Skip to main content
SpringerLink
Log in

Amyotrophe Lateralsklerose

Eine Multisystemdegeneration

Amyotrophic lateral sclerosis

Multisystem degeneration

  • Übersichten
  • Published:
Der Nervenarzt Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

In den letzten Jahren haben sich zunehmend Hinweise darauf ergeben, dass es sich bei der amyotrophen Lateralsklerose (ALS) nicht um eine reine Motoneuronerkrankung, sondern um eine Multisystemdegeneration mit einer Vielzahl nichtmotorischer Symptome handelt. Diese moderne Auffassung untermauerten neuropathologische und bildgebende Erkenntnisse.

Fragestellung

Es soll die Frage beantwortet werden, welche Erkenntnisse für das Vorliegen einer Multisystemdegeneration sprechen und was dies für Diagnostik und Therapie der Erkrankung bedeutet.

Material und Methode

Zusammenfassung und Bewertung neuester klinischer, bildgebender und neuropathologischer Studien.

Ergebnisse

Die aktuelle Studienlage belegt, dass Symptome der ALS weit über das motorische Nervensystem hinausgehen und insbesondere kognitive Funktionen, die Okulomotorik, das extrapyramidale System und die Sensibilität betreffen. Als neuropathologisches Korrelat findet sich eine stadienhafte Ausbreitung des Proteins „transactive response DNA binding protein 43 kDa“ (TDP-43) über funktionell verbundene kortikale Strukturen.

Schlussfolgerungen

Nichtmotorische Symptome kommen bei der ALS regelmäßig vor, auch wenn sie klinisch zumeist nicht im Vordergrund stehen. Das Wissen um ihr neuropathologisches Korrelat bietet neue Perspektiven für die Diagnostik, aber auch für die Therapie.

Summary

Background

There is increasing evidence that amyotrophic lateral sclerosis (ALS) has to be regarded as multisystem degeneration rather than as purely a motor neuron disease, as it also includes various dnonmotor symptoms. This modern view has been confirmed by neuropathological and imaging findings.

Objectives

To review recent findings supporting the idea of multisystem degeneration and to describe the implications for diagnostics and therapy.

Methods

A discussion of recent clinical, imaging, and neuropathological findings is presented.

Results

Symptoms of ALS include not only motor symptoms but also cognitive impairment, oculomotor abnormalities, and extrapyramidal and sensory symptoms. As a neuropathological correlate, a systematic spreading of „transactive response DNA binding protein 43 kDa“ (TDP-43) over functionally connected cortical structures has been described.

Conclusions

Nonmotor symptoms are regularly seen in ALS, although they usually do not dominate the clinical picture. Recent neuropathological findings offer new perspectives for diagnostics and therapy in ALS.

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

Abb. 1
Abb. 2

Literatur

  1. Anderson TJ, Macaskill MR (2013) Eye movements in patients with neurodegenerative disorders. Nature reviews. Neurology 9:74–85

    PubMed  Google Scholar 

  2. Ash S, Olm C, Mcmillan CT et al (2015) Deficits in sentence expression in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 16:31–39

    Article  PubMed Central  PubMed  Google Scholar 

  3. Boeve BF, Boylan KB, Graff-Radford NR et al (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765–783

    Article  PubMed Central  PubMed  Google Scholar 

  4. Braak H, Brettschneider J, Ludolph AC et al (2013) Amyotrophic lateral sclerosis – a model of corticofugal axonal spread. Nature reviews. Neurology 9:708–714

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Braumühl A (1932) Pick’s disease and amyotrophic lateral sclerosis. Allg Zeitschrift Fur Psychiatr Psychol Med 96:364–366

    Google Scholar 

  6. Brettschneider J, Del Tredici K, Toledo JB et al (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74:20–38

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Carlomagno Y, Zhang Y, Davis M et al (2014) Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins. PloS One 9:e90452

    Article  PubMed Central  PubMed  Google Scholar 

  8. Chen AL, Riley DE, King SA et al (2010) The disturbance of gaze in progressive supranuclear palsy: implications for pathogenesis. Front Neurol 1:147

    PubMed Central  PubMed  Google Scholar 

  9. Chio A, Ilardi A, Cammarosano S et al (2012) Neurobehavioral dysfunction in ALS has a negative effect on outcome and use of PEG and NIV. Neurology 78:1085–1089

    Article  CAS  PubMed  Google Scholar 

  10. Choksi DK, Roy B, Chatterjee S et al (2014) TDP-43 Phosphorylation by casein kinase Iepsilon promotes oligomerization and enhances toxicity in vivo. Hum Mol Genet 23:1025–1035

