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Neuropathologically mixed Alzheimer’s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes

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Abstract

Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer’s disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.

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References

  1. Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H, Bugiani O, Del-Tredici K, Ferrer I, Gelpi E, Giaccone G, Graeber MB, Ince P, Kamphorst W, King A, Korkolopoulou P, Kovacs GG, Larionov S, Meyronet D, Monoranu C, Parchi P, Patsouris E, Roggendorf W, Seilhean D, Tagliavini F, Stadelmann C, Streichenberger N, Thal DR, Wharton SB, Kretzschmar H (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496

    PubMed Central  PubMed  Google Scholar 

  2. Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I, Bogdanovic N, Bugiani O, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovacs GG, Meyronet D, Monoranu C, Parchi P, Parkkinen L, Patsouris E, Roggendorf W, Rozemuller A, Stadelmann-Nessler C, Streichenberger N, Thal DR, Kretzschmar H (2009) Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:635–652

    Article  CAS  PubMed  Google Scholar 

  3. Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I, Boluda S, Bugiani O, Duyckaerts C, Gelpi E, Gentleman S, Giaccone G, Graeber M, Hortobagyi T, Hoftberger R, Ince P, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovacs GG, Meyronet D, Monoranu C, Nilsson T, Parchi P, Patsouris E, Pikkarainen M, Revesz T, Rozemuller A, Seilhean D, Schulz-Schaeffer W, Streichenberger N, Wharton SB, Kretzschmar H (2009) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:309–320

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Armstrong RA, Lantos PL, Cairns NJ (2005) Overlap between neurodegenerative disorders. Neuropathology 25:111–124

    Article  PubMed  Google Scholar 

  5. Attems J, Thal DR, Jellinger KA (2012) The relationship between subcortical tau pathology and Alzheimer’s disease. Biochem Soc Trans 40:711–715

    Article  CAS  PubMed  Google Scholar 

  6. Attems J, Thomas A, Jellinger K (2012) Correlations between cortical and subcortical tau pathology. Neuropathol Appl Neurobiol 38:582–590

    Article  CAS  PubMed  Google Scholar 

  7. Attems J, Jellinger K (2013) Neuropathological correlates of cerebral multimorbidity. Curr Alzheimer Res 10:569–577

    Article  CAS  PubMed  Google Scholar 

  8. Attems J, Neltner JH, Nelson PT (2014) Quantitative neuropathological assessment to investigate cerebral multi-morbidity. Alzheimers Res Ther 6:85

    Article  PubMed Central  PubMed  Google Scholar 

  9. Berge G, Sando SB, Rongve A, Aarsland D, White LR (2014) Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry 85:1227–1231

    Article  PubMed Central  PubMed  Google Scholar 

  10. Blacker D, Tanzi RE (1998) The genetics of Alzheimer disease: current status and future prospects. Arch Neurol 55:294–296

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  PubMed  Google Scholar 

  12. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404

    Article  PubMed Central  PubMed  Google Scholar 

  13. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181

    Article  PubMed  Google Scholar 

  14. Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969

    Article  CAS  PubMed  Google Scholar 

  15. Brodaty H, Seeher K, Gibson L (2012) Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr 24:1034–1045

    Article  PubMed  Google Scholar 

  16. Brookmeyer R, Corrada MM, Curriero FC, Kawas C (2002) Survival following a diagnosis of Alzheimer disease. Arch Neurol 59:1764–1767

    Article  PubMed  Google Scholar 

  17. Calderon J, Perry RJ, Erzinclioglu SW, Berrios GE, Dening TR, Hodges JR (2001) Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70:157–164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Calero O, Hortiguela R, Bullido MJ, Calero M (2009) Apolipoprotein E genotyping method by real time PCR, a fast and cost-effective alternative to the TaqMan and FRET assays. J Neurosci Methods 183:238–240

    Article  CAS  PubMed  Google Scholar 

  19. Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281–7289

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Collette F, Van der Linden M, Salmon E (1999) Executive dysfunction in Alzheimer’s disease. Cortex 35:57–72

    Article  CAS  PubMed  Google Scholar 

  21. Colom-Cadena M, Gelpi E, Charif S, Belbin O, Blesa R, Marti MJ, Clarimon J, Lleo A (2013) Confluence of alpha-synuclein, tau, and beta-amyloid pathologies in dementia with Lewy bodies. J Neuropathol Exp Neurol 72:1203–1212

