Striatal (a-)Symmetry Reveals Gender-Specific Autonomic Vulnerabilities in early Parkinson’s Disease

Striatal (a-)Symmetry Reveals Gender-Specific Autonomic Vulnerabilities in early Parkinson’s Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Striatal (a-)Symmetry Reveals Gender-Specific Autonomic Vulnerabilities in early Parkinson’s Disease Anthony Nuber-Champier, Julie Anne Péron This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6953991/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Autonomic symptoms are common in Parkinson’s disease and vary according to patterns of dopaminergic neurodegeneration. Based on the alpha-Synuclein Origin site and Connectome model, which distinguishes “brain-first” and “body-first” Parkinson’s disease phenotypes, this study investigates how striatal denervation asymmetry and gender influence autonomic dysfunction profiles in early-stage, treatment-naive Parkinson’s disease. Using data from the Parkinson's Progression Markers Initiative ( n = 759), we applied generalized linear mixed models to assess SCOPA-AUT scores across subtypes of striatal denervation (left-predominant, right-predominant, symmetric), while accounting for gender. Patients with symmetric striatal denervation exhibited significantly greater overall autonomic dysfunction, particularly in sexual domains. Gender-specific effects emerged: women showed more pronounced thermoregulatory symptoms, whereas men exhibited more severe urinary and sexual dysfunction, especially in the symmetric group. These findings suggest the potential of integrating striatal denervation asymmetry and gender into Parkinson’s disease subtype characterization, with implications for personalized symptom management and therapeutic strategies from the early stages of the disease. Health sciences/Diseases Health sciences/Health care Parkinson Striatal asymmetry Gender Dysautonomia Figures Figure 1 Figure 2 1. Introduction Parkinson’s disease (PD) is a complex neurodegenerative disorder affecting millions worldwide, characterized by hallmark motor symptoms and a wide range of non-motor symptoms, including cognitive decline and dysautonomia 1 , 2 . The Alpha-Synuclein Origin site and Connectome (SOC) model, proposed by Borghammer 3 , posits two primary PD phenotypes based on the origin of pathology: a “brain-first” phenotype, where asymmetric brain damage precedes other manifestations, and a “body-first” phenotype, characterized by symmetrical striatal denervation marked by major dysautonomia and a rapid progression toward neurocognitive major disorders 3 , 4 , 5 . These patterns suggest important differences in disease progression and symptomatic presentation. However, most studies did not consistently differentiate between left- and right- predominant striatal denervation asymmetry in PD, which may result in heterogeneous findings in motor and non-motor symptomatology 6 , 7 , and notably on dysautonomia. Autonomic symptoms significantly affect the quality of life of individuals living with PD, especially given their frequent appearance early in the disease course. Recognizing and addressing these symptoms promptly is crucial, as they can contribute to both physical and emotional burden, influence disease progression, and complicate overall management strategies 8 , 9 . Examining how these symptoms vary across the different patient’s phenotypes therefore appears essential 10 . Preliminary data suggest differential effects according to the lateralization of striatal denervation: Murtomäki, et al. 6 reported that left-predominant striatal denervation PD patients experience heightened gastrointestinal symptoms in comparison to patients with symmetrical or asymmetrical right denervation. However, these results should be qualified in view of the number of patients included, including the fact that 28% of the cohort was already receiving dopaminergic treatment and at more advanced stages of the disease than in this study. Autonomic symptoms often worsen as PD progresses, with increasing prevalence and severity over time. This progressive nature underscores the relevance of early-stage findings, as they can offer insight into the initial patterns and mechanisms of autonomic involvement. However, such findings may be limited in their generalizability, given that symptom burden and trajectories can vary widely across individuals and disease subtypes. Longitudinal data and broader phenotypic comparisons are therefore necessary to fully understand how autonomic dysfunction unfolds and to inform personalized management approaches. In addition to the (a)symmetry of striatal denervation, other variables appear to influence the stratification of PD symptoms, and this relationship has not been extensively examined, particularly in relation to gender . Indeed, emerging evidence suggests that gender may influence the presentation and severity of symptoms in PD 11 , with women often experience a different spectrum and severity of symptoms compared to men 12 . In the domain of dysautonomia, female PD patients are more likely to report gastrointestinal issues and thermoregulation difficulties 13 , 14 . Hormonal differences, particularly the effects of estrogen, may explain these effects 15 : the decline in estrogen during menopause has been associated with an exacerbation of motor and non-motor symptoms, suggesting that hormonal status could modulate dysautonomia 16 , 17 , 18 . In summary, the distinct autonomic symptoms burden can vary based on i) the type of dopaminergic asymmetry (left, right, or symmetrical), and ii) the gender. Gaining insight into how gender influences these asymmetrical patterns in dysautonomia could contribute to more tailored treatment strategies and enhanced patient outcomes. Aim . This study examines how striatal denervation asymmetry and gender shape autonomic dysfunction in early-stage Parkinson’s disease, using data from the treatment-naive cohort of newly diagnosed patients in the Parkinson's Progression Markers Initiative (PPMI). Hypotheses . It is hypothesized that gender and dopaminergic asymmetry jointly influence the presentation of autonomic symptoms in individuals with PD. Specifically, autonomic symptom profiles are expected to differ significantly based on the type of dopaminergic asymmetry (left-sided, right-sided, or symmetric). For example, according to Murtomäki, et al. 6 , left- predominant striatal denervation would be associated with a higher prevalence of gastrointestinal dysautonomia. Gender is also hypothesized to play a critical role, influencing both the type and severity of autonomic symptoms, with women more likely to report gastrointestinal and thermoregulation dysautonomia than men 11 , 13 . Furthermore, the combination between dopaminergic asymmetry and gender may reveal intergroup differences in the burden of dysautonomia symptoms. 2. Method 2.1 Participants Participant criteria. The dataset used in this article was obtained from the PPMI database (www.ppmi-info.org/data) 19 . The global PPMI cohort is composed of male, and female patients diagnosed with PD by a neurologist less than two years before the start of the study, over 30 years of age, not taking any medication. Participants had at least two of the following symptoms: resting tremor, bradykinesia or rigidity. For updated information on this study, see www.ppmi-info.org. Baseline data from sporadic patients were collected (no dopaminergic treatment had been introduced yet). Participants with data available for analysis of SCales for Outcomes in PArkinson's disease - Autonomic Dysfunction (SCOPA-AUT scale) 20 and dopamine transporter single-photon emission computed tomography (DAT-SPECT) were retained. This stage resulted in the selection of 759 patients with early-stage PD, comprising 262 women and 497 men. 2.2 Striatal asymmetry calculation and categorization of group Method. Analysis of striatal asymmetry was based on Kaasinen 21 preliminary calculations of striatal specific binding ratios (SBR) ([striatal region count density/occipital count density]-1). As in the Kaasinen 21 and the Fiorenzato, et al. 22 studies, we used the difference in SBR [(right-left putamen SBR)/ (right + left putamen SBR)] to calculate cerebral asymmetry. We used a similar cut-off to Fiorenzato and Antonini 20 , although the calculation of the level of asymmetry may be refined in the future 23 . Thus, we determined an asymmetry of the putamen when the ratio was strictly superior to 20% or strictly inferior to -20% 22 . Therefore, people with asymmetry greater than 20% were determined to have right-predominant striatal denervation, between 20% and -20% as having symmetrical striatal denervation, and people with striatal asymmetry of -20% were classified as having predominantly left-predominant striatal denervation. Groups. The groups were therefore composed of those with striatal asymmetric denervation ( n = 325) or symmetric denervation ( n = 434), with the asymmetric group further divided into right-predominant striatal denervation ( n = 192) and left-predominant striatal denervation ( n = 133). 