Parkinsonism and Frontotemporal Dementia: The Clinical Overlap

  • Alberto J. Espay
  • Irene LitvanEmail author


Frontotemporal dementia is commonly associated with parkinsonism in several sporadic (i.e., progressive supranuclear palsy, corticobasal degeneration) and familial neurodegenerative disorders (i.e., frontotemporal dementia associated with parkinsonism and MAPT or progranulin mutations in chromosome 17). The clinical diagnosis of these disorders may be challenging in view of overlapping clinical features, particularly in speech, language, and behavior. The motor and cognitive phenotypes can be viewed within a spectrum of clinical, pathologic, and genetic disorders with no discrete clinicopathologic correlations but rather lying within a dementia–parkinsonism continuum. Neuroimaging and cerebrospinal fluid analysis can be helpful, but the poor specificity of clinical and imaging features has enormously challenged the development of biological markers that could differentiate these disorders premortem. This gap is critical to bridge in order to allow testing of novel biological therapies that may slow the progression of these proteinopathies.


Frontotemporal dementia Frontotemporal lobar degeneration Parkinsonism Corticobasal syndrome Progressive supranuclear palsy Corticobasal degeneration 


Conflicts of Interest

The authors report no conflicts of interest.


Dr. Espay is supported by a K23 Mentored Career Development Award (1K23MH092735). Dr. Litvan is partially funded by R01 PAS-03-092 NIA “Genetic and environmental risk factors for PSP.”


