Assessment of Peripheral Neuropathy Using Current Perception Threshold Measurement in Patients with Spinocerebellar Ataxia Type 3

Assessment of Peripheral Neuropathy Using Current Perception Threshold Measurement in Patients with Spinocerebellar Ataxia Type 3 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Assessment of Peripheral Neuropathy Using Current Perception Threshold Measurement in Patients with Spinocerebellar Ataxia Type 3 Xia-Hua Liu, Wei Lin, Hao-Ling Xu, Mao-Lin Cui, Zhuo-Ying Huang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4687118/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Jan, 2025 Read the published version in The Cerebellum → Version 1 posted 11 You are reading this latest preprint version Abstract Background Peripheral neuropathy (PN) identified as a significant contributor to disability in SCA3 patients. Objectives This study seeks to assess the utility of current perception threshold (CPT) measurements in evaluating PN in individuals with SCA3 and aims to identify factors influencing CPT values in SCA3 and ascertain whether these values correlate with the severity of ataxia. Methods Ninety-four patients diagnosed with SCA3 and 44 healthy controls were recruited for this investigation. All participants were performed standard CPT assessments. Comparative analysis was conducted on CPT variables between the groups. Multivariable linear regression models were employed to identify potential risk factors influencing CPT values, and to investigate the association between CPT values and the severity of ataxia in SCA3. Results The case group exhibited significantly higher values across all CPT variables compared to the control group ( P < 0.01). Peripheral neuropathy was prevalent among SCA3 patients, with lower limb nerves demonstrating greater susceptibility than upper limb nerves. Increasing age at onset (AAO) (β = 17.652, P = 0.01) and heightened ataxia severity (β = 33.47, P = 0.011) as predictors of poorer CPT values. Gender also emerged as a predictor of CPT values. Furthermore, CPT values (β = 0, P = 0.011) and disease duration (β = 0.105, P = 0.000) were found to influence the severity of ataxia. Conclusion Our findings suggest that the CPT test holds promise for assessing peripheral neuropathy in SCA3 patients and that CPT values may serve as indicators of disease severity in this population. Peripheral neuropathy Spinocerebellar ataxia type 3 Current perception threshold Figures Figure 1 1. Introduction Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) represents the most prevalent autosomal dominant spinocerebellar ataxia globally, attributed to trinucleotide cytosine-adenine-guanine (CAG) repeats within the gene encoding ataxin-3 1,2 . In patients with SCA3, there are 60–85 CAG-repeat units in ATXN3 while only 12–44 in normal subjects 3 . Notably, peripheral nerve involvement stands as a prominent clinical feature in SCA3, with confirmed presence of peripheral neuropathy (PN) among affected individuals 4 – 9 . Some studies have highlighted the significance of PN as a contributing factor to disability in SCA3 8,10,11 . It has been reported that approximately 60% of SCA3 patients experience PN, with symptoms being more prevalent among those with late-onset disease 8 . As the disease progresses, the severity of PN tends to worsen. Extensive damage to nerve fibers can lead to reduced sensory nerve conduction velocity and, in some cases, paralysis resulting from loss of motor nerve function, which may significantly impair functionality in certain SCA3 patients. Given that clinical symptoms often manifest later than pathological changes, early diagnosis holds crucial importance. Many studies investigating PN in SCAs rely on invasive electrophysiological assessments, such as nerve conduction velocity and needle electromyography 7 – 9 , 12 . However, these electrophysiological methods are primarily capable of detecting damage to large myelinated nerve fibers, thus offering limited diagnostic value in identifying early-stage damage to smaller myelinated nerve fibers. The current perception threshold (CPT) test represents a transcutaneous electrical stimulator capable of noninvasively detecting and quantifying the functional status of three distinct sensory nerve fiber types (Aβ, Aδ, and C) by measuring the CPT at frequencies of 2000, 250, and 5 Hz, respectively 13 . Compared to traditional clinical assessments of sensory function, CPT detection offers heightened sensitivity 14 – 16 . Moreover, CPT is unaffected by scar tissue or edema, enabling effective screening and diagnosis before symptom onset. Prior research has demonstrated the utility of CPT measurement in diagnosing and evaluating peripheral nerve conditions across various clinical diseases, such as diabetes mellitus, chronic ankle instability, lingual nerve injuries, and carpal tunnel syndrome 17 – 26 . Additionally, previous studies have utilized CPT measurement to explore the impact of clinically associated factors such as gender, age, and disease status on CPT values 24 , 26 – 28 . However, to date, no studies have employed CPT measurement to investigate peripheral nerve conditions in SCA3 or other neurodegenerative diseases, including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD). Furthermore, the relationship between clinical characteristics of SCA3 patients and CPT values remains poorly understood. Hence, building upon the aforementioned groundwork, we innovatively applied CPT measurement in SCA3 patients for the first time. In this study, we conducted a quantitative evaluation of CPT values to elucidate the characteristics of peripheral neuropathy in SCA3 patients and explore various factors influencing CPT. It is our aspiration that this study will serve as a valuable reference for the application of CPT measurement in diagnosing and evaluating PN not only in SCA3 but also in other neurodegenerative diseases. 2. Materials and Methods 2.1 Standard protocol approvals, registrations, and patient consents The study received approval from the Ethics Committee of the First Affiliated Hospital of Fujian Medical University and written informed consent was obtained from each participant. 2.2 Study Participants Between October 2018 and April 2024, we recruited 94 subjects with molecular confirmation of SCA3 and 44 healthy controls (HCs) from the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR) in the department of neurology of the First Affiliated Hospital of Fujian Medical University. Healthy controls primarily consisted of spouses, caregivers of SCA3 patients, and unrelated individuals without neurological abnormalities. Exclusion criteria encompassed medical conditions known to predispose to PN, a history of diabetes mellitus, chronic alcoholism, central nervous system diseases, cervical or lumbar spondylosis, malignant tumors, severe liver and kidney dysfunction, and the presence of skin lesions at the testing site. Additionally, participants were not taking any medications for peripheral neuropathy. 2.3 Clinical Evaluation Prior to CPT testing, all subjects underwent a comprehensive medical history investigation and physical examination. The collected information included gender, age, AAO, length of CAG repeats, disease severity, and disease duration. Ataxia severity was evaluated using the Scale for the Assessment and Rating of Ataxia (SARA), which consists of eight cerebellar function tests yielding a total score ranging from 0 (absence of ataxia) to 40 (most severe ataxia) 29 . 