
==== Front
BMC Neurol
BMC Neurol
BMC Neurology
1471-2377
BioMed Central London

3822
10.1186/s12883-024-03822-w
Research
Blunted tachycardia and cardiac sympathetic denervation in isolated rapid eye movement sleep behavior disorder
Saeda Shota 1
Sumi Yukiyoshi 2
Fujiwara Koichi fujiwara.koichi@hps.material.nagoya-u.ac.jp

1
Kadotani Hiroshi 2
1 https://ror.org/04chrp450 grid.27476.30 0000 0001 0943 978X Department of Materials Process Engineering, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, Aichi 464-8601 Japan
2 https://ror.org/00d8gp927 grid.410827.8 0000 0000 9747 6806 Department of Psychiatry, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192 Japan
4 9 2024
4 9 2024
2024
24 31722 5 2024
26 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Isolated rapid eye movement sleep behavior disorder (iRBD) serves as a prodromal phase of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Blunted tachycardia (BT) during postural changes indicates neurogenic orthostatic hypotension, a marker of autonomic dysfunction. We aimed to investigate whether BT is associated with cardiac sympathetic neurogenic denervation. Additionally, we conducted a preliminary short-term follow-up to examine the potential prognostic significance of BT regarding phenoconversion and mortality.

Methods

Forty-three patients with iRBD at Shiga University of Medical Science Hospital underwent active standing tests to identify BT, defined by a specific ratio of decrease in systolic blood pressure to inadequate increase in heart rate after standing, and orthostatic hypotension. 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG) and dopamine transporter single-photon emission computed tomography (DAT-SPECT) were performed. Participants were followed up for 3.4 ± 2.4 years for phenoconversion and 4.0 ± 2.3 years for mortality assessment, and the risk of events was analyzed using log-rank tests.

Results

Among the 43 participants (mean age, 72.3 ± 7.9 years; 8 female), 17 met the BT criteria. We found no significant comorbidity-related differences in hypertension or diabetes between the BT(+) and BT(-) groups. Orthostatic hypotension was more prevalent in the BT(+) group than in the BT(-) group (47.1% vs 7.7%, p = 0.003). BT(+) patients were older with a lower early and delayed MIBG uptake; however, no significant differences were observed in DAT accumulation. Phenoconversion was observed in seven (41.2%) BT(+) and seven (26.9%) BT(-) patients. Three deaths were recorded in the BT(+) group (17.6%) and three in the BT(-) group (11.5%). No significant differences were observed in the risk of phenoconversion or mortality between the groups.

Conclusions

We have identified the possibility that BT reflects cardiac sympathetic neurogenic denervation in patients with iRBD. Future research is needed to elucidate the potential prognostic value of BT.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12883-024-03822-w.

Keywords

Autonomic dysfunction
Blunted tachycardia
Longitudinal study
Orthostatic hypotension
Phenoconversion
Rapid eye movement sleep behavior disorder
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Rapid eye movement (REM) sleep behavior disorder (RBD) is a type of REM parasomnia characterized by dream-enacting behaviors [1, 2]. Approximately 1% of middle-aged and older adults have RBD, confirmed by polysomnography [3, 4]. RBD has been considered a prodromal phase and an early manifestation of various neurodegenerative diseases, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) [2, 5]. RBD that occurs independently and has not yet progressed to PD, DLB, or MSA and is not associated with other causative conditions, such as tumors, brainstem strokes, or autoimmune diseases, is termed isolated RBD (iRBD) [6]. Notably, a significant proportion of patients with iRBD eventually develop neurodegenerative diseases, such as PD or DLB (82.4% at 10.5 years of follow-up) [7]. In iRBD, various symptoms and abnormalities emerge, similar to those in PD or DLB, including autonomic nervous system dysfunctions, such as orthostatic hypotension (OH) [8], constipation, and urinary symptoms [9]; minor cognitive impairments [10]; psychiatric symptoms, such as minor hallucinations [11] and depression [12]; and abnormal findings in cardiac sympathetic innervation assessed using 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG) and dopamine transporter (DAT) single-photon emission computed tomography (DAT-SPECT) [13–16].

OH is a persistent, consistent, orthostatic decrease in blood pressure (BP) 3 min after standing, with a decrease in systolic BP (sBP) of 20 mmHg or diastolic BP (dBP) of 10 mmHg [17]. It affects one- to two-thirds of older adults [18–20] and can manifest asymptomatically or with symptoms such as lightheadedness or syncope [21]. Various factors contribute to OH, including drug-induced effects (e.g., those of vasodilators, diuretics, and tricyclic antidepressants), secondary non-neurogenic causes (e.g., hypovolemia and cardiac pump failure), secondary neurogenic causes (e.g., peripheral neuropathies due to diabetes mellitus and spinal cord problems), and primary neurogenic causes [21]. Cases of neurogenic OH (nOH) can be further classified into two categories: those with sympathetic neurogenic denervation (e.g., PD, DLB, and pure autonomic failure) and those with intact sympathetic neurogenic innervation (e.g., MSA and autoimmune ganglionopathy). 123I-MIBG imaging can help identify cardiac sympathetic neurogenic denervation [22, 23]. When OH complicates neurodegenerative diseases, such as PD and DLB, they are associated with poor prognoses, including increased mortality, falls, trauma-related falls, and cognitive decline [24–27]. Given that neurodegenerative diseases predominantly affect older adults and OH are commonly observed in older individuals, it is important to differentiate between OH and nOH. Although diagnosing nOH involves abnormalities in beat-to-beat BP variability during the Valsalva maneuver [28] and poor plasma norepinephrine response to orthostasis [29], these tests can be burdensome for patients and healthcare providers in routine clinical practice.

Recently, blunted tachycardia (BT) during postural change has gained attention as an indicator of nOH in patients with neurodegenerative diseases [30]. BT, defined as a decrease in the heart rate (HR) relative to sBP change (ΔHR/ΔsBP) of < 0.5 bpm/mmHg after postural change on a tilt table, has been reported to distinguish nOH from non-neurogenic OH with a sensitivity of 91% and specificity of 88% [30]. The use of HR and sBP observations during postural changes for detecting nOH is easily applicable in routine clinical settings. A recent report indicated that BT in patients with pure autonomic failure is a risk factor for future phenoconversion to PD [31]. Thus, BT could be a specific marker of neurodegenerative diseases and may indicate prognosis.

However, the clinical significance of BT in iRBD remains elusive, particularly considering its role as an indicator of nOH. A recent cross-sectional study revealed a notable prevalence of OH in approximately 27% of the patients with iRBD, and 77% of those with OH exhibited an impaired HR response, indicative of BT [32]. However, the previous study is limited by their cross-sectional design and the absence of nuclear medicine assessments, underscoring a critical gap in our understanding of the significance of BT predictive in iRBD. 123I-MIBG distinguishes iRBD and Lewy body diseases from other neurological disorders, such as corticobasal degeneration and progressive supranuclear palsy, as well as healthy individuals [16, 33, 34]. A recent nuclear imaging study has shown that PD subtypes with reduced 123I-MIBG uptake in the early stages of the disease have a poor prognosis [35]. DAT-SPECT robustly predicts future phenoconversion in iRBD [10, 13, 36–38]. To establish a strong connection between the cardiovascular pathology of BT and neurodegeneration, nuclear medicine examinations are crucial. Moreover, longitudinal outcomes in patients with iRBD are important, especially given their pre-phenoconversion status, for informing prognosis, including phenoconversion and mortality, essential for both patients, their families, and researchers focused on disease-modifying trials [39].

We recommend using BT as an early assessment tool for autonomic dysfunction in patients with iRBD. Focusing on nOH often involves consideration of the influences of cardiovascular diseases and medications. Furthermore, autonomic dysfunctions are less pronounced in iRBD compared with in PD and DLB, suggesting that BT might be more commonly applicable than nOH. The pathological significance of BT in individuals without OH remains unclear. However, focusing on BT regardless of the presence of OH in iRBD patients may elucidate its pathological significance.

Therefore, in this study, we aimed to bridge this gap by leveraging nuclear medicine tests, such as 123I-MIBG and DAT-SPECT. Additionally, we conducted a short-term preliminary follow-up investigation. By elucidating the relationship between BT, nuclear medicine findings, and long-term outcomes, including phenoconversion, death, and trauma-related falls, we aimed to investigate the pathological significance of BT and its prognostic potential in iRBD.

Methods

Patient selection

This retrospective cohort study was conducted between the comprehensive clinical assessment (baseline evaluation) and censoring date to investigate whether the events (of phenoconversion, death, or fractures due to falls) occurred.

The inclusion criteria were as follows: patients who met the diagnostic criteria for RBD based on the International Classification of Sleep Disorders, third edition [1], confirmed by polysomnography, and those with medical records of iRBD (without a diagnosis of PD [40], DLB [41], MSA [42], or dementia according to the Diagnostic and Statistical Manual of Mental Disorders-5 [43]) who visited the Shiga University of Medical Science Hospital between June 1, 2016, and July 31, 2023. The exclusion criteria were as follows: those who took antidepressants or antiparkinsonian agents, had severe sleep apnea (apnea–hypopnea index of 30) [44], schizophrenia spectrum disorders or other psychotic disorders (Diagnostic and Statistical Manual of Mental Disorders-5) [43], and with RBD secondary to stroke.

The patients underwent baseline evaluation between June 1, 2016, and July 31, 2023, including the active standing test (described below), with censoring on February 5, 2024. During the baseline evaluation, we excluded patients for whom data measurements failed during the active standing test. In addition, patients who did not undergo DAT-SPECT using [123I] N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane were excluded because DAT-SPECT findings serve as a valuable marker for phenoconversion and provide a reference of neurodegeneration [10, 13, 36–38].

We did not calculate the required sample size due to the exploratory nature of the study. This study was approved by the Research Ethics Committee of Shiga University of Medical Science (R2017-199). This study was part of the investigation into risk factors for phenoconversion and had been approved by the committee (R2017-160). Written informed consent to participate was obtained from all patients.

Baseline evaluation

Demographic data

Demographic data collected at baseline included age, sex, years of education, disease duration since RBD occurrence (the first time the symptoms of RBD were observed, as confirmed by the family members), and age at onset of RBD. Alcohol consumption, smoking habits, comorbidities (arterial hypertension, coronary artery disease, myocardial infarction, diabetes mellitus, arrhythmia, atrial fibrillation, hypercholesterolemia, thyroid disease, and stroke), and medications (calcium-channel blockers, angiotensin-converting enzyme and angiotensin II type inhibitors, beta-blockers, organic nitrates, antipsychotics, melatonin, clonazepam, and pramipexole) were also assessed because these factors would affect BP dynamics and autonomic nervous system function [45]. We interviewed first-degree relatives of patients with a family history of PD or dementia.

Active standing test

Procedures of active standing test and HRV measurement

We conducted the active standing test, also known as the orthostatic challenge test, and divided patients into two groups, BT (+) or BT(-). The test consists of two phases: supine and standing positions. Detailed information regarding the procedure has been previously reported [8]. We conducted the active standing test following a standardized protocol, carefully designed to control for variables such as alcohol, tobacco, and caffeine consumption; the timing of the last meal before the test; and room temperature. These controls are crucial because various factors, including diet and ambient temperature, can influence the autonomic functions associated with regulating BP and HR [46–48].

Before the test, the patients were equipped with a wearable sensor to detect the R-R interval (RRI) of an electrocardiogram [49] and a sphygmomanometer. They were instructed to lie on a bed approximately 40 cm above the floor without talking and sleeping during the tests. After confirming the operation of the measuring devices in the supine position (> 2 min), the patients’ BP (sBP and dBP) and HR were measured. In the supine position, BP and HR were measured five times at 3-min intervals. After 15 min in the supine position, the patients were asked to stand for 15 min. BP and HR were measured in the standing position 15 times at 1-min intervals. The examiner carefully observed each patient. After the active standing test, the examiner asked the patients confirmed the presence or absence of symptoms, such as dizziness, titubation, blurry vision, syncope, or nausea.

