Acta Neuropathologica

, 118:587

The morbid anatomy of dementia in Parkinson’s disease



Dementia in Parkinson’s disease (PD/PDD) is a common complication with a prevalence of up to 50%, but the specific changes underlying the cognitive decline remain undefined. Neuronal degeneration resulting in the dysfunction of multiple subcortical neurochemical projection systems has been described along with Lewy body-type pathology in cortical and limbic regions. Advanced alpha-synuclein (αSyn) pathology is not necessarily sufficient for producing dementia and concomitant Alzheimer’s disease (AD) change has also been proposed as a possible substrate of PDD. A lack of consensus in the extant literature likely stems from clinical heterogeneity and variable reliability in clinical characterisation as well as other historical and methodological issues. The concurrent presence of abnormally deposited αSyn, amyloid-β and tau proteins in the PDD brain and the interaction of these molecules in a linked pathological cascade of AD and PD-related mechanisms may prove important in determining the underlying pathological process for the development of dementia in PD and this concept of combined pathologies awaits further investigation.


Parkinson’s disease Alpha-synuclein Lewy body Neuropathology Dementia Cognitive dysfunction Beta-amyloid Tau 


  1. 1.
    Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P (2003) Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 60:387–392PubMedCrossRefGoogle Scholar
  2. 2.
    Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P (2001) Risk of dementia in Parkinson’s disease: a community-based, prospective study. Neurology 56:730–736PubMedGoogle Scholar
  3. 3.
    Aarsland D, Larsen JP, Karlsen K, Lim NG, Tandberg E (1999) Mental symptoms in Parkinson’s disease are important contributors to caregiver distress. Int J Geriatr Psychiatry 14:866–874PubMedCrossRefGoogle Scholar
  4. 4.
    Aarsland D, Larsen JP, Tandberg E, Laake K (2000) Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc 48:938–942PubMedGoogle Scholar
  5. 5.
    Aarsland D, Perry R, Brown A, Larsen JP, Ballard C (2005) Neuropathology of dementia in Parkinson’s disease: a prospective, community-based study. Ann Neurol 58:773–776PubMedCrossRefGoogle Scholar
  6. 6.
    Aarsland D, Tandberg E, Larsen JP, Cummings JL (1996) Frequency of dementia in Parkinson disease. Arch Neurol 53:538–542PubMedGoogle Scholar
  7. 7.
    Agid Y, Graybiel AM, Ruberg M, Hirsch E, Blin J, Dubois B, Javoy-Agid F (1990) The efficacy of levodopa treatment declines in the course of Parkinson’s disease: do nondopaminergic lesions play a role? Adv Neurol 53:83–100PubMedGoogle Scholar
  8. 8.
    Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW (2002) Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch Neurol 59:102–112PubMedCrossRefGoogle Scholar
  9. 9.
    Arawaka S, Saito Y, Murayama S, Mori H (1998) Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein. Neurology 51:887–889PubMedGoogle Scholar
  10. 10.
    Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1:103–116PubMedCrossRefGoogle Scholar
  11. 11.
    Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639PubMedGoogle Scholar
  12. 12.
    Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–1688PubMedGoogle Scholar
  13. 13.
    Bayer TA, Jakala P, Hartmann T, Havas L, McLean C, Culvenor JG, Li QX, Masters CL, Falkai P, Beyreuther K (1999) Alpha-synuclein accumulates in Lewy bodies in Parkinson’s disease and dementia with Lewy bodies but not in Alzheimer’s disease beta-amyloid plaque cores. Neurosci Lett 266:213–216PubMedCrossRefGoogle Scholar
  14. 14.
    Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White CL 3rd, Akiyama H, Caviness J, Shill HA, Connor DJ, Sabbagh MN, Walker DG (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634PubMedCrossRefGoogle Scholar
  15. 15.
    Bertrand E, Lechowicz W, Lewandowska E, Szpak GM, Dymecki J, Kosno-Kruszewska E, Wierzba-Bobrowicz T (2003) Degenerative axonal changes in the hippocampus and amygdala in Parkinson’s disease. Folia Neuropathol 41:197–207PubMedGoogle Scholar
  16. 16.
