Dysphagia Linked to Clinical Phenotype and Disease Progression in Spinocerebellar Ataxia Type 3

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Dysphagia frequently arises in SCA3 and other neurological disorders, representing a significant threat to patient survival. Objective Examining the Prevalence of Dysphagia among SCA3 Patients and Its correlation with Clinical phenotype and Disease Progression Methods We retrospectively analyzed 182 SCA3 patients, divided into dysphagia and non-dysphagia groups. Spearman's rho tested factor associations with dysphagia, logistic regression identified dysphagia risk factors, and multivariable linear regression assessed dysphagia's effect on ataxia severity. Kaplan-Meier curves with first derivative fitting explored dysphagia progression over the disease duration. Results The study found 77.0% of SCA3 patients had dysphagia, with disease duration most strongly linked to its onset (r = 0.456, p < 0.001). Gender, age at onset, SARA scores, and disease duration were independent dysphagia risk factors (all p < 0.001 or 0.001). Dysphagia also affected SARA scores (p = 0.048). Dysphagia progression rate peaks within the first decade of disease onset, reaching maximal velocity at 6.5 years, with a median time to dysphagia onset of 9 years Conclusion In China, dysphagia frequently occurs in SCA3 patients and can impact the severity of ataxia. The prevalence of dysphagia varies as the disease advances. These findings highlight the importance of timely intervention for dysphagia in SCA3 patients, particularly during the late stages of the first decade. Spinocerebellar Ataxia Type 3 dysphagia clinical phenotype disease progression Figures Figure 1 Introduction Spinocerebellar ataxia type 3 (SCA3), also referred to as Machado-Joseph disease, is a neurodegenerative condition and one of the most prevalent forms of autosomal dominant cerebellar ataxia, representing 20–50% of all spinocerebellar ataxias (SCAs) 1 – 4 . The prevalence of SCA3 differs by region and ethnicity, with a notably high incidence in China 4 , 5 . This disorder results from an expanded polyglutamine repeat in the associated disease gene, categorizing it within the glutamine family of diseases 6 , 7 . The polyQ expansion in SCA3 leads to the formation of intranuclear aggregates, neuronal loss, and atrophy of both gray and white matter, accompanied by enlargement of the fourth ventricle and a decline in dopaminergic neurons 8 . These changes give rise to a range of motor and non-motor symptoms, including ataxia, dystonia, dysphagia, tremors, oculomotor palsy, dysphagia, anxiety, depression, and cognitive impairments 4 , 9 – 12 . Dysphagia refers to the impairment of the complex and integrated sensorimotor system that coordinates the semi-automatic actions of the respiratory, oropharyngeal, and pharyngeal muscles to propel food from the oral cavity to the stomach 13 . This symptom commonly appears in various neurodegenerative diseases. In Parkinson's disease (PD), approximately 80% of patients experience dysphagia as the disease progresses 14 . Among patients with multiple system atrophy (MSA), dysphagia often presents in the early stages and has a high incidence 4 . In progressive supranuclear palsy (PSP), the prevalence of dysphagia increases with disease advancement 4 . Dysphagia is also prevalent in other neurological conditions, such as stroke, cerebral palsy, and vascular dementia 15 . The complications arising from dysphagia, including difficulties in medication intake, malnutrition, and aspiration pneumonia, are among the leading causes of mortality in these patient populations 4 , 16 . Dysphagia is a common symptom among patients with SCA 4 , 17 . Previous research on survival in SCA has shown that dysphagia impacts patients' overall survival duration 16 . Dysphagia, a common symptom in SCA3, has limited evidence of correlation with core clinical phenotypes. Current understanding predominantly relies on landmark studies by Yang et al. 17 and Lowell ER et al. 18 , which identified significant associations between dysphagia severity and ataxia progression. Despite the high prevalence of dysphagia in SCA3, the likelihood of developing this symptom and its occurrence rate throughout disease progression remain unclear. Thus, our study aims to investigate the prevalence and clinical correlations of dysphagia within a cohort of Chinese patients with SCA3. Additionally, we will examine the probability of dysphagia and how the rate of occurrence changes as the disease advances over time. Methods Study subjects We identified 182 patients with molecularly confirmed SCA3 from the clinical registry database of the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR) at the First Affiliated Hospital of Fujian Medical University. The recruitment period spanned from October 2014 to May 2019, after which we conducted a retrospective analysis of the patient cohort. The inclusion criteria for participation were: (a) the presence of ataxia, (b) a clear recollection of symptoms, (c) a willingness to participate, and (d) an age of 14 years or older. We excluded individuals who met any of the following criteria: (a) previous exclusion of SCA3 confirmed by genetic testing, (b) homozygous status, and (c) coexisting medical conditions that could influence the Scale for the Assessment and Rating of Ataxia (SARA) and other assessment measures utilized in this study. Genotype and phenotype analyses We requested peripheral blood samples from each patient and extracted genomic DNA using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). To assess the CAG repeat number within the ATXN3 gene, we performed polymerase chain reaction (PCR) followed by Sanger sequencing, as described in a previous report 5 . Ataxia specialists conducted face-to-face interviews with each patient to collect essential information for our study. Participants underwent standardized evaluation using the Inventory of Non-Ataxia Symptoms (INAS), a validated tool for assessing non-ataxic manifestations in SCA 19 . Dysphagia, as an item within INAS, was assessed by ataxia specialists primarily based on patient-reported symptoms, supplemented by caregiver or family input when available. Although INAS categorizes dysphagia severity as mild, moderate, or severe, it lacks standardized objective thresholds to differentiate these grades. Therefore, the analysis dichotomized dysphagia into present or absent. 