RRI, which represents the interval between consecutive R-waves on an electrocardiogram, characterizes the biological phenomenon known as HRV [50]. The quantitative assessment of HRV involves HRV indices comprising time-domain indices and Poincaré plots [50]. The filtering and analysis processes of RRI have been described in a previous report [8]. Six HRV indices in the 5 min preceding standing were calculated, including the standard deviation of all RRIs, root mean square of successive differences, percentage of adjacent intervals that varied by > 50 ms, standard deviation of the Poincaré plot along its minor axis (SD1), standard deviation of the Poincaré plot along its major axis (SD2), and ratio of SD1 to SD2 on the Poincaré plot (SD1/SD2). Although frequency-domain analysis is commonly used for HRV assessment, short-term frequency-domain analysis is vulnerable to arrhythmias. Given the prevalence of premature atrial contractions or premature ventricular contractions among older adults [51, 52], frequency-domain analysis is not considered appropriate and was not employed as an input feature for this demographic.

BT and OH definition and grouping

Based on the outcomes of the active standing test, BT and OH were defined as follows. The mean values of the supine BP and HR for each participant were defined as supine BP and HR, respectively.

Criteria for BT

Based on previous research [30], patients were defined as BT(+) if they satisfied the following two criteria: (i) sBP at 3 min after standing was lower than supine sBP and (ii) the ratio of the increase in the HR (ΔHR) to the decrease in the sBP (ΔsBP) (ΔHR/ΔsBP) at 3 min after standing was < 0.5 bpm/mmHg. Those who did not meet either criterion (i) or (ii) were defined as BT(-). Patients with ΔsBP of ≤ 0, that is, those with standing sBP equal to or greater than supine sBP, were not included in the calculation of ΔHR/ΔsBP because these patients did not satisfy criterion (i).

Criteria for OH

Based on previous studies, OH was defined as follows [19, 53–55]: (i) decrease in sBP by ≥ 20 mmHg or dBP by ≥ 10 mmHg compared with supine BP at 1 or 3 min after standing; and (ii) decrease in sBP to ≤ 90 mmHg. For patients with a supine sBP of ≥ 160 mmHg, a decrease in sBP of ≥ 30 mmHg and/or decrease in dBP of ≥ 15 mmHg was defined as OH (+) instead of an sBP of ≥ 20 mmHg or a dBP of ≥ 10 mmHg [20].

Clinical investigation

Autonomic nervous system examination

The Scale for Outcomes in PD-Autonomic (SCOPA-AUT), a validated scale for autonomic dysfunction in patients with PD, was used to assess autonomic dysfunction [56]. Twenty-five items (0–3 points per item) were included in the SCOPA-AUT, which evaluated the following domains: gastrointestinal (7 items), urinary (6 items), cardiovascular (3 items), thermoregulatory (4 items), pupillomotor (1 item), and sexual dysfunction domains (two items for male individuals and two for female individuals), as well as a total score (23).

Nuclear medicine examination

As part of our study on risk factors for phenoconversion, all patients underwent nuclear medicine imaging, specifically DAT-SPECT. However, the decision to perform 123I-MIBG imaging was left to the discretion of the patients, given the substantial financial burden associated with the procedure.

To assess the extent of dopaminergic neuronal degeneration, DAT-SPECT was performed. We calculated the specific-to-non-displaceable binding ratios in the right and left striata, as well as the average value.

123I-MIBG scintigraphy was performed using a dual-head camera equipped with an extended low-energy general-purpose ELEGP collimator (GE Healthcare, Chicago, IL, USA). Data were collected at 15-min (early) and 3-h time (delayed) points after the injection of 111 MBq of 123I-MIBG. A static image was obtained using a 256 × 256 matrix. The regions of interest surrounding the heart and mediastinum were drawn manually. To calculate the heart-to-mediastinum (H/M) ratio, tracer uptake was measured within each region of interest. Following previous studies on neurodegenerative disorders, we defined an early H/M ratio of < 2.28 [57] and a delayed H/M ratio of < 1.78 [58, 59] as abnormal. The washout rate was calculated as follows:washoutratio=earlyH/Mmean-delayedH/Mmean/earlyH/Mmean×100

Cognitive function

The following examinations were used to assess patients’ cognitive functions:Mini-Mental State Examination (MMSE): A screening examination for dementia with a cut-off score of < 24 (maximum score of 30) [60].

Frontal Assessment Battery (FAB): An assessment of frontal lobe functioning with a cut-off score of < 12 (maximum of 18) [61, 62].

Montréal Cognitive Assessment: A screening test designed to detect mild cognitive impairment with a cut-off score of < 23 (maximum score of 30) [63, 64].

Psychiatric symptoms

Minor hallucinations, common psychotic symptoms of iRBD, include visual illusions, presence hallucinations, and passage hallucinations [11]. A trained physician (YS and HK) conducted semi-structured interviews to assess minor hallucinations [11]. In addition, we conducted a noise pareidolia test. We measured pareidolic responses to 32 images without a face (maximum score 32) [65], and the cut-off score was set as ≥ 2 [66].

We assessed depression and apathy using the following methods. The Beck Depression Inventory Second Edition [67] and Hamilton Depression Rating Scale [68] were used to assess subjective and objective depressive symptoms. Both instruments include 21 items, with a maximum score of 63. Apathy was further evaluated using the Apathy Scale (14 items with a cut-off score of ≥ 16 and a maximum score of 42) [69, 70].

Dream-enactment behaviors and parkinsonism

The patients were asked to complete the REM Sleep Behavior Disorder Screening Questionnaire-Japanese Version (RBDSQ-J), which consists of 13 questions (cut-off score: 5; maximum score: 13) [71, 72]. A modified Hoehn and Yahr Staging Scale was used to assess motor symptoms [73].

Olfactory test

The Odor Stick Identification Test-Japanese, a valid Japanese olfactory test, was used [74]. Using 12 sticks with different odors, the respondents had to identify the correct odor from four options (maximum score, 12) with minimal false-negative or false-positive cut-off values (< 6 or < 4, respectively) for older patients [75].

Preliminary follow-up investigation and events definition

Following baseline evaluation, events during follow-up were observed through regular outpatient visits and a review of medical records. The patients visited the hospital every 1–4 months. It should be noted that the follow-up visits were not blinded as they were conducted by the same authors who conducted the semi-structured interviews (YS and HK).

The observed events included the following: a) phenoconversion, b) death, and c) fractures due to falls.Phenoconversion: In the event of exacerbation of parkinsonism or cognitive decline during follow-up, the patient was referred to a trained neurologist (not the authors) who diagnosed them with PD, DLB, or MSA, all of which were defined as phenoconversion.

Death: In cases where a patient died during the follow-up period, the date and cause of death were collected.

Fractures due to falls: In patients with iRBD often experience falls. Therefore, information on fractures, which are a significant outcome of falls, was collected. During the follow-up period, if a patient experienced a fracture due to a fall, the date and details of the fracture were recorded.

Regarding the above (a–c), the progression-free survival period was defined as the date from baseline to the date of each event or “the censoring date” (February 5, 2024). Patients who dropped out during the follow-up were censored based on the date of their last visit. For patients who were transferred to another medical facility due to relocation or worsening of their condition, information following their transfer was not tracked.

Statistical analyses

Continuous variables are summarized as means and standard deviations, and categorical variables are summarized as counts and percentages. For between-group comparisons, continuous variables were compared using Student’s t-tests. Categorical variables were compared using the chi-squared test. A logistic regression model was used to calculate the odds ratio with 95% confidence intervals for the risk of BT with iRBD. We conducted an unadjusted multivariate logistic regression (model 1) and adjusted for age and sex (model 2); age, sex, and comorbidity of hypertension (model 3); and age, sex, comorbidity of hypertension, and medication use (calcium blocker, angiotensin-converting enzyme or angiotensin II type inhibitor, or beta blocker) (model 4). Events during follow-up were assessed using Kaplan–Meier curves and log-rank tests. Sensitivity analysis was performed by excluding patients with arrhythmia to account for potential confounding by comorbid arrhythmia. The threshold for statistical significance was set at p < 0.05. To evaluate the pairwise differences, Cohen’s effect size d was calculated and classified into small (d = 0.2), medium (d = 0.5), or large (r = 0.8) effect size. All statistical analyses were performed using MATLAB (version 2023a, MathWorks, Natick, MA, USA).

Results

The flowchart of the study is illustrated in Fig. 1. Of 55 eligible patients with iRBD, 48 underwent active standing tests. One patient was excluded from further analysis because of the inability to accurately measure BP owing to frequent arrhythmias during the test. Additionally, four patients who did not undergo DAT-SPECT were excluded from the analysis. Consequently, the study included 43 patients with iRBD (mean age, 72.3 ± 7.9 years; 8 females). Among them, 17 patients (39.5%) met the criteria for BT, while 26 (60.5%) did not (details are described in 3.2 Active standing test section).Fig. 1 Flowchart of the patients’ inclusion and follow-up. Abbreviations: BP, blood pressure; HR, heart rate; BT, blunted tachycardia

Demographic data

Table 1 presents the patients’ demographic data, and supplementary information is summarized in Table S1. The analysis revealed a significantly higher age in the BT(+) group than in the BT(-) group (p = 0.029, Cohen’s d = 0.692). The prevalence of comorbidities, such as hypertension and diabetes mellitus, was comparable between the groups. This finding extended to the use of medications for hypertension and proportion of patients using clonazepam; no significant differences were observed. The sensitivity analysis, excluding patients with arrhythmias, showed similar trends (Table S2, Table S3). Table 1 Demographic data of the patients with isolated RBD with and without blunted tachycardia

	ALL	BT (+)	BT (-)		Effect size	
(n = 43)	(n = 17)	(n = 26)	p-value	BT (+)—BT (-)	
Age [years]	72.3 ± 7.9	75.5 ± 3.1	70.2 ± 9.3	0.029	0.692	
Sex (Female [n, %])	8 [18.6%]	2 [11.8%]	6 [23.1%]	0.351	N/A	
Age at RBD onset [years]	63.6 ± 10.1	66.9 ± 7.8	61.5 ± 11.0	0.087	0.538	
Comorbidity	
 Hypertension [n, %]	16 [37.2%]	8 [47.1%]	8 [30.8%]	0.280	N/A	
 Coronary artery disease [n, %]	8 [18.6%]	5 [29.4%]	3 [11.5%]	0.141	N/A	
 Myocardial infarction [n, %]	2 [4.7%]	1 [5.9%]	1 [3.8%]	0.757	N/A	
 Diabetes mellitus [n, %]	8 [18.6%]	3 [17.6%]	5 [19.2%]	0.896	N/A	
 Arrhythmia [n, %]	4 [9.3%]	2 [11.8%]	2 [7.7%]	0.653	N/A	
 Atrial fibrillation [n, %]	5 [11.6%]	2 [11.8%]	3 [11.5%]	0.982	N/A	
 Hypercholesterolemia [n, %]	9 [20.9%]	3 [17.6%]	6 [23.1%]	0.669	N/A	
 Thyroid disease [n, %]	1 [2.3%]	0 [0%]	1 [3.8%]	0.413	N/A	
 Stroke [n, %]	5 [11.6%]	2 [11.8%]	3 [11.5%]	0.982	N/A	
Abbreviations: BT blunted tachycardia, RBD rapid eye movement sleep behavior disorder

Active standing test

The active standing test results and HRV indices are presented in Table 2. There were no significant differences between the groups regarding sBP, dBP, or HR in the supine position. However, the changes in sBP, dBP, and HR upon standing differed significantly between the groups. Table 2 Results of the active standing test

