Abstract
In motor neuron disease (MND) cases associated with dementia, neurons often contain ubiquitin-positive, taunegative cytoplasmic inclusions that are numerous in the granule cell neurons of the hippocampal complex. Dot or threadlike ubiquitinated neurites are also observed in the surrounding neuropil and in other frontotemporal regions. Cases of frontotemporal dementia (FTD) with identical appearing ubiquitinated deposits have been described in FTD cases lacking signs of MND. The underlying pathobiology of these cases remains obscure. We describe a case from a familial FTD kindred and use immunohistochemistry to evaluate the hippocampal ubiquitin-positive cytoplasmic granule cell inclusions in relationship to the threads and dots that surround them. Ubiquitin-positive threads were more numerous in the overlying molecular layer of the dentate gyrus (DG) compared with the underlying polymorphic layer, suggesting that threads are formed primarily in the dendrites of the affected granule cells. In contrast, dot-like inclusions were uniformly distributed. Using antibodies to synapticterminal specific proteins, we observed loss of perforant pathway synapses in the outer molecular layer of the DG. The numbers of thread-and dot-like inclusions were no greater in the region of synaptic loss than in the layer that lacked detectable synaptic loss. Similarly, ubiquitinated aggregates were more numerous in rostral sections, and they tended to cluster, whereas synapse loss was uniform. These findings expand upon previous data by suggesting that formation of these ubiquitinated aggregates relate to an inherent susceptibility in the granule cell neuron, rather than solely to a deafferentation effect. This study contributes to our understanding of what might be a common pathological process underlying FTD and MND cases with ubiquitinated inclusions.