2.3 Data selection and extraction We extracted the following sociodemographic and clinical data. Participant information. Age, gender, years of education, handedness, time from diagnosis to the start of the study, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS 3) 24 scores and Hoehn and Yahr stages. Autonomic Symptom. Autonomic symptoms were assessed using the SCOPA-AUT scale 20 within the PPMI cohort. The SCOPA-AUT score ranges from 0 to 25 and covers several subdomains, including gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual symptoms, providing a comprehensive evaluation of dysautonomia in PD. 2.4 Statistical analysis First, the normality of data distribution was tested using the Kolmogorov-Smirnov test. The statistical significance threshold was set at p < 0.05 with adjustments using the Benjamini-Hochberg false discovery rate (FDR) correction. Analyses were performed using SPSS version 27.0.0.0.a. Socio-demographical and clinical data. Kruskall-Wallis were used to compare continuous data (e.g., age) and Chi 2 to compare categorical data (e.g., handedness). We performed these analyses on the one hand by considering only the type of striatal denervation, then, on the other hand, by considering the asymmetry of striatal denervation as a function of gender (see Table 1). Differences in autonomic symptoms as a function of striatal denervation and gender. A Generalized Linear Mixed Model (GLMM) was used to analyze the autonomic symptom scores measured by the SCOPA-AUT scale, treated as continuous variables. Fixed effects included gender (male, female), type of striatal denervation (left, right, symmetric) and their combinations (gender x dopaminergic asymmetry). A random effect (factors controlled for in the models) for age, handedness, time between diagnosis and start of study, education, MD-UPDRS 3 total scores and Hoehn and Yahr stages was added to account for inter-individual variability and within-subject correlations. This approach allowed for the evaluation of both fixed and random factors influencing autonomic symptom scores. 2.5 Ethics The study was conducted in accordance with the Declaration of Helsinki. All participants in the PPMI clinical database had the ability to provide informed consent in accordance with Good Clinical Practice (GCP), the International Conference on Harmonization (ICH) and local regulations. 3. Results 3.1 Sociodemographic and clinical data Table 1 below showed the sociodemographic and clinical differences according to both the different striatal denervation groups and the gender. We presented these data for a total of 759 patients. Clinical and sociodemographic differences according to the subgroups of interest revealed significative differences in terms of age, handedness and for the MDS-UPDRS 3 total score. Notably, the symmetrical group was significantly older and exhibited higher UPDRS scores. Since both age and disease severity are known to influence autonomic dysfunction, it is important to note that these variables were included as covariates in the GLMM model, the results of which are presented below. 3.2 Generalized linear mixed model analysis of factors influencing SCOPA-AUT ( n =759) Main effects (Table 2) Left vs Right vs Sym. The group with symmetrical striatal denervation had significantly higher total dysautonomia scores compared to patients with right-predominant striatal denervation asymmetry ( p = .045; t = 2.01) and on sexual dysautonomia symptom scores compared to patients with left and right-predominant striatal denervation asymmetry ( p = .038; t = 2.07; p = .001; t = 3.31, respectively). Men vs women. The women's group had a significantly higher thermoregulatory dysautonomia scores as compared to men ( p = .001; t = 3.22), while men had significantly higher scores than women in terms of symptoms of sexual dysautonomia ( p < .0001; t = 7.36). Table 2. Autonomic symptoms among striatal denervation asymmetry and gender groups. Group / p value SCOPA-AUT mean (± SD) SCOPA-GI mean (± SD) SCOPA-UR mean (± SD) SCOPA-CAR mean (± SD) SCOPA-THER mean (± SD) SCOPA-PUP mean (± SD) SCOPA-SEX mean (± SD) Left – Total 9.76 ± 7.24 2.41 ± 2.35 4.32 ± 3.46 0.44 ± 1.00 1.17 ± 1.40 0.41 ± 0.67 1.02 ± 1.51 Left – Women 9.56 ± 6.44 2.51 ± 2.36 4.07 ± 3.16 0.33 ± 0.64 1.33 ± 1.62 0.42 ± 0.81 0.89 ± 1.43 Left – Men 9.86 ± 7.64 2.35 ± 2.36 4.44 ± 3.62 0.50 ± 1.14 1.09 ± 1.28 0.40 ± 0.59 1.08 ± 1.55 Right – Total 9.11 ± 6.71 1.90 ± 2.01 4.13 ± 2.88 0.46 ± 0.94 1.21 ± 1.54 0.39 ± 0.67 1.02 ± 1.53 Right – Women 9.36 ± 7.01 1.91 ± 2.29 4.05 ± 2.98 0.45 ± 0.92 1.56 ± 1.99 0.47 ± 0.79 0.92 ± 1.28 Right – Men 8.99 ± 6.58 1.89 ± 1.86 4.17 ± 2.83 0.47 ± 0.95 1.04 ± 1.23 0.35 ± 0.61 1.07 ± 1.64 Symmetric – Total 10.51 ± 6.51 2.53 ± 2.25 4.71 ± 3.14 0.48 ± 0.76 1.13 ± 1.37 0.40 ± 0.67 1.26 ± 1.69 Symmetric – Women 9.62 ± 5.67 2.52 ± 2.25 4.05 ± 2.57 0.41 ± 0.67 1.41 ± 1.48 0.41 ± 0.62 0.83 ± 1.40 Symmetric – Men 11.00 ± 6.89 2.54 ± 2.25 5.07 ± 3.35 0.52 ± 0.81 0.99 ± 1.29 0.39 ± 0.69 1.49 ± 1.78 p-value: Left vs Symmetric 0.45 0.99 0.29 0.90 0.77 1.00 0.038 p-value: Right vs Symmetric 0.045 0.95 0.10 0.82 0.74 1.00 0.001 p-value: Left vs Right 0.37 0.96 0.74 0.77 0.99 1.00 0.46 p-value: Men vs Women .94 .98 .19 .27 .001 1.00 <0.0001 p-value: Gender × Left 0.74 0.98 0.84 0.71 0.20 1.00 0.013 p-value: Gender × Right 0.62 0.99 0.91 0.82 0.06 1.00 0.012 p-value: Gender × Sym 0.13 0.99 0.006 0.08 0.001 1.00 <0.0001 Note. The scores and p-values obtained by the n =759 patients on the SCOPA-AUT scale and the sub-dimensions are shown in the table. The terms Left, Right and Symmetric (Sym) refer to the asymmetry of striatal denervation, which is predominantly left, right or symmetrical. SCOPA-AUT: total dysautonomia score; SCOPA-GI: gastrointestinal dysautonomia score; SCOPA-UR: urogenital dysautonomia score; SCOPA-CAR: cardiovascular dysautonomia score; SCOPA-THER: thermoregulatory dysautonomia score; SCOPA-PUP: pupillomotor dysautonomia score; SCOPA-SEX: sexual dysautonomia score. 3.2.2 Interaction effects integrating the combination of gender and striatal denervation asymmetry (Table 2, Fig. 1&2) Urinary dysautonomia . Men with symmetrical denervation had significantly more urinary dysautonomia than women with symmetrical denervation ( p = .006; t = 2.73) (See Figure 1). Sexual dysautonomia . Men with symmetric striatal denervation ( p < .0001; t = 10.90), left-predominant striatal denervation ( p = .013; t = 2.49) or right-predominant striatal denervation ( p = .012; t = 2.50) had significantly more sexual dysautonomia than their women counterparts. Thermoregulatory dysautonomia . Women with symmetrical denervation had significantly more thermoregulatory dysautonomia than men with symmetrical denervation ( p = .001; t = 3.21) (See Figure 2). No other significant results were observed. 4. Discussion In this study, we investigated how striatal denervation asymmetry and gender interact to influence autonomic dysfunction in early-stage, treatment-naive PD. Our findings partially support the initial hypotheses. First, patients with symmetric striatal denervation exhibited higher overall autonomic dysfunction, compared to those with asymmetric denervation, suggesting a distinct clinical phenotype associated with the patterns of dopaminergic degeneration. Second, gender-related differences emerged across specific autonomic domains: women reported greater thermoregulatory dysfunction, while men experienced more severe sexual and urinary symptoms, particularly in the symmetric denervation group. Contrary to expectations, no significant differences were found in gastrointestinal dysautonomia between asymmetry subtypes or between genders. These findings indicate that both striatal denervation patterns and gender significantly shape the autonomic symptom burden in early PD, though not always in line with previous literature. Below, we discuss our findings in relation to the original hypotheses, their integration into current theoretical models, clinical implications, and study limitations. Confirmation of the main hypothesis . Our results confirm the main hypothesis that striatal denervation asymmetry on DAT-SPECT scan is associated with variations in dysautonomia. Specifically, patients with symmetrical striatal denervation exhibit significantly higher overall dysautonomia scores compared to those with right-predominant denervation. This finding aligns with prior studies indicating that symmetrical degeneration, "body-first" phenotypes in the SOC model 4 is associated with more pronounced non-motor symptoms, including dysautonomia 3 . In this sense, we also observed that patients with symmetrical striatal denervation have significantly higher total and sexual dysautonomia scores than those with left or right predominant striatal denervation asymmetry. Domain-specific null findings: interpretation and implications. Contrary to previous studies 6 , 11 , our results did not reveal significant group differences in gastrointestinal, cardiovascular, or pupillomotor dysautonomia. These domain-specific null findings warrant critical evaluation. Regarding gastrointestinal symptoms , discrepancies with prior work, such as the study by Murtomäki, et al. 6 , may stem from methodological and clinical differences. Their study used different asymmetry metrics, assessed dysautonomia with other scales, and included patients with longer disease duration and dopaminergic treatment. In contrast, our cohort was drug-naive, with a mean disease duration of 8.5 months, suggesting that gastrointestinal dysautonomia may reflect later disease stages or treatment effects. A compensatory role of the cerebellum has also been hypothesized in this domain 25 . For cardiovascular and pupillomotor symptoms , neuroanatomical and methodological factors may explain the absence of significant associations with striatal asymmetry or gender. These domains are regulated by brainstem and hypothalamic structures, such as the nucleus tractus solitarius, dorsal motor nucleus of the vagus, and midbrain areas 26 , less directly involved in striatal dopaminergic circuits and not adequately captured by DAT-SPECT imaging. Moreover, the SCOPA-AUT scale may lack sensitivity to detect subtle or early abnormalities in these systems. Objective measures such as orthostatic heart rate variability or pupillometry would offer more precise evaluation. It is also possible that these autonomic domains follow different temporal trajectories: thermoregulatory and urinary symptoms may emerge earlier, while cardiovascular and pupillomotor dysfunction might manifest later or under different patterns. Individual variability and compensatory mechanisms, such as cerebellar modulation or differences in vagal tone, could further obscure clinical detection in early-stage PD. These findings underscore the importance of using multimodal and domain-specific tools to better characterize autonomic dysfunction