Fig. 4

Sporadic ALS-TDP exhibits broad pathological homogeneity across the motor cortex-spinal cord neuraxis. CD68 and pTDP-43 expression was quantified within the anterior horn (a, red box) and corticospinal tract (a, green circle). The morphology of pTDP-43 pathology was varied in anterior horn lower motor neurons, including large discrete inclusions (b), thread-like skeins (c) and diffuse punctate (d). There was no significant difference in pTDP-43 severity between sporadic and C9ORF72 cases (g). CD68 expression (e, f) was variable across ALS genotypes but was not statistically significant (h, i), and levels of pTDP-43 did not correlate with CD68 expression in the anterior horn (Pearson r; j). pTDP-43 in the motor cortex correlated with pTDP-43 in the anterior horn in sporadic disease but not C9-ALS (Pearson r; k), and CD68 correlated between the corticospinal white matter tract and the subcortical white matter in both FUS and sporadic cases (Pearson r; l) but not other genotypes (p > 0.2). CD68 in the lower anterior horn neuron was plotted against grey matter CD68 in the motor cortex (m). This was used to create a predominance ratio for each case that could be used as a covariate in subsequent models, where a lower ratio represents a tendency towards a burden of CD68 in the anterior horn. The dotted blue line in (m) represents the approximate median ratio of our cohort. Therefore, the further each case is from this line, the more extreme the relative UMN/LMN burden of CD68 the case exhibits. Cases are coloured according to whether they are TDP-proteinopathies (red) or not (green), showing that non-TDP-proteinopathies are more likely to exhibit a LMN neuropathological predominance when assessed via levels of activated microglia (ALS-OPTN case demonstrated extreme UMN predominance, but is excluded from graph for the clarity of other cases). Representative images of this variation across the neuraxis between genotypes, with an OPTN and FUS mutation representing upper and lower motor neuron spectral extremes, respectively (n-u). Asterisk in (t) highlights a seemingly normal Betz cell. AH, anterior horn; CST, corticospinal tract; UMN, upper motor neuron; LMN, lower motor neuron. Scale bars where not indicated (μm): b,c,d = 30, e,f,r,s = 75, all others = 50