2.4 CPT Testing We conducted a CPT assessments on all individuals diagnosed with SCA3 and on healthy controls. We employed the Neurometer CPT/C (Neurotron Inc., Baltimore, MD, USA), a device specifically designed to measure neuroselective CPTs. The CPT involved delivering electrical stimuli via two 10-mm-diameter gold-plated electrodes. Measurements were taken from four detection sites: the median nerve on both index fingers and the sural nerves on both first toes. We utilized three distinct frequencies: 2000 Hz, 250 Hz, and 5 Hz, to evaluate Aβ myelinated, Aδ myelinated, and C fibers, respectively. Participants were seated in a quiet environment with comfortable temperature and lighting conditions. They were briefed thoroughly on the procedure beforehand to ensure comprehension and cooperation during the test. A qualified physician, experienced in administering CPT tests, regulated the stimulation intensity from 0.001 mA to 10 mA. The threshold intensity at which participants first felt the stimulation was recorded. Each frequency was tested sequentially at each site. The total test duration for each participant did not exceed 15 minutes 22 . Normative CPT values were established based on prior clinical trials 30 – 32 , and subsequently integrated into the system's data analysis software (Neurotron, Baltimore, MD, USA, http://www.neurotron.com .). CPT abnormalities follow a two-sided distribution. Threshold values exceeding the upper limit of the normal range indicate hyperesthesia, while values falling below the lower limit suggest hypoesthesia. Symptoms of hyperesthesia or hypoesthesia are indicative of PN 17 , 19 , 33 , 34 . 2.5 Statistical analysis We assessed the normality of variable distribution utilizing the Kolmogorov-Smirnov test. Data were presented as mean ± standard deviation (SD) for continuous variables, while categorical variables were expressed as the number of patients (percentages). To compare baseline data between the two groups, we employed a Chi-square Test to evaluate gender distribution. Continuous variables were compared using Two-independent sample t -tests for normally distributed data, and Mann-Whitney U -test for non-normally distributed data. We evaluated PN in SCA3 by analyzing 12 total CPT variables and aimed to investigate their relationship with phenotypic variability in SCA3 patients. Due to the large number of CPT values and their likely intercorrelation, we performed unsupervised Principal Component Analysis (PCA) with varimax rotation, a technique previously utilized in SCA3 studies 35 . To assess the suitability of our variables for PCA, we first conducted a correlation matrix to ascertain the presence of linear correlation among the 12 CPT variables. We considered a correlation coefficient greater than 0.3 as indicative of suitability. Subsequently, we applied the Kaiser–Meyer–Olkin (KMO) test, where a KMO measure of sampling adequacy exceeding 0.5 was deemed appropriate, along with Bartlett’s test of sphericity, where a significance level below P < 0.05 was considered suitable. To create a lower-dimensional dataset retaining sufficient variance, we filtered the dataset by ensuring that the Eigenvalue is greater than one and validated the results by considering the proportion of total variation in the data. The resulting principal component (PC) served as a composite measure of all CPT variables and was subjected to Mann-Whitney U -test analysis to explore differences in PN between patients and controls. We employed a multivariable linear regression model to examine the CPT variable relationship with phenotype variability in SCA3 patients. Initially, we investigated the predictors of the first principal component (PC1) resulting from the PCA analysis, representing all CPT variables. PC1 served as the dependent variable, while gender (binary), AAO, disease duration, SARA score, and lengths of normal and expanded CAG repeats were considered independent variables. Subsequently, we analyzed factors associated with the severity of ataxia, as measured by the SARA score. The SARA score was designated as the dependent variable, with PC1 and gender (binary), AAO, and lengths of normal and expanded CAG repeats serving as independent variables. Statistical analyses were conducted using SPSS 26.0 (IBM Co., Inc., Chicago, IL, USA), with significance set at P < 0.05. All graphs were produced using GraphPad Prism. 3. Results Abbreviations: AAO = Age at Onest; SARA = Scale for the Assessment and Rating of Ataxia; N =Number; NA = not applicable; LMN = Left median nerve；RMN = Right median nerve; LSN = Left sural nerve; RSN = Right sural nerve. Continuous data are expressed as the mean ± standard deviation. a Independent t -tests b Chi-square test c Mann-Whitney U -test Table 2. Percentages of PN findings, sensory disturbances, and subscale analysis results of the current perception threshold test in SCA3 patients SCA3 (n = 94) PN findings PN Normal 48 (51.1%) 46 (48.9%) Sensory disturbance Hypoesthesia Hyperesthesia 41 (43.6%) 7 (7.4%) Subscale results Abnormal Normal Test sites Median nerve 21 (22.3%) 73 (77.7%) Left median nerve 13 (13.8%) 81 (86.2%) Right median nerve 16 (17.0%) 78 (83.0%) Sural nerve 42 (44.7%) 45 (55.3%) Left sural nerve 28 (29.8%) 66 (70.2%) Right sural nerve 28 (29.8%) 66 (70.2%) Fiber types Aβ 21 (22.3%) 73 (77.7%) Aδ 33 (35.1%) 61 (64.9%) C 24 (25.5%) 53 (74.5%) Abbreviations: PN = Peripheral Neuropathy, Aβ =large-diameter myelinated, Aδ = small-diameter myelinated, C = unmyelinated fibers. To consolidate the 12 CPT variables into comprehensive indicators while minimizing information loss, we conducted PCA with varimax rotation. We selected variables for PCA from the 12 total CPT variables based on the results obtained from all four sites at frequencies of 2000Hz, 250Hz, and 5Hz. We assessed the suitability of these variables for PCA using the linear correlation matrix (correlation coefficient > 0.3), the KMO measure of sampling adequacy (0.759), and Bartlett’s test of sphericity ( P < 0.001), which confirmed the feasibility of PCA on the 12 CPT variables. Our PCA analysis revealed that the eigenvalues of the top four principal components were greater than 1, explaining 40.448%, 15.341%, 9.827%, and 8.657% of the total data variation, respectively. Together, these components accounted for 74.274% of the total variance. Examination of the component matrix indicated a strong correlation between PC1 and all 12 CPT variables. Considering the practical requirements of our study, we selected PC1 as the representative factor for all CPT variables. Furthermore, Mann-Whitney U -test demonstrated significant differences in PC1 factor scores between patients and controls ( P < 0.001), consistent with the findings obtained from individual-dependent measures. We utilized multivariable linear regression to explore the relationship between PC1 (representing all CPT variables) and clinical characteristics in patients. Initially, we examined the predictors of PC1 using regression models ( Table 3 ). The results revealed that increasing AAO (β = 17.652, P = 0.01) and heightened severity of ataxia (β = 33.47, P = 0.011) were predictive of poorer CPT values. Conversely, disease duration (β = 38.193, P = 0.69) and longer lengths of CAG repeats in expanded alleles (β = 50.654, P = 0.96) did