Acquired Immunodeficiency Syndrome Dementia Research Articles

Human Immunodeficiency Virus-Associated Autonomic Neuropathy, Drug Addiction, and Zidovudine Treatment

We would like to make some comments on the work by Rüttimann et al¹on human immunodeficiency virus (HIV)—associated autonomic neuropathy, which we read with interest. In a group of HIV-positive intravenous drug users,²we found that 59.4% of the subjects without neurologic symptoms were showing dysfunction of the autonomic nervous system (ANS) to the same cardiovascular tests mentioned by Rüttimann et al. Also, we have found that more severe ANS involvement is related to the seriousness of the disease (Centers for Disease Control groups). The observation of higher values of circulating immune complex in subjects with more important ANS involvement seems to us a valid support for the hypothesis of an autoimmune pathogenesis of the autonomic neuropathy. In the "Conclusions" section of one of our articles,³we described a subject with acquired immunodeficiency syndrome—dementia complex that manifested a relevant improvement to the ANS functional test response

Expression directed from HIV long terminal repeats in the central nervous system of transgenic mice.

Infection with the human immunodeficiency virus (HIV) is frequently accompanied by the AIDS (acquired immunodeficiency syndrome) dementia complex. The role of specific HIV genetic elements in the pathogenesis of central nervous system (CNS) disease is not clear. Transgenic mice were constructed that contained the long terminal repeats (LTRs) of two CNS-derived strains and a T cell tropic strain of HIV-1. Only mice generated with CNS-derived LTRs directed expression in the CNS, particularly in neurons. Thus, some strains of HIV-1 have a selective advantage for gene expression in the brain, and neurons can supply the cellular factors necessary for their transcription.

Spectrum of human immunodeficiency virus-associated neocortical damage.

A spectrum of neurocognitive defects, termed human immunodeficiency virus type 1 (HIV-1)-associated cognitive/motor complex, has been described in patients with acquired immunodeficiency syndrome (AIDS). AIDS dementia complex (ADC) is a severe form of this disease seen in 20 to 30% of terminally ill patients. The etiology of this complex is distinct from commonly observed opportunistic infections seen in brains of patients with AIDS and has been attributed to HIV infection within the brain. At autopsy, the brains of patients with ADC contain numerous HIV-infected macrophages/microglia with prominent subcortical damage, together termed HIV encephalitis. We retrospectively analyzed all 107 brains from a three-year period (1988-1990) of AIDS autopsies using immunocytochemistry to detect HIV. Rather than breaking into distinct groups of HIV encephalitis versus non-HIV encephalitis, the specimens revealed a spectrum of severity of HIV infection. Although only 16% of the brains showed the histological hallmarks of HIV encephalitis, more than 50% of the autopsies showed moderate to severe HIV infection. In a subset of 23 AIDS autopsies during which short postmortem times and absence of significant opportunistic infection permitted quantitative analysis of dendritic and synaptic complexities, we identified a strong correlation between neocortical dendritic and presynaptic damage and abundance of HIV envelope protein in the neocortical gray and deep white matter. This correlation suggests that the presence of HIV-1 in the neocortex may be responsible by direct or indirect mechanisms for dendritic and synaptic damage.

Human Immunodeficiency Virus-Related Cognitive Impairment and the Acquired Immunodeficiency Syndrome Dementia Complex

Human Immunodeficiency Virus-Related Cognitive Impairment and the Acquired Immunodeficiency Syndrome Dementia Complex

Cerebrospinal fluid myelin basic protein as predictive marker of demyelination in AIDS dementia complex

Myelin basic protein (MBP) was measured in cerebrospinal fluid (CSF) of patients with acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) in order to investigate the degree of white matter destruction. Results show that increased CSF levels of MBP were detected in all patients with severe ADC (10/10) and, less often, in subjects with mild (2/7) or moderate dementia (7/16). No evidence of MBP-elevated concentration was observed in 14 human immunodeficiency virus (HIV)-seropositive subjects without neurological disorders and in nine HIV-seronegative controls. Our findings suggest that the measurement of CSF MBP concentration may represent a predictive marker of myelin injury and neurologic damage during the course of ADC.

Excitotoxicity and Dopaminergic Dysfunction in the Acquired Immunodeficiency Syndrome Dementia Complex

Human immunodeficiency virus infection is frequently complicated by a syndrome of central nervous system dysfunction known as the acquired immunodeficiency syndrome dementia complex (ADC). The ADC is characterized by abnormalities in cognition, motor performance, and behavior, and it produces serious morbidity in a significant number of patients with acquired immunodeficiency syndrome. The pathogenesis of ADC is unclear, but appears to be caused by the human immunodeficiency virus itself, rather than by a secondary opportunistic process. Herein, we review the data regarding the pathogenesis of ADC and hypothesize a mechanism involving excitotoxicity and dopaminergic dysfunction. N-methyl-D-aspartate receptor antagonists may be of therapeutic benefit, as these agents may both limit glutamate-mediated neuronal dysfunction and improve dopaminergic neuronal function.

