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  • Review Article
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Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies

Nature Reviews Neuroscience volume 14, pages 626–636 (2013)Cite this article

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Key Points

  • Notable heterogeneity exists in the neuropathological substrates that underlie dementia in the setting of Parkinson's disease dementia (PDD). Nevertheless, the presumptive caudal-to-rostral spread of Lewy body and neurite pathology from the lower brainstem to telencephalic regions, which culminates in a heavy burden of this α-synuclein (α-syn) pathology in limbic and neocortical structures, is the most characteristic pathological finding in most PDD cases.

  • Up to 50% of patients with PDD can have sufficient amyloid-β (Aβ) plaque and tau neurofibrillary tangle (NFT) pathology for the diagnosis of a second neurodegenerative dementia — that is, Alzheimer's disease (AD) — and this co-morbid pathology is more common in PDD than PD.

  • Tau NFT and Aβ plaque pathology may act synergistically with Lewy body and neurite pathology to confer a worse prognosis and a higher burden of cortical Lewy body and neurite pathology in PDD.

  • Clinical phenotypes of PD may help to identify neuropathological subtypes of PD that exhibit differing propensities for developing dementia. For example, non-tremor-dominant or postural gait instability PD phenotypes may often be associated with greater Aβ plaque pathology and shorter times to dementia in patients with PDD than in patients with PD exhibiting less co-morbid AD neuropathology and a tremor-dominant phenotype.

  • Genetic variations may contribute to the heterogeneity in the neuropathology and the time-of-onset of dementia in PD. For example, the apolipoprotein E (APOE) ε4 genotype may increase both Lewy body and neurite pathology and AD neuropathology and result in an increased risk of dementia in PD. Moreover, heterozygous mutations in β-glucocerebrosidase (GBA) may increase the severity of Lewy body and neurite patholgy in 'pure' synucleinopathies.

  • Further biomarker and detailed clinicopathological correlation studies of prospective patients will help to further elucidate the inter-relationships of AD and α-syn pathology in PD and the development of dementia in patients with PD. These discoveries will be crucial in the development of meaningful disease-modifying therapies for PDD.

Abstract

Dementia is increasingly being recognized in cases of Parkinson's disease (PD); such cases are termed PD dementia (PDD). The spread of fibrillar α-synuclein (α-syn) pathology from the brainstem to limbic and neocortical structures seems to be the strongest neuropathological correlate of emerging dementia in PD. In addition, up to 50% of patients with PDD also develop sufficient numbers of amyloid-β plaques and tau-containing neurofibrillary tangles for a secondary diagnosis of Alzheimer's disease, and these pathologies may act synergistically with α-syn pathology to confer a worse prognosis. An understanding of the relationships between these three distinct pathologies and their resultant clinical phenotypes is crucial for the development of effective disease-modifying treatments for PD and PDD.

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Figure 1: Hypothetical model of α-syn toxicity and spread of pathology in PD and PDD.
Figure 2: Neuropathology of PDD.

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References

  1. Goedert, M., Spillantini, M. G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nature Rev. Neurol. 9, 13–24 (2012).

    Article  CAS  Google Scholar 

  2. Hely, M. A., Reid, W. G., Adena, M. A., Halliday, G. M. & Morris, J. G. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov. Disord. 23, 837–844 (2008).

    Article  PubMed  Google Scholar 

  3. Aarsland, D., Andersen, K., Larsen, J. P., Lolk, A. & Kragh-Sorensen, P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch. Neurol. 60, 387–392 (2003).

    Article  PubMed  Google Scholar 

  4. Kempster, P. A., O'Sullivan, S. S., Holton, J. L., Revesz, T. & Lees, A. J. Relationships between age and late progression of Parkinson's disease: a clinico-pathological study. Brain 133, 1755–1762 (2010).

    Article  PubMed  Google Scholar 

  5. Emre, M. et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov. Disord. 22, 1689–1707 (2007). The Movement Disorder Society Task Force criteria for PDD.

    Article  PubMed  Google Scholar 

  6. Halliday, G., Hely, M., Reid, W. & Morris, J. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol. 115, 409–415 (2008). This is one of the largest prospectively followed PD autopsy series; it found that 80% of patients with PD develop dementia after 20 years.

