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Neurosteroids: Cerebrospinal Fluid Levels for Alzheimer’s Disease and Vascular Dementia Diagnostics

Biotechnologie, Conservatoire National des Arts et Métiers (S.-B.K., R.M.), 75003 Paris, France; Institute of Endocrinology (M.H., R.H.), 11694 Prague, Czech Republic; Yongin Hyoja Hospital (Y.-T.K.), Yongin-City, Kyonggi-do, 449-910, Korea; and Biotechnology, Ajou University (D.-H.J.), Suwon, 441-749, Paldal, Korea

Address all correspondence and requests for reprints to: R. Morfin, D.Sc., Biotechnologie, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France. E-mail: morfin{at}cnam.fr.

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-hydroxy-DHEA, 7ß-hydroxy-DHEA, and 16-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-hydroxy-DHEA, 7ß-hydroxy-DHEA, and 16-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-hydroxy-DHEA + 7ß-hydroxy-DHEA), 7ß-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-hydroxy-DHEA/7ß-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, 7ß, and 16 positions than in controls. The results also suggest that, in AD and VD brains, the sulfotransferase and the cytochromes P450 responsible for the 7-, 7ß-, and 16-hydroxylations of DHEA are either present at lower levels or transformed through natural polymorphism into less-efficient enzymes.

This work was supported in part by Grant NB 6691-3 from Internal Grant Agency of the Czech Republic, by International Project Grant from Korean Science and Engineering Foundation (KOSEF), by a grant from Hunter-Fleming Ltd., and by travel grants from Association for Research with Industrial and Educational Links/KOSEF and from the French North Atlantic Treaty Organization fellowship program. S.-B.K. was a recipient of a French government fellowship for her doctorate in France.

Abbreviations: AD, Alzheimer’s disease; CDR, Clinical Dementia Rating; CSF, cerebrospinal fluid; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; GC, gas chromatography; K_m, Michaelis- Menten constant; MMSE, Mini-Mental State Evaluation; MS, mass spectrometry; P450, cytochrome P450; PREG, pregnenolone; PREGS, PREG sulfate; Rt, retention time; SIM, single-ion monitoring; VD, vascular dementia.

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