Abstract
Patients with amyotrophic lateral sclerosis (ALS) typically present with arm, leg, or bulbar weakness. While genetics plays a clear role, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. In this clinicopathological case series, we examined the relationships between UMN/LMN disease in ten ALS patients. Detailed clinical assessments and motor cortex, brainstem, and spinal cord tissues were collected via rapid autopsy. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43, and RNA-sequencing was performed. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and both UMN/LMN involvement. LMN degeneration and microglial activation were highest at disease onset sites. UMN degeneration was present at all spinal cord levels through the medulla, regardless of onset site. Surprisingly, there was no evidence of UMN axonal degeneration above the brainstem. While extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. RNA-sequencing implicated inflammatory pathways at sites of disease onset. Our findings suggest that some ALS patients without FTD have a dying back of UMN axons rather than a primary upper neuronopathy of neurons.
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Abbreviations
- ALS:
-
Amyotrophic lateral sclerosis
- CST:
-
Corticospinal tract
- LMN:
-
Lower motor neuron
- UMN:
-
Upper motor neuron
- LFB:
-
Luxol fast blue
- H&E:
-
Hematoxylin and eosin
- Iba1:
-
Ionized calcium binding adaptor molecule 1
- NF-H:
-
Neurofilament heavy chain
- pTDP43:
-
Phospho-TAR DNA-binding protein 43
- FTD:
-
Frontotemporal dementia
Acknowledgements
Our most profound gratitude goes out to the ALS patients and their families who, prior to their death, volunteered their clinical histories and their bodies so that hopefully others would someday be helped. We would also like to acknowledge the UIC Genome Research Core and the UIC Research Tissue Imaging Core for their help on with this project. These data were presented in part at the 34th and 35th International Symposium on ALS/MND and 2025 Society for Neuroscience meeting. Biorender was used to make part of Figure 2.
Funding
This study was supported by the Patrick Grange Memorial Foundation, Chicago, IL (JAL and FS) and NIA T32AG057468 (HC). Funding was also received through an investigator initiated grant from Mitsubishi Tanabe Pharma America, Inc. (JAL) and earlier funding from the Hiller Foundation, Wayne State University (JAL and FS).
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C.A. is a consultant for Guidepoint Global, Atheneum Partners, Clarivate and the NIH. The authors report no other potential conflicts of interest.
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Cropper, H.C., Mir, F., Liu, J. et al. Axonal dying back of upper motor neurons in human ALS. Sci Rep (2026). https://doi.org/10.1038/s41598-026-52496-6
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DOI: https://doi.org/10.1038/s41598-026-52496-6
