Neural dysregulation during a working memory task in human immunodeficiency virus-seropositive and hepatitis C coinfected individuals.

Cognitive and functional neural correlates of human immunodeficiency virus (HIV) are only partially understood at present. Variability in neural response, which has been noted in the literature, may relate to clinical factors associated with HIV, including time since HIV diagnosis, CD4 count and nadir, HIV viral load, and comorbid infectious processes, especially hepatitis C. The present investigation evaluated working memory-related functional neural activation in 26 HIV+ participants, 28 demographically matched HIV-seronegative individuals, and 8 HIV+ individuals with hepatitis C coinfection. Analyses examined impact of HIV infection duration, CD4 count and nadir, HIV viral load, and hepatitis C serostatus. Results showed that HIV-seronegative participants had fastest reaction times, and during the working memory task, HIV+ participants with hepatitis C coinfection showed strongest bias toward commission errors; however, signal detection (i.e., overall task performance) was equivalent across groups. Functional magnetic resonance imaging (fMRI) results showed HIV-related greater activation to an easier vigilance task and HIV-related lower activation to a more difficult working memory task, consistent with reduced cognitive reserve. Hepatitis C coinfection related to diffuse neural dysregulation. Correlational analyses suggested relationships of increasingly severe disease with poorer functioning in brain regions linked to error monitoring and attention regulation.

Predictors of CNS injury as measured by proton magnetic resonance spectroscopy in the setting of chronic HIV infection and CART.

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.

HTLV-III infection in brains of children and adults with AIDS encephalopathy.

Unexplained debilitating dementia or encephalopathy occurs frequently in adults and children with the acquired immune deficiency syndrome (AIDS). Brains from 15 individuals with AIDS and encephalopathy were examined by Southern analysis and in situ hybridization for the presence of human T-cell leukemia (lymphotropic) virus type III (HTLV-III), the virus believed to be the causative agent of AIDS. HTLV-III DNA was detected in the brains of five patients, and viral-specific RNA was detected in four of these. In view of these findings and the recent demonstration of morphologic and genetic relatedness between HTLV-III and visna virus, a lentivirus that causes a chronic degenerative neurologic disease in sheep, HTLV-III should be evaluated further as a possible cause of AIDS encephalopathy.

The AIDS dementia complex: clinical and basic neuroscience with implications for novel molecular therapies.

The AIDS dementia complex (ADC, also referred to as HIV-associated cognitive impairment) is a common disorder among HIV-infected patients associated with both inflammatory and neurodegenerative processes. This review describes recent advances in the clinical and basic neurosciences of HIV infection and discusses the multivariable nature of what has become a chronic disorder in the context of highly active antiretroviral therapies (HAART). Since its initial description twenty years ago, advances in cell and molecular biology along with those in neuroimaging have furthered our understanding of the underlying pathogenic mechanisms. The clinical and neuropsychological profile of ADC is generally consistent with a "frontal-subcortical" pattern of injury. Neuropathogenesis is largely driven by indirect mechanisms mediated by infected, or more commonly, immune activated macrophages, which secrete viral and host-derived factors. Magnetic resonance spectroscopy (MRS) provides a robust in vivo method to measure the inflammatory and neurotoxic events triggered by these factors and their associated signals. Although the use of combined or highly active antiretroviral therapies (HAART) has significantly improved survival rates, cerebral injury and cognitive impairment remain common events. Factors such as aging and chronic infection will likely impact the course of this disease, its pathogenesis, and treatment. The combined observations presented in this review suggest a number of critical areas for future inquiry.

Computer-based neuropsychological screening for AIDS dementia complex.

OBJECTIVE: To test the efficacy of reaction time (RT) measures as a screening test for AIDS dementia complex (ADC). DESIGN AND METHODS: Forty-two patients with mild-to-moderate ADC and 33 healthy HIV-1-seronegative control subjects took a computer-administered battery of four RT measures: simple RT, choice RT, and two types of sequential RT (1 and 2). RESULTS: The performance of the ADC group was significantly worse than that of the control group on all four RT measures, but not all tasks were equally sensitive. The two tests of sequential RT were found to be the best discriminators, and receiver operating characteristic curves analyses indicated that the optimal cut-off z score was 1.0 for both tests. CONCLUSIONS: These preliminary results suggest that computer-based RT, using these two measures of sequential RT, may provide a sensitive method of detecting HIV-1-associated cognitive deficits.

Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review.

