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SILAC Based Proteomic Characterization of Exosomes from HIV-1 Infected Cells
Published on: March 3, 2017
Associative and predictive biomarkers of dementia in HIV-1-infected patients
V V R Bandaru1, J C McArthur, N Sacktor
1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Insights
Biomarkers like vitamin E and specific triglycerides can predict HIV dementia onset. Elevated sphingomyelin indicates inactive dementia, while ceramide and aldehydes signal active cognitive decline in HIV patients.
Area of Science:
- Neuroscience
- Biochemistry
- Immunology
Background:
- HIV infection can cause a severe central nervous system (CNS) disorder, HIV dementia (HIV-D).
- While highly active antiretroviral therapy (HAART) reduced HIV-D incidence, its prevalence is rising.
- Traditional biomarkers are less effective in predicting HIV-D in patients on HAART.
Purpose of the Study:
- To identify biomarkers associated with and predictive of HIV dementia.
- To understand the role of specific lipid metabolites in HIV-D pathogenesis.
Main Methods:
- Patients with HIV were categorized based on cognitive status changes over one year.
- Cerebrospinal fluid (CSF) was analyzed for sphingolipids, sterols, triglycerides, antioxidants, and lipid peroxidation.
Main Results:
- Increased vitamin E and triglyceride C52 levels predicted dementia onset or worsening.
- Elevated sphingomyelin levels correlated with inactive dementia.
- Increased ceramide and 4-hydroxynonenal accumulation were associated with active dementia.
Conclusions:
- Early HIV dementia involves increased endogenous antioxidant defenses.
- Failure of these defenses leads to sphingomyelin accumulation and cognitive impairment.
- Sphingomyelin breakdown to ceramide and aldehyde accumulation correlate with cognitive decline, suggesting potential predictive value for elevated protective mechanisms.
Background:
Infection with HIV can result in a debilitating CNS disorder known as HIV dementia (HIV-D). Since the advent of highly active antiretroviral therapy (HAART), the incidence of HIV-D has declined, but the prevalence continues to increase. In this new era of HIV-D, traditional biomarkers such as CSF viral load and monocyte chemotactic protein 1 levels are less likely to be associated with dementia in patients on HAART and biomarkers that can predict HIV-D have not yet been identified.
Objective:
To identify biomarkers that are associated with and can predict HIV-D.
Methods:
We grouped patients with HIV based on changes in cognitive status over a 1-year period and analyzed sphingolipid, sterol, triglyceride, antioxidant, and lipid peroxidation levels in CSF.
Results:
We found that increased levels of the vitamin E and triglyceride C52 predicted the onset or worsening of dementia. Elevated levels of sphingomyelin were associated with inactive dementia. Elevated levels of ceramide and the accumulation of 4-hydroxynonenals were associated with active dementia.
Conclusions:
We interpret these findings to indicate that early in the pathogenesis of HIV dementia, there is an up-regulation of endogenous antioxidant defenses in brain. The failure of this attempted neuroprotective mechanism leads to the accumulation of sphingomyelin and moderate cognitive dysfunction. The breakdown of this enlarged pool of sphingomyelin to ceramide and the accumulation of highly reactive aldehydes are associated with declining cognitive function. Thus, elevations in endogenous protective mechanisms may identify patients who are at increased risk of the development of HIV dementia.
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