The selective anatomical vulnerability of ALS: ‘disease-defining’ and ‘disease-defying’ brain regions

Abstract

A large multiparametric MRI study has been undertaken to evaluate anatomical patterns of basal ganglia, white matter and cortical grey matter involvement in ALS. Unaffected brain regions are mapped in patients with significant disability. Multiple white matter diffusivity measures, cortical grey matter density alterations, basal ganglia volumes and subcortical grey matter atrophy patterns are evaluated. Results demonstrated a strikingly selective anatomical vulnerability pattern in ALS that preferentially affects specific grey matter structures, commissural white matter tracts and basal ganglia regions, suggestive of networkwise neurodegeneration in ALS. In conclusion, ALS pathology exhibits predilection for selective and inter-connected anatomical sites that can be comprehensively characterized in vivo by multiparametric neuroimaging. The systematic characterization of unaffected brain regions in ALS has implications for the development of classifier analyses and elucidation of disease biology. The involvement and sparing of contiguous brain regions raises important pathophysiological, phylogenetic and ontogenetic questions regarding ALS pathogenesis and disease spread.

Key words:

• Amyotrophic lateral sclerosis
• magnetic resonance imaging
• pathophysiology
• diffusion tensor imaging
• basal ganglia
• biomarker

Acknowledgements

We gratefully acknowledge the generous contribution 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. Orla 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.

Declaration of interest

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