GRAPHICAL ABSTRACT

INTRODUCTION

Sympathetic fibers innervate the thyroid gland and are visible on ¹²³I meta-iodobenzylguanidine (¹²³I-MIBG) scintigraphy [1,2]. This observation prompted the investigation of thyroid uptake of the ¹²³I-MIBG ligand during myocardial scintigraphy in Parkinson’s disease (PD). While its significance has been reported in a few studies, clear clinical inferences have not been drawn, except for the finding that thyroid uptake is reduced in PD patients [3,4].

Early- and late-phase heart-to-mediastinum ratios (HMRs) have been extensively studied in PD [5,6]. These ratios are correlated not only with PD-associated neurodegeneration but also with motor and nonmotor burden [7-9]. Cardiac sympathetic denervation represents a promising biomarker for distinguishing between body-first PD and brain-first PD [6].

In contrast, thyroid uptake of the ligand has received limited attention. The thyroid-to-mediastinum ratio (TMR) remains poorly understood, and the optimal phase for its clinical application has not been established. Unbound iodine could confound the TMR estimation. In vivo deiodination of ¹²³I-MIBG over time can release free iodine, biasing the accurate measurement of late TMR [10]. To minimize this potential confounder, early-phase TMR was selected for analysis in this study.

This study aimed to determine whether early-stage TMR could serve as a useful parameter for characterizing the clinical features of PD.

MATERIALS & METHODS

Patients

The study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (Approval number: KC21OIDI0362), and all participants provided informed written consent. Research was conducted in accordance with the relevant guidelines and regulations.

Data from the Korean nationwide hospital-based PD (K-PD) cohort, an observational, prospective, longitudinal cohort study of the Korea National Institute of Health (The Brain Research Infrastructure for DATA Gathering and Exploration [BRIDGE] platform), was used in this study [11]. A total of 233 de novo patients with PD diagnosed between March 2016 and December 2022 at a single participating hospital in the K-PD cohort were enrolled. Diagnosis was established on the basis of the Movement Disorder Society (MDS)-PD diagnostic criteria and substantiated by positron emission tomography imaging studies using ¹⁸F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (¹⁸F-FP-CIT) [12]. Patients showed decreased dopamine transporter uptake in the striatum, predominantly in the posterior putamen.

Baseline characteristics—including age at diagnosis, sex, disease duration at the time of diagnosis, follow-up duration, and history of hypertension, diabetes mellitus, dyslipidemia, and smoking status—were investigated.

Patients were excluded if they met any of the following criteria: 1) had any symptoms or signs of atypical and/or secondary parkinsonism during follow-up; 2) had a history of diabetic neuropathy at the initial evaluation; 3) had a history of symptomatic stroke that could affect general cognition and performance; or 4) had a history of heart failure.

Patients were monitored every 3–6 months for an average follow-up period of 57.3±22.1 months. The diagnosis was confirmed by two neurologists (S.-W.Y. and J.-S.K.).

¹²³I-MIBG scintigraphy

¹²³I-MIBG scintigraphy was performed using a dual-head camera equipped with a low-energy, high-resolution collimator. Data were acquired at 30 minutes (early) and 120 minutes (late) after intravenous injection of 111 MBq of ¹²³I-MIBG. A static image was obtained using a 128×128 matrix. Regions of interest (ROIs) were manually drawn around the heart, thyroid, and mediastinum. Tracer uptake within the ROIs was used to calculate the early and late HMR, and the early TMR [10]. ¹²³IMIBG scintigraphy was repeated two to three times (Supplementary Figure 1). The mean HMR and TMR at each time point were plotted to describe the overall trajectory. Because the thyroid uptake measurements were obtained at later time points (T₁, T₂, and T₃) than the myocardial uptake measurements were, the model-predicted trajectory was extrapolated backward (Supplementary Figure 2). An example of a representative ROI is shown in Supplementary Figure 3. Pretreatment with thyroid blockade was not included in the protocol.

