ABSTRACT
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.
Subject(s)
AIDS Dementia Complex/cerebrospinal fluid , AIDS Dementia Complex/diagnosis , Cerebrospinal Fluid/chemistry , HIV Infections/complications , HIV-1 , AIDS Dementia Complex/physiopathology , Adult , Aldehydes/analysis , Aldehydes/cerebrospinal fluid , Antioxidants/analysis , Antioxidants/metabolism , Biomarkers/cerebrospinal fluid , Brain/immunology , Brain/physiopathology , Brain/virology , Ceramides/analysis , Ceramides/cerebrospinal fluid , Female , Humans , Lipid Peroxidation , Male , Middle Aged , Oxidative Stress , Predictive Value of Tests , Sphingolipids/analysis , Sphingolipids/cerebrospinal fluid , Sterols/analysis , Sterols/cerebrospinal fluid , Triglycerides/analysis , Triglycerides/cerebrospinal fluid , Up-Regulation , Vitamin E/analysis , Vitamin E/cerebrospinal fluidABSTRACT
The role of serotonin in psychiatry has been the focus of speculation for several decades. The literature since 1966 is reviewed (and referenced) and five organizing questions are identified: (1) What are the major hypotheses regarding the involvement of the serotonin system in panic disorder? (2) Is there a serotonin system defect associated with panic disorder? (3) Is a serotonin system defect the cause of panic disorder? (4) Are the 5-HT1A agonists and the 5-HT2 antagonists effective in this condition? (5) Are serotonin selective uptake inhibitors (SSUIs) effective in panic disorder via the serotonin system or some other mechanism? Though the role of the serotonin system in panic disorder and social phobia is uncertain there is increasing agreement that SSUIs effectively treat panic disorder but further double-blind placebo-controlled studies are needed.
