It is possibly a measure of membrane integrity. Instead of reporting absolute signal intensity or concentrations of the metabolites, researchers often measure the ratios between two of these metabolites for experimental reasons.
The interpretation of metabolite ratios, however, is sometimes ambiguous, because it may not be clear whether changes in the metabolite in the numerator, denominator, or both cause a change in the ratio. Despite such limitations, however, measurements of the levels of certain metabolites or their ratios can provide researchers with a picture of the health and function of cells within a living organism as well as of the effects that other substances, such as alcohol, have on the function and viability of those cells.
Consistent with the neuropathological studies described in the previous section, symptomatic HIV- positive patients in MRI studies showed loss of brain volume particularly in white matter, temporal lobe gray matter, the basal ganglia, and the posterior cortex. In particular, shrinkage of the caudate- a small structure in the basal ganglia related to cognition and motivation that is connected to the prefrontal cortex-appears to be associated with dementia and advanced disease stage.
Although MRI studies can be useful in a research setting, the findings are not sensitive enough and not specific for HIV disease in a clinical setting. In other words, MRI might miss some HIV-related changes in brain structure or the observed changes might result from other conditions. Moreover, it is still too early after the introduction of potent antiretroviral medications to state conclusively how well HAART has affected the frequency and degree of HIV-related brain abnormalities other than opportunistic infections of the CNS detectable by MRI.
For example, researchers have measured the levels of a molecule called N-acetyl-aspartate NAA , which serves as an indicator of neuron viability. The NAA changes were largest in white matter of the frontal brain, and preliminary data suggest that the extent of these changes increased with the severity of the patients' cognitive impairment. Subsequent MRS studies have measured metabolites called choline-containing compounds Cho and myo-inositol mIno , which reflect membrane-related metabolic processes in glia cells.
These studies also detected abnormalities in asymptomatic HIV-infected patients whose immune systems were still intact, with increased levels of Cho and mIno primarily in the white matter surrounding the ventricles and in the basal ganglia see Navia and Gonzalez This finding is consistent with the neuropathological studies demonstrating glial proliferation in those brain areas.
Therefore, investigators have suggested that Cho and mIno measures may serve as markers of HIV-induced neuropathological changes or of CNS involvement.
Neuropathology and Neuropsychology of Chronic Alcohol Abusers. Autopsy studies have shown that the brains of chronic alcoholics are smaller, lighter, and exhibit greater atrophy than those of nonalcoholics of the same age and gender for a review, see Kril and Halliday This reduced brain size resulted primarily from white matter loss, especially in the frontal lobe.
The extent of that white matter loss increased proportionally with the drinker's maximum daily alcohol consumption. Overall, pathological studies revealed two kinds of alcohol-related damage to the cortex: loss of neurons primarily from the frontal cortex and widespread shrinkage of the neurons i.
Neuron loss is thought to be permanent whereas the size reduction of neurons and their dendrites is potentially reversible with abstinence. In addition to this cortical damage, severe alcoholics also show reduced size and other abnormalities in various subcortical structures e.
Most of these findings have been confirmed in animals that were given alcohol in their drinking water over a long period, mimicking lifelong chronic alcohol abuse in humans. Scientists also had hypothesized that chronic alcohol abusers, who frequently exhibit memory loss and learning difficulties, would show damage to the hippocampus, a brain area associated with memory and learning.
However, neuropathological studies detected no significant hippocampal neuron loss in alcoholics; instead, dendrites or metabolism in the hippocampus of alcoholics may be damaged see Kril and Halliday The cerebral cortex is the seat of higher intellectual functions. Consistent with the findings of autopsy studies of chronic alcoholics demonstrating widespread cortical damage, neuropsychological studies frequently have demonstrated cognitive deficits in this population Oscar-Berman These include deficits in problem solving, organizing, planning, and abstraction so-called executive functions that are associated with the frontal lobe ; short-term and long-term memory; verbal fluency; learning; and visuospatial perceptions, which generally are associated with subcortical brain structures.
