Pathological changes associated with disease progression in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is identified histologically by the deposition of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43). The progression of this ALS pathology through the brain has been staged pathologically using autopsy samples, and through white matter tracts using diffusion tensor imaging (DTI). A model of corticofugal axonal spread proposes that pTDP-43 aggregates spread to grey matter regions sequentially through connecting white matter tracts. The aims of this thesis were to validate the neuropathological staging scheme of pTDP-43 pathology in a representative cohort of ALS patients, investigate the cellular mechanisms underlying disease spread through white matter tracts, and to test the theory that pTDP-43 pathology spreads along axonal pathways.First, assessment of grey matter regions validated the neuropathological staging scheme, although cases with hippocampal involvement did not fit the same disease pattern as those with typical ALS. In a unique cohort of cases with in vivo imaging that were followed to autopsy, diffusivity changes were determined in the corticospinal tract (CST) using DTI, and peak changes were identified in the midbrain CST. Histological sampling of this region found that pathological changes related to the deposition of pTDP-43 aggregates mainly in oligodendrocytes, with axonal loss preceding demyelination. Axons appeared to drive the pathology, supporting the dying-forward model of disease progression. The pathological burden to axons and oligodendrocytes reflected changes to axial and radial diffusivity measures, respectively. Finally, histological assessment of the posterior limb of the internal capsule, corpus callosum and cingulum revealed no pTDP-43 pathology, suggesting that white matter tract involvement captured by DTI does not reflect pTDP-43 aggregation. Investigations in this thesis have provided novel insights into the pathogenesis of ALS, and suggest future research directions