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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Neurol.</journal-id>
<journal-title-group>
<journal-title>Frontiers in Neurology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Neurol.</abbrev-journal-title>
</journal-title-group>
<issn pub-type="epub">1664-2295</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fneur.2026.1827374</article-id>
<article-version article-version-type="Version of Record" vocab="NISO-RP-8-2008"/>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Original Research</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Associations of non-motor symptoms with perceptual speech impairments in Parkinson&#x2019;s disease</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Liu</surname>
<given-names>Rui</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x002A;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/3412255"/>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="conceptualization" vocab-term-identifier="https://credit.niso.org/contributor-roles/conceptualization/">Conceptualization</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Data curation" vocab-term-identifier="https://credit.niso.org/contributor-roles/data-curation/">Data curation</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Formal analysis" vocab-term-identifier="https://credit.niso.org/contributor-roles/formal-analysis/">Formal analysis</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="investigation" vocab-term-identifier="https://credit.niso.org/contributor-roles/investigation/">Investigation</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="methodology" vocab-term-identifier="https://credit.niso.org/contributor-roles/methodology/">Methodology</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; original draft" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-original-draft/">Writing &#x2013; original draft</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; review &#x0026; editing" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-review-editing/">Writing &#x2013; review &#x0026; editing</role>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Leydon</surname>
<given-names>Ciara</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/3438635"/>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="conceptualization" vocab-term-identifier="https://credit.niso.org/contributor-roles/conceptualization/">Conceptualization</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="investigation" vocab-term-identifier="https://credit.niso.org/contributor-roles/investigation/">Investigation</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; original draft" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-original-draft/">Writing &#x2013; original draft</role>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; review &#x0026; editing" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-review-editing/">Writing &#x2013; review &#x0026; editing</role>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label><institution>Department of Health Sciences, Sacred Heart University</institution>, <city>Fairfield</city>, <state>CT</state>, <country country="us">United States</country></aff>
<aff id="aff2"><label>2</label><institution>Department of Communication Disorders, Sacred Heart University</institution>, <city>Fairfield</city>, <state>CT</state>, <country country="us">United States</country></aff>
<author-notes>
<corresp id="c001"><label>&#x002A;</label>Correspondence: Rui Liu, <email xlink:href="mailto:liur3@sacredheart.edu">liur3@sacredheart.edu</email></corresp>
</author-notes>
<pub-date publication-format="electronic" date-type="pub" iso-8601-date="2026-06-24">
<day>24</day>
<month>06</month>
<year>2026</year>
</pub-date>
<pub-date publication-format="electronic" date-type="collection">
<year>2026</year>
</pub-date>
<volume>17</volume>
<elocation-id>1827374</elocation-id>
<history>
<date date-type="received">
<day>10</day>
<month>03</month>
<year>2026</year>
</date>
<date date-type="rev-recd">
<day>25</day>
<month>05</month>
<year>2026</year>
</date>
<date date-type="accepted">
<day>29</day>
<month>05</month>
<year>2026</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2026 Liu and Leydon.</copyright-statement>
<copyright-year>2026</copyright-year>
<copyright-holder>Liu and Leydon</copyright-holder>
<license>
<ali:license_ref start_date="2026-06-24">https://creativecommons.org/licenses/by/4.0/</ali:license_ref>
<license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License (CC BY)</ext-link>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>Communication impairments are common, multifaceted, and progressive symptoms of Parkinson&#x2019;s disease (PD), and have deleterious impacts on individual wellbeing. Self-awareness of communication impairments and the rate and extent of decline in speech skills vary substantially across individuals and are challenging to predict. To address these, we aimed to (1) evaluate associations between non-motor symptoms (NMS) and speech impairment at year seven and (2) compare the progression of self-perceived and examiner-rated speech impairment ratings scores across a seven-year follow-up period.</p>
</sec>
<sec>
<title>Method</title>
<p>The study included 417 PD participants from the Parkinson&#x2019;s Progression Marker Initiative. NMS were assessed using validated instruments covering sleep, olfaction, neurobehavioral, autonomic, and neuropsychological domains. Speech severity was measured using the Movement Disorder Society&#x2013;Unified Parkinson&#x2019;s Disease Rating Scale. Multivariate ordinal logistic regression examined associations between baseline NMS and speech severity at year seven. Changes in speech severity scores over seven years were analyzed using Friedman&#x2019;s test.</p>
</sec>
<sec>
<title>Results</title>
<p>Several NMS were associated with self-perceived and examiner-rated speech severity at year seven. Baseline REM sleep behavior disorder and autonomic dysfunction were associated with significantly higher odds of speech impairment at year seven. For self-perceived speech, odds ratios (OR) and 95% confidence interval (CI) were 1.58 (1.18&#x2013;2.12) for REM sleep behavior disorder and 1.71 (1.24&#x2013;2.36) for autonomic dysfunction. For examiner-rated speech, ORs were 1.45 (1.06&#x2013;1.98) and 1.71 (1.21&#x2013;2.42), respectively. Daytime sleepiness was associated with worse examiner-rated speech scores at year seven (OR&#x202F;=&#x202F;1.51, 95% CI 1.10&#x2013;2.09). Both self-perceived and examiner-rated speech impairments worsened over seven years (<italic>p</italic>&#x202F;&#x003C;&#x202F;0.001), with no significant differences between the two assessments (<italic>p</italic>&#x202F;&#x003E;&#x202F;0.05).</p>
</sec>
<sec>
<title>Conclusion</title>
<p>Several NMS were associated with worse speech ratings at year seven. These simple and readily accessible instruments may help identify individuals at greater risk of worsening speech skills, with the goal of enabling timely and targeted speech and language therapy. The consistency between self-perceived and examiner-rated speech scores suggests individuals with PD maintain good insight into their speech impairments, despite a decline in communication abilities.</p>
</sec>
</abstract>
<kwd-group>
<kwd>non-motor symptoms</kwd>
<kwd>Parkinson&#x2019;s disease</kwd>
<kwd>perceived speech impairment</kwd>
<kwd>PPMI (Parkinson&#x2019;s Progression Markers Initiative)</kwd>
<kwd>sex-differences</kwd>
</kwd-group>
<funding-group>
<funding-statement>The author(s) declared that financial support was not received for this work and/or its publication.</funding-statement>
</funding-group>
<counts>
<fig-count count="2"/>
<table-count count="3"/>
<equation-count count="0"/>
<ref-count count="33"/>
<page-count count="10"/>
<word-count count="6558"/>
</counts>
<custom-meta-group>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Movement Disorders</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="sec1">
<label>1</label>
<title>Introduction</title>
<p>Parkinson&#x2019;s disease (PD) is a common neurogenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and is associated with a broad range of motor and non-motor symptoms (NMS) (<xref ref-type="bibr" rid="ref1">1</xref>). One prevalent and challenging motor symptom is a decline in communication abilities, including speech skills (<xref ref-type="bibr" rid="ref2">2</xref>). At initial diagnosis, 40% of people with Parkinson&#x2019;s disease (PWPD) exhibit speech impairments (<xref ref-type="bibr" rid="ref3">3</xref>), typically hypokinetic dysarthria, characterized by impaired vocal quality, monopitch, monoloudness, and imprecise articulation causing poor speech intelligibility (<xref ref-type="bibr" rid="ref4">4</xref>). As the disease progresses, up to 90% of PWPD experience speech impairments (<xref ref-type="bibr" rid="ref5">5</xref>), with varying symptoms and phenotypes (<xref ref-type="bibr" rid="ref6">6</xref>). Given that speech is a multi-system complex sensorimotor process involving rapid, precise, coordinated respiratory, laryngeal, and vocal tract movements, multiple factors may contribute to worsening speech skills. Demographic factors, including age of onset and sex, have been associated with differential progression of motor symptoms and speech deficits (<xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref8">8</xref>). Recent studies have also reported a link between PD motor phenotype and both self-perceived and instrumental measures of speech (<xref ref-type="bibr" rid="ref9">9</xref>). However, predictors of a decline in speech remain elusive.</p>
