Skip to main content
SpringerLink
Log in

Amyotrophe Lateralsklerose und frontotemporale Demenz – auf dem Weg zu gemeinsamen genspezifischen Therapieansätzen

Amyotrophic lateral sclerosis and frontotemporal dementia—On the way to common gene-specific treatment approaches

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

Zusammenfassung

Hintergrund

Die amyotrophe Lateralsklerose (ALS) und die frontotemporale Demenz (FTD) teilen gemeinsame neuropathologische und – im Falle einer vorliegenden Genmutation – auch genetische Ursachen. In der Literatur werden derzeit, neben weiteren selteneren Varianten, 5 ALS-FTD-Gene beschrieben.

Ziel der Arbeit

Der aktuelle Forschungsstand zu Therapiemöglichkeiten der ALS und FTD soll dargestellt sowie ein Ausblick auf mögliche Gentherapien für ALS-FTD gegeben werden.

Material und Methoden

Analyse des Zeitverlaufs der ALS- und FTD-Forschung unter Berücksichtigung des steigenden Kenntnisstands der den Erkrankungen zugrunde liegenden Pathomechanismen.

Ergebnisse

Neben antiinflammatorischen Ansätzen oder der Stabilisierung von Proteinfaltungen werden aktuell vielversprechende genspezifische Therapieansätze entwickelt, welche auf gemeinsame Ursachen von ALS und FTD gerichtet sind und somit auch auf beide Erkrankungen wirken sollen.

Diskussion

Bisher gibt es keine kausalen Therapiemöglichkeiten für ALS und FTD. Die steigende Bedeutung genetischer Ursachen lenkt den Fokus auf die Entwicklung genspezifischer Therapien.

Abstract

Background

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common neuropathological features and in the case of a gene mutation, also a genetic cause. To date five ALS-FTD genes are described in the literature in addition to other rare variants.

Objective

The current state of research on treatment options for ALS and FTD is presented and an outlook on possible gene-specific approaches for ALS-FTD is provided.

Material and methods

Analysis of the progression of ALS and FTD research by considering the increasing state of knowledge on the underlying pathomechanisms of the diseases.

Results

In addition to anti-inflammatory approaches and stabilization of protein folding, promising gene-specific treatment approaches are currently being developed, which target common causes of ALS and FTD and therefore have an effect on both diseases.

Conclusion

So far there are no causal treatment options for ALS and FTD. The increasing importance of genetic causes directs the focus to the development of gene-specific treatment.

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

Literatur

  1. Uenal H et al (2014) Plos One 9:4. https://doi.org/10.1371/journal.pone.0093932

    Article  Google Scholar 

  2. A. Al-Chalabi, A. Jones, C. Troakes, A. King, S. Al-Sarraj, and L. H. Van Den Berg, “The genetics and neuropathology of amyotrophic lateral sclerosis,” Acta Neuropathol., vol. 124, no. 3, pp. 339–352, 2012, https://doi.org/10.1007/s00401-012-1022-4.

  3. K. Rascovsky et al., “Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia,” Brain, vol. 134, no. 9, pp. 2456–2477, 2011, https://doi.org/10.1093/brain/awr179.

  4. M. L. Gorno-Tempini et al., “Classification of primary progressive aphasia and its variants,” Neurology, vol. 76, no. 11, pp. 1006–1014, 2011, https://doi.org/10.1212/WNL.0b013e31821103e6.

  5. Woollacott IOC, Rohrer JD (2016) The clinical spectrum of sporadic and familial forms of frontotemporal dementia. J Neurochem 138:6–31. https://doi.org/10.1111/jnc.13654

    Article  PubMed  CAS  Google Scholar 

  6. A. Hübers, A. C. Ludolph, A. Rosenbohm, E. H. Pinkhardt, J. H. Weishaupt, and J. Dorst, “Amyotrophe Lateralsklerose: Eine Multisystemdegeneration,” Nervenarzt, vol. 87, no. 2, pp. 179–188, 2016, https://doi.org/10.1007/s00115-015-0030-8.

