Pathology The principal finding in ALS is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem. The anterior roots are thin, and there is a disproportionate loss of large myelinated fibers in motor nerves (Bradley et al). The muscles show typical denervation atrophy of different ages. Large alpha motor neurons tend to be affected before small ones. In addition to neuronal loss, there is evidence of slight gliosis and proliferation of microglia cells. Many of the surviving nerve cells are small, shrunken, and filled with lipofuscin. It is not uncommon to detect ubiquitin inclusions in threads, skeins, or dense aggregates within the affected neurons by special stains. Occasionally, there is another ill-defined cytoplasmic inclusion that is present in neurons and glia. Most studies indicate that these are made up of TDP-43 and ubiquitin as discussed in the alter section on “Pathogenesis.” Cases ostensibly associated with repeated trauma (see earlier) show an accumulation of tau in anterior horn cells, similar to the findings in the cerebral cortex that characterize chronic traumatic encephalopathy. According to some reports, swelling of the proximal axon is an early finding, presumably antedating visible changes in the cell body itself. There is an understandable depletion of muscarinic, cholinergic, glycinergic, and benzodiazepine receptors in regions of the spinal cord where motor neurons had disappeared.
The corticospinal tract degeneration is most evident in the lower parts of the spinal cord, but it can be traced up through the brainstem to the posterior limb of the internal capsule and corona radiata by means of fat stains, which show the macrophages that accumulate in response to chronic myelin degeneration. There is a loss of Betz cells in the motor cortex; this is manifest as a slight frontal lobe atrophy on the MRI, but it is not a prominent finding in most cases of ALS (Kiernan and Hudson). Other fibers in the ventral and lateral funiculi are depleted, imparting a characteristic pallor in myelin stains. Some pathologists have interpreted this as evidence of involvement of nonmotor neurons and hence object to the term motor system disease. However, this condition of more diffuse pallor may be a result of a loss of collaterals of motor neurons that contribute to the lamina propria. One observes the same effect in long-standing poliomyelitis. In cases of familial ALS resulting from mutations in the SOD1 gene, the nonmotor systems seem to be more affected (Cudkowicz et al).
Neuropathologic studies of cases of ALS with dementia have been increasingly reported and studied histopathologically. In addition to the usual loss of motor neurons, these cases have shown an extensive neuronal loss, gliosis, and vacuolation involving the frontal premotor area, particularly the superior frontal gyri and the inferolateral cortex of the temporal lobes. The neurons in typical cases contain TDP-43 (ubiquitin). The histologic changes of Alzheimer or Pick disease have not been seen but neurofibrillary degeneration (tau) has been observed, but is inconsequential in comparison to that seen in the
Guamanian Parkinson-dementia-ALS complex (Finlayson et al).
This purely lower motor neuron syndrome is more common in men than in women, reportedly in a ratio of 4:1. It probably encompasses several diseases of the lower motor neuron, but most of which are aligned with ALS.