<p>While motor symptoms of rigidity, bradykinesia, and tremor are hallmarks of a clinical diagnosis of PD, by the time these symptoms occur, extensive loss of nigrostriatal neurons has occurred (<xref ref-type="bibr" rid="ref1">1</xref>). Certain NMS, such as olfactory impairment and rapid eye movement sleep behavior disorder (RBD), may reflect these early neuropathological, preclinical changes (<xref ref-type="bibr" rid="ref1">1</xref>). Longitudinal epidemiologic studies have consistently shown that some NMS occur years, or even decades, before PD diagnosis and have been investigated as potential markers of prodromal PD (<xref ref-type="bibr" rid="ref10">10</xref>). For example, about 40% of PWPD present with a mild cognitive impairment at diagnosis of PD (<xref ref-type="bibr" rid="ref11">11</xref>, <xref ref-type="bibr" rid="ref12">12</xref>), with prevalence of cognitive impairment increasing over time. Similarly, depression can disrupt the rhythm of speech resulting in a monotone pitch or reduced loudness (<xref ref-type="bibr" rid="ref13">13</xref>), exacerbating the symptoms commonly associated with PD-related hypokinetic dysarthria. Other NMS, such as autonomic dysfunction and sleep behaviors have been reported to predict severity of examiner ratings of PD-related speech symptoms (<xref ref-type="bibr" rid="ref3">3</xref>). Since multiple NMS can be readily assessed using simple screeners or tests, it warrants consideration whether they could serve as potential predictors of speech impairment in PD.</p>
<p>Accurate self-perception of changes in speech skills is crucial for adjusting speech behaviors to achieve communicative success. Although PWPD frequently report speech difficulties, subjective assessment of their speech may differ in severity from that identified through clinical evaluation (<xref ref-type="bibr" rid="ref14">14</xref>). While longitudinal studies have reported worsening impairments in examiner-rated speech (<xref ref-type="bibr" rid="ref15">15</xref>, <xref ref-type="bibr" rid="ref16">16</xref>), few examined longitudinal changes in self-perceived speech function (<xref ref-type="bibr" rid="ref9">9</xref>). Further, only one study compared self-perceived and examiner-rated speech in PWPD. Pawlukowska et al. (<xref ref-type="bibr" rid="ref17">17</xref>) found that, while some correlation exists between subjective perception of speech severity and objective measures, PDWP did not perceive their speech disorders as having a significant impact on their quality of speech. This study, however, did not examine how self-perceived and objectively measured speech differs over time (<xref ref-type="bibr" rid="ref17">17</xref>). Comparing alignment between self-perceived and examiner-rated speech deficits over time could enhance our understanding of the evolution of speakers&#x2019; awareness of their functional speech impairments as speech symptoms progress. Given the paucity of existing research, the objectives of the current study were twofold: (1) to examine associations between baseline NMS and speech ratings at year seven, and whether these associations vary by sex, and (2) to compare the progression of self-perceived and examiner-rated speech impairment ratings scores across a seven-year follow-up period. Insights from the current study could help identify individuals at greater risk for speech impairments, with the ultimate goal of enabling timely and targeted speech and language therapeutic services.</p>
</sec>
<sec sec-type="materials|methods" id="sec2">
<label>2</label>
<title>Materials and methods</title>
<sec id="sec3">
<label>2.1</label>
<title>Data source and study participants</title>
<p>We used data from the Parkinson&#x2019;s Progression and Markers Initiative (PPMI), a longitudinal multicenter study that collects comprehensive demographic and clinical data aimed to explore markers of PD risk, onset and progression. Detailed PPMI protocol and methodology have been described elsewhere (<xref ref-type="bibr" rid="ref18">18</xref>).<xref ref-type="fn" rid="fn0001"><sup>1</sup></xref> Initial recruitment of the PPMI cohort began in 2010. During the initial enrollment phase, 423 newly diagnosed drug-na&#x00EF;ve PD patients met study inclusion criteria (<xref ref-type="bibr" rid="ref18">18</xref>) and underwent comprehensive assessments. Using the analytic cohort classification defined by the PPMI steering committee and excluding participants labeled &#x2018;not-PD&#x2019;, data for 417 PD participants aged 30&#x202F;years and older (average age 61.6&#x202F;&#x00B1;&#x202F;9.8&#x202F;years) were obtained for our study. Of those, 174 (42%) PD participants (121 male and 53 female) had complete speech assessments data from baseline through year 7 (&#x201C;completers&#x201D;). The remaining 243 participants (58%) were referred to as &#x201C;non-completers&#x201D; in the following analysis. All data for the current study were downloaded from the PPMI database<xref ref-type="fn" rid="fn0002"><sup>2</sup></xref> according to guidelines. Each participating PPMI site obtained written informed consent from all participants and received approval from an ethical standards committee. The data used in this study were fully de-identified and publicly available, and the study was exempted from ethical approval by the Sacred Heart University Institutional Review Board (IRB-FY2025-315).</p>
</sec>
<sec id="sec4">
<label>2.2</label>
<title>Demographics and clinical assessments</title>
<p>Demographic evaluations and comprehensive clinical examinations were performed by investigators at individual study sites. Motor functions were evaluated using the Movement Disorder Society-sponsored revision of the Unified Parkinson&#x2019;s Disease Rating Scale (MDS-UPDRS) Part III-motor ratings. Hoehn and Yahr staging was used to determine PD symptom progression and disease severity. For subtype stratification, we classified PD phenotype into tremor dominant, postural instability and gait disturbance, or intermediate-PD using previously published methods (<xref ref-type="bibr" rid="ref19">19</xref>).</p>
</sec>
<sec id="sec5">
<label>2.3</label>
<title>NMS assessments</title>
<p>NMS assessments at baseline included an extensive set of validated tests and questionnaires that examined five major areas of non-motor functions: sleep, olfaction, neurobehavioral, autonomic function, and cognition (<xref ref-type="supplementary-material" rid="SM1">Supplementary Table S1</xref>). Sleep disturbance was evaluated by the Epworth Sleepiness Scale (ESS) and RBD Screening Questionnaire (RBDSQ). Olfaction was assessed by the University of Pennsylvania Smell Identification Test (UPSIT). Neurobehavioral assessments included the State&#x2013;Trait Anxiety Inventory (STAI) and the 15-item version of the Geriatric Depression Scale (GDS-15). Autonomic dysfunction was evaluated using the Scales for Outcomes in Parkinson&#x2019;s disease &#x2013; Autonomic (SCOPA-AUT). Cognition was evaluated with Montreal Cognitive Assessment (MoCA) as a global cognitive screening test, and a battery of validated neuropsychological tests evaluating four major cognitive domains: memory, visuospatial functions, working memory-executive functions, and attention-processing speed. A composite score was created for each cognitive domain with higher scores indicating better cognitive performance (<xref ref-type="supplementary-material" rid="SM1">Supplementary Table S1</xref>).</p>
</sec>
<sec id="sec6">
<label>2.4</label>
<title>Speech assessments</title>
<p>Speech assessment ratings were obtained using MDS-UPDRS Part-II.1 and Part III.1. The MDS-UPDRS Part II.1 elicited participant ratings of self-perceived speech difficulty over the past week on a 5-point scale ranging from 0&#x2013;4, with zero indicating normal speech and four indicating severe speech impairment. In MDS-UPDRS Part III.1, examiners rated participants&#x2019; speech and conversation abilities, also using a five-point scale.</p>
</sec>
<sec id="sec7">
<label>2.5</label>
<title>Statistical analysis</title>