	ALL	BT (+)	BT (-)		Effect size	
(n = 43)	(n = 17)	(n = 26)	p-value	BT (+)—BT (-)	
Systolic BP (mm Hg)	
 Baseline	130.4 ± 16.8	130.9 ± 17.3	130.0 ± 16.9	0.874	0.049	
 ΔsBP at 1 min after standing	-11.0 ± 12.6	-20.0 ± 11.5	-5.2 ± 9.7	 < 0.001	-1.391	
 ΔsBP at 2 min after standing	-8.7 ± 11.9	-16.7 ± 12.0	-3.5 ± 8.5	 < 0.001	-1.288	
 ΔsBP at 3 min after standing	-9.1 ± 11.1	-17.3 ± 11.3	-3.8 ± 7.0	 < 0.001	-1.480	
Diastolic BP (mm Hg)	
 Baseline	79.8 ± 9.0	81.0 ± 11.1	79.0 ± 7.4	0.486	0.215	
 ΔdBP at 1 min after standing	-3.4 ± 7.9	-8.7 ± 7.2	0.1 ± 6.2	 < 0.001	-1.309	
 ΔdBP at 2 min after standing	-2.0 ± 8.1	-7.7 ± 8.2	1.8 ± 5.5	 < 0.001	-1.405	
 ΔdBP at 3 min after standing	-2.5 ± 7.1	-7.7 ± 6.7	0.8 ± 5.1	 < 0.001	-1.437	
HR (bpm/min)	
 Baseline	65.9 ± 9.4	67.0 ± 9.9	65.2 ± 9.3	0.562	0.179	
 ΔHR at 1 min after standing	5.8 ± 6.0	4.0 ± 3.7	7.0 ± 6.8	0.100	-0.516	
 ΔHR at 2 min after standing	5.7 ± 6.0	2.9 ± 3.1	7.5 ± 6.8	0.014	-0.788	
 ΔHR at 3 min after standing	5.5 ± 6.2	2.3 ± 3.1	7.7 ± 6.9	0.004	-0.926	
ΔHR/ΔsBP (bpm/mm Hg)	
 ΔHR/ΔsBP at 1 min after standinga	0.66 ± 0.65	0.26 ± 0.21	1.01 ± 0.71	 < 0.001	-1.357	
 ΔHR/ΔsBP at 2 min after standingb	1.03 ± 1.83	0.31 ± 0.39	1.85 ± 2.43	0.019	-0.890	
 ΔHR/ΔsBP at 3 min after standingc	0.93 ± 1.54	0.17 ± 0.15	1.57 ± 1.88	0.004	-0.983	
Orthostatic hypotension [n, %]	10 [23.3%]	8 [47.1%]	2 [7.7%]	0.003	N/A	
Spine hypertension [n, %]	14 [32.6%]	6 [35.3%]	8 [30.8%]	0.757	N/A	
Heart rate variability	
 SDNN (ms)d	18.3 ± 9.9	16.6 ± 10.5	19.2 ± 9.7	0.472	-0.255	
 RMSSD (ms)d	13.8 ± 9.1	14.4 ± 11.9	13.5 ± 7.4	0.765	0.106	
 pNN50 (%)d	1.9 ± 5.2	2.9 ± 7.5	1.3 ± 3.4	0.407	0.294	
 Poincaré plots, SD1 (ms)d	9.8 ± 6.4	10.2 ± 8.4	9.5 ± 5.2	0.765	0.106	
 Poincaré plots, SD2 (ms)d	23.8 ± 12.8	21.0 ± 12.4	25.3 ± 13.0	0.355	-0.329	
 Poincaré plots, SD1/SD2d	0.41 ± 0.14	0.45 ± 0.16	0.39 ± 0.12	0.273	0.391	
Abbreviations: BT blunted tachycardia, BP blood pressure, sBP systolic BP, dBP diastolic BP, HR heart rate, SDNN standard deviation of the NN intervals, RMSSD root mean square of successive differences, pNN50 percentage of difference between adjacent normal. RR intervals greater than 50 ms, SD1 Standard Deviation 1 of the Poincaré plot, SD2 Standard Deviation 2 of the Poincaré plot

aBecause ΔHR/ΔSBP was not calculated in patients with increased sBP at 1 min after standing, the number of patients was set to n = 34 for All, n = 16 for BT(+), and n = 18 for BT(-)

bBecause ΔHR/ΔSBP was not calculated in patients with increased sBP at 2 min after standing, the number of patients was set to n = 30 for All, n = 16 for BT(+), and n = 14 for BT(-)

cBecause ΔHR/ΔSBP was not calculated in patients with increased sBP at 3 min after standing, the number of patients was set to n = 37 for All, n = 17 for BT(+), and n = 20 for BT(-)

dBecause of the exclusion due to comorbidity or measurement errors, n = 34 in All; n = 12 in BT(+); n = 22 in BT(-)

The decrease in sBP and dBP upon standing was more pronounced, and the increase in HR was blunted in the BT(+) group compared with in the BT(-) group. ΔHR/ΔsBP was significantly lower in the BT(+) group at 1, 2, and 3 min post-standing with large effect sizes. Fifteen minutes after standing, the sBP and dBP of the BT(-) group generally returned to near-supine levels. In contrast, in the BT( +) group, sBP and dBP remained approximately 20 mmHg and 10 mmHg lower than the supine values, respectively (Fig. 2 (A2, B2)). The sensitivity analysis, excluding patients with arrhythmias, showed similar trends (Table S4, Figure S1).Fig. 2 Changes in BP, HR, and delta index during the active standing test. Comparison of the active standing test results in the BT(+) and BT(-) groups. (A1-C1) indicates absolute change (mean ± standard error of the mean); (A2-C2) indicates changes compared with the supine position (mean ± standard error of the mean); (D) indicates the changes in the BT criteria. Abbreviations: BP, blood pressure; BT, blunted tachycardia; HR, heart rate. x-axis: supine, mean value of the supine position, 1–15 min after standing

Overall, 23.3% (10/43) of the patients met the criteria for OH, of whom 80% (8/10) were in the BT(+) group. Significantly more patients with BT(+) (47.1%, 8/17) met the criteria for OH (thus, they could be considered as having nOH) than those with BT(-) (7.7%, 2/26) (p = 0.003, Table 2). Additionally, 32.6% (14/43) of the participants met the criteria for supine hypertension, with 35.3% (6/17) in the BT(+) group and 30.8% (8/26) in the BT(-) group.

Regarding HRV in the supine position, there were no significant differences between the groups across both time domain and Poincaré plot indices.

Clinical examinations

The clinical examinations are presented in Table 3, and supplementary information is summarized in Table S1. Regarding motor symptoms, all participants were classified as Hoehn and Yahr stage 0. Table 3 Clinical examinations of the patients with isolated RBD with and without blunted tachycardia

	ALL	BT (+)	BT (-)		Effect size	
(n = 43)	(n = 17)	(n = 26)	p-value	BT (+) -BT (-)	
Autonomic nervous examination	
SCOPA-AUT, Totala	9.4 ± 6.9	11.8 ± 9.4	8.0 ± 4.5	0.086	0.549	
 Gastrointestinala	2.7 ± 2.5	3.3 ± 3.1	2.4 ± 2.0	0.302	0.326	
 Urinarya	5.0 ± 2.9	6.1 ± 3.3	4.3 ± 2.4	0.049	0.633	
 Cardiovasculara	0.52 ± 0.97	0.75 ± 1.06	0.38 ± 0.90	0.240	0.372	
 Thermoregulatorya	0.50 ± 0.99	0.75 ± 1.29	0.35 ± 0.75	0.205	0.402	
 Pupillomotora	0.29 ± 0.60	0.31 ± 0.60	0.27 ± 0.60	0.823	0.070	
 Sexuala	0.36 ± 1.14	0.56 ± 1.63	0.23 ± 0.71	0.368	0.284	
DAT-SPECT	
 Striatum, right	3.91 ± 1.31	3.80 ± 1.23	3.98 ± 1.37	0.668	-0.132	
 Striatum, left	3.92 ± 1.20	3.83 ± 1.13	3.98 ± 1.26	0.684	-0.126	
 Striatum, average	3.92 ± 1.22	3.81 ± 1.17	3.98 ± 1.27	0.668	-0.132	
123I-MIBG	
 H/M, earlyb	1.52 ± 0.21	1.39 ± 0.13	1.61 ± 0.22	0.003	-1.089	
 H/M, early < 2.28 [n, %]b	35 [100.0%]	14 [100.0%]	21 [100.0%]	N/A	N/A	
 H/M, delayedb	1.35 ± 0.31	1.18 ± 0.11	1.46 ± 0.34	0.005	-1.017	
 H/M, delayed < 1.91 [n, %]b	33 [94.3%]	14 [100.0%]	19 [90.5%]	0.234	N/A	
 Washout ratio [%]b	35.9 ± 11.3	40.3 ± 16.0	33.0 ± 5.5	0.063	0.648	
Cognitive function	
 MMSE score	28.0 ± 2.3	27.2 ± 3.0	28.4 ± 1.4	0.106	-0.506	
 MMSE score < 24 [n, %]	2 [4.7%]	1 [5.9%]	1 [3.4%]	0.757	N/A	
 FAB score	15.3 ± 2.3	14.8 ± 2.3	15.5 ± 2.2	0.356	-0.286	
 FAB score < 12 [n, %]	2 [4.7%]	1 [5.9%]	1 [3.4%]	0.757	N/A	
 MoCA score	24.7 ± 2.8	24.4 ± 2.8	25.0 ± 2.9	0.535	-0.192	
 MoCA score < 23 [n, %]	9 [20.9%]	5 [29.4%]	4 [15.4%]	0.269	N/A	
Psychiatric symptoms	
 Minor hallucinations [n, %]	18 [41.9%]	10 [58.8%]	8 [30.8%]	0.068	N/A	
Abbreviations: BT blunted tachycardia, SCOPA-AUT the Scale for Outcomes in Parkinson’s disease for Autonomic symptoms, DAT-SPECT dopamine transporter-single-photon emission computed tomography, 123I-MIBG123I-metaiodobenzylguanidine myocardial scintigraphy, H/M heart-to-mediastinum, MMSE Mini-Mental State Examination, FAB Frontal Assessment Battery, MoCA Montreal Cognitive Assessment

aBecause of missing data, n = 42 in All; n = 16 in BT(+); n = 26 in BT(-)

bBecause of missing data, n = 35 in All; n = 14 in BT(+); n = 21 in BT(-)

Regarding autonomic nervous function, no significant difference was observed in total SCOPA-AUT scores between the two groups. However, the urinary domain scores were significantly higher in the BT(+) group.

Nuclear medicine examinations revealed no significant differences in DAT accumulation between the groups. 123I-MIBG myocardial scintigraphy was performed in 81.4% (35/43) of the patients, including 14 in the BT(+) group and 21 in the BT(-) group. All patients exhibited early H/M ratios below the normal threshold of 2.28, and 94% fell below the threshold for delayed H/M ratios of 1.91. When comparing the two groups, significantly lower accumulation in both early and delayed H/M ratios was noted in the BT(+) group, whereas no significant difference was observed in the washout ratio.

There were no significant differences in the olfactory test or cognitive function results between the groups. Furthermore, the prevalence of psychiatric symptoms, including noise pareidolia and minor hallucinations, did not differ significantly between the groups. All patients who experienced minor hallucinations at baseline maintained insight into their experiences with minor hallucinations.

While no significant difference was observed in RBDSQ-J scores between the two groups, a higher proportion of individuals in the BT(-) group exceeded the cut-off point.

The sensitivity analysis generally yielded similar results; however, it revealed a higher incidence of minor hallucinations in the BT(+) group, and no significant differences were observed in SCOPA-AUT Urinary scores (Table S3, Table S5).

Factors associated with BT

Table S6 presents the odds ratio for BT in the patients with iRBD. The sample size was limited; however, the following variables were significantly associated with BT after adjusting for age, sex, hypertension comorbidity, and medication use (model 4): years of education, exceeding the cut-off value of the RBDSQ-J score, early and delayed H/M ratio of 123I-MIBG, MMSE score, and FAB score.

The sensitivity analysis, excluding patients with arrhythmias, generally yielded similar results; however, even after adjusting for various factors (model 4), DAT accumulation in the right striatum, OSIT-J score, and minor hallucinations remained significant (Table S7).

