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Tau and α-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs

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Abstract

Extrapyramidal symptoms (EPS) in Alzheimer disease (AD) often increase with disease severity. Their neuropathological substrate is a matter of discussion. We investigated tau and α-synuclein (AS) pathologies in brainstem in AD patients with and without EPS. Among 160 elderly subjects with autopsy-proven AD (110 female, 50 male, aged 61–102, mean 84.1 ± 8.3 SD years), 151 (94.4%) being demented, 35 (21.9%) had clinically reported EPS (rigidity, bradykinesia, gait impairment). Neuropathological examination included standardized classification of AD according to current criteria, and semiquantitative assessment of neuronal loss in substantia nigra (SN), locus coeruleus (LC), and of tau and AS lesions in brainstem, and, in addition, of cerebrovascular lesions. The prevalence of EPS was only slightly more frequent in higher Braak stages. Tau pathology in brainstem significantly increased with increasing Braak stages, while AS lesions did not. EPS correlated best with SN cell loss (P < 0.001) and much less with AS pathology in several brain areas (P < 0.05), except in medulla oblongata (P < 0.001). Although both pathologies in substantia nigra correlated with neuron loss (P < 0.001), nigral tau lesions, present in 88.5% of EPS positive cases (without AS lesions in 55.6%), did not correlate with EPS. Additional cerebrovascular changes apparently did not influence the development of EPS symptoms in fully developed AD. With other recent data, these results suggest that neuronal loss in SN, partly related to tau lesions, is a major pathological substrate of EPS in AD, but some cases with and without EPS may show no or only minimal nigral changes. However, often associated with nigral tau lesions and higher Braak stages, EPS in elderly patients may be a surrogate marker for severe neuritic AD pathology.

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References

  1. Ala TA, Yang KH, Sung JH, Frey WH (1999) Clinical Parkinsonism in dementia patients with substantia nigra Lewy bodies. J Neural Transm 106:47–57

    Article  PubMed  CAS  Google Scholar 

  2. Ala TA, Yang KH, Sung JH, Frey WH (2000) Inconsistency between severe substantia nigra degeneration with Lewy bodies and clinical Parkinsonism in dementia patients: a cliniconeuropathological study. Acta Neuropathol (Berl) 99:511–516

    Article  CAS  Google Scholar 

  3. Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, Evans DA (1996) Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 334:71–76

    Article  PubMed  CAS  Google Scholar 

  4. Bennett DA, Beckett LA, Wilson RS, Murray AM, Evans DA (1998) Parkinsonian signs and mortality from Alzheimer’s disease. Lancet 351:1631

    Article  PubMed  CAS  Google Scholar 

  5. 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 (Berl), PMID: 16906426

  6. 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 

  7. Braak H, Müller CM, Rüb U, Ackermann H, Bratzke H, de Vos RAI (2006) Pathology associated with sporadic Parkinson’s disease: where does it end? J Neural Transm [Suppl.] 70:89–97

    Article  Google Scholar 

  8. Burns JM, Galvin JE, Roe CM, Morris JC, McKeel DW (2005) The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 64:1397–1403

    PubMed  CAS  Google Scholar 

  9. Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K, Jellinger K, Lantos PL, Lippa CF, Mirra SS, Tabaton M, Vonsattel JP, Wakabayashi K, Litvan I (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946

    PubMed  CAS  Google Scholar 

  10. Dickson DW (2004) Sporadic tauopathies: Pick’s disease, corticobasal degeneration, progressive supranuclear palsy and argyrophilic grain disease. In: Esiri MM, Lee VM-Y, Trojanowski JQ (eds) The neuropathology for dementia, 2nd edn. Cambridge University Press, Cambridge, pp 227–256

    Google Scholar 

  11. Ding ZT, Wang Y, Jiang YP, Hashizume Y, Yoshida M, Mimuro M, Inagaki T, Iwase T (2006) Characteristics of alpha-synucleinopathy in centenarians. Acta Neuropathol (Berl) 111:450–458

    Article  Google Scholar 

  12. Ditter SM, Mirra SS (1987) Neuropathologic and clinical features of Parkinson’s disease in Alzheimer’s disease patients. Neurology 37:754–760

    PubMed  CAS  Google Scholar 

  13. Ellis RJ, Caligiuri M, Galasko D, Thal LJ (1996) Extrapyramidal motor signs in clinically diagnosed Alzheimer disease. Alzheimer Dis Assoc Disord 10:103–114

    Article  PubMed  CAS  Google Scholar 

  14. Galpern WR, Lang AE (2006) Interface between tauopathies and synucleinopathies: a tale of two proteins. Ann Neurol 59:449–458

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378–384

    Article  PubMed  CAS  Google Scholar 

  17. Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, Thal L, Pay MM, Hofstetter R, Klauber M (1990) The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40:1–8