<p>We presented means and standard deviations for continuous variables and proportions for categorical variables. To assess differences between groups, we performed the Mann&#x2013;Whitney U test for continuous demographic and clinical variables and Chi-square test for categorical variables. We examined potential associations between NMS and self-perceived and examiner-rated speech impairment ratings at year seven using multivariate ordinal logistic regression models. All NMS variables were standardized to z-scores to make the <italic>&#x03B2;</italic> coefficient and odds ratios directly comparable across symptoms. All models were adjusted for age, sex, race, education, disease duration, UPDRS III motor scores, and H&#x0026;Y stage. We conducted subgroup analyses by sex. Longitudinal changes in self-perceived and examiner-rated speech severity scores across baseline and seven subsequent visits were analyzed using Friedman&#x2019;s repeated measures analysis of variance (ANOVA) tests. We further conducted Wilcoxon signed-rank tests with Bonferroni correction to compare differences between self-perceived and examiner-rated speech ratings at each visit over the 7-year follow-up. To examine whether longitudinal speech trajectories differed by sex, ordinal generalized estimating equation (GEE) models were conducted separately for repeated measurements of self-perceived and examiner-rated speech severity scores collected across follow-up visits. Statistical analyses were carried out using SAS, version 9.4 (SAS Institute Inc., Cary, NC) and IBM SPSS Statistics 29 (IBM Corp, Armonk, NY) and. All statistical tests were 2-sided with a significance level of with <italic>&#x03B1;</italic>&#x202F;=&#x202F;0.05.</p>
</sec>
</sec>
<sec sec-type="results" id="sec8">
<label>3</label>
<title>Results</title>
<sec id="sec9">
<label>3.1</label>
<title>Demographic characteristics</title>
<p>Baseline demographics and clinical characteristics were similar between completers and non-completers, except for disease severity. A significantly higher proportion of non-completers (61.3%) were in stage 2 of H&#x0026;Y compared to completers (47.7%), <italic>p</italic>&#x202F;=&#x202F;0.02. Demographic and general clinical characteristics of PD cases are summarized in <xref ref-type="table" rid="tab1">Table 1</xref> by sex. Male and female patients were comparable in baseline demographics and most clinical motor presentations, including self-perceived and examiner-rated speech ratings. However, among completers, male cases were more likely to have reported bradykinesia at diagnosis (<italic>p</italic>&#x202F;=&#x202F;0.03). Baseline global cognition was significantly lower among male patients compared to female patients (<italic>p</italic>&#x202F;=&#x202F;0.005).</p>
<table-wrap position="float" id="tab1">
<label>Table 1</label>
<caption>
<p>Demographic and clinical characteristics of PD patients at enrollment, by sex.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Characteristics</th>
<th align="center" valign="top" colspan="2">Enrolled (<italic>N</italic> =&#x202F;417)</th>
<th/>
<th align="center" valign="top" colspan="2">Completers<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref> (<italic>N</italic> =&#x202F;174)</th>
<th/>
</tr>
<tr>
<th/>
<th align="center" valign="top">Male (<italic>N</italic> =&#x202F;273)</th>
<th align="center" valign="top">Female (<italic>N</italic> =&#x202F;144)</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn2"><sup>b</sup></xref></th>
<th align="center" valign="top">Male (<italic>N</italic> =&#x202F;121)</th>
<th align="center" valign="top">Female (<italic>N</italic> =&#x202F;53)</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn2"><sup>b</sup></xref></th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top">Age at enrollment, y</td>
<td align="center" valign="middle">62.1 (9.8)</td>
<td align="center" valign="top">60.7 (9.7)</td>
<td align="center" valign="top">0.08</td>
<td align="center" valign="top">61.3 (10.0)</td>
<td align="center" valign="middle">59.0 (9.2)</td>
<td align="center" valign="top">0.09</td>
</tr>
<tr>
<td align="left" valign="top">Race, % white</td>
<td align="center" valign="top">96.0</td>
<td align="center" valign="top">94.4</td>
<td align="center" valign="top">0.48</td>
<td align="center" valign="top">98.4</td>
<td align="center" valign="top">96.2</td>
<td align="center" valign="top">0.39</td>
</tr>
<tr>
<td align="left" valign="top">Education, y</td>
<td align="center" valign="top">15.7 (2.9)</td>
<td align="center" valign="top">15.3 (3.1)</td>
<td align="center" valign="top">0.11</td>
<td align="center" valign="top">15.7 (3.0)</td>
<td align="center" valign="top">15.1 (2.7)</td>
<td align="center" valign="top">0.08</td>
</tr>
<tr>
<td align="left" valign="top">Disease duration, mo</td>
<td align="center" valign="top">6.2 (5.9)</td>
<td align="center" valign="top">7.1 (7.5)</td>
<td align="center" valign="top">0.49</td>
<td align="center" valign="top">6.4 (6.2)</td>
<td align="center" valign="top">6.6 (6.8)</td>
<td align="center" valign="top">0.66</td>
</tr>
<tr>
<td align="left" valign="top">Global cognition</td>
<td align="center" valign="top">26.9 (2.3)</td>
<td align="center" valign="top">27.6 (2.2)</td>
<td align="center" valign="top"><bold>0.004</bold></td>
<td align="center" valign="top">26.8 (2.3)</td>
<td align="center" valign="top">27.6 (2.5)</td>
<td align="center" valign="top"><bold>0.005</bold></td>
</tr>
<tr>
<td align="left" valign="top">Tremor at diagnosis, %</td>
<td align="center" valign="top">78.0</td>
<td align="center" valign="top">77.8</td>
<td align="center" valign="top">0.95</td>
<td align="center" valign="top">81.0</td>
<td align="center" valign="top">77.4</td>
<td align="center" valign="top">0.58</td>
</tr>
<tr>
<td align="left" valign="top">Rigidity at diagnosis, %</td>
<td align="center" valign="top">78.8</td>
<td align="center" valign="top">70.1</td>
<td align="center" valign="top">0.14</td>
<td align="center" valign="top">82.6</td>
<td align="center" valign="top">69.8</td>
<td align="center" valign="top">0.10</td>
</tr>
<tr>
<td align="left" valign="top">Bradykinesia at diagnosis, %</td>
<td align="center" valign="top">83.2</td>
<td align="center" valign="top">80.6</td>
<td align="center" valign="top">0.79</td>
<td align="center" valign="top">88.4</td>
<td align="center" valign="top">75.5</td>
<td align="center" valign="top"><bold>0.03</bold></td>
</tr>
<tr>
<td align="left" valign="top">Postural instability at diagnosis, %</td>
<td align="center" valign="top">7.0</td>
<td align="center" valign="top">6.9</td>
<td align="center" valign="top">0.34</td>
<td align="center" valign="top">5.0</td>
<td align="center" valign="top">9.4</td>
<td align="center" valign="top">0.35</td>
</tr>
<tr>
<td align="left" valign="top">UPDRS Part III score</td>
<td align="center" valign="top">21.3 (9.1)</td>
<td align="center" valign="top">20.2 (8.4)</td>
<td align="center" valign="top">0.31</td>
<td align="center" valign="top">20.4 (8.9)</td>
<td align="center" valign="top">19.3 (8.2)</td>
<td align="center" valign="top">0.50</td>
</tr>
<tr>
<td align="left" valign="top">Hoehn and Yahr stage, median</td>
<td align="center" valign="top">2.0</td>
<td align="center" valign="top">2.0</td>
<td align="center" valign="top">0.59</td>
<td align="center" valign="top">2.0</td>
<td align="center" valign="top">1.0</td>
<td align="center" valign="top">0.46</td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">PD motor phenotype, %</th>
</tr>
<tr>
<td align="left" valign="top">TD</td>
<td align="center" valign="top">72.5</td>
<td align="center" valign="top">69.4</td>
<td align="center" valign="top">0.71</td>
<td align="center" valign="top">71.1</td>
<td align="center" valign="top">67.9</td>
<td align="center" valign="top">0.58</td>
</tr>
<tr>
<td align="left" valign="top">PIGD</td>
<td align="center" valign="top">16.9</td>
<td align="center" valign="top">20.1</td>
<td/>
<td align="center" valign="top">16.5</td>
<td align="center" valign="top">22.6</td>
<td/>
</tr>
<tr>
<td align="left" valign="top">IND</td>
<td align="center" valign="top">10.6</td>
<td align="center" valign="top">10.4</td>
<td/>
<td align="center" valign="top">12.4</td>
<td align="center" valign="top">9.4</td>
<td/>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>IND&#x202F;=&#x202F;intermediate; PD&#x202F;=&#x202F;Parkinson disease; PIGD&#x202F;=&#x202F;postural instability and gait disturbance; TD&#x202F;=&#x202F;tremor dominant; UPDRS&#x202F;=&#x202F;Unified Parkinson&#x2019;s Disease Rating Scale. Data are given as mean (SD) for continuous variables, and percentage (%) for categorical variables. Bold text indicates statistically significant (<italic>p</italic> &#x003C; 0.05).</p>
<fn id="tfn1">
<label>a</label>
<p>Completers are those among the enrolled cases who completed all annual speech assessments from baseline to year 7.</p>
</fn>
<fn id="tfn2">
<label>b</label>
