The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy
The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy
复制标题
DOI：
10.1093/brain/awh175
复制
发表时间：
2004-07-01
期刊：
影响因子：
14.5
通讯作者：
McArthur, JC
中科院分区：
文献类型：
--
作者：
Polydefkis, M;Hauer, P;McArthur, JC
我们试图建立和验证标准化的皮肤神经再生模型，并首先在健康对照受试者中确定表皮神经纤维(ENF)的再生率，然后在有神经病变和无神经病变的糖尿病受试者中确定。接下来，我们评估了不同因素对神经纤维再生率的影响，并调查了这种方法是否可以为新的试验设计和结果测量提供洞察力。所有受试者的大腿远端外侧都涂有标准化的辣椒素敷料。在基线、辣椒素治疗后和再神经支配的时间点，测定来自皮肤活检组织的ENF密度。对于每个受试者，从去神经后数据中确定最佳拟合线，并将斜率用作再生率。在健康对照受试者中，再生与心理物理感觉测试、电子显微镜研究和免疫组织化学替代轴突膜标记物相关。在对照组和糖尿病患者中，局部应用辣椒素导致表皮完全或几乎完全失去神经。再生率与基线脑神经营养因子密度相关(P<；0.001)，而与年龄(P=0.75)、性别(P=0.18)、表皮厚度(P=0.4)或辣椒素治疗后密度(P=0.7)无关。由脑神经营养因子密度恢复所确定的脑神经营养因子再生，在健康受试者中以0.177+/-0.075纤维/毫米/天的速度发生，而在糖尿病患者中(0.074+/-0.064，P<；0.001)在调整基线脑神经营养因子密度的变化后显著减少。在糖尿病患者中，神经病变的存在与再生率的进一步降低有关(0.10+/-0.07比0.04+/-0.03，P=0.03)，尽管糖尿病类型(P=0.7)、病程(P=0.3)或基础糖化血红蛋白(P=0.6)并不显著。这些结果有几个含义。首先，局部应用辣椒素可以产生安全和耐受性良好的均匀的表皮神经纤维损伤，并为测量和研究人类神经再生提供了一种有效的策略。其次，使用我们的技术，在没有神经病变证据的糖尿病患者中发现神经再生率降低，这表明周围神经功能异常在糖尿病患者早期出现，在体征或症状发展之前。这些结果表明，再生性神经病试验可以包括非神经病受试者，试验持续时间可以大大缩短。
We sought to develop and validate a standardized cutaneous nerve regeneration model and to define the rate of epidermal nerve fibre (ENF) regeneration first in healthy control subjects and then in neuropathic and neuropathy-free subjects with diabetes. Next, we assessed the effect of different factors on the rate of nerve fibre regeneration and investigated whether such an approach might offer insight into novel trial designs and outcome measures. All subjects had a standardized topical capsaicin dressing applied to the distal lateral thigh. ENF densities derived from skin biopsies were determined at baseline, after capsaicin treatment and at reinnervation time points. For each subject, the best fit line from post-denervation data was determined and the slope was used as the rate of regeneration. In healthy control subjects, regeneration was correlated with psychophysical sensory testing, electron microscopy studies and immunohistochemistry with alternative axonal membrane markers. Topical capsaicin application produced complete or nearly complete denervation of the epidermis in both control subjects and people with diabetes. The rate of regeneration was associated with the baseline ENF density (P < 0.001), but not age (P = 0.75), gender (P = 0.18), epidermal thickness (P = 0.4) or post-capsaicin treatment density (P = 0.7). ENF regeneration, as determined by recovery of ENF density, occurred at a rate of 0.177 +/- 0.075 fibres/mm/day in healthy control subjects and was significantly reduced in subjects with diabetes (0.074 +/- 0.064, P < 0.001) after adjusting for changes in baseline ENF density. Among subjects with diabetes, the presence of neuropathy was associated with a further reduction in regenerative rate (0.10 +/- 0.07 versus 0.04 +/- 0.03, P = 0.03), though diabetes type (P = 0.7), duration of diabetes (P = 0.3) or baseline glycated haemoglobin (P = 0.6) were not significant. These results have several implications. First, topical capsaicin application can produce a uniform epidermal nerve fibre injury that is safe and well tolerated, and offers an efficient strategy to measure and study nerve regeneration in man. Secondly, using our techniques, reduced rates of nerve regeneration were found in people with diabetes without evidence of neuropathy and indicate that abnormalities in peripheral nerve function are present early in diabetes, before signs or symptoms develop. These results suggest that regenerative neuropathy trials could include non-neuropathic subjects and that trial duration can be dramatically shortened.