Furthermore, the observed cerebellar shrinkage has been associated with impaired coordination and balance commonly found in alcoholics. Taken together, neuropathological and neuropsychological studies suggest that the frontal lobes are particularly susceptible to the deleterious effects of chronic alcohol use in humans but that other structures also are involved.
Consistent with the neuropathological studies, imaging studies using computed tomography CT scans demonstrated atrophy in various brain regions of alcoholics as indicated by shrinkage of the cerebellum and widening of the ventricles and fluid-filled gaps i. MRI studies also demonstrated volume loss in brain regions that show neuron loss in pathological studies, primarily in cortical gray matter regions of the frontal lobes, but also in gray matter of the parietal and temporal lobes.
This gray matter loss often is accompanied by increases in fluid volume in the same regions. In addition, MRI studies of chronic alcoholics have demonstrated white matter loss in the frontal-parietal brain and corpus callosum, as well as volume loss of subcortical structures e.
As did neuropathological studies, neuroimaging studies found no decrease in the size of the hippocampus, despite the memory and learning deficits observed in alcoholics. Researchers have demonstrated some relationships between volume deficits in some brain areas and measures of neuropsychological impairment; however, these relationships have not been consistent. An alcoholic's age influences how severe alcohol-related changes in brain structure and function are, with more severe and persistent alcohol-related changes evident in the brains of older alcoholics Sullivan Age also appears to affect the brain's ability to recover from alcohol-related damage.
When alcoholics stop drinking, some of the gray and white matter loss and cognitive impairment caused by chronic drinking is reversible. Studies found that the recovery of brain structure and function is greater and more rapid in younger abstinent alcoholics than in older abstinent alcoholics see Sullivan The significance of the recovery of brain structures for the recovery of brain functions is under active investigation.
Despite their potential usefulness, MRS studies on the effects of chronic alcohol abuse on the brains of humans or animals are scarce see Sullivan These observations support those of the neuropathological and neuropsychological studies described in the previous section. Patients with alcoholic dementia also reveal evidence of neuronal damage in the basal ganglia and occipital lobe. One MRS study compared certain brain metabolites in the thalamus and frontal cortical regions between alcoholics who had been abstinent for 1 month and alcoholics who had been abstinent for 6 years see Sullivan The study found elevated mIno levels after short-term abstinence but not after long-term abstinence, suggesting that some alcohol-induced changes are reversible with prolonged abstinence.
Taken together, the pathological, neuropsychological, structural, and metabolic evidence suggests that chronic alcohol abuse predominantly affects the frontal lobe whereas HIV-at least early in the course of the disease-primarily affects white matter deep within the brain as well as subcortical brain structures see table.
Cortical brain regions become involved only during advanced stages of HIV disease, which are associated with cognitive and some clinical impairment. Based on these findings, the brain regions expected to be primarily affected in alcohol-abusing HIV-infected subjects include central white matter, subcortical brain structures, and the frontal cortex.
These regions are the focus of current structural and metabolic MR studies of the combined effects of alcohol abuse and HIV infection on the brain. The findings reviewed so far strongly suggest that chronic alcohol abuse can adversely affect the natural course of HIV disease. This section summarizes studies analyzing the interactive effects of HIV infection and chronic alcohol abuse on the brains of patients not treated with HAART.
The light-drinking and heavy-drinking HIV-positive groups were matched for the degree to which their immune systems were already impaired by the HIV infection, and both groups exhibited mild-to-moderate neuropsychological impairment. The study assessed the levels of two molecules called PCr and ATP, which reflect the cell's energy metabolism, as well as of a group of compounds called PDE, which represent breakdown products of molecules found in the cell membranes.
The study found that chronic alcohol consumption was associated with lower concentrations of PDE, PCr, and ATP in white matter of the region surrounding the ventricles i. The metabolic effects of advanced HIV infection and alcohol abuse were cumulative, because HIV-positive heavy drinkers clearly showed the greatest metabolic deficits in white matter.
