MIBG uptake in the major salivary glands of patients with rapid eye movement sleep behavior disorder: a case-control pilot study

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Furthermore, pathological and neurological alterations are found in peripheral organs such as the submandibular glands (SMG) and heart in RBD, providing support for the “body-first” model of Lewy body disease. This study aimed to compare 123 I-metaiodobenzylguanidine (MIBG) uptake in the parotid glands (PG) and SMG between patients with RBD, PD patients, and controls, using a novel quantitative semi-automatic analysis method. Methods: Using the mediastinum as a reference, we evaluated MIBG uptake in the early and delayed phases in the PG, SMG, and heart. Subsequently, we compared MIBG uptake among the three groups of participants. We also evaluated the correlations between MIBG uptake and clinical data in patients with RBD. Results: Ten patients with RBD (five polysomnography-confirmed and five probable RBD), 81 PD patients, and 25 controls were included in the present study. MIBG uptake in the PG, SMG, and heart was significantly lower in patients with RBD than in controls, except for the delayed phase in the PG and SMG, although its mean value was lower in RBD than in controls. By contrast, cardiac MIBG uptake was comparable between RBD and PD patients, and was lower in both than in controls. MIBG uptake in the PG and SMG was positively correlated in the early and delayed phases in patients with RBD. Conclusions: The early phase of MIBG uptake in the PG and SMG is reduced in patients with RBD, providing support for peripheral as well as cardiac sympathetic denervation as a preclinical stage of α-synucleinopathies. Parkinson’s disease Rapid eye movement sleep behavior disorder MIBG myocardial scintigraphy Autonomic dysfunction Major salivary glands Figures Figure 1 Figure 2 Figure 3 Background Rapid eye movement sleep behavior disorder (RBD) is a parasomnia considered to be a preclinical stage of α-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy, and is an accurate indicator for phenoconversion to α-synucleinopathies [ 1 ]. Furthermore, radiological and physiological abnormalities, such as presynaptic striatal neurodegeneration demonstrated by 123 I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) single photon emission computed tomography (SPECT), known as DAT SPECT, and F-DOPA positron emission tomography, and postganglionic cardiac sympathetic denervation detected by 123 I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy and hyposmia, have been reported [ 2 – 8 ], revealing the neurodegenerative pathway of α-synucleinopathies. Prior to the involvement of the substantia nigra, pathologically hypothesized as Braak stage 3 [ 9 ], pathophysiological findings have been observed peripherally in RBD such as in the submandibular glands (SMG) [ 10 ] and skin [ 11 ] in addition to cardiac sympathetic denervation. This evidence has recently been introduced as the “body-first” model of Lewy body disease in which the onset of RBD precedes the motor symptoms [ 12 ]. We have demonstrated reduced MIBG uptake in the major salivary glands (MSG) of patients with PD and dementia with Lewy bodies using a newly developed quantitative semi-automatic method [ 13 – 15 ], consistent with previous studies [ 16 – 20 ]. Therefore, we hypothesize that patients with RBD, before the onset of motor deficits, might show extracardiac sympathetic denervation in line with PD and dementia with Lewy bodies. This pilot study aimed to evaluate MIBG uptake in the parotid glands (PG) and SMG using MIBG scintigraphy to examine peripheral as well as cardiac sympathetic denervation in patients with RBD. Methods Participants We recruited patients with suspected RBD who visited our department, including those who had already undergone polysomnography at other sleep medicine clinics. Of these, five patients were diagnosed with RBD based on polysomnography (polysomnography-confirmed RBD), and another five patients were diagnosed using the Japanese version of the RBD Screening Questionnaire (RBDSQ-J), consisting of 13 items (probable RBD). Additionally, abnormal sleep behavior was confirmed through reports from the patients’ families or bed partners. Patients with probable RBD had an RBDSQ-J score ≥ 5 [21]. Among those with probable RBD, two did not fully meet the diagnostic criteria by polysomnography and were provisionally categorized as having RBD. Furthermore, one patient scored less than 5 on the RBDSQ-J, likely due to having already started clonazepam treatment before completing the questionnaire. As a comparison with RBD, we also selected patients with PD who were diagnosed according to the current Movement Disorder Society PD diagnostic criteria [22] and clinical early established criteria [23], as well as non-parkinsonian controls, who were described previously [15]. All participants underwent MIBG scintigraphy at Toho University Omori Medical Center between October 2020 and March 2025. We excluded patients taking medications known to affect MIBG uptake, such as reserpine, tricyclic/tetracyclic antidepressants, and other psychiatric drugs [24]. Additionally, we excluded patients who had diabetes and those taking selegiline, a monoamine oxidase-B inhibitor used in PD treatment. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of Toho University Faculty of Medicine (approval number T2024-2087). We obtained written informed consent from all participants. Clinical evaluation We collected clinical data such as age at examination, duration of illness, Mini-Mental State Examination score [25], olfactory disturbance evaluated by the Odor Stick Identification Test for Japanese (OSIT-J), RBDSQ-J score, Hoehn-Yahr stage, and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part Ⅲ score [26]. Two isolated raters (J.E. and S.M.) confirmed the presence of DAT SPECT abnormalities in patients with RBD and PD in terms of the visual assessment of the striatum and the specific binding ratio. Analysis of MIBG scintigraphy After injection of 111 MBq MIBG (MyoMIBG ® ; PDRadiopharma, Inc., Tokyo, Japan), head and chest planar images were scanned at 20 min in the early phase and at 240 min in the delayed phase. The head and chest were each scanned for 5 min. As described previously [13–15], we used different scanners: (A) Infinia GP3 gamma camera (GE Healthcare, Piscataway, NJ, USA) and ELEGP collimator (GE Healthcare) between 2020 and 2021; and (B) Symbia Intevo Bold gamma camera (Siemens, Erlangen, Germany) and LMEGP collimator (Siemens) between 2021 and 2025. Planar images were scanned with a matrix size of 256 × 256. We used the revised smart MIBG software developed by PDRadiopharma, Inc. for data analysis. The detailed analysis scheme was described previously [13–15]. Imaging analysis was conducted using the semi-automatic regions of interest setting between the head and chest planar images and