<p>Based on Mann&#x2013;Whitney U test or Chi-square test.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="sec10">
<label>3.2</label>
<title>Associations of baseline NMS with self-perceived and examiner-rated speech severity</title>
<p>Associations between baseline demographic, motor, and non-motor factors with self- and examiner-rated speech impairment at year seven are shown in <xref ref-type="table" rid="tab2">Table 2</xref>. Males had significantly higher odds of experiencing greater self-perceived (odds ratio [OR]&#x202F;=&#x202F;2.12; 95% confidence interval [CI]: 1.13&#x2013;3.97) and examiner-rated (OR&#x202F;=&#x202F;3.43; 95% CI: 1.74&#x2013;6.80) speech impairment severity ratings at year seven. Several NMS measured at baseline were significantly associated with speech ratings in year seven (<xref ref-type="table" rid="tab2">Table 2</xref>). Each one-unit increase in baseline RBDSQ z-score was significantly associated with higher odds of severe self-perceived (OR&#x202F;=&#x202F;1.58, 95% CI: 1.18&#x2013;2.12) and examiner-rated (OR&#x202F;=&#x202F;1.45, 95% CI: 1.06&#x2013;1.98) speech impairment ratings. A unit increase in SCOPA-AUT was also associated with significantly higher self-perceived (OR&#x202F;=&#x202F;1.71, 95% CI: 1.24&#x2013;2.36) and examiner-rated (OR&#x202F;=&#x202F;1.71, 95% CI: 1.21&#x2013;2.42) speech impairment ratings. Additionally, higher baseline daytime sleepiness was strongly associated with higher examiner-rated speech severity rating at year seven (OR&#x202F;=&#x202F;1.51, 95% CI: 1.10&#x2013;2.09), but not with self-perceived speech severity. Baseline motor phenotype was not significantly associated with self-perceived or examiner-rated speech severity at year seven. Sensitivity analyses were conducted using delta scores from baseline to year 7 as the outcome to assess changes in speech severity over follow-up (<xref ref-type="supplementary-material" rid="SM2">Supplementary Table S2</xref>). Overall, the direction of associations was largely consistent with those observed in the primary analyses. Notably, higher baseline RBDSQ scores were associated with greater worsening in self-perceived speech severity over follow-up (<italic>&#x03B2;</italic>&#x202F;=&#x202F;0.19, 95% CI: 0.04&#x2013;0.34), but not with examiner-rated speech severity. No significant associations were observed between SCOPA-AUT and change in speech severity over follow-up.</p>
<table-wrap position="float" id="tab2">
<label>Table 2</label>
<caption>
<p>Associations of baseline demographic, NMS, and motor subtypes with speech severity rating at year 7.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Baseline variables</th>
<th align="center" valign="top" colspan="3">Self-perceived speech severity rating in year 7</th>
<th align="center" valign="top" colspan="3">Examiner-rated speech severity rating in year 7</th>
</tr>
<tr>
<th/>
<th align="center" valign="top">OR</th>
<th align="center" valign="top">95% CI</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></th>
<th align="center" valign="top">OR</th>
<th align="center" valign="top">95% CI</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></th>
</tr>
</thead>
<tbody>
<tr>
<th align="left" valign="top" colspan="7">Baseline demographics</th>
</tr>
<tr>
<td align="left" valign="top">Age</td>
<td align="center" valign="top">1.03</td>
<td align="center" valign="top">0.99&#x2013;1.06</td>
<td align="center" valign="top">0.07</td>
<td align="center" valign="top">1.03</td>
<td align="center" valign="top">0.99&#x2013;1.06</td>
<td align="center" valign="top">0.08</td>
</tr>
<tr>
<td align="left" valign="top">Sex (male vs. female)</td>
<td align="center" valign="top">2.12</td>
<td align="center" valign="top">1.13&#x2013;3.97</td>
<td align="center" valign="top"><bold>0.02</bold></td>
<td align="center" valign="top">3.43</td>
<td align="center" valign="top">1.74&#x2013;6.80</td>
<td align="center" valign="top"><bold>0.0004</bold></td>
</tr>
<tr>
<td align="left" valign="top">Race (white vs. other)</td>
<td align="center" valign="top">0.28</td>
<td align="center" valign="top">0.04&#x2013;1.73</td>
<td align="center" valign="top">0.17</td>
<td align="center" valign="top">0.13</td>
<td align="center" valign="top">0.02&#x2013;0.92</td>
<td align="center" valign="top"><bold>0.04</bold></td>
</tr>
<tr>
<td align="left" valign="top">Education</td>
<td align="center" valign="top">1.02</td>
<td align="center" valign="top">0.92&#x2013;1.12</td>
<td align="center" valign="top">0.76</td>
<td align="center" valign="top">0.88</td>
<td align="center" valign="top">0.79&#x2013;0.97</td>
<td align="center" valign="top"><bold>0.01</bold></td>
</tr>
<tr>
<td align="left" valign="top">Disease duration</td>
<td align="center" valign="top">0.97</td>
<td align="center" valign="top">0.92&#x2013;1.01</td>
<td align="center" valign="top">0.13</td>
<td align="center" valign="top">1.02</td>
<td align="center" valign="top">0.97&#x2013;1.07</td>
<td align="center" valign="top">0.49</td>
</tr>
<tr>
<td align="left" valign="top">UPDRS motor score</td>
<td align="center" valign="top">1.02</td>
<td align="center" valign="top">0.98&#x2013;1.06</td>
<td align="center" valign="top">0.32</td>
<td align="center" valign="top">1.04</td>
<td align="center" valign="top">0.99&#x2013;1.08</td>
<td align="center" valign="top">0.10</td>
</tr>
<tr>
<td align="left" valign="top">H&#x0026;Y stage</td>
<td align="center" valign="top">1.38</td>
<td align="center" valign="top">0.60&#x2013;2.16</td>
<td align="center" valign="top">0.69</td>
<td align="center" valign="top">1.53</td>
<td align="center" valign="top">0.77&#x2013;3.07</td>
<td align="center" valign="top">0.23</td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">Sleep disorder</th>
</tr>
<tr>
<td align="left" valign="top">Epworth sleepiness scale</td>
<td align="center" valign="top">1.27</td>
<td align="center" valign="top">0.95&#x2013;1.71</td>
<td align="center" valign="top">0.11</td>
<td align="center" valign="top">1.51</td>
<td align="center" valign="top">1.10&#x2013;2.09</td>
<td align="center" valign="top"><bold>0.01</bold></td>
</tr>
<tr>
<td align="left" valign="top">RBDSQ</td>
<td align="center" valign="top">1.58</td>
<td align="center" valign="top">1.18&#x2013;2.12</td>
<td align="center" valign="top"><bold>0.002</bold></td>
<td align="center" valign="top">1.45</td>
<td align="center" valign="top">1.06&#x2013;1.98</td>
<td align="center" valign="top"><bold>0.02</bold></td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">Olfactory</th>
</tr>
<tr>
<td align="left" valign="top">UPSIT</td>
<td align="center" valign="top">0.94</td>
<td align="center" valign="top">0.67&#x2013;1.33</td>
<td align="center" valign="top">0.74</td>
<td align="center" valign="top">1.42</td>
<td align="center" valign="top">0.97&#x2013;2.07</td>
<td align="center" valign="top">0.07</td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">Neurobehavioral</th>
</tr>
<tr>
<td align="left" valign="top">Total anxiety</td>
<td align="center" valign="top">1.02</td>
<td align="center" valign="top">0.77&#x2013;1.36</td>
<td align="center" valign="top">0.88</td>
<td align="center" valign="top">1.03</td>
<td align="center" valign="top">0.76&#x2013;1.41</td>
<td align="center" valign="top">0.84</td>
</tr>
<tr>
<td align="left" valign="top">State anxiety</td>
<td align="center" valign="top">0.94</td>
<td align="center" valign="top">0.71&#x2013;1.23</td>
<td align="center" valign="top">0.64</td>
<td align="center" valign="top">0.96</td>
<td align="center" valign="top">0.71&#x2013;1.29</td>
<td align="center" valign="top">0.78</td>
</tr>
<tr>
<td align="left" valign="top">Trait anxiety</td>
<td align="center" valign="top">1.14</td>
<td align="center" valign="top">0.85&#x2013;1.52</td>
<td align="center" valign="top">0.39</td>
<td align="center" valign="top">1.12</td>
<td align="center" valign="top">0.82&#x2013;1.53</td>
<td align="center" valign="top">0.46</td>
</tr>
<tr>
<td align="left" valign="top">Geriatric depression</td>
<td align="center" valign="top">0.93</td>
<td align="center" valign="top">0.72&#x2013;1.20</td>
<td align="center" valign="top">0.57</td>
<td align="center" valign="top">0.99</td>
<td align="center" valign="top">0.73&#x2013;1.35</td>
<td align="center" valign="top">0.95</td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">Cognitive domains<xref ref-type="table-fn" rid="tfn4"><sup>b</sup></xref></th>
</tr>
<tr>
<td align="left" valign="top">Global</td>
<td align="center" valign="top">0.93</td>
<td align="center" valign="top">0.72&#x2013;1.20</td>
<td align="center" valign="top">0.57</td>
<td align="center" valign="top">0.96</td>
<td align="center" valign="top">0.73&#x2013;1.27</td>
<td align="center" valign="top">0.79</td>
</tr>
<tr>
<td align="left" valign="top">Memory</td>
<td align="center" valign="top">0.91</td>
<td align="center" valign="top">0.58&#x2013;1.43</td>
<td align="center" valign="top">0.67</td>
<td align="center" valign="top">0.69</td>
