Journal of Neurology

, Volume 265, Issue 8, pp 1819–1828 | Cite as

Primary lateral sclerosis and the amyotrophic lateral sclerosis–frontotemporal dementia spectrum

  • Smriti AgarwalEmail author
  • Elizabeth Highton-Williamson
  • Jashelle Caga
  • José M. Matamala
  • Thanuja Dharmadasa
  • James Howells
  • Margaret C. Zoing
  • Kazumoto Shibuya
  • Nimeshan Geevasinga
  • Steve Vucic
  • John R. Hodges
  • Rebekah M. Ahmed
  • Matthew C. Kiernan
Original Communication



To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum of diseases.


Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS–FTD (n = 12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS).


Global cognition was impaired in PLS (mean total ACE score 82.5 ± 13.6), similar to ALS–FTD (mean total ACE score 76.3 ± 7.7, p > 0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5 ± 6.2) compared ALS–FTD (50.1 ± 7.2, p < 0.001) and ALS (62.3 ± 12.6, p = 0.046). Average short-interval intracortical inhibition (SICI) was similar in all three patient groups. The mean survival time was longest in PLS (217.4 ± 22.4 months) and shortest in ALS–FTD (38.5 ± 4.5 months, p = 0.002). Bulbar onset disease (β = − 0.45, p = 0.007) and RMT (β = 0.54, p = 0.001) were independent predictors of global cognition while motor scores (β = 0.47, p = 0.036) and SICI (β = 0.58, p = 0.006) were significantly associated with ALSFRS.


The cognitive profile in PLS resembles ALS–FTD, without prominent behavioural disturbances. A higher RMT in PLS than ALS and ALS–FTD is consistent with differential cortical motor neuronal abnormalities and more severe involvement of corticospinal axons while SICI, indicative of inhibitory interneuronal dysfunction was comparable with ALS and ALS–FTD. Overall, while these findings support the notion that PLS lies on the ALS–FTD spectrum, the mechanisms underlying slow disease progression are likely to be distinct in PLS.


PLS ALS–FTD spectrum Clinical Cognitive TMS Motor cortical function 



This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council (NHMRC) (APP1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE11000102). SA was funded by the Ellison-Cliffe travelling fellowship from the Royal Society of Medicine, UK.

Compliance with ethical standards

Conflicts of interest

The authors have no conflicts of interest.


