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Corticobasal degeneration: a pathologically distinct 4R tauopathy

Abstract

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5th to 7th decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.

Key Points

  • Corticobasal degeneration (CBD) is associated with neuronal and glial tau pathology (including astrocytic plaques) in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem

  • The most common clinical presentation of CBD is asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus, termed corticobasal syndrome

  • CBD pathology can be found in patients with Richardson syndrome (the most common clinical presentation of progressive supranuclear palsy), behavioral variant frontotemporal dementia and primary progressive aphasia

  • The underlying pathology in corticobasal syndrome can be Alzheimer disease, progressive supranuclear palsy, frontotemporal lobar degeneration or Pick disease; corticobasal syndrome is not, therefore, a specific phenotype of CBD

  • Given the remarkable clinical heterogeneity of CBD and poor accuracy of diagnosis in living patients, the findings of studies based on non-autopsy-confirmed cases should be interpreted with caution

  • Current efforts to improve the diagnostic accuracy of CBD include imaging and cerebrospinal fluid biomarkers, as well as genome-wide association studies

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Figure 1: The distinct histological lesions of CBD and PSP visualized with tau immunohistochemistry.
Figure 2: Patterns of gray matter loss in groups of patients with autopsy-confirmed CBD but different clinical syndromes.

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References

  1. Litvan, I. et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology 48, 119–125 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Togasaki, D. M. & Tanner, C. M. Epidemiologic aspects. Adv. Neurol. 82, 53–59 (2000).

    CAS  PubMed  Google Scholar 

  3. Winter, Y. et al. Incidence of Parkinson's disease and atypical parkinsonism: Russian population-based study. Mov. Disord. 25, 349–356 (2010).

    Article  PubMed  Google Scholar 

  4. Rebeiz, J. J., Kolodny, E. H. & Richardson, E. P. Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch. Neurol. 18, 20–33 (1968).

    Article  CAS  PubMed  Google Scholar 

  5. Gibb, W. R., Luthert, P. J. & Marsden, C. D. Corticobasal degeneration. Brain 112, 1171–1192 (1989).

    Article  PubMed  Google Scholar 

  6. Bergeron, C., Davis, A. & Lang, A. E. Corticobasal ganglionic degeneration and progressive supranuclear palsy presenting with cognitive decline. Brain Pathol. 8, 355–365 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Watts, R. L., Mirra, S. S. & Richarson, E. P. Jr in Movement Disorders III: Blue Books of Practical Neurology Vol. 13 (eds Marsden, C. D. & Fahn, S.) 282–299 (Butterworth–Heinemann, Oxford, 1994).

    Google Scholar 

  8. Riley, D. E. & Lang, A. E. Corticobasal ganglionic degeneration (CBGD): further observations in six additional cases. Neurology 38, 360 (1988).

    Article  Google Scholar 

  9. Boeve, B. F. et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53, 795–800 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Riley, D. E. et al. Cortical–basal ganglionic degeneration. Neurology 40, 1203–1212 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Bak, T. H. & Hodges, J. R. Corticobasal degeneration: clinical aspects. Handb. Clin. Neurol. 89, 509–521 (2008).

    Article  PubMed  Google Scholar 

  12. Lang, A. E., Riley, D. E. & Bergeron, C. in Neurodegenerative Diseases Ch. 49 (ed. Calne, D. B.) 877–894 (W. B. Saunders, Philadelphia, 1994).

    Google Scholar 

  13. Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Williams, D. R. et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128, 1247–1258 (2005).

    Article  PubMed  Google Scholar 

  15. Bergeron, C., Pollanen, M. S., Weyer, L., Black, S. E. & Lang, A. E. Unusual clinical presentations of cortical–basal ganglionic degeneration. Ann. Neurol. 40, 893–900 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Murray, R. et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 68, 1274–1283 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Ling, H. et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133, 2045–2057 (2010).

    Article  PubMed  Google Scholar 

  18. Schneider, J. A., Watts, R. L., Gearing, M., Brewer, R. P. & Mirra, S. S. Corticobasal degeneration: neuropathologic and clinical heterogeneity. Neurology 48, 959–969 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Grimes, D. A., Lang, A. E. & Bergeron, C. B. Dementia as the most common presentation of cortical-basal ganglionic degeneration. Neurology 53, 1969–1974 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Kertesz, A., Martinez-Lage, P., Davidson, W. & Munoz, D. G. The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 55, 1368–1375 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Gorno-Tempini, M. L., Murray, R. C., Rankin, K. P., Weiner, M. W. & Miller, B. L. Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report. Neurocase 10, 426–436 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Josephs, K. A. et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 129, 1385–1398 (2006).