PDE levels also were significantly lower in subcortical gray matter, which is associated with learning and memory functions, of heavy drinkers with advanced HIV disease compared with HIV-negative light drinkers. These findings are consistent with the neuropathological and neuropsychological observations demonstrating subcortical damage.
Taken together, these findings suggest that both alcohol abuse and HIV infection alter the brain's energy metabolism and the metabolism of cell membranes and that these alterations are associated with the presence of clinical HIV symptoms. More importantly, the study found that chronic alcohol abuse augmented the adverse effects of HIV on biologically important white matter molecules. Meyerhoff and colleagues also conducted a MRS study assessing different molecules, including NAA, in a similar patient population.
That study found metabolic changes in the regions of the brain stem-a region at the base of the brain that performs motor, sensory, and reflex functions-of active heavy drinkers.
These changes were consistent with pathological evidence for the loss of certain neurons and for gliosis found throughout the brain stem of chronic alcoholics. These changes were particularly pronounced in HIV-positive heavy drinkers, suggesting that HIV infection may have an additional adverse effect on brain stem metabolites. These studies, which were performed before the introduction of HAART therapy, suggest that chronic alcohol abuse exacerbates some metabolic injury in the HIV-infected brain.
Electrophysiological studies, which measure certain aspects of the brain's electrical activity, have provided additional evidence for an additive effect of heavy drinking on brain damage in HIV-infected subjects. One study assessed an electric signal measurable in the frontal lobe that is thought to reflect mental processes requiring attention and memory updating Fein et al.
This signal is delayed in HIV-infected subjects, but the delays occurred earlier in the course of HIV disease in alcohol-abusing than in light-drinking or abstinent HIV-infected subjects. Researchers are currently investigating the cognitive and behavioral significance of these brain changes. The effect of modern antiretroviral treatment i.
The studies found little evidence, however, that chronic alcohol abuse exacerbated the CNS effects of HIV infection in these treated patients. Researchers have begun to investigate the effects of chronic alcohol abuse on HIV-associated CNS disease, integrating studies of immunology, neuropsychology, behavior, and drug-availability i. Longitudinal studies, which follow a group of subjects over extended periods of time, will allow a more powerful assessment of the CNS effects of combined chronic alcohol abuse and HIV disease.
Bang HO, Bang J. Involvement of the Central Nervous System in Mumps. Acta Med Scand. An unusual form of lymphocytic choriomeningitis. Arch Neuro Psychiatr. Herpesvirus infections of the human central nervous system. N Engl J Med. Herpes simplex virus type 1 meningitis. Pediatr Infect Dis J. Hollander H, Stringari S. Human immunodeficiency virus-associated meningitis.
Clinical course and correlations. Am J Med. Infect Dis Clin Prac. Echoviruses are a major cause of aseptic meningitis in infants and young children in Kuwait. Virol J. Romero JR. Pediatric group B coxsackievirus infections.
Curr Top Microbiol Immunol. Choriomeningitis and myocarditis in an adolescent with isolation of coxsackie B-5 virus. Am J Clin Pathol. Evidence for cytotoxic T-lymphocyte-target cell interaction in brains of mice infected intracerebrally with lymphocytic choriomeningitis virus. Acta Neuropathol Berl ; 61 — Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis.
This intravital imaging study provided the first data showing that cytotoxic lymphocytes can promote synchronous extravasaton of myelomonocytic cells that damage meningeal blood vessels, contributing to fatal edema during LCMV meningitis. Migration of cytotoxic lymphocytes in cell cycle permits local MHC I-dependent control of division at sites of viral infection. J Exp Med. This study provided the first data showing that antiviral cytotoxic lymphocytes can migrate through the blood in active stages of cell cycle and undergo cytokinesis upon arrival in the virally infected meninges.
