Dimethylarginines, Homocysteine Metabolism, and Cerebrospinal Fluid Markers for Alzheimer's Disease

Article type: Research Article

Authors: Arlt, Sönke^{a; *} | Schwedhelm, Edzard^b | Kölsch, Heike^c | Jahn, Holger^a | Linnebank, Michael^d | Smulders, Yvo^e | Jessen, Frank^c | Böger, Rainer H.^b | Popp, Julius^{c; f}

Affiliations: [a] Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany | [b] Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany | [c] Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany | [d] Department of Neurology, University Zurich, Zurich, Switzerland | [e] Department of Internal Medicine and Metabolic Unit, VU University Hospital Amsterdam, Amsterdam, The Netherlands | [f] Department of Psychiatry, Division of Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland

Correspondence: [*] Correspondence to: PD Dr. med. Sönke Arlt, Department of Psychiatry and Psychotherapy, University of Hamburg Medical Center, Martinistr. 52, Hamburg 20246, Germany. Tel.: +49/40/7410 53437; Fax: +49/40/7410-58072; E-mail: arlt@uke.uni-hamburg.de and Dr. med. Julius Popp, Department of Psychiatry, Division of Old Age Psychiatry, University Hospital of Lausanne, Route du Mont, Lausanne 1008, Switzerland. Tel.: +41/21 643 62 67; Fax: +41/21 643 62 38; E-mail: julius.popp@chuv.ch.

Abstract: Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis.

Keywords: Alzheimer's disease, asymmetric dimethylarginine, cerebrospinal fluid, homocysteine, S-adenosylhomocysteine, S-adenosylmethionine

DOI: 10.3233/JAD-2012-112138

Journal: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 751-758, 2012