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Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology

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Abstract

We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher’s input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen. PD cases with AD pathology showed increased LRP. The cluster with occipital LRP was associated with non-AD type dementia clinical diagnosis in the Dem-AD-LB group and a faster progression to dementia in the PD groups. We found that (1) LRP pathology in Dem-AD-LB shows a distribution that differs from PD, without significant brainstem or extracranial LRP in initial phases; (2) coincident AD pathology is associated with increased LRP in PD indicating an interaction; (3) LRP and coincident AD pathology independently predict progression to dementia in PD, and (4) evaluation of LRP needs to acknowledge different LRP spreading patterns and evaluate substantia nigra integrity in the neuropathological assessment and consider the implications of neuropathological heterogeneity for clinical and biomarker characterization.

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References

  1. Aarsland D, Ballard CG, Halliday G (2004) Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity? J Geriatr Psychiatry Neurol 17(3):137–145. doi:10.1177/0891988704267470

    Article  PubMed  Google Scholar 

  2. Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117(6):613–634. doi:10.1007/s00401-009-0538-8

    Article  PubMed Central  PubMed  Google Scholar 

  3. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG et al (2015) Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology 35(4):354–389. doi:10.1111/neup.12189

    Article  PubMed Central  PubMed  Google Scholar 

  4. Beach TG, Sue LI, Walker DG, Roher AE, Lue L, Vedders L et al (2008) the sun health research institute brain donation program: description and experience, 1987–2007. Cell Tissue Bank 9(3):229–245. doi:10.1007/s10561-008-9067-2

    Article  PubMed Central  PubMed  Google Scholar 

  5. Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T et al (2014) Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord 29(4):454–462. doi:10.1002/mds.25844

    Article  PubMed Central  PubMed  Google Scholar 

  6. Bohnen NI, Muller ML, Kotagal V, Koeppe RA, Kilbourn MA, Albin RL et al (2010) Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 133(Pt 6):1747–1754. doi:10.1093/brain/awq079

    Article  PubMed Central  PubMed  Google Scholar 

  7. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112(4):389–404. doi:10.1007/s00401-006-0127-z

    Article  PubMed Central  PubMed  Google Scholar 

  8. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259

    Article  PubMed  CAS  Google Scholar 

  9. Braak H, Del Tredici K (2008) Invited article: nervous system pathology in sporadic Parkinson disease. Neurology 70(20):1916–1925. doi:10.1212/01.wnl.0000312279.49272.9f

    Article  PubMed  Google Scholar 

  10. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211 (pii: S0197458002000659)

    Article  PubMed  Google Scholar 

  11. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134. doi:10.1007/s00441-004-0956-9

    Article  PubMed  Google Scholar 

  12. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913. doi:10.1038/ncb1901

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease (1997). Neurobiol Aging 18 (4 Suppl):S1-2

  14. Del Tredici K, Braak H (2012) Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathol 124(5):643–664. doi:10.1007/s00401-012-1028-y

    Article  PubMed  CAS  Google Scholar 

  15. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM et al (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8(12):1150–1157

    Article  PubMed  CAS  Google Scholar 

  16. Dickson DW, Fujishiro H, Orr C, DelleDonne A, Josephs KA, Frigerio R et al (2009) Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 15(Suppl 3):S1–S5. doi:10.1016/S1353-8020(09)70769-2

    Article  PubMed  Google Scholar 

  17. Dickson DW, Uchikado H, Fujishiro H, Tsuboi Y (2010) Evidence in favor of braak staging of Parkinson’s disease. Mov Disord 25(Suppl 1):S78–S82. doi:10.1002/mds.22637

    Article  PubMed  Google Scholar 

  18. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y et al (2007) Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22(12):1689–1707. doi:10.1002/mds.21507 (quiz 1837)

    Article  PubMed  Google Scholar 

  19. Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT et al (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300(5619):636–640. doi:10.1126/science.1082324

    Article  PubMed  CAS  Google Scholar 

  20. Goetz C, Emre M, Dubois B (2008) Parkinson’s disease dementia: definitions, guidelines, and research perspectives in diagnosis. Ann Neurol 64(S2):S81–S92

    Article  PubMed  Google Scholar 

  21. Graff-Radford J, Murray ME, Lowe VJ, Boeve BF, Ferman TJ, Przybelski SA et al (2014) Dementia with Lewy bodies: basis of cingulate island sign. Neurology 83(9):801–809. doi:10.1212/WNL.0000000000000734

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B et al (2013) Distinct alpha-synuclein strains differentially promote tau Inclusions in neurons. Cell 154(1):103–117. doi:10.1016/j.cell.2013.05.057

    Article  PubMed  CAS  Google Scholar 

  23. Hawkes CH, Del Tredici K, Braak H (2010) A timeline for Parkinson’s disease. Parkinsonism Relat Disord 16(2):79–84. doi:10.1016/j.parkreldis.2009.08.007

    Article  PubMed  Google Scholar 

  24. Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A et al (2013) Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice. EMBO Rep 14(11):1017–1022. doi:10.1038/embor.2013.137

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosur Psychiatry 55:181–184. doi:10.1136/jnnp.55.3.181

    Article  CAS  Google Scholar 

  26. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2012) National institute on aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8(1):1–13. doi:10.1016/j.jalz.2011.10.007