Aseptic meningitis caused by the lymphocytic choriomeningitis virus. Clin Neurol Neurosurg. Emerg Infect Dis. Lymphocytic choriomeningitis virus infection in organ transplant recipients--Massachusetts, Rhode Island, Lymphocytic choriomeningitis infection of the central nervous system. Front Biosci. Nat Immunol. This study demonstrated that antiviral cytotoxic lymphocytes form immunological synapses with infected targets in the virally infected meninges and can engage up to three targets simultaneously to improve killing efficiency.
Type I interferon programs innate myeloid dynamics and gene expression in the virally infected nervous system. PLoS Pathog. Type I interferon was determined in this paper to be responsible for all innate immune gene expression and immune cell dynamics in the brain following infection with LCMV.
Functional role of type I and type II interferons in antiviral defense. This study used genetic knockout mice to demonstrate that type I and type II interferons are both required for antiviral immunity.
J Immunol. Aylward B, Yamada T. The polio endgame. The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways. J Neuropathol Exp Neurol. Neurologic complications in children with enterovirus 71 infection. Acute neurologic illness of unknown etiology in children - colorado, august-september Greenlee JE.
The equine encephalitides. Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation. J Gen Virol. Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. Induction of apoptosis by Sindbis virus occurs at cell entry and does not require virus replication. Inflammation is a component of neurodegeneration in response to Venezuelan equine encephalitis virus infection in mice.
J Neuroimmunol. Sindbis virus-induced neuronal death is both necrotic and apoptotic and is ameliorated by N-methyl-D-aspartate receptor antagonists. Using NMDA receptor antagonists, the authors of this study demonstrated that virus-induced death of cortical neurons is mediated by glutamate excitotoxicity. Coxsackievirus targets proliferating neuronal progenitor cells in the neonatal CNS.
This study demonstrated how coxsackievirus B3 seeds the neonatal brain by infecting neuroprogenitor cells, which then migrate along the rostral migratory stream. Pathogenesis of flavivirus encephalitis. Fatal fulminant pan-meningo-polioencephalitis due to West Nile virus. Brain Pathol. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. A preliminary neuropathological study of Japanese encephalitis in humans and a mouse model.
Lindquist L. Tick-borne encephalitis. Toll-like receptor 3 has a protective role against West Nile virus infection. Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis.
The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. J Neuroinflammation. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun. Japanese encephalitis virus-infected macrophages induce neuronal death.
J Neuroimmune Pharmacol. Nitric oxide and viral infection: NO antiviral activity against a flavivirus in vitro, and evidence for contribution to pathogenesis in experimental infection in vivo. Mishra MK, Basu A. Minocycline neuroprotects, reduces microglial activation, inhibits caspase 3 induction, and viral replication following Japanese encephalitis. J Neurochem. Transmission of West Nile virus from an organ donor to four transplant recipients.
Central nervous system HIV-1 infection. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Immunol Rev. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion.
Intercompartmental recombination of HIV-1 contributes to env intrahost diversity and modulates viral tropism and sensitivity to entry inhibitors.
Genetic analyses of HIV-1 from different tissues revealed that intercompartmental recombination leads to viral diversity and phenotypic changes within a single host. Neuronal loss in the frontal cortex in HIV infection. Bagashev A, Sawaya BE. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. This study demonstrated that HIV-1 gp protein induces neurotoxicity by increasing intracellular calcium levels.
Kaul M, Lipton SA. Chemokines and activated macrophages in HIV gpinduced neuronal apoptosis. The high overall genetic diversity that characterizes HIV has been a key factor in its worldwide spread, and poses concerns for disease progression, as well as diagnosis, treatment and prevention efforts Hemelaar et al. Findings from studies conducted in Western countries derive mainly from work on HIV-1 clade B infection in Caucasian populations, and therefore may not be generalizable to HIV clades and human populations globally.
