General pathology. There is considerable evidence to suggest that ALS involves more than just the motor system (Xxxxxxxx et al. 1970; Xxxxxxxx et al. 1995; Xxxxxxxx et al. 1996), although the brunt of the pathology falls on the motor pathways. Characteristically, there is loss and degeneration of large anterior horn cells and brainstem cranial nerve nuclei, with loss of pyramidal neurons of the corticospinal pathway. Astroglial proliferation in affected areas is often marked (Kamo et al. 1983). Skeletal muscles show denervation atrophy. Both upper and lower motor neurons develop proximal and distal axonopathy and show senescent changes including deposition of lipofuscin (XxXxxx et al. 1984). The “dying back” process of axonal damage is particularly marked in the corticospinal tracts (Xxxxxxxx, 1984) and is seen in both sporadic and familial ALS. The oculomotor, abducens and trochlear nuclei are relatively spared, as are neurons of Onuf’s nucleus which innervates the vesicorectal sphincters (Xxxxxx et al. 1977). Interestingly, Xxxx’s nucleus is also unaffected in acute and chronic polio (Xxxxxx et al. 1989). This may be because the neurons are histologically more like autonomic neurons than motor neurons (Xxxxxxxx et al. 1988) but (in the case of polio) could be because putative neurotropic virus receptors might be absent from certain nerve groups (Chou, 1995). Another possibility is that involvement of the androgen receptor which is absent from Onuf’s nucleus and nuclei concerned with eye movement, is required for motor cell death (Xxxxxx, 1980). A further plausible explanation is that oculomotor and Onuf’s neurons express more calcium buffering proteins than more vulnerable upper or lower motor neurons (Xxxx and Xxxx, 1997). The major cytoplasmic pathology is found in the lower motor neurons. Phosphorylated neurofilaments accumulate in the perikarya of lower motor neurons and their proximal axons, resulting in proximal axonal swelling (spheroids). The accumulations retain a filamentous structure. Spheroid formation is thought to be an early pathological event (Xxxxxxx and Xxxxxxxxx, 1984) and may be related to impaired slow axonal transport. Ubiquitin immunoreactive inclusions are almost specific to ALS and are the most characteristic cellular inclusion (Xxxxx et al. 1988; Xxxx et al. 1988; Xxxx et al. 1989). These skein-like or dense rounded structures appear to be filamentous with a tubular cross-section and diameter of 15 to 25 nm. Ubiquitin is found in all eukaryotic ce...
