Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 6, Issue 5 , Pages 378-385 , September 2010

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

  • Michelle M. Mielke

      Affiliations

    • Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • Corresponding Author InformationCorresponding author: Tel.: 443-326-5174; Fax: 410-550-1407.
    • ,
  • Norman J. Haughey

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Veera Venkata Ratnam Bandaru

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Steven Schech

      Affiliations

    • Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Richard Carrick

      Affiliations

    • Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Michelle C. Carlson

      Affiliations

    • Center on Aging and Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
    • ,
  • Susumu Mori

      Affiliations

    • Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • F.M. Kirby Center on Brain Imaging at the Kennedy Kreiger Institute, Johns Hopkins University, Baltimore, MD, USA
    • ,
  • Michael I. Miller

      Affiliations

    • Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA
    • ,
  • Can Ceritoglu

      Affiliations

    • Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA
    • ,
  • Timothy Brown

      Affiliations

    • Center for Imaging Science, The Johns Hopkins University, Baltimore, MD, USA
    • ,
  • Marilyn Albert

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    • ,
  • Constantine G. Lyketsos

      Affiliations

    • Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

References 

  1. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci USA. 2004;101:2070–2075
  2. Han X, M Holtzman D, McKeel DW, Kelley J, Morris JC. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem. 2002;82:809–818
  3. He X, Huang Y, Li B, Gong CX, Schuchman EH. Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging. 2010;31:398–408
  4. Satoi H, Tomimoto H, Ohtani R, Kitano T, Kondo T, Watanabe M, et al. Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis. Neuroscience. 2005;130:657–666
  5. Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci USA. 2003;100:11735–11740
  6. Kalvodova L, Kahya N, Schwille P, Ehehalt R, Verkade P, Drechsel D, et al. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem. 2005;280:36815–36823
  7. Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, et al. Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem. 2004;279:44945–44954
  8. Puglielli L, Ellis BC, Saunders AJ, Kovacs DM. Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. J Biol Chem. 2003;278:19777–19783
  9. Jana A, Pahan K. Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer's disease. J Biol Chem. 2004;279:51451–51459
  10. Lee JT, Xu J, Lee JM, Ku G, Han X, Yang DI, et al. Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol. 2004;164:123–131
  11. Katsel P, Li C, Haroutunian V. Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?. Neurochem Res. 2007;32:845–856
  12. Mielke MM, Bandaru VV, Haughey NJ, Rabins PV, Lyketsos CG, Carlson MC. Serum sphingomyelins and ceramides are early predictors of memory impairment. Neurobiol Aging. 2010;31:17–24
  13. Mielke MM, Kozauer NA, Chan KCG, George M, Toroney J, Zerrate M, et al. Regionally-specific diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease. Neuroimage. 2009;46:47–55
  14. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982;140:566–572
  15. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–194
  16. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer's disease. Neurology. 1984;34:939–944
  17. Alzheimers Association . Research consent for cognitively impaired adults: recommendations for institutional review boards and investigators. Alzheimer Dis Assoc Disord. 2004;18:171–175
  18. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198
  19. Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S13–S21
  20. Delis DC, Freeland J, Kramer JH, Kaplan E. Integrating clinical assessment with cognitive neuroscience: construct validation of the California Verbal Learning Test. J Consult Clin Psychol. 1988;56:123–130
  21. Wechsler D. The Wechsler Adult Intelligence Scale-Revised. New York, NY: Psychological Corporation; 1988;
  22. Reitan R. Trail Making Test: Manual for Administration, Scoring and Interpretation. Indianapolis, IN: Indiana University Medical Center; 1958;
  23. Benton A, Hamsher K. Multilingual Aphasia Examination. Iowa City, IA: University of Iowa; 1976;
  24. Jack CR, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, et al. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging. 2008;27:685–691
  25. Csernansky JG, Joshi S, Wang L, Haller JW, Gado M, Miller JP, et al. Hippocampal morphometry in schizophrenia by high dimensional brain mapping. Proc Natl Acad Sci USA. 1998;95:11406–11411
  26. Umeyama S. Least-squares estimation of transformation parameters between two point patterns. IEEE Trans Pattern AnalMach Intell. 1991;13:376–380
  27. Joshi SC, Miller MI. Landmark matching via large deformation diffeomorphisms. IEEE Trans Image Process. 2000;9:1357–1370
  28. Beg MF, Miller MI, Trouve A, Younes L. Computing large deformation metric mappings via geodesic flows of diffeomorphisms. Int J Comput Vis. 2005;61:139–157
  29. Priebe CE, Marchette DJ. Alternating kernel and mixture density estimates. Comput Stat Data Anal. 2000;35:43–65
  30. Bandaru VV, McArthur JC, Sacktor N, Cutler RG, Knapp EL, Mattson MP, et al. Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology. 2007;68:1481–1487
  31. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366:2112–2117

 While funding for the neuroimaging and participant follow-up was partially obtained through a grant from GlaxoSmithKline, the authors had access to the data at all times and retain the data. Funding for the plasma lipids were obtained from National Institutes of Health grants. All authors report no conflicts of interests with regards to GlaxoSmithKline or any other organization. All participants provided informed consent and the study was approved by the Johns Hopkins University Institutional Review Board.

PII: S1552-5260(10)00099-3

doi: 10.1016/j.jalz.2010.03.014

Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 6, Issue 5 , Pages 378-385 , September 2010

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