pTDP-43 aggregates accumulate in non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: a case series linking archival surgical biopsies with clinical phenotypic data

Samuel B. Pattle, Judi O'shaughnessy, Owen Kantelberg, Olivia M Rifai, Judith Pate, Kristine Nellany, Nadine Hays, Mark J. Arends, Mathew Horrocks, Fergal M Waldron, Jenna Gregory* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
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Abstract

Neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are traditionally considered strictly neurological disorders. However, clinical presentation is not restricted to neurological systems, and noncentral nervous system (CNS) manifestations, particularly gastrointestinal symptoms, are common. Our objective was to understand the systemic distribution of pathology in archived non-CNS tissues, taken as part of routine clinical practice during life from people with ALS. We examined tissue from 13 people who went on to develop ALS; including sporadic ALS (n=12) and C9orf72 hexanucleotide repeat expansion (n=1). The tissue cohort consisted of 68 formalin-fixed paraffin embedded samples from 21 surgical cases (some patients having more than one case over their lifetimes), from 8 organ systems, which we examined for evidence of pTDP-43 pathology. We identified pTDP-43 aggregates in multiple cell types of the gastrointestinaI tract, including macrophages and dendritic cells within the lamina propria; as well as ganglion/neuronal and glial cells of the myenteric plexus. Aggregates were also noted within lymph node parenchyma, blood vessel endothelial cells, and chondrocytes. We note that in all cases with non-CNS pTDP-43 pathology, aggregates were present prior to ALS diagnosis and in some instances preceded neurological symptom onset by more than 10 years. These data imply that patients with microscopically unexplained non-CNS symptoms could have occult protein aggregation that could be detected many years prior to neurological
involvement.
Original languageEnglish
Pages (from-to)44-55
Number of pages12
JournalJournal of Pathology: Clinical Research
Volume9
Issue number1
Early online date13 Oct 2022
DOIs
Publication statusPublished - Jan 2023

Bibliographical note

Acknowledgements
The authors would like to thank the staff at the NHS Lothian BioResource (Vishad Patel and Craig Marshall) and the NHS Grampian biorepository (Joan Wilson) and the staff and corefunded resources of the imaging and histology core facility at the Institute of Medical Sciences (Gillian Milne, Lucinda Wight, and Debbie Wilkinson). This study was funded by the Pathological Society/Jean Shanks Foundation (JSPS CLSG 202002 to JMG and JO’S), The Royal Society (RGS\R1\221396 to JMG) and the Wellcome Trust (108890/Z/15/Z to OR). Funders had no role in study design, data collection, data analyses, interpretation, or writing the manuscript

Data Availability Statement

All clinical and demographic data have been shared in an anonymised format as per ethical restrictions of tissue use from the NHS BioResource. All slides processed in this study have been whole slide scanned and can be requested from the first or senior author and will be transferred as .ndpi files which can be visualized using freely available software. All other data are included in their entirety within the manuscript.

Keywords

  • ALS
  • TDP-43
  • Gastrointestinal tract
  • Non-CNS tissue
  • human tissue
  • pathology

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