    Article  PubMed  Google Scholar 

  23. Raggi, A. et al. The clinical overlap between the corticobasal degeneration syndrome and other diseases of the frontotemporal spectrum: three case reports. Behav. Neurol. 18, 159–164 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gibb, W. R., Luthert, P. J. & Marsden, C. D. Clinical and pathological features of corticobasal degeneration. Adv. Neurol. 53, 51–54 (1990).

    CAS  PubMed  Google Scholar 

  25. Wenning, G. K. et al. Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination. J. Neurol. Neurosurg. Psychiatry 64, 184–189 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Litvan, I., Grimes, D. A. & Lang, A. E. Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv. Neurol. 82, 183–196 (2000).

    CAS  PubMed  Google Scholar 

  27. Kertesz, A., McMonagle, P., Blair, M., Davidson, W. & Munoz, D. G. The evolution and pathology of frontotemporal dementia. Brain 128, 1996–2005 (2005).

    Article  PubMed  Google Scholar 

  28. Lang, A. E., Bergeron, C., Pollanen, M. S. & Ashby, P. Parietal Pick's disease mimicking cortical–basal ganglionic degeneration. Neurology 44, 1436–1440 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Grimes, D. A., Bergeron, C. B. & Lang, A. E. Motor neuron disease-inclusion dementia presenting as cortical–basal ganglionic degeneration. Mov. Disord. 14, 674–680 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Horoupian, D. S. & Wasserstein, P. H. Alzheimer's disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration. Acta Neuropathol. 98, 317–322 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Hu, W. T. et al. Alzheimer's disease and corticobasal degeneration presenting as corticobasal syndrome. Mov. Disord. 24, 1375–1379 (2009).

    Article  PubMed  Google Scholar 

  32. Benussi, L. et al. Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. Neurobiol. Dis. 33, 379–385 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Whitwell, J. L. et al. Imaging correlates of pathology in corticobasal syndrome. Neurology 75, 1879–1887 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Williams, D. R., Lees, A. J., Wherrett, J. R. & Steele, J. C. J. Clifford Richardson and 50 years of progressive supranuclear palsy. Neurology 70, 566–573 (2008).

    Article  PubMed  Google Scholar 

  35. Steele, J. C., Richardson, J. C. & Olszewski, J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch. Neurol. 10, 333–359 (1964).

    Article  CAS  PubMed  Google Scholar 

  36. Tsuboi, Y. et al. Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov. Disord. 20, 982–988 (2005).

    Article  PubMed  Google Scholar 

  37. Oide, T. et al. Progressive supranuclear palsy with asymmetric tau pathology presenting with unilateral limb dystonia. Acta Neuropathol. 104, 209–214 (2002).

    Article  PubMed  Google Scholar 

  38. Litvan, I. et al. Clinical features differentiating patients with postmortem confirmed progressive supranuclear palsy and corticobasal degeneration. J. Neurol. 246 (Suppl. 2), II1–II5 (1999).

    PubMed  Google Scholar 

  39. Dickson, D. W. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J. Neurol. 246 (Suppl. 2), II6–II15 (1999).

    Article  PubMed  Google Scholar 

  40. Shiozawa, M. et al. Corticobasal degeneration: an autopsy case clinically diagnosed as progressive supranuclear palsy. Clin. Neuropathol. 19, 192–199 (2000).

    CAS  PubMed  Google Scholar 

  41. Hassan, A. et al. Symmetric corticobasal degeneration (S-CBD). Parkinsonism Relat. Disord. 16, 208–214 (2010).

    Article  PubMed  Google Scholar 

  42. Vidailhet, M. et al. Eye movements in parkinsonian syndromes. Ann. Neurol. 35, 420–426 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Rivaud-Péchoux, S. et al. Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 54, 1029–1032 (2000).

    Article  PubMed  Google Scholar 

  44. Zadikoff, C. & Lang, A. E. Apraxia in movement disorders. Brain 128, 1480–1497 (2005).

    Article  PubMed  Google Scholar 

  45. Houghton, D. J. & Litvan, I. Unraveling progressive supranuclear palsy: from the bedside back to the bench. Parkinsonism Relat. Disord. 13 (Suppl. 3), S341–S346 (2007).

    Article  PubMed  Google Scholar 

  46. Cummings, J. L. & Litvan, I. Neuropsychiatric aspects of corticobasal degeneration. Adv. Neurol. 82, 147–152 (2000).

    CAS  PubMed  Google Scholar 

  47. Josephs, K. A. et al. Voxel-based morphometry in autopsy proven PSP and CBD. Neurobiol. Aging 29, 280–289 (2008).

    Article  PubMed  Google Scholar 

  48. Neary, D. et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51, 1546–1554 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Hodges, J. R. et al. Clinicopathological correlates in frontotemporal dementia. Ann. Neurol. 56, 399–406 (2004).