    Bertrand E, Lechowicz W, Szpak GM, Lewandowska E, Dymecki J, Wierzba-Bobrowicz T (2004) Limbic neuropathology in idiopathic Parkinson’s disease with concomitant dementia. Folia Neuropathol 42:141–150PubMedGoogle Scholar
  17. 17.
    Bierer LM, Hof PR, Purohit DP, Carlin L, Schmeidler J, Davis KL, Perl DP (1995) Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol 52:81–88PubMedGoogle Scholar
  18. 18.
    Boller F, Mizutani T, Roessmann U, Gambetti P (1980) Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations. Ann Neurol 7:329–335PubMedCrossRefGoogle Scholar
  19. 19.
    Braak E, Braak H (1999) Silver staining method for demonstrating Lewy bodies in Parkinson’s disease and argyrophilic oligodendrocytes in multiple system atrophy. J Neurosci Methods 87:111–115PubMedCrossRefGoogle Scholar
  20. 20.
    Braak H, Braak E (2000) Pathoanatomy of Parkinson’s disease. J Neurol 247(Suppl 2):II3–II10PubMedCrossRefGoogle Scholar
  21. 21.
    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 24:197–211PubMedCrossRefGoogle Scholar
  22. 22.
    Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA (2005) Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 64:1404–1410PubMedGoogle Scholar
  23. 23.
    Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421–429PubMedCrossRefGoogle Scholar
  24. 24.
    Brown DF, Risser RC, Bigio EH, Tripp P, Stiegler A, Welch E, Eagan KP, Hladik CL, White CL 3rd (1998) Neocortical synapse density and Braak stage in the Lewy body variant of Alzheimer disease: a comparison with classic Alzheimer disease and normal aging. J Neuropathol Exp Neurol 57:955–960PubMedCrossRefGoogle Scholar
  25. 25.
    Burke RE, Dauer WT, Vonsattel JP (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491PubMedCrossRefGoogle Scholar
  26. 26.
    Caballol N, Marti MJ, Tolosa E (2007) Cognitive dysfunction and dementia in Parkinson disease. Mov Disord 22(Suppl 17):S358–S366CrossRefGoogle Scholar
  27. 27.
    Churchyard A, Lees AJ (1997) The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson’s disease. Neurology 49:1570–1576PubMedGoogle Scholar
  28. 28.
    Colosimo C, Hughes AJ, Kilford L, Lees AJ (2003) Lewy body cortical involvement may not always predict dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:852–856PubMedCrossRefGoogle Scholar
  29. 29.
    Cummings JL (1988) Intellectual impairment in Parkinson’s disease: clinical, pathologic, and biochemical correlates. J Geriatr Psychiatry Neurol 1:24–36PubMedCrossRefGoogle Scholar
  30. 30.
    Cummings JL (2003) Toward a molecular neuropsychiatry of neurodegenerative diseases. Ann Neurol 54:147–154PubMedCrossRefGoogle Scholar
  31. 31.
    Cummings JL, Benson DF (1984) Subcortical dementia: review of an emerging concept. Arch Neurol 41:874–879PubMedGoogle Scholar
  32. 32.
    Dale GE, Probst A, Luthert P, Martin J, Anderton BH, Leigh PN (1992) Relationships between Lewy bodies and pale bodies in Parkinson’s disease. Acta Neuropathol 83:525–529PubMedCrossRefGoogle Scholar
  33. 33.
    Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122(Pt 8):1437–1448PubMedCrossRefGoogle Scholar
  34. 34.
    Darvesh S, Freedman M (1996) Subcortical dementia: a neurobehavioral approach. Brain Cogn 31:230–249PubMedCrossRefGoogle Scholar
  35. 35.
    de Lau LM, Schipper CM, Hofman A, Koudstaal PJ, Breteler MM (2005) Prognosis of Parkinson disease: risk of dementia and mortality: the Rotterdam Study. Arch Neurol 62:1265–1269PubMedCrossRefGoogle Scholar
  36. 36.
    de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54:S21–S23PubMedGoogle Scholar
  37. 37.
