Diagnosis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Spectrum

  • Vanesa Pytel
  • Jordi A. Matías-Guiu


Around 15% of frontotemporal dementia (FTD) patients develop clinical symptoms of motor neuron dysfunction. Different studies have suggested that roughly 50% of patients with Amyotrophic Lateral Sclerosis (ALS) have some cognitive impairment, and 15% of them accomplish the diagnostic criteria for FTD. Cognitive impairment in ALS patients is key not only for therapeutic trials of this incurable disease, but also for care planning, compliance to interventions and ultimately end-of-life decisions.

In these kinds of diseases, establishing an early diagnosis—through specific neurological and neuropsychological study protocols including all cognitive domains—remains a fundamental challenge. Today, complementary neuroimaging techniques, at both structural and functional levels, allow us to reach more detailed diagnosis, reduce delay in its confirmation, and most importantly, establish different subgroups that could present different progression and outcome.

The aim of this chapter is to review the ALS-FTD complex, its diagnostic criteria and complementary tools that are currently available for study and follow-up of patients.


Amyotrophic lateral sclerosis Frontotemporal dementia Cognitive assessment Magnetic resonance imaging Positron emission tomography 


  1. 1.
    Onyike CU, Diehl-Schmid J. The epidemiology of frontotemporal dementia. Int Rev Psychiatry. 2013;25(2):130–7. Scholar
  2. 2.
    Ikeda M, Ishikawa T, Tanabe H. Epidemiology of frontotemporal lobar degeneration. Dement Geriatr Cogn Disord. 2004;17(4):265–8. Scholar
  3. 3.
    Mitsuyama Y. Presenile dementia with motor neuron disease. Dementia. 1993;4(3–4):137–42.PubMedGoogle Scholar
  4. 4.
    Lillo P, Garcin B, Hornberger M, Bak TH, Hodges JR. Neurobehavioral features in frontotemporal dementia with amyotrophic lateral sclerosis. Arch Neurol. 2010;67(7):826–30. Scholar
  5. 5.
    Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 2013;12(4):368–80. Scholar
  6. 6.
    Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, Power DM. Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett. 1988;93(2–3):197–203.CrossRefGoogle Scholar
  7. 7.
    Leigh PN, Whitwell H, Garofalo O, Buller J, Swash M, Martin JE, et al. Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain. 1991;114(Pt 2):775–88.CrossRefGoogle Scholar
  8. 8.
    Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for Frontotemporal lobar degeneration. Acta Neuropathol. 2007;114(1):5–22. Scholar
  9. 9.
    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119(1):1–4. Scholar
  10. 10.
    Fernandez-Matarrubia M, Matias-Guiu JA, Moreno-Ramos T, Matias-Guiu J. Biomarkers: a new approach to behavioural variant frontotemporal dementia. Neurologia. 2015;30(1):50–61. Scholar
  11. 11.
    Prayson RA. Neuropathology. Philadelphia: Elsevier Churchill Livingstone; 2005.Google Scholar
  12. 12.
    Mackenzie IR, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH, et al. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol. 2006;112(5):539–49. Scholar
  13. 13.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3. Scholar
  14. 14.
    Seelaar H, Kamphorst W, Rosso SM, Azmani A, Masdjedi R, de Koning I, et al. Distinct genetic forms of frontotemporal dementia. Neurology. 2008;71(16):1220–6.CrossRefGoogle Scholar
  15. 15.
    Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–55. Scholar
  16. 16.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56. Scholar
  17. 17.
    Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012;11(1):54–65. Scholar
  18. 18.
    Kaivorinne AL, Moilanen V, Kervinen M, Renton AE, Traynor BJ, Majamaa K, et al. Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia. Alzheimer Dis Assoc Disord. 2014;28(2):190–3. Scholar
  19. 19.
    Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137:2329–234.CrossRefGoogle Scholar
  20. 20.
    Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347:1436.CrossRefGoogle Scholar
  21. 21.
    Williams KL, Topp S, Yang S, Smith B, Fifita JA, Warraich ST, et al. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun. 2016;7:11253.CrossRefGoogle Scholar
  22. 22.
    White MA, Sreedharan J. Amyotrophic lateral sclerosis: recent genetic highlights. Curr Opin Neurol. 2016;29(5):557–64.CrossRefGoogle Scholar
  23. 23.
    Kirshner HS. Frontotemporal dementia and primary progressive aphasia: an update. Curr Neurol Neurosci Rep. 2010;10(6):504–11. Scholar
  24. 24.
    Pena-Casanova J, Bohm P. Neuropsychological exploration in frontotemporal degeneration. Neurologia. 2000;15(1):17–29.PubMedGoogle Scholar
  25. 25.
    Kramer JH, Jurik J, Sha SJ, Rankin KP, Rosen HJ, Johnson JK, et al. Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cogn Behav Neurol. 2003;16(4):211–8.CrossRefGoogle Scholar
  26. 26.
    Piguet O, Hornberger M, Mioshi E, Hodges JR. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol. 2011;10(2):162–72. Scholar
  27. 27.
    Whitwell JL, Przybelski SA, Weigand SD, Ivnik RJ, Vemuri P, Gunter JL, et al. Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study. Brain. 2009;132:2932–46.CrossRefGoogle Scholar
  28. 28.
    Whitwell JL, Jack CR Jr, Parisi JE, Senjem ML, Knopman DS, Boeve BF, et al. Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration? Neurology. 2010;75:2212–20.CrossRefGoogle Scholar
  29. 29.
    Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546–54.CrossRefGoogle Scholar
  30. 30.
    Rascovsky K, Hodges JR, Kipps CM, Johnson JK, Seeley WW, Mendez MF, et al. Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions. Alzheimer Dis Assoc Disord. 2007;21(4):S14–8. Scholar
  31. 31.
    Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76:1006–14.CrossRefGoogle Scholar
  32. 32.
    Bak TH, Hodges JR. Motor neurone disease, dementia and aphasia: coincidence, co-occurrence or continuum? J Neurol. 2001;248(4):260–70.CrossRefGoogle Scholar
  33. 33.
    Neary D. Non Alzheimer’s disease forms of cerebral atrophy. J Neurol Neurosurg Psychiatry. 1990;53(11):929–31.CrossRefGoogle Scholar
  34. 34.
    Bak TH, Hodges JR. Cognition, language and behaviour in motor neurone disease: evidence of frontotemporal dysfunction. Dement Geriatr Cogn Disord. 1999;10(1):29–32.CrossRefGoogle Scholar
  35. 35.
    Velakoulis D, Walterfang M, Mocellin R, Pantelis C, McLean C. Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases. Br J Psychiatry. 2009;194(4):298–305. Scholar
  36. 36.
    Whitwell JL, Josephs KA, Murray ME, Kantarci K, Przybelski SA, Weigand SD, et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology. 2008;71(10):743–9. Scholar
  37. 37.
    Barnes F. Setting standards in the presence of developing scientific understanding. Electromagn Biol Med. 2006;25(4):209–15. Scholar
  38. 38.
    Chao LL, Schuff N, Clevenger EM, Mueller SG, Rosen HJ, Gorno-Tempini ML, et al. Patterns of white matter atrophy in frontotemporal lobar degeneration. Arch Neurol. 2007;64(11):1619–24. Scholar
  39. 39.
    Seeley WW, Crawford R, Rascovsky K, Kramer JH, Weiner M, Miller BL, et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol. 2008;65(2):249–55. Scholar