in relation to disease phenotype, asymmetry, and gender. Gender-specific autonomic patterns. The differential impact of gender on autonomic symptoms across asymmetry types underscores the importance of integrating gender and the striatal denervation asymmetry (i.e., left versus right) into the SOC model framework. For example, in our study, women with symmetrical striatal denervation exhibited significantly higher thermoregulatory dysautonomia compared to their male counterparts. The elevated thermoregulatory dysautonomia among women may also reflect a heightened sensitivity of autonomic systems linked to hormonal and physiological differences, which could exacerbate early autonomic features typical of the body-first pathway. These results are consistent with previous literature suggesting that women are more prone to autonomic disturbances, including thermoregulatory dysautonomia, in PD 14 . Hormonal differences, particularly the effects of estrogen, may underlie this disparity. Estrogen has been implicated in modulating autonomic nervous system activity, and its decline during menopause may exacerbate autonomic symptoms 27 . As observed in PD in other studies, the effects of estrogen may be protective against dementia associated with the disease 28 , and hormone stimulation could slow cognitive decline without preventing the onset of PD 29 . These findings underscore the importance of considering hormonal status in evaluating and managing dysautonomia in women with PD. Women with predominantly right-sided striatal degeneration and the most severe thermoregulatory difficulties could be a target population for hormone replacement therapy trials. Hormone therapy could have an impact on thermoregulation through effects on the central nervous system and have peripheral vasodilatory effects 30 . Conversely, men with symmetrical denervation display more urinary and sexual dysautonomia than women, suggesting potential gender-specific autonomic vulnerabilities 12 . This aligns with reports that men with PD may experience more severe urinary dysautonomia than women 11 . In this sense, it would appear that various sex hormones could impact the nigrostriatal pathways, as may be the case with testosterone. Indeed, testosterone treatment in deficient patients could improve non-motor symptoms, particularly sexual and cognitive symptoms 31 . Additionally, the increased prevalence of sexual disorders involved in the profiles of the groups with left and right predominant striatal denervation asymmetry, supports the hypothesis that asymmetric nigrostriatal degeneration is not merely a motor phenomenon but one with critical autonomic implications. When coupled with gender, this asymmetry appears to stratify patients into further subtypes with distinct autonomic symptom trajectories. That being said, it is important to acknowledge that the SCOPA-AUT scale may have limitations in accurately assessing sexual dysfunction in women. While the scale includes items related to sexual interest and activity, it predominantly reflects male-specific aspects, such as erectile function, and may overlook common female-specific issues like vaginal dryness, pain during intercourse, or difficulties achieving orgasm, difficulty reaching orgasm, loss of libido, and involuntary vaginal contractions. This potential measurement bias could lead to an underestimation of sexual dysautonomia in women and may partly explain the higher sexual dysfunction scores observed in men across all striatal denervation subtypes. Future studies should consider using more comprehensive and gender-sensitive tools to better capture the full spectrum of sexual dysfunction in Parkinson’s disease. Integration into the SOC Model and clinical implications. Borghammer’s model 3 provides an excellent foundation for understanding PD heterogeneity, but our findings suggest that gender and striatal denervation patterns and lateralization may represent additional variables that can refine its application to personalized medicine. Our observations highlight the need to further explore dysautonomia symptoms in relation to different discriminating variables, in order to integrate them into the SOC model. Moreover, our results suggest potential avenues for tailoring management strategies. For patients aligning with the "body-first" phenotype and showing symmetrical denervation, early intervention focusing on autonomic dysfunction may be particularly beneficial. Hormonal therapies or gender-specific approaches to manage thermoregulatory and urinary symptoms could also prove effective. For the "brain-first" phenotype, asymmetric nigrostriatal degeneration should prompt clinicians to monitor for early signs of motor asymmetry and the progression of these signs in the event of lateralization of nigrostriatal degeneration and worsening of dysautonomia symptoms. Furthermore, despite the preliminary nature of our findings, the observed gender differences in autonomic symptom profiles, particularly in relation to striatal denervation pattern, underscore the importance of further validation studies that take into account both gender and biological factors such as hormonal status. Future research should consider stratifying participants by gender and asymmetry pattern, while also exploring the potential role of sex hormones, to better understand the mechanisms underlying these variations and to refine patient-specific approaches to care in PD. Study limitations . First, the cross-sectional design does not allow conclusions to be drawn about the causality of the phenomena or about the generalization of the various possible developments after the early stage. Longitudinal studies are necessary to evaluate how the relationship between asymmetry, gender, and autonomic symptoms evolves over time. Second, the study relies exclusively on the SCOPA-AUT, a self-report questionnaire, which, while widely used, may not capture the full spectrum of dysautonomia. This limitation is particularly relevant when considering the variability of symptoms related to biological hormonal fluctuations or the use of hormonal contraceptives, which may have long-term effects on sexual and thermoregulatory functions, especially in women with PD 15 , 32 . In addition, the sexual dysfunction subscale of the SCOPA-AUT may be less sensitive to female-specific concerns, potentially contributing to the observed gender differences PD. Future studies could benefit from the integration of objective tests of autonomic function, such as measurements of orthostatic heart rate variability 33 , gastrointestinal manometry 34 , pupillary light reflexes 35 or urinary flow rate 36 , in order to validate these results, combined with measures specific to each gender. For example, Miller-Patterson, et al. 12 have suggested that different urinary mechanisms may affect women and men differently. Women are more likely to suffer from urinary incontinence, while men are more likely to experience incomplete bladder emptying and weak urinary flow. Moreover, the interaction of hormonal status with dysautonomia is not explicitly examined. Given the potential role of estrogen in modulating autonomic symptoms 37 , 38 , future research should explore this interaction in more depth with scales more suited to the specificities of dysautonomic disorders according to the population, particularly in postmenopausal women 39 . Finally, although age and disease severity were included as covariates in the GLMM model, residual confounding cannot be entirely ruled out, particularly given the cross-sectional nature of the analysis, underscoring the need for replication in more diverse populations and with longitudinal designs. Conclusion This study highlights the critical role of dopaminergic asymmetry and gender in defining subjective symptom profiles of dysautonomia in PD. The findings support the need for personalized approaches to PD management that take into account striatal denervation patterns and gender-specific symptomatology for non-motor dysfunctions. By refining our understanding of these interactions, future research may pave the way for more targeted and effective therapeutic strategies, ultimately improving patient outcomes. Abbreviations DAT-SPECT: dopamine transporter single-photon emission computed tomography; FDR: false discovery rate; GLMM: generalized linear mixed models; MDS-UPDRS 3: Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale; PD: Parkinson’s disease; PPMI: Parkinson's Progression Markers Initiative; PwPD: patients with Parkinson’s disease; SBR: Striatal specific binding ratios; SCOPA-AUT: SCales for Outcomes in PArkinson’s disease - Autonomic Dysfunction; SOC: alpha-Synuclein Origin site and Connectome. Declarations Financial disclosure and acknowledgements This work was supported by funding from the PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson'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 & 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. Data used in the preparation of this article were obtained on [2020–04–01] for cognitive and DAT-SPECT data from the Parkinson's Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit http://www.ppmi-info.org. Open access funding provided by University of Geneva. This work was supported by the Swiss National Foundation, grant N°: 105314_215015 (PI: Prof. Julie Anne Péron). The funders had no role in data collection, discussion of content, preparation of the manuscript, or decision to publish. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability The data used in this study were obtained from the PPMI database (www.ppmi-info.org/data). All data analyzed are available at www.ppmi-info.org/access-data-specimens/download-data. Authors contribution AN-C: writing—original draft preparation; data curation; formal analysis; writing—review and editing / JAP: writing-original draft; formal analysis; data curation; resources; investigation; project administration; writing—review and editing; funding acquisition References Poewe, W. 