Study of the proximal axon of anterior horn neurons in amyotrophic lateral sclerosis

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The proximal portions of axons of large anterior horn cells were investigated in the lumbar cords of 1 0 normal human autopsy cases. Light-microscopically, the length of the axon hillock plus initial segment (AH+IS) of normal-looking neurons (n=77) was 64.0 + 12.3 mm (average + SEM), ranging from 47.5 to 110.0 mm, while the diameter of the thinnest portion of the initial segment was 2.40 + 0.30 mm (average + SEM), ranging from 1.32 to 3.92 mm. Electron-microscopically, the cell membrane of the initial segment consisted of a layer of electron-dense material (undercoating). The cytoplasm of the initial segment contained many neurofilaments, running parallel to the longitudinal axis of the initial segment. Among the neurofilaments, lysosomes, smooth endoplasmic reticulum, dense bodies and vesicular profiles aswell as mitochondria were seen. At the beginning of the myelin sheath, the axoplasm contained mitochondria, many neurofilaments and occasional lysosomes. We also measured the diamete … More r of the most distal portion of the axonal initial segment, the neuronal size of anterior horn cells, and the length of AH+IS in the lumbar spinal cord in three patients with amyotrophic lateral sclerosis (ALS), one with lower motor neuron disease (LMND) and 11 controls. Serial plastic sections stained with toluidine blue and electron micrographs were studied. A total of 214 axons directly emanating from the somata (n=207) and the primary dendrites (n=7) were observed in the patients. Approximately 19% of the proximal myelinated axons (24 axons out of 155 in ALS, and 17 axons out of 59 in LMND) were swollen at the first internode, and most of the swellings extended to the middle portion of the initial segment. Electron microscopy showed that the swellings of the proximal axons (the initial segment and the first internode) directly connected with their somata consisted mainly of accumulations of 10-nm neurofilaments. The average diameter of the most distal initial segment was markedly larger in ALS(n=155)(p<0.0001) and LMND(n=5 9)(p<0.0001) than in the controls (n=258). Moreover, the average diameter of the most distal portion of even normal-appearing initial segments of the non-swollen axons was larger in ALS(n=131)(p<0.0001) than in the controls. The perikarya and axon hillocks connected with the normal-appearing and swollen proximal axons and their dendrites almost always appeared normal. These findings suggest that increasing diameter of the axonal initial segment which reflects the abnormal accumulation of neurofilaments represents an early pathological change in motor neuron disease and that slow axonal transport of neurofilaments is probably impaired in this portion of the axon at an early stage in the disease process. The average size of the normal-appearing cell bodies from which axons emanated was smaller in ALS(p<0.0001) and LMND(p<0.0001) than in the controls. There was no significant difference in the AH+IS length among ALS having normal-appearing initia Less