Dementia in patients with the acquired immunodeficiency syndrome

Central nervous system (CNS) manifestations are common in patients with the acquired immunodeficiency syndrome (AIDS). The most common CNS syndrome is a dementing illness referred to as the AIDS dementia complex, in which motor and cognitive changes may also be seen. Neurodiagnostic studies are fairly characteristic, though highly nonspecific. Dementia may precede overt manifestations of AIDS, and either an insidious or a fulminant course may be seen. Appropriate management of the patient with AIDS includes differentiating dementia from psychologic responses to the disease.

Dementia in patients with the acquired immunodeficiency syndrome.

Central nervous system (CNS) manifestations are common in patients with the acquired immunodeficiency syndrome (AIDS). The most common CNS syndrome is a dementing illness referred to as the AIDS dementia complex, in which motor and cognitive changes may also be seen. Neurodiagnostic studies are fairly characteristic, though highly nonspecific. Dementia may precede overt manifestations of AIDS, and either an insidious or a fulminant course may be seen. Appropriate management of the patient with AIDS includes differentiating dementia from psychologic responses to the disease.

Quinolinic acid in cerebrospinal fluid and serum in HIV‐1 Infection: Relationship to clinical and neurological status

Quinolinic acid is an "excitotoxic" metabolite and an agonist of N-methyl-D-aspartate receptors. Of patients infected with human immunodeficiency virus type 1 (HIV-1) who were neurologically normal or exhibited only equivocal and subclinical signs of the acquired immunodeficiency syndrome (AIDS) dementia complex, concentrations of quinolinic acid in cerebrospinal fluid (CSF) were increased twofold in patients in the early stages of disease (Walter Reed stages 1 and 2) and averaged 3.8 times above normal in later-stage patients (Walter Reed stages 4 through 6). However, in patients with either clinically overt AIDS dementia complex, aseptic meningitis, opportunistic infections, or neoplasms, CSF levels were elevated over 20-fold and generally paralleled the severity of cognitive and motor dysfunction. CSF concentrations of quinolinic acid were significantly correlated to the severity of the neuropsychological deficits. After treatment of AIDS dementia complex with zidovudine and treatment of the opportunistic infections with specific antimicrobial therapies, CSF levels of quinolinic acid decreased in parallel with clinical neurological improvement. By analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood-brain barrier, as measured by the CSF:serum albumin ratio, it appears that CSF levels of quinolinic acid may be derived predominantly from intracerebral sources and perhaps from the serum. While quinolinic acid may be another "marker" of host- and virus-mediated events in the brain, the established excitotoxic effects of quinolinic acid and the magnitude of the increases in CSF levels of the acid raise the possibility that quinolinic acid plays a direct role in the pathogenesis of brain dysfunction associated with HIV-1 infection.

Reduced Cerebral Blood Flow in Early Stages of Human Immunodeficiency Virus Infection

In order to determine if brain perfusion abnormalities, which are known in patients with acquiredimmunodeficiency syndrome dementia, occur in early stages of human immunodeficiency virus infection, technetium 99m hexamethyl-propyleneamine oxime-single-photon emission computed tomography studies were performed in 20 patients infected with human immunodeficiency virus who belonged to Walter Reed stages I through IV. None of these patients demonstrated signs of dementia or severe neurological dysfunction. Pathological patterns of hexamethyl-propyleneamine oxime uptake were seen in 14 patients, seven of whom had normal results during neurological examination. Only four patients had signs of cerebral atrophy on cranial computed tomographic scan. These data suggest that subtle changes in cerebral perfusion seem to arise early in the course of human immunodeficiency virus infection and may indicate human immunodeficiency virus encephalopathy before neurological symptoms or noticeable structural damage occurs.