Phenoconversion, death, and fractures due to falls during short-term follow-up

Data regarding the follow-up events are summarized in Table 4 and Figure S2. Table 4 Summary of the follow-up events

Events	All (n = 43)	BT (+) (n = 17)	BT (-) (n = 26)	p-value	
a) Phenoconversion	
 Number of events [n (%)]	14 (32.6%)	7 (41.2%)	7 (26.9%)		
	(7 PD, 7 DLB)	(2 PD, 5 DLB)	(5 PD, 2 DLB)		
 Dropout [n (%)]	7 (16.3%)	3 (17.6%)	4 (15.4%)		
 Follow-up duration [years]	3.39 ± 2.43	3.39 ± 2.86	3.15 ± 2.14	0.429	
b) Death	
 Number of events [n (%)]	6 (14.0%)	3 (17.6%)	3 (11.5%)		
 Dropout [n (%)]	7 (16.3%)	3 (17.6%)	4 (15.4%)		
 Follow-up duration [years]	3.98 ± 2.32	4.22 ± 2.84	3.82 ± 1.95	0.585	
c) Fractures due to falls	
 Number of events [n (%)]	2 (4.7%)	1 (5.9%)	1 (3.8%)		
 Dropout [n (%)]	11 (25.6%)	5 (29.4%)	6 (23.1%)		
 Follow-up duration [years]	3.91 ± 2.30	4.13 ± 2.84	3.76 ± 1.92	0.585	
Abbreviations: BT blunted tachycardia, PD Parkinson’s disease, DLB dementia with Lewy bodies

Phenoconversion

Overall, 14 (32.6%) individuals experienced phenoconversion (seven PD and seven DLB) with no progression to MSA. Among those with BT(+), seven (41.2%) achieved phenoconversion (two with PD and five with DLB), with three dropouts during follow-up (due to relocation, self-discontinuation of outpatient visits, and death from cancer). Among those with BT(-), seven (26.9%) reached phenoconversion (five PD and two DLB), with four dropouts during follow-up (one self-discontinuation of outpatient visits and three deaths due to cancer).b) Death

In total, six (14.0%) individuals died. Among those with BT(+), three (17.6%) died. The causes of death were pneumonia (n = 1, progression to PD), tuberculosis (n = 1, progression to DLB), and cancer (n = 1, not phenoconverted), with three dropouts during follow-up (due to relocation, hospitalization for comorbidities, and self-discontinuation of outpatient visits). Among those with BT(-), three (11.5%) died. The causes of death were pneumonia (progression to PD) in one case and cancer (not phenoconverted) in two, with four dropouts during follow-up (one self-discontinuation of outpatient visits, one hospitalization for worsened DLB, and two relocations).c) Fractures due to falls

Two (4.7%) individuals experienced fractures due to falls. Among those with BT(+), one (6.5%) fell and fractured the knee. He had already progressed to DLB by the time of the fall, with five dropouts during follow-up (one relocation, one self-discontinuation of outpatient visits, and three deaths). Among those with BT(-), one (3.9%) fell and sustained a skull fracture and traumatic brain injury. This patient had already progressed to DLB by the time of the fall, with six dropouts during follow-up (one self-discontinuation of outpatient visits, one relocation, one hospitalization for worsened DLB, and two deaths).

In all cases (a, b, and c), there was no significant difference in the follow-up duration between the BT(+) and BT(-) groups (Table 4). Figure S2 illustrates the Kaplan–Meier survival curves with the results of the log-rank tests and hazard ratios related to the incidence of phenoconversion, death, and fractures due to falls. BT was not a significant risk factor for any event.

The analysis about follow-up events, excluding patients with arrhythmias, showed similar trends (Table S8, Figure S3).

Discussion

To the best of our knowledge, this is the first study to elucidate the clinical and diagnostic features of patients with iRBD exhibiting BT, including nuclear medicine examinations. Approximately 40% of patients in our cohort met the criteria for BT, and approximately half of these patients also met the criteria for OH during the active standing test. The patients in the BT(+) group tended to be older and exhibited lower 123I-MIBG uptake values. However, there were no significant differences between the BT(+) and BT(-) groups concerning DAT-SPECT uptake. The characteristics observed in the BT(+) iRBD group in this study were consistent with findings from research on patients with PD, where the severity of autonomic dysfunction does not correlate with the extent of dopaminergic neurodegeneration or motor symptom [76]. During the longitudinal follow-up, approximately one-third of all patients phenoconverted, 15% died, and 5% had fractures due to falls. In the preliminary longitudinal survey, no significant differences were observed in the risks of these events between the two groups. To ensure the robustness of the analysis results, a sensitivity analysis was conducted by excluding five patients with arrhythmias. The outcomes were largely consistent with those of the original analysis.

Our study provides evidence of decreased MIBG uptake in relation to BT in patients with iRBD. BT is considered a characteristic autonomic dysfunction reflecting cardiac sympathetic denervation. The severe autonomic dysfunction indicated by BT may suggest a more advanced progression of Lewy body pathology in the brain stem [77, 78]. While reduced 123I-MIBG uptake in the early stages of PD has been reported to be associated with poor prognosis [35], our preliminary longitudinal investigation did not demonstrate an association between BT and specific events. Considering the prevalence of iRBD in older patients, our findings underscore the importance of considering non-neurological conditions, such as cancer, in long-term clinical management that may impact life expectancy. Future research could include conducting more extensive long-term follow-ups in a larger cohort of patients with iRBD to comprehensively ascertain the relationship between BT and long-term outcomes.

Demographic and clinical examination

OH is not only a common condition in older adults related to neurodegenerative diseases but can also be induced by medications, diabetes, and cardiovascular diseases [21, 24]. Given the prevalence of iRBD in middle-aged and older adults [3, 4], it is crucial to consider these comorbidities and medications when evaluating OH in this population. BT has been identified as a feasible method for detecting nOH [30].

Our findings revealed that approximately 40% (17/43) of the patients with iRBD exhibited BT during the active standing test. Patients in the BT(+) group were older and showed a more significant reduction in MIBG uptake. Logistic analysis, adjusted for age, sex, comorbidities, and medication use, indicated that MIBG uptake values, along with MMSE and FAB scores, were associated with BT. This suggests that BT is linked to abnormalities in postganglionic cardiac chronotropic responses, underscoring its significance in the context of neurodegeneration. Pronounced decline in MIBG uptake in iRBD with BT may have clinical relevance and potentially serve as a marker for more severe autonomic responses. The sensitivity analysis demonstrated a correlation between BT and minor hallucinations, as well as reduced accumulation of DAT in the right striatum and decreased olfaction (Table S7). These findings suggest that BT is associated with the potential progression of neurodegeneration.

The association between BT and cognitive decline aligns with that reported in a study on α-synucleinopathies, suggesting a link between BP regulation and cognitive impairment [26]. Furthermore, a lower proportion of patients in the BT(+) group exceeding the RBDSQ-J cut-off score reflected the temporal changes in RBD symptoms, including symptom alleviation or disappearance with neurodegenerative disease progression [79, 80].

This study’s significance is further enhanced by the concurrent use of 123I-MIBG and DAT-SPECT, a methodology not widely adopted in iRBD research to date. Notably, the large-scale longitudinal study by Miyamoto T. and Miyamoto M. (306 patients with iRBD) [81] represents a significant investigation in this field. In contrast, other existing literature contains limited studies incorporating 123I-MIBG to investigate iRBD, with cross-sectional analyses reporting sample sizes of 108 [14] and 32 [33], and longitudinal studies documenting sample sizes of 36 [82] and 40 [83].

In previous studies, reduced 123I-MIBG uptake has been shown to qualitatively support the presence of Lewy body pathology in iRBD [15, 16]. Additionally, the large-scale study by Miyamoto T. and Miyamoto M. in 2024 [81] demonstrated a progressive decline in 123I-MIBG uptake in 33 patients with iRBD who underwent follow-up, with those exhibiting reduced uptake progressing to PD or DLB, while those without reduced uptake progressed to MSA. This study highlights the quantitative significance of 123I-MIBG uptake in tracking disease progression.

In our study, the BT(+) showed a more pronounced reduction in 123I-MIBG uptake. After adjusting for age and sex, BT remained significantly associated with 123I-MIBG uptake levels. These results suggest that 123I-MIBG is not only qualitatively but also quantitatively significant in iRBD. The majority of patients exhibited 123I-MIBG uptake below the cutoff value, aligning with previous qualitative findings [15, 16]. Our study did not find an increased risk of phenoconversion or mortality in the BT(+) group within our limited sample size and follow-up period. However, considering the findings of the longitudinal 123I-MIBG follow-up study [81], a more significant reduction in 123I-MIBG uptake in iRBD may indicate the progression towards PD or DLB. To confirm whether BT is associated with 123I-MIBG uptake reductions related to PD or DLB, it will be necessary to conduct longitudinal follow-up studies of 123I-MIBG and BT assessments using active standing or postural tests.

Our investigation sets a new precedent by executing DAT-SPECT across all 43 patients, 123I-MIBG in 35 patients, and longitudinal follow-up. Our study provides nuclear medical insights pertinent to iRBD, thereby advancing the understanding of the neurodegenerative diseases.

Active standing test

OH is a prevalent symptom among older adults and has serious prognostic implications for patients with neurodegenerative diseases set the stage for our investigation [21]. Recent advancements have shown that BT during a tilt test can accurately detect nOH [30].

The North American Prodromal Synucleinopathy (NAPS) Consortium’s cross-sectional study on a large cohort of patients with iRBD indicated a commonality of nOH within this population, revealing that 27% met the criteria for OH, with 77% of them exhibiting reduced HR augmentation (ΔHR/ΔsBP < 0.5) [32]. This suggests a potentially widespread prevalence of nOH among patients with iRBD. Furthermore, the consortium highlighted that patients with OH (with or without BT) demonstrated a significant presence of supine hypertension (approximately 70%), indicating abnormalities in BP regulation both during standing and at rest. Our previous study underscored the diminished HRV during spine positioning in patients with iRBD compared with in healthy controls, suggesting the predictive value of HRV metrics for subsequent OH occurrence [8].

The strength of the current study lies in the successful implementation of a standardized protocol for the active standing test, allowing the observation of BP and HR fluctuations over 15 min after standing and the identification of delayed BP drops. We observed that 23.3% (10/43) of the patients met the criteria for OH, and 80% (8/10) of these patients fulfilled the criteria for BT. This proportion aligns closely with the findings of the NAPS Consortium [32]. While the comorbidity of hypertension was 37.2% (16/43) of our study population (Table 1), only 32.6% (14/43) met the criteria for supine hypertension, with no significant differences of supine hypertension between the BT (+) and BT (-) groups. There were also no differences between the groups in terms of the HRV time-domain metrics or Poincaré plot indices at rest. These observations suggest that the pathophysiology of BT, detected during the active standing test, may not be easily discernible at rest.

In our previous study, which included some patients from the current study, we observed that resting HRV in patients with iRBD was significantly attenuated compared to healthy controls [8]. Specifically, reductions in RMSSD, pNN50, SD1, and SD2 indicated diminished parasympathetic function, while the decrease in SDNN suggested a concurrent reduction in both sympathetic and parasympathetic functions [50, 84, 85] In the present study, the H/M ratio of 123I-MIBG was observed to be reduced across the entire group of patients with iRBD, with a further reduction in the BT(+) group compared to the BT(-) group. These findings suggest that even within the iRBD population characterized by reduced autonomic function, BT is more likely to be present in individuals with more pronounced sympathetic dysfunction.

The results of the “15 min after standing” of the active standing test are pivotal for understanding the BP dynamics in patients with iRBD. Even after compensatory mechanisms should have adjusted to postural changes [86], the BT(+) group exhibited lower sBP and dBP than their supine measurements, suggesting that supine BP is usually relatively high. This indicates the influence of supine hypertension and underscores the necessity of evaluating BP regulation across different postures for a more comprehensive assessment of autonomic dysfunction. Therefore, further research considering the comorbidities and treatment status (the extent of hypertension control) is needed to accurately evaluate the neurodegenerative impact.

The BT(+) group had a higher proportion of patients with OH than the BT(-) group (47.1% vs. 7.7%, p = 0.003). The pronounced decline in MIBG uptake in the BT(+) group underscores the potential clinical relevance and quantitative relationship between MIBG uptake and clinical manifestations [87]. Future research should focus on multifaceted assessments to unravel the nuanced interplay between BP regulation, HRV, and neurodegenerative disease progression.

Preliminary longitudinal follow-up

In this study, patients with iRBD with and without BT were followed up to investigate significant outcomes, including phenoconversion, death, and trauma-related falls, particularly fractures. Systematic reviews and meta-analyses identified OH as a risk factor for phenoconversion to PD in patients with iRBD [88]. Furthermore, BT has been suggested as a predictive factor for the progression from pure autonomic failure to PD [31]. OH is associated with increased mortality and trauma-related falls in patients with PD and DLB [24, 25, 27]. Overall, it is crucial to consider these events in patients with iRBD, not only for phenoconversion but also for mortality and trauma-related falls.

