Journal of the Peripheral Nervous System最新文献_第7页

Neuroprotective Effect of Mas Activation by BIO101 in Vincristine-Induced Small Fiber Neuropathy BIO101激活Mas对长春新碱诱导的小纤维神经病的神经保护作用

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-20 DOI: 10.1111/jns.70055

Simon Frachet, Aurore Danigo, Mathilde Latil, Pierre J. Dilda, Flavien Bessaguet, Laurence Richard, Franck Sturtz, Laurent Magy, Claire Demiot

Background and Aims

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect that limits the dosage of many anticancer therapies, such as vincristine. At present, there are no effective pharmacological treatments to prevent CIPN. The Mas receptor (MasR) is expressed in the peripheral nervous system and plays a role in pain modulation. While the antinociceptive properties of MasR activation in CIPN have been documented, its potential neuroprotective effects have not been explored in the peripheral nervous system. BIO101, a highly purified form of the MasR activator 20-hydroxyecdysone, exhibits a positive safety profile in a Phase 1 study without any serious adverse events.

Methods

This study aimed to investigate the neuroprotective effects of BIO101 in a mouse model of vincristine-induced peripheral neuropathy (VIPN). Swiss mice were treated with daily doses of vincristine. VIPN was evaluated through repeated measurements of tactile sensitivity, quantification of intraepidermal nerve fibers (IENF) and dorsal root ganglion (DRG) neurons, and ultrastructural analysis of the sciatic nerve.

Results

Vincristine led to mechanical allodynia and reduced the density of IENF, DRG neurons, and unmyelinated nerve fibers in the sciatic nerve. Prophylactic administration of BIO101 mitigated vincristine-induced symptoms and nerve damage. The neuroprotective effect of BIO101 was nullified when the MasR antagonist A779 was administered; confirming the involvement of MasR.

Interpretation

Therefore, BIO101 emerges as a safe and promising preventive treatment against vincristine-induced small fiber neuropathy.

背景和目的化疗引起的周围神经病变（CIPN）是一个重要的副作用，限制了许多抗癌疗法的剂量，如长春新碱。目前，还没有有效的药物治疗来预防CIPN。Mas受体（MasR）在周围神经系统中表达，在疼痛调节中起作用。虽然CIPN中MasR激活的抗感觉特性已被证实，但其在周围神经系统中的潜在神经保护作用尚未被探索。BIO101是MasR激活剂20-羟基蜕皮激素的高度纯化形式，在1期研究中显示出积极的安全性，没有任何严重的不良事件。方法研究BIO101对长春新碱诱导的周围神经病变（VIPN）小鼠模型的神经保护作用。瑞士小鼠每天服用一定剂量的长春新碱。通过触觉敏感性的重复测量、表皮内神经纤维（IENF）和背根神经节（DRG）神经元的量化以及坐骨神经的超微结构分析来评估VIPN。结果长春新碱可引起机械异常性疼痛，降低坐骨神经中IENF、DRG神经元和无髓神经纤维的密度。预防性给药BIO101可减轻长春新碱引起的症状和神经损伤。当给予MasR拮抗剂A779时，BIO101的神经保护作用无效；证实了MasR的参与。因此，BIO101是一种安全且有前景的预防长春新碱诱导的小纤维神经病变的治疗方法。

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引用次数: 0

SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease 三种腓骨-玛丽-牙病小鼠模型中的SARM1抑制

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-20 DOI: 10.1111/jns.70053

Alaura D. Rice, Abigail L. D. Tadenev, Timothy J. Hines, Jonathan R. Funke, Robert W. Burgess

Background

Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear.

Aims

Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: Gars^ETAQ/CTM2D, Nefl^N98S/CMT2E, and Ighmbp2^Y918C/CMT2S.

Methods

For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes.

Results

We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology.

Interpretation

Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.

