Top

Published in:

01-07-2007 | Review

Frontotemporal lobar degeneration: clinical and pathological relationships

Authors: Julie Snowden, David Neary, David Mann

Published in: Acta Neuropathologica | Issue 1/2007

Abstract

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2 ) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, T Oda (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRef

Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in Progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919PubMedCrossRef

Basun H, Almkvist O, Axelman K, Brun A, Campbell TA, Collinge J, Forsell C, Froelich S, Wahlund LO, Wetterberg L, Lannfelt L (1997) Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia. Arch Neurol 54:539–544PubMed

Cairns NJ, Bigio EH, Mackenzie IRA, Hatanpaa KJ, White CL, Schneider JA, Morris JC, Lee VM-Y, Trojanowski JQ, Mann DMA (2007) Neuropathological diagnostic criteria and nosology of the frontotemporal lobar degenerations: consensus criteria of the Consortium for frontotemporal lobar degeneration. Acta Neuropathol (this issue)

Caselli RJ, Windebank AJ, Petersen RC, Komori T, Parisi JE, Okazaki H, Kokmen E, Iverson R, Dinapoli RP, Graff-Radford NR (1993) Rapidly progressive aphasic dementia and motor neuron disease. Ann Neurol 33:200–207PubMedCrossRef

Catani M, Piccirilli M, Geloso MC, Cherubino A, Finali G, Pelliccioli G, Senin U, Mecocci P (2004) Rapidly progressive aphasic dementia with motor neuron disease: a distinctive clinical entity. Dement Geriatr Cogn Disord 17:21–28PubMedCrossRef

Davidson Y, Kelley T, Mackenzie IRA, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DMA (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl) 113:521–533CrossRef

De Renzi E (1986) Slowly progressive visual agnosia or apraxia without dementia. Cortex 22:171–180PubMed

Dick J, Snowden JS, Goulding PJ, Northen B, Neary D (1989) Slowly progressive apraxia. Behav Neurol 2:101–114

10.

Ferrer I, Hernandez I, Boada M, Llorente A, Rey MJ, Cardozo A, Ezquerra M, Puig B (2003) Primary progressive aphasia as the initial manifestation of corticobasal degeneration and unusual tauopathies. Acta Neuropathol (Berl) 106:419–435CrossRef

11.

Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, VanDeerlin V, Lee VM, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962PubMedCrossRef

12.

Fukui T, Sugita K, Kawamura M, Shiota J, Nakano I (1996) Primary progressive apraxia in Pick’s disease: a clinicopathologic study. Neurology 47:467–473PubMed

13.

Galton CJ, Patterson K, Xuereb JH, Hodges JR (2000) Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 123: 484–498PubMedCrossRef

14.

Hodges JR, Patterson K, Oxbury S, Funnell E (1992) Semantic dementia. progressive fluent aphasia with temporal lobe atrophy. Brain 115:1783–1806PubMedCrossRef

15.

Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM (2004) Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56:399–406PubMedCrossRef

16.

Hodges JR, Patterson K (1995) Is semantic memory consistently impaired early in the course of Alzheimer’s disease? Neuroanatomical and diagnostic implications. Neuropsychologia 33:441–459PubMedCrossRef

17.

Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed JC, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5’ splice site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705PubMedCrossRef

18.

Ioannides P, Karacostas D, Hatzipantazi M (2005) Primary progressive aphasia as the initial manifestation of corticobasal degeneration. A “three-in-one” syndrome? Funct Neurol 20:135–137PubMed

19.

Josephs KA, Holton JL, Rossor MN, Godbolt AK, Ozawa T, Strand K, Khan N, Al-Sarraj S, Revesz T (2004) Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropath Appl Neurobiol 30:369–373CrossRef

20.

Josephs KA, Ahmed Z, Katsuse O, Parisi JF, Boeve BF, Knopman DS, Petersen RC, Davies P, Duara R, Graff-Radford NR, Uitti RJ, Rademakers R, Adamson J, Baker M, Hutton ML, Dickson DW (2007) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 66:142–151PubMedCrossRef

21.

Josephs KA, Duffy JR, Strand EA, Whitwell JL, Layton KF, Parisi JE, Hauser MF, Witte RJ, Boeve BF, Knopman DS, Dickson DW, Jack CR, Petersen RC (2006) Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 129:1385–1398PubMedCrossRef

22.

Kertesz A (2003) Pick complex: an integrative approach to frontotemporal dementia: primary progressive aphasia, corticobasal degeneration and progressive supranuclear palsy. Neurologist 9:311–317PubMedCrossRef

23.

Knibb JA, Xuereb JH, Patterson K, Hodges JR (2006) Clinical and pathological characterization of progressive aphasia. Ann Neurol 59:156–165PubMedCrossRef

24.

Knopman DS, Boeve BF, Parisi JE, Dickson DW, Smith GE, Ivnik RJ, Josephs KA, Petersen RC (2005) Antemortem diagnosis of frontotemporal lobar degeneration. Ann Neurol 57:480–488PubMedCrossRef

25.

