4.5 Article

A Longitudinal Study of Total and Phosphorylated alpha-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment

Journal

JOURNAL OF ALZHEIMERS DISEASE
Volume 61, Issue 4, Pages 1541-1553

Publisher

IOS PRESS
DOI: 10.3233/JAD-171013

Keywords

alpha-synuclein; Alzheimer's disease; biomarkers; cerebrospinal fluid; mild cognitive impairment; pS129-alpha-synuclein

Categories

Funding

  1. National Institutes of Health (NIH) [U01 NS082137, U01 NS091272]
  2. Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01 AG024904]
  3. DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
  4. National Institute on Aging
  5. National Institute of Biomedical Imaging and Bioengineering
  6. AbbVie
  7. Alzheimer's Association
  8. Alzheimer's Drug Discovery Foundation
  9. Araclon Biotech
  10. BioClinica, Inc.
  11. Biogen
  12. BristolMyers Squibb Company
  13. CereSpir, Inc.
  14. Cogstate
  15. Eisai Inc.
  16. Elan Pharmaceuticals, Inc.
  17. Eli Lilly and Company
  18. EuroImmun
  19. F. Hoffmann-La Roche Ltd
  20. Genentech, Inc.
  21. Fujirebio
  22. GE Healthcare
  23. IXICO Ltd.
  24. Janssen Alzheimer Immunotherapy Research & Development, LLC.
  25. Johnson & Johnson Pharmaceutical Research & Development LLC.
  26. Lumosity
  27. Lundbeck
  28. Merck Co., Inc.
  29. Meso Scale Diagnostics, LLC.
  30. NeuroRx Research
  31. Neurotrack Technologies
  32. Novartis Pharmaceuticals Corporation
  33. Pfizer Inc.
  34. Piramal Imaging
  35. Servier
  36. Takeda Pharmaceutical Company
  37. Transition Therapeutics
  38. Canadian Institutes of Health Research
  39. NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U01NS082137, U01NS091272] Funding Source: NIH RePORTER
  40. NATIONAL INSTITUTE ON AGING [U01AG024904, P30AG010124, U19AG024904, R01AG056711] Funding Source: NIH RePORTER
  41. Lundbeck Foundation [R248-2016-2518, R223-2015-4222] Funding Source: researchfish

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Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total alpha-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-beta 1-42 (A beta(42)), tau, and phosphorylated tau (p-tau(181))] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total alpha-synuclein, pS129, A beta(42), tau, and p-tau(181). pS129, but not total alpha-synuclein, was weakly associated with diagnosis at baseline when t-tau/A beta 42 was included in the statistical model (beta = 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF alpha-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (beta = -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (beta = 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,< 0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (beta = 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (beta = -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between alpha-synuclein and p-tau181 predicted faster cognitive decline (beta = 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The alpha-synuclein-p-tau(181)-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

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