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To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis.AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses.Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein-Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis.Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.

Objective To analyze changes in frequency of systemic AIDS pathology over time and its relationship to central nervous system pathology. Design and methods A total of 390 AIDS autopsy cases obtained at University of California at San Diego Medical Center from 1982 to 1998 were reviewed retrospectively and linear regression analysis was used to evaluate significance of changes over time. Results Overall, the frequency of cytomegalovirus, Pneumocystis carinii pneumonia and Mycobacterium avium complex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. The frequency of non-Hodgkin's lymphoma showed an upward trend over time, while the frequency of Kaposi's sarcoma remained unchanged. Following involvement of the lung (84%), the brain continued to be the second most frequently affected organ (63%). Whereas alterations of the brain by opportunistic infections or non-Hodgkin's lymphoma showed a downward trend, HIV encephalitis continued to be detected in at least 25% of the cases. Cases with advanced HIV-related neuropathology and cases with no HIV involvement of the brain showed significant systemic pathology with opportunistic infections and neoplasms. In contrast, cases with early brain pathology (e.g., lymphocytic meningitis) showed minimal systemic pathology. Overall these trends remained unchanged throughout the total period covered by this study. Conclusions This study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding.

The expression levels of three synaptic proteins (synaptophysin, synaptotagmin, and growth-associated protein 43 [GAP43]) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR = 0), mild (early) AD (CDR = 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of >1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD.

Article abstract The expression patterns of alternatively spliced forms of the CYP2D (6, 7, 7A, 7B) gene were analyzed in the brains of individuals with Lewy body disease (LBD) and correlated with CYP2D6 polymorphisms. Five different alternatively spliced transcripts were identified. The most common was the deletion of exon 6 (87.3% of cases), followed by a 91–base pair fragment deletion at the 3′ end of the gene (63.9% of cases). There was no correlation between the polymorphisms in the CYP2D6B gene or presence of LBD and these five alternatively spliced transcripts. Susceptibility to LBD may occur through mechanisms other than altered mRNA splicing of the CYP2D6 gene.