between the early and delayed phase images. We set the regions of interest in the left and right PG and SMG, with the heart and mediastinum as reference regions of interest. We set the size of the regions of interest in the PG and SMG as 4/radius, while we set the heart as 12/radius. We calculated MIBG uptake in the parotid/mediastinum (P/M), submandibular/mediastinum (S/M), and heart/mediastinum (H/M) using the mediastinum as a reference area. To preserve data continuity, we used the conversion coefficient because of the different scanners [27, 28]. Statistical analysis We performed all statistical analyses using SPSS statistics (IBM Japan, Tokyo, Japan). We used the Mann-Whitney U test, unpaired t -test, and Kruskal-Wallis test considering a Gaussian distribution for group comparisons. Subsequently, when statistical significance was found, we performed Dunn’s test as a post-hoc test among each two groups of all three groups. For the nominal scale, we used the chi-squared test. We additionally analyzed clinical correlations using Pearson’s or Spearman’s correlation coefficient, considering a Gaussian distribution between the MSG, heart, and clinically evaluated items, adjusting the false discovery rate in patients with RBD. Of note, the correlation analysis of patients with PD was reported previously [15]. For correlation analysis, since the PG and SMG are left-right paired organs, we used mean values for the analysis. Additionally, we investigated the difference in MIBG uptake in the MSG based on the prevalence of abnormalities in cardiac MIBG/DAT SPECT to clarify the distribution of sympathetic innervation in patients with RBD. Of note, we did not perform statistical analysis among categorized RBD groups because the number of patients with RBD was small. In MIBG myocardial scintigraphy, we set the cut-off value for cardiac MIBG uptake as 2.2 in the early and delayed phases as the Japanese standardized MIBG scintigraphic analysis method [28]. By contrast, we used DAT SPECT to determine the prevalence of abnormalities in terms of visual inspection and the specific binding ratio, as mentioned earlier. We set statistical significance at p < 0.05. Results Demographic and clinical characteristics The demographic and clinical characteristics of the participants are shown in Table 1. Among the three groups, age at examination and Mini-Mental State Examination score were comparable. Between RBD and PD, the OSIT-J score was comparable, but the RBDSQ-J score was higher in RBD. Conversely, the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part Ⅲ score was worse in patients with PD compared to those with RBD. Furthermore, we found significant differences in MIBG uptake in the MSG and heart in group comparisons. We identified DAT SPECT abnormalities in three out of nine patients with RBD (33.3%), in which one patient was polysomnography-confirmed RBD and the others were probable RBD. Table 1. Demographic and clinical characteristics RBD PD Control p -value Number of subjects (female) 10 (3)* 81 (44) 25 (9) 0.133 Age at examination (years) 75.6 ± 7.6 71.7 ±9.2 68.7 ± 14.4 0.450 MMSE 28.7 ± 2.5 26.6 ± 4.6 27.8 ± 1.8 0.133 Disease duration (years) 8.9 ± 8.1 a 3.2 ± 3.1 b NA NA OSIT-J 3.6 ± 2.2 3.5 ± 2.8 NA 0.730 RBDSQ-J 6.9 ± 3.7 4.2 ± 2.9 NA 0.031 Hoehn-Yahr stage 1.6 ± 0.2 2.4 ± 0.7 NA <0.001 MDS-UPDRS Ⅰ 3.8 ± 1.9 10.1 ± 6.1 NA <0.001 MDS-UPDRS Ⅱ 1.7 ± 2.2 11.3 ± 8.8 NA <0.001 MDS-UPDRS Ⅲ 5.6 ± 4.4 29.6 ± 16.6 NA <0.001 DAT SPECT abnormalities (%) 3/9 (33.3%)** 81/81 (100%) NA NA Early P/M 1.06 ± 0.28 1.12 ± 0.38 1.42 ± 0.33 <0.001 Delayed P/M 1.72 ± 0.35 1.65 ± 0.49 2.05 ± 0.42 <0.001 Early S/M 1.42 ± 0.31 1.34 ± 0.28 1.64 ± 0.28 <0.001 Delayed S/M 2.00 ± 0.41 1.70 ± 0.30 2.06 ± 0.29 <0.001 Early H/M 1.92 ± 0.45 2.09 ± 0.55 3.01 ± 0.40 <0.001 Delayed H/M 1.57 ± 0.40 1.74 ± 0.63 3.01 ± 0.62 <0.001 *Polysomnography-confirmed RBD = five, probable RBD = five; **Nine of 10 patients were available for DAT SPECT a Time from RBD symptoms; b Time from motor symptoms MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; MMSE, Mini-Mental State Examination; NA, not applicable Comparisons of MIBG uptake in the MSG and heart The results of the post-hoc Dunn’s test are shown in Figure 1. In the early phase in the PG and SMG, patients with RBD showed lower MIBG uptake than controls. By contrast, MIBG uptake in the delayed phase in the PG and SMG was comparable between RBD and controls. MIBG uptake in the MSG in RBD and PD was not significantly different, except for the delayed phase S/M. Conversely, cardiac MIBG uptake was lower in patients with RBD and PD than in controls in the early and delayed phases. Clinical correlations in patients with RBD P/M and S/M were positively correlated in the early and delayed phases in patients with RBD (early: r = 0.577, p = 0.008; delayed: r = 0.747, p < 0.001) (Fig. 2). Conversely, there were no significant correlations between any of the clinical features and MIBG uptake in patients with RBD. Differences in MIBG uptake in the MSG based on the prevalence of cardiac MIBG uptake and DAT SPECT abnormalities The differences in MIBG uptake in the PG and SMG in patients with RBD based on cardiac MIBG uptake and DAT SPECT abnormalities are shown in Figure 3. Of note, a patient with RBD showed a normal early phase and an abnormal delayed phase (<2.2). Therefore, the number of categorized groups of RBD was different between the early and delayed phases. P/M and S/M tended to be lower in the early and delayed phases according to the prevalence of nuclear medicine abnormalities. Discussion We demonstrated reduced MIBG uptake in the MSG and heart in the early phase in patients with RBD compared with controls. Conversely, MIBG uptake in the MSG and heart was comparable between RBD and PD patients, except for the delayed phase. To our knowledge, this is the first study to investigate MIBG uptake in the MSG in patients with RBD using a quantitative semi-automatic method. Our findings support the hypothesis that patients with RBD have decreased peripheral sympathetic innervation not only in the heart but also in the MSG, progressing from outside the nigrostriatal system in α-synucleinopathies. The present study also showed lower cardiac MIBG uptake in patients with RBD, consistent with previous studies [ 4 – 6 , 8 ], providing support for the “body-first” model of Lewy body disease [ 12 ] as a preclinical stage of α-synucleinopathies. We found similar correlations between MIBG uptake in the PG and SMG; however, we did not find a correlation between the MSG and heart in patients with RBD, as well as in patients with Lewy body disease, but not in patients with progressive supranuclear palsy and non-parkinsonian controls, as shown in our previous studies [ 13 , 15 ]. We hypothesize that this probably shows the widespread distribution of sympathetic denervation in α-synucleinopathies. In fact, we previously demonstrated that patients with