  7. A. Montuschi et al., “Cognitive correlates in amyotrophic lateral sclerosis: A population-based study in Italy,” J. Neurol. Neurosurg. Psychiatry, vol. 86, no. 2, pp. 168–173, 2015, https://doi.org/10.1136/jnnp-2013-307223.

  8. R. H. Tan et al., “The underacknowledged PPA-ALS: A unique clinicopathologic subtype with strong heritability,” Neurology, vol. 92, no. 12, pp. E1354–E1366, 2019, https://doi.org/10.1212/WNL.0000000000007146.

  9. J. R. Burrell, M. C. Kiernan, S. Vucic, and J. R. Hodges, “Motor Neuron dysfunction in frontotemporal dementia,” Brain, vol. 134, no. 9, pp. 2582–2594, 2011, https://doi.org/10.1093/brain/awr195.

  10. D. Brenner and J. H. Weishaupt, “Update on amyotrophic lateral sclerosis genetics,” Curr. Opin. Neurol., vol. 32, no. 5, pp. 735–739, 2019, https://doi.org/10.1097/WCO.0000000000000737.

  11. D. W. Sirkis, E. G. Geier, L. W. Bonham, C. M. Karch, and J. S. Yokoyama, “Recent advances in the genetics of frontotemporal dementia,” Curr. Genet Med Rep., vol. 7, no. 1, pp. 41–52, 2019.

  12. R. Ranganathan, S. Haque, K. Coley, S. Shepheard, J. Cooper-Knock, and J. Kirby, “Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia,” Front. Neurosci., vol. 14, no. July, pp. 1–21, 2020, https://doi.org/10.3389/fnins.2020.00684.

  13. Gitler AD, Tsuiji H (2016) There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS. Brain Res 1647:19–29. https://doi.org/10.1016/j.brainres.2016.04.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. K. Müller et al., “Comprehensive analysis of the mutation spectrum in 301 German ALS families,” J. Neurol. Neurosurg. Psychiatry, vol. 89, no. 8, pp. 817–827, 2018, https://doi.org/10.1136/jnnp-2017-317611.

  15. G. Bensimon, L. Lacomblez, V. Meininger, and and the A. study Group, “A controlled trial of RILUZOLE in amyotrophic lateral sclerosis,” N. Engl. J. Med., vol. 330, no. 3, pp. 153–158, 1994.

  16. J. C. Desport, P. M. Preux, T. C. Truong, J. M. Vallat, D. Sautereau, and P. Couratier, “Nutritional status is a prognostic factor for survival in ALS patients,” Neurology, vol. 53, no. 5, pp. 1059–1063, 1999, doi: 10.1212/wnl.53. Mai 1059.

  17. J. C. Desport et al., “Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis,” Am. J. Clin. Nutr., vol. 74, no. 3, pp. 328–334, 2001, https://doi.org/10.1093/ajcn/74.3.328.

  18. A. C. Ludolph et al., “Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis,” Ann. Neurol., vol. 87, no. 2, pp. 206–216, 2020, https://doi.org/10.1002/ana.25661.

  19. J. Dorst et al., “Effect of high-caloric nutrition on serum neurofilament light chain levels in amyotrophic lateral sclerosis,” J. Neurol. Neurosurg. Psychiatry, vol. 91, no. 9, pp. 1007–1009, 2020, https://doi.org/10.1136/jnnp-2020-323372.

  20. J. Dorst et al., “Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: a prospective observational study,” J. Neurol., vol. 262, no. 4, pp. 849–858, 2015, https://doi.org/10.1007/s00415-015-7646-2.

  21. J. Dorst, G. Behrendt, and A. C. Ludolph, “Non-invasive ventilation and hypercapnia-associated symptoms in amyotrophic lateral sclerosis,” Acta Neurol. Scand., vol. 139, no. 2, pp. 128–134, 2019, https://doi.org/10.1111/ane.13043.