  1. 1.
    Le Forestier N, Maisonobe T, Piquard A et al (2001) Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature. Brain 124:1989–1999CrossRefPubMedGoogle Scholar
  2. 2.
    Pringle CE, Hudson AJ, Munoz DG et al (1992) Primary lateral sclerosis: clinical features, neuropathology and diagnostic criteria. Brain 115:495–520CrossRefPubMedGoogle Scholar
  3. 3.
    Caselli RJ, Smith BE, Osborne D (1995) Primary lateral sclerosis: a neuropsychological study. Neurology 45:2005–2009CrossRefPubMedGoogle Scholar
  4. 4.
    Grace GM, Orange JB, Rowe A et al (2011) Neuropsychological functioning in PLS: a comparison with ALS. Can J Neurol Sci 38:88–97PubMedGoogle Scholar
  5. 5.
    Canu E, Agosta F, Galantucci S et al (2013) Extramotor damage is associated with cognition in primary lateral sclerosis patients. PLoS ONE 8:e82017–e82018. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Agosta F, Galantucci S, Riva N et al (2013) Intrahemispheric and interhemispheric structural network abnormalities in PLS and ALS. Hum Brain Mapp 35:1710–1722. CrossRefPubMedGoogle Scholar
  7. 7.
    Agosta F, Canu E, Inuggi A et al (2014) Resting state functional connectivity alterations in primary lateral sclerosis. Neurobiol Aging 35:916–925. CrossRefPubMedGoogle Scholar
  8. 8.
    Gallagher JP (1989) Pathologic laughter and crying in ALS: a search for their origin. Acta Neurol Scand 80:114–117. CrossRefPubMedGoogle Scholar
  9. 9.
    Abrahams S, Goldstein LH, Al-Chalabi A et al (1997) Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 62:464–472. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Floeter MK, Katipally R, Kim MP et al (2014) Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders. Neurology 83:620–627. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pringle CE, Hudson AJ, Munoz DG et al (1992) Primary lateral sclerosis—clinical-features, neuropathology and diagnostic-criteria. Brain 115:495–520. CrossRefPubMedGoogle Scholar
  12. 12.
    Nihei K, McKee AC, Kowall NW (1993) Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol 86:55–64. CrossRefPubMedGoogle Scholar
  13. 13.
    Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955. CrossRefPubMedGoogle Scholar
  14. 14.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. CrossRefPubMedGoogle Scholar
  15. 15.
    Turner MR, Hardiman O, Benatar M et al (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–322. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Dickson DW, Josephs KA, Amador-Ortiz C (2007) TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol 114:71–79. CrossRefPubMedGoogle Scholar
  17. 17.
    Josephs KA, Dickson DW (2007) Frontotemporal lobar degeneration with upper motor neuron disease/primary lateral sclerosis. Neurology 69:1800–1801. CrossRefPubMedGoogle Scholar
  18. 18.
    Agosta F, Ferraro PM, Riva N et al (2016) Structural brain correlates of cognitive and behavioral impairment in MND. Hum Brain Mapp 37:1614–1626. CrossRefPubMedGoogle Scholar
  19. 19.
    Mioshi E, Lillo P, Yew B et al (2013) Cortical atrophy in ALS is critically associated with neuropsychiatric and cognitive changes. Neurology 80:1117–1123. CrossRefPubMedGoogle Scholar
  20. 20.
    Menon P, Geevasinga N, Yiannikas C et al (2015) Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol 14:478–484. CrossRefPubMedGoogle Scholar
  21. 21.
    Vucic S, Ziemann U, Eisen A et al (2013) Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg Psychiatry 84:1161–1170. CrossRefPubMedGoogle Scholar
  22. 22.
    Mills KR (2003) The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain 126:2558–2566. CrossRefPubMedGoogle Scholar
  23. 23.
    Kuipers-Upmeijer J, de Jager AE, Hew JM et al (2001) Primary lateral sclerosis: clinical, neurophysiological, and magnetic resonance findings. J Neurol Neurosurg Psychiatry 71:615–620CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Geevasinga N, Menon P, Sue CM et al (2015) Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia. Eur J Neurol 22:826–858. CrossRefPubMedGoogle Scholar
  25. 25.
    Burrell JR, Halliday GM, Kril JJ et al (2016) The frontotemporal dementia-motor neuron disease continuum. Lancet 388:919–931. CrossRefPubMedGoogle Scholar
  26. 26.
    Costa J, Swash M, de Carvalho M (2012) Awaji criteria for the diagnosis of amyotrophic lateral sclerosis. Arch Neurol 69:1410–1417. CrossRefPubMedGoogle Scholar
  27. 27.
    Strong MJ, Abrahams S, Goldstein LH et al (2017) Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 18:153–174. CrossRefPubMedGoogle Scholar
  28. 28.
    O’Brien M (2010) Aids to the examination of the peripheral nervous system. Saunders Limited, PhiladelphiaGoogle Scholar
  29. 29.
    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. CrossRefPubMedGoogle Scholar
  30. 30.
    Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci 169:13–21. CrossRefPubMedGoogle Scholar
  31. 31.
    Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265–267. CrossRefPubMedGoogle Scholar
  32. 32.
    Labra J, Menon P, Byth K et al (2016) Rate of disease progression: a prognostic biomarker in ALS. J Neurol Neurosurg Psychiatry 87:628–632. CrossRefPubMedGoogle Scholar
  33. 33.
    Hsieh S, Schubert S, Hoon C et al (2013) Validation of the Addenbrooke’s cognitive examination III in frontotemporal dementia and Alzheimer’s disease. Dement Geriatr Cogn Disord 36:242–250. CrossRefPubMedGoogle Scholar