17 . We defined the age at onset (AAO) as the age at which the patient, a close relative, or a caregiver first noticed symptoms. The duration of the disease is calculated as the time elapsed from the AAO to the age of initial diagnosis. We evaluated the severity of ataxia using an ataxia rating scale that includes eight distinct domains of ataxic symptoms. The Scale for the SARA serves as a widely used tool in ataxia research, providing a continuous variable score ranging from 0 to 40, where higher scores indicate greater severity of ataxia 20 . Statistical analyses We categorized patients into two groups: those with dysphagia and those without. We then evaluated the demographic characteristics of SCA3 patients in both groups. We employed chi-square tests to compare categorical variables. For normally distributed continuous variables, we used Student's t -test to assess differences between the dysphagia and non-dysphagia groups. For non-normally distributed variables, we applied Mann-Whitney U tests to compare the two groups. To explore correlations between dysphagia and other clinical phenotypes—such as gender, AAO, disease duration, SARA score, and CAG repeat counts—we utilized Spearman's rho test. To identify factors associated with dysphagia, we conducted a multivariate logistic regression analysis. This analysis assessed the impact of various independent variables, including gender, AAO, disease duration, SARA score, and length of expanded CAG repeat sequences, while controlling for their intercorrelations. Dysphagia served as the dependent variable in this analysis. We also examined whether dysphagia affects the SARA score through multivariate linear regression analysis. In this model, the SARA score was the dependent variable, with dysphagia, gender, AAO, disease duration, and length of expanded CAG repeat sequences as independent variables. The Kaplan-Meier survival analysis was performed to estimate the risk of dysphagia onset in patients. Dysphagia onset was defined as the event of interest. Between 2014 and 2019, no participants withdrew from the study, but 42 (21.8%) participants remained free of dysphagia.The Kaplan-Meier step function was transformed into a continuous curve via spline smoothing (5 knots), from which the first derivative was computed to quantify the instantaneous rate of dysphagia onset. In all analyses, p < 0.05 represents statistically significant. We performed all statistical analyses using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). Results In this study, we found that approximately 77.0% of participants experienced dysphagia, while about 23.0% reported no dysphagia. The prevalence of dysphagia was higher in women (85.4%) than in men (69.1%) ( p = 0.009, χ² = 6.82). We observed significantly higher SARA scores in the dysphagia group compared to the non-dysphagia group (Dysphagia group: 11.00 (7.00, 18.00) vs. Non-dysphagia group: 6.00 (3.12, 9.75), p < 0.001). Additionally, the dysphagia group exhibited a longer disease duration (Dysphagia group: 8.00 (6.00, 12.00) vs. Non-dysphagia group: 3.00 (2.00, 5.00), p < 0.001). However, we found no significant differences in AAO ( p = 0.212, t = 1.25), length of normal CAG repeat sequences ( p = 0.296, z = -1.04), or length of expanded CAG repeat sequences ( p = 0.141, z = -1.48). Table 1 presents the demographic characteristics of SCA3 subjects. Table 1 Demographic features of SCA3 participants. Variables Total ( n = 183) non-Dysphagia ( n = 42) Dysphagia ( n = 141) Statistic p Gender, M/F 94:89 29:13 65:76 χ² = 6.82 0.009 Age, Mean ± SD 42.30 ± 11.89 40.40 ± 12.72 42.87 ± 11.62 t = -1.18 0.24 AAO, Mean ± SD 34.39 ± 11.02 36.26 ± 11.97 33.84 ± 10.71 t = 1.25 0.212 CAGexp, Mean ± SD 74.96 ± 3.62 74.24 ± 3.77 75.18 ± 3.56 t = -1.48 0.141 CAGnorm, M (Q₁, Q₃) 14.00 (14.00, 27.00) 14.00 (14.00, 25.50) 14.00 (14.00, 27.00) Z = -1.04 0.296 Disease duration, Year, M (Q₁, Q₃) 7.00 (4.00, 10.00) 3.00 (2.00, 5.00) 8.00 (6.00, 12.00) Z = -6.15 < 0.001 SARA, M (Q₁, Q₃) 10.00 (6.00, 15.50) 6.00 (3.12, 9.75) 11.00 (7.00, 18.00) Z = -5.07 < 0.001 Bold value showed significance t: t -test, Z: Mann-Whitney test, χ² : Chi-square test Abbreviations: SARA, Ataxia severity (SARA score); Severity, Ataxia severity (SARA) CAGexp, expanded CAG repeat; CAGnorm, normal CAG repeat; SD, standard deviation; M, Median; Q₁, 1st Quartile; Q₃, 3st Quartile We used the Spearman test to assess correlations between dysphagia and various factors in SCA3 patients, including age, gender, disease duration, normal CAG repeats, expanded CAG repeats, AAO, and SARA scores. Our analysis revealed significant correlations: dysphagia correlated with gender ( r = -0.193, p = 0.009), disease duration ( r = 0.456, p < 0.001), and SARA scores ( r = 0.376, p < 0.001), with disease duration showing the strongest association (Table 2 ). To explore risk factors for dysphagia in SCA3 patients, we conducted a logistic regression analysis. The multivariate logistic analysis, which controlled for confounding effects between variables, identified gender ( p = 0.001; OR = 4.69, 95% CI = 1.85 to 11.88), AAO ( p = 0.031; OR = 0.93, 95% CI = 0.87 to 0.99), SARA scores ( p = 0.034; OR = 1.12, 95% CI = 1.01 to 1.25), and disease duration ( p < 0.001; OR = 1.34, 95% CI = 1.14 to 1.57) as independent risk factors for dysphagia (Table 3 ). Table 2 Relationship between dysphagia and other clinical phenotypes in SCA3 patients. Parameters Dysphagia Coefficient p -value Gender -0.193 0.009 Age 0.103 0.165 Disease duration 0.456 < 0.001 AAO -0.082 0.272 CAGnorm, M (Q₁, Q₃) 0.078 0.297 CAGexp, Mean ± SD 0.099 0.18 SARA 0.376 < 0.001 Bold values denoted significance. Variables assessed with Spearman’s rho test. Table 3 Risk factors of dysphagia. Variables Multivariate β S.E Z p OR (95% CI) AAO -0.07 0.03 -2.16 0.031 0.93 (0.87 ~ 0.99) CAGexp -0.08 0.09 -0.92 0.358 0.92 (0.77 ~ 1.10) SARA 0.11 0.05 2.12 0.034 1.12 (1.01 ~ 1.25) Gender 1.55 0.47 3.26 0.001 4.69 (1.85 ~ 11.88) Disease duration 0.29 0.08 3.52 < 0.001 1.34 (1.14 ~ 1.57) Bold values denoted significance. OR: Odds Ratio, CI: Confidence Interval To investigate the impact of dysphagia on the SARA score, we conducted a multivariate regression analysis. After adjusting for potential confounders, we identified four independent risk factors for the SARA score: disease duration ( p < 0.001; β = 0.83, 95% CI = 0.65 to 1.02), AAO ( p < 0.001; β = 0.27, 95% CI = 0.15 to 0.39), length of expanded CAG repeat ( p < 0.001; β = 0.69, 95% CI = 0.34 to 1.05), and dysphagia ( p = 0.048; β = 2.30, 95% CI = 0.04 to 4.56) (Table 4 ). Table 4 Risk factors of SARA scores Variables Multivariate β S.E t p β (95% CI) Gender -1.13 0.9 -1.25 0.213 -1.13 (-2.89 ~ 0.64) Dysphagia 2.3 1.15 1.99 0.048 2.30 (0.04 ~ 4.56) CAGexp 0.69 0.18 3.81 < 0.001 0.69 (0.34 ~ 1.05) Disease duration 0.83 0.09 8.78 < 0.001 0.83 (0.65 ~ 1.02) AAO 0.27 0.06 4.45 < 0.001 0.27 (0.15 ~ 0.39) Bold values denoted significance. CI: Confidence Interval Our analysis revealed that the progression rate of dysphagia is dynamic throughout disease progression. Specifically, the progression rate of dysphagia initially accelerates before gradually decelerating. Notably, 50% of patients exhibited dysphagia by the ninth year of their disease (Fig. 1 A). Furthermore, we found that the velocity of dysphagia onset peaked during the later stages of the first decade, reaching its highest point at 6.5 years, and then declined incrementally each subsequent year (Fig. 1 B). Discussion Our study is the first large-scale investigation of the prevalence and impact of dysphagia in Chinese patients with SCA3. We found that dysphagia is highly prevalent in this population, with a notably higher incidence among females than males. Patients in the dysphagia group displayed significantly elevated SARA scores and a longer disease duration compared to those without dysphagia. We identified several risk factors for developing dysphagia, including gender, disease duration, AAO, and SARA scores. Additionally, dysphagia emerged as a significant factor influencing the severity of ataxia. Importantly, disease duration closely correlates with the onset of dysphagia. We observed the progression rate of dysphagia fluctuates with disease progression, peaking in the later stages of the first decade following diagnosis. Swallowing is a complex physiological process that involves multiple brainstem structures and neural pathways. The central pattern generator (CPG) for swallowing, which produces the organized and rhythmic motor patterns necessary for deglutition, is located in the medulla oblongata 21 . Research has shown that the medulla oblongata is one of the first areas affected in the progression of SCA3, along with other brainstem regions such as the pons, making it a critical site of impairment in this disease 4 , 22 . In addition to housing the swallowing center, the medulla contains the lateral reticular nucleus (LRT), a brainstem structure that plays a role in proprioception and the regulation of somatic motor activity. Thus, dysphagia in SCA3 patients arises from damage to the medulla 23 , where impairment of the swallowing center often coincides with damage to the LRT. These injuries develop progressively over the course of the disease. This understanding helps explain why dysphagia affects the severity of ataxia and why disease duration is the factor most closely linked to swallowing impairment. We observed a notable difference in the incidence of dysphagia between males and females, a finding not reported in prior studies 17 . Our results show that female patients experience dysphagia more frequently in the early stages of the disease, though this disparity diminishes as the disease progresses. A similar trend is noted in PSP, where female patients often exhibit symptoms such as dysphagia, severe dysphagia, and significant cognitive impairments earlier than their male counterparts 4 . Differences in hormonal and immune responses between genders are widely regarded as key factors influencing the variability in clinical manifestations 4 . However, our study has several limitations. Firstly, we assessed the presence or absence of dysphagia based solely on the subjective judgment of the examiner. More objective methods, such as the Videofluoroscopic Swallow Study (VFSS), should be employed to accurately determine the occurrence of dysphagia. Secondly, we did not quantify the severity of dysphagia using standardized methods, such as Fiberoptic Endoscopic Evaluation of Swallowing (FEES) or High-Resolution Manometry (HRM). Thirdly, we have not conducted follow-up studies on patients with dysphagia to evaluate its impact on their quality of life and survival duration. In conclusion, dysphagia is a prevalent comorbidity among individuals with SCA3, significantly affecting the severity of ataxia independently of other factors. The incidence of dysphagia fluctuates with disease progression, reaching its peak during the late stages of the first decade following diagnosis. These findings highlight the urgent need for targeted interventions to manage dysphagia in SCA3 patients, especially as they progress to the advanced stages of the disease within the first decade. Declarations Acknowledgments The authors would like to thank the kind patients, families, caregivers, and members who participated in this research. Author contributions SRG and BC formulated and designed the study concept; CPC, MLC and SRG analyzed the data and manuscript drafting or manuscript revision for important intellectual content; enrolled the patients and conducted clinical assessments, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors. Funding Sources and Conflict of Interest This work was supported by the National Natural Science Foundation of China (82371879, Beijing, S-R-G; 82071277 and 82471299, Beijing, B-C). This work was also supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province(2021Y9128, Fujian, S-R-G).The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months The authors declare that there are no additional disclosures to report. Ethical Compliance Statement We obtained ethical approval for this study from the Ethics Committee of the First Affiliated Hospital of Fujian Medical University. Additionally, we secured written informed consent from all participants. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.. References Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. 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The Cerebellum 2008;7:125-137. Rüb U, de Vos RA, Schultz C, Brunt ER, Paulson H, Braak H. Spinocerebellar ataxia type 3 (Machado-Joseph disease): severe destruction of the lateral reticular nucleus. Brain : a journal of neurology 2002;125:2115-2124. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6484743","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":450373341,"identity":"98a04ddd-3830-42b8-9987-29c2f4001b37","order_by":0,"name":"Cai-Ping Chen","email":"","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Cai-Ping","middleName":"","lastName":"Chen","suffix":""},{"id":450373342,"identity":"ec00a8c7-7ca4-41fd-956d-40e7afed7e0a","order_by":1,"name":"Mao-Lin Cui","email":"","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Mao-Lin","middleName":"","lastName":"Cui","suffix":""},{"id":450373343,"identity":"7fbb429e-a83b-4db1-8de6-1517bb90a04b","order_by":2,"name":"Wei Lin","email":"","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Lin","suffix":""},{"id":450373344,"identity":"915ff83e-c9ef-4043-b259-958a2b22c4ac","order_by":3,"name":"Zhuo-Ying Huang","email":"","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Zhuo-Ying","middleName":"","lastName":"Huang","suffix":""},{"id":450373345,"identity":"0cb4b2c4-4200-4b43-bfb9-9c0c3647e535","order_by":4,"name":"Bei-Ning Ye","email":"","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Bei-Ning","middleName":"","lastName":"Ye","suffix":""},{"id":450373346,"identity":"f42d0129-dd97-4d35-8077-8084903a91e1","order_by":5,"name":"Bin Cai","email":"","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Cai","suffix":""},{"id":450373347,"identity":"52c27735-cc39-41ba-a7bd-76e5bd797f49","order_by":6,"name":"Shi-Rui Gan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYJACZgYDBgY29sYHBmDuAaK18Bw2IEULCEgkQ3QQ1CLvfvbw54KCe4l9ko8Zim62Mcjx3Uhg/FyAR4vhmbw06RkGxYlt0skMxrltDMaSNxKYpWfg09KQY8bMY5AA1JJ/AKQlccONBDZmHnxa+t8YfwZrkTwMtqWeoBZ5iRwDabAWCWawlgQDQloMJN6YgbQYt/EA/ZJzTsJw5pmHzdJ4benPATrsT4Ls/PbDbMY5ZTbyfMeTD37Ga8sBBJsNGDESQJqxAY8GoC1I0swP8CodBaNgFIyCEQsAjIxElEENcxYAAAAASUVORK5CYII=","orcid":"","institution":"Department of Neurology, Fujian Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.","correspondingAuthor":true,"prefix":"","firstName":"Shi-Rui","middleName":"","lastName":"Gan","suffix":""}],"badges":[],"createdAt":"2025-04-19 12:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6484743/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6484743/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82147652,"identity":"c526740f-990f-45b0-998e-f79c2330f11c","added_by":"auto","created_at":"2025-05-07 07:02:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1163529,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Kaplan-Meier curve showing No-dysphagia proportion over duration (B) Survival curve's first derivative shows a negative correlation, indicating a rising dysphagia incidence with disease progression. The derivative's absolute value signifies the disease's progression speed, with potential minor inaccuracies at the extremes.\u003c/p\u003e","description":"","filename":"FIG1.png","url":"https://assets-eu.researchsquare.com/files/rs-6484743/v1/ddb2f44e536ae2d6f2ce1230.png"},{"id":85546534,"identity":"5c1bb01e-0678-4f68-a1a5-bbe1d8d6bfe0","added_by":"auto","created_at":"2025-06-27 08:32:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1749310,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6484743/v1/f77d9c4d-2808-4c99-a475-78708e7e7298.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Dysphagia Linked to Clinical Phenotype and Disease Progression in Spinocerebellar Ataxia Type 3","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpinocerebellar ataxia type 3 (SCA3), also referred to as Machado-Joseph disease, is a neurodegenerative condition and one of the most prevalent forms of autosomal dominant cerebellar ataxia, representing 20\u0026ndash;50% of all spinocerebellar ataxias (SCAs) \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The prevalence of SCA3 differs by region and ethnicity, with a notably high incidence in China\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. This disorder results from an expanded polyglutamine repeat in the associated disease gene, categorizing it within the glutamine family of diseases \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The polyQ expansion in SCA3 leads to the formation of intranuclear aggregates, neuronal loss, and atrophy of both gray and white matter, accompanied by enlargement of the fourth ventricle and a decline in dopaminergic neurons \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. These changes give rise to a range of motor and non-motor symptoms, including ataxia, dystonia, dysphagia, tremors, oculomotor palsy, dysphagia, anxiety, depression, and cognitive impairments\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDysphagia refers to the impairment of the complex and integrated sensorimotor system that coordinates the semi-automatic actions of the respiratory, oropharyngeal, and pharyngeal muscles to propel food from the oral cavity to the stomach \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. This symptom commonly appears in various neurodegenerative diseases. In Parkinson's disease (PD), approximately 80% of patients experience dysphagia as the disease progresses \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Among patients with multiple system atrophy (MSA), dysphagia often presents in the early stages and has a high incidence \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In progressive supranuclear palsy (PSP), the prevalence of dysphagia increases with disease advancement \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Dysphagia is also prevalent in other neurological conditions, such as stroke, cerebral palsy, and vascular dementia\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The complications arising from dysphagia, including difficulties in medication intake, malnutrition, and aspiration pneumonia, are among the leading causes of mortality in these patient populations\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDysphagia is a common symptom among patients with SCA\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Previous research on survival in SCA has shown that dysphagia impacts patients' overall survival duration \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Dysphagia, a common symptom in SCA3, has limited evidence of correlation with core clinical phenotypes. Current understanding predominantly relies on landmark studies by Yang et al. \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e and Lowell ER et al. \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, which identified significant associations between dysphagia severity and ataxia progression. Despite the high prevalence of dysphagia in SCA3, the likelihood of developing this symptom and its occurrence rate throughout disease progression remain unclear.