In the brains and spinal cords of 153 adult patients dying with acquired immunodeficiency syndrome (AIDS) at New York and Memorial Hospitals a subacute encephalitis with multinucleated cells was present in 28% of all patients. This encephalitis was characterized by multinucleated cells primarily located in the white matter and associated with myelin pallor and sparse infiltrates of rod cells, macrophages, gemistocytic astrocytes and lymphocytes. The incidence per 12 month period ranged from 0 to 43% and significantly increased between 1983-84 (14%) and 1984-85 (43%). Recent virologic and pathologic studies suggest that this encephalitis may be caused by direct LAV/HTLV-III infection of the central nervous system (CNS). Cytomegalovirus encephalomyelitis and toxoplasmosis were the most common opportunistic infections (26% and 10%, respectively). Progressive multifocal leukoencephalopathy, herpes simplex ventriculitis, varicella-zoster leukoencephalitis and fungal infections were infrequent (less than 3% each). A nonspecific encephalitis with microglial nodules and with mild white matter changes occurred in 17%, vacuolar myelopathy in 29% and CNS lymphoma in 6%. Less than 20% of patients had either normal brains or terminal metabolic encephalopathies. This survey shows that neuropathologic complications of AIDS are frequent. Infections are the most common complication and are caused by probable LAV/HTLV-III infection, or by opportunistic organisms.

The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection.

Twenty-nine patients at risk of developing acquired immunodeficiency syndrome (AIDS) presented with cognitive, motor, and behavioral dysfunctions characteristic of the AIDS dementia complex, either preceding or in the absence of major systemic opportunistic infections or neoplasms. Six of these patients were medically well, while the remainder suffered only milder manifestations of the AIDS-related complex at the time of their neurologic presentation. Over half of these patients either survived for five to 16 months or died without exhibiting systemic manifestations of AIDS. This experience indicates that the AIDS dementia complex may be the earliest, and, at times, the only evidence of human immunodeficiency infection, and that its development in this context may present a diagnostic challenge, particularly in individuals in whom risk for infection by the AIDS virus is cryptic.

Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: A proton magnetic resonance spectroscopic study.

The CNS is frequently involved in human immunodeficiency virus (HIV) infection. In recent studies using proton magnetic resonance spectroscopy, investigators found a significant reduction in N-acetyl aspartate, a metabolic marker of neurons, in late stages of dementia. To further understand the relationship between proton magnetic resonance spectroscopy changes and clinical disease and dementia, we compared 20 HIV-infected patients presenting at varying stages of acquired immunodeficiency syndrome (AIDS) dementia complex and infection to 10 age-matched controls. We found a significant reduction in N-acetyl aspartate/creatine only in patients who had advanced dementia and CD4 counts less that 200/microliter. By contrast, a significant elevation in compounds containing choline was present in patients in the early stages of HIV infection of who had CD4 counts greater than 200/microliter, in patients with normal MRI scans, and in all AIDS dementia complex groups, including subjects with no or minimal cognitive impairment. An elevated choline level also occurred in later stages of HIV infection (CD4 < 200/microliter). Our results suggest that an increase in choline occurs before N-acetyl aspartate decrements, MRI abnormalities, and the onset of dementia, and may therefore provide a useful marker for early detection of brain injury associated with HIV infection.

Increased cerebral blood volume in HIV-positive patients detected by functional MRI.

OBJECTIVE: To study changes in cerebral hemodynamics related to HIV infection. BACKGROUND: Cerebral injury is a well-known manifestation of HIV infection. Physiologic changes in the HIV brain may precede structural changes and may be detected by functional MRI (fMRI). METHODS: Dynamic contrast fMRI was used to measure the cerebral blood volume (CBV) in 13 patients infected with HIV and in 7 healthy control subjects. RESULTS: Significant increases in dynamic CBV were found in the deep (p < 0.001) and cortical gray matter (p < 0.05) of HIV-positive (HIV+) patients. Patients with definite cognitive impairment showed significantly greater increases in CBV in the deep gray matter (DGM) compared with those without impairment. In one patient with rapidly progressive cognitive impairment, these abnormalities reversed and paralleled clinical improvement after initiation of zidovudine monotherapy. CONCLUSIONS: This study supports the hypothesis that HIV infection is associated with significant cerebral hemodynamic changes, particularly in the DGM, that may contribute to cognitive dysfunction in AIDS. Functional MRI may be useful for early detection of cerebral injury and for the assessment of novel therapies.

A phase I/II trial of nimodipine for HIV-related neurologic complications.

BACKGROUND: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders. METHODS: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study. Nimodipine at 60 mg p.o., five times daily; 30 mg p.o., three times daily; or placebo was administered for 16 weeks as adjuvant treatment to antiretroviral therapy. RESULTS: Neuropsychological performance at baseline, measured by the composite neuropsychological Z score (NPZ-8), correlated significantly with the ADC stage and with CSF levels of neopterin, a marker of immune activation. No significant differences in toxicity were observed among the three arms. Intent-to-treat analysis showed no significant change in the NPZ-8, although improvement was suggested in the high-dose arm. In addition, a trend toward stabilization in peripheral neuropathy was observed in both nimodipine arms compared with placebo. CONCLUSIONS: Nimodipine and other similar nonantiretroviral agents may provide a safe and promising avenue of treatment for neurologic disorders associated with HIV infection. The results of this study indicate that further clinical trials are warranted.