PD who had sympathetic denervation in the MSG and heart showed more advanced non-motor features [ 14 ]. Furthermore, we found that RBD patients with a combination of abnormalities, i.e., nigrostriatal degeneration and cardiac sympathetic denervation, tended to have lower MIBG uptake in the MSG than those without either of these abnormalities. Thus, this evidence provides support for the expansion of sympathetic denervation in α-synucleinopathies. Conversely, we did not find a significant difference in the delayed phase P/M and S/M between RBD and controls, although their mean values were lower in RBD patients than in controls. We hypothesized that the small number of patients with RBD was the reason for the absence of a difference from non-parkinsonian controls. Furthermore, generally in cardiac MIBG uptake in Lewy body disease, injected MIBG, which is a physiological analog of noradrenaline, passes through the cardiac sympathetic nerves between the early (20 min) and delayed (240 min) phases because of sympathetic denervation, thereby increasing the washout ratio. Thus, the early phase contributes to disease specificity, while the delayed phase contributes to disease sensitivity. Although it remains unclear why there are differences in the physiological dynamics of MIBG in a living body between the MSG and heart, cardiac sympathetic nerves are more likely to be affected by neuronal damage [ 29 ]. However, we previously demonstrated that the early phase MIBG uptake in the MSG, particularly in the PG, showed higher specificity than MIBG uptake in the delayed phase [ 13 – 15 ]. Therefore, further large-scale investigations of polysomnography-confirmed cases are needed. The present study has several limitations that should be considered. First, as mentioned earlier, since it included a small number of patients with RBD, statistical robustness should be reconsidered in larger-scale studies, especially focusing on the delayed phase values. Additionally, we should objectively confirm the presence of rapid eye movement sleep without atonia by polysomnography since sufficient specificity cannot be gained using the RBD screening questionnaire [ 30 ]. Second, the relationship between sympathetic innervation and pathological alterations in the MSG remains unclear in α-synucleinopathies. Additionally, it remains unknown whether the pathological progression of α-synucleinopathies simply shows dichotomization, for example, in terms of the cognitive dysfunction observed in RBD [ 31 – 33 ]. However, a recent study demonstrated that patients with body-first Lewy body disease showed not only parasympathetic tract involvement but also sympathetic tract involvement, indicating the progression of neurodegeneration outside of the brain [ 34 ]. Lastly, this was a cross-sectional study and we should pay attention to phenoconversion to Lewy body disease in future studies. Conclusions This current cross-sectional pilot study examining MIBG uptake in the MSG in patients with RBD demonstrated sympathetic denervation in the early phase, probably supporting peripheral lesions as a preclinical stage of α-synucleinopathies. Abbreviations H/M, heart/mediastinum MIBG, 123 I-metaiodobenzylguanidine MSG, major salivary glands OSIT-J, Odor Stick Identification Test for Japanese PD, Parkinson’s disease PG, parotid glands P/M, parotid/mediastinum RBD, rapid eye movement sleep behavior disorder RBDSQ-J, Japanese version of the RBD Screening Questionnaire S/M, submandibular/mediastinum SMG, submandibular glands SPECT, single photon emission computed tomography Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of Toho University Faculty of Medicine (approval number T2024-2087). Written informed consent was obtained from all participants. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by Akira Nemoto Research Grant, Toho University Faculty of Medicine, and JSPS KAKENHI Grant Number JP25K19041. Authors' contributions JE contributed to the conception of the study, design of the work, data acquisition, analysis, interpretation of data, drafting of the manuscript, and its revision. MS, JN, and TH contributed to the interpretation of data. SM contributed to the conception of the study and interpretation of data. OK contributed to the conception of the study, interpretation of data, and manuscript revision. All authors approved the submitted version of the manuscript, and agreed to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Acknowledgements We thank the participants in the present study. We thank PDRadiopharma, Inc. for revising the smart MIBG ® software used in the present study. References Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson's disease. Mov Disord. 2015;30:1600–11. Iranzo A, Santamaría J, Valldeoriola F, et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann Neurol. 2017;82:419–28. Arnaldi D, Chincarini A, Hu MT, et al. 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Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals. Nat Neurosci. 2025;28:925–36. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 22 Mar, 2026 Reviews received at journal 13 Mar, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers invited by journal 26 Dec, 2025 Editor assigned by journal 26 Dec, 2025 Editor invited by journal 10 Dec, 2025 Submission checks completed at journal 08 Dec, 2025 First submitted to journal 08 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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10:33:49","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":92547,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7955348/v1/83b77dc090795f3131b719b4.html"},{"id":99320253,"identity":"a624fe09-49a6-4efb-b3c9-54502c06d495","added_by":"auto","created_at":"2025-12-31 16:38:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":153883,"visible":true,"origin":"","legend":"\u003cp\u003eComparisons of MIBG uptake among the three groups\u003c/p\u003e\n\u003cp\u003eThe results of the \u003cem\u003epost-hoc\u003c/em\u003eDunn’s test are shown for the P/M, S/M, and H/M in the early and delayed phases. The \u003cem\u003ep\u003c/em\u003e-values shown are between two groups. MIBG uptake in the early and delayed phase P/M, early phase S/M, and early and delayed phase H/M was lower in RBD patients than in controls, except for the delayed phase S/M. By contrast, MIBG uptake in the early and delayed phase P/M, S/M, and H/M was lower in PD patients than in controls. Conversely, the delayed phase S/M was lower in PD patients than in RBD patients, but the other items were comparable.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7955348/v1/0e5ae93c77145520f1484f03.png"},{"id":99290842,"identity":"348c5ed8-396d-4e74-838d-8a5a29164cb7","added_by":"auto","created_at":"2025-12-31 10:33:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36389,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between P/M and S/M in patients with RBD\u003c/p\u003e\n\u003cp\u003eScatter plots between P/M and S/M are shown in the early and delayed phases. In patients with RBD, a positive correlation was found between P/M and S/M in the early and delayed phases.