    PubMed  CAS  Google Scholar 

  18. Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097

    PubMed  CAS  Google Scholar 

  19. Iseki E, Togo T, Suzuki K, Katsuse O, Marui W, de Silva R, Lees A, Yamamoto T, Kosaka K (2003) Dementia with Lewy bodies from the perspective of tauopathy. Acta Neuropathol (Berl) 105:265–270

    CAS  Google Scholar 

  20. Jellinger KA, Bancher C (1998) Senile dementia with tangles (tangle predominant form of senile dementia). Brain Pathol 8:367–376

    Article  PubMed  CAS  Google Scholar 

  21. Jellinger KA (2003) Prevalence of cerebrovascular lesions in Parkinson’s disease. A postmortem study. Acta Neuropathol (Berl) 105:415–419

    Google Scholar 

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

    Google Scholar 

  23. Jellinger KA, Mitter-Ferstl E (2003) The impact of cerebrovascular lesions in Alzheimer disease: a comparative autopsy study. J Neurol 250:1050–1055

    Article  PubMed  Google Scholar 

  24. Jellinger KA (2004) Lewy body-related alpha-synucleinopathy in the aged human brain. J Neural Transm 111:1219–1235

    Article  PubMed  CAS  Google Scholar 

  25. Jellinger KA (2004) Pathology and pathophysiology of vascular cognitive impairment. A critical update. Panminerva Med 46:217–226

    PubMed  CAS  Google Scholar 

  26. Jellinger KA (2005) Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore longitudinal study of aging (BLSA). J Neuropathol Exp Neurol 64:554

    PubMed  Google Scholar 

  27. Jellinger KA (2005) Neuropathology and tau. In: Hanin I, Cacabelos R, Fisher A (eds) Recent progress in Alzheimer’s and Parkinson’s diseases. Taylor & Francis Group, New York, pp 317–327

    Google Scholar 

  28. Jellinger KA (2005) Understanding the pathology of vascular cognitive impairment. J Neurol Sci 229–230:57–63

    Article  PubMed  Google Scholar 

  29. 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 

  30. Jellinger KA, Attems J (2006) Prevalence and impact of cerebrovascular pathology in Alzheimer’s disease and parkinsonism. Acta Neurol Scand 114:38–46

    Article  PubMed  CAS  Google Scholar 

  31. Kazee AM, Cox C, Richfield EK (1995) Substantia nigra lesions in Alzheimer disease and normal aging. Alzheimer Dis Assoc Disord 9:61–67

    Article  PubMed  CAS  Google Scholar 

  32. Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ, Smith GE, Dickson DW, Johnson KA, Petersen LE, McDonald WC, Braak H, Petersen RC (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095

    PubMed  CAS  Google Scholar 

  33. Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ, Lee VM (2004) Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Exp Neurol 187:279–288

    Article  PubMed  CAS  Google Scholar 

  34. Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    Article  PubMed  CAS  Google Scholar 

  35. Lee VM, Giasson BI, Trojanowski JQ (2004) More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends Neurosci 27:129–134

    Article  PubMed  CAS  Google Scholar 

  36. Li W, Lesuisse C, Xu Y, Troncoso JC, Price DL, Lee MK (2004) Stabilization of alpha-synuclein protein with aging and familial Parkinson’s disease-linked A53T mutation. J Neurosci 24:7400–7409

    Article  PubMed  CAS  Google Scholar 

  37. Liu Y, Stern Y, Chun MR, Jacobs DM, Yau P, Goldman JE (1997) Pathological correlates of extrapyramidal signs in Alzheimer’s disease. Ann Neurol 41:368–374

    Article  PubMed  CAS  Google Scholar 

  38. Louis ED, Tang MX, Mayeux R (2004) Parkinsonian signs in older people in a community-based study: risk of incident dementia. Arch Neurol 61:1273–1276

    Article  PubMed  Google Scholar 

  39. McGeer PL, McGeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34:33–35

    PubMed  CAS  Google Scholar 

  40. 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

    PubMed  CAS  Google Scholar 

  41. 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  PubMed  CAS  Google Scholar 

  42. Mikolaenko I, Pletnikova O, Kawas CH, O’Brien R, Resnick SM, Crain B, Troncoso JC (2005) Alpha-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

    PubMed  CAS  Google Scholar 

  43. 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

    PubMed  CAS  Google Scholar 

  44. Morris JC, Drazner M, Fulling K, Grant EA, Goldring J (1989) Clinical and pathological aspects of Parkinsonism in Alzheimer’s disease. A role for extranigral factors? Arch Neurol 46:651–657

    PubMed  CAS  Google Scholar 

  45. Nichols ME, Meador KJ, Loring DW, Poon LW, Clayton GM, Martin P (1994) Age-related changes in the neurologic examination of healthy sexagenarians, octogenarians, and centenarians. J Geriatr Psychiatry Neurol 7:1–7