Phenoconversion occurred in 41.2% of the patients in the BT(+) group compared with 26.9% in the BT(-) group. Among the patients in the BT(+) group, progression to DLB was more common (two PD and five DLB cases), whereas patients in the BT(-) group were more likely to progress to PD (five PD and two DLB cases). None of the cases progressed to MSA. There was no significant difference in the risk of phenoconversion, death, or fall-related fractures between the two groups (Figure S2).

The limited sample size and follow-up duration may have contributed to the lack of statistical power to detect differences between the events, warranting further investigation. Patients in the BT(+) group were more likely to progress to DLB than those in the BT(-) group, suggesting that individuals exhibiting BT at the iRBD stage, indicative of more pronounced autonomic dysfunction, are more prone to progression to DLB. Our observations align with the notion that autonomic dysfunction is more pronounced in patients with DLB than in those with PD [89]. This is supported by logistic regression results linking BT with cognitive decline, suggesting an association between BT and phenoconversion to DLB.

These causes of death highlight the need to focus on common issues among older adults. Those who progressed to PD or DLB died of pneumonia or tuberculosis, whereas those who did not progress died of cancer. Although OH in patients with PD and DLB has been reported to be related to life prognosis [24, 25, 27], iRBD spans years to decades before phenoconversion [2, 7]. The long-term life prognosis in iRBD may be influenced independently or synergistically by neurodegenerative issues and common older adult conditions such as tumors and infections. Fractures due to falls were rare; however, both cases progressed to DLB. A possible link has been suggested between DLB-associated parkinsonism, attentional and visuospatial impairments, and fatal falls [90, 91].

Limitations

This study has some limitations. First, the small sample size and the fact that the study was conducted at a single center may limit the generalizability of our findings. Furthermore, due to the exploratory nature of the current study, an a priori calculation of sample size was not performed, which could potentially limit the ability to identify significant associations.

Second, the follow-up period was limited to an average of 3–4 years. The longitudinal investigation in this study is considered preliminary due to the small sample size and short follow-up period. While it might take up to a decade to observe a significant number of patients with iRBD undergoing phenoconversion [2, 7], in this study, approximately one-third of the patients phenoconverted, indicating that the follow-up duration was not negligible. Nonetheless, there was a notable dropout rate during the follow-up period, including patients who died or were admitted to multiple institutions owing to worsening physical conditions. In studies involving older participants, an extended follow-up period may increase the dropout rates owing to issues specific to this population, such as cancer. Hence, a 3- to 4-year follow-up period may be considered reasonable.

Another limitation of this study is the lack of longitudinal assessment for BP and HR after standing, which were evaluated at a single time point. Moreover, this study used the active standing test instead of the tilt-table test to define BT. The active standing test, which is considered a natural movement in daily life that imposes less burden on patients, is ethically favorable. Previous studies on nOH and BT in patients with iRBD have also employed the active standing test to ensure consistency in methodology [32].

Another limitation is the focus on BT rather than nOH for patient classification. OH can occur from a complex interplay of factors, including cardiovascular diseases, and not solely from neurodegenerative diseases [21, 24]. At the early stages of a neurodegenerative disease, such as iRBD, focusing on BT may allow for a more direct assessment of neurodegenerative pathology.

Notably, in our patient cohort, 47.1% (8/17) of patients with BT also had OH (thus, having nOH), which is significantly higher more than those without BT (p = 0.003, Table 2). Given that only eight patients met the criteria for nOH, the statistical analysis was limited. Despite the small sample size in this study, future studies categorizing patients based on the presence or absence of BT and OH may prove beneficial.

Conclusions

In this study, approximately 40% of the patients with iRBD exhibited BT during the active standing test. Even after adjusting for age, sex, comorbidities, and medication use, BT was significantly associated with reduced MIBG uptake. We have identified the possibility that BT in iRBD reflects cardiac sympathetic neurogenic denervation. Moreover, our findings suggest that reduced 123I-MIBG uptake may be quantitatively significant in assessing the severity of autonomic dysfunction in iRBD. However, the preliminary longitudinal follow-up did not clearly establish a relationship between BT and events such as phenoconversion, death, or fractures due to falls. Future research is needed to elucidate the potential prognostic value of BT.

Supplementary Information

Supplementary Material 1.

Supplementary Material 2.

Abbreviations

BT Blunted tachycardia

dBP Diastolic blood pressure

DLB Dementia with Lewy bodies

FAB Frontal Assessment Battery

H/M Heart-to-mediastinum

HRV Heart rate variability

iRBD Isolated rapid eye movement sleep behavior disorder

MMSE Mini-Mental State Examination

MSA Multiple system atrophy

nOH Neurogenic orthostatic hypotension

OH Orthostatic hypotension

PD Parkinson's disease

RBD Rapid eye movement sleep behavior disorder

RBDSQ-J REM Sleep Behavior Disorder Screening Questionnaire-Japanese Version

RRI R-R interval

SCOPA-AUT Scale for Outcomes in PD-Autonomic

sBP Systolic blood pressure

Acknowledgements

The authors would like to thank Dr. Arichika Matsuda of Shiga University of Medical Science for his support with the examination procedures. The authors would also like to thank Harumi Iguchi of Shiga University of Medical Science for advice on the methodology of nuclear medicine examinations.

Authors’ contributions

Shota Saeda: Conceptualization, Methodology, Software, Formal analysis, Writing - Original Draft, Writing - Review & Editing. Yukiyoshi Sumi: Conceptualization, Methodology, Investigation, Formal analysis, Writing - Original Draft, Writing - Review & Editing, Funding acquisition. Koichi Fujiwara: Writing - Review & Editing, Supervision. Hiroshi Kadotani: Investigation, Writing - Review & Editing, Funding acquisition.

Funding

This study was supported by JSPS KAKENHI (Grant Numbers 21K15745 and 21H03851). This study is also supported by research grants form Japan Foundation of Institute for Neuropsychiatry.

Availability of data and materials

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee of Shiga University of Medical Science (R2017-199). This study was part of the investigation into risk factors for phenoconversion and also had been approved by the committee (R2017-160). Written informed consent to participate was obtained from all patients.

Consent for publication

Not applicable.

