Abstract
BackgroundBecause of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.MethodsIn this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ), amyloid beta fragment 1-42 (Aβ1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.ResultsCSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.ConclusionsParallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.
Highlights
Because of the emerging intersections of human immunodeficiency virus (HIV) infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV seronegative (HIV-)infected patients
They included: 40 HIV-infected without AIDS dementia complex (ADC) referred to as neuroasymptomatic subjects who were either wholly without neurological symptoms or signs or showed only mild neurological signs attributed to static Central nervous system (CNS) conditions, all from San Francisco; 21 with a diagnosis of ADC (3 ADC stage 1 and 18 stage 2 - 4), all from Milan except two from San Francisco; and 25 with major CNS opportunistic infections - 4 with cytomegalovirus encephalitis (CMV-E), 6 cryptococcal meningitis, 6 cerebral toxoplasmosis and 9 progressive multifocal leucoencephalitis (PML) - all from Milan
The ages were similar in the HIV+ groups and younger HIV- controls in which males predominated, but differed from the Alzheimer's disease and older HIV- controls in which ages were again similar and there was a higher ratio of women
Summary
Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients. The salutary effects of potent antiretroviral therapy that have transformed systemic infection from an almost invariably fatal condition into a chronic disease amenable to medical management with prolonged survival have had a major impact on its CNS manifestations. This includes a marked reduction in the incidence of CNS opportunistic infections, but a similar decline in ADC/HIVE [7]. The latter parallels the potent effects of antiretroviral therapy on CSF HIV RNA concentrations [812]
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