    Article  PubMed  Google Scholar 

  7. Levy, G. et al. Combined effect of age and severity on the risk of dementia in Parkinson's disease. Ann. Neurol. 51, 722–729 (2002).

    Article  PubMed  Google Scholar 

  8. Williams-Gray, C. H. et al. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain 132, 2958–2969 (2009).

    Article  PubMed  Google Scholar 

  9. Muslimovic, D., Post, B., Speelman, J. D. & Schmand, B. Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology 65, 1239–1245 (2005).

    Article  PubMed  Google Scholar 

  10. Rosenthal, E. et al. Association between cognition and function in patients with Parkinson disease with and without dementia. Mov. Disord. 25, 1170–1176 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lo, R. Y. et al. Clinical features in early Parkinson disease and survival. Arch. Neurol. 66, 1353–1358 (2009).

    Article  PubMed  Google Scholar 

  12. Litvan, I. et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Mov. Disord. 27, 349–356 (2012). The Movement Disorder Society Task Force criteria for PD-MCI.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Grossman, M. et al. Difficulty processing temporary syntactic ambiguities in Lewy body spectrum disorder. Brain Lang. 120, 52–60 (2012).

    Article  PubMed  Google Scholar 

  14. Lippa, C. F. et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68, 812–819 (2007). An in-depth discussion of the clinicopathological overlap between PDD and DLB.

    Article  CAS  PubMed  Google Scholar 

  15. Galvin, J. E., Pollack, J. & Morris, J. C. Clinical phenotype of Parkinson disease dementia. Neurology 67, 1605–1611 (2006).

    Article  PubMed  Google Scholar 

  16. McKeith, I. G. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J. Alzheimers Dis. 9, 417–423 (2006). In this paper, the DLB Consortium outlines its clinical and neuropathological diagnostic criteria for DLB.

    Article  PubMed  Google Scholar 

  17. Weintraub, D. Dopamine and impulse control disorders in Parkinson's disease. Ann. Neurol. 64 (Suppl. 2), 93–100 (2008).

    Google Scholar 

  18. Weintraub, D., Papay, K., Siderowf, A. & Parkinson's Progression Markers Initiative. Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study. Neurology 80, 176–180 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Schrag, A., Ben-Shlomo, Y., Brown, R., Marsden, C. D. & Quinn, N. Young-onset Parkinson's disease revisited — clinical features, natural history, and mortality. Mov. Disord. 13, 885–894 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Aarsland, D. et al. The effect of age of onset of PD on risk of dementia. J. Neurol. 254, 38–45 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Braak, H., Rub, U., Jansen Steur, E. N., Del Tredici, K. & de Vos, R. A. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 64, 1404–1410 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Levy, G. et al. Motor impairment in PD: relationship to incident dementia and age. Neurology 55, 539–544 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Jankovic, J. et al. Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 40, 1529–1534 (1990).

    Article  CAS  PubMed  Google Scholar 

  24. Levy, G. et al. Memory and executive function impairment predict dementia in Parkinson's disease. Mov. Disord. 17, 1221–1226 (2002).

    Article  PubMed  Google Scholar 

  25. Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997). This study made the landmark discovery of SNCA mutations in PD.

    Article  CAS  PubMed  Google Scholar 

  26. Poulopoulos, M., Levy, O. A. & Alcalay, R. N. The neuropathology of genetic Parkinson's disease. Mov. Disord. 27, 831–842 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Singleton, A. B. et al. α-synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Conway, K. A., Harper, J. D. & Lansbury, P. T. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nature Med. 4, 1318–1320 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997). This study made the landmark discovery of α-syn as the major component of Lewy pathology.

    Article  CAS  PubMed  Google Scholar 

  30. Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521–533 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Lim, Y. et al. α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J. Neurosci. 31, 10076–10087 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Magen, I. & Chesselet, M. F. Genetic mouse models of Parkinson's disease: the state of the art. Prog. Brain Res. 184, 53–87 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  34. Del Tredici, K., Rub, U., De Vos, R. A., Bohl, J. R. & Braak, H. Where does parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426 (2002).