CMT可由100多种不同基因的突变引起，其中大多数导致外周运动和感觉轴突脱髓鞘（1型）或变性（2型）。SARM1是一种参与轴突损伤后沃勒氏变性活跃过程的蛋白。抑制SARM1可以防止损伤后的轴突变性或化疗引起的周围神经病变。然而，在遗传疾病如CMT中，SARM1抑制对轴突退化的影响尚不清楚。本研究在GarsETAQ/CTM2D、NeflN98S/CMT2E和Ighmbp2Y918C/CMT2S三种不同的轴突CMT小鼠模型中检测SARM1抑制是否有益。方法在这些概念验证研究中，小鼠作为新生儿接受AAV9治疗，通过脑室内注射将显性阴性SARM1构建体（dnSARM1）传递到神经系统。在适合每个小鼠模型的年龄，然后对动物进行行为、神经生理和组织学结果的综合评估。结果我们在阳性对照实验中重现了dnSARM1结构对坐骨神经压迫后的保护作用。然而，我们没有看到任何CMT小鼠模型的表型变化。神经病变相关表型既没有恶化也没有改善。与未治疗的对照组相比，使用AAV9 dnSARM1治疗的野生型窝鼠对照组体重轻微减少，运动表现发生可变变化，但没有神经生理学或组织学上的缺陷。在我们测试的三种CMT小鼠模型中，使用病毒传递的显性阴性构建体抑制SARM1无效。选择这些小鼠模型是因为它们与人类疾病及其突出的轴突变性相关，而不是因为代谢变化表明SARM1可以作为治疗靶点。SARM1抑制可能仍然是某些形式CMT的一种选择，但需要一种预筛选CMT亚型以预测疗效的方法。

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引用次数: 0

Real-World Multinational Survey of Chronic Inflammatory Demyelinating Polyneuropathy: Disease Characteristics and Therapeutic Landscape 慢性炎症性脱髓鞘性多神经病变的世界多国调查：疾病特征和治疗前景

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-18 DOI: 10.1111/jns.70047

Luis Querol, Simon Rinaldi, Andras Borsi, Giorgio Maria Boggia, Jonathan de Courcy, Yasmin Taylor, Jack Wright, Wisam Karmous, Wim Noel, Charlotte Gary, Gerd Meyer zu Hörste

Background and Aims

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated syndrome characterized by progressive muscle weakness and sensory impairment. Clinical similarities with other neuropathies can cause misdiagnoses and delayed diagnoses. Additionally, a large proportion of patients appropriately treated according to current guidelines still show residual disability. This real-world study aimed to characterize a global cohort of patients with CIDP.

Methods

Data were drawn from the Adelphi CIDP Disease Specific Programme, a cross-sectional survey with retrospective data collection, conducted in China, France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States between September 2022 and April 2023. Neurologists and neuromuscular specialists reported on patient demographic and clinical characteristics at the time of the survey. Patients self-reported treatment satisfaction, disease control, and health-related outcome measures.

Results

Overall, 164 physicians provided data for 1056 patients, with 428 (40.5%) providing self-reported data. Patients were diagnosed with typical CIDP (69.2%) and variant CIDP (30.8%). Overall, initial misdiagnosis occurred in 37.2% of patients, with a median (interquartile range) diagnostic delay of 6.0 (3.0–12.0) months. Maintenance therapy was prescribed for 81.6% of patients, with corticosteroid use ranging from 25.7% in the United States to 80.0% in China. Some patients were dissatisfied by treatment outcomes (11.0%) and symptom control (12.2%). Overall, mean (SD) patient-reported scores were 62.1 (20.4) for I-RODS, 35.0 (11.1) for FACIT fatigue, and 0.662 (0.253) for EQ-5D-5L.

Interpretation

Diagnostic delay and misdiagnoses were common occurrences across typical CIDP and variant CIDP. Despite the use of guideline treatments, there were unmet needs and a continued disease burden for patients.

背景和目的慢性炎症性脱髓鞘性多神经病变（CIDP）是一种以进行性肌肉无力和感觉障碍为特征的免疫介导综合征。与其他神经病变的临床相似可导致误诊和延误诊断。此外，根据现行指南进行适当治疗的很大一部分患者仍然表现出残障。这项真实世界的研究旨在描述全球CIDP患者队列的特征。方法数据来自Adelphi CIDP疾病特定计划，这是一项横断面调查，回顾性数据收集，于2022年9月至2023年4月在中国、法国、德国、意大利、日本、西班牙、英国和美国进行。神经学家和神经肌肉专家在调查时报告了患者的人口统计学和临床特征。患者自我报告治疗满意度、疾病控制和健康相关结果测量。结果164名医生为1056名患者提供了数据，其中428名（40.5%）提供了自我报告的数据。诊断为典型CIDP（69.2%）和变异性CIDP（30.8%）。总体而言，37.2%的患者出现了最初的误诊，诊断延迟的中位数（四分位数范围）为6.0（3.0-12.0）个月。81.6%的患者开了维持治疗处方，使用皮质类固醇的比例从美国的25.7%到中国的80.0%不等。部分患者对治疗结果不满意（11.0%），对症状控制不满意（12.2%）。总体而言，患者报告的I-RODS平均（SD）评分为62.1 (20.4)，FACIT疲劳评分为35.0 (11.1)，EQ-5D-5L评分为0.662（0.253）。诊断延迟和误诊在典型CIDP和变异型CIDP中常见。尽管使用了指南治疗方法，但仍存在未满足的需求和患者持续的疾病负担。

