INTRODUCTION

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the accumulation of Lewy bodies and loss of dopaminergic neurons within the substantia nigra. Preceding the emergence of motor symptoms, patients experience a spectrum of non-motor symptoms, among which lower urinary tract symptoms (LUTS) are notably prevalent, affecting 27%–85% of PD patients [1]. Typically, LUTS in PD manifest as storage symptoms such as nocturia, frequency, urgency, and incontinence, which significantly disrupt social life, sleep quality, and overall quality of life [2, 3]. Despite their clinical significance, the precise mechanisms and predictive factors of LUTS in PD remain unclear. While dopaminergic dysfunction and frontal disinhibition are proposed as major contributors [4, 5], LUTS likely involves various central and peripheral neuroanatomical structures, requiring comprehensive evaluation.

The Lewy body, composed of misfolded α-synuclein, is a hallmark of PD pathology and its propagation is key to disease progression and clinical manifestations. Recently, the “body-first” versus “brain-first” PD subtypes have been proposed based on the origination and spread of α-synuclein pathology [6-8]. In the body-first subtype it is proposed that there is initial α-synuclein emergence in the enteric nervous system, followed by propagation to the central nervous system via autonomic nerves. Conversely, in the brain-first subtype it is proposed that Lewy pathology originates within the central nervous system, such as the amygdala and olfactory bulb [9]. While people with body-first PD exhibited a higher prevalence of non-motor symptoms including orthostatic hypotension, cognitive impairment, and constipation, differences in LUTS between subtypes remain unclear, as questionnaire-based studies revealed conflicting results [9].

Urodynamic studies (UDS) are a useful method to assess urological function, particularly in patients with neurogenic bladder. Although numerous studies have characterized UDS findings in PD, comparative investigations across PD subtypes are lacking. In this study, we aimed to identify whether the urological functions showed disparities between body-first and brain-first PD subtypes, based on UDS and urological questionnaire assessments.

METHODS

Patient population

In this retrospective study, participants were enrolled in two university hospitals in South Korea between August 2017 and May 2021. We included patients diagnosed with PD, aged between 40 and 85 years, with a disease duration of less than 3 years, and who had undergone uroflowmetry (UFM) or UDS. The diagnosis of PD was made by movement disorder specialists according to the UK Parkinson's Disease Society Brain Bank criteria, and dopaminergic denervation was confirmed by 18F-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography scans [10]. Brain magnetic resonance imaging was also performed to exclude other structural causes. Patients who did not undergo cardiac meta-iodobenzylguanidine (MIBG) or complete a rapid eye movement sleep behavior disorder (RBD) questionnaire were excluded. Participants visited the outpatient clinic regularly and, during the follow-up period of at least 2 years, individuals exhibiting indicative signs of atypical parkinsonian syndromes were excluded. In particular, multiple system atrophy was excluded if participants fulfilled clinically established/probable multiple system atrophy criteria based on recent diagnostic criteria [11]. Patients who had comorbidities possibly influencing cardiac MIBG, such as diabetic or autonomic neuropathy, heart failure or ischemic heart disease, and end-stage renal disease were excluded. Participants with a history of pelvic organ surgery were also excluded. For male participants, benign prostatic hypertrophy was excluded from comprehensive evaluation through clinical history and transrectal ultrasonography by an experienced urologist (J.K.K.) [12]. Patients with prostate-specific antigen levels >4.0 ng/mL were also excluded (Figure 1).

RESULTS

Comparison of UDS and urological questionnaires

Urodynamic parameters of voiding volume (from free UFM) and FDV (in the filling phase of UDS) were significantly lower in the body-first PD group. Q_max, P_detQ_max and PVR were comparable between the groups. The prevalence of detrusor overactivity was higher in the body-first PD group but did not achieve statistical significance (Figure 2a). There were no significant differences in the prevalence of detrusor underactivity, compliance, or bladder outlet obstruction between the groups (Table 2).

TABLE 2. Comparison of urodynamic study and urological questionnaires between body-first PD and brain-first PD groups.