Liu W, Miller BL, Kramer, Rankin K, Wyss-Coray C, Gearhart R, Phengrasamy L, Weiner M, Rosen HJ (2004) Behavioral disorders in the frontal and temporal variants of frontotemporal dementia. Neurology 62:742–748PubMed

26.

Lipton AM, White CL, Bigio EH (2004) Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropath 108:379–385PubMedCrossRef

27.

Lund, Manchester groups (1994) Consensus statement. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57:416–418

28.

Mackenzie IRA, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl) 112:539–549CrossRef

29.

Mackenzie IRA, Baker M, Pickering-Brown S, Hsiung G-Y R, Lindholm C, Dwosh E, Gass J, Cannon A, Rademakers R, Hutton M, Feldman H (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090PubMedCrossRef

30.

Mackenzie IR (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropath (Berl) (this issue)

31.

McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia. Report of the Work Group on frontotemporal dementia and Pick’s disease. Arch Neurol 58:1803–1809PubMedCrossRef

32.

Mesulam M-M (1982) Slowly progressive aphasia without generalized dementia. Ann Neurol 11:592–598PubMedCrossRef

33.

Mesulam M-M (2001) Primary progressive aphasia. Ann Neurol 49:425–432PubMedCrossRef

34.

Mesulam M, Johnson N, Krefft TA, Gass JM, Cannon AD, Adamson JL, Bigio EH, Weintraub S, Dickson DW, Hutton ML, Graff-Radford NR (2007) Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol 64:43–47PubMedCrossRef

35.

Miller BL, Ikonte BS, Ponton M, Levy M, Boone K, Darby A, Berman N, Mena I, Cummings J (1997) A study of the Lund-Manchester research criteria for frontotemporal dementia: clinical and single photon emission CT correlations. Neurology 48:937–942PubMed

36.

Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMed

37.

Neary D, Snowden JS, Mann DMA (1993) Familial progressive aphasia: its relationship to other forms of lobar atrophy. J Neurol Neurosurg Psychiatry 56:1122–1125PubMedCrossRef

38.

Neary D, Snowden JS, Mann DMA, Northen B, Goulding, Mcdermott N (1990) Frontal lobe dementia and motor neurone disease. J Neurol Neurosurg Psychiatry 53:23–32PubMed

39.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzchmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRef

40.

Paviour DC, Lees AJ, Josephs KA, Ozawa T, Ganguly M, Strand C, Godbolt A, Howard RS, Revesz T, Holton JL (2004) Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes: broadening the clinical picture to include progressive supranuclear palsy. Brain 127:2441–2451PubMedCrossRef

41.

Perry RJ, Hodges JR (2000) Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer’s disease. Neurology 54:2277–2284PubMed

42.

Pickering-Brown SM, Richardson AMT, Snowden JS, McDonagh AM, Burns A, Braude W, Baker M, Liu W-K, Yen S-H, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D, Mann DMA (2002) Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain 125:732–751PubMedCrossRef

43.

Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352PubMedCrossRef

44.

Shi J, Shaw CL, Du Plessis D, Richardson AM, Bailey KL, Julien C, Stopford C, Thompson J, Varma A, Craufurd D, Tian J, Pickering-Brown S, Neary D, Snowden JS, Mann DM (2005) Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol (Berl) 110:501–512CrossRef

45.

Snowden JS, Neary D, Mann DMA (1996) Fronto-temporal lobar degeneration: fronto-temporal dementia, progressive aphasia, semantic dementia. Churchill-Livingstone, London

46.

Snowden JS, Goulding PJ, Neary D (1989) Semantic dementia: a form of circumscribed cerebral atrophy. Behav Neurol 2:167–182

47.

Snowden JS, Thompson JC, Neary D (2004) Knowledge of famous faces and names in semantic dementia. Brain 127:860–872PubMedCrossRef

48.

Snowden JS, Neary D, Mann DM (2004) Autopsy proven sporadic frontotemporal dementia due to microvacuolar-type histology, with onset at 21 years of age. J Neurol Neurosurg Psychiatry 75:1337–1339PubMedCrossRef

49.

Snowden JS, Pickering-Brown SM, Mackenzie IR, Richardson AMT, Varma A, Neary D, Mann DMA (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129:3091–3102PubMedCrossRef

50.

Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D (2001) Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 70:323–332PubMedCrossRef

51.

Stopford CL, Snowden JS, Thompson JC, Neary D (2007) Variability in cognitive presentation of Alzheimer’s disease. Cortex, in press

52.

Van Swieten JC, Rosso SM, van Herpen E, Kamphorst W, Ravid R, Heutink P (2004) Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17. Dement Geriatr Cogn Disord 17:261–264PubMedCrossRef

Title: Frontotemporal lobar degeneration: clinical and pathological relationships
Authors: Julie Snowden
David Neary
David Mann
Publication date: 01-07-2007
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 1/2007
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-007-0236-3

At a glance: The STEP trials

Springer Medicine

Frontotemporal lobar degeneration: clinical and pathological relationships

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2007

Announcements

Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration

TDP-43 in differential diagnosis of motor neuron disorders

TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease

The neuropathology and clinical phenotype of FTD with progranulin mutations

Progranulin and frontotemporal lobar degeneration