    Article  PubMed  Google Scholar 

  50. Forman, M. S. et al. Frontotemporal dementia: clinicopathological correlations. Ann. Neurol. 59, 952–962 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Whitwell, J. L. et al. MRI correlates of protein deposition and disease severity in postmortem frontotemporal lobar degeneration. Neurodegener. Dis. 6, 106–117 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Josephs, K. A. et al. Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66, 41–48 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Grossman, M. et al. Longitudinal decline in autopsy-defined frontotemporal lobar degeneration. Neurology 70, 2036–2045 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Mesulam, M. M. Primary progressive aphasia. Ann. Neurol. 49, 425–432 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Knibb, J. A., Xuereb, J. H., Patterson, K. & Hodges, J. R. Clinical and pathological characterization of progressive aphasia. Ann. Neurol. 59, 156–165 (2006).

    Article  PubMed  Google Scholar 

  56. Grossman, M. Primary progressive aphasia: clinicopathological correlations. Nat. Rev. Neurol. 6, 88–97 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Josephs, K. A. et al. Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol. Appl. Neurobiol. 30, 369–373 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Benson, D. F., Davis, R. J. & Snyder, B. D. Posterior cortical atrophy. Arch. Neurol. 45, 789–793 (1988).

    Article  CAS  PubMed  Google Scholar 

  59. Renner, J. A. et al. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology 63, 1175–1180 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Tang-Wai, D. F. et al. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology 63, 1168–1174 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Jellinger, K. A. et al. Four-repeat tauopathy clinically presenting as posterior cortical atrophy: atypical corticobasal degeneration? Acta Neuropathol. 121, 267–277 (2011).

    Article  PubMed  Google Scholar 

  62. Dickson, D. W. et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J. Neuropathol. Exp. Neurol. 61, 935–946 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Fujino, Y., Delucia, M. W., Davies, P. & Dickson, D. W. Ballooned neurones in the limbic lobe are associated with Alzheimer type pathology and lack diagnostic specificity. Neuropathol. Appl. Neurobiol. 30, 676–682 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Josephs, K. A. et al. Atypical progressive supranuclear palsy with corticospinal tract degeneration. J. Neuropathol. Exp. Neurol. 65, 396–405 (2006).

    Article  PubMed  Google Scholar 

  65. Dickson, D. W. in The Neuropathology of Dementia Ch. 11 (eds Esiri, M. M. et al.) 227–256 (Cambridge University Press, Cambridge, 2004).

    Book  Google Scholar 

  66. Komori, T. et al. Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. 96, 401–408 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Feany, M. B. & Dickson, D. W. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am. J. Pathol. 146, 1388–1396 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Yamada, T., McGeer, P. L. & McGeer, E. G. Appearance of paired nucleated, tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci. Lett. 135, 99–102 (1992).

    Article  CAS  PubMed  Google Scholar 

  69. Arai, T. et al. Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration. Ann. Neurol. 55, 72–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Arai, T. et al. Intracellular processing of aggregated tau differs between corticobasal degeneration and progressive supranuclear palsy. Neuroreport 12, 935–938 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Ishizawa, K. & Dickson, D. W. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 60, 647–657 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Gerhard, A. et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov. Disord. 21, 89–93 (2006).

    Article  PubMed  Google Scholar 

  73. Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimers's disease mouse models. Cell 142, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Brunden, K. R. et al. Tau-directed drug discovery for Alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors. Exp. Neurol. 223, 304–310 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M. & Harrington, C. R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl Acad. Sci. USA 93, 11213–11218 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gong, C. X., Grundke-Iqbal, I. & Iqbal, K. Targeting tau protein in Alzheimer's disease. Drugs Aging 27, 351–365 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Mandelkow, E. M. et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314, 315–321 (1992).

    Article  CAS  PubMed  Google Scholar 

  80. Pérez, M., Hernandez, F., Lim, F., Diaz-Nido, J. & Avila, J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J. Alzheimers Dis. 5, 301–308 (2003).

    Article  PubMed  Google Scholar 

  81. Noble, W. et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl Acad. Sci. USA 102, 6990–6995 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nakashima, H. et al. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 110, 547–556 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Engel, T., Goñi-Oliver, P., Lucas, J. J., Avila, J. & Hernández, F. Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J. Neurochem. 99, 1445–1455 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Caccamo, A., Oddo, S., Tran, L. X. & LaFerla, F. M. Lithium reduces tau phosphorylation but not Aβ or working memory deficits in a transgenic model with both plaques and tangles. Am. J. Pathol. 170, 1669–1675 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee, V. M., Kenyon, T. K. & Trojanowski, J. Q. Transgenic animal models of tauopathies. Biochim. Biophys. Acta 1739, 251–259 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Zhang, B. et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc. Natl Acad. Sci. USA 102, 227–231 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Gozes, I. & Divinski, I. The femtomolar-acting NAP interacts with microtubules: novel aspects of astrocyte protection. J. Alzheimers Dis. 6, S37–S41 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Matsuoka, Y. et al. Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage. J. Mol. Neurosci. 31, 165–170 (2007).