    Article  PubMed  Google Scholar 

  35. Dickson, D. W., Uchikado, H., Fujishiro, H. & Tsuboi, Y. Evidence in favor of Braak staging of Parkinson's disease. Mov. Disord. 25 (Suppl. 1), 78–82 (2010).

    Article  Google Scholar 

  36. Jellinger, K. A. Lewy body-related α-synucleinopathy in the aged human brain. J. Neural Transm. 111, 1219–1235 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Parkkinen, L., Pirttila, T. & Alafuzoff, I. Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol. 115, 399–407 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Beach, T. G. et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 117, 613–634 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Mikolaenko, I. et al. α-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA). J. Neuropathol. Exp. Neurol. 64, 156–162 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Parkkinen, L., Kauppinen, T., Pirttila, T., Autere, J. M. & Alafuzoff, I. α-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann. Neurol. 57, 82–91 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Dickson, D. W. et al. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol. 115, 437–444 (2008).

    Article  PubMed  Google Scholar 

  42. Saito, Y. et al. Accumulation of phosphorylated α-synuclein in aging human brain. J. Neuropathol. Exp. Neurol. 62, 644–654 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Wakabayashi, K. et al. The Lewy body in Parkinson's disease and related neurodegenerative disorders. Mol. Neurobiol. 47, 495–508 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Milber, J. M. et al. Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 79, 2307–2314 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Parkkinen, L. et al. Disentangling the relationship between Lewy bodies and nigral neuronal loss in Parkinson's disease. J. Park Dis. 1, 277–286 (2011).

    CAS  Google Scholar 

  46. Braak, H. et al. Pathology associated with sporadic Parkinson's disease — where does it end? J. Neural Transm. Suppl. 70, 89–97 (2006).

    Google Scholar 

  47. Hamilton, R. L. Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using α-synuclein immunohistochemistry. Brain Pathol. 10, 378–384 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Lippa, C. F. et al. Lewy bodies contain altered α-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365–1370 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Iseki, E. Dementia with Lewy bodies: reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease. Neuropathology 24, 72–78 (2004).

    Article  PubMed  Google Scholar 

  50. Leverenz, J. B. et al. Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient. Brain Pathol. 18, 220–224 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Jellinger, K. A. A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol. 116, 1–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature Med. 14, 501–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature Med. 14, 504–506 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Kordower, J. H., Chu, Y., Hauser, R. A., Olanow, C. W. & Freeman, T. B. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov. Disord. 23, 2303–2306 (2008).

    Article  PubMed  Google Scholar 

  55. Luk, K. C. et al. Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl Acad. Sci. USA 106, 20051–20056 (2009).

    Article  PubMed  Google Scholar 

  56. Volpicelli-Daley, L. A. et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Luk, K. C. et al. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975–986 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012). This study made the landmark discovery of how the transmission of α-syn fibrils alone recapitulates human disease in wild-type animals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee, H. J. et al. Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int. J. Biochem. Cell Biol. 40, 1835–1849 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    Article  PubMed  Google Scholar 

  61. Mougenot, A. L. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225–2228 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Masuda-Suzukake, M. et al. Prion-like spreading of pathological α-synuclein in brain. Brain 136, 1128–1138 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Steiner, J. A., Angot, E. & Brundin, P. A deadly spread: cellular mechanisms of α-synuclein transfer. Cell Death Differ. 18, 1425–1433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Olanow, C. W. & Brundin, P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov. Disord. 28, 31–40 (2013). A timely review of PD model transmission studies.

    Article  CAS  PubMed  Google Scholar 

  65. Lee, V. M. & Trojanowski, J. Q. Mechanisms of Parkinson's disease linked to pathological α-synuclein: new targets for drug discovery. Neuron 52, 33–38 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Irwin, D. J. et al. Evaluation of potential infectivity of Alzheimer's and Parkinson's disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 70, 462–468 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hurtig, H. I. et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology 54, 1916–1921 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Duda, J. E., Giasson, B. I., Mabon, M. E., Lee, V. M. & Trojanowski, J. Q. Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann. Neurol. 52, 205–210 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Apaydin, H., Ahlskog, J. E., Parisi, J. E., Boeve, B. F. & Dickson, D. W. Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch. Neurol. 59, 102–112 (2002).

