Marked Involvement of the Striatal Efferent System in TAR DNA-Binding Protein 43 kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Recent pathological studies indicate that neuronal loss and/or TAR DNA-binding protein-43 kDa (TDP-43) inclusions are frequent in the striatum of patients with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP). However, no investigations have clarified the impact of such pathological changes on striatal neuronal outputs in these diseases. We analyzed pathological changes in the striatal efferent system of 59 consecutively autopsied patients with sporadic FTLD-TDP or ALS-TDP. The axon terminals of striatal efferent neurons were immunohistochemically assessed in the substantia nigra pars reticulata (SNr) and globus pallidus (GP). All of the FTLD-TDP patients exhibited a marked depletion of axon terminals, irrespective of disease duration. In particular, losses of substance-P-positive projections to the SNr and internal segment of GP were consistently severe. Similar findings were also observed in 69.0% of the ALS-TDP patients, although the severity was much less than that in the FTLD-TDP patients (p<0.001). The accumulation of phosphorylated TDP-43 was observed in the striatal efferent neurons, efferent tracts, or their axon terminals in the SNr and GP in both groups. Thus, striatal efferent projections are essentially and commonly involved in the TDP-43-related FTLD/ALS disease spectrum.