    Dickson DW (2005) Required techniques and useful molecular markers in the neuropathologic diagnosis of neurodegenerative diseases. Acta Neuropathol 109:14–24PubMedCrossRefGoogle Scholar
  38. 38.
    Dickson DW, Liu W, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Sima A, D’Amato C, Albin R, Gilman S, Yen SH (1999) Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 155:1241–1251PubMedGoogle Scholar
  39. 39.
    Duda JE, Giasson BI, Mabon ME, Lee VM, Trojanowski JQ (2002) Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 52:205–210PubMedCrossRefGoogle Scholar
  40. 40.
    Edison P, Rowe CC, Rinne JO, Ng S, Ahmed I, Kemppainen N, Villemagne VL, O’Keefe G, Nagren K, Chaudhury KR, Masters CL, Brooks DJ (2008) Amyloid load in Parkinson’s disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J Neurol Neurosurg Psychiatry 79:1331–1338PubMedCrossRefGoogle Scholar
  41. 41.
    Emre M (2003) What causes mental dysfunction in Parkinson’s disease? Mov Disord 18(Suppl 6):S63–S71PubMedCrossRefGoogle Scholar
  42. 42.
    Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B (2007) Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22:1689–1707 (quiz 1837)PubMedCrossRefGoogle Scholar
  43. 43.
    Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301PubMedCrossRefGoogle Scholar
  44. 44.
    Foltynie T, Brayne CE, Robbins TW, Barker RA (2004) The cognitive ability of an incident cohort of Parkinson’s patients in the UK: the CamPaIGN study. Brain 127:550–560PubMedCrossRefGoogle Scholar
  45. 45.
    Gai WP, Power JH, Blumbergs PC, Blessing WW (1998) Multiple-system atrophy: a new alpha-synuclein disease? Lancet 352:547–548PubMedCrossRefGoogle Scholar
  46. 46.
    Galvin JE, Lee VM, Trojanowski JQ (2001) Synucleinopathies: clinical and pathological implications. Arch Neurol 58:186–190PubMedCrossRefGoogle Scholar
  47. 47.
    Gaspar P, Gray F (1984) Dementia in idiopathic Parkinson’s disease: a neuropathological study of 32 cases. Acta Neuropathol 64:43–52PubMedCrossRefGoogle Scholar
  48. 48.
    Gearing M, Wilson RW, Unger ER, Shelton ER, Chan HW, Masters CL, Beyreuther K, Mirra SS (1993) Amyloid precursor protein (APP) in the striatum in Alzheimer’s disease: an immunohistochemical study. J Neuropathol Exp Neurol 52:22–30PubMedCrossRefGoogle Scholar
  49. 49.
    Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640PubMedCrossRefGoogle Scholar
  50. 50.
    Goetz CG, Emre M, Dubois B (2008) Parkinson’s disease dementia: definitions, guidelines, and research perspectives in diagnosis. Ann Neurol 64(Suppl 2):S81–S92PubMedGoogle Scholar
  51. 51.
    Goldman JE, Yen SH, Chiu FC, Peress NS (1983) Lewy bodies of Parkinson’s disease contain neurofilament antigens. Science 221:1082–1084PubMedCrossRefGoogle Scholar
  52. 52.
    Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE, Mathis CA, Elmaleh DR, Shoup T, Fischman AJ, Hyman BT, Growdon JH, Johnson KA (2008) Imaging amyloid deposition in Lewy body diseases. Neurology 71:903–910PubMedCrossRefGoogle Scholar
  53. 53.
    Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495PubMedCrossRefGoogle Scholar
  54. 54.
    Hakim AM, Mathieson G (1979) Dementia in Parkinson disease: a neuropathologic study. Neurology 29:1209–1214PubMedGoogle Scholar
  55. 55.
    Harding AJ, Halliday GM (2001) Cortical Lewy body pathology in the diagnosis of dementia. Acta Neuropathol 102:355–363PubMedGoogle Scholar
  56. 56.
    Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney multicenter study of Parkinson’s disease: non-l-dopa-responsive problems dominate at 15 years. Mov Disord 20:190–199PubMedCrossRefGoogle Scholar
  57. 57.
    Hietanen M, Teravainen H (1988) The effect of age of disease onset on neuropsychological performance in Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:244–249PubMedCrossRefGoogle Scholar
  58. 58.
    Hobson P, Meara J (1999) The detection of dementia and cognitive impairment in a community population of elderly people with Parkinson’s disease by use of the CAMCOG neuropsychological test. Age Ageing 28:39–43PubMedCrossRefGoogle Scholar
  59. 59.
    Hoogendijk WJ, Pool CW, Troost D, van Zwieten E, Swaab DF (1995) Image analyser-assisted morphometry of the locus coeruleus in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Brain 118(Pt 1):131–143PubMedCrossRefGoogle Scholar
  60. 60.
    Huang X, Chen P, Kaufer DI, Troster AI, Poole C (2006) Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch Neurol 63:189–193PubMedCrossRefGoogle Scholar
  61. 61.
    Hughes AJ, Daniel SE, Blankson S, Lees AJ (1993) A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol 50:140–148PubMedGoogle Scholar
  62. 62.
    Hughes TA, Ross HF, Musa S, Bhattacherjee S, Nathan RN, Mindham RH, Spokes EG (2000) A 10-year study of the incidence of and factors predicting dementia in Parkinson’s disease. Neurology 54:1596–1602PubMedGoogle Scholar
  63. 63.
    Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM, Clark CM, Glosser G, Stern MB, Gollomp SM, Arnold SE (2000) Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 54:1916–1921PubMedGoogle Scholar
  64. 64.
    Inzelberg R, Chapman J, Treves TA, Asherov A, Kipervasser S, Hilkewicz O, Verchovsky R, Klimowitzky S, Korczyn AD (1998) Apolipoprotein E4 in Parkinson disease and dementia: new data and meta-analysis of published studies. Alzheimer Dis Assoc Disord 12:45–48PubMedCrossRefGoogle Scholar
  65. 65.
    Inzelberg R, Schechtman E, Paleacu D (2002) Onset age of Parkinson disease. Am J Med Genet 111:459–460 (author reply 461)PubMedCrossRefGoogle Scholar
  66. 66.
    Jellinger K, Grisold W (1982) Cerebral atrophy in Parkinson syndrome. Exp Brain Res Suppl 5:26–35Google Scholar
  67. 67.
    Jellinger KA (1991) Pathology of Parkinson’s disease: changes other than the nigrostriatal pathway. Mol Chem Neuropathol 14:153–197PubMedCrossRefGoogle Scholar
  68. 68.
    Jellinger KA (1997) Morphological substrates of dementia in parkinsonism: a critical update. J Neural Transm Suppl 51:57–82PubMedGoogle Scholar
  69. 69.
    Jellinger KA (2000) Morphological substrates of mental dysfunction in Lewy body disease: an update. J Neural Transm Suppl 59:185–212PubMedGoogle Scholar
  70. 70.
    Jellinger KA (2008) A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol 116:1–16PubMedCrossRefGoogle Scholar
  71. 71.
    Jellinger KA (2009) A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta 1792:730–740PubMedGoogle Scholar
  72. 72.
    Jellinger KA (2009) Significance of brain lesions in Parkinson disease dementia and Lewy body dementia. Front Neurol Neurosci 24:114–125PubMedCrossRefGoogle Scholar
  73. 73.
    Jellinger KA, Attems J (2006) Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathol 112:253–260PubMedCrossRefGoogle Scholar
  74. 74.
    Jellinger KA, Attems J (2008) Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol 115:427–436PubMedCrossRefGoogle Scholar
  75. 75.
    Jellinger KA, Paulus W (1992) Clinico-pathological correlations in Parkinson’s disease. Clin Neurol Neurosurg 94(Suppl):S86–S88PubMedCrossRefGoogle Scholar
  76. 76.
    Jellinger KA, Seppi K, Wenning GK (2003) Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol 106:188–189 author reply 190PubMedCrossRefGoogle Scholar
  77. 77.