    Article  PubMed  Google Scholar 

  70. Irwin, D. J. et al. Neuropathologic substrates of Parkinson disease dementia. Ann. Neurol. 72, 587–598 (2012). A large autopsy cohort involving multivariate analysis of multiple clinical, genetic and neuropathological variables that implicate Lewy body and neurite pathology as the strongest correlate of PDD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Compta, Y. et al. Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? Brain. 134, 1493–1505 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Tsuboi, Y., Uchikado, H. & Dickson, D. W. Neuropathology of Parkinson's disease dementia and dementia with Lewy bodies with reference to striatal pathology. Parkinsonism Relat. Disord. 13 (Suppl. 3), 221–224 (2007).

    Article  Google Scholar 

  73. Jellinger, K. A. & Attems, J. Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol. 115, 427–436 (2008).

    Article  PubMed  Google Scholar 

  74. Harding, A. J. & Halliday, G. M. Cortical Lewy body pathology in the diagnosis of dementia. Acta Neuropathol. 102, 355–363 (2001).

    CAS  PubMed  Google Scholar 

  75. Kovari, E. et al. Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson's disease. Acta Neuropathol. 106, 83–88 (2003).

    PubMed  Google Scholar 

  76. Mattila, P. M., Rinne, J. O., Helenius, H., Dickson, D. W. & Roytta, M. α-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease. Acta Neuropathol. 100, 285–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Pletnikova, O. et al. Aβ deposition is associated with enhanced cortical α-synuclein lesions in Lewy body diseases. Neurobiol. Aging 26, 1183–1192 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Ballard, C. et al. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology 67, 1931–1934 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Perry, E. K. et al. Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 48, 413–421 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Whitehouse, P. J., Hedreen, J. C., White, C. L., & Price, D. L. Basal forebrain neurons in the dementia of Parkinson disease. Ann. Neurol. 13, 243–248 (1983).

    Article  CAS  PubMed  Google Scholar 

  81. Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M. & Pearce, R. K. Striatal β-amyloid deposition in Parkinson disease with dementia. J. Neuropathol. Exp. Neurol. 67, 155–161 (2008).

    Article  PubMed  Google Scholar 

  82. Jellinger, K. A. Morphological substrates of parkinsonism with and without dementia: a retrospective clinico-pathological study. J. Neural. Transm. Suppl. 72, 91–104 (2007).

    Article  Google Scholar 

  83. Jellinger, K. A., Seppi, K., Wenning, G. K. & Poewe, W. Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J. Neural Transm. 109, 329–339 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Kotzbauer, P. T. et al. Pathologic accumulation of α-synuclein and Aβ in Parkinson disease patients with dementia. Arch. Neurol. 69, 1326–1331 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Hughes, A. J., Daniel, S. E., Blankson, S. & Lees, A. J. A clinicopathologic study of 100 cases of Parkinson's disease. Arch. Neurol. 50, 140–148 (1993).

    Article  CAS  PubMed  Google Scholar 

  86. Sabbagh, M. N. et al. Parkinson disease with dementia: comparing patients with and without Alzheimer pathology. Alzheimer Dis. Assoc. Disord. 23, 295–297 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Lashley, T. et al. Cortical α-synuclein load is associated with amyloid-β plaque burden in a subset of Parkinson's disease patients. Acta Neuropathol. 115, 417–425 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Masliah, E. et al. β-amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc. Natl Acad. Sci. USA 98, 12245–12250 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q. & LaFerla, F. M. Synergistic interactions between Aβ, tau, and α-synuclein: acceleration of neuropathology and cognitive decline. J. Neurosci. 30, 7281–7289 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Duda, J. E. et al. Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol. 104, 7–11 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Lee, V. M., Giasson, B. I. & Trojanowski, J. Q. More than just two peas in a pod: common amyloidogenic properties of tau and α-synuclein in neurodegenerative diseases. Trends Neurosci. 27, 129–134 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Giasson, B. I. et al. Initiation and synergistic fibrillization of tau and α-synuclein. Science 300, 636–640 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Jellinger, K. A., Wenning, G. K. & Seppi, K. Predictors of survival in dementia with lewy bodies and Parkinson dementia. Neurodegener. Dis. 4, 428–430 (2007).

