Parkinson’s disease: premotor clinico-pathological correlations

  • E. Ch. Wolters
  • H. Braak
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 70)


Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson’s disease (PD). Progressive loss of nigral neurons with Lewy bodies is considered an essential neuropathological feature. Recent studies, however, indicate that nigral degeneration is only a part of this synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, autonomic dysfunction, pain, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms suggests multiple causes and/or pathogeneses within the present diagnostic disease entity. In this article, a recently proposed staging of PD-related brain pathology will be correlated with the various clinical expressions. It will be argued that the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites, may explain the individually variable expression of this disease.


Lewy Body Dementia With Lewy Body Autonomic Failure Premature Ejaculation Pure Autonomic Failure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15: 29–34PubMedCrossRefGoogle Scholar
  2. Arnulf I, Konofal E, Merino-Andreu M, Houeto JL, Mesnage V, Welter ML, Lacomblenz L, Golmard JL, Derenne JP, Agid Y (2002) Parkinson’s disease and sleepiness: an integral part of PD. Neurology 58: 1019–1024PubMedGoogle Scholar
  3. Berendse HW, Booij J, Francot Ch, Bergmans PLM, Hijman R, Stoof JC, Wolters ECh (2001) Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell. Ann Neurol 50: 34–41PubMedCrossRefGoogle Scholar
  4. Bonuccelli U, Lucetti C, Del Dotto P, Ceravolo R, Gambaccini G, Bernardini S, Rossi G, Piaggesi A (2003) Orthostatic hypotension in de novo Parkinson disease. Arch Neurol 60: 1400–1404PubMedCrossRefGoogle Scholar
  5. Booij J, Tissingh G, Winogrodzka A, van Royen EA et al. (1999) Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism. Eur J Nucl Med 26: 171–182PubMedCrossRefGoogle Scholar
  6. Bosboom H, Stoffers D, Wolters ECh (2004) Cognitive function in Parkinson’s disease. J Neural Transm 111: 1303–1315PubMedCrossRefGoogle Scholar
  7. Braak H, Braak E (2000) Pathoanatomy of Parkinson’s disease. J Neurol 247[Suppl 2]: S3–S10Google Scholar
  8. Braak H, Del Tredici K, Rueb U, de Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24: 197–211PubMedCrossRefGoogle Scholar
  9. Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110: 517–536PubMedCrossRefGoogle Scholar
  10. Braak H, Ghebremedhin E, Rueb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318: 121–134PubMedCrossRefGoogle Scholar
  11. Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA (2005) Cognitive status correlates with neuropathologic stage in Parkinson’s disease. Neurology 64: 1404–1410PubMedGoogle Scholar
  12. Bronner G, Royter V, Korczyn AD, Giladi N (2004) Sexual dysfunction in Parkinson’s disease. J Sex Marital Ther 30: 95–105PubMedCrossRefGoogle Scholar
  13. Brown RG, Soliveri P, Jahanshahi M (1998) Executive processes in Parkinson’s disease — random number generation and response suppression. Neuropsychol 36: 1355–1362CrossRefGoogle Scholar
  14. Calne D (2005) A definition of Parkinson’s disease. J Parkinsonism Relat Disord 1: S39–S40CrossRefGoogle Scholar
  15. Chaudhuri KR, Yates L, Martinez-Martin P (2005) The Non-motor symptom complex of Parkinson’s disease: a comprehensive assessment is essential. Curr Neurol Neurosci Rep 5: 275–283PubMedGoogle Scholar
  16. Cummings JL (2004) Dementia with lewy bodies: molecular pathogenesis and implications for classification. J Geriatr Psychiatry Neurol 17: 112–119PubMedCrossRefGoogle Scholar
  17. Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61: 413–426PubMedGoogle Scholar
  18. Dubois B, Pillon B (1997) Cognitive deficits in Parkinson’s disease. J Neurol 244: 2–8PubMedCrossRefGoogle Scholar