    CAS  PubMed  Google Scholar 

  89. Matsuoka, Y. et al. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease. J. Pharmacol. Exp. Ther. 325, 146–153 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Brunden, K. R. et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J. Neurosci. 30, 13861–13866 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Luo, W. et al. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc. Natl Acad. Sci. USA 104, 9511–9516 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dickey, C. A. et al. The high-affinity HSP90–CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 117, 648–658 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pickhardt, M. et al. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. J. Biol. Chem. 280, 3628–3635 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Urakami, K. et al. A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy. Neurosci. Lett. 259, 127–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Urakami, K. et al. Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J. Neurol. Sci. 183, 95–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Borroni, B. et al. Pattern of tau forms in CSF is altered in progressive supranuclear palsy. Neurobiol. Aging 30, 34–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Noguchi, M. et al. Decreased β-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. J. Neurol. Sci. 237, 61–65 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Mitani, K. et al. Increased CSF tau protein in corticobasal degeneration. J. Neurol. 245, 44–46 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Arai, H. et al. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochem. Biophys. Res. Commun. 236, 262–264 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Portelius, E. et al. Characterization of tau in cerebrospinal fluid using mass spectrometry. J. Proteome Res. 7, 2114–2120 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Guillozet-Bongaarts, A. L. et al. Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol. 113, 513–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Holmberg, B., Rosengren, L., Karlsson, J. E. & Johnels, B. Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple-system atrophy compared with Parkinson's disease. Mov. Disord. 13, 70–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Brettschneider, J. et al. Neurofilament heavy-chain NfHSMI35 in cerebrospinal fluid supports the differential diagnosis of parkinsonian syndromes. Mov. Disord. 21, 2224–2227 (2006).

    Article  PubMed  Google Scholar 

  104. Müller, U. GWAS in PSP: results at disease-associated loci other than MAPT. Proc. CurePSP 2010 International Research Symposium (San Diego, CA, November 18, 2010).

    Google Scholar 

  105. Sergeant, N., Wattez, A. & Delacourte, A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J. Neurochem. 72, 1243–1249 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Delacourte, A., Sergeant, N., Wattez, A., Gauvreau, D. & Robitaille, Y. Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their tau isoform distribution and phosphorylation. Ann. Neurol. 43, 193–204 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Hutton, M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 56, S21–S25 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Binder, L. I., Frankfurter, A. & Rebhun, L. I. The distribution of tau in the mammalian central nervous system. J. Cell. Biol. 101, 1371–1378 (1985).

    Article  CAS  PubMed  Google Scholar 

  109. LoPresti, P., Szuchet, S., Papasozomenos, S. C., Zinkowski, R. P. & Binder, L. I. Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc. Natl Acad. Sci. USA 92, 10369–10373 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Witman, G. B., Cleveland, D. W., Weingarten, M. D. & Kirschner, M. W. Tubulin requires tau for growth onto microtubule initiating sites. Proc. Natl Acad. Sci. USA 73, 4070–4074 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Andreadis, A., Brown, W. M. & Kosik, K. S. Structure and novel exons of the human tau gene. Biochemistry 31, 10626–10633 (1992).

    Article  CAS  PubMed  Google Scholar 

  112. Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3, 519–526 (1989).

    Article  CAS  PubMed  Google Scholar 

  113. Baker, M. et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711–715 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Conrad, C. et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann. Neurol. 41, 277–281 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Houlden, H. et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56, 1702–1706 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Rademakers, R. et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum. Mol. Genet. 14, 3281–3292 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Pittman, A. M. et al. Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J. Med. Genet. 42, 837–846 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bugiani, O. et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J. Neuropathol. Exp. Neurol. 58, 667–677 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Spillantini, M. G. et al. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann. Neurol. 48, 939–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Rossi, G. et al. The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome. Mov. Disord. 23, 892–895 (2008).

    Article  PubMed  Google Scholar 

  122. Rademakers, R., Cruts, M. & van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. Mutat. 24, 277–295 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

K. A. Josephs is supported by NIH grants R01-DC10367 and R01-AG37491. J. L. Whitwell is supported by NIH grant R21-AG38736. D. W. Dickson is supported by the Mayo Foundation (Robert E. Jacoby Professorship for Alzheimer's Research), Mangurian Foundation, CurePSP The Society for Progressive Supranuclear Palsy and NIH grants P50-AG16574, P50-NS72187 and P01-AG17216.

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All authors wrote the article, contributed to discussions of the content and researched data for the article. D. W. Dickson edited and reviewed the manuscript before submission.

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Kouri, N., Whitwell, J., Josephs, K. et al. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 7, 263–272 (2011). https://doi.org/10.1038/nrneurol.2011.43

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