Serum neurofilament light chain correlates with nerve damage but not pain in diabetic polyneuropathy

Aims: To evaluate serum neurofilament light chain (sNfL) as a biomarker of nerve fiber damage in individuals with painful and painless diabetic polyneuropathy (DPN), and to explore its relationship with clinical severity, pain, structural, and functional nerve assessments.

Methods: In this cross-sectional study of 201 individuals with probable or confirmed DPN from the PiNS/DOLORisk cohort, serum sNfL was measured using single molecule array technology. Associations with neuropathic pain, clinical DPN scores, quantitative sensory testing (QST), and intraepidermal nerve fiber density (IENFD, in a subset) were analyzed.

Results: sNfL concentrations did not differ between individuals with painful and painless DPN and were not associated with pain severity or clinical DPN scores. However, higher sNfL levels were correlated with reduced IENFD and impaired somatosensory function as measured by QST. Participants with both large and small fiber dysfunction showed the highest sNfL levels, suggesting a link between sNfL and cumulative nerve fiber damage.

Conclusions: While sNfL is not associated with neuropathic pain or clinical DPN scores, it reflects structural and functional nerve fiber loss in DPN. These findings support the potential of sNfL as an objective biomarker for nerve degeneration, particularly in individuals with combined large and small fiber involvement.

Comments: This study provides important insights into the utility of sNfL as a biomarker for nerve fiber damage in DPN. Unlike traditional clinical scores and symptom-based assessments, which may not reliably reflect the extent of neuroaxonal damage, sNfL demonstrated robust associations with objective markers of both structural (IENFD) and functional (QST) nerve fiber integrity. The absence of a correlation with pain presence or intensity highlights the well-recognized clinicopathological dissociation in DPN, where pain does not reliably reflect the extent of nerve fiber degeneration.

A notable strength of the study lies in the deep phenotyping of participants, including QST and IENFD assessments, though the latter was only available in a subset. While the large and well-characterized cohort supports the robustness of the findings, the absence of renal function data, a known confounder of sNfL, and the lack of a diabetic control group without DPN limit conclusions regarding diagnostic utility and early detection.

These findings build upon previous studies demonstrating elevated sNfL concentrations in individuals with recent-onset diabetes and subclinical nerve dysfunction. In the German Diabetes Study (Maalmi H et al Diabetologia. 2023;66:579-589), higher sNfL levels were linked to the presence of DPN, even among participants with a diabetes duration of less than one year, indicating the potential of sNfL as an early marker of neuroaxonal injury. Complementary evidence from the ADDITION-Denmark cohort (Määttä LL et al Diabetes Care. 2024;47:986-994) showed a progressive increase in sNfL over time, particularly in individuals who developed DPN. Collectively, these data support the role of sNfL as a biomarker for both disease severity and early detection, as well as for longitudinal monitoring of neuropathy progression.

Zoltan Kender

Reference: Määttä LL, Andersen ST, Parkner T, Hviid CVB, Witte DR, John J, Pascal MMV, Ferris E, Baskozos G, Ramirez JD, Tesfaye S, Shillo PR, Rice ASC, Laycock HC, Jensen TS, Bennett DL, Themistocleous AC. Serum Neurofilament Light Chain and Structural and Functional Nerve Fiber Loss in Painful and Painless Diabetic Polyneuropathy. Diabetes Res Clin Pract. 2025 Mar 19;223:112098. doi: 10.1016/j.diabres.2025.112098. Epub ahead of print. PMID: 40118191.

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