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7955348/v1/613e79996aacf3738840f717.png"},{"id":99319218,"identity":"c09f78f4-2c54-4214-9bfb-69bee3f676da","added_by":"auto","created_at":"2025-12-31 16:36:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":70090,"visible":true,"origin":"","legend":"\u003cp\u003eDifferences in MIBG uptake in the MSG based on cardiac MIBG uptake/DAT SPECT abnormalities\u003c/p\u003e\n\u003cp\u003eOn the basis of the prevalence of abnormalities in cardiac MIBG uptake and DAT SPECT, MIBG uptake in the MSG was divided into four groups in the early phase and three groups in the delayed phase. Despite no significant differences between the groups, MIBG uptake in the PG and SMG tended to be lower according to the number of cardiac MIBG uptake and DAT SPECT abnormalities.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7955348/v1/8e0301fb38c4158f7ff17f11.png"},{"id":99324036,"identity":"aa3f2058-8c0e-4b1b-9c20-ceb90b8b0f13","added_by":"auto","created_at":"2025-12-31 16:46:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":836909,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7955348/v1/ae97b822-49ab-4d55-a406-a13ac114d260.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"MIBG uptake in the major salivary glands of patients with rapid eye movement sleep behavior disorder: a case-control pilot study","fulltext":[{"header":"Background","content":"\u003cp\u003eRapid eye movement sleep behavior disorder (RBD) is a parasomnia considered to be a preclinical stage of α-synucleinopathies, such as Parkinson\u0026rsquo;s disease (PD), dementia with Lewy bodies, and multiple system atrophy, and is an accurate indicator for phenoconversion to α-synucleinopathies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, radiological and physiological abnormalities, such as presynaptic striatal neurodegeneration demonstrated by \u003csup\u003e123\u003c/sup\u003eI-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) single photon emission computed tomography (SPECT), known as DAT SPECT, and F-DOPA positron emission tomography, and postganglionic cardiac sympathetic denervation detected by \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine (MIBG) myocardial scintigraphy and hyposmia, have been reported [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], revealing the neurodegenerative pathway of α-synucleinopathies.\u003c/p\u003e \u003cp\u003ePrior to the involvement of the substantia nigra, pathologically hypothesized as Braak stage 3 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], pathophysiological findings have been observed peripherally in RBD such as in the submandibular glands (SMG) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and skin [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] in addition to cardiac sympathetic denervation. This evidence has recently been introduced as the \u0026ldquo;body-first\u0026rdquo; model of Lewy body disease in which the onset of RBD precedes the motor symptoms [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. We have demonstrated reduced MIBG uptake in the major salivary glands (MSG) of patients with PD and dementia with Lewy bodies using a newly developed quantitative semi-automatic method [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], consistent with previous studies [\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, we hypothesize that patients with RBD, before the onset of motor deficits, might show extracardiac sympathetic denervation in line with PD and dementia with Lewy bodies. This pilot study aimed to evaluate MIBG uptake in the parotid glands (PG) and SMG using MIBG scintigraphy to examine peripheral as well as cardiac sympathetic denervation in patients with RBD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe recruited patients with suspected RBD who visited our department, including those who had already undergone polysomnography at other sleep medicine clinics. Of these, five patients were diagnosed with RBD based on polysomnography (polysomnography-confirmed RBD), and another five patients were diagnosed using the Japanese version of the RBD Screening Questionnaire (RBDSQ-J), consisting of 13 items (probable RBD). Additionally, abnormal sleep behavior was confirmed through reports from the patients\u0026rsquo; families or bed partners. Patients with probable RBD had an RBDSQ-J score \u0026ge; 5 [21]. Among those with probable RBD, two did not fully meet the diagnostic criteria by polysomnography and were provisionally categorized as having RBD. Furthermore, one patient scored less than 5 on the RBDSQ-J, likely due to having already started clonazepam treatment before completing the questionnaire. As a comparison with RBD, we also selected patients with PD who were diagnosed according to the current Movement Disorder Society PD diagnostic criteria [22] and clinical early established criteria [23], as well as non-parkinsonian controls, who were described previously [15].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll participants underwent MIBG scintigraphy at Toho University Omori Medical Center between October 2020 and March 2025. We excluded patients taking medications known to affect MIBG uptake, such as reserpine, tricyclic/tetracyclic antidepressants, and other psychiatric drugs [24]. Additionally, we excluded patients who had diabetes and those taking selegiline, a monoamine oxidase-B inhibitor used in PD treatment.\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of Toho University Faculty of Medicine (approval number T2024-2087). We obtained written informed consent from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe collected clinical data such as age at examination, duration of illness, Mini-Mental State Examination score [25], olfactory disturbance evaluated by the Odor Stick Identification Test for Japanese (OSIT-J), RBDSQ-J score, Hoehn-Yahr stage, and Movement Disorder Society-Unified Parkinson\u0026rsquo;s Disease Rating Scale part Ⅲ score [26]. Two isolated raters (J.E. and S.M.) confirmed the presence of DAT SPECT abnormalities in patients with RBD and PD in terms of the visual assessment of the striatum and the specific binding ratio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of MIBG scintigraphy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter injection of 111 MBq MIBG (MyoMIBG\u003csup\u003e\u0026reg;\u003c/sup\u003e; PDRadiopharma, Inc., Tokyo, Japan), head and chest planar images were scanned at 20 min in the early phase and at 240 min in the delayed phase. The head and chest were each scanned for 5 min. As described previously [13\u0026ndash;15], we used different scanners: (A) Infinia GP3 gamma camera (GE Healthcare, Piscataway, NJ, USA) and ELEGP collimator (GE Healthcare) between 2020 and 2021; and (B) Symbia Intevo Bold gamma camera (Siemens, Erlangen, Germany) and LMEGP collimator (Siemens) between 2021 and 2025. Planar images were scanned with a matrix size of 256 \u0026times; 256.