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Front. Aging Neurosci. | doi: 10.3389/fnagi.2018.00045

Atrophy in the thalamus but not cerebellum is specific for C9orf72 FTD and ALS patients – An atlas-based volumetric MRI study

 Sonja Schönecker1, Christiane Neuhofer1,  Markus Otto2,  Albert Ludolph2,  Jan Kassubek2, Bernhard Landwehrmeyer2, Sarah Anderl-Straub2, Elisa Semler2, Janine Diehl-Schmid3, Catharina Prix1,  Christian Vollmar1,  Juan Fortea4, Deutsches FTLD-Konsortium2, Hans-Jürgen Huppertz5, Thomas Arzberger6,  Dieter Edbauer7, 8, 9,  Berend Feddersen10,  Marianne Dieterich1, 7, 9,  Matthias L. Schröter11, 12, Alexander E. Volk13, Klaus Fließbach14, 15, Anja Schneider14, 15,  Johannes Kornhuber16,  Manuel Maler16, Johannes Prudlo17, 18, Holger Jahn19, 20, Tobias Boeckh-Behrens21, Adrian Danek1,  Thomas Klopstock1, 7, 9 and Johannes Levin1, 7*
  • 1Department of Neurology with Friedrich Baur Institute, University Hospital LMU Munich, Germany
  • 2Department of Neurology, University of Ulm, Germany
  • 3Department of Psychiatry and Psychotherapy, Technical University of Munich, Germany
  • 4Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Spain
  • 5Swiss Epilepsy Clinic, Klinik Lengg, Switzerland
  • 6Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Germany
  • 7German Center for Neurodegenerative Diseases (DZNE), Germany
  • 8Institute for Metabolic Biochemistry, Ludwig-Maximilians Universität München, Germany
  • 9Munich Cluster of Systems Neurology (SyNergy), Germany
  • 10Department of Palliative Medicine, Ludwig-Maximilians-Universität München, Germany
  • 11Max Planck Institute for Human Cognitive and Brain Sciences (MPG), Germany
  • 12Clinic for Cognitive Neurology, Universitätsklinikum Leipzig, Germany
  • 13Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany
  • 14Deutsche Zentrum für Neurodegenerative Erkrankungen (DZNE), Germany
  • 15Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Germany
  • 16Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
  • 17Department of Neurology, Universitätsmedizin Rostock, Germany
  • 18German Center for Neurodegenerative Diseases (DZNE) Rostock, Germany
  • 19Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Germany
  • 20AMEOS Klinikum Heiligenhafen, Germany
  • 21Department of Diagnostic and Interventional Neuroradiology, Technical University of Munich, Germany

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers.
Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls.
Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status.
Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82.
Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

Keywords: C9orf72, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, atlas based volumetric MRI analysis, Thalamus, Cerebellum, salience network

Received: 29 Sep 2017; Accepted: 12 Feb 2018.

Edited by:

Javier Ramírez, University of Granada, Spain

Reviewed by:

Stavros I. Dimitriadis, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK, United Kingdom
Iman Beheshti, National Center of Neurology and Psychiatry (Japan), Japan  

Copyright: © 2018 Schönecker, Neuhofer, Otto, Ludolph, Kassubek, Landwehrmeyer, Anderl-Straub, Semler, Diehl-Schmid, Prix, Vollmar, Fortea, FTLD-Konsortium, Huppertz, Arzberger, Edbauer, Feddersen, Dieterich, Schröter, Volk, Fließbach, Schneider, Kornhuber, Maler, Prudlo, Jahn, Boeckh-Behrens, Danek, Klopstock and Levin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Johannes Levin, University Hospital LMU Munich, Department of Neurology with Friedrich Baur Institute, Munich, Germany,