Competing interests

Hiroshi Kadotani was supported by donations from Fukuda Life Tech Co., Ltd., Fukuda Life Tech Keiji Co., Ltd., and Kadotani Kids Clinic to the Shiga University of Medical Science. Hiroshi Kadotani received Merck Sharp and Dohme Corp/MSD K.K. (the Investigator-initiated Studies Program), Eisai Co., Ltd., and the SECOM Science and Technology Foundation. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp and Dohme Corp/MSD K.K. The other authors declare no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien. American Academy of Sleep Medicine; 2014.
2. Dauvilliers Y Schenck CH Postuma RB Iranzo A Luppi PH Plazzi G REM sleep behaviour disorder Nat Rev Dis Primers 2018 4 1 19 10.1038/s41572-018-0016-5 30166532
Dauvilliers Y, Schenck CH, Postuma RB, Iranzo A, Luppi PH, Plazzi G, et al. REM sleep behaviour disorder. Nat Rev Dis Primers. 2018;4(1):19. 10.1038/s41572-018-0016-5.30166532 10.1038/s41572-018-0016-5
3. Haba-Rubio J Frauscher B Marques-Vidal P Toriel J Tobback N Andries D Prevalence and determinants of rapid eye movement sleep behavior disorder in the general population Sleep 2018 41 2 10.1093/sleep/zsx197
Haba-Rubio J, Frauscher B, Marques-Vidal P, Toriel J, Tobback N, Andries D, et al. Prevalence and determinants of rapid eye movement sleep behavior disorder in the general population. Sleep. 2018;41:2. 10.1093/sleep/zsx197.10.1093/sleep/zsx197
4. Sasai-Sakuma T Takeuchi N Asai Y Inoue Y Inoue Y Prevalence and clinical characteristics of REM sleep behavior disorder in Japanese elderly people Sleep 2020 43 8 10.1093/sleep/zsaa024
Sasai-Sakuma T, Takeuchi N, Asai Y, Inoue Y, Inoue Y. Prevalence and clinical characteristics of REM sleep behavior disorder in Japanese elderly people. Sleep. 2020;43:8. 10.1093/sleep/zsaa024.10.1093/sleep/zsaa024
5. Boeve BF REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions Ann N Y Acad Sci 2010 1184 15 54 10.1111/j.1749-6632.2009.05115.x 20146689
Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci. 2010;1184:15–54. 10.1111/j.1749-6632.2009.05115.x.20146689 10.1111/j.1749-6632.2009.05115.x
6. Schenck CH REM sleep behavior disorder as a complex condition with heterogeneous underlying disorders: clinical management and prognostic implications [commentary] Sleep Breath 2022 26 3 1289 1298 10.1007/s11325-022-02574-6 35239134
Schenck CH. REM sleep behavior disorder as a complex condition with heterogeneous underlying disorders: clinical management and prognostic implications [commentary]. Sleep Breath. 2022;26(3):1289–98. 10.1007/s11325-022-02574-6.35239134 10.1007/s11325-022-02574-6
7. Galbiati A Verga L Giora E Zucconi M Ferini-Strambi L The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta-analysis of longitudinal studies Sleep Med Rev 2019 43 37 46 10.1016/j.smrv.2018.09.008 30503716
Galbiati A, Verga L, Giora E, Zucconi M, Ferini-Strambi L. The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta-analysis of longitudinal studies. Sleep Med Rev. 2019;43:37–46. 10.1016/j.smrv.2018.09.008.30503716 10.1016/j.smrv.2018.09.008
8. Sumi Y Nakayama C Kadotani H Matsuo M Ozeki Y Kinoshita T Resting heart rate variability is associated with subsequent orthostatic hypotension: comparison between healthy older people and patients with rapid eye movement sleep behavior disorder Front Neurol 2020 11 567984 10.3389/fneur.2020.567984 33329309
Sumi Y, Nakayama C, Kadotani H, Matsuo M, Ozeki Y, Kinoshita T, et al. Resting heart rate variability is associated with subsequent orthostatic hypotension: comparison between healthy older people and patients with rapid eye movement sleep behavior disorder. Front Neurol. 2020;11:567984. 10.3389/fneur.2020.567984.33329309 10.3389/fneur.2020.567984
9. Chiaro G Calandra-Buonaura G Cecere A Mignani F Sambati L Loddo G REM sleep behavior disorder, autonomic dysfunction and synuclein-related neurodegeneration: where do we stand? Clin Auton Res 2018 28 6 519 533 10.1007/s10286-017-0460-4 28871332
Chiaro G, Calandra-Buonaura G, Cecere A, Mignani F, Sambati L, Loddo G, et al. REM sleep behavior disorder, autonomic dysfunction and synuclein-related neurodegeneration: where do we stand?. Clin Auton Res. 2018;28(6):519–33. 10.1007/s10286-017-0460-4.28871332 10.1007/s10286-017-0460-4
10. Postuma RB Iranzo A Hu M Hogl B Boeve BF Manni R Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study Brain 2019 142 3 744 759 10.1093/brain/awz030 30789229
Postuma RB, Iranzo A, Hu M, Hogl B, Boeve BF, Manni R, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. 2019;142(3):744–59. 10.1093/brain/awz030.30789229 10.1093/brain/awz030
11. Sumi Y Ubara A Ozeki Y Kadotani H Minor hallucinations in isolated rapid eye movement sleep behavior disorder indicative of early phenoconversion: a preliminary study Acta Neurol Scand 2022 145 3 348 359 10.1111/ane.13555 34816426
Sumi Y, Ubara A, Ozeki Y, Kadotani H. Minor hallucinations in isolated rapid eye movement sleep behavior disorder indicative of early phenoconversion: a preliminary study. Acta Neurol Scand. 2022;145(3):348–59. 10.1111/ane.13555.34816426 10.1111/ane.13555
12. Sumi Y Masuda F Kadotani H Ozeki Y The prevalence of depression in isolated/idiopathic rapid eye movement sleep behavior disorder: a systematic review and meta-analysis Sleep Med Rev 2022 65 101684 10.1016/j.smrv.2022.101684 36150254
Sumi Y, Masuda F, Kadotani H, Ozeki Y. The prevalence of depression in isolated/idiopathic rapid eye movement sleep behavior disorder: a systematic review and meta-analysis. Sleep Med Rev. 2022;65: 101684. 10.1016/j.smrv.2022.101684.36150254 10.1016/j.smrv.2022.101684
13. Miglis MG Adler CH Antelmi E Arnaldi D Baldelli L Boeve BF Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder Lancet Neurol 2021 20 671 684 10.1016/s1474-4422(21)00176-9 34302789
Miglis MG, Adler CH, Antelmi E, Arnaldi D, Baldelli L, Boeve BF, et al. Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder. Lancet Neurol. 2021;20:671–84. 10.1016/s1474-4422(21)00176-9.34302789 10.1016/s1474-4422(21)00176-9
14. Nishikawa N Murata M Hatano T Mukai Y Saitoh Y Sakamoto T Idiopathic rapid eye movement sleep behavior disorder in Japan: an observational study Parkinsonism Relat Disord 2022 103 129 135 10.1016/j.parkreldis.2022.08.011 36113390
Nishikawa N, Murata M, Hatano T, Mukai Y, Saitoh Y, Sakamoto T, et al. Idiopathic rapid eye movement sleep behavior disorder in Japan: an observational study. Parkinsonism Relat Disord. 2022;103:129–35. 10.1016/j.parkreldis.2022.08.011.36113390 10.1016/j.parkreldis.2022.08.011
15. Miyamoto T Miyamoto M Inoue Y Usui Y Suzuki K Hirata K Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder Neurology 2006 67 12 2236 2238 10.1212/01.wnl.0000249313.25627.2e 17190953
Miyamoto T, Miyamoto M, Inoue Y, Usui Y, Suzuki K, Hirata K. Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder. Neurology. 2006;67(12):2236–8. 10.1212/01.wnl.0000249313.25627.2e.17190953 10.1212/01.wnl.0000249313.25627.2e
16. Miyamoto T Miyamoto M Suzuki K Nishibayashi M Iwanami M Hirata K 123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder Sleep 2008 31 5 717 723 10.1093/sleep/31.5.717 18517041
Miyamoto T, Miyamoto M, Suzuki K, Nishibayashi M, Iwanami M, Hirata K. 123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder. Sleep. 2008;31(5):717–23. 10.1093/sleep/31.5.717.18517041 10.1093/sleep/31.5.717
17. Kaufmann H Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy Clin Auton Res 1996 6 2 125 126 10.1007/bf02291236 8726100
Kaufmann H. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res. 1996;6(2):125–6. 10.1007/bf02291236.8726100 10.1007/bf02291236
18. Tilvis RS Hakala SM Valvanne J Erkinjuntti T Postural hypotension and dizziness in a general aged population: a four-year follow-up of the Helsinki Aging Study J Am Geriatr Soc 1996 44 809 814 10.1111/j.1532-5415.1996.tb03738.x 8675929
Tilvis RS, Hakala SM, Valvanne J, Erkinjuntti T. Postural hypotension and dizziness in a general aged population: a four-year follow-up of the Helsinki Aging Study. J Am Geriatr Soc. 1996;44:809–14. 10.1111/j.1532-5415.1996.tb03738.x.8675929 10.1111/j.1532-5415.1996.tb03738.x
19. Freeman R Wieling W Axelrod FB Benditt DG Benarroch E Biaggioni I Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome Clin Auton Res 2011 21 69 72 10.1007/s10286-011-0119-5 21431947
Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21:69–72. 10.1007/s10286-011-0119-5.21431947 10.1007/s10286-011-0119-5
20. Frith J Diagnosing orthostatic hypotension: a narrative review of the evidence Br Med Bull 2015 115 123 134 10.1093/bmb/ldv025 25995335
Frith J. Diagnosing orthostatic hypotension: a narrative review of the evidence. Br Med Bull. 2015;115:123–34. 10.1093/bmb/ldv025.25995335 10.1093/bmb/ldv025
21. Goldstein DS Sharabi Y Neurogenic orthostatic hypotension: a pathophysiological approach Circulation 2009 119 139 146 10.1161/CIRCULATIONAHA.108.805887 19124673
Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation. 2009;119:139–46. 10.1161/CIRCULATIONAHA.108.805887.19124673 10.1161/CIRCULATIONAHA.108.805887
22. Goldstein DS Holmes C Cannon RO 3rd Eisenhofer G Kopin IJ Sympathetic cardioneuropathy in dysautonomias N Engl J Med 1997 336 696 702 10.1056/NEJM199703063361004 9041100
Goldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ. Sympathetic cardioneuropathy in dysautonomias. N Engl J Med. 1997;336:696–702. 10.1056/NEJM199703063361004.9041100 10.1056/NEJM199703063361004
23. Satoh A Serita T Tsujihata M [Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson's disease: assessment of cardiac sympathetic denervation] Nihon Rinsho 1997 55 202 6 9014450
Satoh A, Serita T, Tsujihata M. [Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson’s disease: assessment of cardiac sympathetic denervation]. Nihon Rinsho. 1997;55:202–6.9014450
24. Freeman R Abuzinadah AR Gibbons C Jones P Miglis MG Sinn DI Orthostatic hypotension: JACC state-of-the-art review J Am Coll Cardiol 2018 72 1294 1309 10.1016/j.jacc.2018.05.079 30190008
Freeman R, Abuzinadah AR, Gibbons C, Jones P, Miglis MG, Sinn DI. Orthostatic hypotension: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72:1294–309. 10.1016/j.jacc.2018.05.079.30190008 10.1016/j.jacc.2018.05.079
25. Shibao CA Kaufmann H Pharmacotherapy of cardiovascular autonomic dysfunction in Parkinson disease CNS Drugs 2017 31 975 989 10.1007/s40263-017-0473-5 29076058
Shibao CA, Kaufmann H. Pharmacotherapy of cardiovascular autonomic dysfunction in Parkinson disease. CNS Drugs. 2017;31:975–89. 10.1007/s40263-017-0473-5.29076058 10.1007/s40263-017-0473-5
26. McDonald C Newton JL Burn DJ Orthostatic hypotension and cognitive impairment in Parkinson's disease: causation or association? Mov Disord 2016 31 937 946 10.1002/mds.26632 27091624
McDonald C, Newton JL, Burn DJ. Orthostatic hypotension and cognitive impairment in Parkinson’s disease: causation or association?. Mov Disord. 2016;31:937–46. 10.1002/mds.26632.27091624 10.1002/mds.26632
27. Stubendorff K Aarsland D Minthon L Londos E The impact of autonomic dysfunction on survival in patients with dementia with Lewy bodies and Parkinson's disease with dementia PLoS One 2012 7 e45451 10.1371/journal.pone.0045451 23049679
Stubendorff K, Aarsland D, Minthon L, Londos E. The impact of autonomic dysfunction on survival in patients with dementia with Lewy bodies and Parkinson’s disease with dementia. PLoS One. 2012;7:e45451. 10.1371/journal.pone.0045451.23049679 10.1371/journal.pone.0045451
28. Vogel ER Sandroni P Low PA Blood pressure recovery from valsalva maneuver in patients with autonomic failure Neurology 2005 65 1533 1537 10.1212/01.wnl.0000184504.13173.ef 16301478
Vogel ER, Sandroni P, Low PA. Blood pressure recovery from valsalva maneuver in patients with autonomic failure. Neurology. 2005;65:1533–7. 10.1212/01.wnl.0000184504.13173.ef.16301478 10.1212/01.wnl.0000184504.13173.ef
29. Ziegler MG Lake CR Kopin IJ The sympathetic-nervous-system defect in primary orthostatic hypotension N Engl J Med 1977 296 293 297 10.1056/NEJM197702102960601 831126
Ziegler MG, Lake CR, Kopin IJ. The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med. 1977;296:293–7. 10.1056/NEJM197702102960601.831126 10.1056/NEJM197702102960601
30. Norcliffe-Kaufmann L Kaufmann H Palma JA Shibao CA Biaggioni I Peltier AC Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies Ann Neurol 2018 83 522 531 10.1002/ana.25170 29405350
