Background & Aims

The axonal protein neurofilament light chain (NfL) has been proposed as a possible biomarker for peripheral neuropathies including diabetic polyneuropathy (DPN) (1-3). Detailed investigation of the relationship between NfL and DPN severity is however missing. We aimed to explore the potential of NfL as a biomarker for DPN severity as quantified by clinical scales, quantitative sensory testing (QST), intraepidermal nerve fiber density (IENFD) and pain status.

Methods

We performed cross-sectional analysis of biobank serum samples and data from a subset of the PiNS/DOLORisk cohort of people with DPN with and without neuropathic pain (4, 5). Biobank samples were analyzed for serum NfL (s-NfL) using single molecule array (Simoa®). DPN was defined according to Toronto criteria for probable or confirmed DPN (6). Presence of painful DPN (PDPN) was evaluated according to IASP Neuropathic Pain Special Interest Group criteria (7). Pain severity was reported via the Brief Pain Inventory-item rating average pain on a scale from 0 to 10 (8). Applied clinical DPN scales included the Toronto Clinical Scoring System (TCSS) and the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) (9, 10). Standard protocols were utilized for quantification of IENFD from skin biopsies from the distal leg and QST at the foot (11, 12).

Results

Participants with confirmed (N=172) or probable DPN (N=29) were included. There was no s-NfL difference between participants with DPN (N=79, 22.8 ng/L [IQR 17.4; 31.3]) and PDPN (N=122, 22.3 ng/L [16.0; 34.4]). S-NfL was not associated to pain severity or to the severity of DPN as evaluated by TCSS and MNSIq. Higher s-NfL was associated to lower IENFD (13.6% [95% CI 3.1; 22.9] higher s-NfL per 1 fiber/mm reduction in IENFD, N=24) and to more pronounced loss of nerve fiber function measured by QST (p trend=0.02). Participants with combined loss of small and large fiber function had higher s-NfL than participants with either no loss or with isolated loss of small fiber function (p-values<0.01). S-NfL had a significant and inverse correlation with QST measures of loss of function, cold and heat pain thresholds and mechanical pain sensitivity (partial Spearman r: -0.15 to -0.23).

Conclusions

Higher s-NfL was associated with nerve fiber dysfunction and loss as quantified by QST and IENFD, but not with pain or clinical DPN scales. S-NfL may hence reflect the severity of the nerve fiber damage underlying DPN and have value as an objective marker of DPN severity.

References

1.Fundaun J, Kolski M, Molina-Álvarez M, Baskozos G, Schmid AB. Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022;5(12):e2248593. doi:10.1001/jamanetworkopen.2022.48593.
2.Maalmi H, Strom A, Petrera A, et al. Serum neurofilament light chain: a novel biomarker for early diabetic sensorimotor polyneuropathy. Diabetologia. 2023;66(3):579-589. doi:10.1007/s00125-022-05846-8.
3.Fridman V, Sillau S, Ritchie A, et al. Plasma Neurofilament Light Chain Concentrations are Elevated in Youth-onset Type 2 Diabetes and Associate with Neuropathy. Journal of the peripheral nervous system : JPNS. 2023. doi:10.1111/jns.12575.
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5.Pascal MMV, Themistocleous AC, Baron R, et al. DOLORisk: study protocol for a multi-centre observational study to understand the risk factors and determinants of neuropathic pain. Wellcome Open Res. 2018;3:63. doi:10.12688/wellcomeopenres.14576.2.
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7.Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016;157(8):1599-1606. doi:10.1097/j.pain.0000000000000492.
8.Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain. 2004;5(2):133-137. doi:10.1016/j.jpain.2003.12.005.
9.Bril V, Perkins BA. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care. 2002;25(11):2048-2052. doi:10.2337/diacare.25.11.2048.
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12.Lauria G, Hsieh ST, Johansson O, et al. European federation of neurological societies/peripheral nerve society guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. report of a joint task force of the european fe-deration of neurological societies and the peripheral nerve society. European Journal of Neurology. 2010;17(7):903-912. doi:10.1111/j.1468-1331.2010.03023.x.

Presenting Author

Laura L. Määttä

Poster Authors

Laura Linnea Määttä

MD

Danish Pain Research Center, Department of Clinical Medicine, Aarhus University

Lead Author

E-mail

Signe T. Andersen

MD

Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

Lead Author

E-mail

Tina Parkner

MD

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

Lead Author

E-mail

Claus V.B. Hviid

MD

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

Lead Author

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Daniel R. Witte

MD

Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

Lead Author

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JISHI JOHN

University of Oxford

Lead Author

E-mail

Mathilde M.V. Pascal

MA

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Lead Author

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Eleanor Ferris

BA

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Lead Author

E-mail

Georgios Baskozos

PhD

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Lead Author

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Juan D. Ramirez

MD

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Lead Author

E-mail

Solomon Tesfaye

MB ChB

Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom

Lead Author

E-mail

Pallai R. Shillo

MD

Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom

Lead Author

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Andrew Rice

MD

Imperial College London

Lead Author

E-mail

Helen C. Laycock

MD

Pain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom

Lead Author

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Troels S. Jensen

MD

Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

Lead Author

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David Bennett

PhD

University of Oxford

Lead Author

E-mail

Andreas Themistocleous

University Of Oxford

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral

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