Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype

Objective: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). Background: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. Methods: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. Results: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X2 = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X2 = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). Conclusions: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

[1]  R. A. Crowther,et al.  Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease , 1989, Neuron.

[2]  John X. Morris,et al.  Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. , 1998, Science.

[3]  I. Litvan,et al.  Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the alpha-synuclein gene. , 1998, Neurology.

[4]  D. Dickson,et al.  Tau gene mutation in familial progressive subcortical gliosis , 1999, Nature Medicine.

[5]  A. Lang,et al.  Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. , 2000, Advances in neurology.

[6]  L. Thal,et al.  Genetic evidence for the involvement of τ in progressive supranuclear palsy , 1997, Annals of neurology.

[7]  K. Kosik,et al.  Structure and novel exons of the human tau gene. , 1992, Biochemistry.

[8]  E. Richardson,et al.  Corticodentatonigral degeneration with neuronal achromasia. , 1968, Archives of neurology.

[9]  A Klug,et al.  Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Tabaton,et al.  Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy , 2000, Annals of neurology.

[11]  C. Marsden,et al.  Clinical and pathological features of corticobasal degeneration. , 1990, Advances in neurology.

[12]  J. Molinuevo,et al.  Significant changes in the tau A0 and A3 alleles in progressive supranuclear palsy and improved genotyping by silver detection. , 1998, Archives of neurology.

[13]  R. Petersen,et al.  Frequency of tau mutations in three series of non‐Alzheimer's degenerative dementia , 1999, Annals of neurology.

[14]  C D Marsden,et al.  Corticobasal degeneration: A clinical study of 36 cases , 1994 .

[15]  B. Vogt,et al.  PCR-based apolipoprotein E genotype analysis from archival fixed brain , 1998, Journal of Neuroscience Methods.

[16]  P. Lantos,et al.  Familial dementia lacking specific pathological features presenting with clinical features of corticobasal degeneration , 1998, Journal of neurology, neurosurgery, and psychiatry.

[17]  I Litvan,et al.  Association of an extended haplotype in the tau gene with progressive supranuclear palsy. , 1999, Human molecular genetics.

[18]  D. Geschwind,et al.  Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Rossor,et al.  The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases , 1999, Journal of neurology, neurosurgery, and psychiatry.

[20]  T. Komori,et al.  Tau‐positive dial Inclusions in Progressive Supranuclear Palsy, Corticobasal Degeneration and Pick's Disease , 1999, Brain pathology.

[21]  R. Marconi,et al.  Direct genetic evidence for involvement of tau in progressive supranuclear palsy , 1998, Neurology.

[22]  M. Goedert,et al.  Tau protein pathology in neurodegenerative diseases , 1998, Trends in Neurosciences.

[23]  M. Hallett,et al.  Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) , 1996, Neurology.

[24]  J. P. Brandel,et al.  Accuracy of the Clinical Diagnosis of Corticobasal Degeneration , 1997, Neurology.

[25]  M. S. Lee,et al.  Corticobasal degeneration look-alikes. , 2000, Advances in neurology.

[26]  J R Hodges,et al.  Corticobasal ganglionic degeneration and/or frontotemporal dementia? A report of two overlap cases and review of literature , 2000, Journal of neurology, neurosurgery, and psychiatry.

[27]  G. Schellenberg,et al.  Tau is a candidate gene for chromosome 17 frontotemporal dementia , 1998, Annals of neurology.

[28]  Y. Agid,et al.  Eye movements in parkinsonian syndromes , 1994, Annals of neurology.

[29]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[30]  I. Litvan,et al.  Progressive supranuclear gaze palsy is in linkage disequilibrium with theτ and not the α-synuclein gene , 1998, Neurology.