  19. Fantini ML, Ferini-Strambi L, Montplaisir J (2005) Idiopathic REM sleep behavior disorder: toward a better nosologic definition. Neurology 64: 780–786PubMedGoogle Scholar
  20. Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114: 2283–2301PubMedGoogle Scholar
  21. Giuffrida R, Vingerhoets FJ, Bogousslavsky J, Ghika J (2005) Pain in Parkinson’s disease. Rev Neurol (Paris) 161: 407–418PubMedGoogle Scholar
  22. Gonera EG, van’t Hof M, Berger HJ, van Weel C, Horstink MW (1997) Symptoms and duration of the prodromal phase in Parkinson’s disease. Mov Disord 12: 871–876PubMedCrossRefGoogle Scholar
  23. Hague K, Lento P, Morgello S, Caro S, Kaufmann H (1997) The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol (Berl) 94: 192–196PubMedCrossRefGoogle Scholar
  24. Hocherman S, Giladi N (1998) Visuomotor control abnormalities in patients with unilateral parkinsonism. Neurology 50: 1648–1654PubMedGoogle Scholar
  25. Huisman E, Uylings HB, Hoogland PV (2004) A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson’s disease. Mov Disord 19: 687–692PubMedCrossRefGoogle Scholar
  26. Iwanaga K, Wakabayashi K, Yoshimoto M, Tomita I, Satoh H, Takashima H, Satoh A, Seto M, Tsujihata M, Takahashi H (1999) Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52: 1269–1271PubMedGoogle Scholar
  27. Jellinger KA (1999) Post mortem studies in Parkinson’s disease-is it possible to detect brain areas for specific symptoms? J Neural Transm 56: 1–29Google Scholar
  28. Kaufmann H, Nahm K, Purohit D, Wolfe D (2004) Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63: 953–954Google Scholar
  29. Koller WC (1998) Neuroprotection for Parkinson’s disease. Ann Neurol 44[Suppl 1]: S155–S159PubMedGoogle Scholar
  30. Larner AJ, Mathias CJ, Rossor MN (2000) Autonomic failure preceding dementia with Lewy bodies. J Neurol 247: 229–231PubMedCrossRefGoogle Scholar
  31. Lewis SJG, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA (2005) Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 76: 343–348PubMedCrossRefGoogle Scholar
  32. Magerkurth C, Schnitzer R, Braune S (2005) Symptoms of autonomic failure in Parkinson’s disease: prevalence and impact on daily life. Clin Auton Res 15: 76–82PubMedCrossRefGoogle Scholar
  33. Mahieux F, Fenelon G, Flahault A, Manifacier MJ, Michelet D, Boller F (1998) Neuropsychological prediction of dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 64: 178–183PubMedGoogle Scholar
  34. Marek K, Innis R, van Dyck C, Fussell B, Early M, Eberly S, Oakes D, Seybil J (2001) [(123)I]beta-CIT SPECT imaging assessment of the rate of Parkinson’s disease progression. Neurology 57: 2089–2094PubMedGoogle Scholar
  35. Micieli G, Tosi P, Marcheselli S, Cavallini A (2003) Autonomic dysfunction in Parkinson’s disease. Neurol Sci 24[Suppl 1]: S32–S34PubMedCrossRefGoogle Scholar
  36. Montgomery EB, Baker KB, Lyons K, Koller W (1999) Abnormal performance on the PD test battery by asymptomatic first degree relatives. Neurology 52: 757–762PubMedGoogle Scholar
  37. Morris RG, Downes JJ, Sahakian BJ, Evenden JL, Heald A, Robbins TW (1988) Planning and spatial working memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 51: 757–766PubMedGoogle Scholar
  38. Morrish PK, Rakshi JS, Bailey DL, Sawle GV, Brooks DJ (1998) Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry 64: 314–319PubMedCrossRefGoogle Scholar
  39. Oppenheimer DR (1980) Lateral horn cells in progressive autonomic failure. J Neurol Sci 46: 393–404PubMedCrossRefGoogle Scholar
  40. Pacchetti C, Manni R, Zangaglia R, Mancini F, Marchioni E, Tassorelli C, Terzaghi M, Ossola M, Martignoni E, Moglia A, Nappi G (2005) Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson’s disease. Mov Disord, October 14 (Epub ahead of print)Google Scholar
  41. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BLF, Wolters ECh, Berendse HW (2004) Idiopatic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56: 173–181PubMedCrossRefGoogle Scholar