	Body-first PD (n = 37)	Brain-first PD (n = 18)	p
UFM
Qmax, cm/s	15.0 ± 10.3	18.7 ± 6.8	0.219
Voided volume, mL	161.4 ± 93.6	268.3 ± 122.4	<0.001 *
PVR, mL	45.1 ± 64.6	18.6 ± 21.6	0.158
UDS
MBC, mL	333.6 ± 111.8	358.1 ± 108.2	0.315
FDV, mL	145.3 ± 59.7	204.3 ± 90.0	0.023 *
P det Q max	34.4 ± 16.1	21.7 ± 9.7	0.123
BCI	92.5 ± 32.5	72.4 ± 39.9	0.109
Detrusor overactivity, n (%)	12 (50.0)	2 (22.2)	0.241
Bladder outlet obstruction, n (%)	2 (8.3)	0 (0)	0.999
Detrusor underactivity, n (%)	3 (12.5)	3 (33)	0.309
IPSS
Quality of life	3.1 ± 1.2	2.5 ± 2.4	0.216
Storage score	5.8 ± 4.1	3.5 ± 3.2	0.016 *
Voiding score	5.1 ± 5.0	2.6 ± 2.8	0.083
Total score	10.9 ± 7.8	6.1 ± 5.6	0.023 *
OABSS
Total score	5.2 ± 3.3	2.7 ± 2.1	0.010 *
OAB, n (%)	20 (60.6)	2 (12.5)	0.001 *
Voiding diary
MVV, mL	341.9 ± 128.5	250.6 ± 68.4	0.020 *
AVV, mL	3965 ± 1678	3623 ± 1427	0.350
Number of voids	7.9 ± 2.8	7.0 ± 3.1	0.472
Number of nocturia events	1.3 ± 0.8	1.8 ± 1.4	0.251

• Note: Mean ± standard deviation or number (percentage).
• Abbreviations: AVV, average voided volume; BCI, bladder compliance index; FDV, first-desire volume; IPSS, International Prostate Symptom Scale; MBC, maximal bladder capacity; MVV, maximum voided volume; OAB, overactive bladder; OABSS, Overactive Bladder Symptom Score; PVR, post-void residual volume; P_detQ_max, detrusor pressure at maximum flow rate; Q_max, maximal flow rate; UDS, urodynamic study; UFM, uroflowmetry.
• * Bold indicate significant p < 0.05; p value was adjusted for age, sex, and H&Y stage.

Urological questionnaire scores showed significant differences between groups. The OABSS total score, IPSS total score, and IPSS-s score were significantly higher in the body-first PD group than the brain-first PD group. Voiding diary parameters were comparable between groups, but maximum voided volume was higher in the body-first PD group (Table 2). The prevalence of OAB determined by OABSS was higher in the body-first PD than the brain-first PD group (60.6% vs. 12.5%; p = 0.001 [Figure 2b]). Among questions on LUTS, the “frequency” score from the IPSS questionnaire and “urgency” from the OABSS questionnaire showed higher scores in the body-first PD group. The urinary domain of the NMSS questionnaires did not differ between groups (Table S1).

Correlation between cardiac MIBG scintigraphy and urological parameters

Delayed H/M ratio showed a positive correlation with voiding volume (r = 0.376, p = 0.005), and was negatively correlated with OABSS (Figure 3 and Table S2). Between the urological evaluations, the OABSS score and IPSS-s score exhibited a strong correlation with each other (r = 0.773, p < 0.001).

Multiple linear regression analysis identified that delayed H/M ratio was independently associated with urological parameters, including voiding volume (ß = 0.369, p = 0.009) and FDV (ß = 0.390, p = 0.031), and was negatively associated with total OABSS, IPSS, and IPSS-s. PVR and IPSS-v scores did not show a significant association (Table 3).

TABLE 3. Multiple linear regression of factors associated with urological parameters.

	Voiding volume	FDV	PVR	OABSS	IPSS	IPSS-s	IPSS-v
Age
β	−0.105	−0.195	−0.006	0.182	0.005	0.103	−0.082
p	0.520	0.389	0.975	0.291	0.977	0.552	0.685
Disease duration (years)
β	0.129	−0.323	0.222	0.052	0.158	0.091	0.179
p	0.520	0.087	0.152	0.722	0.343	0.551	0.313
MIBG delayed H/M ratio
β	0.369	0.390	−0.138	−0.356	−0.361	−0.379	−0.260
p	0.009 *	0.031 *	0.357	0.016 *	0.035 *	0.017 *	0.148
H&Y stage
β	0.031	0.188	−0.160	0.199	0.256	0.375	0.092
p	0.181	0.447	0.403	0.276	0.235	0.063	0.688
UPDRS-III
β	−0.271	−0.258	−0.055	−0.114	−0.068	−0.065	−0.054
p	0.079	0.198	0.741	0.369	0.709	0.697	0.779
K-MMSE
β	0.080	0.187	−0.064	−0.141	−0.164	−0.160	−0.129
p	0.618	0.409	0.721	0.406	0.382	0.355	0.520

• Abbreviations: FDV, first-desire volume; H&Y, Hoehn and Yarr; H/M, heart-to-mediastinum; IPSS, International Prostate Symptom Score; IPSS-s, IPSS storage subscore; IPSS-v, IPSS voiding subscore; MIBG, meta-iodobenzylguanidine; MMSE, Mini-Mental State Examination; OABSS, Overactive Bladder Symptom Score; PVR, post-void residual volume; UPDRS, Unified Parkinson's Disease Rating Scale; β, standardized regression coefficient.
• * Bold indicate significant p < 0.05.