  1. Baba Y, Baker MC, Le BI et al (2007) Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation. J Neural Transm 114(7):947–950PubMedCrossRefGoogle Scholar
  2. Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442(7105):916–919PubMedCrossRefGoogle Scholar
  3. Baron JC, Maziere B, Loc’h C (1986) Loss of striatal [76Br]bromospiperone binding sites demonstrated by positron tomography in progressive supranuclear palsy. J Cereb Blood Flow Metab 6(2):131–136PubMedCrossRefGoogle Scholar
  4. Boeve BF, Hutton M (2008) Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Arch Neurol 65(4):460–464PubMedCrossRefGoogle Scholar
  5. Boeve BF, Baker M, Dickson DW et al (2006) Frontotemporal dementia and parkinsonism associated with the IVS1 + 1G->A mutation in progranulin: a clinicopathologic study. Brain 129(Pt 11):3103–3114PubMedCrossRefGoogle Scholar
  6. Borroni B, Malinverno M, Gardoni F et al (2008) Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy. Neurology 71(22):1796–1803PubMedCrossRefGoogle Scholar
  7. Borroni B, Del BR, Goldwurm S et al (2010) VEGF haplotypes are associated with increased risk to progressive supranuclear palsy and corticobasal syndrome. J Alzheimers Dis 21(1):87–94PubMedGoogle Scholar
  8. Brooks DJ, Ibanez V, Sawle GV et al (1992) Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann Neurol 31(2):184–192PubMedCrossRefGoogle Scholar
  9. Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol (Berl) 114(1):5–22CrossRefGoogle Scholar
  10. Eckert T, Barnes A, Dhawan V et al (2005) FDG PET in the differential diagnosis of parkinsonian disorders. Neuroimage 26(3):912–921PubMedCrossRefGoogle Scholar
  11. Esmonde T, Giles E, Xuereb J et al (1996) Progressive supranuclear palsy presenting with dynamic aphasia. J Neurol Neurosurg Psychiatr 60(4):403–410PubMedCrossRefGoogle Scholar
  12. Farrer MJ, Hulihan MM, Kachergus JM et al (2009) DCTN1 mutations in Perry syndrome. Nat Genet 41(2):163–165PubMedCrossRefGoogle Scholar
  13. Gabryelewicz T, Masellis M, Berdynski M et al (2010) Intra-familial clinical heterogeneity due to FTLD-U with TDP-43 proteinopathy caused by a novel deletion in progranulin gene (PGRN). J Alzheimers Dis 22(4):1123–1133PubMedGoogle Scholar
  14. Goldman JS, Rademakers R, Huey ED et al (2011) An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology 76(5):475–483PubMedCrossRefGoogle Scholar
  15. Graham NL, Bak T, Patterson K et al (2003) Language function and dysfunction in corticobasal degeneration. Neurology 61(4):493–499PubMedGoogle Scholar
  16. Groschel K, Kastrup A, Litvan I et al (2006) Penguins and hummingbirds: midbrain atrophy in progressive supranuclear palsy. Neurology 66(6):949–950PubMedCrossRefGoogle Scholar
  17. Guerreiro RJ, Santana I, Bras JM et al (2008) Novel progranulin mutation: screening for PGRN mutations in a Portuguese series of FTD/CBS cases. Mov Disord 23(9):1269–1273PubMedCrossRefGoogle Scholar
  18. Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393(6686):702–705PubMedCrossRefGoogle Scholar
  19. Iseki E, Matsumura T, Marui W et al (2001) Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells. Acta Neuropathol 102(3):285–292PubMedGoogle Scholar
  20. Josephs KA, Duffy JR (2008) Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy. Curr Opin Neurol 21(6):688–692PubMedCrossRefGoogle Scholar
  21. Josephs KA, Knopman DS, Whitwell JL et al (2005) Survival in two variants of tau-negative frontotemporal lobar degeneration: FTLD-U vs FTLD-MND. Neurology 65(4):645–647PubMedCrossRefGoogle Scholar
  22. Josephs KA, Duffy JR, Strand EA et al (2006a) Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 129(Pt 6):1385–1398PubMedCrossRefGoogle Scholar
  23. Josephs KA, Petersen RC, Knopman DS et al (2006b) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66(1):41–48PubMedCrossRefGoogle Scholar
  24. Josephs KA, Whitwell JL, Parisi JE et al (2010) Caudate atrophy on MRI is a characteristic feature of FTLD-FUS. Eur J Neurol 17(7):969–975PubMedCrossRefGoogle Scholar
  25. Kelley BJ, Haidar W, Boeve BF et al (2009) Prominent phenotypic variability associated with mutations in progranulin. Neurobiol Aging 30(5):739–751PubMedCrossRefGoogle Scholar
  26. Kim EJ, Rabinovici GD, Seeley WW et al (2007) Patterns of MRI atrophy in tau positive and ubiquitin positive frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatr 78(12):1375–1378PubMedCrossRefGoogle Scholar
  27. Kouri N, Murray ME, Hassan A, et al. (2011) Neuropathologic features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome. Brain (in press).Google Scholar
  28. Kovacs GG, Majtenyi K, Spina S et al (2008) White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67(10):963–975PubMedCrossRefGoogle Scholar