The effects of HIV subtypes, or clades, on disease progression and treatment remain unclear Liner et al. While numerous studies indicate that reverse transcriptase inhibitors and protease inhibitors are equally effective treating all HIV subtypes Alexander et al. HIV infection results in disruption of neuronal function by a variety of mechanisms that can be grouped into three general categories: viral factors, host factors and co-factors. Viral factors derive from the virus itself, and include several proteins encoded by the viral genome.
Host factors, on the other hand, evolve indirectly or secondarily from infection, but may damage even uninfected cells such as neurons. Co-factors are social or behavioral characteristics or co-morbid conditions that may contribute to or amplify the pathogenicity of HIV.
In the nervous system, these factors converge in producing damage to the elaborate network of connections between neurons that take place at dendrites and synapses. This synaptodendritic injury, described in detail below, disrupts the highly integrated functioning of neural systems that is required to process information, leading to HIV-associated neurocognitive disorders HAND.
The brain, however, does not respond passively to synaptodendritic injury, but instead actively upregulates pathways promoting repair and regeneration.
These pathways have become particularly important today, as survival has been prolonged by cART. Patterns of neuronal injury seen in the brains of cognitively impaired HIV-infected individuals that come to autopsy can be replicated in cultures of human nervous tissue exposed to gp Iskander et al. These changes include synaptodendritic injury, reactive astrocytosis, and microgliosis, and loss of large pyramidal neurons Kaul and Lipton One molecular mechanism by which gp might induce these changes is through glutamate-mediated excitotoxicity, which can initiate caspase cascades Tenneti and Lipton Another viral protein reported to cause neuronal injury is Tat, which is produced by infected astrocytes Nath In experiments in which Tat-expressing astrocytes were injected into the rat dentate gyrus, Tat was taken up by granule cells and transported along neuronal pathways to the CA3 region of the hippocampus, where it caused glial cell activation and neurotoxicity Bruce-Keller et al.
HIV Tat can cause mitochondrial dysfunction, dendritic loss, and cell death in neurons at concentrations lower than those needed to support viral replication Chauhan et al. Secondary effects of HIV infection on the immune system can amplify nervous system damage.
Many of the host factors relevant to HIV CNS injury are chemical mediators of inflammation and immunity—cytokines and chemokines. Cytokines are produced by immune cells including macrophages that traffic into the CNS from the peripheral circulation, as well as by brain astrocytes and microglia activated or infected by HIV. Chemokines represent a subset of cytokines with chemo-attractant properties, and are particularly important in HIV-related pathology.
Chemokine receptors are distributed throughout the brain on microglia, astrocytes, oligodendrocytes and neurons. Abnormal activation of cytokine and chemokine receptors results in ultrastructural and functional neuronal alterations that are at least partially reversible. This suggests that appropriate treatments might enhance neuronal repair and ameliorate the damage arising from abnormal activation of cytokine or chemokine receptors.
Importantly, host factors can differ between individuals. For example, increased susceptibility to neurodegeneration in HIV is associated with host genetic variations that might account for differential susceptibility to HAND between different individuals infected with the same viral strain Gonzalez et al. HIV-infected individuals frequently have co-morbidities such as abuse of drugs and alcohol or infection with viral co-pathogens such as hepatitis C virus HCV.
These cofactors may contribute to CNS injury. For example, in neuropathological studies, HIV-infected individuals dying with histories of injection drug use show more activated microglia and diffuse astrogliosis in the white matter of the brain than their HIV-infected non-addicted counterparts Cook et al.
In vitro studies Bagasra et al. In addition, several studies have demonstrated that HCV co-infection was associated with a greater risk of neurocognitive disorders among those with HIV, with or without drug use Cherner et al. Because HCV is also associated with systemic and possibly CNS immune activation, it is possible that there may be some common immuno-neuropathogenic mechanisms leading to a heightened likelihood of CNS disease in co-infected individuals. Synaptodendritic injury is a general term encompassing a variety of structural and chemical changes that ultimately can impair the normal functioning of neuronal networks.