Unified Parkinson’s Disease Rating Scale and MDS-UPDRS

Disease severity was evaluated using either the Unified Parkinson’s Disease Rating Scale (UPDRS) or the MDS-UPDRS. A total of 134 (57.5%) patients were initially assessed using the UPDRS, and 99 (42.5%) patients were assessed using the MDS-UPDRS. Patients were subsequently re-evaluated using either instrument, as appropriate. Motor scores (Parts II and III) from the original UPDRS were converted to MDS-UPDRS equivalents according to a previously validated method [13]. Total motor scores were calculated as the sum of scaled Part II and III scores. Patients were reexamined two to five times (Supplementary Figure 1).

Neuropsychological evaluation

Neuropsychological assessments were administered by experienced psychologists who were blinded to the clinical data. Five cognitive domains were evaluated using a comprehensive neuropsychological battery, the Seoul Neuropsychological Screening Battery, 2nd edition (SNSB-II) [14-17]. Subtests representing each domain were selected as follows: the attention/working memory domain comprised the Digit Span Forward Test and the Korean-Color Word Stroop Test (K-CWST); the frontal/executive domain included the Digit Span Backward Test and the Controlled Oral Word Association Test (COWAT) of phonemic fluency. Language and visuospatial domains were assessed using the Korean-Boston Naming Test (K-BNT) and the Rey Complex Figure Test (RCFT), respectively. Verbal and visual memory domains were investigated separately, with subdomains of immediate recall, delayed recall, and recognition, using the Seoul Verbal Learning Test (SVLT) and RCFT, respectively. Z scores of each subtest were averaged within their respective domains.

Global cognitive efficiency, calculated as the mean of the domain scores, as well as the Clinical Dementia Rating (CDR) and its Sum of Box (SOB), were analyzed. Cognitive function was reevaluated two to five times (Supplementary Figure 1).

Questionnaires

Patients were evaluated using the following questionnaires: 1) the Non-Motor Symptoms Scale (NMSS) [18], 2) the 39-item Parkinson’s Disease Questionnaire (PDQ39) [19], and 3) the Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT) [20]. Each patient was re-evaluated two to three times with the same set of questionnaires (Supplementary Figure 1). All assessments were conducted by raters who were blinded to the patients’ clinical information.

Head-up tilt test

All patients were examined in the full resting state. Continuous electrocardiography and noninvasive BP monitoring were applied. Patients remained in the supine position for 20 minutes, while BP and heart rate (HR) were recorded every 5 minutes before tilting to 60°. During the tilt phase, measurements were taken at 0, 3, 5, 10, 15, and 20 minutes.

After excluding the supine BP at 0 minutes, the mean supine SBP and DBP were calculated from the values obtained at 5, 10, 15, and 20 minutes. Supine hypertension (SH) was defined as an average supine SBP and/or DBP ≥140/90 mm Hg [21].

The lowest orthostatic SBP and DBP values (SBP_min/DBP_min) observed at 3 or 5 minutes during tilting were used to diagnose orthostatic hypotension (OH). Orthostatic BP changes in systole (ΔSBP_min) and diastole (ΔDBP_min) were calculated as the difference between the average supine BP and the lowest orthostatic BP. For patients with SH, OH was defined as an ΔSBP_min and/or an ΔDBP_min ≥30/15 mm Hg within 5 minutes; otherwise, a threshold of ≥20/10 mm Hg was applied [22]. The orthostatic HR at 3 minutes was used to calculate the change in HR (ΔHR) from the mean supine HR. The ΔHR/ΔSBP ratio at 3 minutes was calculated to identify neurogenic OH [23,24].

The mean arterial pressure (MAP) in the supine and orthostatic MAP (MAP_standing) were computed from the corresponding SBP/DBP and SBP_min/DBP_min, respectively. A MAP_standing <75 mm Hg (MAP75) was considered clinically significant [25,26]. A total of 233 patients were evaluated at the time of diagnosis (Supplementary Figure 1).