<td align="center" valign="top">0.42&#x2013;1.13</td>
<td align="center" valign="top">0.14</td>
</tr>
<tr>
<td align="left" valign="top">Visuospatial</td>
<td align="center" valign="top">0.96</td>
<td align="center" valign="top">0.70&#x2013;1.32</td>
<td align="center" valign="top">0.80</td>
<td align="center" valign="top">0.82</td>
<td align="center" valign="top">0.58&#x2013;1.15</td>
<td align="center" valign="top">0.25</td>
</tr>
<tr>
<td align="left" valign="top">Working memory-executive</td>
<td align="center" valign="top">1.04</td>
<td align="center" valign="top">0.78&#x2013;1.40</td>
<td align="center" valign="top">0.82</td>
<td align="center" valign="top">1.05</td>
<td align="center" valign="top">0.76&#x2013;1.45</td>
<td align="center" valign="top">0.76</td>
</tr>
<tr>
<td align="left" valign="top">Attention-processing speed</td>
<td align="center" valign="top">0.83</td>
<td align="center" valign="top">0.60&#x2013;1.16</td>
<td align="center" valign="top">0.28</td>
<td align="center" valign="top">0.72</td>
<td align="center" valign="top">0.50&#x2013;1.03</td>
<td align="center" valign="top">0.07</td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">Autonomic</th>
</tr>
<tr>
<td align="left" valign="top">SCOPA-AUT</td>
<td align="center" valign="top">1.71</td>
<td align="center" valign="top">1.24&#x2013;2.36</td>
<td align="center" valign="top"><bold>0.001</bold></td>
<td align="center" valign="top">1.71</td>
<td align="center" valign="top">1.21&#x2013;2.42</td>
<td align="center" valign="top"><bold>0.003</bold></td>
</tr>
<tr>
<th align="left" valign="top" colspan="7">PD motor subtypes</th>
</tr>
<tr>
<td align="left" valign="top">PIGD vs. TD</td>
<td align="center" valign="top">1.29</td>
<td align="center" valign="top">0.62&#x2013;2.66</td>
<td align="center" valign="top">0.50</td>
<td align="center" valign="top">0.85</td>
<td align="center" valign="top">0.39&#x2013;1.87</td>
<td align="center" valign="top">0.68</td>
</tr>
<tr>
<td align="left" valign="top">IND vs. TD</td>
<td align="center" valign="top">1.05</td>
<td align="center" valign="top">0.42&#x2013;2.61</td>
<td align="center" valign="top">0.91</td>
<td align="center" valign="top">0.98</td>
<td align="center" valign="top">0.37&#x2013;2.62</td>
<td align="center" valign="top">0.96</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>CI&#x202F;=&#x202F;Confidence Interval; OR&#x202F;=&#x202F;Odds Ratio; IND&#x202F;=&#x202F;intermediate; PD&#x202F;=&#x202F;Parkinson disease; PIGD&#x202F;=&#x202F;postural instability and gait disturbance; TD&#x202F;=&#x202F;tremor dominant; UPDRS&#x202F;=&#x202F;Unified Parkinson&#x2019;s Disease Rating Scale. Bold text indicates statistically significant (<italic>p</italic> &#x003C; 0.05).</p>
<fn id="tfn3">
<label>a</label>
<p>Adjusted for age at baseline, race, education, disease duration, UPDRS III motor scores, and H&#x0026;Y stage.</p>
</fn>
<fn id="tfn4">
<label>b</label>
<p>The global domain included the Montreal cognitive assessment test. The memory domain included the immediate recall, delayed recall, and delayed recognition of the Hopkins verbal learning test&#x2013;revised. The visuospatial domain included the Benton judgment of line orientation. The working memory&#x2013;executive domain included the letter number sequencing and the semantic fluency&#x2013;animal tests. The attention processing speed included the symbol digit modalities test.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="sec11">
<label>3.3</label>
<title>Sex-specific associations of baseline NMS with self-perceived and examiner-rated speech severity</title>
<p>To examine potential sex-related differences in the association between baseline NMS and speech severity ratings at year seven, we further conducted stratified analyses by sex (<xref ref-type="table" rid="tab3">Table 3</xref>). For females with PD, each one-unit increase in Epworth Sleepiness Scale (OR&#x202F;=&#x202F;1.78, 95% CI: 1.00&#x2013;3.18) and SCOPA-AUT (OR&#x202F;=&#x202F;2.05, 95% CI: 1.12&#x2013;3.74) z-scores were associated with higher odds of more severe self-perceived speech ratings. In males with PD, higher baseline RBDSQ z-score was significantly associated with higher self-perceived speech severity rating (OR&#x202F;=&#x202F;1.51, 95% CI: 1.07&#x2013;2.12). For examiner-rated speech ratings, higher baseline RBDSQ z-score (OR&#x202F;=&#x202F;2.16, 95% CI: 0.99&#x2013;4.73) and UPSIT (OR: 2.37, 95% CI: 1.11&#x2013;5.05) were associated with higher odds of severe ratings in female PD patients. In contrast, higher baseline SCOPA-AUT z-scores were associated with higher odds severe examiner-rated speech ratings (OR&#x202F;=&#x202F;1.75, 95% CI: 1.12&#x2013;2.73) in male PD patients.</p>
<table-wrap position="float" id="tab3">
<label>Table 3</label>
<caption>
<p>Associations of NMS and motor subtypes with speech severity ratings at year 7, by sex.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top" rowspan="3">NMS and PD motor subtypes</th>
<th align="center" valign="top" colspan="6">Self-perceived speech severity rating in year 7</th>
<th align="center" valign="top" colspan="6">Examiner-rated speech severity rating in year 7</th>
<th align="center" valign="top" colspan="3">Male (<italic>N</italic> =&#x202F;121)</th>
<th align="center" valign="top" colspan="3">Female (<italic>N</italic> =&#x202F;53)</th>
<th align="center" valign="top" colspan="3">Male (<italic>N</italic> =&#x202F;121)</th>
<th align="center" valign="top" colspan="3">Female (<italic>N</italic> =&#x202F;53)</th>
<th align="center" valign="top">OR</th>
<th align="center" valign="top">95% CI</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn5"><sup>a</sup></xref></th>
<th align="center" valign="top">OR</th>
<th align="center" valign="top">95% CI</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn5"><sup>a</sup></xref></th>
<th align="center" valign="top">OR</th>
<th align="center" valign="top">95% CI</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn5"><sup>a</sup></xref></th>
<th align="center" valign="top">OR</th>
<th align="center" valign="top">95% CI</th>
<th align="center" valign="top"><italic>p</italic> value<xref ref-type="table-fn" rid="tfn5"><sup>a</sup></xref></th>
</tr>
</thead>
<tbody>
<tr>
<th align="left" valign="top" colspan="13">Sleep disorder</th>
</tr>
<tr>
<td align="left" valign="top">Epworth sleepiness scale</td>
<td align="center" valign="top">1.05</td>
<td align="center" valign="top">0.72&#x2013;1.54</td>
<td align="center" valign="top">0.793</td>
<td align="center" valign="top">1.78</td>
<td align="center" valign="top">1.00&#x2013;3.18</td>
<td align="center" valign="top"><bold>0.05</bold></td>
<td align="center" valign="top">1.35</td>
<td align="center" valign="top">0.89&#x2013;2.06</td>
<td align="center" valign="top">0.16</td>
<td align="center" valign="top">1.80</td>
<td align="center" valign="top">0.98&#x2013;3.32</td>
<td align="center" valign="top">0.06</td>
</tr>
<tr>
<td align="left" valign="top">RBDSQ</td>
<td align="center" valign="top">1.51</td>
<td align="center" valign="top">1.07&#x2013;2.12</td>
<td align="center" valign="top"><bold>0.02</bold></td>
<td align="center" valign="top">1.40</td>
<td align="center" valign="top">0.69&#x2013;2.83</td>
<td align="center" valign="top">0.35</td>
<td align="center" valign="top">1.22</td>
<td align="center" valign="top">0.84&#x2013;1.75</td>
<td align="center" valign="top">0.29</td>
<td align="center" valign="top">2.16</td>
<td align="center" valign="top">0.99&#x2013;4.73</td>
<td align="center" valign="top"><bold>0.05</bold></td>
</tr>
<tr>
<th align="left" valign="top" colspan="13">Olfactory</th>
</tr>
<tr>
<td align="left" valign="top">UPSIT</td>
<td align="center" valign="top">0.78</td>
<td align="center" valign="top">0.52&#x2013;1.18</td>
<td align="center" valign="top">0.2</td>
<td align="center" valign="top">1.32</td>
<td align="center" valign="top">0.67&#x2013;2.60</td>
<td align="center" valign="top">0.42</td>
<td align="center" valign="top">1.15</td>
<td align="center" valign="top">0.74&#x2013;1.80</td>
<td align="center" valign="top">0.54</td>
<td align="center" valign="top">2.37</td>
<td align="center" valign="top">1.11&#x2013;5.05</td>
<td align="center" valign="top"><bold>0.03</bold></td>
</tr>
<tr>
<th align="left" valign="top" colspan="13">Neurobehavioral</th>
</tr>
<tr>
<td align="left" valign="top">Total anxiety</td>
<td align="center" valign="top">0.13</td>
<td align="center" valign="top">0.51&#x2013;0.48</td>
<td align="center" valign="top">0.48</td>
<td align="center" valign="top">0.89</td>
<td align="center" valign="top">0.52&#x2013;1.54</td>
<td align="center" valign="top">0.68</td>
<td align="center" valign="top">1.13</td>
<td align="center" valign="top">0.78&#x2013;1.65</td>
<td align="center" valign="top">0.52</td>
<td align="center" valign="top">0.89</td>
<td align="center" valign="top">0.51&#x2013;1.55</td>