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引用次数: 0

Impact of Social Deprivation on Diagnosis, Management and Outcome of Chronic Inflammatory Demyelinating Polyneuropathy at a Tertiary UK Centre 社会剥夺对慢性炎症性脱髓鞘性多神经病变的诊断、管理和结果的影响

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-13 DOI: 10.1111/jns.70054

Zeinab Rajabally, Mahmoud A. Mohamed, Lydia Spencer, Niraj Mistry, Yusuf A. Rajabally

Background

Whether social deprivation may affect diagnosis, management, and outcomes of subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) is unknown.

Methods

We conducted a retrospective study of subjects with CIDP attending University Hospitals Birmingham, UK. Demographics, clinical characteristics, treatment data, post-treatment outcomes and Index of Multiple Deprivation 2019 were collected. Postcodes were categorised in local vs. non-local and travelling distances to the hospital were ascertained.

Results

We included 155 consecutive subjects with CIDP. Mean age was 62.2 years (SD: 15.1). Male to female ratio was 1.67:1. One-hundred and eighteen subjects (76.1%) had typical CIDP. Greater pre-treatment disability was independently associated with greater social deprivation (p = 0.031) and longer pre-treatment disease duration (p = 0.001). Neither use of high-cost first-line therapies, nor immunosuppressant usage, were associated with social deprivation. Post-treatment outcomes were not associated with social deprivation. Greater social deprivation was independently associated with younger age (p = 0.002), having a local post-code (p = 0.001) and living closer to the hospital (p < 0.001). Subjects from the two most socially deprived deciles were younger (p = 0.025) and more disabled pre-treatment (p = 0.028) than those from the two least deprived deciles. Significantly fewer tertiary referrals were received for the two most socially deprived deciles compared to the two least deprived deciles (9.9% vs. 31.3%; p = 0.001).

Conclusions

Despite a publicly funded healthcare system with universal access, social deprivation independently contributed to greater pre-treatment disability in subjects with CIDP in this UK cohort. Social deprivation did not impact on treatments administered and post-treatment outcomes but may have influenced tertiary referral decisions to our centre.

背景：社会剥夺是否会影响慢性炎症性脱髓鞘性多神经病变（CIDP）患者的诊断、治疗和预后尚不清楚。方法对在英国伯明翰大学医院就诊的CIDP患者进行回顾性研究。收集人口统计学、临床特征、治疗数据、治疗后结局和多重剥夺指数2019。邮政编码按本地与非本地分类，并确定到医院的旅行距离。结果我们纳入155例连续的CIDP受试者。平均年龄62.2岁（SD: 15.1）。男女比例为1.67:1。典型CIDP 118例（76.1%）。更严重的治疗前残疾与更严重的社会剥夺（p = 0.031）和更长的治疗前疾病持续时间（p = 0.001）独立相关。无论是使用高成本的一线疗法，还是使用免疫抑制剂，都与社会剥夺无关。治疗后的结果与社会剥夺无关。更严重的社会剥夺与年龄更小（p = 0.002）、拥有当地邮政编码（p = 0.001）和住得离医院更近（p < 0.001）独立相关。来自两个社会最贫困十分位数的受试者比来自两个社会最贫困十分位数的受试者更年轻（p = 0.025），并且在治疗前更残疾（p = 0.028）。与两个最贫困的十分位数相比，两个最贫困的十分位数收到的三级转诊明显减少(9.9%对31.3%；p = 0.001)。结论：尽管英国有一个全民可及的公共医疗保健系统，但社会剥夺独立地导致了CIDP受试者更大的治疗前残疾。社会剥夺对治疗实施和治疗后的结果没有影响，但可能影响到我们中心的三级转诊决定。

