Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis

Abstract

Phrenic nerves of 11 patients with amyotrophic lateral sclerosis studied postmortem contained only 33% of the normal number of large myelinated fibers (9 controls; p less than 0.001). In the phrenic nerves of these patients, there were 18% fewer large myelinated fibers in the distal segment than in the proximal segment (p less than 0.025). The ratio of axonal circumference to myelin lamellae in large myelinated fibers in the distal segment was 34% greater than that in control fibers (p less than 0.002). The proportion of acute axonal degeneration was the same at all levels (48.0 +/- 13.7%). Sural nerves of 21 patients with amyotrophic lateral sclerosis had more acute axonal degeneration and 30% fewer myelinated fibers (p less than 0.05) than controls; evidence of degeneration also extended to unmyelinated fibers. The amount of axonal transport of acetylcholinesterase in 9 sural nerves determined in vitro was reduced by 24% (p less than 0.05) and the apparent transport rate was reduced by 44% (p less than 0.01) compared with 4 controls. These findings show that in amyotrophic lateral sclerosis a small degree of dying-back change and of distal axonal atrophy is superimposed on the degeneration of motor neuron cell bodies, and that the disease effects spread beyond the motor neurons.

Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS

“…Although this observation is consistent with in vivo observations that axonal degeneration appears to be an early defect that precedes the onset of ALS symptoms and motor neuron death (Fischer and Glass, 2007;Bradley et al, 1983;Fischer et al, 2004), the stem-cell-based culture system used in this study does not allow us to distinguish between developmental and degenerative changes. This issue will be addressed in future work.…”

Actions of CNTF and neurotrophins on degenerating motoneurons: Preclinical studies and clinical implications

“…These morphological characteristics very much resemble the changes occurring during apoptosis (for a review see Cohen 1993). Many pieces of evidence, such as the finding that more myelinated nerve fibers are detectable in proximal than in distal parts of motor nerves of ALS patients (Bradley et al 1983), have led to the model that ALS starts at the endplates, proceeds as degeneration of the axons in a dying back-fashion and finally Ieads to degeneration of the cell bodies in the spinal cord and brain stem (Chou 1992). This would be consistent with the pathological findings in pmn mice (Schmalbruch et al 1991 ).…”

Immunoglobulins from amyotrophic lateral sclerosis patients enhance spontaneous transmitter release from motor-nerve terminals.

“…The experiments were performed with hemidiaphragms dissected after cervical dislocation from male BALB/c or Swiss mice weighing [25][26][27][28][29][30] Control experiments were carried out to assure the stability of the nerve terminal properties during the incubation and recording time. No differences were observed in MEPP frequency after 4-8 hr at 23°C or 4 hr at 32°C.…”

“…The sera were heated at 560C for 30 min, and the immunoglobulins were enriched by Rivanol (ethacridine lactate) precipitation followed by lyophilization followed by dialysis against Krebs-Ringer solution with no Ca (Mr 12,000 cutoff) and was subsequently stored after lyophilization (16 The IgG fraction prepared from two of the positive ALS immunoglobulins was as effective in increasing the MEPP frequency as was the total immunoglobulin fraction (data not shown).…”

“…It is also possible that sustained levels of high intracellular Ca2+ leading to enhanced MEPP frequency could also be responsible for deleterious effects on motor neurons (29). However, since dying-back of the motor axon is not the main pathology in ALS (30), either the altered signal in the axon terminal is communicated to the soma or the immunoglobulins themselves could be transported back to the cell body. Either process could lead to overall cell dysfunction.…”