4.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

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Study Design. A retrospective multicenter observational study. Objective. To investigate correction surgeries that were performed in relatively aged patients in terms of mechanical complications (MCs) and their predictive factors. Summary of Background Data. The risk factors associated with MCs have not yet been well examined, especially in aged populations. Methods. We retrospectively reviewed 230 surgically treated ASD patients with an average age of 72.2 years. Twenty-eight patients with ASD caused by vertebral fractures were excluded. The minimum follow-up was 2 years. Postoperative MCs were defined as proximal junction kyphosis, distal junction kyphosis, pseudoarthrosis, rod breakage, and vertebral fractures. We divided all the ASD patients into two groups: patients with MC (the MC (+) group) and patients without MC (the MC (−) group). Radiographic parameters were evaluated before and immediately after surgery. The SRS-Schwab ASD classification and global alignment and proportion (GAP) score were also evaluated. Results. Of the 202 patients, 91 (45.0%) had MCs. The age at surgery was significantly higher in the MC (+) group than in the MC (−) group. Regarding radiographic parameters, postoperative global tilt (GT), pre- and postoperative thoracolumbar kyphosis (TLK), and postoperative thoracic kyphosis were significantly higher in the MC (+) group than in the MC (−) group. Other parameters, such as the proposed ideal alignment target of PI-LL<10, did not significantly affect MC rates. The GAP score was high in both groups and not significantly related to a higher rate of MC. Forward stepwise logistic regression indicated that the age at surgery, postoperative GT, and preoperative TLK were significant risk factors for MCs. Conclusion. Older age, higher postoperative GT, and higher pre and postoperative TLK can be risk factors for MCs. The GAP score was high in both groups and not significantly related to a higher rate of MC. Level of Evidence: 4