Abstract
Amyloid-β (Aβ) peptide pathology in Alzheimer’s disease (AD) comprises extracellular plaques and cerebral amyloid angiopathy (CAA). In Parkinson’s disease (PD), α-synuclein forms intraneuronal Lewy bodies (LBs), and cortical LBs are thought to play a major role in cognitive decline designated as PD with dementia. As there is increasing evidence that Aβ may also promote α-synuclein fibrillization, we assessed the relationship between LB pathology and Aβ deposition in 40 cases of PD and 20 age-matched controls. In five cortical areas, we established the severity of Aβ plaque load using an approach similar to that recommended by CERAD in AD. LB densities were determined using a morphometric approach. CAA was graded using previously described scales. The APOE genotype was established in 38 PD and 19 control cases. We have found that the overall Aβ plaque burden and, in particular, the diffuse plaque load shows a statistically significant ‘large’ correlation with the overall cortical LB burden. The strength of this correlation further increases in PD cases (about 50% of the cases) with moderate to high Aβ plaque load. The APOE ε4 allele is over-represented in this subgroup. Our data indicate a strong association between pathologically identifiable Aβ plaque burden and α-synuclein load in cerebral cortex and provide indirect evidence that Aβ pathology is likely to be an important factor contributing to cognitive decline in a subgroup of PD patients.
Similar content being viewed by others
References
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 17:137–145
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421
Beyer K, Lao JI, Carrato C, Mate JL, Lopez D, Ferrer I, Ariza A (2004) Upregulation of amyloid precursor protein isoforms containing Kunitz protease inhibitor in dementia with Lewy bodies. Brain Res Mol Brain Res 131:131–135
Bland JM, Altman DG (1986) Statistical-methods for assessing agreement between 2 methods of clinical measurement. Lancet 1:307–310
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del TK (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol (Berl) 112:389–404
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 24:197–211
Burn DJ (2004) Cortical Lewy body disease. J Neurol Neurosurg Psychiatry 75:175–178
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 74:852–856
Deramecourt V, Bombois S, Maurage CA, Ghestem A, Drobecq H, Vanmechelen E, Lebert F, Pasquier F, Delacourte A (2006) Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies. J Neuropathol Exp Neurol 65:278–288
Dickson DW (1997) The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56: 321–339
Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM, Trojanowski JQ (2002) Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol (Berl) 104:7–11
Frasier M, Walzer M, McCarthy L, Magnuson D, Lee JM, Haas C, Kahle P, Wolozin B (2005) Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol 192:274–287
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 300:636–640
Harding AJ, Broe GA, Halliday GM (2002) Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 125:391–403
Harding AJ, Halliday GM (2001) Cortical Lewy body pathology in the diagnosis of dementia. Acta Neuropathol (Berl) 102:355–363
Holton JL, Lashley T, Ghiso J, Braendgaard H, Vidal R, Guerin CJ, Gibb G, Hanger DP, Rostagno A, Anderton BH, Strand C, Ayling H, Plant G, Frangione B, Bojsen-Moller M, Revesz T (2002) Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. J Neuropathol Exp Neurol 61:254–267
Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, Wood NW, Kumar-Singh S, Geddes J, Swash M, Scaravilli F, Holton JL, Lashley T, Tomita T, Hashimoto T, Verkkoniemi A, Kalimo H, Somer M, Paetau A, Martin JJ, Van Broeckhoven C, Golde T, Hardy J, Haltia M, Revesz T (2000) Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 48:806–808
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 54:1916–1921
Ince PG, Clark B, Holton JL, Revesz T, Whatley W. Disorders of movement and system degenerations. In: Ellison DW, Louis DN, Love S (eds) Greenfield’s neuropathology. Arnold, London (in press)
Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397
Jellinger KA, Attems J (2006) Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathol 112:253–260
Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T, McGowan E (2007) Abeta40 inhibits amyloid deposition in vivo. J Neurosci 27:627–633
Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291
Lee VM, Trojanowski JQ (2006) Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 52:33–38
Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D Jr, Price DL (2007) The etiopathogenesis of Parkinson disease and suggestions for future research. Part I. J Neuropathol Exp Neurol 66:251–257
Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R (2006) Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer’s and Parkinson’s in dementia with Lewy body disease. Neurochem Res 31:1153–1162
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 98:12245–12250
Mastaglia FL, Johnsen RD, Byrnes ML, Kakulas BA (2003) Prevalence of amyloid-beta deposition in the cerebral cortex in Parkinson’s disease. Mov Disord 18:81–86
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 (Berl) 100:285–290
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 ST, 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 65:1863–1872
Mirra SS, Heyman A, Mckeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486
Olichney J, Hansen L, Galasko D, Saitoh T, Hofstetter C, Katzman R, Thal L (1996) The apolipoprotein E e4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer’s disease and Lewy body variant. Neurology 47:190–196
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 26:1183–1192
Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL (2003) Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol 62:885–898
Rosand J, Muzikansky A, Kumar A, Wisco JJ, Smith EE, Betensky RA, Greenberg SM (2005) Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol 58:459–462
Rostagno A, Revesz T, Lashley T, Tomidokoro Y, Magnotti L, Braendgaard H, Plant G, Bojsen-Moller M, Holton J, Frangione B, Ghiso J (2002) Complement activation in chromosome 13 dementias. Similarities with Alzheimer’s disease. J Biol Chem 277:49782–49790
Selkoe DJ (1996) Amyloid beta-protein and the genetics of Alzheimer’s disease. J Biol Chem 271:18295–18298
Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766
Sigurdsson EM, Wisniewski T, Frangione B (2002) Infectivity of amyloid diseases. Trends Mol Med 8:411–413
Snyder SW, Ladror US, Wade WS, Wang GT, Barrett LW, Matayoshi ED, Huffaker HJ, Krafft GA, Holzman TF (1994) Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths. Biophys J 67:1216–1228
Suzuki N, Iwatsubo T, Odaka A, Ishibashi Y, Kitada C, Ihara Y (1994) High tissue content of soluble beta 1–40 is linked to cerebral amyloid angiopathy. Am J Pathol 145:452–460
Trojanowski JQ, Revesz T (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615–620
Verga L, Frangione B, Tagliavini F, Giaccone G, Migheli A, Bugiani O (1989) Alzheimer patients and Down patients: cerebral preamyloid deposits differ ultrastructurally and histochemically from the amyloid of senile plaques. Neurosci Lett 105:294–299
Verkkoniemi A, Kalimo H, Paetau A, Somer M, Iwatsubo T, Hardy J, Haltia M (2001) Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. J Neuropathol Exp Neurol 60:483–492
Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924–928
Wenham P, Price W, Blundell G (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337:1158–1159
Wisniewski T, Golabek AA, Kida E, Wisniewski KE, Frangione B (1995) Conformational mimicry in Alzheimer’s disease. Role of apolipoproteins in amyloidogenesis. Am J Pathol 147:238–244
Zou K, Kim D, Kakio A, Byun K, Gong JS, Kim J, Kim M, Sawamura N, Nishimoto S, Matsuzaki K, Lee B, Yanagisawa K, Michikawa M (2003) Amyloid beta-protein (Abeta)1–40 protects neurons from damage induced by Abeta1–42 in culture and in rat brain. J Neurochem 87:609–619
Acknowledgments
The Queen Square Brain Bank, UCL Institute of Neurology is supported by the Reta Lila Weston Institute of Neurological Studies and the Progressive Supranuclear Palsy (Europe) Association. TL is supported by a grant from the Parkinson’s Disease Society, UK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lashley, T., Holton, J.L., Gray, E. 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). https://doi.org/10.1007/s00401-007-0336-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-007-0336-0