  34. 34.
    Mioshi E, Caga J, Lillo P et al (2014) Neuropsychiatric changes precede classic motor symptoms in ALS and do not affect survival. Neurology 82:149–155. CrossRefPubMedGoogle Scholar
  35. 35.
    Vucic S, Kiernan MC (2006) Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 129:2436–2446. CrossRefPubMedGoogle Scholar
  36. 36.
    Vucic S, Howells J, Trevillion L, Kiernan MC (2006) Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve 33:477–486. CrossRefPubMedGoogle Scholar
  37. 37.
    Fisher RJ, Nakamura Y, Bestmann S et al (2002) Two phases of intracortical inhibition revealed by transcranial magnetic threshold tracking. Exp Brain Res 143:240–248. CrossRefPubMedGoogle Scholar
  38. 38.
    Cantello R, Gianelli M, Civardi C, Mutani R (1992) Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 42:1951–1959CrossRefPubMedGoogle Scholar
  39. 39.
    Mathuranath PS, Nestor PJ, Berrios GE et al (2000) A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 55:1613–1620CrossRefPubMedGoogle Scholar
  40. 40.
    Burrell JR, Kiernan MC, Vucic S, Hodges JR (2011) Motor neuron dysfunction in frontotemporal dementia. Brain 134:2582–2594. CrossRefPubMedGoogle Scholar
  41. 41.
    Benussi A, Di Lorenzo F, Dell’Era V et al (2017) Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia. Neurology 89:665–672. CrossRefPubMedGoogle Scholar
  42. 42.
    Vucic S, Kiernan MC (2017) Transcranial magnetic stimulation for the assessment of neurodegenerative disease. Neurotherapeutics 14:91–106. CrossRefPubMedGoogle Scholar
  43. 43.
    Menon P, Geevasinga N, Yiannikas C, Howells J (2015) Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet 14:478–484. CrossRefPubMedGoogle Scholar
  44. 44.
    Turner MR, Hammers A, Al-Chalabi A et al (2007) Cortical involvement in four cases of primary lateral sclerosis using [(11)C]-flumazenil PET. J Neurol 254:1033–1036. CrossRefPubMedGoogle Scholar
  45. 45.
    Gordon PH, Cheng B, Salachas F et al (2010) Progression in ALS is not linear but is curvilinear. J Neurol 257:1713–1717. CrossRefPubMedGoogle Scholar
  46. 46.
    Singer MA, Statland JM, Wolfe GI, Barohn RJ (2007) Primary lateral sclerosis. Muscle Nerve 35:291–302. CrossRefPubMedGoogle Scholar
  47. 47.
    Hossaini M, Cardona Cano S, van Dis V et al (2011) Spinal inhibitory interneuron pathology follows motor neuron degeneration independent of glial mutant superoxide dismutase 1 expression in SOD1-ALS mice. J Neuropathol Exp Neurol 70:662–677. CrossRefPubMedGoogle Scholar
  48. 48.
    Turner MR, Agosta F, Bede P et al (2012) Neuroimaging in amyotrophic lateral sclerosis. Biomark Med 6:319–337. CrossRefPubMedGoogle Scholar
  49. 49.
    Van Laere K, Vanhee A, Verschueren J et al (2014) Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurol 71:553–561. CrossRefPubMedGoogle Scholar
  50. 50.
    Vucic S, Lin CS-Y, Cheah BC et al (2013) Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain 136:1361–1370. CrossRefPubMedGoogle Scholar
  51. 51.
    Saxon JA, Thompson JC, Jones M et al (2017) Examining the language and behavioural profile in FTD and ALS–FTD. J Neurol Neurosurg Psychiatry 88:675–680. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Woolley JD, Gorno-Tempini M-L, Seeley WW et al (2007) Binge eating is associated with right orbitofrontal–insular–striatal atrophy in frontotemporal dementia. Neurology 69:1424–1433. CrossRefPubMedGoogle Scholar
  53. 53.
    Ahmed RM, Latheef S, Bartley L et al (2015) Eating behavior in frontotemporal dementia: peripheral hormones vs hypothalamic pathology. Neurology 85:1310–1317. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Tartaglia MC, Laluz V, Rowe A et al (2009) Brain atrophy in primary lateral sclerosis. Neurology 72:1236–1241. CrossRefPubMedGoogle Scholar
  55. 55.
    Hsieh S, Caga J, Leslie FVC et al (2016) Cognitive and behavioral symptoms in ALSFTD: detection, differentiation, and progression. J Geriatr Psychiatry Neurol 29:3–10. CrossRefPubMedGoogle Scholar
  56. 56.
    Niven E, Newton J, Foley J et al (2015) Validation of the edinburgh cognitive and behavioural amyotrophic lateral sclerosis screen (ECAS): a cognitive tool for motor disorders. Amyotroph Lateral Scler Frontotemporal Degener 16:172–179. CrossRefPubMedGoogle Scholar
  57. 57.
    Shibuya K, Park SB, Geevasinga N et al (2016) Motor cortical function determines prognosis in sporadic ALS. Neurology 87:513–520. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Smriti Agarwal
    • 1
    • 2
    • 4
    Email author
  • Elizabeth Highton-Williamson
    • 1
    • 2
  • Jashelle Caga
    • 1
    • 2
  • José M. Matamala
    • 1
    • 2
  • Thanuja Dharmadasa
    • 1
    • 2
  • James Howells
    • 1
    • 2
  • Margaret C. Zoing
    • 1
    • 2
  • Kazumoto Shibuya
    • 1
    • 2
  • Nimeshan Geevasinga
    • 3
  • Steve Vucic
    • 3
  • John R. Hodges
    • 1
  • Rebekah M. Ahmed
    • 1
    • 2
  • Matthew C. Kiernan
    • 1
    • 2
  1. 1.Brain and Mind Centre, Sydney Medical SchoolUniversity of SydneySydneyAustralia
  2. 2.Institute of Clinical NeurosciencesRoyal Prince Alfred HospitalSydneyAustralia
  3. 3.Westmead Clinical SchoolUniversity of SydneySydneyAustralia
  4. 4.Neurology UnitAddenbrooke’s HospitalCambridgeUK

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