  42. Przuntek H, Muller T, Riederer P (2004) Diagnostic staging of Parkinson’s disease: conceptual aspects. J Neural Transm 111: 201–216PubMedCrossRefGoogle Scholar
  43. Remy P, Doder M, Lees A, Turjanski N, Brooks D (2005) Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128: 1314–1322PubMedCrossRefGoogle Scholar
  44. Sage JI, Mark MH (1995) Drenching sweats as an off phenomenon in Parkinson’s disease: treatment and relation to plasma levodopa profile. Ann Neurol 37: 120–122PubMedCrossRefGoogle Scholar
  45. Schenck CH, Bundlie SR, Mahowald MW (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic REM sleep disorder behavior. Neurology 46: 388–393PubMedGoogle Scholar
  46. Scherder E, Wolters E, Polman C, Sergeant J, Swaab D (2005) Pain in Parkinson’s disease and multiple sclerosis: its relation to the medial and lateral pain systems. Neurosci Biobehav Rev 29: 1047–1056PubMedCrossRefGoogle Scholar
  47. Schuurman AG, van den Akker M, Ensinck KTJL, Metsemakers JF, Knottnerus JA, Leentjens AF, Buntix F (2002) Increased risk of Parkinson’s disease after depression: a retrospective cohort study. Neurology 58: 1501–1504PubMedGoogle Scholar
  48. Simard M, van Reekum R, Cohen T (2000) A review of the cognitive and behavioral symptoms in dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci 12: 425–450PubMedGoogle Scholar
  49. Singleton A, Gwinn-Hardy K, Sharabi Y, Li ST, Holmes C, Dendi R, Hardy J, Singleton A, Crawley A, Goldstein DS (2004) Association between cardiac denervation and parkinsonism caused by alphasynuclein gene triplication. Brain 127: 768–772PubMedCrossRefGoogle Scholar
  50. Soler JM, Le Portz B (2004) Bladder sphincter disorders in Parkinson’s disease Ann Urol (Paris) 38[Suppl 2]: S57–S61CrossRefGoogle Scholar
  51. Stiasny-Kolster K, Doerr Y, Moller JC, Hoffken H, Behr TM, Oertel WH, Mayer G (2005) Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128: 126–137PubMedCrossRefGoogle Scholar
  52. Stoffers D, Berendse HW, Deijen JB, Wolters ECh (2001) Motor perseveration is an early sign in Parkinson’s disease. Neurology 57: 2111–2113PubMedGoogle Scholar
  53. Tissingh G, Bergmans P, Booij J, Winogrodzka A, van Royen EA, Stoof JC, Wolters EC (1998) Drug-naive patients with Parkinson’s disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta-CIT SPECT. J Neurol 245: 14–20PubMedCrossRefGoogle Scholar
  54. Tissingh G, Booij J, Bergmans P et al. (1998) Iodine-123-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson’s disease. J Nucl Med 39: 1143–1148PubMedGoogle Scholar
  55. Tissingh G, de Waard R, Bergmans P, Drukarch B, Stoof JC, Wolters ECh (2001) Loss of olfactory discrimination in de-novo Parkinson’s disease patients. Mov Disord 16: 41–46PubMedCrossRefGoogle Scholar
  56. Uitti RJ, Baba Y, Wszolek ZK, Putzke DJ (2005) Defining the Parkinson disease phenotype: initial symptoms and baseline characteristics in a clinical cohort. J Parkinsonism Relat Disord 11: 139–145CrossRefGoogle Scholar
  57. Vanderhaeghen JJ, Perier O, Sternon JE (1970) Pathological findings in idiopathic orthostatic hypotension: its relationship with Parkinson’s disease. Arch Neurol 22: 207–214PubMedGoogle Scholar
  58. Waxman MJ, Durfee D, Moore M, Morantz RA, Koller W (1990) Nutritional aspects and swallowing function of patients with Parkinson’s disease. Nutr Clin Pract 5: 196–199PubMedCrossRefGoogle Scholar
  59. Yu M, Roane DM, Miner CR, Fleming M, Rogers JD (2004) Dimensions of sexual dysfunction in Parkinson’s disease. Am J Geratr Psychiatry 12: 221–226CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • E. Ch. Wolters
    • 1
  • H. Braak
    • 2
  1. 1.Department of NeurologyVU University Medical CenterAmsterdamThe Netherlands
  2. 2.Institute for Clinical NeuroanatomyJ.W. Goethe UniversityFrankfurt/MainGermany

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