\u003c/p\u003e \u003cp\u003eThus, our study aims to investigate the prevalence and clinical correlations of dysphagia within a cohort of Chinese patients with SCA3. Additionally, we will examine the probability of dysphagia and how the rate of occurrence changes as the disease advances over time.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy subjects\u003c/h2\u003e \u003cp\u003eWe identified 182 patients with molecularly confirmed SCA3 from the clinical registry database of the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR) at the First Affiliated Hospital of Fujian Medical University. The recruitment period spanned from October 2014 to May 2019, after which we conducted a retrospective analysis of the patient cohort. The inclusion criteria for participation were: (a) the presence of ataxia, (b) a clear recollection of symptoms, (c) a willingness to participate, and (d) an age of 14 years or older. We excluded individuals who met any of the following criteria: (a) previous exclusion of SCA3 confirmed by genetic testing, (b) homozygous status, and (c) coexisting medical conditions that could influence the Scale for the Assessment and Rating of Ataxia (SARA) and other assessment measures utilized in this study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGenotype and phenotype analyses\u003c/h3\u003e\n\u003cp\u003eWe requested peripheral blood samples from each patient and extracted genomic DNA using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). To assess the CAG repeat number within the \u003cem\u003eATXN3\u003c/em\u003e gene, we performed polymerase chain reaction (PCR) followed by Sanger sequencing, as described in a previous report\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAtaxia specialists conducted face-to-face interviews with each patient to collect essential information for our study. Participants underwent standardized evaluation using the Inventory of Non-Ataxia Symptoms (INAS), a validated tool for assessing non-ataxic manifestations in SCA \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Dysphagia, as an item within INAS, was assessed by ataxia specialists primarily based on patient-reported symptoms, supplemented by caregiver or family input when available. Although INAS categorizes dysphagia severity as mild, moderate, or severe, it lacks standardized objective thresholds to differentiate these grades. Therefore, the analysis dichotomized dysphagia into present or absent. \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. We defined the age at onset (AAO) as the age at which the patient, a close relative, or a caregiver first noticed symptoms. The duration of the disease is calculated as the time elapsed from the AAO to the age of initial diagnosis. We evaluated the severity of ataxia using an ataxia rating scale that includes eight distinct domains of ataxic symptoms. The Scale for the SARA serves as a widely used tool in ataxia research, providing a continuous variable score ranging from 0 to 40, where higher scores indicate greater severity of ataxia\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eWe categorized patients into two groups: those with dysphagia and those without. We then evaluated the demographic characteristics of SCA3 patients in both groups. We employed chi-square tests to compare categorical variables. For normally distributed continuous variables, we used Student's \u003cem\u003et\u003c/em\u003e-test to assess differences between the dysphagia and non-dysphagia groups. For non-normally distributed variables, we applied Mann-Whitney U tests to compare the two groups. To explore correlations between dysphagia and other clinical phenotypes\u0026mdash;such as gender, AAO, disease duration, SARA score, and CAG repeat counts\u0026mdash;we utilized Spearman's rho test. To identify factors associated with dysphagia, we conducted a multivariate logistic regression analysis. This analysis assessed the impact of various independent variables, including gender, AAO, disease duration, SARA score, and length of expanded CAG repeat sequences, while controlling for their intercorrelations. Dysphagia served as the dependent variable in this analysis.\u003c/p\u003e \u003cp\u003eWe also examined whether dysphagia affects the SARA score through multivariate linear regression analysis. In this model, the SARA score was the dependent variable, with dysphagia, gender, AAO, disease duration, and length of expanded CAG repeat sequences as independent variables. The Kaplan-Meier survival analysis was performed to estimate the risk of dysphagia onset in patients. Dysphagia onset was defined as the event of interest. Between 2014 and 2019, no participants withdrew from the study, but 42 (21.8%) participants remained free of dysphagia.The Kaplan-Meier step function was transformed into a continuous curve via spline smoothing (5 knots), from which the first derivative was computed to quantify the instantaneous rate of dysphagia onset. In all analyses, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 represents statistically significant. We performed all statistical analyses using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study, we found that approximately 77.0% of participants experienced dysphagia, while about 23.0% reported no dysphagia. The prevalence of dysphagia was higher in women (85.4%) than in men (69.1%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, \u003cem\u003eχ\u0026sup2;\u003c/em\u003e = 6.82). We observed significantly higher SARA scores in the dysphagia group compared to the non-dysphagia group (Dysphagia group: 11.00 (7.00, 18.00) vs. Non-dysphagia group: 6.00 (3.12, 9.75), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Additionally, the dysphagia group exhibited a longer disease duration (Dysphagia group: 8.00 (6.00, 12.00) vs. Non-dysphagia group: 3.00 (2.00, 5.00), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, we found no significant differences in AAO (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.212, \u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.25), length of normal CAG repeat sequences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.296, \u003cem\u003ez\u003c/em\u003e = -1.04), or length of expanded CAG repeat sequences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.141, \u003cem\u003ez\u003c/em\u003e = -1.48). