Over the past 20 years, the Braak staging system has played a pivotal role in shaping our understanding of Parkinson’s disease (PD), proposing that α-synuclein—the defining neuropathological hallmark of PD—first emerges in the dorsal motor nucleus of the vagus nerve (Braak et al., 2003). Nevertheless, compelling postmortem studies have revealed significant limitations to this model, demonstrating that not all cases conform to its predicted progression (Parkkinen et al., 2008; Zaccai et al., 2008). Recent work has hypothesized two divergent α-synuclein spreading pathways, classified by the originating site of inclusion formation: In body-first cases, pathology first emerges in the gut or autonomic nervous system before spreading to the central nervous system (CNS), leading to earlier autonomic symptoms, while pathology in brain-first subtype originates in the CNS and spreads descendingly to the peripheral nervous system, causing prior impairment of the nigrostriatal dopaminergic system (Borghammer and Van Den Berge, 2019; Horsager et al., 2020). Our previous study represents the first longitudinal analysis of motor and non-motor symptom trajectories in brain-first and body-first PD subtypes, thereby providing further validation for the robustness of this subtyping classification system (Xu et al., 2024). However, initial body-first and brain-first models primarily focused on the propagation of α-synuclein via the vagal parasympathetic and olfactory pathways, with relatively little attention given to the role of the sympathetic nervous system. Although studies have suggested that the sympathetic nervous system may be involved in α-synuclein pathology and could serve as a potential route for its propagation, pathological validation of this pathway has long been lacking (Orimo et al., 2008; Van Den Berge et al., 2019).

Recently, Andersen et al. (2025) performed an analysis on two large postmortem datasets comprising Lewy pathology-positive cases. Unsupervised SuStaIn disease progression modeling revealed that body-first PD can be further divided into two subtypes: a sympathetic-predominant subtype, in which disease initiates in sympathetic trunk and heart, and a parasympathetic-predominant subtype, where pathology originates from DMV and locus coeruleus (Andersen et al., 2025). Although the pattern of Lewy pathology in the two subtypes was well-established in this study, clinical data remain limited. Therefore, we aimed to conduct a longitudinal analysis with clinical cohorts to investigate potential differences in PD progression between the sympathetic-predominant subtype and parasympathetic-predominant subtype.

Between putative body-first PD patients with sympathetic and parasympathetic predominance, we compared baseline demographics, motor/non-motor symptoms, and longitudinal symptom trajectories.

At baseline, a statistically significant difference in age was found between the two groups (p = 0.045). No substantial differences were observed in MDS UPDRS-III score, NMSS score, ESS score, MMSE score, BDI score, PDQ-39 score and LEDD (Table 1).

We utilized linear mixed models to assess longitudinal change in the aforementioned scales. For MDS UPDRS-III, NMSS, and ESS scores, gender, baseline age, and LEDD were included as covariates to control for potential confounders. Years of education was further adjusted when MMSE score, BDI score, and PDQ-39 score were analyzed. The results showed significant difference in MMSE score (p = 0.045), with SPS declined more rapidly (SPS group estimate β = −0.041 ± 0.008, PPS group estimate β = −0.022 ± 0.006) (Table 1 and Figure 1d). No statistical differences were found in other scales (Table 1 and Figure 1).

We then focused on assessments of specific cognitive domains, including SDMT, similarities test, VFT, AVLT, and CFT, which represent attention-processing speed domain, executive function domain, language domain, memory domain and visuospatial function domain, respectively. However, no significant differences in these assessments were observed both at baseline and during disease progression between the two groups (Supplementary Table 1 and Supplementary Figure 1).

To account for potential confounding by age, we performed propensity score matching between groups and re-analyzed the data. After eliminating the difference of baseline age, no statistical differences exist in demographic profiles and baseline clinical characteristics, while the rate of MMSE decline remained significantly higher in the putative SPS group (p = 0.045) (Supplementary Table 2).

The present study represents the first attempt to utilized clinical cohorts to investigate the symptomatic differences of the putative sympathetic and parasympathetic body-first PD. Results revealed that the putative sympathetic body-first PD patients exhibited faster cognitive decline.

