Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants

Abstract

The neuropathologic molecular signature common to almost all sporadic amyotrophic lateral sclerosis (ALS) and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathologic and molecular neuropathologic features of ALS variants, primarily lateral sclerosis and progressive muscular atrophy, are less certain but also seem to share the primary features of ALS. Genetic causes, including mutations in SOD1, TDP-43, FUS, and C9orf72, all have distinctive molecular neuropathologic signatures. Neuropathology will continue to play an increasingly key role in solving the puzzle of ALS pathogenesis.

Keywords: Amyotrophic lateral sclerosis; C9orf72; Motor neuron degeneration; Neuropathology; TDP-43.

Figure 1. Amyotrophic lateral sclerosis (ALS)

Lateral sclerosis is shown in the thoracic spinal cord in sporadic ALS (A) and compared to control (B). The inserts show loss of myelin in the white matter tracts. Loss of motor neurons is shown in the lumbar spinal cord in sporadic ALS (C) and compared to control (D). The inserts show the motor neurons in the anterior horns under higher power. [Luxol fast blue with hematoxylin and eosin (A, B); hematoxylin and eosin (C, D)]

Figure 2. Classic ALS neuropathology

Loss of motor neurons is shown in an anterior horn of the spinal cord (A) and motor cortex (C) of ALS and compared to control (B, D). Shrinkage and contraction of motor neuron in ALS (E) is compared to control (F). Vacuolization and spongiosis in motor cortex is shown in ALS (G) and compared to control (H). Bunina bodies are seen in the cytoplasm of motor neurons of ALS (I) and compared to control (J). Bunina bodies are positive for cystatin c in ALS (K) and compared to the effect of the stain in control (L). Microglial activation is shown by IBA1 in the anterior horn of the spinal cord in ALS (M) but not control (N). [Hematoxylin and eosin (A-J)]

Figure 3. Inclusions in ALS neuropathology

Ubiquitin skein-like inclusions (arrows) are shown in spinal motor neurons of the lumbar anterior horn (A) and Betz cells of the motor cortex (C) in ALS but not control (B, D). TDP-43 inclusions are shown to be diffuse (arrow) and skein-like (arrow-head) and there is nuclear clearing in the spinal motor neurons of ALS (E), features not seen in controls. Note the normal nuclear TDP-43 in control (F). TDP-43 dense round inclusions (arrowhead) are shown in the motor cortex of ALS (G) but not in controls, which show normal nuclear TDP-43 (H). Phospho-TDP-43 staining shows skein-like (arrow) and dense round (arrow-head) inclusions in ALS lower motor neurons (I), which are not seen in controls. Note pTDP is not seen in normal nuclei (unlike TDP-43) (J).

Figure 4. Neuropathology of familial ALS

Lewy body-like inclusion in a spinal motor neuron from a nervous system of a patient with an SOD1 A4V mutation (A). A subsequent histological section showing co-localization of misfolded SOD1 and the Lewy body-like inclusion (B). Misfolded SOD1 is not seen in spinal motor neurons of controls (C) or in the motor cortex of SOD1 patients (D). Skein-like inclusions (arrow) and dense round inclusions (arrow-head) in spinal motor neurons of lumbar spinal cord of a nervous system of a patient with repeat expanded C9orf72 using anti-TDP antibody (E). Same as (E), using an anti-phospho-TDP-43 antibody (F). Poly GA dipeptide repeat proteins in the hippocampus of a nervous system from a patient with a repeat expansion in C9orf72 (G) that are not seen in sporadic ALS (H). PolyGP dipeptide repeat proteins in the hipppcampus of a nervous system from a patient with repeat expansion in C9orf72 (I) are not seen in sporadic ALS (J). RNA foci from the sense (K) and antisense (L) directions from cultured fibroblasts of a patient with repeat expansion in C9orf72 using fluorescent in situ hybridization.