\u003c/p\u003e\n\u003cp\u003eWe used the revised smart MIBG software developed by PDRadiopharma, Inc. for data analysis. The detailed analysis scheme was described previously [13\u0026ndash;15]. Imaging analysis was conducted using the semi-automatic regions of interest setting between the head and chest planar images and between the early and delayed phase images. We set the regions of interest in the left and right PG and SMG, with the heart and mediastinum as reference regions of interest. We set the size of the regions of interest in the PG and SMG as 4/radius, while we set the heart as 12/radius. We calculated MIBG uptake in the parotid/mediastinum (P/M), submandibular/mediastinum (S/M), and heart/mediastinum (H/M) using the mediastinum as a reference area. To preserve data continuity, we used the conversion coefficient because of the different scanners [27, 28].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe performed all statistical analyses using SPSS statistics (IBM Japan, Tokyo, Japan). We used the Mann-Whitney U test, unpaired \u003cem\u003et\u003c/em\u003e-test, and Kruskal-Wallis test considering a Gaussian distribution for group comparisons. Subsequently, when statistical significance was found, we performed Dunn\u0026rsquo;s test as a \u003cem\u003epost-hoc\u003c/em\u003e test among each two groups of all three groups. For the nominal scale, we used the chi-squared test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe additionally analyzed clinical correlations using Pearson\u0026rsquo;s or Spearman\u0026rsquo;s correlation coefficient, considering a Gaussian distribution between the MSG, heart, and clinically evaluated items, adjusting the false discovery rate in patients with RBD. Of note, the correlation analysis of patients with PD was reported previously [15]. For correlation analysis, since the PG and SMG are left-right paired organs, we used mean values for the analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, we investigated the difference in MIBG uptake in the MSG based on the prevalence of abnormalities in cardiac MIBG/DAT SPECT to clarify the distribution of sympathetic innervation in patients with RBD. Of note, we did not perform statistical analysis among categorized RBD groups because the number of patients with RBD was small. In MIBG myocardial scintigraphy, we set the cut-off value for cardiac MIBG uptake as 2.2 in the early and delayed phases as the Japanese standardized MIBG scintigraphic analysis method [28]. By contrast, we used DAT SPECT to determine the prevalence of abnormalities in terms of visual inspection and the specific binding ratio, as mentioned earlier. We set statistical significance at \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic and clinical characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe demographic and clinical characteristics of the participants are shown in Table 1. Among the three groups, age at examination and Mini-Mental State Examination score were comparable. Between RBD and PD, the OSIT-J score was comparable, but the RBDSQ-J score was higher in RBD. Conversely, the Movement Disorder Society-Unified Parkinson\u0026rsquo;s Disease Rating Scale part Ⅲ score was worse in patients with PD compared to those with RBD.\u003c/p\u003e\n\u003cp\u003eFurthermore, we found significant differences in MIBG uptake in the MSG and heart in group comparisons. We identified DAT SPECT abnormalities in three out of nine patients with RBD (33.3%), in which one patient was polysomnography-confirmed RBD and the others were probable RBD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eDemographic and clinical characteristics\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eRBD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNumber of subjects\u0026nbsp;\u003cbr\u003e\u0026nbsp;(female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e10 (3)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e81 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e25 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge at examination\u003cbr\u003e\u0026nbsp;(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e75.6 \u0026plusmn; 7.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e71.7 \u0026plusmn;9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e68.7 \u0026plusmn; 14.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMMSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e28.7 \u0026plusmn; 2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e26.6 \u0026plusmn; 4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e27.8 \u0026plusmn; 1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDisease duration (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8.9 \u0026plusmn; 8.1\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3.2 \u0026plusmn; 3.1\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eOSIT-J\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.6 \u0026plusmn; 2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3.5 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.730\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eRBDSQ-J\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6.9 \u0026plusmn; 3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4.2 \u0026plusmn; 2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eHoehn-Yahr stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.6 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.4 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMDS-UPDRS Ⅰ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.8 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e10.1 \u0026plusmn; 6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMDS-UPDRS Ⅱ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.7 \u0026plusmn; 2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11.3 \u0026plusmn; 8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMDS-UPDRS Ⅲ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5.6 \u0026plusmn; 4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e29.6 \u0026plusmn; 16.