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Cutaneous expression of growth-associated protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndrome.

ABSTRACT: Growth-associated protein 43 (GAP-43) has long been used as a marker for nerve regeneration following nerve injury, with numerous in vitro and animal studies showing its upregulation in regenerating neurons. In humans, expression of GAP-43 has predominantly been examined in skin biopsies from patients with peripheral neuropathies; with several studies showing a reduction in GAP-43 immunoreactive cutaneous nerve fibres. However, it remains elusive whether cutaneous GAP-43 is a valid marker for human nerve regeneration. Here, we present a cohort of 22 patients with electrodiagnostically confirmed carpal tunnel syndrome (CTS), used as a model system for focal nerve injury and neural regeneration after decompression surgery. We evaluate GAP-43 immunoreactivity and RNA expression levels in finger skin biopsies taken before and 6 months after surgery, relative to healthy controls. We further classify patients as 'regenerators' or 'non-regenerators' based on post-surgical epidermal re-innervation. We demonstrate that patients with CTS have lower GAP-43 positive intra-epidermal nerve fibre density (IENFD) before surgery than healthy controls. However, this difference disappears when normalising for total IENFD. Of note, we found surgery did not change GAP-43 expression in IENF, with no differences both in patients who were classified as regenerators and non-regenerators. We also did not identify pre-post surgical differences in cutaneous GAP-43 gene expression or associations with regeneration. These findings suggest cutaneous GAP-43 may not be a compelling marker for nerve regeneration in humans.

SUBMITTER: Carroll L

PROVIDER: S-EPMC9668135 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Cutaneous expression of growth-associated protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndrome.

Carroll Liam L Sandy-Hindmarch Oliver O Baskozos Georgios G Zhu Guan Cheng GC McCarthy Julia J Schmid Annina A

PloS one 20221116 11

Growth-associated protein 43 (GAP-43) has long been used as a marker for nerve regeneration following nerve injury, with numerous in vitro and animal studies showing its upregulation in regenerating neurons. In humans, expression of GAP-43 has predominantly been examined in skin biopsies from patients with peripheral neuropathies; with several studies showing a reduction in GAP-43 immunoreactive cutaneous nerve fibres. However, it remains elusive whether cutaneous GAP-43 is a valid marker for hu ...[more]

PMID: 36383568

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Project description:In Sweden, a large family with a point mutation in the nerve growth factor-beta gene has previously been identified. The carriers of this mutation have reduced small-fibre density and selective deficits in deep pain and temperature modalities. The clinical findings in this population are described as hereditary sensory and autonomic neuropathy type V. The purpose of the current study was to investigate the prevalence of carpal tunnel syndrome in hereditary sensory and autonomic neuropathy type V based on clinical examinations and electrophysiological measurements. Furthermore, the cross-sectional area of the median nerve at the carpal tunnel inlet was measured with ultrasonography. Out of 52 known individuals heterozygous for the nerve growth factor-beta mutation in Sweden, 23 participated in the current study (12 males, 11 females; mean age 55 years; range 25-86 years). All participants answered a health questionnaire and underwent clinical examination followed by median nerve conduction study in a case-control design, and measurement of the nerve cross-sectional area with ultrasonography. The diagnosis of carpal tunnel syndrome was made based on consensus criteria using patient history and nerve conduction study. The prevalence of carpal tunnel syndrome in the hereditary sensory and autonomic neuropathy group was 35% or 52% depending on whether those individuals who had classic symptoms of carpal tunnel syndrome but negative nerve conduction studies were included or not. Those who had a high likelihood of carpal tunnel syndrome based on classic/probable patient history with positive nerve conduction study had a significantly larger median nerve cross-sectional area than those who had an unlikely patient history with negative nerve conduction study. The prevalence of carpal tunnel syndrome was 10-25 times higher in individuals heterozygous for the nerve growth factor-beta mutation than the general Swedish population. Further studies are needed to better understand the underlying pathophysiological mechanisms.

Project description:BackgroundCarpal tunnel syndrome (CTS) is the most common form of peripheral nerve injury, affecting approximately 3 % of the population. While surgery is effective in mild and moderate cases, nerve and functional recovery are often not complete in severe cases. Therefore, there is a need for adjuvant methods to improve nerve regeneration in those cases. Acetyl-L-carnitine (ALCAR) is involved in lipid transport, vital for mitochondrial function. Although it has been shown to be effective in various forms of neuropathies, it has not been used in traumatic or compressive peripheral nerve injury.MethodsIn this pilot study we will utilize a double-blind, randomized, placebo-controlled design. Inclusion criteria will include adult patients with severe CTS. This will be confirmed by nerve conduction studies and motor unit number estimation (MUNE). Only those with severe motor unit loss in the thenar muscles (2 standard deviations [SD] below the mean for the age group) will be included. Eligible patients will be randomized to receive 3,000 mg/day of ALCAR orally or placebo following carpal tunnel release surgery for 2 months. The primary outcome will be MUNE with supplementary secondary outcome measures that include: 1) two-point discrimination; 2) Semmes-Weinstein monofilaments for pressure sensitivity; 3) cold and pain threshold for small fiber function; 4) Boston self-assessment Carpal Tunnel Questionnaire and 5) Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire for symptom severity; and 6) Purdue Pegboard Test for hand functional performance. To follow post treatment recovery and monitor safety, patients will be seen at 3 months, 6 months and 1 year. The outcome measures will be analyzed using two-way ANOVA, with treatment assignment and time points being the independent factors. If significant associations are detected, a post hoc analysis will be completed. We aim to recruit ten patients into each of the two groups. Data from this pilot will provide the basis for power calculation for a full-scale trial.DiscussionALCAR is a physiologic peptide crucial for fatty acid transport. ALCAR has been shown to be effective in neuroprotection in the central nervous system and increase peripheral nerve regeneration. This has been applied clinically to various systemic peripheral neuropathies including diabetic neuropathy, antiretroviral toxic neuropathy, and chemotherapy-induced peripheral neuropathy. While animal evidence exists for the benefit of ALCAR in compression neuropathy, there have been no human studies to date. This trial will represent the first use of ALCAR in peripheral nerve injury/compression neuropathy.Trial registrationNCT02141035 ; 20 April 2015.

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Cutaneous expression of growth-associated protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndrome.

Publications

Cutaneous expression of growth-associated protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndrome.

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