DISCUSSION

This is the first study to compare urological function between the body-first and brain-first subtypes of PD using comprehensive urodynamic assessments. The major findings of our study were as follows. First, patients with body-first PD had lower FDV and voiding volume, indicative of decreased bladder storage function in the UDS. Second, the body-first PD group had a higher incidence of OAB and exhibited more severe LUTS than the brain-first PD group, based on the questionnaire. Third, cardiac MIBG uptake was significantly associated with urological parameters in early-stage PD.

In our study, the UDS results indicated reduced FDV and voiding volume in the body-first subtype of PD, aligning with findings from previous studies on PD populations at large [20-23]. In addition, the questionnaire results in our study revealed a higher prevalence of urgency and frequency, with relatively rare occurrences of incontinence, consistent with observations in early PD reported in prior studies [22, 23]. These findings suggest that urinary dysfunction in body-first PD follows a similar trajectory to that observed in the general PD population, albeit with more pronounced symptoms, suggesting accelerated pathogenic processes underlying the manifestation of LUTS.

Previous research has indicated that the main pathophysiology underlying OAB in PD patients is related to the degeneration of dopaminergic pathways and disruption of the prefrontal cortex-basal ganglia circuit [1, 5]. This theory is supported by the imaging studies delineating the association between LUTS and dopamine transporter uptake [5, 24-26], as well as the improvement in LUTS symptoms following deep brain stimulation of the subthalamic nucleus or globus pallidus [27-29]. The hypothesis of dopaminergic denervation is also plausible in our findings of severe OAB in body-first PD, as explained by the faster progression of dopaminergic degeneration in this subtype [6].

Furthermore, our study revealed a correlation between CSD, as evidenced by decreased MIBG uptake, and urological dysfunction, particularly in parameters associated with storage dysfunction. These findings implicate sympathetic noradrenergic mechanisms in the development of LUTS, extending beyond the established dopaminergic contributions. The sympathetic nervous system plays a role in urine storage by facilitating the relaxation of the detrusor muscle, hence its dysfunction could contribute to OAB symptoms. Early Lewy pathology has been documented in the sympathetic trunk, including the celiac and stellate ganglia [30, 31], but the presence of α-synuclein pathology in the inferior pelvic plexus, crucial for bladder relaxation, remains underexplored. Additionally, α-synuclein deposition in the sacral dorsal root ganglia, the central hub for bladder filling sensations, may disrupt afferent signaling and contribute to detrusor overactivity [32]. Taken together, our findings raise the possibility that peripheral sympathetic denervation could contribute to LUTS in early PD. Further pathological studies providing α-synuclein pathology in the sympathetic nervous system are warranted.

Accumulating evidence suggests that PD patients with RBD, suggestive of the body-first subtype, experienced more severe autonomic dysfunction [33-37]. Nonetheless, the impact of RBD on urinary function in PD has been subject to debate. While some studies have reported a higher burden of urinary symptoms among patients with PD with RBD [36, 37], others have not observed such associations [33-35]. We hypothesized that the discrepancy might be attributed to confounding factors such as peripheral organ dysfunction or levodopa usage, or variation in RBD diagnostic methods [38]. In our study, we found significant differences in the prevalence of OAB and UDS parameters between PD patients with and without RBD. Interestingly, previous studies identified that patients with urinary dysfunction had a higher prevalence of RBD [23], earlier requirement for levodopa, and a faster disease progression [39]. These findings suggest a possible association between urinary dysfunction and the body-first PD subtype.

Our study identified significant differences in OABSS, IPSS total score and IPSS-s subscore between the body-first PD and brain-first PD groups. In contrast, no significant differences were observed within the urinary domain of the NMSS, a tool commonly applied to assess non-motor symptoms in PD patients. This discrepancy could be associated with differences in questionnaire design: the IPSS and OABSS specifically inquire about the frequency of each symptom, whereas the NMSS evaluates both the severity and frequency of symptoms, with a particular emphasis on disturbance to the patient [15]. Given that urinary symptoms are prevalent but have a lesser impact on quality of life in the early stage of PD [19], additional questionnaires such as the OABSS or IPSS could be beneficial for the assessment of urinary symptoms in early-stage PD.