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDAT SPECT abnormalities (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3/9 (33.3%)**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e81/81 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eEarly P/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.06 \u0026plusmn; 0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.12 \u0026plusmn; 0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.42 \u0026plusmn; 0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDelayed P/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.72 \u0026plusmn; 0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.65 \u0026plusmn; 0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.05 \u0026plusmn; 0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eEarly S/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.42 \u0026plusmn; 0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.34 \u0026plusmn; 0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.64 \u0026plusmn; 0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDelayed S/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.00 \u0026plusmn; 0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.70 \u0026plusmn; 0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.06 \u0026plusmn; 0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eEarly H/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.92 \u0026plusmn; 0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.09 \u0026plusmn; 0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3.01 \u0026plusmn; 0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDelayed H/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.57 \u0026plusmn; 0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.74 \u0026plusmn; 0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3.01 \u0026plusmn; 0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e*Polysomnography-confirmed RBD = five, probable RBD = five; **Nine of 10 patients were available for DAT SPECT\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Time from RBD symptoms; \u003csup\u003eb\u003c/sup\u003e Time from motor symptoms\u003c/p\u003e\n\u003cp\u003eMDS-UPDRS, Movement Disorder Society-Unified Parkinson\u0026rsquo;s Disease Rating Scale; MMSE, Mini-Mental State Examination; NA, not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of MIBG uptake in the MSG and heart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the \u003cem\u003epost-hoc\u003c/em\u003e Dunn\u0026rsquo;s test are shown in Figure 1. In the early phase in the PG and SMG, patients with RBD showed lower MIBG uptake than controls. By contrast, MIBG uptake in the delayed phase in the PG and SMG was comparable between RBD and controls. MIBG uptake in the MSG in RBD and PD was not significantly different, except for the delayed phase S/M. Conversely, cardiac MIBG uptake was lower in patients with RBD and PD than in controls in the early and delayed phases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical correlations in patients with RBD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP/M and S/M were positively correlated in the early and delayed phases in patients with RBD (early: \u003cem\u003er\u0026nbsp;\u003c/em\u003e= 0.577, \u003cem\u003ep\u003c/em\u003e = 0.008; delayed: \u003cem\u003er\u003c/em\u003e = 0.747, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) (Fig. 2). Conversely, there were no significant correlations between any of the clinical features and MIBG uptake in patients with RBD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDifferences in MIBG uptake in the MSG based on the prevalence of cardiac MIBG uptake and DAT SPECT abnormalities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe differences in MIBG uptake in the PG and SMG in patients with RBD based on cardiac MIBG uptake and DAT SPECT abnormalities are shown in Figure 3. Of note, a patient with RBD showed a normal early phase and an abnormal delayed phase (\u0026lt;2.2). Therefore, the number of categorized groups of RBD was different between the early and delayed phases. P/M and S/M tended to be lower in the early and delayed phases according to the prevalence of nuclear medicine abnormalities.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe demonstrated reduced MIBG uptake in the MSG and heart in the early phase in patients with RBD compared with controls. Conversely, MIBG uptake in the MSG and heart was comparable between RBD and PD patients, except for the delayed phase. To our knowledge, this is the first study to investigate MIBG uptake in the MSG in patients with RBD using a quantitative semi-automatic method. Our findings support the hypothesis that patients with RBD have decreased peripheral sympathetic innervation not only in the heart but also in the MSG, progressing from outside the nigrostriatal system in α-synucleinopathies. The present study also showed lower cardiac MIBG uptake in patients with RBD, consistent with previous studies [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], providing support for the \u0026ldquo;body-first\u0026rdquo; model of Lewy body disease [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] as a preclinical stage of α-synucleinopathies.\u003c/p\u003e \u003cp\u003eWe found similar correlations between MIBG uptake in the PG and SMG; however, we did not find a correlation between the MSG and heart in patients with RBD, as well as in patients with Lewy body disease, but not in patients with progressive supranuclear palsy and non-parkinsonian controls, as shown in our previous studies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We hypothesize that this probably shows the widespread distribution of sympathetic denervation in α-synucleinopathies. In fact, we previously demonstrated that patients with PD who had sympathetic denervation in the MSG and heart showed more advanced non-motor features [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, we found that RBD patients with a combination of abnormalities, i.e., nigrostriatal degeneration and cardiac sympathetic denervation, tended to have lower MIBG uptake in the MSG than those without either of these abnormalities. Thus, this evidence provides support for the expansion of sympathetic denervation in α-synucleinopathies.\u003c/p\u003e \u003cp\u003eConversely, we did not find a significant difference in the delayed phase P/M and S/M between RBD and controls, although their mean values were lower in RBD patients than in controls. We hypothesized that the small number of patients with RBD was the reason for the absence of a difference from non-parkinsonian controls. Furthermore, generally in cardiac MIBG uptake in Lewy body disease, injected MIBG, which is a physiological analog of noradrenaline, passes through the cardiac sympathetic nerves between the early (20 min) and delayed (240 min) phases because of sympathetic denervation, thereby increasing the washout ratio. Thus, the early phase contributes to disease specificity, while the delayed phase contributes to disease sensitivity. Although it remains unclear why there are differences in the physiological dynamics of MIBG in a living body between the MSG and heart, cardiac sympathetic nerves are more likely to be affected by neuronal damage [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. However, we previously demonstrated that the early phase MIBG uptake in the MSG, particularly in the PG, showed higher specificity than MIBG uptake in the delayed phase [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, further large-scale investigations of polysomnography-confirmed cases are needed.