Normal synaptodendritic networks are complex and highly branching, whereas injured networks are simplified. Features of syndaptodendritic injury include dendritic spine retraction, beading and aberrant sprouting. Higher cognitive functions depend on the integrity of complex synaptodendritic networks, therefore damage results in deficient cognitive skills and behavior.
Synaptodendritic injury is demonstrated by immunostaining with antibodies to presynaptic synaptophysin SYN and postsynaptic microtubule associated protein-2 MAP2 Orenstein et al. MAP2 is expressed on neuronal cell bodies and dendrites. This technique has provided evidence that the striatum and the hippocampus are particularly affected Bruce-Keller et al.
This regional vulnerability parallels the higher burden of HIV proteins and viral RNA in the striatum and white matter connecting the striatum to the prefrontal cortex Masliah et al. Techniques for measuring synaptodendritic injury in living humans are indirect and imprecise. Proteins released from damaged neurons into the extracellular space can be detected in the cerebrospinal fluid CSF or blood.
Elevated CSF neurofilament protein NFL concentrations, for example, are thought to reflect injury to myelinated axons. However, it is not known whether increased NFL can result from neuronal injury alone or requires cell death, and there are no data on the dynamic relationship between changes in neurological status in HIV patients and changes in NFL levels.
It is reasonable to propose that synaptodendritic loss will reduce the overall volume of brain gray and white matter. Gross structural atrophy can be visualized by brain computed tomography CT and magnetic resonance imaging MRI , and careful radiological-neuropathological correlation studies have shown that white matter loss and abnormal white matter signal are closely correlated with the loss of MAP-2 immunostaining, particularly in the presence of HIV encephalitis Archibald et al.
Worsening white matter abnormalities correlate with worsening cognitive impairment Everall et al. Synaptic dendritic networks in the healthy brain undergo continuous remodeling, reflecting plasticity, which can include increased dendritic branching, augmentation of axonal collaterals, generation of new synaptic connections and activity-dependent modification of existing synapses Makrigeorgi-Butera et al. Neurogenesis may also participate in restoration of function after brain injury Langford et al.
Neurocognitive disorders can range in severity from slight deficits to debilitating dementia. ANI describes individuals with usually mild impairment in two or more cognitive areas, demonstrated by neuropsychological testing, without a clear effect on everyday functioning.
MND refers to the presence of mild to moderate deficits in two or more cognitive areas which create at least mild interference in everyday functioning. Finally, HAD describes individuals with documented moderate to severe deficits in two or more cognitive areas, with substantial impairment in every day functioning making the person incapable of employment and often unable to live independently.
Despite this, the overall prevalence of HAND has not declined, possibly because HIV infected individuals with milder neurocognitive disorders are living longer, or because cART is not as effective in the brain as in the periphery. The notion that cART might not be as effective in the brain as it is systemically derives from the observation that the blood brain barrier BBB frequently limits the movement of antiretrovirals from the circulation into the CNS.
Several factors affect the CNS penetration of antiretroviral medications. Vacuolar myelopathy. This condition occurs when tiny holes develop in the fibers of the nerves of the spinal cord. It causes difficulty walking, particularly as the condition gets worse. Psychological conditions. They may also experience hallucinations and significant changes in behavior.
Tumors called lymphomas often strike the brain of people with HIV. They're often related to another virus, similar to the herpes virus.
Lymphomas can be life-threatening, but good management of HIV can make treating lymphomas more successful. If an HIV-infected person also has syphilis that goes untreated, it can quickly progress and damage the nervous system. It can cause the nerve cells to break down and lead to loss of vision and hearing, dementia, and difficulty walking. Once HIV begins affecting your immune system, it can cause many different symptoms.
HIV-related neurological complications may lead to:. Although a blood test can diagnose HIV and AIDS, a number of other diagnostic tests are needed to look at the different parts of the nervous system and diagnose neurological problems. Tests often include:. Biopsy to analyze a sample of tissues and to help identify tumors in the brain or inflammation in the muscles.
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