{"title":"Impact of Social Deprivation on Diagnosis, Management and Outcome of Chronic Inflammatory Demyelinating Polyneuropathy at a Tertiary UK Centre","authors":"Zeinab Rajabally, Mahmoud A. Mohamed, Lydia Spencer, Niraj Mistry, Yusuf A. Rajabally","doi":"10.1111/jns.70054","DOIUrl":"https://doi.org/10.1111/jns.70054","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Whether social deprivation may affect diagnosis, management, and outcomes of subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective study of subjects with CIDP attending University Hospitals Birmingham, UK. Demographics, clinical characteristics, treatment data, post-treatment outcomes and Index of Multiple Deprivation 2019 were collected. Postcodes were categorised in local vs. non-local and travelling distances to the hospital were ascertained.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 155 consecutive subjects with CIDP. Mean age was 62.2 years (SD: 15.1). Male to female ratio was 1.67:1. One-hundred and eighteen subjects (76.1%) had typical CIDP. Greater pre-treatment disability was independently associated with greater social deprivation (<i>p</i> = 0.031) and longer pre-treatment disease duration (<i>p</i> = 0.001). Neither use of high-cost first-line therapies, nor immunosuppressant usage, were associated with social deprivation. Post-treatment outcomes were not associated with social deprivation. Greater social deprivation was independently associated with younger age (<i>p</i> = 0.002), having a local post-code (<i>p</i> = 0.001) and living closer to the hospital (<i>p</i> < 0.001). Subjects from the two most socially deprived deciles were younger (<i>p</i> = 0.025) and more disabled pre-treatment (<i>p</i> = 0.028) than those from the two least deprived deciles. Significantly fewer tertiary referrals were received for the two most socially deprived deciles compared to the two least deprived deciles (9.9% vs. 31.3%; <i>p</i> = 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Despite a publicly funded healthcare system with universal access, social deprivation independently contributed to greater pre-treatment disability in subjects with CIDP in this UK cohort. Social deprivation did not impact on treatments administered and post-treatment outcomes but may have influenced tertiary referral decisions to our centre.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Influence of Genomic Ancestry and Other Traditional Risk Factors on the Prevalence of Diabetic Peripheral Neuropathy in Admixed Individuals With Type 1 Diabetes in Brazil: A Pioneer Multicenter Study 基因组血统和其他传统危险因素对巴西1型糖尿病混合个体糖尿病周围神经病变患病率的影响：一项开创性的多中心研究

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-13 DOI: 10.1111/jns.70049

Cejana Hamu Aguiar, Hermelinda Cordeiro Pedrosa, Lucianne Righeti Monteiro Tannus, Livia Leite Ferreira, Dayse Silva, Luís Cristóvão Porto, Carlos Antonio Negrato, Marilia Brito Gomes

Aims

To assess the influence of genomic ancestry (GA) and other traditional risk factors on the prevalence of diabetic peripheral neuropathy (DPN) in admixed Brazilian individuals with type 1 diabetes (T1D).

Methods

This cross-sectional, multicenter, pioneer study was conducted in 14 public clinics in 10 Brazilian cities. From 1760 individuals, 1732 were included (98.4%), aged 29.9 ± 11.9 years, diabetes duration 15.4 ± 9.2 years, 968 females (55.9%), 939 (55.7%) self-reported as White. DPN was evaluated by the validated neuropathy disability score (NDS) and neuropathy symptoms score (NSS).

Results

The prevalence of DPN was 14.8%. In hierarchical multivariate logistic regression, the covariates associated with DPN were age, diabetes duration, HbA1c, type of health care insurance, insulin therapeutic regimen, number of yearly clinical visits, low exercise practice rates, hypertension, dyslipidemia, heart rate, statin use, uric acid levels, lower health-related quality of life, presence of diabetic retinopathy, and amputations. Among the sociodemographic characteristics, African GA, a contemporary emerging factor, showed the highest association.

Conclusions

DPN was related to several comorbidities, diabetes-related complications, and lower health-related quality of life. These individuals were young, implying a high lifetime cost of this disease. The association with the emerging factor African GA warrants further studies involving other admixed populations.

目的评估基因组血统（GA）和其他传统危险因素对巴西混合1型糖尿病（T1D）患者糖尿病周围神经病变（DPN）患病率的影响。方法在巴西10个城市的14家公立诊所进行了横断面、多中心、开拓性研究。1760例中，1732例（98.4%），年龄29.9±11.9岁，糖尿病病程15.4±9.2年，女性968例（55.9%），939例（55.7%）。采用神经病变失能评分（NDS）和神经病变症状评分（NSS）对DPN进行评估。结果DPN患病率为14.8%。在分层多变量logistic回归中，与DPN相关的协变量为年龄、糖尿病病程、HbA1c、医疗保险类型、胰岛素治疗方案、每年临床就诊次数、低运动练习率、高血压、血脂异常、心率、他汀类药物使用、尿酸水平、较低的健康相关生活质量、糖尿病视网膜病变的存在和截肢。在社会人口学特征中，当代新兴因素非洲GA的相关性最高。结论DPN与几种合并症、糖尿病相关并发症和较低的健康相关生活质量有关。这些人都很年轻，这意味着这种疾病的终生成本很高。与新兴因素非洲GA的关联值得涉及其他混合种群的进一步研究。