24-hour ambulatory BP monitoring

Automated 24-hour BPs were measured every 15 minutes during the day and every 30 minutes at night. The average SBP, DBP, and HR during the day, night, and over 24-hour periods were evaluated. The coefficients of variation (CVs) for SBP and DBP were calculated as the parameters of BP variability [27]. Nocturnal falls in mean BP between daytime and nighttime were manipulated to subdivide patients. Those with more than 10% nocturnal fall in mean BP were considered “dippers”; those without this fall were otherwise considered as “nondippers” [27]. Nocturnal hypertension (NH) was defined as an average nighttime BP ≥120/70 mm Hg [27].

Two hundred thirty-three patients were assessed at the time of diagnosis (Supplementary Figure 1).

Statistical analyses

Statistical analyses were conducted with R (version 4.5.1; https://cran.r-project.org) for Mac (Apple Inc., Cupertino, CA, USA). Partial correlations adjusted for age and disease duration at diagnosis were estimated by the psych package (version 2.5.6; https://CRAN.R-project.org/package=psych) and correlation package (version 0.8.8; https://CRAN.R-project.org/package=correlation). Random intercept linear mixed models with repeated measures adjusted for appropriate covariates were constructed using the nlme package (version 3.1; https://CRAN.R-project.org/package=nlme). Dependent variables were square root or log transformed when their distributions were right skewed. To accommodate zero values, a log-plus-one transformation was performed on the variable when needed.

The initial TMR (T0) for the early phase was predicted by the mixed model adjusted for age and disease duration (Supplementary Figure 2 and Supplementary Table 1). Its model-implied predictions were utilized for partial correlations between the initial work-ups, and they also served as a person-level predictor for cross-level interaction with time to explore its influence on the progression of other clinical indicators in mixed models.

Random intercept mixed modeling, controlled by covariates, was applied with the residual correlation structure restricted by the autoregressive process of order 1 (AR1). The models were estimated by restricted maximum likelihood to investigate the influence of estimated TMR (T₀; time-invariant predictor) on motor function, nonmotor severity, cognition, and quality of life (QoL) across cumulative disease duration. Within-subject intervals of any specific investigations between two consecutive time points were not evenly spaced, and every examination was not performed simultaneously. At each time point other than T₀, only subsets of investigations were performed for each individual. Thus, the cumulative disease duration was calculated separately for its respective evaluation tools. The intervals of the successive assessments were summed to determine the disease duration at diagnosis.

Statistical significance was defined as a two-tailed p value<0.05. Multiple comparisons were adjusted by the false discovery rate correction method, as appropriate.

RESULTS

Baseline characteristics

Patients with early PD (n=233) were enrolled and followed longitudinally (Table 1 and Supplementary Figure 1). The mean age at diagnosis was 68.7±8.7 years, and 121 patients (51.9%) were male. The median disease duration at diagnosis was 1.0 years (interquartile range [IQR], 0.5–1.5 years), and the mean follow-up period was 57.3±22.1 months. The median Hoehn & Yahr (H&Y) stage was 2.0 (IQR, 1.0–2.0). The converted MDS-UPDRS parts II and III and their sum were 5.0 (IQR, 3.0–9.0), 18.8±10.6, and 22.6±15.6, respectively.

¹²³I-MIBG scintigraphy was performed at 2–3-year intervals (Supplementary Figure 1). The average heart and thyroid uptake ratios were plotted over time, revealing linear negative associations (Supplementary Figure 2). The early-phase TMR at T0 was predicted using a mixed model on the basis of its empirical linearity (the dark blue dotted-dashed line, Supplementary Figure 2 and Supplementary Table 1). The observed early and late HMRs and model-expected TMR at baseline were 1.54± 0.30, 1.52±0.36, and 1.50±0.15, respectively.

At baseline, 34 (14.6%) patients had SH, and 57 (24.5%) had OH. Sixty-eight (29.2%) patients showed a clinically significant drop in MAP75_standing. A total of 205 patients (88.0%) were classified as nondippers, and approximately 58% (119/205) of these had concomitant NH.

The mean z score across all the cognitive domains was -0.22±0.71, and the median CDR score was 0.5. The median nonmotor burden was 19.0 (IQR, 10.0–39.0). The PDQ39 summary index (SI) score was 7.8 (IQR, 4.1–15.0), and the total SCOPA-AUT score was 6.0 (IQR, 3.0–14.0).