A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291.

OBJECTIVE: To evaluate the safety and efficacy of recombinant human nerve growth factor (rhNGF) in HIV-associated sensory neuropathy (SN) within a multicenter, placebo-controlled, randomized trial (ACTG 291). BACKGROUND: SN affects 30% of individuals with AIDS, is worsened by neurotoxic antiretrovirals, and its treatment is often ineffective. NGF is trophic for small sensory neurons and stimulates the regeneration of damaged nerve fibers. METHODS: A total of 270 patients with HIV-associated SN were randomized to receive placebo, 0.1 microg/kg rhNGF, or 0.3 microg/kg rhNGF by double-blinded subcutaneous injection twice weekly for 18 weeks. The primary outcome was change in self-reported neuropathic pain intensity (Gracely Pain Scale). Secondary outcomes included an assessment of global improvement in neuropathy by patients and investigators, neurologic examination, use of prescription analgesics, and quantitative sensory testing. In a subset, epidermal nerve fiber densities were determined in punch skin biopsies. RESULTS: Both doses of NGF produced significant improvements in average and maximum daily pain compared with placebo. Positive treatment effects were also observed for global pain assessments (p = 0.001) and for pin sensitivity (p = 0.019). No treatment differences were found with respect to mood, analgesic use, or epidermal nerve fiber densities. Injection site pain was the most frequent adverse event, and resulted in unblinding in 39% of subjects. Severe transient myalgic pain occurred in eight patients, usually from accidental overdosing. There were no changes in HIV RNA levels or other laboratory indices. CONCLUSIONS: We found a positive effect of recombinant human nerve growth factor on neuropathic pain and pin sensitivity in HIV-associated sensory neuropathy. rhNGF was safe and well tolerated, but injection site pain was frequent.

AIDS encephalopathy.

It is now recognized that AIDS is frequently complicated by a progressive encephalopathy characterized by dementia and motor dysfunction. This article reviews the early and late clinical features of this disorder and examines current evidence that it is due to direct brain infection by the retrovirus that causes AIDS.

Clinical and biologic features of the AIDS dementia complex.

Human immunodeficiency virus type 1 infection is frequently associated with complications of the nervous system, involving all levels of the neuraxis. Many of these represent focal disorders, such as toxoplasmosis, lymphoma, and progressive multifocal leukoencephalopathy. This article reviews the salient clinical and biological features of these disorders.

Functional imaging of the AIDS dementia complex and the metabolic pathology of the HIV-1-infected brain.

The AIDS-dementia complex remains one of the more common neurologic disorders associated with human immunodeficiency virus (HIV) infection. Despite several advances that have been made in elucidating some of its clinical and biological features, pathogenesis is not well understood, and effective treatments are scarce. This article reveals the results of these studies and discusses how these different approaches have already enabled clinicians to study further the effects of HIV infection on brain function and to explore the functional anatomy of this important clinical syndrome.

Neurological syndromes complicating AIDS.

PIP: This article presents a preliminary analysis of 118 acquired immunodeficiency syndrome (AIDS) patients with neurologic disease. 86% of patients in this series were homosexual, and the AIDS diagnosis was made on the basis of opportunistic infection in almost 50% and of Kaposi's sarcoma with or without opportunistic infection in 38%. Central nervous system (CNS) infections (e.g., subacute encephalitis, toxoplasmosis, primary CNS lymphoma) were the most common group of complications, and autopsy findings indicated that 87% of patients eventually developed CNS complications. Subacute encephalitis was found alone or with other pathology in over 2/3 of autopsied brains. Principal neuropathologic changes in AIDS include the presence of scattered glial nodules, especially in gray matter. To define the clinical features of the glial nodule subacute encephalitis, the clinical features of 18 patients exhibiting these changes at postmortem examination were further analyzed. With the exception of seizures, clinical manifestations were nonfocal, correlating with the diffuse distribution of the microscopic pathology. CNS symptoms most commonly followed the diagnosis of AIDS by 2-9 months, and 11 of these 18 patients died within 6 months of onset of CNS dysfunction. The electroencephalogram (EEG) was abnormal in 100% of patients tested, while computerized tomographic (CT) scans were abnormal in 70%, with cortical atrophy being the most common finding. The cerebral spinal fluid (CSF) was abnormal in 67%. Early complaints were difficulty in concentration or memory loss which progressed in some to severe global dementia or coma. Neither the etiology nor the pathogenesis of subacute encephalitis have been established, although cytomegalovirus is regarded as a prime etiologic candidate.^ieng

Selegiline and oxidative stress in HIV-associated cognitive impairment.