not significantly predict CPT values. Gender also emerged as a predictor, with males potentially at higher risk for poorer CPT values (β = 273.946, P = 0.017). Subsequently, we conducted multivariable linear regression to determine whether CPT values could influence the severity of ataxia ( Table 4 ). Our findings indicated that CPT values (β = 0, P = 0.011) along with disease duration (β = 0.105, P = 0.000) could impact the severity of ataxia. However, AAO (β = 0.059, P = 0.439) and lengths of CAG repeats in expanded alleles (β = 0.161, P = 0.247) did not serve as significant predictors. Table 3. Influencing factors on CPT values in SCA3 patients Coefficient estimate Standard error P -value CPT values a Gender b 0.246 31.056 0.017 AAO 0.314 2.001 0.016 Disease duration 0.057 4.33 0.634 SARA 0.308 3.794 0.013 Normal alleles 0.04 2.282 0.697 Expanded alleles -0.006 5.742 0.962 Abbreviations: AAO = Age at Onset; SARA = Scale for the Assessment and Rating of Ataxia. Bold value showed significance. a CPT values were measured by PC1. b Male vs. Female. Table 4. Influence of CPT values on disease severity in SCA3 patients Coefficient estimate Standard error P -value SARA Gender a -0.035 0.911 0.709 AAO -0.084 0.059 0.472 Disease duration 0.492 0.105 0 Normal alleles -0.108 0.064 0.234 Expanded alleles 0.133 0.161 0.235 CPT values b 0.242 0.003 0.013 Abbreviations: AAO = Age at Onset; SARA = Scale for the Assessment and Rating of Ataxia. Bold value showed significance. a Male vs. Female. b CPT values were measured by PC1. 4. Discussion The study highlights the efficacy of CPT testing in evaluating peripheral nerve function in individuals with SCA3, revealing a high prevalence of peripheral neuropathy among SCA3 patients. Notably, SCA3 patients exhibit notable impairments in CPT values compared to age- and gender-matched controls, with lower limb peripheral nerves showing greater vulnerability than upper limb nerves. Regression analyses within the patient group underscored significant associations between CPT values and patient characteristics, including gender, AAO, and disease severity. Furthermore, CPT values proved predictive of the severity of ataxia in SCA3. Our findings demonstrate that CPT values in SCA3 patients differ significantly from those in healthy controls across all three frequencies in both bilateral median and sural nerves. These distinctions may suggest inherent differences or alterations in SCA3. Notably, the sural nerve exhibited a higher rate of abnormal CPT values compared to the median nerve, indicative of greater vulnerability of lower limb peripheral nerves, consistent with prior research 17 . This disparity may be attributed to variances in sensory nerve fiber density across different body regions, as nerve fiber density in the epidermis of the distal leg is lower than that of the distal forearm 36, 37 . Previous studies on CPT testing have yielded inconsistent findings regarding the impact of gender on CPT values 24,26-28 . Our study reveals that gender is a significant risk factor influencing CPT values in SCA3, consistent with reports by Nakatani-Enomoto et al. and Seno et al., indicating notable gender-based differences in CPT values among healthy individuals 27,28 . Specifically, CPT values are higher in males compared to females, suggesting male gender as a potential risk factor for poorer CPT values. Conversely, Uddin et al. and Chang et al. did not observe gender effects on CPT values 24,26 . The underlying reasons for these discrepancies remain unclear but may be attributed to variations in tissue conformation, skin structure, skin hydration, temperature characteristics, or neural response potentially influenced by sex hormone levels 27,28 . Furthermore, our findings indicate no correlation between CPT values and disease duration or lengths of CAG repeats at all three frequencies, aligning with prior research 6,7,17,18,38 . However, AAO emerges as a predictor of CPT values. This finding is supported by Tseng et al., who reported a positive correlation between age and CPT values across all three frequencies 39 . Additionally, studies have highlighted a correlation between peripheral neuropathy and age in SCA3, with age serving as a determinant for peripheral nerve impairment in SCA3 patients 6,12,37 , likely due to age-related decreases in the number of mechanoreceptors and nerve fiber density in the skin 17 . Moreover, SCA3 patients with higher SARA scores exhibit more severe peripheral neuropathy, as reflected in CPT values. This study represents the first investigation into the application of CPT measurement for diagnosing PN in SCA3 patients. Our findings endorse the utility of CPT testing as a quantitative sensory detection method for SCA3. Future research exploring CPT testing in PN across various neurodegenerative diseases stands to benefit from our methodology and findings. However, several limitations warrant acknowledgment. Firstly, our study lacks additional physical and perceptual examinations that could offer a more objective evaluation of peripheral sensory nerves. Future studies should aim to address this gap. Secondly, the CPT testing process entails significant variability, necessitating participants' comprehension and responsiveness, as well as the close collaboration of experienced operators and participants. Lastly, given the cross-sectional observational design of our study, long-term follow-up is imperative. 5. Conclusions In summary, our study underscores the potential of CPT testing in assessing peripheral neuropathy in SCA3 patients, with CPT values potentially serving as indicators of disease severity in this population. Declarations Acknowledgments The authors would like to thank the kind patients, families, caregivers, and members who participated in this research. Author contributions SRG, ZYW, and NW formulated and designed the study concept; XHL, ZYW, and SRG analyzed the data and manuscript drafting or manuscript revision for important intellectual content; XHL, WL, HLX, MLC, ZYH, YL, NNZ, and SRG enrolled the patients and conducted clinical assessments; XHL, MLC, and YL conducted a CPT evaluation; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors. Funding This work was supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province (2021Y9128, Fujian; S-R-G). This work was also supported by the National Natural Science Foundation of China (82230039, Beijing; N-W), the Local Science and Technology Development Project guided by the central government grants (2022L3011, Fujian; N-W) as well as the Natural Science Fundation of Fujian Province (2023J01603, Fujian; X-H-L). The authors declare that there are no conflicts of interest relevant to this work. Availability of data and materials The data and materials that support the findings of this study are available from the corresponding author, upon reasonable request. Ethical Approval The study was approved by the ethics committee of the First Affiliated Hospital of Fujian Medical University. Written informed consent forms were signed by all subjects. Competing Interests The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4687118","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":333345743,"identity":"98943c80-ff73-41a1-baa8-86d3f85f8d59","order_by":0,"name":"Xia-Hua Liu","email":"","orcid":"","institution":"Department of Rehabilitation Medicine, The First