Brain imaging in acquired immunodeficiency syndrome dementia complex

Human immunodeficiency virus (HIV) infections are accompanied by many different types of neurological complications. Opportunistic infections and neoplasms, particularly lymphoma, are often an underlying cause for these complications in patients with acquired immunodeficiency syndrome (AIDS). Frequently, these can be detected by cerebrospinal fluid (CSF) examination, double-dose contrast transmission computed tomography (CT), and/or magnetic resonance imaging (MRI). It has become apparent that the HIV itself is responsible for a significant percentage of neurological disease in the HIV-seropositive individual. The onset may be subtle and may occur before the onset of frank immunosuppression. Diagnosis of HIV encephalitis or AIDS dementia complex (ADC) is complicated by the frequent coexistence of opportunistic infections. Structural neuroimaging (CT or MRI) shows atrophy and in some case white matter abnormalities, but imaging-pathological correlation suggests that these modalities are relatively insensitive to the presence of HIV brain infection. Functional neuroimaging, both 18fluorodeoxyglucose positron emission tomography (PET) for evaluation of glucose metabolism and 123I iodoamphetamine or 99mTc-HMPAO single-photon emission computed tomography (SPECT) for evaluation of cerebral perfusion, can demonstrate abnormalities in the subcortical gray matter structures and the cerebral cortex in patients with ADC. These abnormalities may be observed early in the course of ADC even when MRI is negative and the patient is relatively asymptomatic. Also, PET and SPECT may be useful to follow progression of the dementia or response to therapy.

Cerebrospinal fluid neopterin in human immunodeficiency virus type 1 infection

We evaluated cerebrospinal fluid (CSF) concentrations of neopterin, a putative marker of activated macrophages, in 97 subjects infected with human immunodeficiency virus type 1 who had a spectrum of neurological complications. The highest CSF neopterin concentrations occurred in those with neurological opportunistic infections, primary central nervous systems lymphoma, and acquired immunodeficiency syndrome (AIDS) dementia complex. In general, the CSF concentration of neopterin was independent of CSF cell count and blood-brain barrier disruption to albumin. In the patients with AIDS dementia complex, CSF neopterin concentrations correlated with severity of disease and decreased in conjunction with clinical improvement following treatment with zidovudine. These results suggest that CSF neopterin, although not disease-specific, may be useful as a surrogate marker for the presence of AIDS dementia complex and its response to antiviral therapy.

AIDS dementia complex: brain high-energy phosphate metabolite deficits.

To test whether compromised high-energy phosphate metabolism is implicated in the neurologic impairment of acquired immunodeficiency syndrome dementia complex (ADC), brain phosphate metabolite concentrations and ratios were measured noninvasively in 12 patients with mild to moderate ADC and 29 healthy volunteers by use of localized phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy and proton (hydrogen-1) magnetic resonance (MR) imaging. In patients, brain phosphocreatine (PCr) and nucleoside triphosphate (NTP) concentrations in sections through the centrum semiovale that were seen with NMR spectroscopy were reduced significantly from normal values of 4.92 mmol/kg wet weight +/- .13 (standard error of the mean) and 2.79 mmol/kg +/- .11, respectively, to 3.33 mmol/kg +/- .26 and 1.99 mmol/kg +/- .13 (P less than .0001). The ratios of metabolites detectable with P-31 NMR spectroscopy did not differ significantly from those of control subjects. The magnitude of the PCr and NTP deficits in ADC was not explicable by focal abnormalities or cerebral atrophy quantified in images of the same regions. These results are consistent with the hypothesis of a generalized virus-associated toxic process affecting brain cell function in ADC. Noninvasive measurement of metabolite concentrations with NMR spectroscopy provides new functional information that may help quantify disease progression and response to therapy.

AIDS Dementia May Be Linked to Metabolite of Tryptophan

QUINOLINIC ACID is intriguing researchers as a possible cause and marker of neurological damage in human immunodeficiency virus (HIV) disease. It is a neurotoxic convulsant metabolite of tryptophan that is activated by interferon gamma. It is elevated with any infection, from a common rhinovirus to the mysterious lentivirus linked to acquired immunodeficiency syndrome (AIDS). But quinolinic acid remains elevated for extended periods with HIV and increases as much as a 1000-fold over controls in patients with AIDS dementia complex, says Melvyn Heyes, PhD, a visiting scientist in the analytical biochemistry section at the National Institute for Mental Health in suburban Washington, DC (Maryland). It binds to and may down-regulate Nmethyl-D-aspartate receptors, which are involved in normal neurotransmission, neural regeneration, memory, and synaptic plasticity. It can also induce seizures and nerve cell death, says Heyes. There is a wide spectrum of possible consequences known to occur in AIDS and other infectious

Magnetic Resonance Imaging Findings in HIV Cognitive Impairment

Atrophy and white matter changes seen on magnetic resonance imaging scans have been observed in association with the acquired immunodeficiency syndrome dementia complex, but these appear to be late findings relative to clinical expression. We report a new magnetic resonance imaging observation in patients with early cognitive impairment due to human immunodeficiency virus infection. Fifty-two patients had a total of 86 magnetic resonance imaging scans during the study period. All scans were obtained with a 1.5-T system. The proton density spin echo (repetition time of 2000 milliseconds and echo delay time of 30 milliseconds) study demonstrated high-signal lesions in the region of the splenium of the corpus callosum and in the crura of the fornices. The lesions demonstrated no contrast enhancement with gadopentate dimeglumine. Pathological examination was performed in five patients. The fornix-subcallosal abnormality may be related to the memory dysfunction in patients with human immunodeficiency virus-related cognitive impairment.

