- Email: [email protected]
The mechanisms and clinical relevance of HIV associated brain damage
S-16 Growing Points in the Psychopharmacology of Sleep and lower hemoglobin. In patients with a CD4 cell count < 2OG/ttl, hemoglobin is not predictive of ADC, but there is a correlation with CD4 cell counts < SO/ttl and elevated concentrations ofCSF fh microglobulin and neopterin. ADC may respond to treatment with zidovudine and preliminary data suggest a response to atevirdine.
I5-15-21 The Mechanisms and Clinical Relevance of HIV Associated Brain Damage
J.P.Everall. Department ofNeuropathology, Institute of Psychiatry, London 5£5. UK Clinically HIV can result in a severe dementia, and pathologically it is known that the brain is a major target of infection by HIY. There is a spectrum of damage associated with HIV brain infection, which is still being clarified. This includes inflammatory disorders such as encephalitis and leucoencephalopathy, as well as significant neuronal loss and synaptic and dendritic damage. Utilizing a combination of morphometric, stereological and spatial analytic techniques studies have been undertaken to quantify neuronal and synaptic damage in combination with immunocytochemistry and in situ hybridization. These have been performed in HIV infected symptomatic individuals, those who died of AIDS, and those whose dementia was prospectively rated prior to death. From these studies it is becoming clear that neuronal loss is limited to the symptomatic stage of the disease. Importantly, the severity of the dementia, while not related to the presence of multinucleated giant cells, does seems to be correlated to the load of virus in the brain and also to the pattern of neuronal loss. Evidence is emerging that neuronal loss is selective. The mechanism of neurotoxicity is being examined as neurons are not directly infected. The two main hypotheses of neuronal death are firstly, excess cytokine production, e.g. tumour necrosis factor-a, and secondly, toxic viral products, e.g. the viral protein gp120 and the regulatory protein tat. The latter are proposed to act via glutamate activated calcium channels and recently in a cerebellum study we have shown a significant alteration in the expression of the flop isoform of the GluR-A AMPA glutamate receptor (Everall et aI., Nature Medicine 1995; I: 1174-1178). While these changes were demonstrated in Purkinje cells which are relatively resistant to loss, they may be significant in other vulnerable brain regions.
I5-15-31
NMRSpectroscopy as a Tool for In Vivo Detection and Monitoring of Progress of HIV CNS Disease
G. Fein, D. Meyerhoff, M. Weiner. Departments of Psychiatry and Radiology, University of California, and Veterans Affairs Medical Center, San Francisco, California, USA Neuronal loss at autopsy and brain atrophy by MRI have been documented in many AIDS patients. We hypothesized that, because of glial proliferation as neurons are lost or damaged, MRI measures of atrophy underestimate neuronal loss. Proton Magnetic Resonance Spectroscopic Imaging (MRSI) allows in vivo measurement ofN-acetylaspartate (NAA), a putative neuronal marker. We have completed two long echo time Proton MRSI studies documenting NAA reductions of about 15% throughout a supraventricular brain slice in severely cognitively impaired HIV seropositive patients compared to high- and low-risk controls, with asymptomatic seropositive patients being indistinguishable from controls. These NAA reductions were present in patients without atrophy evident on MRJ. More recently, we have replicated these supraventricular findings at shorter echo times and have extended the studies to include basal ganglia and thalamic volumes (sites of earlier HIV infection than the supraventricular volumes studied previously) and to include patients who have no or minimal cognitive impairment, but whose HIV disease has progressed so that their CD4 percent is below 20%. The replication of the supraventricular volume effects at shorter echo times strongly suggests that those results indicate actual loss of NAA rather than a reduction in the NAA relaxation time. Preliminary analysis of the thalamic and basal ganglia results reveals NAA reductions in the thalamus but unchanged NAA and increased choline in the basal ganglia, consistent with macrophage infiltration but not glial proliferation in that area. The results for the patients with low CD4 were intermediate between those of cognitively impaired patients and controls, suggesting the presence of earlier but less dramatic changes
31 with progressing HIV disease before frank neurocognitive impairments are present. At the time of the presentation, longitudinal data for 25-35 patients will be presented.
I5-15-41
The Epidemiology of Psychiatric Disorders in HIV Infection: Depression, Mania and Dementia
C.G. Lyketsos, GJ. Treisman. Department of Psychiatry, The Johns Hopkins University. Baltimore, Maryland, USA There is a high prevalence of psychiatric disorders-particularly depression, mania, dementia, anxiety and substance use disorders, in HIV-infected individuals in community and clinical settings and across cultures. These are in part accounted for by the high prevalence of certain disorders in persons at risk for infection. Dementia and mania are also consequences of the HIV brain infection as they are more prevalent in later stage of the disease and associated with subcortical brain injury. Depression, whose prevalence appears to increase considerably around the time of AIDS, may be a consequence of the immune dysregulation that develops around the same time. This paper will review the epidemiology of psychiatric disorders in HIV infection with a special emphasis on depression, mania, and dementia. Distinctions will be made between findings in community, clinical, and cross-cultural settings and across stages of HIV infection.