Affiliated Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xia-Hua","middleName":"","lastName":"Liu","suffix":""},{"id":333345744,"identity":"2ecce24b-7092-4884-91e1-18fdcff924ca","order_by":1,"name":"Wei Lin","email":"","orcid":"","institution":"Fujian Institute of Neurology, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Lin","suffix":""},{"id":333345745,"identity":"ce83d954-e749-44e6-acf6-9a32777513fb","order_by":2,"name":"Hao-Ling Xu","email":"","orcid":"","institution":"Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hao-Ling","middleName":"","lastName":"Xu","suffix":""},{"id":333345746,"identity":"0426d32f-b030-4076-9e76-2bcaa762c221","order_by":3,"name":"Mao-Lin Cui","email":"","orcid":"","institution":"School of Special Education and Rehabilitation, Binzhou Medical University, Yantai 264003, People’s Republic of China","correspondingAuthor":false,"prefix":"","firstName":"Mao-Lin","middleName":"","lastName":"Cui","suffix":""},{"id":333345747,"identity":"edb592ef-5785-4426-8e85-9b0795cfe80a","order_by":4,"name":"Zhuo-Ying Huang","email":"","orcid":"","institution":"Fujian Institute of Neurology, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhuo-Ying","middleName":"","lastName":"Huang","suffix":""},{"id":333345748,"identity":"8ea58b18-4202-4bb2-b90d-b63c59c305e4","order_by":5,"name":"Ying Li","email":"","orcid":"","institution":"Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital（Fujian Branch of Fudan University Shanghai Cancer Center）, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Li","suffix":""},{"id":333345749,"identity":"e290ded7-1b5c-46d7-9fde-59c04a54637b","order_by":6,"name":"Nan-Nan Zhang","email":"","orcid":"","institution":"Department of Rehabilitation Medicine, The First Affiliated Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nan-Nan","middleName":"","lastName":"Zhang","suffix":""},{"id":333345750,"identity":"585b786c-d6b9-4e74-aae0-e48d8f855337","order_by":7,"name":"Ning Wang","email":"","orcid":"","institution":"Fujian Institute of Neurology, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ning","middleName":"","lastName":"Wang","suffix":""},{"id":333345751,"identity":"5bca32e4-0837-483e-b3f8-4dac820385a5","order_by":8,"name":"Zhi-Yong Wang","email":"","orcid":"","institution":"Department of Rehabilitation Medicine, The First Affiliated Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhi-Yong","middleName":"","lastName":"Wang","suffix":""},{"id":333345752,"identity":"3e0d4e34-6f00-419e-873c-ca39953857b4","order_by":9,"name":"Shi-Rui Gan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYJACZgYDBgY29sYHBmDuAaK18Bw2IEULCEgkQ3QQ1CLvfvbw54KCe4l9ko8Zim62Mcjx3Uhg/FyAR4vhmbw06RkGxYlt0skMxrltDMaSNxKYpWfg09KQY8bMY5AA1JJ/AKQlccONBDZmHnxa+t8YfwZrkTwMtqWeoBZ5iRwDabAWCWawlgQDQloMJN6YgbQYt/EA/ZJzTsJw5pmHzdJ4benPATrsT4Ls/PbDbMY5ZTbyfMeTD37Ga8sBBJsNGDESQJqxAY8GoC1I0swP8CodBaNgFIyCEQsAjIxElEENcxYAAAAASUVORK5CYII=","orcid":"","institution":"Fujian Institute of Neurology, Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shi-Rui","middleName":"","lastName":"Gan","suffix":""}],"badges":[],"createdAt":"2024-07-04 14:06:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4687118/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4687118/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12311-024-01769-9","type":"published","date":"2025-01-25T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62138642,"identity":"c87e41ed-c235-48fc-992e-a4a4fbda10b0","added_by":"auto","created_at":"2024-08-09 16:46:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":946750,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of current perception thresholds (CPTs) of the four detection sites at three frequencies between the groups. Asterisks denote a significant difference between the groups (*** \u003cem\u003eP\u003c/em\u003e \u0026lt;0.001). LMN : Left median nerve；RMN : Right median nerve; LSN : Left sural nerve; RSN : Right sural nerve; S : Spinocerebellar ataxia type 3; H : healthy control.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4687118/v1/94017316456fe3299170d031.jpeg"},{"id":74858442,"identity":"9e21650e-7bd1-48a2-b425-c714561efbfb","added_by":"auto","created_at":"2025-01-27 16:09:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1776484,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4687118/v1/9dadcf94-2946-4333-b69a-1e626e4b4d76.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Assessment of Peripheral Neuropathy Using Current Perception Threshold Measurement in Patients with Spinocerebellar Ataxia Type 3","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSpinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) represents the most prevalent autosomal dominant spinocerebellar ataxia globally, attributed to trinucleotide cytosine-adenine-guanine (CAG) repeats within the gene encoding ataxin-3\u003csup\u003e1,2\u003c/sup\u003e. In patients with SCA3, there are 60\u0026ndash;85 CAG-repeat units in ATXN3 while only 12\u0026ndash;44 in normal subjects\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Notably, peripheral nerve involvement stands as a prominent clinical feature in SCA3, with confirmed presence of peripheral neuropathy (PN) among affected individuals\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSome studies have highlighted the significance of PN as a contributing factor to disability in SCA3\u003csup\u003e8,10,11\u003c/sup\u003e. It has been reported that approximately 60% of SCA3 patients experience PN, with symptoms being more prevalent among those with late-onset disease\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. As the disease progresses, the severity of PN tends to worsen. Extensive damage to nerve fibers can lead to reduced sensory nerve conduction velocity and, in some cases, paralysis resulting from loss of motor nerve function, which may significantly impair functionality in certain SCA3 patients. Given that clinical symptoms often manifest later than pathological changes, early diagnosis holds crucial importance. Many studies investigating PN in SCAs rely on invasive electrophysiological assessments, such as nerve conduction velocity and needle electromyography\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, these electrophysiological methods are primarily capable of detecting damage to large myelinated nerve fibers, thus offering limited diagnostic value in identifying early-stage damage to smaller myelinated nerve fibers.\u003c/p\u003e \u003cp\u003eThe current perception threshold (CPT) test represents a transcutaneous electrical stimulator capable of noninvasively detecting and quantifying the functional status of three distinct sensory nerve fiber types (Aβ, Aδ, and C) by measuring the CPT at frequencies of 2000, 250, and 5 Hz, respectively\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Compared to traditional clinical assessments of sensory function, CPT detection offers heightened sensitivity\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Moreover, CPT is unaffected by scar tissue or edema, enabling effective screening and diagnosis before symptom onset. Prior research has demonstrated the utility of CPT measurement in diagnosing and evaluating peripheral nerve conditions across various clinical diseases, such as diabetes mellitus, chronic ankle instability, lingual nerve injuries, and carpal tunnel syndrome\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Additionally, previous studies have utilized CPT measurement to explore the impact of clinically associated factors such as gender, age, and disease status on CPT values\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. However, to date, no studies have employed CPT measurement to investigate peripheral nerve conditions in SCA3 or other neurodegenerative diseases, including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or Parkinson's disease (PD). Furthermore, the relationship between clinical characteristics of SCA3 patients and CPT values remains poorly understood.