Skip to main content

Advertisement

SpringerLink
Log in

The Frontotemporal Syndromes of ALS. Clinicopathological Correlates

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a syndromic disorder in which the degeneration of motor neurons is frequently accompanied by a range of syndromes reflective of frontotemporal dysfunction, including a behavioural or cognitive syndrome, a dysexecutive syndrome or a frontotemporal dementia. Both sporadic and familial variants of ALS can be affected. The anatomic substrate of each is a frontotemporal lobar degeneration (FTLD) characterized by superficial linear spongiosus, atrophy and neuronal loss, and both astrocytic and neuronal deposition of TDP-43 as pathological inclusions. Largely unrecognized however is the extent of alterations in tau protein metabolism, particularly in cognitively impaired patients (ALSci). This includes hyper-phosphorylation (pThr175) and tau phosphatase resistance, increased fibril formation ex vivo of tau isolated from ALSci and tau immunoreactive aggregates in neurons, dystrophic neurites and astrocytes. In this article, we will review the contemporary clinical, genetic and neuropathological characteristics of the frontotemporal syndromes of ALS and propose that as opposed to being a FTLD in which TDP-43 is the primary disease protein (FTLD-TDP) and that the frontotemporal syndromes of ALS represent a hybrid of both TDP-43 and tau pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Al-Chalabi A, Enayat ZE, Bakker MC et al (1996) Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease. Lancet 347:159–160

    Article  PubMed  CAS  Google Scholar 

  • Amador-Ortiz C, Lin W-L, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 61:435–445

    Article  PubMed  CAS  Google Scholar 

  • Andersen PM, Nilsson P, Keränen M-L et al (1997) Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain 120:1723–1737

    Article  PubMed  Google Scholar 

  • Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611

    Article  PubMed  CAS  Google Scholar 

  • Bachus R, Bader S, Gessner R, Ludolph AC (1997) Lack of association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease. Ann Neurol 41:417

    Article  PubMed  CAS  Google Scholar 

  • Battistini S, Giannini F, Greco G et al (2005) SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study. J Neurol 252:782–788

    Article  PubMed  CAS  Google Scholar 

  • Blair IP, Williams KL, Warraich ST et al (2010) FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry 81:639–645

    Article  PubMed  Google Scholar 

  • Boxer AL, Mackenzie IR, Boeve BF et al (2011) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196–203

    Article  PubMed  Google Scholar 

  • Broustal O, Camuzat A, Guillot-Noel L et al (2010) FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis. J Alzheimers Dis 22:765–769

    PubMed  CAS  Google Scholar 

  • Colombrita C, Onesto E, Tiloca C, Ticozzi N, Silani V, Ratti A (2011) RNA-binding proteins and RNA metabolism: a new scenario in the pathogenesis of amyotrophic lateral sclerosis. Arch Ital Biol 149:83–99

    PubMed  Google Scholar 

  • Donaghy C, Thurtell MJ, Pioro EP, Gibson JM, Leigh RJ (2011) Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases. J Neurol Neurosurg Psychiatry 82:110–116

    Article  PubMed  Google Scholar 

  • Drory VE, Birnbaum M, Korczyn AD, Chapman J (2001) Association of APOE ε4 allele with survival in amyotrophic lateral sclerosis. J Neurol Sci 190:17–20

    Article  PubMed  CAS  Google Scholar 

  • Forno LS, Langston JW, Herrick MK, Wilson JD, Murayama S (2002) Ubiquitin-positive neuronal and tau 2-positive glial inclusions in frontotemporal dementia of motor neuron type. Acta Neuropathol 103:599–606

    Article  PubMed  CAS  Google Scholar 

  • Gellera C, Colobrita C, Ticozzi N et al (2008) Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics 9:33–40

    Article  PubMed  CAS  Google Scholar 

  • Geser F, Brandmeir NJ, Kwong LK et al (2008) Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol 65:636–641

    Article  PubMed  Google Scholar 

  • Gibbons ZC, Snowden JS, Thompson JC, Happe F, Richardson A, Neary D (2007) Inferring thought and action in motor neurone disease. Neuropsychologia 45:1196–1207

