines were also detectable in CSF of ADC patients with minimal symptoms. In contrast, the majority of both ADC and OND patients did not contain detectable serum levels of cytokines. Our data support the notion of intrathecal synthesis of cytokines in ADC patients and raise the possibility that activated macrophages may play a significant role in the pathogenesis of ADC.

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Subacute cerebellar syndrome as the first manifestation of AIDS dementia complex.

A patient presented with a subacute cerebellar syndrome in absence of cognitive impairment or other symptoms. He became demented several months after the onset of the disease. Necropsy demonstrated the typical features of the AIDS dementia complex and severe loss of Purkinje cells of the cerebellum. Patients with subacute cerebellar dysfunction should be evaluated for the presence of human immunodeficiency virus infection.

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The assessment of cognitive function in advanced HIV-1 infection and AIDS dementia complex using a new computerised cognitive test battery.

The validity of a new computerised battery called CogState was determined in 60 individuals with advanced human immunodeficiency virus-1 (HIV-1) infection from which eleven were assessed as AIDS dementia complex (ADC) stage 1 or 2. Twenty-one seronegative individuals were recruited as controls. Participants were evaluated with a brief computerised examination, lasting 10-15 min, assessing reaction time, accuracy in working memory and learning. They were also assessed with a standard neuropsychological examination lasting 1h 30 min on average. The computerised assessment demonstrated a good sensitivity of 81.1% and specificity of 69.9% as well as good positive predictive value (81%) and acceptable construct validity (.45-.62). Slowed reaction time and learning deficits in the computerised battery were characteristic of ADC. This study supports the utility of a brief computerised battery in the detection of HIV-associated neurocognitive impairment that could be used for wide-scale screening.

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Low levels of specific T cell activation marker CD27 accompanied by elevated levels of markers for non-specific immune activation in the cerebrospinal fluid of patients with AIDS dementia complex.

Concentrations of soluble receptors for tumor necrosis factor (sTNFR-p55 and sTNFR-p75) and soluble T cell antigens CD25 and CD27 (sCD25 and sCD27) were measured in paired serum/cerebrospinal fluid (CSF) samples of 15 patients with AIDS dementia complex (ADC) and 15 HIV-infected control subjects (11 with other central nervous system (CNS) infections and four without CNS infection). In this study levels of sTNFR-p55, sTNFR-p75 and sCD25 were elevated in the CSF of ADC patients and of the 11 patients with other CNS infections, whereas CSF-levels of the specific T cell marker sCD27 were lower in patients with ADC as compared to the control subjects with and without other CNS infections. This pattern suggests a relative failure of eliciting a T cell-mediated immune response intrathecally in patients with ADC.

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