\u003c/p\u003e \u003cp\u003eHence, building upon the aforementioned groundwork, we innovatively applied CPT measurement in SCA3 patients for the first time. In this study, we conducted a quantitative evaluation of CPT values to elucidate the characteristics of peripheral neuropathy in SCA3 patients and explore various factors influencing CPT. It is our aspiration that this study will serve as a valuable reference for the application of CPT measurement in diagnosing and evaluating PN not only in SCA3 but also in other neurodegenerative diseases.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Standard protocol approvals, registrations, and patient consents\u003c/h2\u003e \u003cp\u003e The study received approval from the Ethics Committee of the First Affiliated Hospital of Fujian Medical University and written informed consent was obtained from each participant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study Participants\u003c/h2\u003e \u003cp\u003eBetween October 2018 and April 2024, we recruited 94 subjects with molecular confirmation of SCA3 and 44 healthy controls (HCs) from the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR) in the department of neurology of the First Affiliated Hospital of Fujian Medical University. Healthy controls primarily consisted of spouses, caregivers of SCA3 patients, and unrelated individuals without neurological abnormalities.\u003c/p\u003e \u003cp\u003eExclusion criteria encompassed medical conditions known to predispose to PN, a history of diabetes mellitus, chronic alcoholism, central nervous system diseases, cervical or lumbar spondylosis, malignant tumors, severe liver and kidney dysfunction, and the presence of skin lesions at the testing site. Additionally, participants were not taking any medications for peripheral neuropathy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Clinical Evaluation\u003c/h2\u003e \u003cp\u003ePrior to CPT testing, all subjects underwent a comprehensive medical history investigation and physical examination. The collected information included gender, age, AAO, length of CAG repeats, disease severity, and disease duration. Ataxia severity was evaluated using the Scale for the Assessment and Rating of Ataxia (SARA), which consists of eight cerebellar function tests yielding a total score ranging from 0 (absence of ataxia) to 40 (most severe ataxia) \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 CPT Testing\u003c/h2\u003e \u003cp\u003eWe conducted a CPT assessments on all individuals diagnosed with SCA3 and on healthy controls. We employed the Neurometer CPT/C (Neurotron Inc., Baltimore, MD, USA), a device specifically designed to measure neuroselective CPTs. The CPT involved delivering electrical stimuli via two 10-mm-diameter gold-plated electrodes. Measurements were taken from four detection sites: the median nerve on both index fingers and the sural nerves on both first toes. We utilized three distinct frequencies: 2000 Hz, 250 Hz, and 5 Hz, to evaluate Aβ myelinated, Aδ myelinated, and C fibers, respectively.\u003c/p\u003e \u003cp\u003eParticipants were seated in a quiet environment with comfortable temperature and lighting conditions. They were briefed thoroughly on the procedure beforehand to ensure comprehension and cooperation during the test. A qualified physician, experienced in administering CPT tests, regulated the stimulation intensity from 0.001 mA to 10 mA. The threshold intensity at which participants first felt the stimulation was recorded. Each frequency was tested sequentially at each site. The total test duration for each participant did not exceed 15 minutes\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNormative CPT values were established based on prior clinical trials\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, and subsequently integrated into the system's data analysis software (Neurotron, Baltimore, MD, USA, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.neurotron.com\u003c/span\u003e\u003cspan address=\"http://www.neurotron.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.). CPT abnormalities follow a two-sided distribution. Threshold values exceeding the upper limit of the normal range indicate hyperesthesia, while values falling below the lower limit suggest hypoesthesia. Symptoms of hyperesthesia or hypoesthesia are indicative of PN\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003eWe assessed the normality of variable distribution utilizing the Kolmogorov-Smirnov test. Data were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) for continuous variables, while categorical variables were expressed as the number of patients (percentages). To compare baseline data between the two groups, we employed a Chi-square Test to evaluate gender distribution. Continuous variables were compared using Two-independent sample \u003cem\u003et\u003c/em\u003e-tests for normally distributed data, and Mann-Whitney \u003cem\u003eU\u003c/em\u003e-test for non-normally distributed data.\u003c/p\u003e \u003cp\u003eWe evaluated PN in SCA3 by analyzing 12 total CPT variables and aimed to investigate their relationship with phenotypic variability in SCA3 patients. Due to the large number of CPT values and their likely intercorrelation, we performed unsupervised Principal Component Analysis (PCA) with varimax rotation, a technique previously utilized in SCA3 studies\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo assess the suitability of our variables for PCA, we first conducted a correlation matrix to ascertain the presence of linear correlation among the 12 CPT variables. We considered a correlation coefficient greater than 0.3 as indicative of suitability. Subsequently, we applied the Kaiser\u0026ndash;Meyer\u0026ndash;Olkin (KMO) test, where a KMO measure of sampling adequacy exceeding 0.5 was deemed appropriate, along with Bartlett\u0026rsquo;s test of sphericity, where a significance level below \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered suitable. To create a lower-dimensional dataset retaining sufficient variance, we filtered the dataset by ensuring that the Eigenvalue is greater than one and validated the results by considering the proportion of total variation in the data. The resulting principal component (PC) served as a composite measure of all CPT variables and was subjected to Mann-Whitney \u003cem\u003eU\u003c/em\u003e-test analysis to explore differences in PN between patients and controls.