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Motor asymmetry in Parkinson’s disease: Diagnostic thresholds based on clinical scores and DaTSCAN imaging. Clinical Parkinsonism & Related Disorders , 100350 (2025). Goetz, C. G. et al. Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS): scale presentation and clinimetric testing results. Movement disorders: official journal of the Movement Disorder Society 23 , 2129-2170 (2008). Pfeiffer, R. F. Gastrointestinal dysfunction in Parkinson's disease. The Lancet Neurology 2 , 107-116 (2003). Foster, P. S. et al. Influence of left versus right hemibody onset Parkinson's disease on cardiovascular control. Laterality 16 , 164-173 (2011). Benedetti, M. D. et al. Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case‐control study. Movement disorders 16 , 830-837 (2001). Marder, K. et al. Postmenopausal estrogen use and Parkinson's disease with and without dementia. Neurology 50 , 1141-1143 (1998). Saunders-Pullman, R. Estrogens and Parkinson disease: neuroprotective, symptomatic, neither, or both? Endocrine 21 , 81-87 (2003). Brooks, E. et al. Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women. Journal of Applied Physiology 83 , 477-484 (1997). Okun, M. S., McDonald, W. M. & DeLong, M. R. Refractory nonmotor symptoms in male patients with Parkinson disease due to testosterone deficiency: a common unrecognized comorbidity. Archives of Neurology 59 , 807-811 (2002). Nicoletti, A. et al. Reproductive factors and Parkinson's disease: A multicenter case–control study. Movement disorders 26 , 2563-2566 (2011). Mihci, E., Kardelen, F., Dora, B. & Balkan, S. Orthostatic heart rate variability analysis in idiopathic Parkinson's disease. Acta neurologica scandinavica 113 , 288-293 (2006). Kornum, D. S. et al. Assessment of gastrointestinal autonomic dysfunction: present and future perspectives. Journal of clinical medicine 10 , 1392 (2021). İşcan, D., Türkoğlu, C. & Arslan, E. Evaluation of autonomic involvement in Parkinson’s disease using pupillometry. Neurological Sciences , 1-6 (2025). Badri, A. V., Purohit, R. S., Skenazy, J., Weiss, J. P. & Blaivas, J. G. A review of lower urinary tract symptoms in patients with Parkinson’s disease. Current urology reports 15 , 1-9 (2014). Shulman, L. M. Is there a connection between estrogen and Parkinson's disease? Parkinsonism & related disorders 8 , 289-295 (2002). Kaciuba-Uscilko, H. & Grucza, R. Gender differences in thermoregulation. Current Opinion in Clinical Nutrition & Metabolic Care 4 , 533-536 (2001). Scatà, C. et al. Blunted cardiac autonomic dynamics to active standing test in postmenopausal women. Frontiers in Cardiovascular Medicine 11 , 1402086 (2024). Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6953991","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":483148306,"identity":"326862ff-d1e2-4215-a503-0acaa55114ac","order_by":0,"name":"Anthony Nuber-Champier","email":"","orcid":"","institution":"University of Geneva","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Nuber-Champier","suffix":""},{"id":483148307,"identity":"f3734d65-3b9e-4adf-8333-ff2f309586cf","order_by":1,"name":"Julie Anne Péron","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYBACxgbmhgMw9gMGBgkQg42AFka4FmYDorSANMFYbBIwBl4NzDMSGw98YLgjZ97ee6yad4eFXT8D87MHeO2YkdhwcAbDM2OZM+fSbvOekUie2cBmbkBIy2EehsOJMyRyzG7ztkkkGxzggbsQt5Y/DIfrQVqKQVrsidLCwHA4QQKohRmoxc6AgZCWnocNB3sMnhnO4DljLDm3TSJB4jCbGV4thu3Jhz/8qLgjL8HeY/jhbVudPX978zP8WhpApMEBuEBiAzM+9UAgD6EQWuwJaBgFo2AUjIIRCAA11kcns1803wAAAABJRU5ErkJggg==","orcid":"","institution":"University of Geneva","correspondingAuthor":true,"prefix":"","firstName":"Julie","middleName":"Anne","lastName":"Péron","suffix":""}],"badges":[],"createdAt":"2025-06-23 07:38:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6953991/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6953991/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86645039,"identity":"5add044d-f82a-479f-8619-3eb88335e48b","added_by":"auto","created_at":"2025-07-14 08:50:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74910,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean Urinary dysautonomia\u003c/strong\u003e \u003cstrong\u003e(and one standard error) as a function of gender and striatal denervation asymmetry\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6953991/v1/4e70670fb8ce9cbe536fd38d.png"},{"id":86645049,"identity":"8f7edd6e-24af-49bd-98bc-4d285bb170c5","added_by":"auto","created_at":"2025-07-14 08:50:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":114491,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean thermoregulatory dysautonomia (and one standard error) as a function of gender and striatal denervation asymmetry\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6953991/v1/ffd8a0276f88095f41bedc8f.png"},{"id":86646428,"identity":"c4a1e656-dcd3-4bb2-86ae-1aa0702ad946","added_by":"auto","created_at":"2025-07-14 08:58:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1119762,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6953991/v1/57eb4fda-42ad-4314-b710-86a10e04db16.pdf"},{"id":86645038,"identity":"fd6e3f62-0653-43ae-aea8-327ccdfc96fc","added_by":"auto","created_at":"2025-07-14 08:50:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20542,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6953991/v1/404d395b7e558158124efb4f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Striatal (a-)Symmetry Reveals Gender-Specific Autonomic Vulnerabilities in early Parkinson’s Disease","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eParkinson\u0026rsquo;s disease (PD) is a complex neurodegenerative disorder affecting millions worldwide, characterized by hallmark motor symptoms and a wide range of non-motor symptoms, including cognitive decline and dysautonomia\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The Alpha-Synuclein Origin site and Connectome (SOC) model, proposed by Borghammer \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, posits two primary PD phenotypes based on the origin of pathology: a \u0026ldquo;brain-first\u0026rdquo; phenotype, where asymmetric brain damage precedes other manifestations, and a \u0026ldquo;body-first\u0026rdquo; phenotype, characterized by symmetrical striatal denervation marked by major dysautonomia and a rapid progression toward neurocognitive major disorders \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. These patterns suggest important differences in disease progression and symptomatic presentation. However, most studies did not consistently differentiate between left- and right- predominant striatal denervation asymmetry in PD, which may result in heterogeneous findings in motor and non-motor symptomatology\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, and notably on dysautonomia.\u003c/p\u003e\u003cp\u003eAutonomic symptoms significantly affect the quality of life of individuals living with PD, especially given their frequent appearance early in the disease course. Recognizing and addressing these symptoms promptly is crucial, as they can contribute to both physical and emotional burden, influence disease progression, and complicate overall management strategies\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Examining how these symptoms vary across the different patient\u0026rsquo;s phenotypes therefore appears essential\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Preliminary data suggest differential effects according to the lateralization of striatal denervation: Murtom\u0026auml;ki, et al. \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e reported that left-predominant striatal denervation PD patients experience heightened gastrointestinal symptoms in comparison to patients with symmetrical or asymmetrical right denervation. However, these results should be qualified in view of the number of patients included, including the fact that 28% of the cohort was already receiving dopaminergic treatment and at more advanced stages of the disease than in this study.\u003c/p\u003e\u003cp\u003eAutonomic symptoms often worsen as PD progresses, with increasing prevalence and severity over time. This progressive nature underscores the relevance of early-stage findings, as they can offer insight into the initial patterns and mechanisms of autonomic involvement. However, such findings may be limited in their generalizability, given that symptom burden and trajectories can vary widely across individuals and disease subtypes. Longitudinal data and broader phenotypic comparisons are therefore necessary to fully understand how autonomic dysfunction unfolds and to inform personalized management approaches.\u003c/p\u003e\u003cp\u003eIn addition to the (a)symmetry of striatal denervation, other variables appear to influence the stratification of PD symptoms, and this relationship has not been extensively examined, particularly in relation to \u003cem\u003egender\u003c/em\u003e. Indeed, emerging evidence suggests that gender may influence the presentation and severity of symptoms in PD\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, with women often experience a different spectrum and severity of symptoms compared to men \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In the domain of dysautonomia, female PD patients are more likely to report gastrointestinal issues and thermoregulation difficulties\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Hormonal differences, particularly the effects of estrogen, may explain these effects\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e: the decline in estrogen during menopause has been associated with an exacerbation of motor and non-motor symptoms, suggesting that hormonal status could modulate dysautonomia \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn summary, the distinct autonomic symptoms burden can vary based on i) the type of dopaminergic asymmetry (left, right, or symmetrical), and ii) the gender. Gaining insight into how gender influences these asymmetrical patterns in dysautonomia could contribute to more tailored treatment strategies and enhanced patient outcomes.