I5-15-51
Treatment of Neuropsychiatric Disorders Associated with HIVand AIDS
GJ. Treisman, M. Fishman, P.R. McHugh, C.G. Lyketsos. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University. Baltimore, Maryland, USA Studies from several groups have demonstrated high rates of psychiatric disorders in HIV-infected patients. We have reported rates of 20% for Major Depressive Disorder (MDD), 20% for adjustment disorder, 18% for cognitive impairment, 75% for substance use disorders, as well as a prevalence of mania of 8% in AIDS patients. As many as 14% of patients suffer from AIDS dementia prior to their death, and with the prolongation of life this number may be increasing. Several lines of investigation have suggested that affective disorders are increased in disorders associated with subcortical damage and dementia. We have shown that MDD and mania are increased with the development of AIDS, and that a specific manic syndrome occurs in conjunction with AIDS dementia. Longitudinal epidemiological data from the U.S. Multicenter AIDS Cohort Study (MACS) show a 1.5-2 fold increase in depressive syndromes as AIDS develops. Current treatment data suggest that the neuropsychiatric disorders associated with HlV respond to treatment. High dose AZT has been indicated for the treatment of AIDS dementia. Several other treatments are under investigation. The affective disorders associated with HIV respond to treatment with traditional agents with the caveat that these patients are extremely sensitive to the side effects and toxicities of psychoactive medications, and may have altered pharmacodynamics. AIDS mania may have specific characteristics that differentiate it from bipolar mania, and requires special treatment strategies. Research efforts with new agents such as nucleoside analogs, protease inhibitors, peptides, and antioxidants are examining whether treatments that slow progress of HIV infection may also prevent or treat neuropsychiatric sequelae.
IS-161 Growing Points in the Psychopharmacology of Sleep 1
8-16-1
I
Neuropeptides in Human Sleep Regulation
A. Steiger, I. Antonijevic, S. Bohlhalter, R-M. Frieboes, T. Schier, F. Holsboer. Max Planck Institute ofPsychiatry, Clinical Institute.
Department of Psychiatry, Munich. Germany
Sleep EEG and hormone secretion show characteristic patterns in men. In
I5-15-21 The Mechanisms and Clinical Relevance of HIV Associated Brain Damage
J.P.Everall. Department ofNeuropathology, Institute of Psychiatry, London 5£5. UK Clinically HIV can result in a severe dementia, and pathologically it is known that the brain is a major target of infection by HIY. There is a spectrum of damage associated with HIV brain infection, which is still being clarified. This includes inflammatory disorders such as encephalitis and leucoencephalopathy, as well as significant neuronal loss and synaptic and dendritic damage. Utilizing a combination of morphometric, stereological and spatial analytic techniques studies have been undertaken to quantify neuronal and synaptic damage in combination with immunocytochemistry and in situ hybridization. These have been performed in HIV infected symptomatic individuals, those who died of AIDS, and those whose dementia was prospectively rated prior to death. From these studies it is becoming clear that neuronal loss is limited to the symptomatic stage of the disease. Importantly, the severity of the dementia, while not related to the presence of multinucleated giant cells, does seems to be correlated to the load of virus in the brain and also to the pattern of neuronal loss. Evidence is emerging that neuronal loss is selective. The mechanism of neurotoxicity is being examined as neurons are not directly infected. The two main hypotheses of neuronal death are firstly, excess cytokine production, e.g. tumour necrosis factor-a, and secondly, toxic viral products, e.g. the viral protein gp120 and the regulatory protein tat. The latter are proposed to act via glutamate activated calcium channels and recently in a cerebellum study we have shown a significant alteration in the expression of the flop isoform of the GluR-A AMPA glutamate receptor (Everall et aI., Nature Medicine 1995; I: 1174-1178). While these changes were demonstrated in Purkinje cells which are relatively resistant to loss, they may be significant in other vulnerable brain regions.