\u003c/p\u003e \u003cp\u003eThe present study has several limitations that should be considered. First, as mentioned earlier, since it included a small number of patients with RBD, statistical robustness should be reconsidered in larger-scale studies, especially focusing on the delayed phase values. Additionally, we should objectively confirm the presence of rapid eye movement sleep without atonia by polysomnography since sufficient specificity cannot be gained using the RBD screening questionnaire [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Second, the relationship between sympathetic innervation and pathological alterations in the MSG remains unclear in α-synucleinopathies. Additionally, it remains unknown whether the pathological progression of α-synucleinopathies simply shows dichotomization, for example, in terms of the cognitive dysfunction observed in RBD [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, a recent study demonstrated that patients with body-first Lewy body disease showed not only parasympathetic tract involvement but also sympathetic tract involvement, indicating the progression of neurodegeneration outside of the brain [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Lastly, this was a cross-sectional study and we should pay attention to phenoconversion to Lewy body disease in future studies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis current cross-sectional pilot study examining MIBG uptake in the MSG in patients with RBD demonstrated sympathetic denervation in the early phase, probably supporting peripheral lesions as a preclinical stage of α-synucleinopathies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eH/M, heart/mediastinum\u003c/p\u003e\n\u003cp\u003eMIBG, \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine\u003c/p\u003e\n\u003cp\u003eMSG, major salivary glands\u003c/p\u003e\n\u003cp\u003eOSIT-J, Odor Stick Identification Test for Japanese\u003c/p\u003e\n\u003cp\u003ePD, Parkinson\u0026rsquo;s disease\u003c/p\u003e\n\u003cp\u003ePG, parotid glands\u003c/p\u003e\n\u003cp\u003eP/M, parotid/mediastinum\u003c/p\u003e\n\u003cp\u003eRBD, rapid eye movement sleep behavior disorder\u003c/p\u003e\n\u003cp\u003eRBDSQ-J, Japanese version of the RBD Screening Questionnaire\u003c/p\u003e\n\u003cp\u003eS/M, submandibular/mediastinum\u003c/p\u003e\n\u003cp\u003eSMG, submandibular glands\u003c/p\u003e\n\u003cp\u003eSPECT, single photon emission computed tomography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of Toho University Faculty of Medicine (approval number T2024-2087). Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Akira Nemoto Research Grant, Toho University Faculty of Medicine, and JSPS KAKENHI Grant Number JP25K19041.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJE contributed to the conception of the study, design of the work, data acquisition, analysis, interpretation of data, drafting of the manuscript, and its revision. MS, JN, and TH contributed to the interpretation of data. SM contributed to the conception of the study and interpretation of data. OK contributed to the conception of the study, interpretation of data, and manuscript revision. All authors approved the submitted version of the manuscript, and agreed to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the participants in the present study. We thank PDRadiopharma, Inc. for revising the smart MIBG\u003csup\u003e\u0026reg;\u003c/sup\u003e software used in the present study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBerg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson\u0026apos;s disease. Mov Disord. 2015;30:1600\u0026ndash;11.\u003c/li\u003e\n\u003cli\u003eIranzo A, Santamar\u0026iacute;a J, Valldeoriola F, et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann Neurol. 2017;82:419\u0026ndash;28.\u003c/li\u003e\n\u003cli\u003eArnaldi D, Chincarini A, Hu MT, et al. Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder. Brain. 2021;144:278\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eKnudsen K, Fedorova TD, Hansen AK, et al. 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Parkinsonism Relat Disord. 2022;103:129\u0026ndash;35.\u003c/li\u003e\n\u003cli\u003eBraak H, Del Tredici K, R\u0026uuml;b U, et al. Staging of brain pathology related to sporadic Parkinson\u0026apos;s disease. Neurobiol Aging. 2003;24:197\u0026ndash;211.\u003c/li\u003e\n\u003cli\u003eVilas D, Iranzo A, Tolosa E, et al. Assessment of \u0026alpha;-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol. 2016;15:708\u0026ndash;18.\u003c/li\u003e\n\u003cli\u003eIranzo A, Mammana A, Mu\u0026ntilde;oz-Lopetegi A, et al. Misfolded \u0026alpha;-synuclein assessment in the skin and CSF by RT-QuIC in isolated REM sleep behavior disorder. Neurology. 2023;100:e1944\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eHorsager J, Andersen KB, Knudsen K, et al. Brain-first versus body-first Parkinson\u0026apos;s disease: a multimodal imaging case-control study. Brain. 2020;143:3077\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eEbina J, Mizumura S, Ishii N, et al. Reduced \u003csup\u003e123\u003c/sup\u003eI-MIBG uptake in the parotid and submandibular glands in patients with Parkinson\u0026apos;s disease identified using a quantitative semi-automatic method. J Neurol. 2023;270:4385\u0026ndash;92.\u003c/li\u003e\n\u003cli\u003eEbina J, Mizumura S, Morioka H, et al. Clinical characteristics of patients with Parkinson\u0026apos;s disease with reduced \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine uptake in the major salivary glands and heart. J Neurol Sci. 2024;458:122932.\u003c/li\u003e\n\u003cli\u003eEbina J, Mizumura S, Shibukawa M, et al. Comparison of MIBG uptake in the major salivary glands between Lewy body disease and progressive supranuclear palsy. Clin Park Relat Disord. 2024;11:100287.\u003c/li\u003e\n\u003cli\u003eHaqparwar J, Pepe A, Fassbender K, et al. Reduced MIBG accumulation of the parotid and submandibular glands in idiopathic Parkinson\u0026apos;s disease. Parkinsonism Relat Disord. 2017;34:26\u0026ndash;30.\u003c/li\u003e\n\u003cli\u003eSoboll L, Leppert D, Dillmann U, et al. MIBG scintigraphy of the major salivary glands in multiple system atrophy. Parkinsonism Relat Disord. 2018;53:112\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eSchubert E, Dogan S, Dillmann U, et al. MIBG scintigraphy of the major salivary glands in progressive supranuclear palsy and corticobasal degeneration. Parkinsonism Relat Disord. 2019;66:247\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eLi S, Yue L, Chen S, et al. High clinical diagnostic accuracy of combined salivary gland and myocardial metaiodobenzylguanidine scintigraphy in the diagnosis of Parkinson\u0026apos;s disease. Front Aging Neurosci. 2023;14:1066331.\u003c/li\u003e\n\u003cli\u003eLamotte G, Holmes C, Sullivan P, et al. Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies. Ann Clin Transl Neurol. 2020;7:2450\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eMiyamoto T, Miyamoto M, Iwanami M, et al. The REM sleep behavior disorder screening questionnaire: validation study of a Japanese version. Sleep Med. 2009;10:1151\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003ePostuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson\u0026apos;s disease. Mov Disord. 2015;30:1591\u0026ndash;601.\u003c/li\u003e\n\u003cli\u003eBerg D, Adler CH, Bloem BR, et al. Movement disorder society criteria for clinically established early Parkinson\u0026apos;s disease. Mov Disord. 2018;33:1643\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eJacobson AF, Travin MI. Impact of medications on mIBG uptake, with specific attention to the heart: comprehensive review of the literature. J Nucl Cardiol. 2015;22:980\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eMori E, Mitani Y, Yamadori A. Usefulness of a Japanese version of the Mini-Mental State Test in neurological patients. Jpn J Neuropsychol. 1985;1:82-90 (in Japanese). \u003c/li\u003e\n\u003cli\u003eGoetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson\u0026apos;s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23:2129\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eNakajima K, Okuda K, Matsuo S, et al. Standardization of metaiodobenzylguanidine heart to mediastinum ratio using a calibration phantom: effects of correction on normal databases and a multicentre study. Eur J Nucl Med Mol Imaging. 2012;39:113\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eNakajima K, Okuda K, Yoshimura M, et al. Multicenter crosscalibration of I-123 metaiodobenzylguanidine heart-to-mediastinum ratios to overcome camera-collimator variations. J Nucl Cardiol. 2014;21:970\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eIsonaka R, Sullivan P, Goldstein DS. Pathophysiological significance of increased \u0026alpha;-synuclein deposition in sympathetic nerves in Parkinson\u0026rsquo;s disease: a post-mortem observational study. Transl Neurodegener. 2022;11:15.\u003c/li\u003e\n\u003cli\u003eStefani A, Serradell M, Holzknecht E, et al. Low specificity of rapid eye movement sleep behavior disorder questionnaires: need for better screening methods. Mov Disord. 2023;38:1000\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eMiyamoto M, Miyamoto T. Montreal Cognitive Assessment predicts the short-term risk of Lewy body disease in isolated REM sleep behavior disorder with reduced MIBG scintigraphy. Mov Disord Clin Pract. 2022;10:32\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eCogn\u0026eacute; \u0026Eacute;, Postuma RB, Chasles MJ, et al. Montreal Cognitive Assessment and the Clock Drawing Test to identify MCI and predict dementia in isolated REM sleep behavior disorder. Neurology. 2024;102:e208020.\u003c/li\u003e\n\u003cli\u003eMay\u0026agrave; G, Iranzo A, Gaig C, et al. Post-mortem neuropathology of idiopathic rapid eye movement sleep behaviour disorder: a case series. Lancet Neurol. 2024;23:1238\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eAndersen KB, Krishnamurthy A, Just MK, et al. Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals. Nat Neurosci. 2025;28:925\u0026ndash;36.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, Rapid eye movement sleep behavior disorder, MIBG myocardial scintigraphy, Autonomic dysfunction, Major salivary glands","lastPublishedDoi":"10.21203/rs.3.rs-7955348/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7955348/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Rapid eye movement sleep behavior disorder (RBD) is a preclinical stage of α-synucleinopathies such as Parkinson’s disease (PD). Furthermore, pathological and neurological alterations are found in peripheral organs such as the submandibular glands (SMG) and heart in RBD, providing support for the “body-first” model of Lewy body disease. This study aimed to compare \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine (MIBG) uptake in the parotid glands (PG) and SMG between patients with RBD, PD patients, and controls, using a novel quantitative semi-automatic analysis method.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Using the mediastinum as a reference, we evaluated MIBG uptake in the early and delayed phases in the PG, SMG, and heart. Subsequently, we compared MIBG uptake among the three groups of participants. We also evaluated the correlations between MIBG uptake and clinical data in patients with RBD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Ten patients with RBD (five polysomnography-confirmed and five probable RBD), 81 PD patients, and 25 controls were included in the present study. MIBG uptake in the PG, SMG, and heart was significantly lower in patients with RBD than in controls, except for the delayed phase in the PG and SMG, although its mean value was lower in RBD than in controls. By contrast, cardiac MIBG uptake was comparable between RBD and PD patients, and was lower in both than in controls. MIBG uptake in the PG and SMG was positively correlated in the early and delayed phases in patients with RBD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e The early phase of MIBG uptake in the PG and SMG is reduced in patients with RBD, providing support for peripheral as well as cardiac sympathetic denervation as a preclinical stage of α-synucleinopathies.\u003c/p\u003e","manuscriptTitle":"MIBG uptake in the major salivary glands of patients with rapid eye movement sleep behavior disorder: a case-control pilot study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-31 10:33:44","doi":"10.21203/rs.3.rs-7955348/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-22T12:29:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-13T18:15:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251246382947538220205567183122167905234","date":"2026-02-18T21:37:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"147964831662509625009632817974323464017","date":"2026-02-17T20:14:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"250234951506523659514442540252513675265","date":"2026-02-16T21:57:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-26T08:16:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-26T08:13:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-10T18:49:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-08T08:49:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-12-08T08:41:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a98e5387-6193-4ea5-85d6-1001f21658b4","owner":[],"postedDate":"December 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-31T10:33:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-31 10:33:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7955348","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7955348","identity":"rs-7955348","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}