    Jellinger KA, Seppi K, Wenning GK, Poewe W (2002) Impact of coexistent Alzheimer pathology on the natural history of Parkinson’s disease. J Neural Transm 109:329–339PubMedCrossRefGoogle Scholar
  78. 78.
    Jendroska K, Lees AJ, Poewe W, Daniel SE (1996) Amyloid beta-peptide and the dementia of Parkinson’s disease. Mov Disord 11:647–653PubMedCrossRefGoogle Scholar
  79. 79.
    Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (1999) alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274:25481–25489PubMedCrossRefGoogle Scholar
  80. 80.
    Kalaitzakis ME, Christian LM, Moran LB, Graeber MB, Pearce RK, Gentleman SM (2008) Dementia and visual hallucinations associate with limbic pathology in Parkinson’s disease. Parkinsonism Relat Disord 15:196–204PubMedCrossRefGoogle Scholar
  81. 81.
    Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) Controversies over the staging of alpha-synuclein pathology in Parkinson’s disease. Acta Neuropathol 116:125–128 (author reply 129–131)PubMedCrossRefGoogle Scholar
  82. 82.
    Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) Striatal beta-amyloid deposition in Parkinson disease with dementia. J Neuropathol Exp Neurol 67:155–161PubMedCrossRefGoogle Scholar
  83. 83.
    Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of alpha-synuclein staging. Neuropathol Appl Neurobiol 34:284–295PubMedCrossRefGoogle Scholar
  84. 84.
    Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2009) Evidence against a reliable staging system of alpha-synuclein pathology in Parkinson’s disease. Neuropathol Appl Neurobiol 35:125–126PubMedCrossRefGoogle Scholar
  85. 85.
    Kalaitzakis ME, Pearce RK, Gentleman SM (2009) Clinical correlates of pathology in the claustrum in Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 461:12–15PubMedCrossRefGoogle Scholar
  86. 86.
    Kosaka K, Tsuchiya K, Yoshimura M (1988) Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 7:299–305PubMedGoogle Scholar
  87. 87.
    Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, Giannakopoulos P (2003) Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson’s disease. Acta Neuropathol 106:83–88PubMedGoogle Scholar
  88. 88.
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108PubMedCrossRefGoogle Scholar
  89. 89.
    Kulisevsky J, Pagonabarraga J (2009) Cognitive impairment in Parkinson’s disease: tools for diagnosis and assessment. Mov Disord 24:1103–1110PubMedCrossRefGoogle Scholar
  90. 90.
    Levy G, Tang MX, Louis ED, Cote LJ, Alfaro B, Mejia H, Stern Y, Marder K (2002) The association of incident dementia with mortality in PD. Neurology 59:1708–1713PubMedGoogle Scholar
  91. 91.
    NJ LiangT, Duda JE (2006) Does striatal pathology distinguish DLB from PDD? Mov Disord 21:S69–S70CrossRefGoogle Scholar
  92. 92.
    Louis ED, Marder K, Cote L, Tang M, Mayeux R (1997) Mortality from Parkinson disease. Arch Neurol 54:260–264PubMedGoogle Scholar
  93. 93.
    Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett M, Landon M, Mayer RJ (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol 155:9–15PubMedCrossRefGoogle Scholar
  94. 94.
    Maetzler W, Reimold M, Liepelt I, Solbach C, Leyhe T, Schweitzer K, Eschweiler GW, Mittelbronn M, Gaenslen A, Uebele M, Reischl G, Gasser T, Machulla HJ, Bares R, Berg D (2008) [11C]PIB binding in Parkinson’s disease dementia. Neuroimage 39:1027–1033PubMedCrossRefGoogle Scholar
  95. 95.
    Mann DM, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 21:193–203PubMedCrossRefGoogle Scholar
  96. 96.
    Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250PubMedCrossRefGoogle Scholar
  97. 97.
    Mastaglia FL, Johnsen RD, Byrnes ML, Kakulas BA (2003) Prevalence of amyloid-beta deposition in the cerebral cortex in Parkinson’s disease. Mov Disord 18:81–86PubMedCrossRefGoogle Scholar
  98. 98.
    Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M (2000) Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta Neuropathol 100:285–290PubMedCrossRefGoogle Scholar
  99. 99.
    Mattila PM, Rinne JO, Helenius H, Roytta M (1999) Neuritic degeneration in the hippocampus and amygdala in Parkinson’s disease in relation to Alzheimer pathology. Acta Neuropathol 98:157–164PubMedCrossRefGoogle Scholar
  100. 100.
    Mattila PM, Roytta M, Torikka H, Dickson DW, Rinne JO (1998) Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease. Acta Neuropathol 95:576–582PubMedCrossRefGoogle Scholar
  101. 101.
    Mayeux R, Denaro J, Hemenegildo N, Marder K, Tang MX, Cote LJ, Stern Y (1992) A population-based investigation of Parkinson’s disease with and without dementia: relationship to age and gender. Arch Neurol 49:492–497PubMedGoogle Scholar
  102. 102.
    Mayeux R, Stern Y, Rosenstein R, Marder K, Hauser A, Cote L, Fahn S (1988) An estimate of the prevalence of dementia in idiopathic Parkinson’s disease. Arch Neurol 45:260–262PubMedGoogle Scholar
  103. 103.
    McKee AC, Kosik KS, Kowall NW (1991) Neuritic pathology and dementia in Alzheimer’s disease. Ann Neurol 30:156–165PubMedCrossRefGoogle Scholar
  104. 104.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  105. 105.
    Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M, Concha A, Munoz DG (2007) Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders? A cohort study. Neurology 68:2012–2018PubMedCrossRefGoogle Scholar
  106. 106.
    Muslimovic D, Post B, Speelman JD, Schmand B (2005) Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology 65:1239–1245PubMedCrossRefGoogle Scholar
  107. 107.
    Papp MI, Lantos PL (1994) The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 117(Pt 2):235–243PubMedCrossRefGoogle Scholar
  108. 108.
    Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91PubMedCrossRefGoogle Scholar
  109. 109.
    Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 115:399–407PubMedCrossRefGoogle Scholar
  110. 110.
    Parsian A, Racette B, Goldsmith LJ, Perlmutter JS (2002) Parkinson’s disease and apolipoprotein E: possible association with dementia but not age at onset. Genomics 79:458–461PubMedCrossRefGoogle Scholar
  111. 111.
    Pillon B, Deweer B, Agid Y, Dubois B (1993) Explicit memory in Alzheimer’s, Huntington’s, and Parkinson’s diseases. Arch Neurol 50:374–379PubMedGoogle Scholar
  112. 112.
    Pletnikova O, West N, Lee MK, Rudow GL, Skolasky RL, Dawson TM, Marsh L, Troncoso JC (2005) Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases. Neurobiol Aging 26:1183–1192PubMedCrossRefGoogle Scholar
  113. 113.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  114. 114.
    Rajput AH, Rozdilsky B, Rajput A, Ang L (1990) Levodopa efficacy and pathological basis of Parkinson syndrome. Clin Neuropharmacol 13:553–558PubMedCrossRefGoogle Scholar
  115. 115.
    Reid WG, Hely MA, Morris JG, Broe GA, Adena M, Sullivan DJ, Williamson PM (1996) A longitudinal of Parkinson’s disease: clinical and neuropsychological correlates of dementia. J Clin Neurosci 3:327–333PubMedCrossRefGoogle Scholar
  116. 116.
    Richard IH, Papka M, Rubio A, Kurlan R (2002) Parkinson’s disease and dementia with Lewy bodies: one disease or two? Mov Disord 17:1161–1165PubMedCrossRefGoogle Scholar
  117. 117.
    Rinne JO, Rummukainen J, Paljarvi L, Rinne UK (1989) Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Ann Neurol 26:47–50PubMedCrossRefGoogle Scholar
  118. 118.
    Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O’Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL (2007) Imaging beta-amyloid burden in aging and dementia. Neurology 68:1718–1725PubMedCrossRefGoogle Scholar
  119. 119.