Ethics

Treatment of human immunodeficiency virus infection poses some of the most difficult dilemmas in clinical medicine. As new data on natural history, treatment, and prevention appear, some new ethical questions are raised and older ones reexamined. This review focuses on the ethical impact of recent research, particularly the availability of early treatment. The most significant recent findings include the potential effectiveness of the early use of zidovudine (formerly known as azidothymidine [AZT]) in delaying the emergence of the acquired immunodeficiency syndrome (AIDS) and the use of sulfamethoxazole and aerosolized pentamidine isethionate in preventing opportunistic infections.^1-3In addition, zidovudine has shown some reversing effect on AIDS dementia in children.⁴Dideoxyinosine seems effective in zidovudine-resistant and intolerant patients. Other more promising and more sophisticated therapies are in the offing.⁵ None of these measures is curative, but they change the physician's approach to management dramatically. Early diagnosis, early treatment, and

Mental changes in patients with AIDS

Mental changes are common in patients with acquired immunodeficiency syndrome (AIDS). Neuropsychological data of 32 patients with AIDS and cognitive symptoms were reviewed. All patients were neurologically examined and ancilliary investigations were performed. According to the neuropsychological data three groups could be distinguished: I) 4 patients with dementia and cortical deficits; II) 16 patients with subcortical dementia; III) 12 patients with subcortical cognitive deficits without global intellectual deterioration. AIDS Dementia Complex (ADC) was diagnosed in 12 patients and occurred in all three groups. The most frequent form of dementia in patients with AIDS is of a subcortical type. Impaired memory or reduced psychomotor speed, or both, are common in patients without global intellectual deterioration. ADC seems an unlikely diagnosis in patients with cortical dementia. Neuropsychological examination is important for diagnosing ADC but the diagnosis cannot be made without regarding the neurological findings and ancilliary investigations.

The Acquired Immunodeficiency Syndrome (AIDS) Dementia Complex

The acquired immunodeficiency syndrome (AIDS) dementia complex is a frequent and devastating complication of infection with human immunodeficiency virus-type 1 (HIV-1). Features of the AIDS dementia complex include decreased memory, the inability to concentrate, apathy, and psychomotor retardation. Typical neuropathologic findings include gliosis, focal necrosis of neurons, perivascular inflammation, formation of microglial nodules, multinucleated giant cells, and demyelination. That HIV-1 is the direct cause of this neurologic syndrome is strongly supported by the available evidence. In addition, several studies have identified the monocyte-macrophage as the predominant cell type in the brain infected with HIV-1. However, the mechanisms by which the infected monocytes-macrophages mediate neurologic dysfunction and destruction have not been elucidated.

AIDS dementia complex. Characteristics of a unique aspect of HIV infection.

A common complication of acquired immunodeficiency syndrome (AIDS) is being increasingly recognized. Known as AIDS dementia complex, the disorder is characterized by global impairment of intellectual and cognitive functions, personality and behavioral disturbances, and motor dysfunction manifested by impaired speech, gait, and coordination. AIDS dementia complex progresses rapidly and inexorably from psychomotor slowing to dementia, then to an akinetic mute state in which the patient becomes immobile and incapable of speaking, and finally to coma. Differentiation of AIDS dementia complex from a potentially treatable condition, such as reactive depression, is important. Zidovudine (Retrovir), the drug currently used to treat AIDS, has shown promise in the treatment of AIDS dementia complex. Clinical trials are now under way to determine its efficacy in this application.

Tumor necrosis factor alpha (TNFα) and neurological diseases Failure in detecting TNFα in the cerebrospinal fluid from patients with multiple sclerosis, AIDS dementia complex, and brain tumours

The presence of tumor necrosis factor alpha (TNFα)/cachetin was investigated in 180 paired cerebrospinal fluid (CSF) and serum samples from patients with neurological diseases, and in five paired CSF and serum samples of Macacus cynomolgus monkeys with acute monophasic experimental autoimmune encephalomyelitis (AMEAE). TNFα was never detected in human CSF, even when an extensive demyelination was documented (active multiple sclerosis, acquired immunodeficiency syndrome (AIDS) dementia complex). Only one Macacus with AMEAE had detectable levels of TNFα in CSF but not in serum, suggesting an intrathecal synthesis of this cytokine in AMEAE.