    Article  CAS  PubMed  Google Scholar 

  22. Cummings JL, Benson F, Hill MA, Read S (1985) Aphasia in dementia of the Alzheimer type. Neurology 35:394–397

    Article  CAS  PubMed  Google Scholar 

  23. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    Article  PubMed  Google Scholar 

  24. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36

    Article  CAS  PubMed  Google Scholar 

  25. 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 79:1331–1338

    Article  CAS  PubMed  Google Scholar 

  26. 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)

  27. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis, APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278:1349–1356

    Article  CAS  PubMed  Google Scholar 

  28. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  CAS  PubMed  Google Scholar 

  29. Fujishiro H, Ahn TB, Frigerio R, Delle Donne A, Josephs KA, Parisi JE, Eric Ahlskog J, Dickson DW (2008) Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy? Acta Neuropathol 116:269–275

    Article  PubMed Central  PubMed  Google Scholar 

  30. Ganguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST (2005) Alzheimer disease and mortality: a 15-year epidemiological study. Arch Neurol 62:779–784

    Article  PubMed  Google Scholar 

  31. Garcia-Ptacek S, Farahmand B, Kareholt I, Religa D, Cuadrado ML, Eriksdotter M (2014) Mortality risk after dementia diagnosis by dementia type and underlying factors: a cohort of 15,209 patients based on the Swedish Dementia Registry. J Alzheimers Dis 41:467–477

    PubMed  Google Scholar 

  32. Gentleman SM, Allsop D, Bruton CJ, Jagoe R, Polak JM, Roberts GW (1992) Quantitative differences in the deposition of beta A4 protein in the sulci and gyri of frontal and temporal isocortex in Alzheimer’s disease. Neurosci Lett 136:27–30

    Article  CAS  PubMed  Google Scholar 

  33. Gill DP, Hubbard RA, Koepsell TD, Borrie MJ, Petrella RJ, Knopman DS, Kukull WA (2013) Differences in rate of functional decline across three dementia types. Alzheimers Dement 9:S63–71

    Article  PubMed Central  PubMed  Google Scholar 

  34. Halliday GM, Song YJ, Harding AJ (2011) Striatal beta-amyloid in dementia with Lewy bodies but not Parkinson’s disease. J Neural Transm 118:713–719

    Article  CAS  PubMed  Google Scholar 

  35. Howlett DR, Whitfield D, Johnson M, Attems J, O’Brien JT, Aarsland D, Lai MK, Lee JH, Chen C, Ballard C, Hortobagyi T, Francis PT (2014) Regional Multiple Pathology Scores are associated with cognitive decline in Lewy body dementias. Brain Pathol (Epub ahead of print)

  36. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13

    Article  PubMed Central  PubMed  Google Scholar 

  37. Ince PG (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 357:169–175

    Article  Google Scholar 

  38. 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

    CAS  PubMed  Google Scholar 

  39. Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:257–262

    Article  PubMed Central  PubMed  Google Scholar 

  40. Jellinger KA, Attems J (2003) Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathol 105:14–17

    PubMed  Google Scholar 

  41. Jellinger KA, Attems J (2006) Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathol 112:253–260

    Article  PubMed  Google Scholar 

  42. Jellinger KA (2007) The enigma of mixed dementia. Alzheimers Dement 3:40–53

    Article  PubMed  Google Scholar 

  43. Jellinger KA (2007) The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol 113:349–388

    Article  PubMed  Google Scholar 

  44. Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci 257:80–87

    Article  CAS  PubMed  Google Scholar 

  45. Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433

    Article  PubMed  Google Scholar 

  46. Jellinger KA, Attems J (2014) Challenges of multimorbidity of the aging brain: a critical update. J Neural Transm (Epub ahead of print)

  47. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF, Ivnik RJ, Smith GE, Jack CR Jr, Parisi JE, Petersen RC, Dickson DW (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127:811–824

    Article  CAS  PubMed  Google Scholar 

  48. Jung Y, Dickson DW, Murray ME, Whitwell JL, Knopman DS, Boeve BF, Jack CR Jr, Parisi JE, Petersen RC, Josephs KA (2014) TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism. J Neurol 261:1344–1348