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引用次数: 0

Neurofilament Light Chain Levels in a Large Idiopathic Peripheral Neuropathy Cohort 特发性周围神经病变队列中的神经丝轻链水平

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-13 DOI: 10.1111/jns.70050

Simone Thomas, Maaz Khan, Mehmet Can Sari, Xindan Hu, Alexandria Lewis, Jashandeep Lobana, Bipasha Mukherjee-Clavin, Abhay Moghekar, Brett M. Morrison, Charlotte Sumner, Samuel Xie, Ahmet Höke

Background

Neurofilament light chain (Nf-L) has been identified as a biomarker of neurodegeneration in many neuromuscular conditions, including several subtypes of polyneuropathies. The purpose of this research was to investigate whether Nf-L is also a promising biomarker for idiopathic peripheral neuropathy (IPN), the second most common subtype of axonal polyneuropathy.

Methods

Nf-L levels were quantified using an ultrasensitive digital immunoassay SiMoA in plasma samples from 294 subjects. Participant inclusion required a diagnosis of IPN confirmed by electrodiagnostic testing, intraepidermal nerve fiber density (IENFD), and/or neuromuscular examination. Laboratory testing recommended by the American Academy of Neurology for the evaluation of polyneuropathy was normal in all subjects.

Results

In our cohort, the majority of participants (78.1%, N = 228) had Nf-L levels in the age-adjusted normal range. Those with elevated Nf-L levels had higher scores on two different neuropathy severity scores and were more likely to have abnormal electrodiagnostic testing, including reduced action potential amplitude in peroneal motor and sural sensory nerves. No differences in blood Nf-L levels were observed in those participants with a short duration (≤ 1.5 years) versus long duration (≥ 5 years) of disease. Nf-L levels were also not correlated with the presence of neuropathic pain, nor the location of paresthesia. Nf-L expression had the strongest correlation with age.

Conclusions

In this cohort with IPN, Nf-L levels correlated with disease severity as assessed by clinical examination and electrophysiology. However, given that Nf-L was in the normal range for the majority of subjects in our cohort, its use as a biomarker for clinical trials evaluating new treatments for IPN will be limited.

神经丝轻链（Nf-L）已被确定为许多神经肌肉疾病（包括几种亚型的多神经病变）神经退行性变的生物标志物。本研究的目的是研究Nf-L是否也是特发性周围神经病变（IPN）的一种有希望的生物标志物，IPN是轴突多发性神经病变的第二常见亚型。方法采用超灵敏数字免疫分析法（SiMoA）测定294例患者血浆中Nf-L水平。纳入受试者需要通过电诊断试验、表皮内神经纤维密度（IENFD）和/或神经肌肉检查确诊IPN。美国神经病学学会推荐的用于评估多发性神经病变的实验室测试在所有受试者中都是正常的。在我们的队列中，大多数参与者（78.1%,N = 228）的Nf-L水平在年龄调整后的正常范围内。Nf-L水平升高的患者在两种不同的神经病严重程度评分上得分更高，更有可能出现异常的电诊断测试，包括腓神经运动神经和腓肠感觉神经的动作电位幅度降低。在病程短（≤1.5年）和病程长（≥5年）的受试者中，血液Nf-L水平无差异。Nf-L水平也与神经性疼痛的存在无关，也与感觉异常的位置无关。Nf-L表达与年龄的相关性最强。结论：在IPN患者队列中，Nf-L水平与临床检查和电生理评估的疾病严重程度相关。然而，考虑到我们队列中大多数受试者的Nf-L在正常范围内，其作为评估IPN新治疗方法的临床试验生物标志物的使用将受到限制。

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引用次数: 0

The Correlation Between Functional and Morphometric Small Fiber Assessment in Mixed Etiology Polyneuropathy 混合病因多发性神经病变的小纤维功能与形态学评估的相关性

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-12 DOI: 10.1111/jns.70051

Farah A. Ghadban, Charlotte N. Bay-Smidt, Asger Bjørnkær, Laura M. Gaist, Jakob V. Holbech, David Gaist, Martin Wirenfeldt, Søren H. Sindrup, Thomas Krøigård

Background and Aims

Skin biopsies are the primary diagnostic test for small fiber neuropathy, but recently corneal confocal microscopy (CCM) has been developed as an alternative. We compared the correlations of each of these morphometric assessments with peripheral nerve function evaluated through comprehensive quantitative sensory testing (QST) in a mixed etiology polyneuropathy cohort.