  22. S. C. Bourke, M. Tomlinson, T. L. Williams, R. E. Bullock, P. J. Shaw, and G. J. Gibson, “Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: A randomised controlled trial,” Lancet Neurol., vol. 5, no. 2, pp. 140–147, 2006, https://doi.org/10.1016/S1474-4422(05)70326-4.

  23. R. M. Tsai and A. L. Boxer, “Therapy and clinical trials in frontotemporal dementia: past, present, and future,” J Neurochem, vol. 138, no. 1, pp. 211–221, 2016, https://doi.org/10.1111/jnc.13640.

  24. R. Moretti, P. Torre, R. M. Antonello, G. Cazzato, and A. Bava, “Frontotemporal dementia: Paroxetine as a possible treatment of behavior symptoms: A randomized, controlled, open 14-month study,” Eur. Neurol., vol. 49, no. 1, pp. 13–19, 2003, https://doi.org/10.1159/000067021.

  25. E. D. Huey, K. T. Putnam, and J. Grafman, “A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia,” Neurology, vol. 66, no. 1, pp. 17–22, 2015, https://doi.org/10.1212/01.wnl.0000191304.55196.4d.

  26. H. Mitsumoto, B. R. Brooks, and V. Silani, “Clinical trials in amyotrophic lateral sclerosis: Why so many negative trials and how can trials be improved?,” Lancet Neurol., vol. 13, no. 11, pp. 1127–1138, 2014, https://doi.org/10.1016/S1474-4422(14)70129-2.

  27. K. Abe et al., “Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial,” Lancet Neurol., vol. 16, no. 7, pp. 505–512, 2017, https://doi.org/10.1016/S1474-4422(17)30115-1.

  28. A. C. Ludolph et al., “Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial,” Lancet Neurol., vol. 17, no. 8, pp. 681–688, 2018, https://doi.org/10.1016/S1474-4422(18)30176-5.

  29. J. M. Statland et al., “Rasagiline for Amyotrophic Lateral Sclerosis: a Randomized Controlled Trial,” Muscle Nerve, vol. 59, no. 2, pp. 201–207, 2019, https://doi.org/10.1002/mus.26335.Rasagiline.

  30. S. Paganoni et al., “Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis,” N. Engl. J. Med., vol. 383, no. 10, pp. 919–930, 2020, https://doi.org/10.1056/nejmoa1916945.

  31. M. Otto et al., “Konsortium zur Erforschung der frontotemporalen Lobärdegeneration,” Nervenarzt, vol. 82, no. 8, pp. 1002–1005, 2011, https://doi.org/10.1007/s00115-011-3261-3.

  32. P. Novak et al., “AADvac1, an Active Immunotherapy for Alzheimer’s Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development,” J. Prev. Alzheimer’s Dis., vol. 6, pp. 63–69, 2019, https://doi.org/10.14283/jpad.2018.45.

  33. T. Miller et al., “Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS ,” N. Engl. J. Med., vol. 383, no. 2, pp. 109–119, 2020, https://doi.org/10.1056/nejmoa2003715.

Download references

Author information

Authors and Affiliations

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

    Sarah Anderl-Straub, Joachim Schuster, Johannes Dorst &  Albert C. Ludolph

Authors
  1. Sarah Anderl-Straub
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joachim Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johannes Dorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Albert C. Ludolph
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert C. Ludolph.

Ethics declarations

Interessenkonflikt

S. Anderl-Straub, J. Schuster, J. Dorst und A.C. Ludolph geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Die Autoren S. Anderl-Straub und J. Schuster teilen sich die Erstautorenschaft.

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Anderl-Straub, S., Schuster, J., Dorst, J. et al. Amyotrophe Lateralsklerose und frontotemporale Demenz – auf dem Weg zu gemeinsamen genspezifischen Therapieansätzen. Nervenarzt 92, 1219–1226 (2021). https://doi.org/10.1007/s00115-021-01209-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-021-01209-7

Schlüsselwörter

Keywords

Search

Navigation