    Article  CAS  PubMed  Google Scholar 

  49. Kovacs GG, Alafuzoff I, Al-Sarraj S, Arzberger T, Bogdanovic N, Capellari S, Ferrer I, Gelpi E, Kovari V, Kretzschmar H, Nagy Z, Parchi P, Seilhean D, Soininen H, Troakes C, Budka H (2008) Mixed brain pathologies in dementia: the BrainNet Europe Consortium Experience. Dement Geriatr Cogn Disord 26:343–350

    Article  PubMed  Google Scholar 

  50. Kovacs GG, Milenkovic I, Wohrer A, Hoftberger R, Gelpi E, Haberler C, Honigschnabl S, Reiner-Concin A, Heinzl H, Jungwirth S, Krampla W, Fischer P, Budka H (2013) Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol 126:365–384

    Article  CAS  PubMed  Google Scholar 

  51. Kraybill ML, Larson EB, Tsuang DW, Teri L, McCormick WC, Bowen JD, Kukull WA, Leverenz JB, Cherrier MM (2005) Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64:2069–2073

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Leverenz JB, Hamilton R, Tsuang DW, Schantz A, Vavrek D, Larson EB, Kukull WA, Lopez O, Galasko D, Masliah E, Kaye J, Woltjer R, Clark C, Trojanowski JQ, Montine TJ (2008) Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient. Brain Pathol 18:220–224

    Article  PubMed Central  PubMed  Google Scholar 

  53. Lewy FH (1912) Paralysis Agitans Pathologische Anatomie. In: Lewandowski M (ed) Handbuch der Neurologie. Springer, Berlin, pp 920–933

    Google Scholar 

  54. Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK (2007) DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68:812–819

    Article  CAS  PubMed  Google Scholar 

  55. Mandler M, Walker L, Santic R, Hanson P, Upadhaya AR, Colloby SJ, Morris CM, Thal DR, Thomas AJ, Schneeberger A, Attems J (2014) Pyroglutamylated amyloid-beta is associated with hyperphosphorylated tau and severity of Alzheimer’s disease. Acta Neuropathol 128:67–79

    Article  CAS  PubMed  Google Scholar 

  56. Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH (1998) Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease: Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 338:506–511

    Article  CAS  PubMed  Google Scholar 

  57. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124

    Article  CAS  PubMed  Google Scholar 

  58. 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 65:1863–1872

    Article  CAS  PubMed  Google Scholar 

  59. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944

    Article  CAS  PubMed  Google Scholar 

  60. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269

    Article  PubMed Central  PubMed  Google Scholar 

  61. Meyer MR, Tschanz JT, Norton MC, Welsh-Bohmer KA, Steffens DC, Wyse BW, Breitner JC (1998) APOE genotype predicts when–not whether–one is predisposed to develop Alzheimer disease. Nat Genet 19:321–322

    Article  CAS  PubMed  Google Scholar 

  62. 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

    Article  CAS  PubMed  Google Scholar 

  63. Montine T, Phelps C, Beach T, Bigio E, Cairns N, Dickson D, Duyckaerts C, Frosch M, Masliah E, Mirra S, Nelson P, Schneider J, Thal D, Trojanowski J, Vinters H, Hyman B (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease a practical approach. Acta Neuropathologica pp 1-11

  64. Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R, Thal LJ (1995) Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol 52:702–708

    Article  CAS  PubMed  Google Scholar 

  65. Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R, Thal LJ (1998) Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51:351–357

    Article  CAS  PubMed  Google Scholar 

  66. Pollanen MS, Dickson DW, Bergeron C (1993) Pathology and biology of the Lewy body. J Neuropathol Exp Neurol 52:183–191

    Article  CAS  PubMed  Google Scholar 

  67. Rahimi J, Kovacs GG (2014) Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther 6:82

    Article  PubMed Central  PubMed  Google Scholar 

  68. Savica R, Grossardt BR, Bower JH, Boeve BF, Ahlskog JE, Rocca WA (2013) Incidence of dementia with Lewy bodies and Parkinson disease dementia. JAMA Neurol 70:1396–1402