Methods

CCM and skin biopsies were performed in a prospective cohort of unselected patients undergoing polyneuropathy diagnostic work-up. We used predefined criteria to identify patients with small or mixed fiber neuropathy. The correlations between corneal nerve fiber density (CNFD), fiber length (CNFL), branch density (CNBD), and tortuosity (CNFT) and the intraepidermal nerve fiber density (IENFD) at the distal leg and the results of QST at the foot were determined.

Results

Two-hundred and forty-four patients were included in the analysis. CNFD was negligibly correlated with warm detection threshold (WDT) (r = −0.15; p = 0.023), while there was no statistically significant correlation with other QST measures. There were no statistically significant correlations between neither CNFL nor CNBD and any of the QST measures. CNFT correlated negligibly with WDT (r = 0.17; p = 0.008) and vibration detection threshold (VDT) (r = −0.13; p = 0.044). IENFD correlated moderately with WDT (r = −0.33; p < 0.0001) and mechanical pain threshold (r = −0.37; p < 0.0001) and weakly with cold detection threshold (r = 0.21; p = 0.0008), mechanical detection threshold (r = −0.21; p = 0.0008) and VDT (r = 0.23; p = 0.0004).

Interpretation

IENFD correlated better with small and large fiber function at the foot than CCM measures in patients with mixed etiology polyneuropathy. Longitudinal studies are needed to assess the clinical utility for neuropathy progression.

背景和目的皮肤活检是小纤维神经病变的主要诊断方法，但最近角膜共聚焦显微镜（CCM）已发展成为一种替代方法。我们比较了每种形态测量评估与周围神经功能的相关性，通过综合定量感觉测试（QST）在混合病因多发性神经病变队列中评估。方法对未选定的接受多神经病变诊断检查的患者进行CCM和皮肤活检。我们使用预先定义的标准来识别小纤维或混合纤维神经病患者。测定角膜神经纤维密度（CNFD）、纤维长度（CNFL）、分支密度（CNBD）和弯曲度（CNFT）与远端小腿表皮内神经纤维密度（IENFD）和足部QST结果的相关性。结果244例患者纳入分析。CNFD与温暖检测阈值（WDT）的相关性可忽略不计(r = - 0.15；p = 0.023)，而与其他QST指标无统计学意义相关。CNFL和CNBD与任何QST测量之间均无统计学显著相关性。CNFT与WDT的相关性可忽略(r = 0.17；p = 0.008)和振动检测阈值（VDT） (r =−0.13；p = 0.044)。IENFD与WDT呈正相关(r = - 0.33；P < 0.0001)和机械痛阈(r = - 0.37；P < 0.0001)，与冷检测阈值关系弱(r = 0.21；P = 0.0008)，机械检测阈值(r =−0.21；p = 0.0008)和VDT (r = 0.23；p = 0.0004)。解释在混合病因多发性神经病患者中，IENFD与足部小纤维和大纤维功能的相关性优于CCM测量。需要纵向研究来评估神经病变进展的临床应用。

{"title":"The Correlation Between Functional and Morphometric Small Fiber Assessment in Mixed Etiology Polyneuropathy","authors":"Farah A. Ghadban, Charlotte N. Bay-Smidt, Asger Bjørnkær, Laura M. Gaist, Jakob V. Holbech, David Gaist, Martin Wirenfeldt, Søren H. Sindrup, Thomas Krøigård","doi":"10.1111/jns.70051","DOIUrl":"https://doi.org/10.1111/jns.70051","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Skin biopsies are the primary diagnostic test for small fiber neuropathy, but recently corneal confocal microscopy (CCM) has been developed as an alternative. We compared the correlations of each of these morphometric assessments with peripheral nerve function evaluated through comprehensive quantitative sensory testing (QST) in a mixed etiology polyneuropathy cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CCM and skin biopsies were performed in a prospective cohort of unselected patients undergoing polyneuropathy diagnostic work-up. We used predefined criteria to identify patients with small or mixed fiber neuropathy. The correlations between corneal nerve fiber density (CNFD), fiber length (CNFL), branch density (CNBD), and tortuosity (CNFT) and the intraepidermal nerve fiber density (IENFD) at the distal leg and the results of QST at the foot were determined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two-hundred and forty-four patients were included in the analysis. CNFD was negligibly correlated with warm detection threshold (WDT) (<i>r</i> = −0.15; <i>p</i> = 0.023), while there was no statistically significant correlation with other QST measures. There were no statistically significant correlations between neither CNFL nor CNBD and any of the QST measures. CNFT correlated negligibly with WDT (<i>r</i> = 0.17; <i>p</i> = 0.008) and vibration detection threshold (VDT) (<i>r</i> = −0.13; <i>p</i> = 0.044). IENFD correlated moderately with WDT (<i>r</i> = −0.33; <i>p</i> < 0.0001) and mechanical pain threshold (<i>r</i> = −0.37; <i>p</i> < 0.0001) and weakly with cold detection threshold (<i>r</i> = 0.21; <i>p</i> = 0.0008), mechanical detection threshold (<i>r</i> = −0.21; <i>p</i> = 0.0008) and VDT (<i>r</i> = 0.23; <i>p</i> = 0.0004).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>IENFD correlated better with small and large fiber function at the foot than CCM measures in patients with mixed etiology polyneuropathy. Longitudinal studies are needed to assess the clinical utility for neuropathy progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144814766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic Deletion of Sarm1 in Mouse Models of Three Neurological Diseases 三种神经系统疾病小鼠模型中Sarm1基因缺失

