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In amyotrophic lateral sclerosis (ALS), it remains elusive how the initial lesions develop and further extend in the upper and lower motor neuron (UMN and LMN) systems. Several studies of ALS using cell or animal models have demonstrated that the disease-related protein, transactive response DNA-binding protein 43 kDa (TDP-43), propagates in the nervous system by sequential cell-to-cell transmission and/or anterograde/retrograde axonal transport.1 However, it is often difficult to trace the trajectory of disease progression in living patients, or propagation of TDP-43 in human autopsied tissues. This is partly due to the diverse clinical phenotypes of ALS and the resulting inter-individual variations in both the rate and manner of disease progression.2
Among the variants of ALS, hemiplegic-type ALS is characterised by prominent asymmetry of the clinical symptoms throughout the illness.3 Here we report the clinicopathological features of two autopsy cases of hemiplegic-type ALS with special reference to the clinicopathological link between chronological evolution of lateralised clinical symptoms and asymmetric lesion extension and a degenerative link between the UMN and LMN systems. We further discuss the possible pathomechanism that may facilitate the above-mentioned links, or more strictly the propagation routes of TDP-43 that may be inherent to this rare variant of ALS.
The patients, two unrelated men in their 70s and 80s, initially presented with unilateral (patient 1, left; patient 2, right) leg weakness that spread to involve the ipsilateral arm and bulbar muscles within the following 3 and 2 years, respectively. In both patients, UMN signs including spasticity and hyper-reflexia were also lateralised to the predominant side of muscle weakness. They died of respiratory failure 3 and 4 years after onset, when limb weakness asymmetry was still evident online supplemental method. Autopsy revealed that the degree of degeneration in the motor systems apparently reflected the clinical asymmetry and chronological …
MS and HT contributed equally.
Contributors MS and HT contributed equally. MS, HT, HS and AK designed research project, and performed pathological analysis and drafted the manuscript for intellectual content. TM, TF and KM collected clinical data. YH, TI and OO designed the genetic testing.
Funding This work was supported in part by JSPS Grants-in-Aid for Scientific Research to HS (19K07841), HT (19K16908), TI (17K09750) and AK (19H01061 and 19H05559) and Grants-in-Aid from the Research Committee of CNS Degenerative Disease, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Science Research Grants, the Ministry of Health, Labour and Welfare, Japan to OO and AK.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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