    Article  PubMed  CAS  Google Scholar 

  • Giordana MT, Ferrero P, Grifoni S, Pellerino A, Naldi A, Montuschi A (2011) Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review. Neurol Sci 32:9–16

    Article  PubMed  Google Scholar 

  • Girardi A, Macpherson SE, Abrahams S (2011) Deficits in emotional and social cognition in amyotrophic lateral sclerosis. Neuropsychology 25:53–65

    Article  PubMed  Google Scholar 

  • Gitcho MA, Bigio EH, Mishra M et al (2009) TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. Acta Neuropathol 118:633–645

    Article  PubMed  CAS  Google Scholar 

  • Gohar M, Yang W, Strong WL, Volkening K, Leystra-Lantz C, Strong MJ (2009) Tau phosphorylation at 175Thr leads to fibril formation. Implications for the tauopathy of amyotrophic lateral sclerosis. J Neurochem 108:634–643

    Article  PubMed  CAS  Google Scholar 

  • Grace GM, Orange JB, Rowe A, Findlater K, Freedman M, Strong MJ (2011) Neuropsychological functioning in PLS: a comparison with ALS. Can J Neurol Sci 38:88–97

    PubMed  Google Scholar 

  • Hamilton RL, Bowser R (2004) Alzheimer disease pathology in amyotrophic lateral sclerosis. Acta Neuropathol 107:515–522

    Article  PubMed  Google Scholar 

  • Hirano A, Malamud N, Elizan TS, Kurland LT (1966) Amyotrophic lateral sclerosis and Parkinsonism–dementia complex on Guam. Further pathologic studies. Arch Neurol 15:35–51

    PubMed  CAS  Google Scholar 

  • Hirano A, Arumugasamy N, Zimmerman HM (1967) Amyotrophic lateral sclerosis. A comparison of Guam and classical cases. Arch Neurol 16:357–363

    PubMed  CAS  Google Scholar 

  • Hirano A, Dembitzer HM, Kurland LT, Zimmerman HM (1968) The fine structure of some intraganglionic alterations: neurofibrillary tangles, granulovacuolar bodies, and “rod-like” structures in Guam amyotrophic lateral sclerosis and parkinsonism–dementia complex. J Neuropathol Exp Neurol 27:167–182

    Article  PubMed  CAS  Google Scholar 

  • Hulette CM, Pericak-Vance MA, Roses AD et al (1999) Neuropathological features of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke family 1684. J Neuropathol Exp Neurol 58:859–866

    Article  PubMed  CAS  Google Scholar 

  • Ito H, Nakamura M, Komure O et al (2011) Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation. Acta Neuropathol 122:223–229

    Article  PubMed  Google Scholar 

  • Johansson A, Engler H, Blomquist G et al (2007) Evidence for astrocytosis in ALS demonstrated by [11C](l)-deprenyl-D2 PET. J Neurol Sci 255:17–22

    Article  PubMed  CAS  Google Scholar 

  • Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208

    Article  PubMed  CAS  Google Scholar 

  • Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19:R46–R64

    Article  PubMed  CAS  Google Scholar 

  • Lillo P, Garcin B, Hornberger M, Bak TH, Hodges JR (2010) Neurobehavioral features in frontotemporal dementia with amyotrophic lateral sclerosis. Arch Neurol 67:826–830

    Article  PubMed  Google Scholar 

  • Lomen-Hoerth C, Strong MJ (2006) Cognition in amyotrophic lateral sclerosis. In: Mitsumoto H, Przedborksi S, Gordon P, De Bene M (eds) Amyotrophic lateral sclerosis. Marcel Dekker, London, pp 115–138

    Google Scholar 

  • Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079

    PubMed  Google Scholar 

  • Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B (2003) Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 60:1094–1097

    PubMed  CAS  Google Scholar 

  • Lynch T, Sano M, Marder KS et al (1994) Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology 44:1878–1884

    PubMed  CAS  Google Scholar 

  • Mackenzie IR, Neumann M, Bigio EH et al (2010a) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4

    Article  PubMed  Google Scholar 

  • Mackenzie IR, Rademakers R, Neumann M (2010b) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007

