What does imaging reveal about the pathology of amyotrophic lateral sclerosis?

Abstract

Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape.

Fig. 1

Summary of the pathogenic insights from post mortem histopathological and neuroimaging research in ALS. The findings in the primary motor regions are separately shown from the findings in extra-motor regions. The primary motor regions are defined as the motor cortex (precentral gyrus and paracentral lobule or Brodmann area 4 and 6), the major white matter tracts (corticospinal tracts [CST] and corpus callosum [CC]), the motor nuclei in the brainstem and motoneurons arising from the spinal cord anterior horns. The extra-motor regions are here defined as all other brain regions. TDP-43 pathology is defined according to the post mortem histological stages proposed by Brettschnieder and colleagues [•]. pTDP-43 phosphorylated, 43-kDa TAR DNA-binding protein, CST corticospinal tracts, CC corpus callosum, CN cranial nerves, PET positron emission tomography, GABA-A receptor gamma-aminobutyric acid receptor type A, 5-HT1A receptor 5-hydroxytryptamine receptor type 1A