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Cognitive neurology
Original research
Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers—a developmental disorder
  1. Dorothée E Lulé1,
  2. Hans-Peter Müller2,
  3. Julia Finsel2,
  4. Patrick Weydt3,
  5. Antje Knehr2,
  6. Ivar Winroth4,
  7. Peter Andersen5,
  8. Jochen Weishaupt2,
  9. Ingo Uttner2,
  10. Jan Kassubek2,
  11. Albert C Ludolph2
  1. 1 Department of Neurology, Neuropsychology, Ulm University, Ulm, Germany
  2. 2 Department of Neurology, University of Ulm, Ulm, Germany
  3. 3 Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Bonn, Germany
  4. 4 Clinical Science, Umeå University, Umeå, Sweden
  5. 5 Neurology, Umeå University, Umeå, Sweden
  1. Correspondence to Dorothée E Lulé, Department of Neurology, Neuropsychology, University of Ulm, Ulm 89081, Germany; dorothee.lule{at}uni-ulm.de

Abstract

Background A mutation in C9orf72 constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).

Methods In total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72 and 15 with SOD1 mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.

Results C9orf72 expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1 mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.

Discussion Reduced verbal fluency performance seems to be a distinct clinical feature of C9orf72 carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72 carriers.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jnnp-2020-323671

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    Footnotes

    • DEL and H-PM are joint first authors.

    • JK and ACL are joint senior authors.

    • Contributors DEL, PW, PA, JW: design or conceptualisation of the study, analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. HPM, JF: analysis or interpretation of the data, drafting or revising the manuscript for intellectual content. AK: design or conceptualisation of the study. IW, JK, ACL: design or conceptualisation of the study, drafting or revising the manuscript for intellectual content. IU: drafting or revising the manuscript for intellectual content. A

    • Funding This is an EU Joint Programme—Neurodegenerative Disease Research (JPND) project ('NEEDSinALS' 01ED1405 and PreFrontAls 01ED1512). The project is supported through the following organisations under the aegis of JPND—www.jpnd.eu for example, Germany, Bundesministerium für Bildung und Forschung (BMBF, FKZ), Sweden, Vetenskaprådet Sverige, Poland, Narodowe Centrum Badań i Rozwoju (NCBR). This work was additionally funded by the Deutsche Forschungsgemeinschaft (DFG, LU 336/13–2), the Bundesministerium für Bildung und Forschung (FTLDc O1GI1007A, MND-Net 01GM1103A; PaCeMed 01DS18031) and the foundation of the state Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009), Thierry Latran Foundation. Also, this project is funded by the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), and the Knut and Alice Wallenberg Foundation.

    • Disclaimer The funding sources played no role in the preparation of this manuscript.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the Ethics Committee of the University of Ulm (reference 68/19), in accordance with the ethical standards of the current version of the revised Helsinki Declaration. All participants gave verbal and written informed consent prior to inclusion in the study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. Reasonable data sharing requests are made in writing through Dorothée Lulé (dorothee.lule@uni-ulm.de) and require a formal data sharing agreement. Data sharing agreements must include details on how the data will be stored, who will have access to the data and intended use of the data, and agreements as to the allocation of intellectual property.

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