\u003c/p\u003e \u003cp\u003eWe employed a multivariable linear regression model to examine the CPT variable relationship with phenotype variability in SCA3 patients. Initially, we investigated the predictors of the first principal component (PC1) resulting from the PCA analysis, representing all CPT variables. PC1 served as the dependent variable, while gender (binary), AAO, disease duration, SARA score, and lengths of normal and expanded CAG repeats were considered independent variables. Subsequently, we analyzed factors associated with the severity of ataxia, as measured by the SARA score. The SARA score was designated as the dependent variable, with PC1 and gender (binary), AAO, and lengths of normal and expanded CAG repeats serving as independent variables. Statistical analyses were conducted using SPSS 26.0 (IBM Co., Inc., Chicago, IL, USA), with significance set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All graphs were produced using GraphPad Prism.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eAbbreviations: AAO = Age at Onest; SARA = Scale for the Assessment and Rating of Ataxia; N =Number; NA = not applicable; LMN = Left median nerve；RMN = Right median nerve; LSN = Left sural nerve; RSN = Right sural nerve.\u003c/p\u003e\n\u003cp\u003eContinuous data are expressed as the mean \u0026plusmn; standard deviation.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Independent \u003cem\u003et\u003c/em\u003e-tests\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Chi-square test\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Mann-Whitney \u003cem\u003eU\u003c/em\u003e-test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Percentages of PN findings, sensory disturbances, and subscale analysis results of the current perception threshold test in SCA3 patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"383\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.78590078328982%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eSCA3 (n = 94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ePN findings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003ePN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e48 (51.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e46 (48.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSensory disturbance\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003eHypoesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003eHyperesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e41 (43.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e7 (7.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubscale results\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest sites\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian nerve\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e21 (22.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e73 (77.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eLeft median nerve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e13 (13.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e81 (86.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eRight median nerve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e16 (17.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e78 (83.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSural nerve\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e42 (44.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e45 (55.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eLeft sural nerve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e28 (29.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e66 (70.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eRight sural nerve\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e28 (29.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e66 (70.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eFiber types\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eA\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e21 (22.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e73 (77.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eA\u0026delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e33 (35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e61 (64.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.21409921671018%\" valign=\"bottom\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.37075718015666%\" valign=\"bottom\"\u003e\n \u003cp\u003e24 (25.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.41514360313316%\" valign=\"bottom\"\u003e\n \u003cp\u003e53 (74.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAbbreviations: PN = Peripheral Neuropathy, A\u0026beta; =large-diameter myelinated, A\u0026delta; = small-diameter myelinated, C = unmyelinated fibers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo consolidate the\u0026nbsp;12 CPT variables into comprehensive indicators while minimizing information loss, we conducted PCA with varimax rotation. We selected variables for PCA from the 12 total CPT variables based on the results obtained from all four sites at frequencies of 2000Hz, 250Hz, and 5Hz. We assessed the suitability of these variables for PCA using the linear correlation matrix (correlation coefficient \u0026gt; 0.3), the KMO measure of sampling adequacy (0.759), and Bartlett\u0026rsquo;s test of sphericity (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), which confirmed the feasibility of PCA on the 12 CPT variables. Our PCA analysis revealed that the eigenvalues of the top four principal components were greater than 1, explaining 40.448%, 15.341%, 9.827%, and 8.657% of the total data variation, respectively. Together, these components accounted for 74.274% of the total variance. Examination of the component matrix indicated a strong correlation between PC1 and all 12 CPT variables. Considering the practical requirements of our study, we selected PC1 as the representative factor for all CPT variables. Furthermore, Mann-Whitney \u003cem\u003eU\u003c/em\u003e-test demonstrated significant differences in PC1 factor scores between patients and controls (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), consistent with the findings obtained from individual-dependent measures.\u003c/p\u003e\n\u003cp\u003eWe utilized multivariable linear regression to explore the relationship between PC1 (representing all CPT variables) and clinical characteristics in patients. Initially, we examined the predictors of PC1 using regression models (\u003cstrong\u003eTable 3\u003c/strong\u003e). The results revealed that increasing AAO (\u0026beta; = 17.652, \u003cem\u003eP\u003c/em\u003e = 0.01) and heightened severity of ataxia (\u0026beta; = 33.47, \u003cem\u003eP\u003c/em\u003e = 0.011) were predictive of poorer CPT values. Conversely, disease duration (\u0026beta; = 38.193, \u003cem\u003eP\u003c/em\u003e = 0.69) and longer lengths of CAG repeats in expanded alleles (\u0026beta; = 50.654, \u003cem\u003eP\u003c/em\u003e = 0.96) did not significantly predict CPT values. Gender also emerged as a predictor, with males potentially at higher risk for poorer CPT values (\u0026beta; = 273.946, \u003cem\u003eP\u003c/em\u003e = 0.017). Subsequently, we conducted multivariable linear regression to determine whether CPT values could influence the severity of ataxia (\u003cstrong\u003eTable 4\u003c/strong\u003e). Our findings indicated that CPT values (\u0026beta; = 0, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.011) along with disease duration (\u0026beta; = 0.105, \u003cem\u003eP\u003c/em\u003e = 0.000) could impact the severity of ataxia. However, AAO (\u0026beta; = 0.059, \u003cem\u003eP\u003c/em\u003e = 0.439) and lengths of CAG repeats in expanded alleles (\u0026beta; = 0.161, \u003cem\u003eP\u003c/em\u003e = 0.247) did not serve as significant predictors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. \u0026nbsp;Influencing factors on CPT values in SCA3 patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"524\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003eCoefficient estimate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eStandard error\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCPT values\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eGender\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.246\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e31.056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.017\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eAAO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e2.