    Rub U, Del Tredici K, Schultz C, Ghebremedhin E, de Vos RA, Jansen Steur E, Braak H (2002) Parkinson’s disease: the thalamic components of the limbic loop are severely impaired by alpha-synuclein immunopositive inclusion body pathology. Neurobiol Aging 23:245–254PubMedCrossRefGoogle Scholar
  120. 120.
    Samuel W, Alford M, Hofstetter CR, Hansen L (1997) Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 56:499–508PubMedCrossRefGoogle Scholar
  121. 121.
    Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473PubMedCrossRefGoogle Scholar
  122. 122.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  123. 123.
    Starkstein SE, Bolduc PL, Mayberg HS, Preziosi TJ, Robinson RG (1990) Cognitive impairments and depression in Parkinson’s disease: a follow up study. J Neurol Neurosurg Psychiatry 53:597–602PubMedCrossRefGoogle Scholar
  124. 124.
    Sudarsky L, Morris J, Romero J, Walshe TM (1989) Dementia in Parkinson’s disease: the problem of clinicopathological correlation. J Neuropsychiatry Clin Neurosci 1:159–166PubMedGoogle Scholar
  125. 125.
    Suenaga T, Hirano A, Llena JF, Yen SH, Dickson DW (1990) Modified Bielschowsky stain and immunohistochemical studies on striatal plaques in Alzheimer’s disease. Acta Neuropathol 80:280–286PubMedCrossRefGoogle Scholar
  126. 126.
    Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–944PubMedCrossRefGoogle Scholar
  127. 127.
    Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 152:367–372PubMedGoogle Scholar
  128. 128.
    Terry RD (1996) The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J Neuropathol Exp Neurol 55:1023–1025PubMedGoogle Scholar
  129. 129.
    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 58:1791–1800PubMedGoogle Scholar
  130. 130.
    Tooyama I, Kawamata T, Walker D, Yamada T, Hanai K, Kimura H, Iwane M, Igarashi K, McGeer EG, McGeer PL (1993) Loss of basic fibroblast growth factor in substantia nigra neurons in Parkinson’s disease. Neurology 43:372–376PubMedGoogle Scholar
  131. 131.
    Tsuboi Y, Uchikado H, Dickson DW (2007) Neuropathology of Parkinson’s disease dementia and dementia with Lewy bodies with reference to striatal pathology. Parkinsonism Relat Disord 13(Suppl 3):S221–S224PubMedCrossRefGoogle Scholar
  132. 132.
    Vickers JC, Dickson TC, Adlard PA, Saunders HL, King CE, McCormack G (2000) The cause of neuronal degeneration in Alzheimer’s disease. Prog Neurobiol 60:139–165PubMedCrossRefGoogle Scholar
  133. 133.
    Wakabayashi K, Honer WG, Masliah E (1994) Synapse alterations in the hippocampal-entorhinal formation in Alzheimer’s disease with and without Lewy body disease. Brain Res 667:24–32PubMedCrossRefGoogle Scholar
  134. 134.
    Williams-Gray CH, Goris A, Saiki M, Foltynie T, Compston DA, Sawcer SJ, Barker RA (2009) Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson’s disease. J Neurol 256:493–498PubMedCrossRefGoogle Scholar
  135. 135.
    Yoshimura M (1988) Pathological basis for dementia in elderly patients with idiopathic Parkinson’s disease. Eur Neurol 28(Suppl 1):29–35PubMedGoogle Scholar
  136. 136.
    Zhan SS, Beyreuther K, Schmitt HP (1993) Quantitative assessment of the synaptophysin immuno-reactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 4:66–74PubMedGoogle Scholar
  137. 137.
    Zweig RM, Cardillo JE, Cohen M, Giere S, Hedreen JC (1993) The locus coeruleus and dementia in Parkinson’s disease. Neurology 43:986–991PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Michail E. Kalaitzakis
    • 1
  • Ronald K. B. Pearce
    • 1
  1. 1.Neuropathology Unit, Division of Neuroscience and Mental Health, Department of Clinical NeuroscienceImperial College Healthcare NHS TrustLondonUK

Personalised recommendations