Fig. 4

Loss of Neuronal GCase in FTD-GRN. a, GCase immunostained sections were counterstained with hematoxylin to identify neurons, which revealed both fewer neurons (t test, p = 0.0437) and less neuronal area (b, t test, p = 0.0458) in layer III of FTD-GRN patients than controls, consistent with neurodegeneration. c, Within these hematoxylin-labeled neurons, FTD-GRN patients had less GCase immunolabeling than controls (t test, p = 0.031). This observation survived correction for the lower total neuronal area (d, t test, p = 0.048), indicating that the reduced GCase in FTD-GRN brains is unlikely to be explained solely by neuronal loss. n = 5 controls and 7 FTD-GRN patients. e, The intensity of fluorescent GCase immunolabeling in cortical neurons was also reduced in FTD-GRN patients, with quantification of neuronal GCase intensity shown in f, cumulative probability plots and g, density plots. These data were analyzed first by Kolmogorov-Smirnov test, showing significantly lower neuronal GCase in FTD-GRN (p < 0.0001). A more conservative mixed-model regression of the fluorescent intensity distribution data confirmed that the distribution of FTD-GRN neurons was skewed toward less intense labeling than controls, with significant group differences found in the 60th (p = 0.007), 70th (p = 0.001), 80th (p = 0.005) and 90th (p = 0.022) deciles. n = 519 neurons from 5 controls and 262 neurons from 6 FTD-GRN patients. All images are labeled with the corresponding case number from Table 1. Representative 40X images of GCase and NeuN immunostaining are shown in e with a 20 μm scale bar