OBJECTIVE: To assess the effectiveness of the selegiline transdermal system (STS) in reversing HIV-induced metabolic brain injury (as measured by proton magnetic resonance spectroscopy [MRS]) and in decreasing oxidative stress, measured by CSF protein carbonyl concentration. METHODS: Sixty-two subjects with HIV-associated cognitive impairment were coenrolled in a 24-week placebo-controlled study (AIDS Clinical Trial Group protocol A5090) and were randomly assigned to receive STS 3 mg/24 h, STS 6 mg/24 h, or matching placebo. Cognitive performance was evaluated using the neuropsychological z score (NPZ)-8 and NPZ-6, as well as cognitive domain scores. Subjects underwent proton MRS at study entry and weeks 12 and 24. CSF protein carbonyl was measured at baseline and week 24. RESULTS: A slight increase in N-acetyl aspartate/creatine from baseline to week 24 was found in the basal ganglia (p = 0.023) and centrum semiovale (p = 0.072) of the placebo group compared with the STS groups; however, there were no significant changes when the absolute metabolite concentrations were analyzed. The levels of choline/creatine in the midfrontal cortex were also significantly higher during the week 12 visit in the combined STS groups. This persisted to the week 24 visit (p = 0.002). Evaluation of the change in NPZ-8, NPZ-6, and cognitive domain scores from baseline to weeks 12 and 24 revealed no significant differences between treatment arms. Protein carbonyl analysis revealed no significant changes among the groups. CONCLUSION: In this 24-week study, the selegiline transdermal system (STS) had no effect on either magnetic resonance spectroscopy (MRS) metabolites or oxidative stress, as measured by CSF protein carbonyl concentration. The lack of effect on these biomarkers is also reflected in the lack of cognitive improvement in the STS groups compared to placebo. LEVEL OF EVIDENCE: This study provides Class II evidence that STS had no effect on either MRS metabolites or oxidative stress, as measured by CSF protein carbonyl concentration over a period of 24 weeks.

HIV leucoencephalopathy and TNFalpha expression in neurones.

BACKGROUND: Human immunodeficiency virus (HIV) leucoencephalopathy (HIVL) is an uncommon and rapidly progressive form of AIDS dementia complex (ADC) that has remained poorly understood. Tumour necrosis factor alpha (TNFalpha), which has been implicated in the pathogenesis of ADC, is predominantly localised in macrophages in the HIV infected brain, although in vitro studies indicate that neurones can express this cytokine. OBJECTIVE: To examine the clinical/neuroradiological features of HIVL and the expression of TNFalpha in HIVL. METHODS: Six patients who presented with rapidly progressive dementia within four to 12 weeks of the primary manifestation of their HIV infection were evaluated. Clinical history, treatment regimens, and imaging studies were reviewed, and brain samples from three of the patients were studied by means of immunohistochemistry. RESULTS: Imaging studies showed diffuse bilateral deep white matter changes in all six patients. Clinical and imaging abnormalities improved in five of the six patients within weeks after initiation of antiretroviral treatment. Brain biopsies of two showed pronounced microglia/macrophage activation, but only scant viral protein (gp41) expression. Staining for TNFalpha was found in microglia/macrophages, and surprisingly, in neurones also. Postmortem analysis of a third patient also showed TNFalpha expression in neurones of the frontal cortex and basal ganglia. CONCLUSION: This study provides the first demonstration of staining for TNFalpha in the neurones of the HIV infected brain, and suggests that the process underlying this rapidly progressive form of ADC may reflect indirect mechanisms mediated by host factors, particularly TNFalpha.

The AIDS dementia complex: I. Clinical features.

Of 70 autopsied patients with the acquired immune deficiency syndrome (AIDS), 46 suffered progressive dementia that was frequently accompanied by motor and behavioral dysfunction. Impaired memory and concentration with psychomotor slowing represented the most common early presentation of this disorder, but in nearly one half of the patients either motor or behavioral changes predominated. Early motor deficits commonly included ataxia, leg weakness, tremor, and loss of fine-motor coordination, while behavioral disturbances were manifested most commonly as apathy or withdrawal, but occasionally as a frank organic psychosis. The course of the disease was steadily progressive in most patients, and at times was punctuated by an abrupt acceleration. However, in 20% of patients a more protracted indolent course was observed. In the most advanced stage of this disease, patients exhibited a stereotyped picture of severe dementia, mutism, incontinence, paraplegia, and in some cases, myoclonus. The high incidence and unique clinical presentation of this AIDS dementia complex is consistent with the emerging concept that this complication is due to direct brain infection by the retrovirus that causes AIDS.