    Article  PubMed  Google Scholar 

  94. Sabbagh, M. N. et al. Correlation of clinical features with argyrophilic grains at autopsy. Alzheimer Dis. Assoc. Disord. 23, 229–233 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Nakashima-Yasuda, H. et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 114, 221–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Colosimo, C., Hughes, A. J., Kilford, L. & Lees, A. J. Lewy body cortical involvement may not always predict dementia in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 74, 852–856 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Richard, I. H., Papka, M., Rubio, A. & Kurlan, R. Parkinson's disease and dementia with Lewy bodies: one disease or two? Mov. Disord. 17, 1161–1165 (2002).

    Article  PubMed  Google Scholar 

  98. Jellinger, K. A. & Attems, J. Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathol. 112, 253–260 (2006).

    Article  PubMed  Google Scholar 

  99. Halliday, G. M., Song, Y. J. & Harding, A. J. Striatal β-amyloid in dementia with Lewy bodies but not Parkinson's disease. J. Neural Transm. 118, 713–719 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Merdes, A. R. et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 60, 1586–1590 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Verghese, J., Crystal, H. A., Dickson, D. W. & Lipton, R. B. Validity of clinical criteria for the diagnosis of dementia with Lewy bodies. Neurology 53, 1974–1982 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Litvan, I. et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study. Arch. Neurol. 55, 969–978 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Nelson, P. T. et al. Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J. Neurol. 257, 359–366 (2010).

    Article  PubMed  Google Scholar 

  104. Kraybill, M. L. et al. Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64, 2069–2073 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. van Rooden, S. M. et al. The identification of Parkinson's disease subtypes using cluster analysis: a systematic review. Mov. Disord. 25, 969–978 (2010).

    Article  PubMed  Google Scholar 

  106. Selikhova, M. et al. A clinico-pathological study of subtypes in Parkinson's disease. Brain 132, 2947–2957 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Alves, G., Larsen, J. P., Emre, M., Wentzel-Larsen, T. & Aarsland, D. Changes in motor subtype and risk for incident dementia in Parkinson's disease. Mov. Disord. 21, 1123–1130 (2006).

    Article  PubMed  Google Scholar 

  108. Prikrylova Vranova, H. et al. CSF markers of neurodegeneration in Parkinson's disease. J. Neural Transm. 117, 1177–1181 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Alves, G. et al. Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 85, 537–543 (2012).

    Google Scholar 

  110. Kang, J. H. et al. Association of cerebrospinal fluid Aβ1-42, t-tau, p-tau181 and α-synuclein levels with clinical 1 features of early drug naïve Parkinson's disease patients. JAMA Neurol. (in the press).

  111. Müller, M. L. et al. β-amyloid and postural instability and gait difficulty in Parkinson's disease at risk for dementia. Mov. Disord. 28, 296–301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Halliday, G. M., Holton, J. L., Revesz, T. & Dickson, D. W. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 122, 187–204 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Svenningsson, P., Westman, E., Ballard, C. & Aarsland, D. Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol. 11, 697–707 (2012).

    Article  PubMed  Google Scholar 

  114. Sidransky, E. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361, 1651–1661 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tsuang, D. et al. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology 79, 1944–1950 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Neumann, J. et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 132, 1783–1794 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Nalls, M. A. et al. A multicenter study of glucocerebrosidase mutations in dementia with lewy bodies. JAMA Neurol. 70, 727–735 (2013).