Norcliffe-Kaufmann L, Kaufmann H, Palma JA, Shibao CA, Biaggioni I, Peltier AC, et al. Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol. 2018;83:522–31. 10.1002/ana.25170.29405350 10.1002/ana.25170
31. Millar Vernetti P, Norcliffe-Kaufmann L, Palma JA, Biaggioni I, Shibao CA, Peltier A, et al. Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study. Brain. 2024. 10.1093/brain/awae033.
32. Elliott JE Bryant-Ekstrand MD Keil AT Ligman BR Lim MM Zitser J Frequency of orthostatic hypotension in isolated REM sleep behavior disorder Neurology 2023 101 e2545 e2559 10.1212/WNL.0000000000207883 37857496
Elliott JE, Bryant-Ekstrand MD, Keil AT, Ligman BR, Lim MM, Zitser J, et al. Frequency of orthostatic hypotension in isolated REM sleep behavior disorder. Neurology. 2023;101:e2545–59. 10.1212/WNL.0000000000207883.37857496 10.1212/WNL.0000000000207883
33. Tsukita K Tachibana N Hamano T Appropriate assessment method of 123I-MIBG myocardial scintigraphy for the diagnosis of Lewy body diseases and idiopathic REM sleep behavior disorder J Neurol 2020 267 3248 3257 10.1007/s00415-020-09992-0 32556568
Tsukita K, Tachibana N, Hamano T. Appropriate assessment method of 123I-MIBG myocardial scintigraphy for the diagnosis of Lewy body diseases and idiopathic REM sleep behavior disorder. J Neurol. 2020;267:3248–57. 10.1007/s00415-020-09992-0.32556568 10.1007/s00415-020-09992-0
34. Chung EJ Kim SJ (123)I-metaiodobenzylguanidine myocardial scintigraphy in lewy body-related disorders: a literature review J Mov Disord 2015 8 55 66 10.14802/jmd.15015 26090077
Chung EJ, Kim SJ. (123)I-metaiodobenzylguanidine myocardial scintigraphy in lewy body-related disorders: a literature review. J Mov Disord. 2015;8:55–66. 10.14802/jmd.15015.26090077 10.14802/jmd.15015
35. Totsune T Baba T Sugimura Y Oizumi H Tanaka H Takahashi T Nuclear imaging data-driven classification of Parkinson's disease Mov Disord 2023 38 11 2053 2063 10.1002/mds.29582 37638533
Totsune T, Baba T, Sugimura Y, Oizumi H, Tanaka H, Takahashi T, et al. Nuclear imaging data-driven classification of Parkinson’s disease. Mov Disord. 2023;38(11):2053–63. 10.1002/mds.29582.37638533 10.1002/mds.29582
36. Arnaldi D, Mattioli P, Raffa S, Pardini M, Massa F, Iranzo A, et al. Presynaptic dopaminergic imaging characterizes patients with REM sleep behavior disorder due to synucleinopathy. Ann Neurol. 2024. 10.1002/ana.26902.
37. Heller J Brcina N Dogan I Holtbernd F Romanzetti S Schulz JB Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) - a systematic review on potential biomarkers for neurodegeneration Sleep Med Rev 2017 34 23 33 10.1016/j.smrv.2016.06.006 27542516
Heller J, Brcina N, Dogan I, Holtbernd F, Romanzetti S, Schulz JB, et al. Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) - a systematic review on potential biomarkers for neurodegeneration. Sleep Med Rev. 2017;34:23–33. 10.1016/j.smrv.2016.06.006.27542516 10.1016/j.smrv.2016.06.006
38. Iranzo A Santamaría J Valldeoriola F Serradell M Salamero M Gaig C Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder Ann Neurol 2017 82 419 428 10.1002/ana.25026 28833467
Iranzo A, Santamaría J, Valldeoriola F, Serradell M, Salamero M, Gaig C, 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. 10.1002/ana.25026.28833467 10.1002/ana.25026
39. Videnovic A Ju YS Arnulf I Cochen-De Cock V Högl B Kunz D Clinical trials in REM sleep behavioural disorder: challenges and opportunities J Neurol Neurosurg Psychiatry 2020 91 740 749 10.1136/jnnp-2020-322875 32404379
Videnovic A, Ju YS, Arnulf I, Cochen-De Cock V, Högl B, Kunz D, et al. Clinical trials in REM sleep behavioural disorder: challenges and opportunities. J Neurol Neurosurg Psychiatry. 2020;91:740–9. 10.1136/jnnp-2020-322875.32404379 10.1136/jnnp-2020-322875
40. Wirdefeldt K Adami HO Cole P Trichopoulos D Mandel J Epidemiology and etiology of Parkinson's disease: a review of the evidence Eur J Epidemiol 2011 26 S1 58 10.1007/s10654-011-9581-6 21626386
Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26:S1–58. 10.1007/s10654-011-9581-6.21626386 10.1007/s10654-011-9581-6
41. McKeith IG Boeve BF Dickson DW Halliday G Taylor JP Weintraub D Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium Neurology 2017 89 88 100 10.1212/WNL.0000000000004058 28592453
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology. 2017;89:88–100. 10.1212/WNL.0000000000004058.28592453 10.1212/WNL.0000000000004058
42. Gilman S Wenning GK Low PA Brooks DJ Mathias CJ Trojanowski JQ Second consensus statement on the diagnosis of multiple system atrophy Neurology 2008 71 670 676 10.1212/01.wnl.0000324625.00404.15 18725592
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670–6. 10.1212/01.wnl.0000324625.00404.15.18725592 10.1212/01.wnl.0000324625.00404.15
43. American Psychiatric A, American Psychiatric A, Force DSMT Diagnostic and statistical manual of mental disorders 2017 Arlington American Psychiatric Association DSM-5
American Psychiatric A, American Psychiatric A, Force DSMT. Diagnostic and statistical manual of mental disorders. Arlington: American Psychiatric Association; 2017. p. DSM-5.
44. Iranzo A Santamaría J Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior disorder Sleep 2005 28 203 206 10.1093/sleep/28.2.203 16171244
Iranzo A, Santamaría J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior disorder. Sleep. 2005;28:203–6. 10.1093/sleep/28.2.203.16171244 10.1093/sleep/28.2.203
45. Dahms C Guenther A Schwab M Schultze T Nowack S Hoyer D Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration Eur J Neurol 2016 23 878 890 10.1111/ene.12957 26842960
Dahms C, Guenther A, Schwab M, Schultze T, Nowack S, Hoyer D, et al. Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration. Eur J Neurol. 2016;23:878–90. 10.1111/ene.12957.26842960 10.1111/ene.12957
46. Young HA Cousins AL Watkins HT Benton D Is the link between depressed mood and heart rate variability explained by disinhibited eating and diet? Biol Psychol 2017 123 94 102 10.1016/j.biopsycho.2016.12.001 27939700
Young HA, Cousins AL, Watkins HT, Benton D. Is the link between depressed mood and heart rate variability explained by disinhibited eating and diet? Biol Psychol. 2017;123:94–102. 10.1016/j.biopsycho.2016.12.001.27939700 10.1016/j.biopsycho.2016.12.001
47. Young HA Benton D Heart-rate variability: a biomarker to study the influence of nutrition on physiological and psychological health? Behav Pharmacol 2018 29 140 151 10.1097/FBP.0000000000000383 29543648
Young HA, Benton D. Heart-rate variability: a biomarker to study the influence of nutrition on physiological and psychological health? Behav Pharmacol. 2018;29:140–51. 10.1097/FBP.0000000000000383.29543648 10.1097/FBP.0000000000000383
48. Zygmunt A Stanczyk J Methods of evaluation of autonomic nervous system function Arch Med Sci 2010 6 11 18 10.5114/aoms.2010.13500 22371714
Zygmunt A, Stanczyk J. Methods of evaluation of autonomic nervous system function. Arch Med Sci. 2010;6:11–8. 10.5114/aoms.2010.13500.22371714 10.5114/aoms.2010.13500
49. Yamakawa T Miyajima M Fujiwara K Kano M Suzuki Y Watanabe Y Wearable epileptic seizure prediction system with machine-learning-based anomaly detection of heart rate variability Sensors (Basel) 2020 20 3987 10.3390/s20143987 32709064
Yamakawa T, Miyajima M, Fujiwara K, Kano M, Suzuki Y, Watanabe Y, et al. Wearable epileptic seizure prediction system with machine-learning-based anomaly detection of heart rate variability. Sensors (Basel). 2020;20: 3987. 10.3390/s20143987.32709064 10.3390/s20143987
50. Shaffer F Ginsberg JP An overview of heart rate variability metrics and norms Front Public Health 2017 5 258 10.3389/fpubh.2017.00258 29034226
Shaffer F, Ginsberg JP. An overview of heart rate variability metrics and norms. Front Public Health. 2017;5:258.  10.3389/fpubh.2017.00258.29034226 10.3389/fpubh.2017.00258
51. Conen D Adam M Roche F Barthelemy JC Felber Dietrich D Imboden M Premature atrial contractions in the general population: frequency and risk factors Circulation 2012 126 2302 2308 10.1161/CIRCULATIONAHA.112.112300 23048073
Conen D, Adam M, Roche F, Barthelemy JC, Felber Dietrich D, Imboden M, et al. Premature atrial contractions in the general population: frequency and risk factors. Circulation. 2012;126:2302–8. 10.1161/CIRCULATIONAHA.112.112300.23048073 10.1161/CIRCULATIONAHA.112.112300
52. Callans DJ Premature ventricular contraction-induced cardiomyopathy Arrhythm Electrophysiol Rev 2017 6 153 155 10.15420/aer.2017/6.4/EO1 29326827
Callans DJ. Premature ventricular contraction-induced cardiomyopathy. Arrhythm Electrophysiol Rev. 2017;6:153–5. 10.15420/aer.2017/6.4/EO1.29326827 10.15420/aer.2017/6.4/EO1
53. Raj SR What is the optimal orthostatic stress to diagnose orthostatic hypotension? Clin Auton Res 2005 15 67 68 10.1007/s10286-005-0265-8 15834760
Raj SR. What is the optimal orthostatic stress to diagnose orthostatic hypotension?. Clin Auton Res. 2005;15:67–8. 10.1007/s10286-005-0265-8.15834760 10.1007/s10286-005-0265-8
54. Brignole M Moya A de Lange FJ Deharo JC Elliott PM Fanciulli A 2018 ESC guidelines for the diagnosis and management of syncope Eur Heart J 2018 39 1883 1948 10.1093/eurheartj/ehy037 29562304
Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39:1883–948. 10.1093/eurheartj/ehy037.29562304 10.1093/eurheartj/ehy037
55. Shibao C Lipsitz LA Biaggioni I American Society of Hypertension Writing Group Evaluation and treatment of orthostatic hypotension J Am Soc Hypertens 2013 7 317 24 10.1016/j.jash.2013.04.006 23721882
Shibao C, Lipsitz LA, Biaggioni I, American Society of Hypertension Writing Group. Evaluation and treatment of orthostatic hypotension. J Am Soc Hypertens. 2013;7:317–24. 10.1016/j.jash.2013.04.006.23721882 10.1016/j.jash.2013.04.006
56. Visser M Marinus J Stiggelbout AM Van Hilten JJ Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT Mov Disord 2004 19 1306 1312 10.1002/mds.20153 15390007
Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord. 2004;19:1306–12. 10.1002/mds.20153.15390007 10.1002/mds.20153
57. Maruyama Y Yamada T Murakami K Kumano R Comparison of the diagnostic performance of H/M ratio between early and delayed phases for lewy body disease Nucl Med Commun 2015 36 477 480 10.1097/MNM.0000000000000271 25714666
Maruyama Y, Yamada T, Murakami K, Kumano R. Comparison of the diagnostic performance of H/M ratio between early and delayed phases for lewy body disease. Nucl Med Commun. 2015;36:477–80. 10.1097/MNM.0000000000000271.25714666 10.1097/MNM.0000000000000271
58. Lee JE Kim JS Ryu DW Oh YS Yoo IR Lee KS Cardiac sympathetic denervation can predict the wearing-off phenomenon in patients with Parkinson disease J Nucl Med 2018 59 1728 1733 10.2967/jnumed.118.208686 29572255
Lee JE, Kim JS, Ryu DW, Oh YS, Yoo IR, Lee KS. Cardiac sympathetic denervation can predict the wearing-off phenomenon in patients with Parkinson disease. J Nucl Med. 2018;59:1728–33. 10.2967/jnumed.118.208686.29572255 10.2967/jnumed.118.208686
59. Ryu DW Kim JS Lee JE Oh YS Yoo SW Yoo IR Initial versus follow-up sequential myocardial 123I-MIBG scintigraphy to discriminate Parkinson disease from atypical parkinsonian syndromes Clin Nucl Med 2019 44 282 288 10.1097/RLU.0000000000002424 30589669
Ryu DW, Kim JS, Lee JE, Oh YS, Yoo SW, Yoo IR, et al. Initial versus follow-up sequential myocardial 123I-MIBG scintigraphy to discriminate Parkinson disease from atypical parkinsonian syndromes. Clin Nucl Med. 2019;44:282–8. 10.1097/RLU.0000000000002424.30589669 10.1097/RLU.0000000000002424
60. Folstein MF Folstein SE McHugh PR “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician J Psychiatr Res 1975 12 189 98 10.1016/0022-3956(75)90026-6 1202204
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98. 10.1016/0022-3956(75)90026-6.1202204 10.1016/0022-3956(75)90026-6
61. Dubois B Slachevsky A Litvan I Pillon B The FAB: a frontal assessment battery at bedside Neurology 2000 55 1621 1626 10.1212/wnl.55.11.1621 11113214
Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology. 2000;55:1621–6. 10.1212/wnl.55.11.1621.11113214 10.1212/wnl.55.11.1621
62. Slachevsky A Villalpando JM Sarazin M Hahn-Barma V Pillon B Dubois B Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease Arch Neurol 2004 61 1104 1107 10.1001/archneur.61.7.1104 15262742
