The study covered in this summary was published on bioRxiv.org as a preprint and has not yet been peer reviewed.
Aggregates of phosphorylated TAR DNA binding protein 43 (pTDP-43), the major pathologic protein that accumulates in the central nervous system (CNS) of individuals with amyotrophic lateral sclerosis (ALS), were identified in multiple non-CNS cell types in ALS patients.
In all such cases, these non-CNS pTDP-43 aggregates had been present a median of 2 years — and in one case, for 14 years — before the patients' ALS diagnosis, which has implications for their use as early indicators of the disease before neurologic involvement.
Why This Matters
Many patients with neurodegenerative diseases, including ALS, Parkinson's disease, and Alzheimer's disease, experience non-CNS symptoms, particularly gastrointestinal (GI) symptoms, such as altered bowel habits, before receiving their neurologic diagnoses.
This is the first study to systematically evaluate and present evidence of pTDP-43 aggregation in GI and other non-CNS tissue samples taken in routine clinical practice from ALS patients before diagnosis of their motor signs and symptoms.
The authors' findings support those of other studies hypothesizing that GI pathology precedes CNS symptoms in some neurodegenerative diseases.
Diagnosis via non-CNS tissue could usher in new consideration of neurodegenerative diseases as systemic disorders rather than end-stage neurologic disorders only, with the potential for early screening and intervention.
For a cohort of 48 patients in Scotland in whom pTDP-43 pathology had previously been identified in the CNS after death, the authors acquired all non-CNS surgical specimens obtained for diagnostic or surgical reasons at any time during the patients' lives (median age at tissue removal, 62.4 years; median time of tissue removal before death, 6.3 years). All patients had been diagnosed with sporadic ALS or ALS with a C9orf72 hexanucleotide repeat expansion.
Of these 48 patients, sufficient evaluable tissue (determined by two independent histopathologists) was available for 13, 12 of whom had sporadic ALS. From these 13 patients, 68 formalin-fixed, paraffin-embedded tissue samples were available from 22 surgical cases, which involved the skin (eight cases), female gynecologic tissue (five cases), lymph nodes (three cases; one surgical case involved both lymph node and soft tissue), GI tissue (two cases), soft tissue (two cases), urethra (one case), pleura (one case), and thyroid (one case).
pTDP-43 staining revealed aggregates in GI tissue (two of two cases; multiple cell types of the gallbladder and colon), lymph node (one of three cases; parenchyma and T-cell–rich areas), and skin (two of eight cases; endothelial cells and nerve bundles, dendritic cells, chondrocytes). Aggregates were not identified in the samples from the other five organ systems.
For the patients with non-CNS pTDP-43 aggregates, the median time from tissue removal to ALS symptom onset was 12 months (range, 0–144 months) and to diagnosis was 24 months (range, 2–168 months).
The study's conclusions are limited by its small sample size and its bias toward individuals with sporadic ALS.
The cohort was limited to patients already known to have pTDP-43 pathology in the CNS.
Therefore, future research to investigate the population dynamics and feasibility of population screening for this pathology should include larger cohorts of unselected individuals.
The study was funded by the Wellcome Trust and the Pathological Society of Great Britain and Ireland.
The authors have disclosed no relevant financial relationships.
This is a summary of a preprint research study, "pTDP-43 Aggregates Accumulate in the Gut and Other Non–Central Nervous System Tissues Prior to Symptom Onset in Amyotrophic Lateral Sclerosis," written by Samuel B. Pattle of the NHS Lothian Department of Pathology, Edinburgh, United Kingdom, and colleagues, published on bioRxiv.org and provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on bioRxiv.org.
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Cite this: Jennifer Herrin for Medscape. Protein in Gut Predicts ALS - Medscape - Mar 29, 2022.