Associations between initial organ-specific sympathetic tone and clinical features

Linear associations between heart and thyroid uptake ratios and clinical characteristics were analyzed (Figure 1 and Table 2). Although the associations were modest, lower HMRs were inversely correlated with orthostatic BP fluctuations, severe motor dysfunction, great nonmotor burden, overall dysautonomia, and poor QoL. Reduced cardiac sympathetic tone was associated with greater orthostatic drops in BP (ΔSBP_min, ΔDBP_min, and ΔMAP) and greater autonomic burden (SCOPA-AUT, total). A decreased HMR also corresponded to greater impairment in motor and nonmotor functions and poorer QoL (UPDRS Part II, NMSS score, PDQ39SI). These associations remained significant after correction for multiple comparisons.

Conversely, the TMR did not show any consistent relationships with the other clinical indicators, and the correlations were too weak to yield meaningful inferences. However, when BP fluctuations were dichotomized into clinical subtypes, lower HMR and early TMR were comparably associated with the occurrence of SH and OH. Furthermore, reduced thyroid uptake was correlated with the occurrence of NH and the combined nondipper/NH phenotype, both of which remained significant after multiple comparison adjustment. Interestingly, TMR was inversely associated with ΔSBP_min, ΔMAP and the presence of OH but lost its associations with the nondipper/NH phenotype after normalization of the late HMR (Supplementary Table 2).

Longitudinal significance of the TMR

The sum of motor scores (converted MDS-UPDRS Part II and III), global cognition (average z scores of subdomains), and nonmotor burden and QoL (NMSS score, PDQ39SI) were repeatedly assessed (Supplementary Figure 1). The effect of the predicted TMR (T₀) on the progression of each score was analyzed across the disease course (Figure 2 and Supplementary Table 3). Overall, the associations were inconsistent and did not reach statistical significance (predicted TMR vs. cumulative disease duration; Supplementary Table 3). A more preserved TMR was associated with a steeper increase in motor severity but with slower rates of cognitive decline over time (Models A and C; estimates of slopes 0.14 and 0.01, respectively). Conversely, reduced thyroid sympathetic integrity was associated with increased NMSS and PDQ39SI scores over the disease course (Models B and D).

DISCUSSION

Patients with early PD were evaluated for sympathetic innervation in both the heart and thyroid glands simultaneously. Uptake ratios referenced to the mediastinum were calculated for both early- and delayed-phase cardiac scans and for the early phase of the thyroid. Orthostatic and circadian BP instabilities were also assessed at diagnosis. Motor severity, cognition, nonmotor burden, and QoL were repeatedly evaluated in this cohort.

The initial observed and predicted sympathetic tone of the heart and thyroid were associated with various clinical indicators. Myocardial denervation correlated with orthostatic BP fluctuations, greater nonmotor burdens, and poorer QoL. In contrast, thyroid sympathetic tone showed no consistent associations and did not predict clinically meaningful disease progression. However, reduced thyroid uptake was related to specific phenotypes of orthostatic and circadian BP dysregulation.

This cohort comprised early PD patients in mild stages who were followed for a considerable period. The disease stage at diagnosis was relatively homogeneous, and diagnoses were confirmed by regular monitoring. This homogeneity strengthened the validity of the observed linear associations between organ-specific ratios and clinical markers, minimizing potential confounding effects.

The initial TMR (T₀) was estimated rather than directly measured (Supplementary Figure 2). The prediction was comparable to the ratios of the heart (T₀). The homogeneity of the cohort enhanced the reliability of the model-implied predictions, enabling subsequent association analyses.

Longitudinally, the decreasing pattern of the TMR paralleled that of the late-phase HMR. Both started at similar baseline values, declined at comparable rates, and eventually converged (Supplementary Figure 2; T₀–T₃). Late-phase HMR is recognized as a robust indicator of cardiac sympathetic nerve integrity and pathology [28]. Previous studies have also suggested that its values closely reflect PD-related characteristics [6,8,9]. The similarity between early-phase TMR and late-phase HMR trajectories suggests that TMR might also serve as an adequate marker of PD-related sympathetic dysfunction. As in myocardial nerve endings, the uptake of the ¹²³I-MIBG radioligand in the thyroid (TMR) reflects the integrity of presynaptic sympathetic innervation through its noradrenaline transporter mechanism [8].