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the demographic characteristics of SCA3 subjects.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic features of SCA3 participants.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;183)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003enon-Dysphagia\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDysphagia\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;141)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStatistic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, M/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94:89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29:13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65:76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eχ\u0026sup2;\u003c/em\u003e = 6.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.30\u0026thinsp;\u0026plusmn;\u0026thinsp;11.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.40\u0026thinsp;\u0026plusmn;\u0026thinsp;12.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42.87\u0026thinsp;\u0026plusmn;\u0026thinsp;11.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e = -1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAAO, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.39\u0026thinsp;\u0026plusmn;\u0026thinsp;11.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.26\u0026thinsp;\u0026plusmn;\u0026thinsp;11.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.84\u0026thinsp;\u0026plusmn;\u0026thinsp;10.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.212\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAGexp, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.96\u0026thinsp;\u0026plusmn;\u0026thinsp;3.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.24\u0026thinsp;\u0026plusmn;\u0026thinsp;3.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75.18\u0026thinsp;\u0026plusmn;\u0026thinsp;3.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e = -1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAGnorm, M (Q₁, Q₃)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.00\u003c/p\u003e \u003cp\u003e(14.00, 27.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.00\u003c/p\u003e \u003cp\u003e(14.00, 25.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.00\u003c/p\u003e \u003cp\u003e(14.00, 27.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ = -1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.296\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration, Year, M (Q₁, Q₃)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.00\u003c/p\u003e \u003cp\u003e(4.00, 10.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.00\u003c/p\u003e \u003cp\u003e(2.00, 5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.00\u003c/p\u003e \u003cp\u003e(6.00, 12.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ = -6.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSARA, M (Q₁, Q₃)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003cp\u003e(6.00, 15.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.00\u003c/p\u003e \u003cp\u003e(3.12, 9.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.00\u003c/p\u003e \u003cp\u003e(7.00, 18.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eZ = -5.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eBold value showed significance\u003c/p\u003e \u003cp\u003et: \u003cem\u003et\u003c/em\u003e-test, Z: Mann-Whitney test, \u003cem\u003eχ\u0026sup2;\u003c/em\u003e: Chi-square test\u003c/p\u003e \u003cp\u003eAbbreviations: SARA, Ataxia severity (SARA score); Severity, Ataxia severity (SARA)\u003c/p\u003e \u003cp\u003eCAGexp, expanded CAG repeat; CAGnorm, normal CAG repeat; SD, standard deviation; M, Median; Q₁, 1st Quartile; Q₃, 3st Quartile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe used the Spearman test to assess correlations between dysphagia and various factors in SCA3 patients, including age, gender, disease duration, normal CAG repeats, expanded CAG repeats, AAO, and SARA scores. Our analysis revealed significant correlations: dysphagia correlated with gender (\u003cem\u003er\u003c/em\u003e = -0.193, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009), disease duration (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.456, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and SARA scores (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.376, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with disease duration showing the strongest association (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). To explore risk factors for dysphagia in SCA3 patients, we conducted a logistic regression analysis. The multivariate logistic analysis, which controlled for confounding effects between variables, identified gender (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; OR\u0026thinsp;=\u0026thinsp;4.69, 95% CI\u0026thinsp;=\u0026thinsp;1.85 to 11.88), AAO (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031; OR\u0026thinsp;=\u0026thinsp;0.93, 95% CI\u0026thinsp;=\u0026thinsp;0.87 to 0.99), SARA scores (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034; OR\u0026thinsp;=\u0026thinsp;1.12, 95% CI\u0026thinsp;=\u0026thinsp;1.01 to 1.25), and disease duration (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; OR\u0026thinsp;=\u0026thinsp;1.34, 95% CI\u0026thinsp;=\u0026thinsp;1.14 to 1.57) as independent risk factors for dysphagia (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between dysphagia and other clinical phenotypes in SCA3 patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eDysphagia\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoefficient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAAO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAGnorm, M (Q₁, Q₃)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.297\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAGexp, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSARA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.376\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eBold values denoted significance.\u003c/p\u003e \u003cp\u003eVariables assessed with Spearman\u0026rsquo;s rho test.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors of dysphagia.