Plasma Sphingomyelins are Associated with Cognitive Progression in Alzheimer's Disease

Article type: Research Article

Authors: Mielke, Michelle M.^{a; b; *} | Haughey, Norman J.^{a; c} | Bandaru, Veera Venkata Ratnam^c | Weinberg, Danielle D.^a | Darby, Eveleen^d | Zaidi, Noman^d | Pavlik, Valory^d | Doody, Rachelle S.^d | Lyketsos, Constantine G.^a

Affiliations: [a] Department of Psychiatry, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [b] Division of Epidemiology, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, USA | [c] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [d] Alzheimer's Disease and Memory Disorder Center, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

Correspondence: [*] Correspondence to: Dr. Michelle M. Mielke, Ph.D., Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA. Tel.: +(507)284 5545; Fax: +(507)284 1516; E-mail: [email protected].

Abstract: Plasma sphingolipids have been shown to predict cognitive impairment and hippocampal volume loss, but there is little research in patients with Alzheimer's disease (AD). In this study we sought to determine whether plasma ceramides, dihydroceramides (DHCer), sphingomyelins (SM), or dihydrosphingomyelin (DHSM) levels and ratios of SM/ceramide or DHSM/DHCer were predictive of progression in AD. Probable AD patients (n = 120) were enrolled in the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine. Plasma sphingolipids were assessed using ESI/MS/MS. Linear mixed effects models were used to examine the relation between baseline plasma sphingolipid levels and cross-sectional and longitudinal performance on the Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating-Sum of Boxes (CDR-Sum). Participants were followed a mean of 4.2 visits and 2.3 years. There were no cross-sectional associations. In longitudinal analyses, high levels of DHCer and ceramide were associated with greater progression, but findings did not reach significance (p > 0.05). In contrast, higher plasma levels of SM, DHSM, SM/ceramide, and DHSM/DHCer ratios were associated with less progression on the MMSE and ADAS-Cog; the ratios were the strongest predictors of clinical progression. Compared to the lowest tertiles, the highest tertiles of DHSM/DHCer and SM/ceramide ratios declined 1.35 points (p = 0.001) and 1.19 (p = 0.004) points less per year on the MMSE and increased 3.18 (p = 0.001) and 2.42 (p = 0.016) points less per year on the ADAS-Cog. These results suggest that increased SM/ceramide and DHSM/DHCer ratios dose-dependently predict slower progression among AD patients and may be sensitive blood-based biomarkers for clinical progression.

Keywords: Alzheimer's disease, biomarker, ceramide, dihydroceramide, sphingosine, dihydrosphingomyelin, plasma, sphinganine, sphingomyelin

DOI: 10.3233/JAD-2011-110405

Journal: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 259-269, 2011