    Article  PubMed  Google Scholar 

  118. Clark, L. N. et al. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch. Neurol. 66, 578–583 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Morley, J. F. et al. Genetic influences on cognitive decline in Parkinson's disease. Mov. Disord. 27, 512–518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tsuang, D. et al. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223–228 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Williams-Gray, C. H. et al. Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson's disease. J. Neurol. 256, 493–498 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Wakabayashi, K. et al. Apolipoprotein E ε4 allele and progression of cortical Lewy body pathology in Parkinson's disease. Acta Neuropathol. 95, 450–454 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Siderowf, A. et al. CSF amyloid β1–42 predicts cognitive decline in Parkinson disease. Neurology 75, 1055–1061 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Baker, M. et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711–715 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Zabetian, C. P. et al. Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease. Ann. Neurol. 62, 137–144 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Goris, A. et al. Tau and α-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann. Neurol. 62, 145–153 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Compta, Y. et al. High cerebrospinal tau levels are associated with the rs242557 tau gene variant and low cerebrospinal β-amyloid in Parkinson disease. Neurosci. Lett. 487, 169–173 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Chen-Plotkin, A. S. et al. Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease. Ann. Neurol. 69, 655–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Pellecchia, M. T. et al. Serum epidermal growth factor predicts cognitive functions in early, drug-naive Parkinson's disease patients. J. Neurol. 260, 438–444 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Compta, Y. et al. Cerebrospinal tau, phospho-tau, and β-amyloid and neuropsychological functions in Parkinson's disease. Mov. Disord. 24, 2203–2210 (2009).

    Article  PubMed  Google Scholar 

  131. Hall, S. et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. JAMA Neurol. 69, 1445–1452 (2012).

    Google Scholar 

  132. Alves, G. et al. CSF amyloid-β and tau proteins, and cognitive performance, in early and untreated Parkinson's disease: the Norwegian ParkWest study. J. Neurol. Neurosurg. Psychiatry 81, 1080–1086 (2010).

    Article  PubMed  Google Scholar 

  133. Montine, T. J. et al. CSF Aβ42 and tau in Parkinson's disease with cognitive impairment. Mov. Disord. 25, 2682–2685 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Leverenz, J. B. et al. Cerebrospinal fluid biomarkers and cognitive performance in non-demented patients with Parkinson's disease. Parkinsonism Relat. Disord. 17, 61–64 (2011).

    Article  PubMed  Google Scholar 

  135. Mollenhauer, B. et al. Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp. Neurol. 213, 315–325 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Wang, Y. et al. Phosphorylated α-synuclein in Parkinson's disease. Sci. Transl. Med. 4, 121ra20 (2012).

    PubMed  PubMed Central  Google Scholar 

  137. Tokuda, T. et al. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 75, 1766–1772 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Hong, Z. et al. DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease. Brain 133, 713–726 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Shi, M. et al. Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Ann. Neurol. 69, 570–580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Compta, Y. et al. Grey matter volume correlates of cerebrospinal markers of Alzheimer-pathology in Parkinson's disease and related dementia. Parkinsonism Relat. Disord. 18, 941–947 (2012).

    Article  PubMed  Google Scholar 

  141. Weintraub, D. et al. Alzheimer's disease pattern of brain atrophy predicts cognitive decline in Parkinson's disease. Brain 135, 170–180 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Gomperts, S. N. et al. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia. Neurology 80, 85–91 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Petrou, M. et al. Aβ-amyloid deposition in patients with Parkinson disease at risk for development of dementia. Neurology 79, 1161–1167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Bohnen, N. I. et al. Cerebral glucose metabolic features of Parkinson disease and incident dementia: longitudinal study. J. Nucl. Med. 52, 848–855 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Beyer, M. K. et al. Cerebrospinal fluid Aβ levels correlate with structural brain changes in Parkinson's disease. Mov. Disord. 28, 302–310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Marek, K. et al. The Parkinson Progression Marker Initiative (PPMI). Prog. Neurobiol. 95, 629–635 (2011).

    Article  Google Scholar 

  147. Rolinski, M., Fox, C., Maidment, I. & McShane, R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease. Cochrane Database Syst. Rev. 3, CD006504 (2012).

    Google Scholar 

  148. Seppi, K. et al. The movement disorder society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease. Mov. Disord. 26 (Suppl. 3), 42–80 (2011).