In this cohort, cardiac denervation demonstrated inverse linear relationships with several measures of dysautonomia and motor and nonmotor features. Although these associations were modest, the results aligned with those of previous reports [9,29]. Reduced myocardial sympathetic tone correlated with greater motor and nonmotor severity and blunting of the overshoot phase IV during the Valsalva maneuver [30]. These findings implied impaired baroreflex-mediated sympathetic regulation, explaining the inverse relationship between cardiac denervation and reductions in systolic, diastolic, and mean arterial BP. More extensive denervation in the myocardium was also associated with worse motor function, greater dysautonomia and a greater nonmotor burden, and poorer QoL in this study.

Thyroid uptake ratios did not indicate how much BP variability was attributable to thyroid denervation. Nevertheless, lower thyroid sympathetic tone correlated with the presence of SH, OH, and a clinically significant decrease in orthostatic BP. Reduced thyroid uptake was also associated with circadian BP dysregulation, a relationship not observed with the HMR. These findings indicate that thyroid uptake evaluation may complement cardiac denervation assessment in early PD patients with cardiovascular comorbidities [3,31].

Because of the close parallel trajectories between the early TMR and late HMR, the late HMR was additionally adjusted for the partial correlation analyses (Supplementary Table 2). The results for the thyroid uptake ratios differed: a loss of association with circadian BP dysregulation but a gain of an inverse relationship with positional changes in BP. These findings were consistent with the association between cardiac denervation and orthostatic BP fluctuations, bolstering the role of thyroid uptake measurement. This finding could be attributed to the indirect impairment of baroreflex-mediated sympathetic tone as a result of cardiac denervation [30]. These findings need to be interpreted with caution because the organ-specific ratios were measured at different time points (early vs. late).

The thyroid uptake ratios did not significantly influence longitudinal changes in the motor or nonmotor domains of PD patients (Figure 2 and Supplementary Table 3). However, the data suggested that worsening nonmotor burden, cognitive decline, and QoL deterioration might be related to the extent of thyroid denervation. Interestingly, greater preservation of thyroid innervation was associated with paradoxical motor progression. Motor and nonmotor features and QoL in PD patients are interrelated. The effects of more preserved nonmotor features and QoL in the less denervated subpopulation could translate into better motor performance in the early development of the disease. Its mediational influence needs to be tested in another study.

Overall, in early PD, the initial status of the sympathetic innervation of the thyroid appeared to reflect positional and circadian adrenergic dysregulation. This measure may also serve as a prognostic marker for disease progression, particularly for nonmotor symptoms and QoL.

Concurrent assessment of thyroid uptake with myocardial sympathetic imaging minimized additional radioligand exposure and enabled direct comparisons between thyroid and cardiac uptake ratios using the mediastinum as a shared reference. Because PD patients frequently have comorbid cardiovascular diseases, interpreting myocardial uptake alone can be challenging. Simultaneous thyroid uptake evaluation may thus provide an alternative approach to assessing sympathetic dysfunction in PD patients. The concurrent measurement of thyroid uptake could also reflect the pathobiology of body-first PD, particularly in its prodrome, when myocardial uptake could be confounded by comorbidity [6,7]. This study also included a large, longitudinally followed cohort and performed extensive correlation analyses with multiple clinical markers—an approach not accomplished in previous research.