\u003c/p\u003e\u003cp\u003e\u003cem\u003eAim\u003c/em\u003e. This study examines how striatal denervation asymmetry and gender shape autonomic dysfunction in early-stage Parkinson\u0026rsquo;s disease, using data from the treatment-naive cohort of newly diagnosed patients in the Parkinson's Progression Markers Initiative (PPMI).\u003c/p\u003e\u003cp\u003e\u003cem\u003eHypotheses\u003c/em\u003e. It is hypothesized that gender and dopaminergic asymmetry jointly influence the presentation of autonomic symptoms in individuals with PD. Specifically, autonomic symptom profiles are expected to differ significantly based on the type of dopaminergic asymmetry (left-sided, right-sided, or symmetric). For example, according to Murtom\u0026auml;ki, et al. \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, left- predominant striatal denervation would be associated with a higher prevalence of gastrointestinal dysautonomia. Gender is also hypothesized to play a critical role, influencing both the type and severity of autonomic symptoms, with women more likely to report gastrointestinal and thermoregulation dysautonomia than men \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Furthermore, the combination between dopaminergic asymmetry and gender may reveal intergroup differences in the burden of dysautonomia symptoms.\u003c/p\u003e"},{"header":"2. Method","content":"\u003cp\u003e\u003cstrong\u003e2.1 Participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eParticipant criteria.\u003c/em\u003e The dataset used in this article was obtained from the PPMI database (www.ppmi-info.org/data)\u003csup\u003e19\u003c/sup\u003e. The global PPMI cohort is composed of male, and female patients diagnosed with PD by a neurologist less than two years before the start of the study, over 30 years of age, not taking any medication. Participants had at least two of the following symptoms: resting tremor, bradykinesia or rigidity. For updated information on this study, see www.ppmi-info.org. Baseline data from sporadic patients were collected (no dopaminergic treatment had been introduced yet). Participants with data available for analysis of SCales for Outcomes in PArkinson\u0026apos;s disease - Autonomic Dysfunction (SCOPA-AUT scale)\u003csup\u003e20\u003c/sup\u003e and dopamine transporter single-photon emission computed tomography (DAT-SPECT) were retained. This stage resulted in the selection of 759 patients with early-stage PD, comprising 262 women and 497 men.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Striatal asymmetry calculation and categorization of group\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethod.\u003c/em\u003e Analysis of striatal asymmetry was based on Kaasinen \u003csup\u003e21\u003c/sup\u003e preliminary calculations of striatal specific binding ratios (SBR) ([striatal region count density/occipital count density]-1). As in the Kaasinen \u003csup\u003e21\u003c/sup\u003e and the Fiorenzato, et al. \u003csup\u003e22\u003c/sup\u003e studies, we used the difference in SBR [(right-left putamen SBR)/ (right + left putamen SBR)] to calculate cerebral asymmetry. We used a similar cut-off to Fiorenzato and Antonini \u003csup\u003e20\u003c/sup\u003e, although the calculation of the level of asymmetry may be refined in the future \u003csup\u003e23\u003c/sup\u003e. Thus, we determined an asymmetry of the putamen when the ratio was strictly superior to 20% or strictly inferior to -20% \u003csup\u003e22\u003c/sup\u003e. \u0026nbsp;Therefore, people with asymmetry greater than 20% were determined to have right-predominant striatal denervation, between 20% and -20% as having symmetrical striatal denervation, and people with striatal asymmetry of -20% were classified as having predominantly left-predominant striatal denervation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGroups.\u003c/em\u003e The groups were therefore composed of those with striatal asymmetric denervation (\u003cem\u003en\u003c/em\u003e = 325) or symmetric denervation (\u003cem\u003en\u003c/em\u003e= 434), with the asymmetric group further divided into right-predominant striatal denervation (\u003cem\u003en\u003c/em\u003e = 192) and left-predominant striatal denervation (\u003cem\u003en\u003c/em\u003e = 133).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Data selection and extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extracted the following sociodemographic and clinical data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eParticipant information.\u003c/em\u003e Age, gender, years of education, handedness, time from diagnosis to the start of the study, Movement Disorder Society-Sponsored Revision of the Unified Parkinson\u0026apos;s Disease Rating Scale (MDS-UPDRS 3)\u003csup\u003e24\u003c/sup\u003e scores and Hoehn and Yahr stages.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAutonomic Symptom.\u003c/em\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAutonomic symptoms were assessed using the SCOPA-AUT scale \u003csup\u003e20\u003c/sup\u003e within the PPMI cohort. The SCOPA-AUT score ranges from 0 to 25 and covers several subdomains, including gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual symptoms, providing a comprehensive evaluation of dysautonomia in PD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Statistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, the normality of data distribution was tested using the Kolmogorov-Smirnov test. The statistical significance threshold was set at \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 with adjustments using the\u0026nbsp;Benjamini-Hochberg\u0026nbsp;false discovery rate (FDR) correction. Analyses were performed using SPSS version 27.0.0.0.a.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSocio-demographical and clinical data.\u003c/em\u003e Kruskall-Wallis were used to compare continuous data (e.g., age) and Chi\u003csup\u003e2\u003c/sup\u003e to compare categorical data (e.g., handedness). We performed these analyses on the one hand by considering only the type of striatal denervation, then, on the other hand, by considering the asymmetry of striatal denervation as a function of gender (see Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDifferences in autonomic symptoms as a function of striatal denervation and gender.\u003c/em\u003e A Generalized Linear Mixed Model (GLMM) was used to analyze the autonomic symptom scores measured by the SCOPA-AUT scale, treated as continuous variables. Fixed effects included gender (male, female), type of striatal denervation (left, right, symmetric) and their combinations (gender x dopaminergic asymmetry). A random effect (factors controlled for in the models) for age, handedness, time between diagnosis and start of study, education, MD-UPDRS 3 total scores and Hoehn and Yahr stages was added to account for inter-individual variability and within-subject correlations. This approach allowed for the evaluation of both fixed and random factors influencing autonomic symptom scores.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Ethics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. All participants in the PPMI clinical database had the ability to provide informed consent in accordance with Good Clinical Practice (GCP), the International Conference on Harmonization (ICH) and local regulations.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Sociodemographic and clinical data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 below showed the sociodemographic and clinical differences according to both the different striatal denervation groups and the gender. We presented these data for a total of 759 patients. Clinical and sociodemographic differences according to the subgroups of interest revealed significative differences in terms of age, handedness and for the MDS-UPDRS 3 total score. Notably, the symmetrical group was significantly older and exhibited higher UPDRS scores. Since both age and disease severity are known to influence autonomic dysfunction, it is important to note that these variables were included as covariates in the GLMM model, the results of which are presented below.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Generalized linear mixed model analysis of factors influencing SCOPA-AUT (\u003cem\u003en\u003c/em\u003e=759)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain effects\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(Table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLeft vs Right vs Sym.\u003c/em\u003e The group with symmetrical striatal denervation had significantly higher total dysautonomia scores compared to patients with right-predominant striatal denervation asymmetry (\u003cem\u003ep\u003c/em\u003e = .045; \u003cem\u003et\u003c/em\u003e = 2.01) and on sexual dysautonomia symptom scores compared to patients with left and right-predominant striatal denervation asymmetry (\u003cem\u003ep\u003c/em\u003e = .038; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 2.07; \u003cem\u003ep\u003c/em\u003e = .001; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 3.31, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMen vs women.\u0026nbsp;\u003c/em\u003eThe women\u0026apos;s group had a significantly higher thermoregulatory dysautonomia scores as compared to men (\u003cem\u003ep\u003c/em\u003e= .001; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 3.22), while men had significantly higher scores than women in terms of symptoms of sexual dysautonomia (\u003cem\u003ep\u003c/em\u003e\u0026lt; .0001; \u003cem\u003et\u003c/em\u003e= 7.36).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2. Autonomic symptoms among striatal denervation asymmetry and gender groups.