<td align="center" valign="top">0.68</td>
</tr>
<tr>
<td align="left" valign="top">State anxiety</td>
<td align="center" valign="top">1.05</td>
<td align="center" valign="top">0.75&#x2013;1.45</td>
<td align="center" valign="top">0.79</td>
<td align="center" valign="top">0.79</td>
<td align="center" valign="top">0.47&#x2013;1.36</td>
<td align="center" valign="top">0.40</td>
<td align="center" valign="top">1.07</td>
<td align="center" valign="top">0.75&#x2013;1.54</td>
<td align="center" valign="top">0.71</td>
<td align="center" valign="top">0.77</td>
<td align="center" valign="top">0.45&#x2013;1.34</td>
<td align="center" valign="top">0.36</td>
</tr>
<tr>
<td align="left" valign="top">Trait anxiety</td>
<td align="center" valign="top">1.24</td>
<td align="center" valign="top">0.86&#x2013;1.78</td>
<td align="center" valign="top">0.25</td>
<td align="center" valign="top">1.05</td>
<td align="center" valign="top">0.63&#x2013;1.74</td>
<td align="center" valign="top">0.86</td>
<td align="center" valign="top">1.18</td>
<td align="center" valign="top">0.80&#x2013;1.75</td>
<td align="center" valign="top">0.41</td>
<td align="center" valign="top">1.09</td>
<td align="center" valign="top">0.64&#x2013;1.83</td>
<td align="center" valign="top">0.76</td>
</tr>
<tr>
<td align="left" valign="top">Geriatric depression</td>
<td align="center" valign="top">0.91</td>
<td align="center" valign="top">0.64&#x2013;1.30</td>
<td align="center" valign="top">0.61</td>
<td align="center" valign="top">0.82</td>
<td align="center" valign="top">0.45&#x2013;1.48</td>
<td align="center" valign="top">0.50</td>
<td align="center" valign="top">1.05</td>
<td align="center" valign="top">0.71&#x2013;1.55</td>
<td align="center" valign="top">0.82</td>
<td align="center" valign="top">0.90</td>
<td align="center" valign="top">0.51&#x2013;1.58</td>
<td align="center" valign="top">0.71</td>
</tr>
<tr>
<th align="left" valign="top" colspan="13">Cognitive domains<xref ref-type="table-fn" rid="tfn6"><sup>b</sup></xref></th>
</tr>
<tr>
<td align="left" valign="top">Global</td>
<td align="center" valign="top">0.95</td>
<td align="center" valign="top">0.69&#x2013;1.31</td>
<td align="center" valign="top">0.74</td>
<td align="center" valign="top">0.91</td>
<td align="center" valign="top">0.58&#x2013;1.43</td>
<td align="center" valign="top">0.69</td>
<td align="center" valign="top">1.11</td>
<td align="center" valign="top">0.78&#x2013;1.58</td>
<td align="center" valign="top">0.56</td>
<td align="center" valign="top">0.70</td>
<td align="center" valign="top">0.43&#x2013;1.16</td>
<td align="center" valign="top">0.17</td>
</tr>
<tr>
<td align="left" valign="top">Memory</td>
<td align="center" valign="top">0.93</td>
<td align="center" valign="top">0.55&#x2013;1.59</td>
<td align="center" valign="top">0.80</td>
<td align="center" valign="top">1.09</td>
<td align="center" valign="top">0.42&#x2013;2.82</td>
<td align="center" valign="top">0.87</td>
<td align="center" valign="top">0.77</td>
<td align="center" valign="top">0.43&#x2013;1.38</td>
<td align="center" valign="top">0.38</td>
<td align="center" valign="top">0.61</td>
<td align="center" valign="top">0.23&#x2013;1.64</td>
<td align="center" valign="top">0.33</td>
</tr>
<tr>
<td align="left" valign="top">Visuospatial</td>
<td align="center" valign="top">0.95</td>
<td align="center" valign="top">0.65&#x2013;1.40</td>
<td align="center" valign="top">0.80</td>
<td align="center" valign="top">0.94</td>
<td align="center" valign="top">0.51&#x2013;1.74</td>
<td align="center" valign="top">0.84</td>
<td align="center" valign="top">0.83</td>
<td align="center" valign="top">0.54&#x2013;1.26</td>
<td align="center" valign="top">0.38</td>
<td align="center" valign="top">0.72</td>
<td align="center" valign="top">0.38&#x2013;1.37</td>
<td align="center" valign="top">0.32</td>
</tr>
<tr>
<td align="left" valign="top">Working memory-executive</td>
<td align="center" valign="top">1.08</td>
<td align="center" valign="top">0.76&#x2013;1.53</td>
<td align="center" valign="top">0.67</td>
<td align="center" valign="top">0.98</td>
<td align="center" valign="top">0.53&#x2013;1.84</td>
<td align="center" valign="top">0.96</td>
<td align="center" valign="top">1.07</td>
<td align="center" valign="top">0.74&#x2013;1.56</td>
<td align="center" valign="top">0.71</td>
<td align="center" valign="top">1.12</td>
<td align="center" valign="top">0.59&#x2013;2.14</td>
<td align="center" valign="top">0.73</td>
</tr>
<tr>
<td align="left" valign="top">Attention-processing speed</td>
<td align="center" valign="top">0.85</td>
<td align="center" valign="top">0.57&#x2013;1.27</td>
<td align="center" valign="top">0.44</td>
<td align="center" valign="top">0.83</td>
<td align="center" valign="top">0.42&#x2013;1.61</td>
<td align="center" valign="top">0.57</td>
<td align="center" valign="top">0.79</td>
<td align="center" valign="top">0.51&#x2013;1.23</td>
<td align="center" valign="top">0.30</td>
<td align="center" valign="top">0.66</td>
<td align="center" valign="top">0.32&#x2013;1.34</td>
<td align="center" valign="top">0.25</td>
</tr>
<tr>
<th align="left" valign="top" colspan="13">Autonomic</th>
</tr>
<tr>
<td align="left" valign="top">SCOPA-AUT</td>
<td align="center" valign="top">1.46</td>
<td align="center" valign="top">0.98&#x2013;2.19</td>
<td align="center" valign="top">0.07</td>
<td align="center" valign="top">2.05</td>
<td align="center" valign="top">1.12&#x2013;3.74</td>
<td align="center" valign="top"><bold>0.02</bold></td>
<td align="center" valign="top">1.75</td>
<td align="center" valign="top">1.12&#x2013;2.73</td>
<td align="center" valign="top"><bold>0.01</bold></td>
<td align="center" valign="top">1.55</td>
<td align="center" valign="top">0.8&#x2013;2.89</td>
<td align="center" valign="top">0.16</td>
</tr>
<tr>
<th align="left" valign="top" colspan="13">PD motor subtypes</th>
</tr>
<tr>
<td align="left" valign="top">PIGD vs. TD</td>
<td align="center" valign="top">2.16</td>
<td align="center" valign="top">0.86&#x2013;5.40</td>
<td align="center" valign="top">0.10</td>
<td align="center" valign="top">0.37</td>
<td align="center" valign="top">0.09&#x2013;1.57</td>
<td align="center" valign="top">0.18</td>
<td align="center" valign="top">0.98</td>
<td align="center" valign="top">0.37&#x2013;2.63</td>
<td align="center" valign="top">0.97</td>
<td align="center" valign="top">0.72</td>
<td align="center" valign="top">0.19&#x2013;2.81</td>
<td align="center" valign="top">0.64</td>
</tr>
<tr>
<td align="left" valign="top">IND vs. TD</td>
<td align="center" valign="top">1.84</td>
<td align="center" valign="top">0.64&#x2013;5.24</td>
<td align="center" valign="top">0.26</td>
<td align="center" valign="top">0.06</td>
<td align="center" valign="top">0.01&#x2013;0.86</td>
<td align="center" valign="top"><bold>0.04</bold></td>
<td align="center" valign="top">0.99</td>
<td align="center" valign="top">0.32&#x2013;3.07</td>
<td align="center" valign="top">0.98</td>
<td align="center" valign="top">0.57</td>
<td align="center" valign="top">0.07&#x2013;4.43</td>
<td align="center" valign="top">0.59</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>CI&#x202F;=&#x202F;Confidence Interval; NMS&#x202F;=&#x202F;non-motor symptoms; OR&#x202F;=&#x202F;Odds Ratio; IND&#x202F;=&#x202F;intermediate; PD&#x202F;=&#x202F;Parkinson disease; PIGD&#x202F;=&#x202F;postural instability and gait disturbance; TD&#x202F;=&#x202F;tremor dominant; UPDRS&#x202F;=&#x202F;Unified Parkinson&#x2019;s Disease Rating Scale. Bold text indicates statistically significant (<italic>p</italic> &#x003C; 0.05).</p>
<fn id="tfn5">
<label>a</label>
<p>Adjusted for age at baseline, race, education, disease duration, UPDRS III motor scores, and H&#x0026;Y stage.</p>
</fn>
<fn id="tfn6">
<label>b</label>
<p>The global domain included the Montreal cognitive assessment test. The memory domain included the immediate recall, delayed recall, and delayed recognition of the Hopkins verbal learning test&#x2013;revised. The visuospatial domain included the Benton judgment of line orientation. The working memory&#x2013;executive domain included the letter number sequencing and the semantic fluency&#x2013;animal tests. The attention processing speed included the symbol digit modalities test.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="sec12">
<label>3.4</label>
<title>Comparisons between self-perceived and examiner-rated speech severity</title>
<p>Friedman&#x2019;s repeated measures test showed a significant difference in speech severity across the seven visits for both self-perceived (&#x03C7;<sup>2</sup>&#x202F;=&#x202F;140.77, <italic>p</italic>&#x202F;&#x003C;&#x202F;0.001) and examiner-rated ratings (&#x03C7;<sup>2</sup>&#x202F;=&#x202F;98.77, <italic>p</italic>&#x202F;&#x003C;&#x202F;0.001). <xref ref-type="fig" rid="fig1">Figure 1</xref> shows the progression of self-perceived and examiner-rated speech severity ratings at baseline and across a seven-year period. Self-perceived and examiner-rated speech impairment severity ratings were similar at baseline and years 1 to 5, but significantly higher self-perceived ratings at year six (<italic>p</italic>&#x202F;=&#x202F;0.013) and seven (<italic>p</italic>&#x202F;=&#x202F;0.013). However, after Bonferroni correction (<italic>p</italic>&#x202F;&#x003C;&#x202F;0.006) was applied to account for multiple comparisons, no statistically significant pairwise differences remained.</p>