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-12 DOI: 10.1111/jns.70052

Courtney L. Hatton, Markus Terrey, Maximiliano Presa, Jennifer Ryan, Sara Perkins, Vicki Kennedy, Cathleen M. Lutz, Robert W. Burgess

Background

Degeneration of peripheral motor and sensory axons is a key aspect of the pathophysiology of Charcot–Marie–Tooth disease and related inherited neurodegenerative conditions.

Aims

Given that mutations in many (> 100) genes can cause these disorders, it is unclear if a generalized therapeutic strategy can be identified that will apply across these disease subtypes; however, strategies to prevent or slow axon degeneration are attractive candidates. Wallerian axon degeneration is an active process following insults such as nerve injury, and SARM1 is a central mediator of this process. When SARM1 is inhibited, axons distal to the site of injury persist for weeks rather than degenerating. In addition, SARM1 inhibition or genetic deletion has been shown to provide benefit in acquired neuropathies such as diabetic/metabolic neuropathy and chemotherapy-induced neuropathy in animal models. Here we examined the effects of genetically deleting Sarm1 in mouse models of CMT.

Methods

We bred knockout mice lacking Sarm1 to three different mouse models of CMT or related disorders. These include mice lacking Gjb1, modeling CMT1X, mice with mutations in Kif1a, modeling hereditary sensory neuropathy IIC and spastic paraplegia type 30, and mice lacking Fig4, modeling CMT4J and Yunis-Varon syndrome. Clinically relevant outcomes measures including survival (Kif1a and Fig4), grip strength and motor behavior, peripheral neurophysiology, molecular biomarkers, and nerve histopathology were assessed for each model with and without Sarm1 expression.

Results

No improvement in the mutant phenotype was found for any model, although elevated levels of circulating neurofilament light chain levels were delayed in the Fig4 mice. Kif1a mice showed deficits slightly earlier in the absence of Sarm1.

Interpretation

While we found no benefit from deleting Sarm1 in these mouse models, they were chosen for their human disease relevance and not for biochemical indicators that SARM1 may be a good target. Thus, SARM1 inhibition may still be effective in other forms of inherited neuropathy, but additional research will be required to identify those candidate subtypes.

外周运动和感觉轴突的变性是腓骨肌萎缩症和相关遗传性神经退行性疾病病理生理学的一个关键方面。鉴于许多（> 100）基因突变可导致这些疾病，目前尚不清楚是否可以确定适用于这些疾病亚型的通用治疗策略；然而，预防或减缓轴突退化的策略是有吸引力的候选人。沃勒氏轴突变性是神经损伤后的一个活跃过程，而SARM1是这一过程的中心介质。当SARM1被抑制时，损伤部位远端轴突持续数周而不是退化。此外，在动物模型中，SARM1抑制或基因缺失已被证明对获得性神经病变（如糖尿病/代谢性神经病变和化疗诱导的神经病变）有益。在这里，我们研究了基因删除Sarm1对CMT小鼠模型的影响。方法将缺乏Sarm1的敲除小鼠培养到三种不同的CMT或相关疾病小鼠模型中。这些小鼠包括缺乏Gjb1的小鼠，模拟CMT1X， Kif1a突变的小鼠，模拟遗传性感觉神经病变IIC和痉挛性截瘫30型，以及缺乏Fig4的小鼠，模拟CMT4J和Yunis-Varon综合征。临床相关指标包括生存率（Kif1a和图4）、握力和运动行为、周围神经生理学、分子生物标志物和神经组织病理学，对有无Sarm1表达的每个模型进行评估。结果在任何模型中都没有发现突变表型的改善，尽管在图4小鼠中循环神经丝轻链水平的升高被延迟。在缺乏Sarm1的情况下，Kif1a小鼠表现出稍早的缺陷。虽然我们在这些小鼠模型中没有发现删除Sarm1的好处，但选择它们是因为它们与人类疾病相关，而不是因为Sarm1可能是一个很好的靶点的生化指标。因此，SARM1抑制可能在其他形式的遗传性神经病变中仍然有效，但需要进一步的研究来确定这些候选亚型。