  40. 40.
    Rohrer JD, Geser F, Zhou J, Gennatas ED, Sidhu M, Trojanowski JQ, et al. TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia. Neurology. 2010;75(24):2204–11.CrossRefGoogle Scholar
  41. 41.
    Lillo P, Mioshi E, Burrell JR, Kiernan MC, Hodges JR, Hornberger M. Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One. 2012;7:e43993.CrossRefGoogle Scholar
  42. 42.
    Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA. 2001;286(17):2120–7.CrossRefGoogle Scholar
  43. 43.
    Poljansky S, Ibach B, Vogel M, Manner P, Marienhagen J, Hajak G. Differences in cerebral glucose metabolism between frontotemporal lobar degeneration and Alzheimer’s disease. Psychiatr Prax. 2004;31(Suppl 1):S73–5. Scholar
  44. 44.
    Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR, et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer’s disease. Brain. 2007;130(Pt 10):2616–35. Scholar
  45. 45.
    Dalakas MC, Hatazawa J, Brooks RA, Di Chiro G. Lowered cerebral glucose utilization in amyotrophic lateral sclerosis. Ann Neurol. 1987;22(5):580–6. Scholar
  46. 46.
    Hatazawa J, Brooks RA, Dalakas MC, Mansi L, Di Chiro G. Cortical motor-sensory hypometabolism in amyotrophic lateral sclerosis: a PET study. J Comput Assist Tomogr. 1988;12(4):630–6.CrossRefGoogle Scholar
  47. 47.
    Ludolph AC, Langen KJ, Regard M, Herzog H, Kemper B, Kuwert T, et al. Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study. Acta Neurol Scand. 1992;85(2):81–9.CrossRefGoogle Scholar
  48. 48.
    Abrahams S, Goldstein LH, Kew JJ, Brooks DJ, Lloyd CM, Frith CD, et al. Frontal lobe dysfunction in amyotrophic lateral sclerosis. A PET study. Brain. 1996;119(Pt 6):2105–20.CrossRefGoogle Scholar
  49. 49.
    Renard D, Verd A, Labauge P. Bilateral choroid plexus cyst: the interest of DWI imaging. Acta Neurol Belg. 2011;111(1):80.PubMedGoogle Scholar
  50. 50.
    Chio A, Pagani M, Agosta F, Calvo A, Cistaro A, Filippi M. Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes. Lancet Neurol. 2014;13(12):1228–40. Scholar
  51. 51.
    Canosa A, Pagani M, Cistaro A, Montuschi A, Iazzolino B, Fania P, et al. 18F-FDG-PET correlates of cognitive impairment in ALS. Neurology. 2016;86(1):44–9. Scholar
  52. 52.
    Matias-Guiu JA, Pytel V, Cabrera-Martin MN, Galan L, Valles-Salgado M, Guerrero A, et al. Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis. Eur J Nucl Med Mol Imaging. 2016;43(11):2050–60. Scholar
  53. 53.
    Cistaro A, Pagani M, Montuschi A, Calvo A, Moglia C, Canosa A, et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging. 2014;41(5):844–52.CrossRefGoogle Scholar
  54. 54.
    Duclos Y, Grapperon AM, Jouve E, Truillet R, Zemmor C, Verschueren A, et al. Motor-evoked potential gain is a helpful test for the detection of corticospinal tract dysfunction in amyotrophic lateral sclerosis. Clin Neurophysiol. 2017;128(2):357–64. Scholar
  55. 55.
    Tsuji Y, Noto YI, Shiga K, Teramukai S, Nakagawa M, Mizuno T. A muscle ultrasound score in the diagnosis of amyotrophic lateral sclerosis. Clin Neuropshysiol. 2017;128(6):1069–74. Scholar
  56. 56.
    Vucic S, Kiernan MC. Transcranial magnetic stimulation for the assessment of neurodegenerative disease. Neurotherapeutics. 2017;14(1):91–106. Scholar
  57. 57.
    Elder GJ, Taylor JP. Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias? Alzheimers Res Ther. 2014;6(9):74. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Vanesa Pytel
    • 1
  • Jordi A. Matías-Guiu
    • 1
  1. 1.Department of NeurologyHospital Clínico San CarlosMadridSpain

Personalised recommendations