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

doi:10.21203/rs.3.rs-4687118/v1

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Research Article

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

https://doi.org/10.21203/rs.3.rs-4687118/v1

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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

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 subjects³. 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 disease⁸. 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, respectively¹³. 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.

2.1 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 minutes²².

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 studies³⁵.

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.

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.

^aCPT values were measured by PC1.

^bMale 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.

^aMale vs. Female.

^bCPT values were measured by PC1.

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 research¹⁷. 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 frequencies³⁹. 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 skin¹⁷. 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.

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.

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

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Abstract

Background

Objectives

Methods

Results

Conclusion

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1. Introduction

2. Materials and Methods

2.1 Standard protocol approvals, registrations, and patient consents

2.2 Study Participants

2.3 Clinical Evaluation

2.4 CPT Testing

2.5 Statistical analysis

3. Results

4. Discussion

5. Conclusions

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References

Additional Declarations

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