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"709\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003eGroup / p value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-AUT mean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-GI\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003emean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-UR mean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-CAR\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003emean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-THER\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003emean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-PUP\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003emean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cem\u003eSCOPA-SEX\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003emean\u0026nbsp;\u003c/em\u003e\u003cem\u003e(\u0026plusmn; SD)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003eLeft \u0026ndash; Total\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9.76 \u0026plusmn; 7.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2.41 \u0026plusmn; 2.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.32 \u0026plusmn; 3.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.44 \u0026plusmn; 1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.17 \u0026plusmn; 1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.41 \u0026plusmn; 0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1.02 \u0026plusmn; 1.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cem\u003eLeft \u0026ndash; Women\u003c/em\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9.56 \u0026plusmn; 6.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2.51 \u0026plusmn; 2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.07 \u0026plusmn; 3.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.33 \u0026nbsp;\u0026plusmn; 0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.33 \u0026plusmn; 1.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.42 \u0026plusmn; 0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.89 \u0026plusmn; 1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cem\u003eLeft \u0026ndash; Men\u003c/em\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9.86 \u0026plusmn; 7.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2.35 \u0026plusmn; 2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.44 \u0026plusmn; 3.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.50 \u0026plusmn; 1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.09 \u0026plusmn; 1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.40 \u0026plusmn; 0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1.08 \u0026plusmn; 1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003eRight \u0026ndash; Total\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9.11 \u0026plusmn; 6.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1.90 \u0026plusmn; 2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.13 \u0026plusmn; 2.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.46 \u0026plusmn; 0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.21 \u0026plusmn; 1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.39 \u0026plusmn; 0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1.02 \u0026plusmn; 1.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cem\u003eRight \u0026ndash; Women\u003c/em\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9.36 \u0026plusmn; 7.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1.91 \u0026plusmn; 2.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.05 \u0026plusmn; 2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.45 \u0026plusmn; 0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.56 \u0026plusmn; 1.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.47 \u0026plusmn; 0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.92 \u0026plusmn; 1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cem\u003eRight \u0026ndash; Men\u003c/em\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e8.99 \u0026plusmn; 6.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e1.89 \u0026plusmn; 1.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.17 \u0026plusmn; 2.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.47 \u0026plusmn; 0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.04 \u0026plusmn; 1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.35 \u0026plusmn; 0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1.07 \u0026plusmn; 1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003eSymmetric \u0026ndash; Total\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e10.51 \u0026plusmn; 6.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2.53 \u0026plusmn; 2.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.71 \u0026plusmn; 3.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.48 \u0026plusmn; 0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.13 \u0026plusmn; 1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.40 \u0026plusmn; 0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1.26 \u0026plusmn; 1.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cem\u003eSymmetric \u0026ndash; Women\u003c/em\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9.62 \u0026plusmn; 5.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2.52 \u0026plusmn; 2.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e4.05 \u0026plusmn; 2.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.41 \u0026plusmn; 0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1.41 \u0026plusmn; 1.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.41 \u0026plusmn; 0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.83 \u0026plusmn; 1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u003cem\u003eSymmetric \u0026ndash; Men\u003c/em\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e11.00 \u0026plusmn; 6.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e2.54 \u0026plusmn; 2.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e5.07 \u0026plusmn; 3.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.52 \u0026plusmn; 0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0.99 \u0026plusmn; 1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e0.39 \u0026plusmn; 0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e1.49 \u0026plusmn; 1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Left vs Symmetric\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.038\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Right vs Symmetric\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.045\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Left vs Right\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Men vs Women\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Gender \u0026times; Left\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Gender \u0026times; Right\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value: Gender \u0026times; Sym\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote.\u0026nbsp;\u003c/em\u003eThe scores and p-values obtained by the \u003cem\u003en\u003c/em\u003e=759 patients on the SCOPA-AUT scale and the sub-dimensions are shown in the table. The terms Left, Right and Symmetric (Sym) refer to the asymmetry of striatal denervation, which is predominantly left, right or symmetrical. SCOPA-AUT: total dysautonomia score; SCOPA-GI: gastrointestinal dysautonomia score; SCOPA-UR: urogenital dysautonomia score; SCOPA-CAR: cardiovascular dysautonomia score; SCOPA-THER: thermoregulatory dysautonomia score; SCOPA-PUP: pupillomotor dysautonomia score; SCOPA-SEX: sexual dysautonomia score.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2.2 Interaction effects integrating the combination of gender and striatal denervation asymmetry (Table 2, Fig. 1\u0026amp;2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUrinary\u0026nbsp;\u003c/em\u003e\u003cem\u003edysautonomia\u003c/em\u003e. Men with symmetrical denervation had significantly more\u0026nbsp;urinary\u0026nbsp;dysautonomia\u0026nbsp;than women with symmetrical denervation (\u003cem\u003ep\u003c/em\u003e = .006; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 2.73) (See Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSexual dysautonomia\u003c/em\u003e. Men with symmetric striatal denervation (\u003cem\u003ep\u003c/em\u003e \u0026lt; .0001; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 10.90), left-predominant striatal denervation (\u003cem\u003ep\u003c/em\u003e = .013; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 2.49) or right-predominant striatal denervation (\u003cem\u003ep\u003c/em\u003e = .012; \u003cem\u003et\u0026nbsp;\u003c/em\u003e= 2.50) had significantly more sexual dysautonomia than their women counterparts.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThermoregulatory dysautonomia\u003c/em\u003e. Women with symmetrical denervation had significantly more thermoregulatory dysautonomia than men with symmetrical denervation (\u003cem\u003ep\u003c/em\u003e= .001; \u003cem\u003et\u003c/em\u003e = 3.21) (See Figure 2). No other significant results were observed.\u0026nbsp;\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we investigated how striatal denervation asymmetry and gender interact to influence autonomic dysfunction in early-stage, treatment-naive PD. Our findings partially support the initial hypotheses. First, patients with symmetric striatal denervation exhibited higher overall autonomic dysfunction, compared to those with asymmetric denervation, suggesting a distinct clinical phenotype associated with the patterns of dopaminergic degeneration. Second, gender-related differences emerged across specific autonomic domains: women reported greater thermoregulatory dysfunction, while men experienced more severe sexual and urinary symptoms, particularly in the symmetric denervation group. Contrary to expectations, no significant differences were found in gastrointestinal dysautonomia between asymmetry subtypes or between genders. These findings indicate that both striatal denervation patterns and gender significantly shape the autonomic symptom burden in early PD, though not always in line with previous literature. Below, we discuss our findings in relation to the original hypotheses, their integration into current theoretical models, clinical implications, and study limitations.