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The Skin You’re In: A Window to the Nervous System

By August 12, 2024September 17th, 2024No Comments

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The Skin You’re In: A Window to the Nervous System

As an interface to the outside world and the largest organ in the body, the skin is easily accessible and can provide important clues about a multitude of conditions. Skin biopsy is a simple office-based procedure that was first described in the 1800s and continues to be frequently performed for diagnostic purposes for various pathologies.1 While the procedure had primarily been performed by dermatologists for the diagnosis of skin conditions or infections, in more recent years, skin biopsy has also been adopted by neurologists, primary care physicians, and geriatricians in the diagnosis of conditions involving the peripheral, autonomic, and central nervous systems.

To understand how the skin may hold answers to questions pertaining to the nervous system, we can look to the earliest stages of human development. The skin and the nervous system share a common embryonic origin, the neuroectoderm, with shared molecular factors, including neuropeptides, neurotransmitters, growth factors and receptors. Both systems are susceptible to similar disease mechanisms involving oxidative stress, inflammation, autophagic dysfunction, and protein aggregation.2

CND Life Sciences has leveraged an extensive background of work in the immunohistochemical characterization of nerves of the skin to develop a reliable neurodiagnostic platform utilized by more than 1,700 clinicians to date. The methodology for identifying additional key pathological markers is notable for a high degree of accuracy for some conditions that impact the nervous system, notably small fiber neuropathy and synucleinopathies.3-5

Small fiber neuropathy
One utilization for skin biopsy in neurology is to confirm the clinical suspicion of small fiber neuropathy, a condition characterized by pain, numbness, tingling, and/or burning sensations. Small fibers consist of unmyelinated C-fibers and myelinated A-delta fibers that convey pain and temperature sensation. These small fibers can be quantified in healthy controls and are reduced in disease states.6,7

The Small Fiber Dx® test utilizes 3-mm skin samples retrieved after local anesthetic, utilizing a small punch tool. The samples are processed for immunohistochemical staining and the pan-axonal marker, PGP 9.5, allows for visualization and quantification of nerve fibers in the epidermis. Intraepidermal nerve fiber density (IENFD) can be compared to established normative data (based on age, location on body, and sex), with reduced IENFD supportive of a diagnosis of small fiber neuropathy, which can be associated with or caused by metabolic, toxic, inflammatory, or autoimmune conditions.3,4,6,7

Synucleinopathies
Synucleinopathies affect over 2.5 million people in the US, with incidence rates on the rise. Despite this growing prevalence, diagnostic clarity is often lacking, particularly early in the course of these diseases. Synucleinopathies include Parkinson’s disease, multiple system atrophy, dementia with Lewy bodies (DLB), and pure autonomic failure.8-10 These disorders are characterized by the abnormal deposition of misfolded alpha-synuclein protein in the central nervous system, biofluids, and peripheral tissues including the skin.4,5,11

The Syn-One Test® allows for visualization of phosphorylated alpha-synuclein (P-SYN) within axonal nerve fibers of the dermis, utilizing double immunostaining of skin biopsy tissue for axonal fibers (PGP 9.5) and P-SYN.12 In the Synuclein-One Study, an NIH-supported, prospective, blinded, cross-sectional study of 428 patients in academic and community-based neurology practices, the Syn-One Test demonstrated greater than 95% sensitivity and specificity across the synucleinopathies.13

Ongoing research
Recognizing the potential for skin-based diagnostic clarity even earlier in the neurodegenerative process, CND has initiated additional NIH-supported studies evaluating skin biopsies from patients with mild cognitive impairment (MCI) in Alzheimer’s disease (AD) and DLB, as well as idiopathic REM sleep behavior disorder (iRBD), which is considered to be a prodromal condition for the synucleinopathies.

Syn-D (ClinicalTrials.gov ID NCT05479552): In collaboration with approximately 10 centers that specialize in DLB and dementia, the 12-month longitudinal Syn-D Study will evaluate skin biopsy-based α-synuclein and clinical characterization of 80 patients with suspected MCI-AD and MCI-DLB at baseline and 1-year study visits.

Syn-Sleep (ClinicalTrials.gov ID NCT05757206): In collaboration with approximately 8 centers that specialize in iRBD, the two-year longitudinal Syn-Sleep Study will evaluate skin biopsy-based α-synuclein and clinical characterization of 80 individuals with iRBD at baseline, one-, and two-year study visits. This study is still enrolling; to learn more, click here.

Detection, visualization, and quantitation of skin-based pathology is transforming the diagnosis of neurodegenerative diseases by opening the window to the central nervous system through the skin, and CND Life Sciences is leading the way.

About the Author:
As Director of Medical Affairs, Dr. Padma Mahant plays a key role in patient engagement and advocacy while also providing education and guidance on CND’s diagnostic technologies and conducting physician case reviews. She maintains a private practice specializing in movement disorders and serves as the Clinical Assistant Professor of Neurology with the University of Arizona Medical School in Phoenix, AZ.

References:

  1. Mufti A, Jackson R. Biopsy–What’s in the Name? JAMA Dermatol. 2016;152(2):190. doi:10.1001/jamadermatol.2015.3677
  2. Ravn AH, Thyssen JP, Egeberg A. Skin disorders in Parkinson’s disease: potential biomarkers and risk factors. Clin Cosmet Investig Dermatol. 2017;10:87-92. doi:10.2147/CCID.S130319
  3. Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009;72(17):1479-1486. doi:10.1212/WNL.0b013e3181a2e8b8
  4. Wang N, Gibbons CH, Freeman R. Novel immunohistochemical techniques using discrete signal amplification systems for human cutaneous peripheral nerve fiber imaging. J Histochem Cytochem. 2011;59(4):382-390. doi:10.1369/0022155410396931
  5. Wang N, Gibbons CH, Lafo J, Freeman R. α-synuclein in cutaneous autonomic nerves. Neurology. 2013;81(18):1604-1610. doi:10.1212/WNL.0b013e3182a9f449
    Thomas S, Enders J, Kaiser A, et al. Abnormal intraepidermal nerve fiber density in disease: A scoping review. Front Neurol. 2023;14:1161077. doi:10.3389/fneur.2023.1161077
  6. Saperstein DS, Levine TD. Diagnosing small fiber neuropathy through the use of skin biopsy. Pract Neurol. 2009;37-40. https://practicalneurology.com/articles/2009-oct/PN1009_06-php
  7. Willis AW, Roberts E, Beck JC, et al. Incidence of Parkinson disease in North America. NPJ Parkinsons Dis. 2022;8(1):170. doi:10.1038/s41531-022-00410-y
  8. Adler CH, Beach TG, Hentz JG, et al. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology. 2014;83(5):406-412. doi:10.1212/WNL.0000000000000641
  9. Martí MJ, Tolosa E, Campdelacreu J. Clinical overview of the synucleinopathies. Mov Disord. 2003;18 Suppl 6:S21-S27. doi:10.1002/mds.10559
  10. Xu L, Pu J. Alpha-synuclein in Parkinson’s disease: from pathogenetic dysfunction to potential clinical application. Parkinsons Dis. 2016;2016:1720621. doi:10.1155/2016/1720621
  11. Gibbons CH, Freeman R, Bellaire B, Adler CH, Moore D, Levine T. Synuclein-One study: skin biopsy detection of phosphorylated α-synuclein for diagnosis of synucleinopathies. Biomark Med. 2022;16(7):499-509. doi:10.2217/bmm-2021-0646
  12. Gibbons CH, Levine T, Adler C, et al. Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. JAMA. 2024;331(15):1298–1306. doi:10.1001/jama.2024.0792
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