I5-15-31
NMRSpectroscopy as a Tool for In Vivo Detection and Monitoring of Progress of HIV CNS Disease
G. Fein, D. Meyerhoff, M. Weiner. Departments of Psychiatry and Radiology, University of California, and Veterans Affairs Medical Center, San Francisco, California, USA Neuronal loss at autopsy and brain atrophy by MRI have been documented in many AIDS patients. We hypothesized that, because of glial proliferation as neurons are lost or damaged, MRI measures of atrophy underestimate neuronal loss. Proton Magnetic Resonance Spectroscopic Imaging (MRSI) allows in vivo measurement ofN-acetylaspartate (NAA), a putative neuronal marker. We have completed two long echo time Proton MRSI studies documenting NAA reductions of about 15% throughout a supraventricular brain slice in severely cognitively impaired HIV seropositive patients compared to high- and low-risk controls, with asymptomatic seropositive patients being indistinguishable from controls. These NAA reductions were present in patients without atrophy evident on MRJ. More recently, we have replicated these supraventricular findings at shorter echo times and have extended the studies to include basal ganglia and thalamic volumes (sites of earlier HIV infection than the supraventricular volumes studied previously) and to include patients who have no or minimal cognitive impairment, but whose HIV disease has progressed so that their CD4 percent is below 20%. The replication of the supraventricular volume effects at shorter echo times strongly suggests that those results indicate actual loss of NAA rather than a reduction in the NAA relaxation time. Preliminary analysis of the thalamic and basal ganglia results reveals NAA reductions in the thalamus but unchanged NAA and increased choline in the basal ganglia, consistent with macrophage infiltration but not glial proliferation in that area. The results for the patients with low CD4 were intermediate between those of cognitively impaired patients and controls, suggesting the presence of earlier but less dramatic changes
31 with progressing HIV disease before frank neurocognitive impairments are present. At the time of the presentation, longitudinal data for 25-35 patients will be presented.
I5-15-41
The Epidemiology of Psychiatric Disorders in HIV Infection: Depression, Mania and Dementia
C.G. Lyketsos, GJ. Treisman. Department of Psychiatry, The Johns Hopkins University. Baltimore, Maryland, USA There is a high prevalence of psychiatric disorders-particularly depression, mania, dementia, anxiety and substance use disorders, in HIV-infected individuals in community and clinical settings and across cultures. These are in part accounted for by the high prevalence of certain disorders in persons at risk for infection. Dementia and mania are also consequences of the HIV brain infection as they are more prevalent in later stage of the disease and associated with subcortical brain injury. Depression, whose prevalence appears to increase considerably around the time of AIDS, may be a consequence of the immune dysregulation that develops around the same time. This paper will review the epidemiology of psychiatric disorders in HIV infection with a special emphasis on depression, mania, and dementia. Distinctions will be made between findings in community, clinical, and cross-cultural settings and across stages of HIV infection.
I5-15-51
Treatment of Neuropsychiatric Disorders Associated with HIVand AIDS
GJ. Treisman, M. Fishman, P.R. McHugh, C.G. Lyketsos. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University. Baltimore, Maryland, USA Studies from several groups have demonstrated high rates of psychiatric disorders in HIV-infected patients. We have reported rates of 20% for Major Depressive Disorder (MDD), 20% for adjustment disorder, 18% for cognitive impairment, 75% for substance use disorders, as well as a prevalence of mania of 8% in AIDS patients. As many as 14% of patients suffer from AIDS dementia prior to their death, and with the prolongation of life this number may be increasing. Several lines of investigation have suggested that affective disorders are increased in disorders associated with subcortical damage and dementia. We have shown that MDD and mania are increased with the development of AIDS, and that a specific manic syndrome occurs in conjunction with AIDS dementia. Longitudinal epidemiological data from the U.S. Multicenter AIDS Cohort Study (MACS) show a 1.5-2 fold increase in depressive syndromes as AIDS develops. Current treatment data suggest that the neuropsychiatric disorders associated with HlV respond to treatment. High dose AZT has been indicated for the treatment of AIDS dementia. Several other treatments are under investigation. The affective disorders associated with HIV respond to treatment with traditional agents with the caveat that these patients are extremely sensitive to the side effects and toxicities of psychoactive medications, and may have altered pharmacodynamics. AIDS mania may have specific characteristics that differentiate it from bipolar mania, and requires special treatment strategies. Research efforts with new agents such as nucleoside analogs, protease inhibitors, peptides, and antioxidants are examining whether treatments that slow progress of HIV infection may also prevent or treat neuropsychiatric sequelae.
IS-161 Growing Points in the Psychopharmacology of Sleep 1
8-16-1
I
Neuropeptides in Human Sleep Regulation
A. Steiger, I. Antonijevic, S. Bohlhalter, R-M. Frieboes, T. Schier, F. Holsboer. Max Planck Institute ofPsychiatry, Clinical Institute.
Department of Psychiatry, Munich. Germany
Sleep EEG and hormone secretion show characteristic patterns in men. In