<fig position="float" id="fig1">
<label>Figure 1</label>
<caption>
<p>Self-perceived and examiner-rated speech severity ratings in Parkinson&#x2019;s disease across a 7-year period from baseline. Error bars represent 95% confidence intervals.</p>
</caption>
<graphic xlink:href="fneur-17-1827374-g001.tif" mimetype="image" mime-subtype="tiff">
<alt-text content-type="machine-generated">Line graph comparing self-perceived and examiner-rated speech severity scores over time from baseline to year seven. Self-perceived and examiner-rated speech impairment severity ratings are similar at baseline and years one to five, but significantly higher self-perceived ratings at year six and seven. Error bars represent ninety-five percent confidence intervals.</alt-text>
</graphic>
</fig>
</sec>
<sec id="sec13">
<label>3.5</label>
<title>Sex-stratified speech severity trajectories across follow-up</title>
<p>Analyses of sex-specific speech severity trajectories over the seven-year follow-up period revealed differential patterns for self-perceived and examiner-rated speech ratings (<xref ref-type="fig" rid="fig2">Figure 2</xref>). For self-perceived speech severity, similar longitudinal trajectories were observed between males and females (Wald &#x03C7;<sup>2</sup>&#x202F;=&#x202F;1.74, <italic>p-interaction</italic>&#x202F;=&#x202F;0.973), with both groups showing a comparable gradual increase in self-perceived speech severity across follow-up visits (<xref ref-type="fig" rid="fig2">Figure 2A</xref>). In contrast, a statistically significant sex difference was observed in examiner-rated speech severity trajectories over the follow-up period (Wald &#x03C7;<sup>2</sup>&#x202F;=&#x202F;18.94, <italic>p-interaction</italic>&#x202F;=&#x202F;0.008), with males showing a greater increase in speech severity over time compared to females (<xref ref-type="fig" rid="fig2">Figure 2B</xref>).</p>
<fig position="float" id="fig2">
<label>Figure 2</label>
<caption>
<p>Sex-stratified self-perceived and examiner-rated speech severity ratings in Parkinson&#x2019;s disease across a 7-year period from baseline. <bold>(A)</bold> Self-perceived speech severity ratings. <bold>(B)</bold> Examiner-rated speech severity ratings. Error bars represent 95% confidence intervals.</p>
</caption>
<graphic xlink:href="fneur-17-1827374-g002.tif" mimetype="image" mime-subtype="tiff">
<alt-text content-type="machine-generated">Two line graphs compare speech severity for males and females from baseline to year seven. Panel A shows self-perceived speech severity ratings, and Panel B shows examiner-rated speech severity ratings. In Panel A, both males and females show a similar, gradual increase in self-perceived speech severity over time. In Panel B, males show a greater increase in examiner-rated speech severity over time compared to females. Error bars represent 95% confidence intervals.</alt-text>
</graphic>
</fig>
</sec>
</sec>
<sec sec-type="discussion" id="sec14">
<label>4</label>
<title>Discussion</title>
<p>This study examined the longitudinal progression of perceptual speech impairments in PWPD and the role of early NMS in relation to speech severity at year seven. Several baseline NMS, including RBD and autonomic dysfunction, were significantly associated with worse speech severity at year seven, with notable sex differences observed. Both self-perceived and examiner-rated speech severity progressively worsened over time in a parallel pattern, showing strong agreement between the two assessments.</p>
<p>In the present study, significant sex differences in self-perceived and examiner-rated speech severity ratings were observed among completers, with males having higher odds of worsening speech severity at year seven. While the neuropathological mechanisms underlying sex differences remain unclear, prior research has suggested that males have a higher prevalence of non-tremor dominant motor phenotype than females (<xref ref-type="bibr" rid="ref20">20</xref>), which, has been associated with more severe speech impairments (<xref ref-type="bibr" rid="ref21">21</xref>, <xref ref-type="bibr" rid="ref22">22</xref>). Although we did not observe an association between PD motor phenotype and speech impairment severity, prior studies have reported that speech impairments are more common in patients with an akinetic-rigid dominant motor subtype (<xref ref-type="bibr" rid="ref3">3</xref>) and more pronounced in those with a postural instability and gait difficulty subtype (<xref ref-type="bibr" rid="ref22">22</xref>), compared to patients with a tremor-dominant subtype. In our study, the tremor-dominant phenotype was the most common motor subtype in both males and females. Further research is needed better understand the interplay between sex and motor phenotype in predicting speech severity and progression in PD.</p>
<p>NMS, such as REM sleep behavior disorder, daytime sleepiness, and depression, often precede motor symptoms (<xref ref-type="bibr" rid="ref23">23</xref>) and contribute significantly to disability (<xref ref-type="bibr" rid="ref12">12</xref>). In the present study, greater baseline RBD and autonomic dysfunction symptoms were associated with worse self-perceived and examiner-rated speech severity at year seven. In contrast, higher baseline daytime sleepiness was associated with worse examiner-rated speech scores at year seven but was not related to self-perceived speech severity. Notably, these associations appeared to differ by sex. Higher RBD scores were associated with worse self-perceived speech ratings in males but not females, whereas in females, RBD symptoms were associated with worse examiner-rated speech severity. Additionally, greater autonomic dysfunction at baseline was linked to higher self-perceived speech severity ratings in females but higher examiner-rated severity in males.</p>
<p>The relationship between early NMS and PD progression remains complex. RBD and autonomic dysfunction have been increasingly recognized as markers of a more severe PD phenotype (<xref ref-type="bibr" rid="ref24 ref25 ref26">24&#x2013;26</xref>). Autonomic dysfunction, in particular, has been shown to be a stronger predictor of disease progression than RBD, and the co-occurrence of these symptoms has been associated with more severe motor and non-motor symptom profiles, possibly resulting from widespread <italic>&#x03B1;</italic>-synuclein pathology (<xref ref-type="bibr" rid="ref25">25</xref>). In addition, recent evidence suggests that RBD is associated with more widespread and symmetric neurodegeneration involving both nigrostriatal and brainstem neurotransmitter systems (<xref ref-type="bibr" rid="ref26">26</xref>). Our findings that baseline RBD and autonomic dysfunction were associated with worse speech impairments at year seven may therefore reflect the impact of widespread neurodegeneration on multiple neural systems involved in speech production (<xref ref-type="bibr" rid="ref27">27</xref>). Moreover, previous studies have also found that PWPD with speech impairments at baseline exhibit significantly greater autonomic dysfunction, RBD symptoms, and daytime sleepiness (<xref ref-type="bibr" rid="ref3">3</xref>). Finally, while depression can negatively impact speech acoustics and prosody, and is more prevalent in PWPD than in healthy controls (<xref ref-type="bibr" rid="ref12">12</xref>), it was not significantly associated with speech ratings at baseline in our study and did not predict worsening speech severity over time. Future longitudinal studies are needed to elucidate the underlying mechanisms of these associations and to determine whether combinations of NMS can better identify individuals at risk for worse speech outcomes over time.</p>