    Article  PubMed Central  PubMed  Google Scholar 

  69. Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204

    Article  PubMed  Google Scholar 

  70. Schneider JA, Bennett DA (2010) Where vascular meets neurodegenerative disease. Stroke 41:S144–146

    Article  PubMed Central  PubMed  Google Scholar 

  71. Serby M, Brickman AM, Haroutunian V, Purohit DP, Marin D, Lantz M, Mohs RC, Davis KL (2003) Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease. Am J Geriatr Psychiatry 11:371–374

    Article  PubMed  Google Scholar 

  72. Singleton AB, Wharton A, O’Brien KK, Walker MP, McKeith IG, Ballard CG, O’Brien J, Perry RH, Ince PG, Edwardson JA, Morris CM (2002) Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with Lewy bodies. Dement Geriatr Cogn Disord 14:167–175

    Article  CAS  PubMed  Google Scholar 

  73. Sonnen JA, Postupna N, Larson EB, Crane PK, Rose SE, Montine KS, Leverenz JB, Montine TJ (2010) Pathologic correlates of dementia in individuals with Lewy body disease. Brain Pathol 20:654–659

    Article  PubMed Central  PubMed  Google Scholar 

  74. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Stubendorff K, Hansson O, Minthon L, Londos E (2011) Differences in survival between patients with dementia with Lewy bodies and patients with Alzheimer’s disease: measured from a fixed cognitive level. Dement Geriatr Cogn Disord 32:408–416

    Article  PubMed  Google Scholar 

  76. Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293

    PubMed  Google Scholar 

  77. 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 58:1791–1800

    Article  PubMed  Google Scholar 

  78. Tiraboschi P, Salmon DP, Hansen LA, Hofstetter RC, Thal LJ, Corey-Bloom J (2006) What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain 129:729–735

    Article  PubMed  Google Scholar 

  79. Tsuang DW, Wilson RK, Lopez OL, Luedecking-Zimmer EK, Leverenz JB, DeKosky ST, Kamboh MI, Hamilton RL (2005) Genetic association between the APOE*4 allele and Lewy bodies in Alzheimer disease. Neurology 64:509–513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697

    Article  CAS  PubMed  Google Scholar 

  81. Whitfield DR, Vallortigara J, Alghamdi A, Howlett D, Hortobagyi T, Johnson M, Attems J, Newhouse S, Ballard C, Thomas AJ, O’Brien JT, Aarsland D, Francis PT (2014) Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer’s disease: association with cognitive impairment. Neurobiol Aging 35:2836–2844

    Article  CAS  PubMed  Google Scholar 

  82. Williams MM, Xiong C, Morris JC, Galvin JE (2006) Survival and mortality differences between dementia with Lewy bodies vs Alzheimer disease. Neurology 67:1935–1941

    Article  PubMed  Google Scholar 

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Acknowledgments

We are very grateful to the individuals who kindly donated their brains to the Newcastle Brain Tissue Resource. We thank Mrs Lynne Ramsay, Mrs Ros Hall and Mrs Claire Kolenda for excellent technical assistance. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age-related disease and the Biomedical Research Unit for Lewy body dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (R:CH/ML/0712), the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Neuroscience and Institute for Ageing, Newcastle University, Campus for Ageing and Vitality, NE4 5PL, Newcastle upon Tyne, UK

    Lauren Walker, Kirsty E. McAleese, Alan J. Thomas, Mary Johnson, Carmen Martin-Ruiz, Craig Parker, Sean J. Colloby & Johannes Attems

  2. Institute of Clinical Neurobiology, Vienna, Austria

    Kurt Jellinger

Authors
  1. Lauren Walker
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  2. Kirsty E. McAleese
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  3. Alan J. Thomas
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  4. Mary Johnson
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  5. Carmen Martin-Ruiz
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  6. Craig Parker
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  7. Sean J. Colloby
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  8. Kurt Jellinger
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  9. Johannes Attems
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Corresponding author

Correspondence to Johannes Attems.

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Walker, L., McAleese, K.E., Thomas, A.J. et al. Neuropathologically mixed Alzheimer’s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol 129, 729–748 (2015). https://doi.org/10.1007/s00401-015-1406-3

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  • DOI: https://doi.org/10.1007/s00401-015-1406-3

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