    Article  Google Scholar 

  149. Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nature Rev. Neurosci. 14, 38–48 (2013). A recent review highlighting the pathophysiology of α-syn toxicity in PD and potential therapeutic strategies.

    Article  CAS  Google Scholar 

  150. Valera, E. & Masliah, E. Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies. Pharmacol. Ther. 138, 311–322 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Montine, T. J. et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 123, 1–11 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Ward, C. D. & Gibb, W. R. Research diagnostic criteria for Parkinson's disease. Adv. Neurol. 53, 245–249 (1990).

    CAS  PubMed  Google Scholar 

  154. Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).

    Article  CAS  PubMed  Google Scholar 

  155. Kordower, J. H. & Brundin, P. Propagation of host disease to grafted neurons: accumulating evidence. Exp. Neurol. 220, 224–225 (2009).

    Article  PubMed  Google Scholar 

  156. Brown, P. et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35, 513–529 (1994).

    Article  CAS  PubMed  Google Scholar 

  157. Brown, P., Gajdusek, D. C., Gibbs, C. J. Jr & Asher, D. M. Potential epidemic of Creutzfeldt–Jakob disease from human growth hormone therapy. N. Engl. J. Med. 313, 728–731 (1985).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the patients and their families who have contributed to the research reviewed here, which has led to meaningful developments in our understanding of Parkinson's disease and related disorders. Funding for our research was provided by the US National Institutes of Health grants P30 AG10124, AG17586, P50 NS53488 and T32-AG000255.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer's Disease Core Center, Institute on Aging, University of Pennsylvania Perelman School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, 19104–4283, Pennsylvania, USA

    David J. Irwin, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Neurology, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, 19104–6021, Pennsylvania, USA

    David J. Irwin

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  1. David J. Irwin
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Glossary

Executive functioning

Abilities in mental flexibility, planning and working memory that are mediated by striatal–frontal networks.

Semantic memory

Memory for the meaning and context of objects and concepts that is mediated by the temporal lobe and its connections throughout the neocortex.

Mild cognitive impairment

(MCI). MCI comprises subjective cognitive complaints with objective findings of cognitive impairment in one or more cognitive domains that does not interfere with the patient's ability to perform tasks of daily living. MCI is thought to represent a prodromal state to Alzheimer's disease and other dementias. Recently, clinical criteria have been defined for MCI in the setting of Parkinson's disease.

Bradykinesia

Symptoms of slowed movement seen in Parkinson's disease and other disorders involving nigral–striatal dopaminergic pathways.

Constructional praxis

The ability to draw or copy a figure (such as clock-drawing or drawing intersecting pentagons), which relies on attention, planning and organization skills (executive function) and visuospatial perceptual abilities.

Verbal memory

Short-term memory for words and verbal information that is partially mediated by language function (for example, memory for words tested through a list-learning task).

Transmission

The spread of a pathological protein in an altered conformation (for example, PrPSc) between neurons within an individual; transmission does not necessarily imply that the disease protein is infectious (that is, it can be spread between individuals).

Amyloid fibrils

Insoluble filamentous structures composed of polymerized protein monomers with notable β-sheet conformation, which can be detected with amyloid-binding dyes (for example, thioflavin S).

Cognitive reserve

This refers to the notion of relative resistance to clinical symptoms of neurodegeneration and other CNS insults that is thought to be mediated by neuroplasticity or an ability to recruit additional brain networks to compensate for the disease state; such plasticity may be influenced by education or other environmental or genetic factors.

Cerebrovascular disease

(CVD). Damage to intracerebral blood vessels from atherosclerosis and lipohyalinosis, which are caused by systemic cardiovascular risk factors (for example, hypertension, diabetes and hyperlipidaemia) and result in ischaemic damage to the brain parenchyma (for example, lacunar infarcts).

Amyloid angiopathy

A form of cerebral vasculopathy that is caused by fibrillar amyloid-β deposition in blood vessel walls.

Tauopathies

A family of neurodegenerative disease proteinopathies that are characterized by inclusions composed primarily of the microtubule-associated protein tau.

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Irwin, D., Lee, VY. & Trojanowski, J. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci 14, 626–636 (2013). https://doi.org/10.1038/nrn3549

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