Cutaneous nerve fiber pathology and function in Parkinson's disease and atypical parkinsonism - a cohort study

doi:10.1038/s41531-025-01030-y

. 2025 Jun 15;11(1):170.

doi: 10.1038/s41531-025-01030-y.

Cutaneous nerve fiber pathology and function in Parkinson's disease and atypical parkinsonism - a cohort study

Mattias Andréasson^{1

2

3}, Wojciech Paslawski⁴, Astrid Juhl Terkelsen⁵, Kristin Samuelsson^{6

4}, Henrik Zetterberg^{7

8

9

10

11

12}, Kaj Blennow^{7

8

13

14}, Páll Karlsson^{5

15}, Per Svenningsson^{16

6

4}

Affiliations

¹ Center for Neurology, Academic Specialist Center, Stockholm, Sweden. mattias.andreasson@ki.se.
² Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. mattias.andreasson@ki.se.
³ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. mattias.andreasson@ki.se.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
⁶ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁰ UK Dementia Research Institute at UCL, London, UK.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹³ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹⁴ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China.
¹⁵ Danish Pain Research Center, Health, Aarhus University, Aarhus, Denmark.
¹⁶ Center for Neurology, Academic Specialist Center, Stockholm, Sweden.

PMID: 40517154
PMCID: PMC12167382
DOI: 10.1038/s41531-025-01030-y

Cutaneous nerve fiber pathology and function in Parkinson's disease and atypical parkinsonism - a cohort study

Mattias Andréasson et al. NPJ Parkinsons Dis. 2025.

. 2025 Jun 15;11(1):170.

doi: 10.1038/s41531-025-01030-y.

Authors

Affiliations

¹ Center for Neurology, Academic Specialist Center, Stockholm, Sweden. mattias.andreasson@ki.se.
² Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. mattias.andreasson@ki.se.
³ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. mattias.andreasson@ki.se.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
⁶ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁰ UK Dementia Research Institute at UCL, London, UK.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹³ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹⁴ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China.
¹⁵ Danish Pain Research Center, Health, Aarhus University, Aarhus, Denmark.
¹⁶ Center for Neurology, Academic Specialist Center, Stockholm, Sweden.

PMID: 40517154
PMCID: PMC12167382
DOI: 10.1038/s41531-025-01030-y

Abstract

There is scientific evidence for ongoing neurodegeneration and alpha-synuclein pathology involving the peripheral nervous system in Parkinson's disease (PD) and multiple system atrophy (MSA). We explored putative disease-mirroring properties of cutaneous nerve fibers in patients with PD (n = 20), MSA (n = 12), four-repeat tauopathies (n = 11), and controls (n = 20). Assessments included clinical rating scales, blood sampling, sudomotor testing, skin punch biopsies from the neck and leg, and 1-year follow-up. Skin alpha-synuclein seeding amplification assay (SAA) and determination of intraepidermal nerve fiber density (IENFD) were performed. Reduced electrochemical skin conductance was evident in MSA, associated with clinical rating scores. Cervical skin SAA (PD vs controls) achieved a 100% sensitivity and 70% specificity for detecting PD. We found no difference in baseline IENFD, nor in 1-year changes, in patients relative to controls. Baseline IENFD, plasma neurofilament light, and SAA kinetics associated with 1-year clinical disease progression in MSA. Skin may harbor promising prognostic properties in MSA.

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Conflict of interest statement

Competing interests: M.A. declares no competing interest. W.P. has received funding from Parkinsonfonden Sweden. A.J.T. is funded by Novo Nordisk Borregaard Clinical Ascending grant (NNF23OC0082689) and has received honorarium from AstraZeneca UK limited, Novo Nordisk Denmark A/S, Alnylam Pharmaceuticals and Sanofi A/S.K.S. declares no competing interest. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the European Partnership on Metrology, co-financed from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States (NEuroBioStand, #22HLT07), the Bluefield Project, Cure Alzheimer’s Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270, and #AF-994551), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer’s Association 2022-2025 Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, and Familjen Rönströms Stiftelse, Stockholm, Sweden. KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. P.K. declares no competing interest. P.S. has received honorarium for lectures or scientific board consultations from Lundbeck, AstraZeneca, Bial, and AbbVie.

Figures

**Fig. 1. Baseline mean skin conductance and associations with disease burden in MSA.**
Mean ESC measured from feet (a) and hands (b). c Significant association between UMSARS part II and ESC_FEET in participants with MSA. *p < 0.05. PD Parkinson’s disease, 4R four-repeat tauopathies, MSA multiple system atrophy, HC healthy controls, UMSARS Unified Multiple System Atrophy Rating Scale, ESC electrochemical skin conductance, µS microsiemens, hash symbol one missing value.

**Fig. 2. Baseline intraepidermal nerve fiber density and cervical skin seeding amplification assay.**
Comparable IENFD between groups at the neck (a), proximal (b), and distal leg (c). Sagittal skin sections from participants with PD (d), MSA (e), and controls (f). Arrows show fibers traversing to the epidermis. g Number of positive replicates per participant from cervical skin SAA. h Kinetic SAA properties in patient samples, based on mean values from all positive replicates. *p < 0.05, ***p < 0.001. IENFD intraepidermal nerve fiber density, PD Parkinson’s disease, 4R four-repeat tauopathies, MSA multiple system atrophy, HC healthy control, ThT thioflavin T, hash symbol one missing value.

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References

1. Nolano, M. et al. Loss of cutaneous large and small fibers in naive and L-DOPA-treated PD patients. Neurology89, 776–784 (2017). - PubMed
1. Nolano, M. et al. Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain131, 1903–1911 (2008). - PubMed
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[1] Nolano, M. et al. Loss of cutaneous large and small fibers in naive and L-DOPA-treated PD patients. Neurology89, 776–784 (2017). - PubMed

[2] Nolano, M. et al. Loss of cutaneous large and small fibers in naive and L-DOPA-treated PD patients. Neurology89, 776–784 (2017). - PubMed

[3] Nolano, M. et al. Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain131, 1903–1911 (2008). - PubMed

[4] Nolano, M. et al. Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain131, 1903–1911 (2008). - PubMed

[5] Vacchi, E. et al. Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson’s disease. NPJ Parkinson's Dis.7, 119 (2021). - PMC - PubMed

[6] Vacchi, E. et al. Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson’s disease. NPJ Parkinson's Dis.7, 119 (2021). - PMC - PubMed

[7] Melli, G. et al. Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease. Ann. Clin. Transl. Neurol.5, 1394–1407 (2018). - PMC - PubMed

[8] Melli, G. et al. Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease. Ann. Clin. Transl. Neurol.5, 1394–1407 (2018). - PMC - PubMed

[9] Doppler, K. et al. Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta Neuropathol.128, 99–109 (2014). - PMC - PubMed

[10] Doppler, K. et al. Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta Neuropathol.128, 99–109 (2014). - PMC - PubMed

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Cutaneous nerve fiber pathology and function in Parkinson's disease and atypical parkinsonism - a cohort study

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Cutaneous nerve fiber pathology and function in Parkinson's disease and atypical parkinsonism - a cohort study

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