    PubMed  CAS  Google Scholar 

  46. Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91

    Article  PubMed  CAS  Google Scholar 

  47. Popescu A, Lippa CF, Lee VM, Trojanowski JQ (2004) Lewy bodies in the amygdala: increase of alpha-synuclein aggregates in neurodegenerative diseases with tau-based inclusions. Arch Neurol 61:1915–1919

    Article  PubMed  Google Scholar 

  48. Reyes MG, Faraldi F, Rydman R, Wang CC (2003) Decreased nigral neuromelanin in Alzheimer’s disease. Neurol Res 25:179–182

    Article  PubMed  Google Scholar 

  49. Richards M, Stern Y, Mayeux R (1993) Subtle extrapyramidal signs can predict the development of dementia in elderly individuals. Neurology 43:2184–2188

    PubMed  CAS  Google Scholar 

  50. Rinne JO, Rummukainen J, Paljarvi L, Sako E, Molsa P, Rinne UK (1989) Neuronal loss in the substantia nigra in patients with Alzheimer’s disease and Parkinson’s disease in relation to extrapyramidal symptoms and dementia. Prog Clin Biol Res 317:325–332

    PubMed  CAS  Google Scholar 

  51. Ross GW, Petrovitch H, Abbott RD, Nelson J, Markesbery W, Davis D, Hardman J, Launer L, Masaki K, Tanner CM, White LR (2004) Parkinsonian signs and substantia nigra neuron density in decendents elders without PD. Ann Neurol 56:532–539

    Article  PubMed  Google Scholar 

  52. Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654

    PubMed  CAS  Google Scholar 

  53. Saito Y, Ruberu NN, Sawabe M, Arai T, Kazama H, Hosoi T, Yamanouchi H, Murayama S (2004) Lewy body-related alpha-synucleinopathy in aging. J Neuropathol Exp Neurol 63:742–749

    PubMed  Google Scholar 

  54. Scarmeas N, Hadjigeorgiou GM, Papadimitriou A, Dubois B, Sarazin M, Brandt J, Albert M, Marder K, Bell K, Honig LS, Wegesin D, Stern Y (2004) Motor signs during the course of Alzheimer disease. Neurology 63:975–982

    PubMed  CAS  Google Scholar 

  55. Schneider JA, Bienias JL, Gilley DW, Kvarnberg DE, Mufson EJ, Bennett DA (2002) Improved detection of substantia nigra pathology in Alzheimer’s disease. J Histochem Cytochem 50:99–106

    PubMed  CAS  Google Scholar 

  56. Schneider JA, Li JL, Li Y, Wilson RS, Kordower JH, Bennett DA (2006) Substantia nigra tangles are related to gait impairment in older persons. Ann Neurol 59:166–173

    Article  PubMed  Google Scholar 

  57. Tiraboschi P, Yaari R, Hansen LA, Ho G, Thal LJ, Salmon D, Corey-Bloom J (2006) Neurofibrillary tangle-predominant dementia (abstr.). Neurology 66, Suppl. 2:A379

  58. Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ, Buschke H (2002) Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med 347:1761–1768

    Article  PubMed  Google Scholar 

  59. Wakisaka Y, Furuta A, Tanizaki Y, Kiyohara Y, Iida M, Iwaki T (2003) Age-associated prevalence and risk factors of Lewy body pathology in a general population: the Hisayama study. Acta Neuropathol (Berl) 106:374–382

    Article  Google Scholar 

  60. Wenning GK, Jellinger KA (2005) The role of alpha-synuclein and tau in neurodegenerative movement disorders. Curr Opin Neurol 18:357–362

    Article  PubMed  CAS  Google Scholar 

  61. Wilson RS, Bennett DA, Gilley DW, Beckett LA, Schneider JA, Evans DA (2000) Progression of parkinsonism and loss of cognitive function in Alzheimer disease. Arch Neurol 57:855–860

    Article  PubMed  CAS  Google Scholar 

  62. Wilson RS, Schneider JA, Beckett LA, Evans DA, Bennett DA (2002) Progression of gait disorder and rigidity and risk of death in older persons. Neurology 58:1815–1819

    PubMed  CAS  Google Scholar 

  63. Wilson RS, Schneider JA, Bienias JL, Evans DA, Bennett DA (2003) Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol 60:539–544

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Society for Support of Experimental Neurology, Vienna, Austria. The authors thank the clinical colleagues of OWS hospital, Vienna, for clinical data, Mrs. V. Rappelsberger for excellent laboratory work, and Mr. E. Mitter-Ferstl, PhD, for secretarial and computer work.

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  1. Institute of Pathology, Otto Wagner Hospital, Vienna, Austria

    Johannes Attems & Magdalena Quass

  2. Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria

    Kurt A. Jellinger

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  1. Johannes Attems
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Correspondence to Kurt A. Jellinger.

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Attems, J., Quass, M. & Jellinger, K.A. Tau and α-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs. Acta Neuropathol 113, 53–62 (2007). https://doi.org/10.1007/s00401-006-0146-9

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