    Article  CAS  PubMed  Google Scholar 

  11. Cirulli ET, Lasseigne BN, Petrovski S et al (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–1441

  12. Czell D, Andersen PM, Neuwirth C et al (2013) Progressive aphasia as the presenting symptom in a patient with amyotrophic lateral sclerosis with a novel mutation in the OPTN gene. Amyotroph Lateral Scler Frontotemporal Degener 14:138–140

    Article  PubMed  Google Scholar 

  13. DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256

  14. Desport JC, Preux PM, Truong TC et al (1999) Nutritional status is a prognostic factor for survival in ALS patients. Neurology 53:1059–1063

    Article  CAS  PubMed  Google Scholar 

  15. Dornblüth O (1889) An anatomical investigation of a case of amyotrophic lateral sclerosis. Neur Zbl 13

  16. Dorst J, Cypionka J, Ludolph AC (2013) High-caloric food supplements in the treatment of amyotrophic lateral sclerosis: A prospective interventional study. Amyotroph Lateral Scler Frontotemporal Degener 14:533–536

    Article  CAS  PubMed  Google Scholar 

  17. Dorst J, Dupuis L, Petri S et al (2015) Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: a prospective observational study. J Neurol 262(4):849–858

    Article  PubMed  Google Scholar 

  18. Dorst J, Kuhnlein P, Hendrich C et al (2011) Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis. J Neurol 258:613–617

    Article  CAS  PubMed  Google Scholar 

  19. Dupuis L, Corcia P, Fergani A et al (2008) Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 70:1004–1009

    Article  CAS  PubMed  Google Scholar 

  20. Fathinia P, Hermann A, Reuner U et al (2013) Parkinson’s disease-like midbrain hyperechogenicity is frequent in amyotrophic lateral sclerosis. J Neurol 260:454–457

    Article  PubMed  Google Scholar 

  21. Feneberg E, Hübers A, Weishaupt JH et al (2014) Genetik und Neurochemische Biomarker bei Amyotropher Lateralsklerose und Frontotemporaler Lobärdegeneration. Akt Neurol 41:239–247

    Article  Google Scholar 

  22. Freischmidt A, Wieland T, Richter B et al (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 18:631–636

    Article  CAS  PubMed  Google Scholar 

  23. Galimberti D, Fenoglio C, Serpente M et al (2013) Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol Psychiatry 74:384–391

    Article  CAS  PubMed  Google Scholar 

  24. Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538

  25. Goldstein LH, Abrahams S (2013) Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol 12:368–380

    Article  PubMed  Google Scholar 

  26. Ichikawa H (2010) Language disorders in ALS/FTLD. Clin Neurol 50:1014–1016

    Google Scholar 

  27. Iglesias C, Sangari S, El Mendili MM et al (2015) Electrophysiological and spinal imaging evidences for sensory dysfunction in amyotrophic lateral sclerosis. BMJ Open 5:e007659

    Article  PubMed Central  PubMed  Google Scholar 

  28. Iwanaga K, Hayashi S, Oyake M et al (1997) Neuropathology of sporadic amyotrophic lateral sclerosis of long duration. J Neurol Sci 146:139–143

    Article  CAS  PubMed  Google Scholar 

  29. Ju JS, Fuentealba RA, Miller SE et al (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187:875–888

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574

  31. Kassubek J, Muller HP, Del Tredici K et al (2014) Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain 137:1733–1740

    Article  PubMed  Google Scholar 

  32. Kim HJ, Raphael AR, Ladow ES et al (2014) Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet 46:152–160

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kleijnen MF, Shih AH, Zhou P et al (2000) The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell 6:409–419

    Article  CAS  PubMed  Google Scholar 

  34. 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

  35. Leveille A, Kiernan J, Goodwin JA et al (1982) Eye movements in amyotrophic lateral sclerosis. Arch Neurol 39:684–686

    Article  CAS  PubMed  Google Scholar 

  36. Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Ludolph A, Drory V, Hardiman O et al (2015) A revision of the El Escorial criteria – 2015. Amyotroph Lateral Scler Frontotemporal Degener. doi:10.3109/21678421.2015.1049183 (Epub ahead of print)

    Google Scholar 

  38. Lule D, Burkhardt C, Abdulla S et al (2015) The edinburgh cognitive and Behavioural Amyotrophic lateral sclerosis screen: a cross-sectional comparison of established screening tools in a German-Swiss population. Amyotroph Lateral Scler Frontotemporal Degener 16:16–23