\u003c/p\u003e\u003cp\u003e\u003cem\u003eConfirmation of the main hypothesis\u003c/em\u003e. Our results confirm the main hypothesis that striatal denervation asymmetry on DAT-SPECT scan is associated with variations in dysautonomia. Specifically, patients with symmetrical striatal denervation exhibit significantly higher overall dysautonomia scores compared to those with right-predominant denervation. This finding aligns with prior studies indicating that symmetrical degeneration, \"body-first\" phenotypes in the SOC model \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e is associated with more pronounced non-motor symptoms, including dysautonomia\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. In this sense, we also observed that patients with symmetrical striatal denervation have significantly higher total and sexual dysautonomia scores than those with left or right predominant striatal denervation asymmetry.\u003c/p\u003e\u003cp\u003e\u003cem\u003eDomain-specific null findings: interpretation and implications.\u003c/em\u003e Contrary to previous studies\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, our results did not reveal significant group differences in gastrointestinal, cardiovascular, or pupillomotor dysautonomia. These domain-specific null findings warrant critical evaluation. \u003cem\u003eRegarding gastrointestinal symptoms\u003c/em\u003e, discrepancies with prior work, such as the study by Murtomäki, et al. \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, may stem from methodological and clinical differences. Their study used different asymmetry metrics, assessed dysautonomia with other scales, and included patients with longer disease duration and dopaminergic treatment. In contrast, our cohort was drug-naive, with a mean disease duration of 8.5 months, suggesting that gastrointestinal dysautonomia may reflect later disease stages or treatment effects. A compensatory role of the cerebellum has also been hypothesized in this domain \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eFor cardiovascular and pupillomotor symptoms\u003c/em\u003e, neuroanatomical and methodological factors may explain the absence of significant associations with striatal asymmetry or gender. These domains are regulated by brainstem and hypothalamic structures, such as the nucleus tractus solitarius, dorsal motor nucleus of the vagus, and midbrain areas \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, less directly involved in striatal dopaminergic circuits and not adequately captured by DAT-SPECT imaging. Moreover, the SCOPA-AUT scale may lack sensitivity to detect subtle or early abnormalities in these systems. Objective measures such as orthostatic heart rate variability or pupillometry would offer more precise evaluation. It is also possible that these autonomic domains follow different temporal trajectories: thermoregulatory and urinary symptoms may emerge earlier, while cardiovascular and pupillomotor dysfunction might manifest later or under different patterns. Individual variability and compensatory mechanisms, such as cerebellar modulation or differences in vagal tone, could further obscure clinical detection in early-stage PD. These findings underscore the importance of using multimodal and domain-specific tools to better characterize autonomic dysfunction in relation to disease phenotype, asymmetry, and gender.\u003c/p\u003e\u003cp\u003e\u003cem\u003eGender-specific autonomic patterns.\u003c/em\u003e The differential impact of gender on autonomic symptoms across asymmetry types underscores the importance of integrating gender and the striatal denervation asymmetry (i.e., left versus right) into the SOC model framework. For example, in our study, women with symmetrical striatal denervation exhibited significantly higher thermoregulatory dysautonomia compared to their male counterparts. The elevated thermoregulatory dysautonomia among women may also reflect a heightened sensitivity of autonomic systems linked to hormonal and physiological differences, which could exacerbate early autonomic features typical of the body-first pathway. These results are consistent with previous literature suggesting that women are more prone to autonomic disturbances, including thermoregulatory dysautonomia, in PD \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Hormonal differences, particularly the effects of estrogen, may underlie this disparity. Estrogen has been implicated in modulating autonomic nervous system activity, and its decline during menopause may exacerbate autonomic symptoms\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. As observed in PD in other studies, the effects of estrogen may be protective against dementia associated with the disease \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, and hormone stimulation could slow cognitive decline without preventing the onset of PD \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. These findings underscore the importance of considering hormonal status in evaluating and managing dysautonomia in women with PD. Women with predominantly right-sided striatal degeneration and the most severe thermoregulatory difficulties could be a target population for hormone replacement therapy trials. Hormone therapy could have an impact on thermoregulation through effects on the central nervous system and have peripheral vasodilatory effects \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eConversely, men with symmetrical denervation display more urinary and sexual dysautonomia than women, suggesting potential gender-specific autonomic vulnerabilities\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This aligns with reports that men with PD may experience more severe urinary dysautonomia than women\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. In this sense, it would appear that various sex hormones could impact the nigrostriatal pathways, as may be the case with testosterone. Indeed, testosterone treatment in deficient patients could improve non-motor symptoms, particularly sexual and cognitive symptoms \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Additionally, the increased prevalence of sexual disorders involved in the profiles of the groups with left and right predominant striatal denervation asymmetry, supports the hypothesis that asymmetric nigrostriatal degeneration is not merely a motor phenomenon but one with critical autonomic implications. When coupled with gender, this asymmetry appears to stratify patients into further subtypes with distinct autonomic symptom trajectories. That being said, it is important to acknowledge that the SCOPA-AUT scale may have limitations in accurately assessing sexual dysfunction in women. While the scale includes items related to sexual interest and activity, it predominantly reflects male-specific aspects, such as erectile function, and may overlook common female-specific issues like vaginal dryness, pain during intercourse, or difficulties achieving orgasm, difficulty reaching orgasm, loss of libido, and involuntary vaginal contractions. This potential measurement bias could lead to an underestimation of sexual dysautonomia in women and may partly explain the higher sexual dysfunction scores observed in men across all striatal denervation subtypes. Future studies should consider using more comprehensive and gender-sensitive tools to better capture the full spectrum of sexual dysfunction in Parkinson’s disease.\u003c/p\u003e\u003cp\u003e\u003cem\u003eIntegration into the SOC Model and clinical implications.\u003c/em\u003e Borghammer’s model\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e provides an excellent foundation for understanding PD heterogeneity, but our findings suggest that gender and striatal denervation patterns and lateralization may represent additional variables that can refine its application to personalized medicine. Our observations highlight the need to further explore dysautonomia symptoms in relation to different discriminating variables, in order to integrate them into the SOC model. Moreover, our results suggest potential avenues for tailoring management strategies. For patients aligning with the \"body-first\" phenotype and showing symmetrical denervation, early intervention focusing on autonomic dysfunction may be particularly beneficial. Hormonal therapies or gender-specific approaches to manage thermoregulatory and urinary symptoms could also prove effective. For the \"brain-first\" phenotype, asymmetric nigrostriatal degeneration should prompt clinicians to monitor for early signs of motor asymmetry and the progression of these signs in the event of lateralization of nigrostriatal degeneration and worsening of dysautonomia symptoms. Furthermore, despite the preliminary nature of our findings, the observed gender differences in autonomic symptom profiles, particularly in relation to striatal denervation pattern, underscore the importance of further validation studies that take into account both gender and biological factors such as hormonal status. Future research should consider stratifying participants by gender and asymmetry pattern, while also exploring the potential role of sex hormones, to better understand the mechanisms underlying these variations and to refine patient-specific approaches to care in PD.