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引用次数: 0

Mitochondrial Trifunctional Protein Deficiency due to HADHA Variants Masquerading as Charcot–Marie–Tooth Disease 伪装成腓骨肌病的HADHA变异导致的线粒体三功能蛋白缺乏

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-11 DOI: 10.1111/jns.70048

Farkhanda Qaiser, John McHugh, Gerard Mullins, Michael Farrell, Loai Shakerdi, James O. Byrne, Sinéad M. Murphy

Background and Aims

Mitochondrial trifunctional protein deficiency (MTPD) is an inherited disorder of fatty acid β-oxidation caused by mutations in HADHA or HADHB genes. It typically presents with cardiomyopathy or hepatic failure in early childhood; however, it may rarely present in adulthood with the neuromyopathic form.

Methods

We describe a patient with MTPD with isolated neuropathy mimicking Charcot–Marie–Tooth disease (CMT) as the first and only presenting symptom. Clinical and electrophysiological examinations were conducted, including nerve conduction studies, needle electromyography, muscle and nerve biopsies. The diagnosis was confirmed with genetic testing and enzymatic analysis of cultured skin fibroblasts.

Results

We report a 40-year-old man diagnosed with axonal CMT2 in childhood. He had pes cavus and hammer toes, mild distal lower limb weakness, and loss of vibration sense with areflexia. He later developed fatigability, improved exercise tolerance with alcohol and an episode of chest infection causing neurological decompensation without evidence of rhabdomyolysis. Neurophysiology showed non-length-dependent axonal sensorimotor neuropathy without myopathic features. Genetic testing confirmed that he was compound heterozygous for two HADHA variants, one of them novel, and enzymatic analysis of cultured skin fibroblasts confirmed MTPD.

Interpretation

We report a very rare isolated neuropathic phenotype of MTPD and confirm the pathogenicity of the novel variant c.1003G>A, p.(Glu335Lys). This case also highlights the need for HADHA and HADHB to be included in neuropathy gene panels as MTPD may present as CMT. Given that dietary management may prevent some complications of MTPD, achieving a diagnosis early is important.

背景与目的线粒体三功能蛋白缺乏症（MTPD）是一种由HADHA或HADHB基因突变引起的脂肪酸β-氧化的遗传性疾病。典型表现为幼儿期心肌病或肝功能衰竭；然而，它可能很少出现在成年的神经肌病形式。方法我们描述了一位MTPD患者，其孤立的神经病变模仿Charcot-Marie-Tooth病（CMT）作为第一和唯一的表现症状。进行了临床和电生理检查，包括神经传导研究、针肌电图、肌肉和神经活检。通过基因检测和培养的皮肤成纤维细胞酶分析证实了诊断。我们报告一位40岁的男性在儿童期被诊断为轴突CMT2。患者有足弓和锤状趾，下肢远端轻度无力，振动感丧失伴反射性屈曲。他后来出现了疲劳，酒精运动耐受性提高，胸部感染引起神经代偿失代偿，但无横纹肌溶解的证据。神经生理学表现为非长度依赖性轴索感觉运动神经病，无肌病特征。基因检测证实他是两个HADHA变体的复合杂合，其中一个是新的，培养的皮肤成纤维细胞的酶分析证实了MTPD。我们报道了一种非常罕见的MTPD分离神经病理表型，并证实了这种新变异的致病性c.1003G> a, p.（Glu335Lys）。该病例还强调了将HADHA和HADHB纳入神经病变基因面板的必要性，因为MTPD可能表现为CMT。考虑到饮食管理可以预防MTPD的一些并发症，早期诊断是重要的。

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引用次数: 0

Abstract 摘要

IF 3.2 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System

Pub Date : 2025-08-03 DOI: 10.1111/jns.70038

引用次数: 0