<p>Self-awareness of speech deficits is important for timely identification of a need for speech therapy. In the present study, self-perceived speech impairment in PWPD worsened over a seven-year period, extending previous findings that indicate a mild but progressive decline in speech self-perception ratings among individuals newly diagnosed with PD (<xref ref-type="bibr" rid="ref9">9</xref>). A similar pattern was observed in examiner-rated speech impairment, showing strong agreement between the two assessments. This suggests that PWPD maintain good insight into the overall severity of their speech deficits. Elucidating the ability of PWPD to accurately self-assess their speech skills has been the target of several studies, with mixed results. Contreras-Ruston et al. (<xref ref-type="bibr" rid="ref28">28</xref>) found that PWPD, despite exhibiting reduced loudness, self-reported fewer voice symptoms than individuals with other voice disorders when assessed using a validated questionnaire. In contrast, another study found that individuals with early to mild stage PD who accurately rated their own speech samples reported lower articulation and speech intelligibility scores compared to healthy controls in supported tasks (<xref ref-type="bibr" rid="ref29">29</xref>). Furthermore, PWPD has been shown to effectively self-identify speech impairment using a tailored screening tool (<xref ref-type="bibr" rid="ref21">21</xref>). Differences in findings across studies may be attributable to the complex nature of PD-related symptoms (<xref ref-type="bibr" rid="ref28">28</xref>), as well as variability in rating tasks (<xref ref-type="bibr" rid="ref29">29</xref>) and instruments used for speech assessment.</p>
<p>In the current study, cognition at baseline did not predict self-perceived or examiner-rated speech impairment severity ratings over time. This lack of relationship between cognition and speech impairments contrasts with previous findings. For example, Polychronis et al. (<xref ref-type="bibr" rid="ref3">3</xref>) observed that presence of observer-perceived speech impairment in <italic>de novo</italic> PWPD predicted cognitive impairment three years later. Similarly, Rektorov&#x00E1; et al. (<xref ref-type="bibr" rid="ref30">30</xref>) noted that impaired speech prosody in individuals diagnosed with mild to moderate PD predicted worsening cognition two years later. The lack of significant findings in the present study may be attributable to differences in study methodology.</p>
<p>Our study has several notable strengths including the use of longitudinal PD cohort data. The large sample size of newly diagnosed PD patients allowed for meaningful sex-specific analyses and between group comparisons. Furthermore, the assessment of a wide range of NMS assessed at baseline, using validated instruments, offered a unique opportunity for us to examine multiple NMS simultaneously in relation to speech progression in subsequent years. Nevertheless, this study has several limitations. First, objective neurophysiological assessments of NMS, such as polysomnography (PSG), the gold standard for the diagnosis of RBD, and autonomic reflex testing for autonomic dysfunction, were not available in the PPMI cohort. Future studies incorporating such objective assessments may provide a more precise characterization of these non-motor symptoms. Second, speech impairments were evaluated based on perceptual judgments using individual item rating scores from the MDS-UPDRS. Speech acoustic data, or other objective measures, were not available. While perceptual measures are important components when developing a profile of speech abilities, speech acoustic or other objectives measures are typically gathered to complement the subjective ratings. Third, in the present study, examiners are instructed to rate &#x201C;modulation, diction of volume&#x201D; (MDS-UPDRS 3.1). These terms are broad, and may be perceived differently by speakers, and inter-rater agreement on ratings is unknown. Indeed, inter-rater and intra-rater reliability in judgement of voice depends upon terms used (<xref ref-type="bibr" rid="ref31">31</xref>), even among trained listeners. Forth, the prompt for examiner ratings of speech differs from the prompt provided to PWPD for self-rating of speech (MDS-UPDRS 2.1). The latter requires the PWPD to indicate whether or not they experienced a problem with speech over the past week. While both prompts elicit judgments of speech, due to differences in wording, caution must be taken when comparing ratings. Additionally, differences in interpretation of instructions for eliciting a speech sample may impact ratings (<xref ref-type="bibr" rid="ref32">32</xref>). Fifth, medication status was not available for all participants at all visits. Consequently, we could not control for &#x201C;on&#x201D;/ &#x201C;off&#x201D; status in the analysis. However, previous studies have shown that the decline in speech motor function is only weakly correlated with motor changes and is largely unaffected by dopaminergic treatment (<xref ref-type="bibr" rid="ref33">33</xref>). Finally, the PPMI cohort comprises predominantly white volunteers, which limits the generalizability of findings. However, the clinical characteristics of PPMI patients are typical of general patients with PD, and the PPMI investigators&#x2019; commitment to detailed clinical examinations ensures high-quality data collection.</p>
</sec>
<sec sec-type="conclusions" id="sec15">
<label>5</label>
<title>Conclusion</title>
<p>Our findings suggest that certain NMS, particularly REM sleep behavior disorder and autonomic dysfunction, are associated with greater perceived speech impairments, with notable differences observed by sex. Both self-perceived and examiner-rated speech impairment severity worsened over time and remained largely consistent. Future studies should further explore factors influencing perceived speech decline to identify candidates who may benefit from early speech interventions aimed at preserving communication skills and quality of life.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="sec16">
<title>Data availability statement</title>
<p>Publicly available datasets were analyzed in this study. This data can be found here: <ext-link xlink:href="https://www.ppmi-info.org/access-data-specimens/download-data" ext-link-type="uri">https://www.ppmi-info.org/access-data-specimens/download-data</ext-link>.</p>
</sec>
<sec sec-type="ethics-statement" id="sec17">
<title>Ethics statement</title>
<p>All participating PPMI clinical sites received approval from an ethical standards committee prior to study initiation (the full list of participating PPMI clinical sites is available in the <xref ref-type="sec" rid="sec22">Supplementary Material</xref>). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.</p>
</sec>
<sec sec-type="author-contributions" id="sec18">
<title>Author contributions</title>
<p>RL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing &#x2013; original draft, Writing &#x2013; review &#x0026; editing. CL: Conceptualization, Investigation, Writing &#x2013; original draft, Writing &#x2013; review &#x0026; editing.</p>
</sec>
<ack>
<title>Acknowledgments</title>
<p>Data used in the preparation of this article were obtained from the Parkinson&#x2019;s Progression Markers Initiative (PPMI) database (<ext-link xlink:href="http://www.ppmi-info.org/access-dataspecimens/download-data" ext-link-type="uri">www.ppmi-info.org/access-dataspecimens/download-data</ext-link>), RRID:SCR_006431. For up-to-date information on the study, visit <ext-link xlink:href="http://www.ppmi-info.org" ext-link-type="uri">www.ppmi-info.org</ext-link>. PPMI&#x2014;a public-private partnership&#x2014;is funded by the Michael J. Fox Foundation for Parkinson&#x2019;s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson&#x2019;s, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson &#x0026; Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.</p>
</ack>
<sec sec-type="COI-statement" id="sec19">
<title>Conflict of interest</title>
<p>The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="ai-statement" id="sec20">
<title>Generative AI statement</title>
<p>The author(s) declared that Generative AI was not used in the creation of this manuscript.</p>
<p>Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.</p>
</sec>
<sec sec-type="disclaimer" id="sec21">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec sec-type="supplementary-material" id="sec22">
<title>Supplementary material</title>
<p>The Supplementary material for this article can be found online at: <ext-link xlink:href="https://www.frontiersin.org/articles/10.3389/fneur.2026.1827374/full#supplementary-material" ext-link-type="uri">https://www.frontiersin.org/articles/10.3389/fneur.2026.1827374/full#supplementary-material</ext-link></p>
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<fn fn-type="custom" custom-type="edited-by" id="fn0003">
<p>Edited by: <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/117598/overview">Weidong Cai</ext-link>, Stanford University, United States</p>
</fn>
<fn fn-type="custom" custom-type="reviewed-by" id="fn0004">
<p>Reviewed by: <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/924861/overview">Elena Garasto</ext-link>, University of Rome Tor Vergata, Italy</p>
<p><ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/3486253/overview">Tong Shan</ext-link>, Stanford University, United States</p>
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<label>1</label>
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