\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy limitations\u003c/em\u003e. First, the cross-sectional design does not allow conclusions to be drawn about the causality of the phenomena or about the generalization of the various possible developments after the early stage. Longitudinal studies are necessary to evaluate how the relationship between asymmetry, gender, and autonomic symptoms evolves over time. Second, the study relies exclusively on the SCOPA-AUT, a self-report questionnaire, which, while widely used, may not capture the full spectrum of dysautonomia. This limitation is particularly relevant when considering the variability of symptoms related to biological hormonal fluctuations or the use of hormonal contraceptives, which may have long-term effects on sexual and thermoregulatory functions, especially in women with PD\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. In addition, the sexual dysfunction subscale of the SCOPA-AUT may be less sensitive to female-specific concerns, potentially contributing to the observed gender differences PD. Future studies could benefit from the integration of objective tests of autonomic function, such as measurements of orthostatic heart rate variability \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, gastrointestinal manometry \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, pupillary light reflexes \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e or urinary flow rate \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, in order to validate these results, combined with measures specific to each gender. For example, Miller-Patterson, et al. \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e have suggested that different urinary mechanisms may affect women and men differently. Women are more likely to suffer from urinary incontinence, while men are more likely to experience incomplete bladder emptying and weak urinary flow. Moreover, the interaction of hormonal status with dysautonomia is not explicitly examined. Given the potential role of estrogen in modulating autonomic symptoms\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, future research should explore this interaction in more depth with scales more suited to the specificities of dysautonomic disorders according to the population, particularly in postmenopausal women\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Finally, although age and disease severity were included as covariates in the GLMM model, residual confounding cannot be entirely ruled out, particularly given the cross-sectional nature of the analysis, underscoring the need for replication in more diverse populations and with longitudinal designs.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study highlights the critical role of dopaminergic asymmetry and gender in defining subjective symptom profiles of dysautonomia in PD. The findings support the need for personalized approaches to PD management that take into account striatal denervation patterns and gender-specific symptomatology for non-motor dysfunctions. By refining our understanding of these interactions, future research may pave the way for more targeted and effective therapeutic strategies, ultimately improving patient outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eDAT-SPECT: dopamine transporter single-photon emission computed tomography; FDR: false discovery rate; GLMM: generalized linear mixed models; MDS-UPDRS 3: Movement Disorder Society-Sponsored Revision of the Unified Parkinson\u0026apos;s Disease Rating Scale; PD: Parkinson\u0026rsquo;s disease; PPMI: Parkinson\u0026apos;s Progression Markers Initiative; PwPD: patients with Parkinson\u0026rsquo;s disease; SBR: Striatal specific binding ratios; SCOPA-AUT: SCales for Outcomes in PArkinson\u0026rsquo;s disease - Autonomic Dysfunction; SOC: alpha-Synuclein Origin site and Connectome.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial disclosure and acknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by funding from the PPMI \u0026ndash; a public-private partnership \u0026ndash; is funded by the Michael J. Fox Foundation for Parkinson\u0026apos;s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson\u0026apos;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 \u0026amp; 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. Data used in the preparation of this article were obtained on [2020\u0026ndash;04\u0026ndash;01] for cognitive and DAT-SPECT data from the Parkinson\u0026apos;s Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit http://www.ppmi-info.org.\u003c/p\u003e\n\u003cp\u003eOpen access funding provided by University of Geneva. This work was supported by the Swiss National Foundation, grant N\u0026deg;: 105314_215015 (PI: Prof. Julie Anne P\u0026eacute;ron). The funders had no role in data collection, discussion of content, preparation of the manuscript, or decision to publish.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study were obtained from the PPMI database (www.ppmi-info.org/data). All data analyzed are available at www.ppmi-info.org/access-data-specimens/download-data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAN-C: writing\u0026mdash;original draft preparation; data curation; formal analysis; writing\u0026mdash;review and editing / JAP: writing-original draft; formal analysis; data curation; resources; investigation; project administration; writing\u0026mdash;review and editing; funding acquisition\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePoewe, W. Dysautonomia and cognitive dysfunction in Parkinson\u0026apos;s disease. \u003cem\u003eMovement disorders: official journal of the Movement Disorder Society\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, S374-S378 (2007).\u003c/li\u003e\n\u003cli\u003eAsahina, M., Vichayanrat, E., Low, D. 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Is there a connection between estrogen and Parkinson\u0026apos;s disease? \u003cem\u003eParkinsonism \u0026amp; related disorders\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 289-295 (2002).\u003c/li\u003e\n\u003cli\u003eKaciuba-Uscilko, H. \u0026amp; Grucza, R. Gender differences in thermoregulation. \u003cem\u003eCurrent Opinion in Clinical Nutrition \u0026amp; Metabolic Care\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 533-536 (2001).\u003c/li\u003e\n\u003cli\u003eScat\u0026agrave;, C.\u003cem\u003e et al.\u003c/em\u003e Blunted cardiac autonomic dynamics to active standing test in postmenopausal women. \u003cem\u003eFrontiers in Cardiovascular Medicine\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 1402086 (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Women's Health](https://www.nature.com/npjwomenshealth/)","snPcode":"44294","submissionUrl":"https://submission.springernature.com/new-submission/44294/3","title":"npj Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Parkinson, Striatal asymmetry, Gender, Dysautonomia","lastPublishedDoi":"10.21203/rs.3.rs-6953991/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6953991/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAutonomic symptoms are common in Parkinson\u0026rsquo;s disease and vary according to patterns of dopaminergic neurodegeneration. Based on the alpha-Synuclein Origin site and Connectome model, which distinguishes \u0026ldquo;brain-first\u0026rdquo; and \u0026ldquo;body-first\u0026rdquo; Parkinson\u0026rsquo;s disease phenotypes, this study investigates how striatal denervation asymmetry and gender influence autonomic dysfunction profiles in early-stage, treatment-naive Parkinson\u0026rsquo;s disease. Using data from the Parkinson's Progression Markers Initiative (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;759), we applied generalized linear mixed models to assess SCOPA-AUT scores across subtypes of striatal denervation (left-predominant, right-predominant, symmetric), while accounting for gender. Patients with symmetric striatal denervation exhibited significantly greater overall autonomic dysfunction, particularly in sexual domains. Gender-specific effects emerged: women showed more pronounced thermoregulatory symptoms, whereas men exhibited more severe urinary and sexual dysfunction, especially in the symmetric group. These findings suggest the potential of integrating striatal denervation asymmetry and gender into Parkinson\u0026rsquo;s disease subtype characterization, with implications for personalized symptom management and therapeutic strategies from the early stages of the disease.\u003c/p\u003e","manuscriptTitle":"Striatal (a-)Symmetry Reveals Gender-Specific Autonomic Vulnerabilities in early Parkinson’s Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 08:50:10","doi":"10.21203/rs.3.rs-6953991/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-09T21:53:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-12T14:58:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-12T01:57:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271167788096101202009453031824113789253","date":"2025-07-22T13:49:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-22T06:58:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144251157830689650455323334315691884142","date":"2025-07-21T12:26:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246912798049371467685906155103594812579","date":"2025-07-09T13:18:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-07T16:25:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-27T16:51:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-25T07:57:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Women's Health","date":"2025-06-23T07:33:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Women's Health](https://www.nature.com/npjwomenshealth/)","snPcode":"44294","submissionUrl":"https://submission.springernature.com/new-submission/44294/3","title":"npj Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"14e1400c-19e0-4b41-bcb2-5bda97bb4368","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":51301788,"name":"Health sciences/Diseases"},{"id":51301789,"name":"Health sciences/Health care"}],"tags":[],"updatedAt":"2025-12-08T23:08:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-14 08:50:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6953991","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6953991","identity":"rs-6953991","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}