Neuroimaging patterns along the ALS-FTD spectrum: a multiparametric imaging study

Abstract

Frontotemporal dementia is associated with considerable clinical, genetic and pathological heterogeneity. The objective of this study is to characterise the imaging signatures of the main FTD phenotypes along the ALS-FTD spectrum. A total of 100 participants underwent comprehensive multimodal neuroimaging, genetic testing and neuropsychological evaluation. Seven patients with behavioural variant FTD (bvFTD), 11 patients with non-fluent-variant primary progressive aphasia (nfvPPA), two patients with sematic-variant primary progressive aphasia(svPPA), 10 patients with amyotrophic lateral sclerosis and FTD carrying the C9orf72 hexanucleotide repeat (C9 + ALS-FTD), 10 patients with ALS-FTD without hexanucleotide repeats (C9-ALS-FTD), 20 ALS patients without behavioural or cognitive deficits (ALSnci) and 40 healthy controls (HC) were included in a prospective quantitative neuroimaging study. Phenotype-specific spatial patterns of pathology were identified along the ALS-FTD spectrum, highlighting a strikingly focal distribution of disease burden as opposed to global atrophy. Significant motor cortex and corticospinal tract degeneration was identified in both bvFTD and nfvPPA patients. C9-ALS-FTD patients exhibited widespread extramotor pathology and significant precentral gyrus atrophy compared to ALSnci patients. ROI analyses confirmed focal grey matter alterations in Broca’s and Wernicke’s area in language variant FTD cohorts. Our findings confirm that the clinical manifestations of FTD are underpinned by phenotype-specific patterns of white and grey matter degeneration.

Keywords:

• Magnetic resonance imaging
• neuroimaging
• neurodegeneration

Acknowledgements

We gratefully acknowledge the kindness and generosity of our patients and their caregivers. This work was supported by the Irish Institute of Clinical Neuroscience (IICN) - Novartis Ireland Research Grant, the The Iris O'Brien Foundation, The Perrigo Clinician-Scientist Research Fellowship, the Health Research Board and the Research Motor Neuron (RMN-Ireland) foundation. Professor Hardiman’s research group has also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° [259867] (EUROMOTOR), the EU-Joint Programme for Neurodegeneration (JPND) SOPHIA project and an unrestricted research grant from Perrigo Company plc. The sponsors of the study had no role in study design, writing of the report, or decision to submit this work for publication.

Declarations

Funding statement

This work was supported by the Irish Institute of Clinical Neuroscience (IICN) - Novartis Ireland Research Grant, the The Iris O'Brien Foundation, The Perrigo Clinician-Scientist Research Fellowship, the Health Research Board and the Research Motor Neuron (RMN-Ireland) foundation. Professor Hardiman’s research group has also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° [259867] (EUROMOTOR), the EU-Joint Programme for Neurodegeneration (JPND) SOPHIA project and an unrestricted research grant from Perrigo Company plc. The sponsors of the study had no role in study design, writing of the report, or decision to submit this work for publication.

Disclosures

Prof. Hardiman has received speaking honoraria from Janssen Cilag, Biogen Idec, Sanofi Aventis and Merck-Serono, and she has been a member of advisory panels for Biogen Idec, Allergen, Cytokinetics, Ono Pharmaceuticals and Sanofi Aventis

Role of the funding source

The sponsors of the study had no role in study design, data analysis, data interpretation, or writing of the report.

Declaration

All participants provided informed consent in accordance to the Medical Ethics Approval of the research project (Ethics (Medical Research) Committee - Beaumont Hospital, Dublin, Ireland).

The corresponding author (Peter Bede) has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.