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS.E\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAAO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.031\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.93 (0.87\u0026thinsp;~\u0026thinsp;0.99)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAGexp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.92 (0.77\u0026thinsp;~\u0026thinsp;1.10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSARA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.12 (1.01\u0026thinsp;~\u0026thinsp;1.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.69 (1.85\u0026thinsp;~\u0026thinsp;11.88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.34 (1.14\u0026thinsp;~\u0026thinsp;1.57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eBold values denoted significance.\u003c/p\u003e \u003cp\u003eOR: Odds Ratio, CI: Confidence Interval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo investigate the impact of dysphagia on the SARA score, we conducted a multivariate regression analysis. After adjusting for potential confounders, we identified four independent risk factors for the SARA score: disease duration (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; \u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.83, 95% CI\u0026thinsp;=\u0026thinsp;0.65 to 1.02), AAO (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; \u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.27, 95% CI\u0026thinsp;=\u0026thinsp;0.15 to 0.39), length of expanded CAG repeat (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; \u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.69, 95% CI\u0026thinsp;=\u0026thinsp;0.34 to 1.05), and dysphagia (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048; \u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.30, 95% CI\u0026thinsp;=\u0026thinsp;0.04 to 4.56) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors of SARA scores\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS.E\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eβ (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.13 (-2.89\u0026thinsp;~\u0026thinsp;0.64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysphagia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.048\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.30 (0.04\u0026thinsp;~\u0026thinsp;4.56)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAGexp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.69 (0.34\u0026thinsp;~\u0026thinsp;1.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.83 (0.65\u0026thinsp;~\u0026thinsp;1.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAAO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27 (0.15\u0026thinsp;~\u0026thinsp;0.39)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eBold values denoted significance.\u003c/p\u003e \u003cp\u003eCI: Confidence Interval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOur analysis revealed that the progression rate of dysphagia is dynamic throughout disease progression. Specifically, the progression rate of dysphagia initially accelerates before gradually decelerating. Notably, 50% of patients exhibited dysphagia by the ninth year of their disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Furthermore, we found that the velocity of dysphagia onset peaked during the later stages of the first decade, reaching its highest point at 6.5 years, and then declined incrementally each subsequent year (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study is the first large-scale investigation of the prevalence and impact of dysphagia in Chinese patients with SCA3. We found that dysphagia is highly prevalent in this population, with a notably higher incidence among females than males. Patients in the dysphagia group displayed significantly elevated SARA scores and a longer disease duration compared to those without dysphagia. We identified several risk factors for developing dysphagia, including gender, disease duration, AAO, and SARA scores. Additionally, dysphagia emerged as a significant factor influencing the severity of ataxia. Importantly, disease duration closely correlates with the onset of dysphagia. We observed the progression rate of dysphagia fluctuates with disease progression, peaking in the later stages of the first decade following diagnosis.\u003c/p\u003e \u003cp\u003eSwallowing is a complex physiological process that involves multiple brainstem structures and neural pathways. The central pattern generator (CPG) for swallowing, which produces the organized and rhythmic motor patterns necessary for deglutition, is located in the medulla oblongata\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Research has shown that the medulla oblongata is one of the first areas affected in the progression of SCA3, along with other brainstem regions such as the pons, making it a critical site of impairment in this disease\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In addition to housing the swallowing center, the medulla contains the lateral reticular nucleus (LRT), a brainstem structure that plays a role in proprioception and the regulation of somatic motor activity. Thus, dysphagia in SCA3 patients arises from damage to the medulla \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, where impairment of the swallowing center often coincides with damage to the LRT. These injuries develop progressively over the course of the disease. This understanding helps explain why dysphagia affects the severity of ataxia and why disease duration is the factor most closely linked to swallowing impairment.\u003c/p\u003e \u003cp\u003eWe observed a notable difference in the incidence of dysphagia between males and females, a finding not reported in prior studies\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Our results show that female patients experience dysphagia more frequently in the early stages of the disease, though this disparity diminishes as the disease progresses. A similar trend is noted in PSP, where female patients often exhibit symptoms such as dysphagia, severe dysphagia, and significant cognitive impairments earlier than their male counterparts \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Differences in hormonal and immune responses between genders are widely regarded as key factors influencing the variability in clinical manifestations \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, our study has several limitations. Firstly, we assessed the presence or absence of dysphagia based solely on the subjective judgment of the examiner. More objective methods, such as the Videofluoroscopic Swallow Study (VFSS), should be employed to accurately determine the occurrence of dysphagia. Secondly, we did not quantify the severity of dysphagia using standardized methods, such as Fiberoptic Endoscopic Evaluation of Swallowing (FEES) or High-Resolution Manometry (HRM). Thirdly, we have not conducted follow-up studies on patients with dysphagia to evaluate its impact on their quality of life and survival duration.