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eDisease duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e4.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.634\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eSARA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.308\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e3.794\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eNormal alleles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e2.282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.697\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003eExpanded alleles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.57142857142857%\" valign=\"bottom\"\u003e\n \u003cp\u003e-0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e5.742\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.142857142857142%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.962\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: AAO = Age at Onset; SARA = Scale for the Assessment and Rating of Ataxia.\u003c/p\u003e\n\u003cp\u003eBold value showed significance.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eCPT values were measured by PC1.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eMale vs. Female. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. \u0026nbsp;Influence of CPT values on disease severity in SCA3 patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"556\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003eCoefficient estimate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003eStandard error\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSARA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003eGender\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e-0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.911\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.709\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003eAAO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e-0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.472\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003eDisease duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.492\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003eNormal alleles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e-0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.234\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003eExpanded alleles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.741007194244606%\" valign=\"bottom\"\u003e\n \u003cp\u003eCPT values\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.510791366906474%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.02158273381295%\" valign=\"bottom\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.72661870503597%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: AAO = Age at Onset; SARA = Scale for the Assessment and Rating of Ataxia.\u003c/p\u003e\n\u003cp\u003eBold value showed significance.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eMale vs. Female.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eCPT values were measured by PC1.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe study highlights the efficacy of CPT testing in evaluating peripheral nerve function in individuals with SCA3, revealing a high prevalence of peripheral neuropathy among SCA3 patients. Notably, SCA3 patients exhibit notable impairments in CPT values compared to age- and gender-matched controls, with lower limb peripheral nerves showing greater vulnerability than upper limb nerves. Regression analyses within the patient group underscored significant associations between CPT values and patient characteristics, including gender, AAO, and disease severity. Furthermore, CPT values proved predictive of the severity of ataxia in SCA3.\u003c/p\u003e\n\u003cp\u003eOur findings demonstrate that CPT values in SCA3 patients differ significantly from those in healthy controls across all three frequencies in both bilateral median and sural nerves. These distinctions may suggest inherent differences or alterations in SCA3. Notably, the sural nerve exhibited a higher rate of abnormal CPT values compared to the median nerve, indicative of greater vulnerability of lower limb peripheral nerves, consistent with prior research\u003csup\u003e17\u003c/sup\u003e. This disparity may be attributed to variances in sensory nerve fiber density across different body regions, as nerve fiber density in the epidermis of the distal leg is lower than that of the distal forearm\u003csup\u003e36,\u003c/sup\u003e\u003csup\u003e37\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePrevious studies on CPT testing have yielded inconsistent findings regarding the impact of gender on CPT values\u003csup\u003e24,26-28\u003c/sup\u003e. Our study reveals that gender is a significant risk factor influencing CPT values in SCA3, consistent with reports by Nakatani-Enomoto et al. and Seno et al., indicating notable gender-based differences in CPT values among healthy individuals\u003csup\u003e27,28\u003c/sup\u003e. Specifically, CPT values are higher in males compared to females, suggesting male gender as a potential risk factor for poorer CPT values. Conversely, Uddin et al. and Chang et al. did not observe gender effects on CPT values\u003csup\u003e24,26\u003c/sup\u003e. The underlying reasons for these discrepancies remain unclear but may be attributed to variations in tissue conformation, skin structure, skin hydration, temperature characteristics, or neural response potentially influenced by sex hormone levels \u003csup\u003e27,28\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, our findings indicate no correlation between CPT values and disease duration or lengths of CAG repeats at all three frequencies, aligning with prior research\u003csup\u003e6,7,17,18,38\u003c/sup\u003e. However, AAO emerges as a predictor of CPT values. This finding is supported by Tseng et al., who reported a positive correlation between age and CPT values across all three frequencies\u003csup\u003e39\u003c/sup\u003e. Additionally, studies have highlighted a correlation between peripheral neuropathy and age in SCA3, with age serving as a determinant for peripheral nerve impairment in SCA3 patients\u003csup\u003e6,12,37\u003c/sup\u003e, likely due to age-related decreases in the number of mechanoreceptors and nerve fiber density in the skin\u003csup\u003e17\u003c/sup\u003e. Moreover, SCA3 patients with higher SARA scores exhibit more severe peripheral neuropathy, as reflected in CPT values.