Slachevsky A, Villalpando JM, Sarazin M, Hahn-Barma V, Pillon B, Dubois B. Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease. Arch Neurol. 2004;61:1104–7. 10.1001/archneur.61.7.1104.15262742 10.1001/archneur.61.7.1104
63. Nasreddine ZS Phillips NA Bédirian V Charbonneau S Whitehead V Collin I The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment J Am Geriatr Soc 2005 53 695 699 10.1111/j.1532-5415.2005.53221.x 15817019
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–9. 10.1111/j.1532-5415.2005.53221.x.15817019 10.1111/j.1532-5415.2005.53221.x
64. Carson N Leach L Murphy KJ A re-examination of Montreal Cognitive Assessment (MoCA) cutoff scores Int J Geriatr Psychiatry 2018 33 379 388 10.1002/gps.4756 28731508
Carson N, Leach L, Murphy KJ. A re-examination of Montreal Cognitive Assessment (MoCA) cutoff scores. Int J Geriatr Psychiatry. 2018;33:379–88. 10.1002/gps.4756.28731508 10.1002/gps.4756
65. Mamiya Y Nishio Y Watanabe H Yokoi K Uchiyama M Baba T The pareidolia test: a simple neuropsychological test measuring visual hallucination-like illusions PLoS One 2016 11 e0154713 10.1371/journal.pone.0154713 27171377
Mamiya Y, Nishio Y, Watanabe H, Yokoi K, Uchiyama M, Baba T, et al. The pareidolia test: a simple neuropsychological test measuring visual hallucination-like illusions. PLoS One. 2016;11:e0154713. 10.1371/journal.pone.0154713.27171377 10.1371/journal.pone.0154713
66. Revankar GS Kajiyama Y Hattori N Shimokawa T Nakano T Mihara M Prestimulus low-alpha frontal networks are associated with pareidolias in Parkinson's disease Brain Connect 2021 11 772 782 10.1089/brain.2020.0992 33858200
Revankar GS, Kajiyama Y, Hattori N, Shimokawa T, Nakano T, Mihara M, et al. Prestimulus low-alpha frontal networks are associated with pareidolias in Parkinson’s disease. Brain Connect. 2021;11:772–82. 10.1089/brain.2020.0992.33858200 10.1089/brain.2020.0992
67. Beck AT Steer RA Brown GK BDI-II: Beck depression inventory 1996 San Antonio Psychological Corp
Beck AT, Steer RA, Brown GK. BDI-II: Beck depression inventory. San Antonio: Psychological Corp; 1996.
68. Hamilton M A rating scale for depression J Neurol Neurosurg Psychiatry 1960 23 56 62 10.1136/jnnp.23.1.56 14399272
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62. 10.1136/jnnp.23.1.56.14399272 10.1136/jnnp.23.1.56
69. Marin RS Biedrzycki RC Firinciogullari S Reliability and validity of the apathy evaluation scale Psychiatry Res 1991 38 143 162 10.1016/0165-1781(91)90040-v 1754629
Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the apathy evaluation scale. Psychiatry Res. 1991;38:143–62. 10.1016/0165-1781(91)90040-v.1754629 10.1016/0165-1781(91)90040-v
70. Okada K Kobayashi S Yamagata S Takahashi K Yamaguchi S Poststroke apathy and regional cerebral blood flow Stroke 1997 28 2437 2441 10.1161/01.str.28.12.2437 9412628
Okada K, Kobayashi S, Yamagata S, Takahashi K, Yamaguchi S. Poststroke apathy and regional cerebral blood flow. Stroke. 1997;28:2437–41. 10.1161/01.str.28.12.2437.9412628 10.1161/01.str.28.12.2437
71. Stiasny-Kolster K Mayer G Schäfer S Möller JC Heinzel-Gutenbrunner M Oertel WH The REM sleep behavior disorder screening questionnaire–a new diagnostic instrument Mov Disord 2007 22 2386 2393 10.1002/mds.21740 17894337
Stiasny-Kolster K, Mayer G, Schäfer S, Möller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire–a new diagnostic instrument. Mov Disord. 2007;22:2386–93. 10.1002/mds.21740.17894337 10.1002/mds.21740
72. Miyamoto T Miyamoto M Iwanami M Kobayashi M Nakamura M Inoue Y The REM sleep behavior disorder screening questionnaire: validation study of a Japanese version Sleep Med 2009 10 1151 1154 10.1016/j.sleep.2009.05.007 19604719
Miyamoto T, Miyamoto M, Iwanami M, Kobayashi M, Nakamura M, Inoue Y, et al. The REM sleep behavior disorder screening questionnaire: validation study of a Japanese version. Sleep Med. 2009;10:1151–4. 10.1016/j.sleep.2009.05.007.19604719 10.1016/j.sleep.2009.05.007
73. Goetz CG Poewe W Rascol O Sampaio C Stebbins GT Counsell C Movement disorder society task force report on the Hoehn and Yahr staging scale: status and recommendations Mov Disord 2004 19 1020 1028 10.1002/mds.20213 15372591
Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement disorder society task force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord. 2004;19:1020–8. 10.1002/mds.20213.15372591 10.1002/mds.20213
74. Kobayashi M Nishida K Nakamura S Oishi M Shiozaki T Majima Y Suitability of the odor stick identification test for the Japanese in patients suffering from olfactory disturbance Acta Otolaryngol Suppl 2004 553 74 9 10.1080/03655230410017715
Kobayashi M, Nishida K, Nakamura S, Oishi M, Shiozaki T, Majima Y, et al. Suitability of the odor stick identification test for the Japanese in patients suffering from olfactory disturbance. Acta Otolaryngol Suppl. 2004;553:74–9. 10.1080/03655230410017715.10.1080/03655230410017715
75. Shino M Furuta A Uchida J Ooki S Suzaki H Odor stick identification test for Japanese patients with olfactory disturbances Nihon Jibiinkoka Gakkai Kaiho 2006 109 689 695 10.3950/jibiinkoka.109.689 17025219
Shino M, Furuta A, Uchida J, Ooki S, Suzaki H. Odor stick identification test for Japanese patients with olfactory disturbances. Nihon Jibiinkoka Gakkai Kaiho. 2006;109:689–95. 10.3950/jibiinkoka.109.689.17025219 10.3950/jibiinkoka.109.689
76. Matsubara T Suzuki K Fujita H Watanabe Y Sakuramoto H Matsubara M Autonomic symptoms correlate with non-autonomic non-motor symptoms and sleep problems in patients with Parkinson's disease Eur Neurol 2018 80 3–4 193 199 10.1159/000495797 30572329
Matsubara T, Suzuki K, Fujita H, Watanabe Y, Sakuramoto H, Matsubara M, et al. Autonomic symptoms correlate with non-autonomic non-motor symptoms and sleep problems in patients with Parkinson’s disease. Eur Neurol. 2018;80(3–4):193–9. 10.1159/000495797.30572329 10.1159/000495797
77. Marras C Chaudhuri KR Nonmotor features of Parkinson's disease subtypes Mov Disord 2016 31 8 1095 1102 10.1002/mds.26510 26861861
Marras C, Chaudhuri KR. Nonmotor features of Parkinson’s disease subtypes. Mov Disord. 2016;31(8):1095–102. 10.1002/mds.26510.26861861 10.1002/mds.26510
78. Horsager J Borghammer P Brain-first vs. body-first Parkinson's disease: an update on recent evidence Parkinsonism Relat Disord. 2024 122 106101 10.1016/j.parkreldis.2024.106101 38519273
Horsager J, Borghammer P. Brain-first vs. body-first Parkinson’s disease: an update on recent evidence. Parkinsonism Relat Disord. 2024;122:106101. 10.1016/j.parkreldis.2024.106101.38519273 10.1016/j.parkreldis.2024.106101
79. Sumi Y Matsuo M Nakabayashi T Masuda F Takahashi M Kanemura T Changes in the symptom frequency of rapid eye movement sleep behavior disorder according to disease duration Sleep Sci Pract 2017 1 1 10.1186/s41606-017-0017-4
Sumi Y, Matsuo M, Nakabayashi T, Masuda F, Takahashi M, Kanemura T, et al. Changes in the symptom frequency of rapid eye movement sleep behavior disorder according to disease duration. Sleep Sci Pract. 2017;1:1. 10.1186/s41606-017-0017-4.10.1186/s41606-017-0017-4
80. Lavault S Leu-Semenescu S Tezenas du Montcel S Cochen de Cock V Vidailhet M Arnulf I Does clinical rapid eye movement behavior disorder predict worse outcomes in Parkinson's disease? J Neurol 2010 257 1154 9 10.1007/s00415-010-5482-y 20148335
Lavault S, Leu-Semenescu S, Tezenas du Montcel S, Cochen de Cock V, Vidailhet M, Arnulf I. Does clinical rapid eye movement behavior disorder predict worse outcomes in Parkinson’s disease?. J Neurol. 2010;257:1154–9. 10.1007/s00415-010-5482-y.20148335 10.1007/s00415-010-5482-y
81. Miyamoto T Miyamoto M Reduced cardiac (123)I-MIBG uptake is a robust biomarker of Lewy body disease in isolated rapid eye movement sleep behaviour disorder Brain Commun 2024 6 3 fcae148 10.1093/braincomms/fcae148 38725707
Miyamoto T, Miyamoto M. Reduced cardiac (123)I-MIBG uptake is a robust biomarker of Lewy body disease in isolated rapid eye movement sleep behaviour disorder. Brain Commun. 2024;6(3):fcae148. 10.1093/braincomms/fcae148.38725707 10.1093/braincomms/fcae148
82. Miyamoto 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 2023 10 32 41 10.1002/mdc3.13569 36698993
Miyamoto 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. 2023;10:32–41. 10.1002/mdc3.13569.36698993 10.1002/mdc3.13569
83. Park DG Kim JY Kim MS Kim MH An YS Chang J Neurofilament light chain and cardiac MIBG uptake as predictors for phenoconversion in isolated REM sleep behavior disorder J Neurol 2023 270 4393 4402 10.1007/s00415-023-11785-0 37233802
Park DG, Kim JY, Kim MS, Kim MH, An YS, Chang J, et al. Neurofilament light chain and cardiac MIBG uptake as predictors for phenoconversion in isolated REM sleep behavior disorder. J Neurol. 2023;270:4393–402. 10.1007/s00415-023-11785-0.37233802 10.1007/s00415-023-11785-0
84. Shaffer F McCraty R Zerr CL A healthy heart is not a metronome: an integrative review of the heart's anatomy and heart rate variability Front Psychol 2014 5 1040 10.3389/fpsyg.2014.01040 25324790
Shaffer F, McCraty R, Zerr CL. A healthy heart is not a metronome: an integrative review of the heart’s anatomy and heart rate variability. Front Psychol. 2014;5:1040. 10.3389/fpsyg.2014.01040.25324790 10.3389/fpsyg.2014.01040
85. Ciccone AB Siedlik JA Wecht JM Deckert JA Nguyen ND Weir JP Reminder: RMSSD and SD1 are identical heart rate variability metrics Muscle Nerve 2017 56 4 674 678 10.1002/mus.25573 28073153
Ciccone AB, Siedlik JA, Wecht JM, Deckert JA, Nguyen ND, Weir JP. Reminder: RMSSD and SD1 are identical heart rate variability metrics. Muscle Nerve. 2017;56(4):674–8. 10.1002/mus.25573.28073153 10.1002/mus.25573
86. Fedorowski A Melander O Syndromes of orthostatic intolerance: a hidden danger J Intern Med 2013 273 322 335 10.1111/joim.12021 23216860
Fedorowski A, Melander O. Syndromes of orthostatic intolerance: a hidden danger. J Intern Med. 2013;273:322–35. 10.1111/joim.12021.23216860 10.1111/joim.12021
87. Tanaka R Hattori N Abnormal circadian blood pressure regulation and cognitive impairment in α-synucleinopathies Hypertens Res 2022 45 1908 1917 10.1038/s41440-022-01032-w 36123397
Tanaka R, Hattori N. Abnormal circadian blood pressure regulation and cognitive impairment in α-synucleinopathies. Hypertens Res. 2022;45:1908–17. 10.1038/s41440-022-01032-w.36123397 10.1038/s41440-022-01032-w
88. Wang C Chen F Li Y Liu J Possible predictors of phenoconversion in isolated REM sleep behaviour disorder: a systematic review and meta-analysis J Neurol Neurosurg Psychiatry 2022 93 395 403 10.1136/jnnp-2021-328062 34937751
Wang C, Chen F, Li Y, Liu J. Possible predictors of phenoconversion in isolated REM sleep behaviour disorder: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2022;93:395–403. 10.1136/jnnp-2021-328062.34937751 10.1136/jnnp-2021-328062
89. Thaisetthawatkul P Boeve BF Benarroch EE Sandroni P Ferman TJ Petersen R Autonomic dysfunction in dementia with Lewy bodies Neurology 2004 62 1804 1809 10.1212/01.wnl.0000125192.69777.6d 15159482
Thaisetthawatkul P, Boeve BF, Benarroch EE, Sandroni P, Ferman TJ, Petersen R, et al. Autonomic dysfunction in dementia with Lewy bodies. Neurology. 2004;62:1804–9. 10.1212/01.wnl.0000125192.69777.6d.15159482 10.1212/01.wnl.0000125192.69777.6d
90. Ballard CG Shaw F Lowery K McKeith I Kenny R The prevalence, assessment and associations of falls in dementia with Lewy bodies and Alzheimer's disease Dement Geriatr Cogn Disord 1999 10 97 103 10.1159/000017108 10026382
Ballard CG, Shaw F, Lowery K, McKeith I, Kenny R. The prevalence, assessment and associations of falls in dementia with Lewy bodies and Alzheimer’s disease. Dement Geriatr Cogn Disord. 1999;10:97–103. 10.1159/000017108.10026382 10.1159/000017108
91. Kudo Y Imamura T Sato A Endo N Risk factors for falls in community-dwelling patients with Alzheimer's disease and dementia with Lewy bodies: walking with visuocognitive impairment may cause a fall Dement Geriatr Cogn Disord 2009 27 139 146 10.1159/000198688 19182481
Kudo Y, Imamura T, Sato A, Endo N. Risk factors for falls in community-dwelling patients with Alzheimer’s disease and dementia with Lewy bodies: walking with visuocognitive impairment may cause a fall. Dement Geriatr Cogn Disord. 2009;27:139–46. 10.1159/000198688.19182481 10.1159/000198688