    Article  PubMed  CAS  Google Scholar 

  • Malamud N, Hirano A, Kurland LT (1961) Pathoanatomic changes in amyotrophic lateral sclerosis on Guam. Arch Neurol 5:401–415

    PubMed  CAS  Google Scholar 

  • Martinaud O, Laquerrière A, Guyant-Maréchal L et al (2005) Frontotemporal dementia, motor neuron disease and tauopathy: clinical and neuropathological study in a family. Acta Neuropathol 110:84–92

    Article  PubMed  CAS  Google Scholar 

  • Masè G, Ros S, Gemma A et al (2001) ALS with variable phenotypes in a six-generation family caused by leu144phe mutation in the SOD1 gene. J Neurol Sci 191:11–18

    Article  PubMed  Google Scholar 

  • Massman PJ, Sims J, Cooke N, Haverkamp LJ, Appel V, Appel SH (1996) Prevalence and correlates of neuropsychological deficits in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 61:450–455

    Article  PubMed  CAS  Google Scholar 

  • Millecamps S, Salachas F, Cazeneuve C et al (2010) SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. J Med Genet 47:554–560

    Article  PubMed  CAS  Google Scholar 

  • Moisse K, Volkening K, Leystra-Lantz C, Welch I, Hill T, Strong MJ (2009) Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy. Brain Res 1249:202–211

    Article  PubMed  CAS  Google Scholar 

  • Morita M, Al-Chalabi A, Andersen PM et al (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839–844

    Article  PubMed  CAS  Google Scholar 

  • Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  • Papps B, Abrahams S, Wicks P, Leigh PN, Goldstein LH (2005) Changes in memory for emotional material in amyotrophic lateral sclerosis (ALS). Neuropsychologia 43:1107–1114

    Article  PubMed  CAS  Google Scholar 

  • Raaphorst J, de Visser M, Linssen WH, de Haan RJ, Schmand B (2010) The cognitive profile of amyotrophic lateral sclerosis: a meta-analysis. Amyotroph Lateral Scler 11:27–37

    Article  PubMed  Google Scholar 

  • Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE (2005) Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65:586–590

    Article  PubMed  CAS  Google Scholar 

  • Smith RG, Haverkamp LJ, Case S, Appel V, Appel SH (1996) Apolipoprotein E epsilon 4 in bulbar-onset motor neuron disease. Lancet 348:334–335

    Article  PubMed  CAS  Google Scholar 

  • Strong MJ (2001) The evidence for ALS as a multisystems disorder of limited phenotypic expression. Can J Neurol Sci 28:283–298

    PubMed  CAS  Google Scholar 

  • Strong MJ (2003) The basic aspects of therapeutics in amyotrophic lateral sclerosis. Pharmacol Ther 98:379–414

    Article  PubMed  CAS  Google Scholar 

  • Strong MJ (2004) Recent developments in the biochemistry and pharmacotherapy of amyotrophic lateral sclerosis. Expert Opin Investig Drugs 13:1593–1614

    Article  PubMed  CAS  Google Scholar 

  • Strong MJ (2008) The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 9:323–338

    Article  PubMed  CAS  Google Scholar 

  • Strong MJ (2010) The evidence for altered RNA metabolism in amyotrophic lateral sclerosis (ALS). J Neurol Sci 288:1–12

    Article  PubMed  CAS  Google Scholar 

  • Strong MJ, Gordon PH (2005) Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis—discrete entities or spectrum? Amyotroph Lateral Scler Other Motor Neuron Disord 6:8–16

    Article  PubMed  Google Scholar 

  • Strong MJ, Grace GM, Orange JB, Leeper HA, Menon R, Aere C (1999) A prospective study of cognitive impairment in ALS. Neurology 53:1665–1670

    PubMed  CAS  Google Scholar 

  • Strong MJ, Yang W, Strong WL, Leystra-Lantz C, Jaffe H, Pant HC (2006) Tau protein hyperphosphorylation in sporadic ALS with cognitive impairment. Neurology 66:1770–1771

    Article  PubMed  CAS  Google Scholar 

  • Strong MJ, Grace GM, Freedman M et al (2009) Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10:131–146