\u003c/p\u003e\n\u003cp\u003eThis study represents the first investigation into the application of CPT measurement for diagnosing PN in SCA3 patients. Our findings endorse the utility of CPT testing as a quantitative sensory detection method for SCA3. Future research exploring CPT testing in PN across various neurodegenerative diseases stands to benefit from our methodology and findings. However, several limitations warrant acknowledgment. Firstly, our study lacks additional physical and perceptual examinations that could offer a more objective evaluation of peripheral sensory nerves. Future studies should aim to address this gap. Secondly, the CPT testing process entails significant variability, necessitating participants\u0026apos; comprehension and responsiveness, as well as the close collaboration of experienced operators and participants. Lastly, given the cross-sectional observational design of our study, long-term follow-up is imperative.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn summary, our study underscores the potential of CPT testing in assessing peripheral neuropathy in SCA3 patients, with CPT values potentially serving as indicators of disease severity in this population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the kind patients, families, caregivers, and members who participated in this research. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions \u003c/strong\u003e SRG, ZYW, and NW formulated and designed the study concept; XHL, ZYW, and SRG analyzed the data and manuscript drafting or manuscript revision for important intellectual content; XHL, WL, HLX, MLC, ZYH, YL, NNZ, and SRG enrolled the patients and conducted clinical assessments; XHL, MLC, and YL conducted a CPT evaluation; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province (2021Y9128, Fujian; S-R-G). This work was also supported by the National Natural Science Foundation of China (82230039, Beijing; N-W), the Local Science and Technology Development Project guided by the central government grants (2022L3011, Fujian; N-W) as well as the Natural Science Fundation of Fujian Province (2023J01603, Fujian; X-H-L). The authors declare that there are no conflicts of interest relevant to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data and materials that support the findings of this study are available from the corresponding author, upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committee of the First Affiliated Hospital of Fujian Medical University. Written informed consent forms were signed by all subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKlockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers. 2019;5(1):24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41572-019-0074-3\u003c/span\u003e\u003cspan address=\"10.1038/s41572-019-0074-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2019 Apr 11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. 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Aging and current perception threshold measured by neurometer in normal Taiwanese adults. J Am Geriatr Soc. 2002;50(12):2094\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1046/j.1532-5415.2002.50627.x\u003c/span\u003e\u003cspan address=\"10.1046/j.1532-5415.2002.50627.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Peripheral neuropathy, Spinocerebellar ataxia type 3, Current perception threshold","lastPublishedDoi":"10.21203/rs.3.rs-4687118/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4687118/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePeripheral neuropathy (PN) identified as a significant contributor to disability in SCA3 patients.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThis study seeks to assess the utility of current perception threshold (CPT) measurements in evaluating PN in individuals with SCA3 and aims to identify factors influencing CPT values in SCA3 and ascertain whether these values correlate with the severity of ataxia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eNinety-four patients diagnosed with SCA3 and 44 healthy controls were recruited for this investigation. All participants were performed standard CPT assessments. Comparative analysis was conducted on CPT variables between the groups. Multivariable linear regression models were employed to identify potential risk factors influencing CPT values, and to investigate the association between CPT values and the severity of ataxia in SCA3.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe case group exhibited significantly higher values across all CPT variables compared to the control group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Peripheral neuropathy was prevalent among SCA3 patients, with lower limb nerves demonstrating greater susceptibility than upper limb nerves. Increasing age at onset (AAO) (β\u0026thinsp;=\u0026thinsp;17.652, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) and heightened ataxia severity (β\u0026thinsp;=\u0026thinsp;33.47, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) as predictors of poorer CPT values. Gender also emerged as a predictor of CPT values. Furthermore, CPT values (β\u0026thinsp;=\u0026thinsp;0, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and disease duration (β\u0026thinsp;=\u0026thinsp;0.105, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000) were found to influence the severity of ataxia.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings suggest that the CPT test holds promise for assessing peripheral neuropathy in SCA3 patients and that CPT values may serve as indicators of disease severity in this population.\u003c/p\u003e","manuscriptTitle":"Assessment of Peripheral Neuropathy Using Current Perception Threshold Measurement in Patients with Spinocerebellar Ataxia Type 3","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 16:46:55","doi":"10.21203/rs.3.rs-4687118/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-15T15:43:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-10T01:01:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-07T01:00:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242747128527507914556492040752148710374","date":"2024-08-21T13:29:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-17T01:23:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268824442121422478683808543792998688808","date":"2024-08-15T06:56:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"133965800475099250426387452644618047489","date":"2024-08-03T11:46:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-12T16:56:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-06T05:04:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-06T05:03:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Cerebellum","date":"2024-07-04T14:02:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"20b2117b-7e6b-4b16-9941-84b17290f5be","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:02:01+00:00","versionOfRecord":{"articleIdentity":"rs-4687118","link":"https://doi.org/10.1007/s12311-024-01769-9","journal":{"identity":"the-cerebellum","isVorOnly":false,"title":"The Cerebellum"},"publishedOn":"2025-01-25 15:57:38","publishedOnDateReadable":"January 25th, 2025"},"versionCreatedAt":"2024-08-09 16:46:55","video":"","vorDoi":"10.1007/s12311-024-01769-9","vorDoiUrl":"https://doi.org/10.1007/s12311-024-01769-9","workflowStages":[]},"version":"v1","identity":"rs-4687118","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4687118","identity":"rs-4687118","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}