Neurosteroids: Cerebrospinal fluid levels for Alzheimer's disease and vascular dementia diagnostics.

A neurodegenerative disease such as Alzheimer's disease (AD) is associated with significantly higher dehydroepiandrosterone (DHEA) levels in cerebrospinal fluid (CSF). Because the human brain is known to transform DHEA into DHEA sulfate (DHEAS), 7 alpha-hydroxy-DHEA, 7 beta-hydroxy-DHEA, and 16 alpha-hydroxy-DHEA, it is possible that DHEA accumulation in the brain results from a decreased production of such metabolites. To test this hypothesis, we have measured and compared CSF levels of DHEA, DHEAS, 7 alpha-hydroxy-DHEA, 7 beta-hydroxy-DHEA, and 16 alpha-hydroxy-DHEA in 14 patients with AD, 12 controls, and eight patients with another common dementia, vascular dementia (VD). Results indicated that DHEAS CSF levels were significantly decreased in AD and VD (P < 0.007), whereas other metabolite levels were not significantly changed. Use of steroid level ratios, such as DHEA/(7 alpha-hydroxy-DHEA + 7 beta-hydroxy-DHEA), 7 beta-hydroxy-DHEA/DHEA, and DHEAS/DHEA ratios, resulted in significant differences between diseased and control patients (P < 0.0003, P < 0.002, and P < 0.002, respectively). In addition, the 7 alpha-hydroxy-DHEA/7 beta-hydroxy-DHEA ratio was significantly different between AD and VD (P < 0.0001) and could be used for differentiating AD from VD. These results indicate that, in AD and VD, increased DHEA levels are not neuroprotective and are neither better sulfated nor better hydroxylated at the 7 alpha, 7 beta, and 16 alpha positions than in controls. The results also suggest that, in AD and VD brains, the sulfotransferase and the cytochromes P450 responsible for the 7 alpha-, 7 beta-, and 16 alpha-hydroxylations of DHEA are either present at lower levels or transformed through natural polymorphism into less-efficient enzymes.