\u003c/p\u003e \u003cp\u003eIn conclusion, dysphagia is a prevalent comorbidity among individuals with SCA3, significantly affecting the severity of ataxia independently of other factors. The incidence of dysphagia fluctuates with disease progression, reaching its peak during the late stages of the first decade following diagnosis. These findings highlight the urgent need for targeted interventions to manage dysphagia in SCA3 patients, especially as they progress to the advanced stages of the disease within the first decade.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments \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\u003eAuthor contributions \u003c/p\u003e\n\u003cp\u003eSRG and BC formulated and designed the study concept; CPC, MLC and SRG analyzed the data and manuscript drafting or manuscript revision for important intellectual content; enrolled the patients and conducted clinical assessments, all authors; 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\u003eFunding Sources and Conflict of Interest \u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (82371879, Beijing, S-R-G; 82071277 and 82471299, Beijing, B-C). This work was also supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province(2021Y9128, Fujian, S-R-G).The authors declare that there are no conflicts of interest relevant to this work.\u003c/p\u003e\n\u003cp\u003eFinancial Disclosures for the previous 12 months\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no additional disclosures to report.\u003c/p\u003e\n\u003cp\u003eEthical Compliance Statement\u003c/p\u003e\n\u003cp\u003eWe obtained ethical approval for this study from the Ethics Committee of the First Affiliated Hospital of Fujian Medical University. Additionally, we secured written informed consent from all participants. We confirm that we have read the Journal\u0026rsquo;s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines..\u003c/p\u003e"},{"header":"References ","content":"\u003col\u003e\n\u003cli\u003eKlockgether T, Mariotti C, Paulson HL. 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Journal of the Neurological Sciences 2020;415.\u003c/li\u003e\n\u003cli\u003eLowell ER, Borders JC, Perry SE, et al. Sensorimotor Cough Dysfunction in Cerebellar Ataxias. Cerebellum (London, England) 2024;23:1338-1347.\u003c/li\u003e\n\u003cli\u003eJacobi H, Rakowicz M, Rola R, et al. Inventory of Non-Ataxia Signs (INAS): Validation of a New Clinical Assessment Instrument. The Cerebellum 2012;12:418-428.\u003c/li\u003e\n\u003cli\u003eSchmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia. Neurology 2006;66:1717-1720.\u003c/li\u003e\n\u003cli\u003eJean A. Brain Stem Control of Swallowing: Neuronal Network and Cellular Mechanisms. Physiological Reviews 2001;81:929-969.\u003c/li\u003e\n\u003cli\u003eRiess O, R\u0026uuml;b U, Pastore A, Bauer P, Sch\u0026ouml;ls L. SCA3: Neurological features, pathogenesis and animal models. The Cerebellum 2008;7:125-137.\u003c/li\u003e\n\u003cli\u003eR\u0026uuml;b U, de Vos RA, Schultz C, Brunt ER, Paulson H, Braak H. Spinocerebellar ataxia type 3 (Machado-Joseph disease): severe destruction of the lateral reticular nucleus. Brain : a journal of neurology 2002;125:2115-2124.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Spinocerebellar Ataxia Type 3, dysphagia, clinical phenotype, disease progression","lastPublishedDoi":"10.21203/rs.3.rs-6484743/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6484743/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSpinocerebellar Ataxia type 3 (SCA3) is a widely recognized autosomal dominant disorder characterized by cerebellar ataxia, particularly prevalent in China. Dysphagia frequently arises in SCA3 and other neurological disorders, representing a significant threat to patient survival.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eExamining the Prevalence of Dysphagia among SCA3 Patients and Its correlation with Clinical phenotype and Disease Progression\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 182 SCA3 patients, divided into dysphagia and non-dysphagia groups. Spearman's rho tested factor associations with dysphagia, logistic regression identified dysphagia risk factors, and multivariable linear regression assessed dysphagia's effect on ataxia severity. Kaplan-Meier curves with first derivative fitting explored dysphagia progression over the disease duration.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study found 77.0% of SCA3 patients had dysphagia, with disease duration most strongly linked to its onset (r\u0026thinsp;=\u0026thinsp;0.456, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Gender, age at onset, SARA scores, and disease duration were independent dysphagia risk factors (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 or 0.001). Dysphagia also affected SARA scores (p\u0026thinsp;=\u0026thinsp;0.048). Dysphagia progression rate peaks within the first decade of disease onset, reaching maximal velocity at 6.5 years, with a median time to dysphagia onset of 9 years\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn China, dysphagia frequently occurs in SCA3 patients and can impact the severity of ataxia. The prevalence of dysphagia varies as the disease advances. These findings highlight the importance of timely intervention for dysphagia in SCA3 patients, particularly during the late stages of the first decade.\u003c/p\u003e","manuscriptTitle":"Dysphagia Linked to Clinical Phenotype and Disease Progression in Spinocerebellar Ataxia Type 3","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 07:02:07","doi":"10.21203/rs.3.rs-6484743/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"20b2117b-7e6b-4b16-9941-84b17290f5be","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-05T15:38:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 07:02:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6484743","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6484743","identity":"rs-6484743","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}