At baseline, several notable differences between two groups were detected. Firstly, the SPS group demonstrated a younger mean age at evaluation and a numerically shorter disease duration (though this difference did not reach statistical significance). Notably, age at symptom onset was similar between two groups. These observations might suggest that autonomic dysfunction may become detectable earlier in SPS patients, prompting earlier clinical attention. Additionally, we noticed that only one female patient was included in the SPS group, which may partly due to the gender differences in autonomic symptoms and could act as a potential confounder in interpreting our findings. In fact, sex differences in OH appear to be reversed between the general population and patients with PD: while OH is more prevalent among women in the general population (Cheng et al., 2011), possibly due to the effects of ovarian hormones (Wenner and Stachenfeld, 2012), it is more commonly associated with male sex in PD (Chen et al., 2021; Velseboer et al., 2017). This reversal may be attributed to the fact that most female PD patients are postmenopausal and have experienced a sharp decline in ovarian hormone levels (Knowlton and Lee, 2012). However, a more recent study reported no substantial difference in overall incidence rates between sexes, although a significant age–sex interaction was observed, with a steeper age-related increase among males than females (Bhanu et al., 2022). In addition, a study focusing on patients with PD found no significant sex difference between patients with and without OH, suggesting that sex distribution in OH remains uncertain (Wang et al., 2025). Although whether gender difference of constipation exists in PD patients remains unclear, evidence from studies on functional gastroenterologic disorders indicates that constipation tends to be more prevalent in women (Narayanan et al., 2021). These findings may partially explain the uneven distribution in sex within our cohort, which still requires validation in larger cohorts.

In the longitudinal analysis, we observed that the putative SPS group demonstrated a significantly faster rate of decline in MMSE score, and this difference persisted even after matching patients for baseline age. No significant differences were observed regarding the progression of cognitive domain-specific tests, possibly due to limited statistical power from the small sample size. To our knowledge, we are the first to investigate sympathetic vs. non-sympathetic subtypes within the body-first phenotype of PD, making it challenging to directly validate our findings against existing study. However, previous studies on PD with OH - a population known to have significant sympathetic involvement - have similarly demonstrated more rapid progression of cognitive decline and quality of life deterioration compared with PD without OH (Merola et al., 2018; Pilleri et al., 2013; Yoo et al., 2021). Our current work takes this a step further by identifying a distinct sympathetic-predominant subtype (SPS) within the body-first classification. However, it worth noticing that OH is a possible factor contributing to cognitive deterioration by causing transient cerebral hypoperfusion (Strumia et al., 2023), and it remains unclear whether OH directly causes cognitive decline or acts indirectly by accelerating PD progression (Wang et al., 2025). Whether the proposed putative SPS represents the most rapidly progressive subtype will require verification through larger prospective cohort studies.

Despite these findings, the study has several limitations. Firstly, given the limited availability of polysomnography, the RBDSQ was used as a pragmatic screening tool. Although it shows good diagnostic accuracy in the general population, misclassification cannot be excluded. Also, due to the lack of pathology information, we used clinical features – OH and constipation – to categorize body-first patients into more specific subtypes. While we recognize these represent only partial manifestations of autonomic dysfunction (with sympathetic involvement potentially including thermoregulatory abnormalities and parasympathetic dysfunction extending to urinary/bowel symptoms), our approach provides a clinically accessible framework for initial subtyping. Future refinements could incorporate comprehensive autonomic assessments using validated scales like SCOPA-AUT, enabling a continuous approach to quantify the relative sympathetic and parasympathetic burden and supporting validation of the proposed PD subtyping. Additionally, based on a small sample size, our use of strict inclusion criteria—which required participants to exhibit only one of the two symptoms (either OH or constipation)—inevitably resulted in fewer eligible participants. This limited sample size may affect the generalizability of our findings. Furthermore, the long duration of the disease could result in recall bias. Therefore, the validity of the results should be verified through both large-scale prospective studies and biomarker corroboration, including PET imaging, ¹²³I-MIBG scintigraphy and α-synuclein seeding amplification assays (α-syn SAA), to establish clinicopathological concordance.

In conclusion, this study provided clinical characteristics of the newly proposed two subtypes within body-first PD. We detected that putative sympathetic body-first PD patients exhibited a significantly faster decline in MMSE score, suggesting a tendency toward more rapid cognitive deterioration. Given the small sample size and the modest effect size, these findings should be interpreted cautiously and considered exploratory in nature. Future investigations should focus on validating this novel subtyping model in independent cohorts and elucidating the distinct neurobiological mechanisms underlying these subtypes. Such efforts will be crucial for developing targeted therapeutic strategies and advancing precision medicine approaches in PD management.