  29. Krack P, Marion MH (1994) “Apraxia of lid opening,” a focal eyelid dystonia: clinical study of 32 patients. Mov Disord 9(6):610–615PubMedCrossRefGoogle Scholar
  30. Lee SE, Rabinovici GD, Mayo MC et al (2011) Clinicopathological correlations in corticobasal degeneration. Ann Neurol 70(2):327–340PubMedCrossRefGoogle Scholar
  31. Ling H, O'Sullivan SS, Holton JL et al (2010) Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133(Pt 7):2045–2057PubMedCrossRefGoogle Scholar
  32. Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117(1):15–18PubMedCrossRefGoogle Scholar
  33. Morris HR, Osaki Y, Holton J et al (2003) Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP. Neurology 61(1):102–104PubMedGoogle Scholar
  34. Newsway V, Fish M, Rohrer JD et al (2010) Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure. Mov Disord 25(6):767–770PubMedCrossRefGoogle Scholar
  35. Ozsancak C, Auzou P, Dujardin K et al (2004) Orofacial apraxia in corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy and Parkinson's disease. J Neurol 251(11):1317–1323PubMedCrossRefGoogle Scholar
  36. Pastor P, Pastor E, Carnero C et al (2001) Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol 49(2):263–267PubMedCrossRefGoogle Scholar
  37. Rivaud-Pechoux S, Vidailhet M, Gallouedec G et al (2000) Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 54(5):1029–1032PubMedGoogle Scholar
  38. Rohrer JD, Guerreiro R, Vandrovcova J et al (2009) The heritability and genetics of frontotemporal lobar degeneration. Neurology 73(18):1451–1456PubMedCrossRefGoogle Scholar
  39. Rohrer JD, Ridgway GR, Modat M et al (2010) Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. Neuroimage 53(3):1070–1076PubMedCrossRefGoogle Scholar
  40. Rohrer JD, Paviour D, Vandrovcova J et al (2011) Novel L284R MAPT mutation in a family with an autosomal dominant progressive supranuclear palsy syndrome. Neurodegener Dis 8(3):149–152PubMedCrossRefGoogle Scholar
  41. Rutherford NJ, Zhang YJ, Baker M et al (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4(9):e1000193PubMedCrossRefGoogle Scholar
  42. Schofield EC, Halliday GM, Kwok J et al (2010) Low serum progranulin predicts the presence of mutations: a prospective study. J Alzheimers Dis 22(3):981–984PubMedGoogle Scholar
  43. Shelley BP, Hodges JR, Kipps CM et al (2009) Is the pathology of corticobasal syndrome predictable in life? Mov Disord 24(11):1593–1599PubMedCrossRefGoogle Scholar
  44. Skoglund L, Viitanen M, Kalimo H et al (2008) The tau S305S mutation causes frontotemporal dementia with parkinsonism. Eur J Neurol 15(2):156–161PubMedCrossRefGoogle Scholar
  45. Soliveri P, Rossi G, Monza D et al (2003) A case of dementia parkinsonism resembling progressive supranuclear palsy due to mutation in the tau protein gene. Arch Neurol 60(10):1454–1456PubMedCrossRefGoogle Scholar
  46. Spina S, Murrell JR, Huey ED et al (2007) Corticobasal syndrome associated with the A9D progranulin mutation. J Neuropathol Exp Neurol 66(10):892–900PubMedCrossRefGoogle Scholar
  47. Tedeschi G, Litvan I, Bonavita S et al (1997) Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson's disease and corticobasal degeneration. Brain 120(Pt 9):1541–1552PubMedCrossRefGoogle Scholar
  48. Tsuboi Y, Baker M, Hutton ML et al (2002) Clinical and genetic studies of families with the tau N279K mutation (FTDP-17). Neurology 59(11):1791–1793PubMedGoogle Scholar
  49. Vidailhet M, Rivaud S, Gouider-Khouja N et al (1994) Eye movements in parkinsonian syndromes. Ann Neurol 35(4):420–426PubMedCrossRefGoogle Scholar
  50. Watts GD, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36(4):377–381PubMedCrossRefGoogle Scholar
  51. Whitwell JL, Jack CR Jr, Parisi JE et al (2010) Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration? Neurology 75(24):2212–2220PubMedCrossRefGoogle Scholar
  52. Wider C, Uitti RJ, Wszolek ZK et al (2008) Progranulin gene mutation with an unusual clinical and neuropathologic presentation. Mov Disord 23(8):1168–1173PubMedCrossRefGoogle Scholar
  53. Wszolek ZK, Tsuboi Y, Uitti RJ et al (2001) Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation. Brain 124(Pt 8):1666–1670PubMedCrossRefGoogle Scholar
  54. Yatabe Y, Hashimoto M, Kaneda K et al (2011) Neuropsychiatric symptoms of progressive supranuclear palsy in a dementia clinic. Psychogeriatrics 11(1):54–59PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Neurology, Movement Disorders Center, UC Neuroscience InstituteUniversity of CincinnatiCincinnatiUSA
  2. 2.Department of Neurology, Division of Movement Disorders CenterUniversity of LouisvilleLouisvilleUSA
  3. 3.Division of Movement Disorders, Department of NeurologyUniversity of Louisville School of Medicine, Frazier Rehab Neuroscience InstituteLouisvilleUSA

Personalised recommendations