    Article  PubMed Central  PubMed  Google Scholar 

  27. Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56(10):1095–1097

    Article  PubMed  CAS  Google Scholar 

  28. Irwin DJ, White MT, Toledo JB, Xie SX, Robinson JL, Van Deerlin V et al (2012) Neuropathologic substrates of Parkinson disease dementia. Ann Neurol 72(4):587–598. doi:10.1002/ana.23659

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Jellinger KA (2009) A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta 1792(7):730–740. doi:10.1016/j.bbadis.2008.07.006

    Article  PubMed  CAS  Google Scholar 

  30. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) Controversies over the staging of alpha-synuclein pathology in Parkinson’s disease. Acta Neuropathol 116(1):125–128. doi:10.1007/s00401-008-0381-3 (author reply 129–131)

    Article  PubMed  Google Scholar 

  31. Leverenz JB, Hamilton R, Tsuang DW, Schantz A, Vavrek D, Larson EB et al (2008) Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient. Brain Pathol 18(2):220–224. doi:10.1111/j.1750-3639.2007.00117.x

    Article  PubMed Central  PubMed  Google Scholar 

  32. Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF et al (2007) DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68(11):812–819. doi:10.1212/01.wnl.0000256715.13907.d3

    Article  PubMed  CAS  Google Scholar 

  33. Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R (2013) Molecular structure of beta-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154(6):1257–1268. doi:10.1016/j.cell.2013.08.035

    Article  PubMed  CAS  Google Scholar 

  34. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65(12):1863–1872. doi:10.1212/01.wnl.0000187889.17253.b1

    Article  PubMed  CAS  Google Scholar 

  35. Mirra SS (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging 18(4 Suppl):S91–S94

    Article  PubMed  CAS  Google Scholar 

  36. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123(1):1–11. doi:10.1007/s00401-011-0910-3

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Olichney JM, Murphy C, Hofstetter CR, Foster K, Hansen LA, Thal LJ et al (2005) Anosmia is very common in the Lewy body variant of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76(10):1342–1347. doi:10.1136/jnnp.2003.032003

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 115(4):399–407. doi:10.1007/s00401-008-0346-6

    Article  PubMed Central  PubMed  Google Scholar 

  39. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. doi:10.1016/j.neuron.2014.04.047

    PubMed Central  PubMed  Google Scholar 

  40. Sumikura H, Takao M, Hatsuta H, Ito S, Nakano Y, Uchino A et al (2015) Distribution of alpha-synuclein in the spinal cord and dorsal root ganglia in an autopsy cohort of elderly persons. Acta Neuropathol Commun 3:57. doi:10.1186/s40478-015-0236-9

    Article  PubMed Central  PubMed  Google Scholar 

  41. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800

    Article  PubMed  Google Scholar 

  42. Toledo JB, Brettschneider J, Grossman M, Arnold SE, Hu WT, Xie SX et al (2012) CSF biomarkers cutoffs: the importance of coincident neuropathological diseases. Acta Neuropathol 124(1):23–35. doi:10.1007/s00401-012-0983-7

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Toledo JB, Cairns NJ, Da X, Chen K, Carter D, Fleisher A et al (2013) Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol Commun 1(1):65. doi:10.1186/2051-5960-1-65

    Article  PubMed Central  PubMed  Google Scholar 

  44. Toledo JB, Van Deerlin VM, Lee EB, Suh E, Baek Y, Robinson JL et al (2014) A platform for discovery: the university of pennsylvania integrated neurodegenerative disease biobank. Alzheimers dement 10(4):477–484. doi:10.1016/j.jalz.2013.06.003 (e471)

    Article  PubMed Central  PubMed  Google Scholar 

  45. Tsuboi Y, Dickson DW (2005) Dementia with Lewy bodies and Parkinson’s disease with dementia: are they different? Parkinsonism Relat Disord 11(Suppl 1):S47–S51. doi:10.1016/j.parkreldis.2004.10.014

    Article  PubMed  Google Scholar 

  46. Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA (2009) Olfactory impairment in presymptomatic Alzheimer’s disease. Ann N Y Acad Sci 1170:730–735. doi:10.1111/j.1749-6632.2009.04013.x

    Article  PubMed Central  PubMed  Google Scholar 

  47. Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG (2008) Patterns and stages of alpha-synucleinopathy: relevance in a population-based cohort. Neurology 70(13):1042–1048. doi:10.1212/01.wnl.0000306697.48738.b6

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by NIH grants: AG05136, AG006781 and Morris K Udall Center for Parkinson’s disease Research Core grants P50 NS053488 and NS062684. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. DJI is supported by NS088341. Finally, we thank our patients and their families for making this research possible.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA

    Jon B. Toledo, Pallavi Gopal, Kevin Raible, David J. Irwin, Johannes Brettschneider, Samantha Sedor, Kayla Waits, Susana Boluda, Vivianna M. Van Deerlin, Edward B. Lee, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

    David J. Irwin, Murray Grossman, Steven E. Arnold & Howard Hurtig

  3. Department of Clinical Neuroanatomy and Neurology, University of Ulm, Ulm, Germany

    Johannes Brettschneider

  4. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    Steven E. Arnold

  5. Philadelphia VA Medical Center, Philadelphia, PA, USA

    John E. Duda

  6. Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

    Charles H. Adler

  7. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA

    Thomas G. Beach

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  1. Jon B. Toledo
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Correspondence to Jon B. Toledo.

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Toledo, J.B., Gopal, P., Raible, K. et al. Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. Acta Neuropathol 131, 393–409 (2016). https://doi.org/10.1007/s00401-015-1526-9

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