This study, however, has several limitations. First, baseline thyroid uptake ratios (T₀) were not directly measured but were estimated using a mixed model. This may have introduced bias in the variance and forced the data to fit a linear trajectory, even if the true empirical trend was nonlinear (e.g., negative exponential). Nonetheless, the estimates were acceptable, as the observed trend was approximately linear and paralleled that of cardiac uptake degradation across the time points (Supplementary Figure 2). The model also explained a substantial proportion of the variance in repeated measures (conditional R², 0.50; Supplementary Table 1). The model-implied estimates had a narrower standard deviation than the measured heart ratios. This could have resulted in a lower autonomic burden than reflected by the HMR. Second, a notable dropout rate occurred during the follow-up period, which may have contributed to inconsistent longitudinal findings. Despite the lack of statistical significance, the trends suggested that preserved baseline thyroid sympathetic innervation could be associated with less cognitive decline, lower nonmotor burden, and better QoL. The prognostic role of thyroid sympathetic tone warrants further investigation in larger cohorts. Unevenly spaced dropout patterns across investigations also limited the comparisons of baseline characteristics between those who completed follow-ups and those who did not. Third, a standardized ROI for thyroid imaging is lacking. In this study, a subregion of the thyroid was selected, and uptake ratios were referenced to the same area of the mediastinum as the heart to minimize overestimation. Finally, pretreatment for thyroid blockade was not included in the myocardial scintigraphy protocol. This could raise concerns about the undesirable uptake of free iodine in the thyroid, limiting the interpretation of our results. However, the amount of free iodine was considered to be less than 2% in its preparation, and a previous study refuted the usefulness of thyroid blockade because there was no significant difference between those who were pretreated and those who were not [1].

In conclusion, ¹²³I-MIBG thyroid uptake did not predict significant disease progression in this cohort but emerged as a potential adjuvant tool for assessing BP dysregulation at diagnosis. Furthermore, the TMR may hold prognostic value for worse outcomes, particularly in patients with more severe baseline sympathetic denervation.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This research was supported by the “Korea National Institute of Health” research project (2024ER100202 awarded to Joong-Seok Kim). The Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1I1A1A01050492/RS-2021-NR065151 awarded to Sang-Won Yoo) supported this. This was also supported by the NRF grant funded by the Korea government (Ministry of Science and ICT, RS-2024-00452428 awarded to Sang-Won Yoo), and the Ministry of Science, ICT and Future Planning (NRF-2017R1D1A1B06028086/RS-2017-NR027859 awarded to Joong-Seok Kim).

Acknowledgments

None

Author Contributions

Conceptualization: Sang-Won Yoo, Joong-Seok Kim. Data curation: Sang-Won Yoo. Formal analysis: Sang-Won Yoo, Joong-Seok Kim. Funding acquisition: Sang-Won Yoo, Joong-Seok Kim. Investigation: Sang-Won Yoo, Dong-Woo Ryu, Yoonsang Oh, Joong-Seok Kim. Methodology: Sang-Won Yoo, Seunggyun Ha, Joong-Seok Kim. Visualization: Sang-Won Yoo. Writing—original draft: Sang-Won Yoo, Joong-Seok Kim. Writing—review & editing: all authors.

Figure 1.

Correlogram between initial workups (T₀). The calculated ratio values of ¹²³I-MIBG scintigraphy were correlated with those of other clinical indicators. Pearson’s or Spearman’s coefficients were estimated after partializing for age and disease duration at diagnosis. *Modelimplied TMRs. SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; CV, coefficient of variation; NMSS, Non-Motor Symptoms Scale; PDQ39SI, 39-item Parkinson’s Disease Questionnaire summary index; SCOPA-AUT, Scale for Outcomes in Parkinson’s Disease-Autonomic; TMR, thyroid-to-mediastinum ratio; HMR, heart-to-mediastinum ratio.

Figure 2.

Trajectories of motor, nonmotor, global cognitive, and quality of life measures across disease duration. (A) Total motor scores (Part II+Part III), (B) nonmotor burden (NMSS), (C) global cognitive function, and (D) quality of life (PDQ39SI). The MDS-UPDRS Part II+III, NMSS, and PDQ39SI scores were square-root or log-transformed for analyses. The colored shaded areas indicate 95% confidence intervals. TMR, thyroid-to-mediastinum ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; CV, coefficient of variation; NMSS, Non-Motor Symptoms Scale; PDQ39SI, 39-item Parkinson’s Disease Questionnaire summary index; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale.

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