O.07 TDP43 accumulates in intramuscular nerve bundles of ALS patients

Abstract

Amyotrophic lateral sclerosis (ALS) shows progressive muscle weakness and atrophy caused by neuronal death associate with TAR DNA-binding protein 43 (TDP43). Meanwhile, Awaji and Gold Coast criterion include an electrophysiological aspect to support clinical findings but not a pathological aspect because myopathological findings of ALS are not considered as specific. However, the advantage of the Awaji criteria is less pronounced in patients with spinal-onset ALS. The Gold Coast criteria enables us to diagnose spinal onset ALS patients and needs to allow for a specific diagnosis including a pathological aspect. Here, we aimed to identify and characterize the histopathology of peripheral axons in muscles of ALS patients. The post-mortem study included 10 sporadic ALS (SALS) patients with TDP43 pathology and 12 patients with non-ALS disease. The muscle biopsy cohort considered 450 patients and enrolled 114 as without family history of ALS or other neuromuscular diseases and not diagnosed with muscle diseases at biopsy. They ensure clinical follow-up in minimum one year. Exclusions were as follows: 51 for not screening clinical records after biopsy, 282 diagnosed with muscular diseases, and 3 harboring known causative genes of ALS. Muscle tissues were evaluated by histochemistry and immunohistochemical analysis. Ten SALS patients exhibited axonal phosphorylated TDP43 (pTDP43)-positive accumulations in intramuscular nerve bundles; 12 non-ALS patients did not. Among the muscle biopsy cohort, 71 patients exhibited intramuscular nerve bundles; 43 did not. Of the former, 33 presenting pTDP43-positive nerve bundles were later diagnosed with ALS. The remaining 38 showed no pTDP43-positive bundles and did not develop ALS. Among those without evident nerve bundles, 3 were later diagnosed with ALS. Among ALS patients in the biopsy cohort, 9 having pTDP43-positive bundles showed only lower motor neuron symptoms at biopsy. Axonal pTDP43 accumulations might be characteristic for ALS patients. As such findings precede clinical fulfillment of the Gold Coast criteria, TDP43 in nerve bundles might be a novel diagnostic biomarker for ALS.