    Article  PubMed  Google Scholar 

  39. Lule D, Kurt A, Jurgens R et al (2005) Emotional responding in amyotrophic lateral sclerosis. J Neurol 252:1517–1524

    Article  PubMed  Google Scholar 

  40. Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226

  41. Mendell JR, Chase TN, Engel WK (1971) Amyotrophic lateral sclerosis: metabolism of central monoamines and treatment with L-dopa. Trans Am Neurol Assoc 96:284–286

    CAS  PubMed  Google Scholar 

  42. 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  CAS  PubMed  Google Scholar 

  43. Piepers S, Van Den Berg JP, Kalmijn S et al (2006) Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature. Amyotroph Lateral Scler 7:195–200

    Article  PubMed  Google Scholar 

  44. Pradat PF, Bruneteau G, Munerati E et al (2009) Extrapyramidal stiffness in patients with amyotrophic lateral sclerosis. Mov Disord 24:2143–2148

    Article  PubMed  Google Scholar 

  45. Ravits J (2014) Focality, stochasticity and neuroanatomic propagation in ALS pathogenesis. Exp Neurol 262(Pt B):121–126

    Article  CAS  PubMed  Google Scholar 

  46. Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268

  47. Rosen DR, Siddique T, Patterson D et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

  48. Schreiber H, Gaigalat T, Wiedemuth-Catrinescu U et al (2005) Cognitive function in bulbar- and spinal-onset amyotrophic lateral sclerosis. A longitudinal study in 52 patients. J Neurol 252:772–781

    Article  PubMed  Google Scholar 

  49. Scotter EL, Chen HJ, Shaw CE (2015) TDP-43 Proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 12:352–363

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Shaunak S, Orrell RW, O’sullivan E et al (1995) Oculomotor function in amyotrophic lateral sclerosis: evidence for frontal impairment. Ann Neurol 38:38–44

    Article  CAS  PubMed  Google Scholar 

  51. Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

  52. Suzuki H, Lee K, Matsuoka M (2011) TDP-43-induced death is associated with altered regulation of BIM and Bcl-xL and attenuated by caspase-mediated TDP-43 cleavage. J Biol Chem 286:13171–13183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Truini A, Biasiotta A, Onesti E et al (2015) Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS. J Neurol 262:1014–1018

    Article  CAS  PubMed  Google Scholar 

  54. Uenal H, Rosenbohm A, Kufeldt J et al (2014) Incidence and geographical variation of amyotrophic lateral sclerosis (ALS) in Southern Germany – completeness of the ALS registry Swabia. PloS One 9:e93932

    Article  PubMed Central  PubMed  Google Scholar 

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

  56. Van Langenhove T, Van Der Zee J, Van Broeckhoven C (2012) The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med 44:817–828

    Article  PubMed Central  PubMed  Google Scholar 

  57. Wang IF, Guo BS, Liu YC et al (2012) Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A 109:15024–15029

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Weis J, Katona I, Muller-Newen G et al (2011) Small-fiber neuropathy in patients with ALS. Neurology 76:2024–2029

    Article  CAS  PubMed  Google Scholar 

  59. Yang C, Tan W, Whittle C et al (2010) The C-terminal TDP-43 fragments have a high aggregation propensity and harm neurons by a dominant-negative mechanism. PloS One 5:e15878

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Yoshizawa K, Yasuda N, Fukuda M et al (2014) Syntactic comprehension in patients with amyotrophic lateral sclerosis. Behav Neurol 2014:230578

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Danksagung

Wir danken D. Ewert für seine Hilfe bei der Erstellung der Grafiken.

Author information

Authors and Affiliations

  1. Klinik für Neurologie, Universitätsklinikum Ulm, Universität Ulm, Oberer Eselsberg 45, 89081, Ulm, Deutschland

    A. Hübers, A. C. Ludolph, A. Rosenbohm, E. H. Pinkhardt, J. H. Weishaupt &  J. Dorst

Authors
  1. A. Hübers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. C. Ludolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Rosenbohm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. H. Pinkhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. H. Weishaupt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Dorst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Dorst.

Ethics declarations

Interessenkonflikt

A. Hübers, A. C. Ludolph, A. Rosenbohm, E. H. Pinkhardt, J. H. Weishaupt und J. Dorst geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hübers, A., Ludolph, A.C., Rosenbohm, A. et al. Amyotrophe Lateralsklerose. Nervenarzt 87, 179–188 (2016). https://doi.org/10.1007/s00115-015-0030-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-015-0030-8

Schlüsselwörter

Keywords

Search

Navigation