Our study employed two methods to classify PD into body-first and brain-first subtypes: cardiac MIBG scintigraphy and premotor RBD. However, there are currently no widely validated criteria for distinguishing these subtypes. Although polysomnography (PSG)-proven RBD criteria are valuable for classification purposes [7], the widespread application of PSG is often challenging, and a large proportion of PD patients still rely on RBD questionnaires, which are limited in their accuracy and inter-rater reliability [40, 41]. Cardiac MIBG scintigraphy provided objective measures of CSD, one of the early-affected structures from α-synuclein propagation in the body-first subtype [42]. The relationship between MIBG uptake and RBD was well documented [43-47], supporting the utility of MIBG imaging in subtype classification of body-first and brain-first PD [17]. However, patients with brain-first PD subtypes may also develop CSD eventually after motor symptoms begin. Given that the time interval between motor onset and CSD is uncertain, categorization relying only on cardiac MIBG could lead to misdiagnosis, especially if MIBG is performed at a late stage. Taking these factors into account, we assume that cardiac MIBG is appliable for categorizing PD subtypes only in the early stage of PD, and cardiac MIBG and the RBD questionnaire provide complementary tools for accurate classification.

The main strength of this study lies in its patient selection. We conducted urological evaluations as baseline assessments for all newly diagnosed PD patients, rather than solely in those reporting LUTS, to reflect the urological characteristics of general PD patients. Additionally, we endeavored to minimize the influence of peripheral organ factors by excluding patients with benign prostatic hypertrophy based on diagnosis by a urologist using transrectal ultrasonography.

This study also has several limitations. Firstly, it was a retrospective study, and although we tried to conduct urological assessment at baseline, the potential for selection bias exists, as patients with more pronounced urological symptoms were more likely to undergo urological evaluation. Secondly, the study lacked a comprehensive evaluation linking LUTS with dopaminergic imaging. However, there were similar UPDRS part III scores in the two groups, and we adjusted for H&Y stage in the analysis of urological parameters to minimize confounding effects. Future research to explore the relationship between urodynamic assessments and dopaminergic activity is warranted to validate and expand on our findings. Thirdly, the body-first PD group was older than the brain-first PD group, without statistical significance. Although the disparity was small, we cannot rule out the influence of age in MIBG classification because of the strong correlation between age and MIBG parameters [44]. Fourthly, the body-first PD and brain-first PD groups had similar motor scores and cognitive status, inconsistent with general reports of worse motor and cognitive functions in body-first PD. These discrepancies could be associated with our study populations, which were restricted to early-stage PD. Follow-up motor and cognitive assessment is warranted to identify differences in disease progression between subtypes. Finally, the lack of PSG confirmation in the RBD diagnosis prevented a direct comparison of usefulness between MIBG scintigraphy and PSG-proven RBD, even though RBD based on the RBD1Q showed a high concordance with PSG-proven RBD [14].

In conclusion, our findings identified that individuals with body-first PD exhibited more severe urinary symptoms, and significantly decreased bladder storage function in early-stage PD. In addition, we demonstrated the association between CSD and urological dysfunction. These findings suggest that LUTS could be regarded as a feature of the body-first subtype in PD.

AUTHOR CONTRIBUTIONS

Min Seung Kim: Software; writing – original draft; conceptualization; investigation; data curation; methodology. Jong Keun Kim: Writing – original draft; methodology; data curation; investigation; validation. In Hee Kwak: Data curation; investigation; methodology. Jeongjae Lee: Data curation; investigation. Young Eun Kim: Conceptualization; writing – review and editing; supervision; funding acquisition; data curation; methodology. Hyeo-Il Ma: Methodology; writing – review and editing; formal analysis; resources. Suk Yun Kang: Conceptualization; writing – review and editing; funding acquisition; validation; supervision.

FUNDING INFORMATION

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare (S.Y.K., grant number: RS-2023-00266948 and Y.E.K., grant number: RS-2023-00265159). Y.E.K has received a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF; grant number: RS-2023-00246655) and the NRF by the Korea government (MSIT; grant number: 2022R1A2C2091254), outside of the submitted work.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

This study was approved by the institutional review boards of Dongtan Sacred Heart Hospitals and Hallym University Sacred Heart Hospitals.