Fig. 2

Pathology of the ALS primary motor cortex is variable both within and across the genotypic spectrum of disease. Relatively little pTDP-43 aggregation was found in a single TARDBP mutation case (a), but this was severe in an OPTN mutation case (d; see also supp. Figure 2). Insets highlight variance of pTDP-43 morphology between genotypes. Average highest pTDP-43 deposition was seen in sporadic cases, which was statistically higher than in C9-ALS (g). Quantification of p62 (b, e, h). Levels of p62 correlated with pTDP-43 in sporadic cases but less so in C9ORF72 disease, reflective of the existence of p62-positive dipeptide repeat protein species unique to C9-ALS (h and j). Cortical microglial activation was highly variable between genotypes (i), and in some cases there was evidence of severe nodular neuronophagia surrounding layer V neurons (f). Grey matter CD68 correlated with the extent of pTDP-43 deposition (k) in both sporadic and C9ORF72 cases, but this relationship was not recapitulated using p62 and CD68 in SOD1/FUS cases (l). Arrows highlight pathology, asterisks highlight Betz cells. r correlations = Pearson (j) or Spearman (k, l), results as on figure. Bars in (i) represent means and SEM. Best-fit lines are manually added for illustrative purposes. All scale bars = 50 μm