Fucosidosis is a fatal inherited neurodegenerative disease. The pathologic changes in brain which occur with progression from preclinical to late clinical disease were investigated in fucosidosis affected dogs. As aging also causes neurodegeneration and lysosomal dysfunction, pathologic markers of fucosidosis were compared to changes in the aging canine brain. Preclinical fucosidosis cerebral cortex and cerebellum revealed early increases in all neurodegenerative markers studied including apoptosis (2.1 fold), pyramidal neuronal loss (0.9 fold decrease) and Purkinje cell loss (1.2 fold decrease) compared to age matched controls. Increased axonal spheroid formation (> 100 fold in cortex, 80 fold in cerebellum), microgliosis (9.2 fold) and astrocytosis (2.1 fold in cortex and 0.5 fold in cerebellum) were distinctive features of preclinical fucosidosis brain in all regions examined. This neuropathology progressed as the dogs developed severe clinical signs, with advanced fucosidosis brain exhibiting the greatest parenchymal destruction. These measures of the neurodegenerative and inflammatory changes in fucosidosis brain will assist monitoring disease progression and response to therapy.