    Article  PubMed  Google Scholar 

  • Sutedja NA, van der Schouw YT, Fischer K et al (2011) Beneficial vascular risk profile is associated with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 82:638–642

    Article  PubMed  CAS  Google Scholar 

  • Tsai KJ, Yang CH, Fang YH et al (2010) Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med 207:1661–1673

    Article  PubMed  CAS  Google Scholar 

  • Turner MR, Cagnin A, Turkheimer FE et al (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15:601–609

    Article  PubMed  CAS  Google Scholar 

  • Turner MR, Hammers A, Al-Chalabi A et al (2005a) Distinct cerebral lesions in sporadic and ‘D90A’ SOD1 ALS: studies with [11C]flumazenil PET. Brain 128:1323–1329

    Article  PubMed  CAS  Google Scholar 

  • Turner MR, Rabiner EA, Hammers A et al (2005b) [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain 128:896–905

    Article  PubMed  CAS  Google Scholar 

  • van Es MA, Diekstra FP, Baas F et al (2009) A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology 72:287–288

    Article  PubMed  Google Scholar 

  • Vance C, Al-Chalabi A, Ruddy D et al (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129:868–876

    Article  PubMed  Google Scholar 

  • Vance C, Rogelj B, Hortobágyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    Article  PubMed  CAS  Google Scholar 

  • Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci USA 106:18809–18814

    Article  PubMed  CAS  Google Scholar 

  • Wicks P, Abrahams S, Papps B et al (2009) SOD1 and cognitive dysfunction in familial amyotrophic lateral sclerosis. J Neurol 256:234–241

    Article  PubMed  CAS  Google Scholar 

  • Wightman G, Anderson VER, Martin J et al (1992) Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139:269–274

    Article  PubMed  CAS  Google Scholar 

  • Wils H, Kleinberger G, Janssens J et al (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 107:3858–3863

    Article  PubMed  CAS  Google Scholar 

  • Wilson CM, Grace GM, Munoz DG, He BP, Strong MJ (2001) Cognitive impairment in sporadic ALS. A pathological continuum underlying a multisystem disorder. Neurology 57:651–657

    PubMed  CAS  Google Scholar 

  • Wilson AC, Dugger BN, Dickson DW, Wang DS (2011) TDP-43 in aging and Alzheimer's disease—a review. Int J Clin Exp Pathol 4:147–155

    PubMed  CAS  Google Scholar 

  • Yan J, Deng HX, Siddique N et al (2010) Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75:807–814

    Article  PubMed  CAS  Google Scholar 

  • Yang W, Sopper MM, Leystra-Lantz C, Strong MJ (2003) Microtubule-associated tau protein positive neuronal and glial inclusions in amyotrophic lateral sclerosis. Neurology 61:1766–1773

    PubMed  CAS  Google Scholar 

  • Yang W, Ang L-C, Strong MJ (2005) Tau protein aggregation in the frontal and entorhinal cortices as a function of aging. Dev Brain Res 156:127–138

    Article  CAS  Google Scholar 

  • Yang W, Leystra-Lantz C, Strong MJ (2008) Upregulation of GSK3β expression in frontal and temporal cortex of ALS with cognitive impairment (ALSci). Brain Res 1196:131–139

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Huang C, Chen H et al (2010) Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 6:e1000887

    Article  PubMed  Google Scholar 

  • Zimmerman EK, Eslinger PJ, Simmons Z, Barrett AM (2007) Emotional perception deficits in amyotrophic lateral sclerosis. Cogn Behav Neurol 20:79–82

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Research supported by the Michael Halls endowment.

Author information

Authors and Affiliations

  1. Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada

    Michael Joseph Strong & Wencheng Yang

  2. University Hospital, Rm C7-120, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Michael Joseph Strong

Authors
  1. Michael Joseph Strong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wencheng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Joseph Strong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strong, M.J., Yang, W. The Frontotemporal Syndromes of ALS. Clinicopathological Correlates. J Mol Neurosci 45, 648–655 (2011). https://doi.org/10.1007/s12031-011-9609-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-011-9609-0

Keywords

Search

Navigation