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Abstract

Background:

REM-sleep behaviour disorder (RBD) is a parasomnia and a common comorbidity in Parkinson’s disease (PD). There is evidence that the presence of RBD is associated with more severe PD. The differences in the clinical manifestations and the natural history are likely to imply underlying differences in the pathophysiology among PD patients with and without RBD. The increasing number of neuroimaging studies support this notion.

Objective:

Our primary objective was to review the current evidence regarding the brain neuroimaging findings in PD patients with RBD (PDRBD).

Methods:

A systematic review of articles, published in PubMed between January 1, 2000 and September 23, 2020 was performed. We evaluate previous studies that assessed PD patients with RBD using various brain structural and functional magnetic resonance imaging (MRI) techniques and brain nuclear medicine imaging.

Results:

Twenty-nine studies, involving a total of 3,347 PD subjects among which 912 subjects with PDRBD, met the selection criteria and were included. The presence of RBD in PD patients is associated with structural and functional alterations in several brain regions, mainly in brainstem, limbic structures, frontotemporal cortex, and basal ganglia, raising the hypothesis of a PDRBD neuroimaging phenotype.

Conclusion:

The current review provides up-to-date knowledge in this field and summarizes the neurobiological/neuroimaging substrate of RBD in PD.

Keywords

RBD Parkinson’s disease structural MRI voxel-based morphometry diffusion tensor imaging neuromelanin-sensitive MRI functional neuroimaging nuclear medicine imaging single photon emission computed tomography positron emission tomography

INTRODUCTION

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia with abnormal nocturnal dream enactment during REM sleep. During REM sleep, the normal sleeping person is mentally active and dreaming, while the skeletal muscles are paralyzed. In RBD, however, REM atonia is altered, resulting in dream enactment that may vary from slight hand movement to loud vocalization and potentially injurious behavior [1, 2]. RBD is very common among patients with Parkinson’s disease (PD), already from the early PD stages [3] and recent evidence suggests that the presence of RBD is associated with a more diffuse malignant PD subtype, mainly with differences in the spectrum of clinical symptoms, in natural history and prognosis of PD [4], which are likely to imply underlying differences in the pathophysiology and possibly the distribution of neurodegeneration among PD patients with and without RBD. Indeed, RBD in PD patients is associated with more motor [5] and non-motor symptoms, in particular psychiatric manifestations, cognitive alterations and sleep-wake disturbances [6, 7]. These data support the notion that RBD should no longer be considered a complication but a biomarker or even a driving force for neurodegeneration [8]. However, the pathophysiological mechanisms leading to RBD in PD are not fully elucidated.

In recent years, an increasing number of structural and functional magnetic resonance imaging (MRI) as well as nuclear medicine imaging studies reported specific brain alterations in PD patients with RBD (PDRBD). Our primary objective was to review the current evidence and provide up-to-date knowledge regarding the brain neuroimaging findings in PDRBD. Secondly, we discuss pathophysiological hypotheses to explain the association between RBD and neurodegeneration in PD, in respect to brain neuroimaging findings.

METHODS

Extraction of articles was performed by two independent observers (R.M. and P.B.) and was evaluated by the rest of the authors. Discrepancies in selection were resolved by discussion. A systematic literature search in Pubmed/Medline via Ovid was conducted for articles published between January 1, 2000 and September 23, 2020. We used MeSH-term (medical subject heading) search as well as the search terms (“Parkinson’s disease” or Parkinson) AND (“rapid eye movement sleep behavior disorder” or “rem sleep behavior disorder”) AND (“imaging” OR “MRI” OR “magnetic resonance imaging” OR “DTi” or “diffusion tensor imaging” OR “diffusion-tensor” OR “SPECT” OR “single photon emission tomography” OR “DatScan” OR “PET” OR “positron emission tomography” OR “spectroscopy” OR “magnetic resonance spectroscopy”.

The inclusion of studies was based on the following inclusion criteria: 1) original studies (reviews, editorials, case reports etc. were excluded), 2) full text was written in English 3) human subjects were involve, 4) aim of the study was to describe structural or functional neuroimaging findings in PD and RBD patients.

The main scope of the study was to assess the brain neuroimaging findings in PD with RBD or in iRBD that converts to PD. To best serve this scope, we excluded from the analysis, studies that reported on other synucleinopathies (i.e., Lewy body dementia).

The reference lists of articles that met the eligibility criteria were further screened to identify additional studies that may fall within the scope of this review.

Quality assessment

To assess risk of bias in the included studies, we applied nine quality criteria as previously published in by Carey et al. [9]: (1) demographics; (2) imaging procedure; (3) spatial normalization method; (4) determination of ROIs; (5) reproducibility of the analyzes; (6) statistical tests used to substantiate the results; (7) correction for the multiple testing problem; (8) figures and tables; (9) quality control measures. A summary of the quality assessment is presented in the Supplementary Material.

RESULTS

The initial search identified 376 records. After exclusion of duplicates, we identified 238 potentially eligible studies. We additionally included 3 relevant studies found in the reference list of review articles (in total 241 studies). Of these, 29 studies, with 3,347 subjects in total and 912 subjects with PDRBD, met all above-mentioned selection criteria and were included in the systematic review (Fig. 1). Among the included studies, 14 used polysomnography for the diagnosis of RBD while 15 studies used RBD questionnaires.

Fig. 1

Flow diagram demonstrating the process of article selection for systematic review.

Magnetic resonance imaging

Structural MRI studies

We identified 11 studies [10 –20] that reported findings from structural MRI methods, including voxel-based morphometry (VBM), DTI, deformation based morphometry, neuromelanin-sensitive MRI and diffusion MRI connectometry. Three studies used PSG and 8 studies used questionnaire to diagnose RBD (Table 1). Four fMRI studies comprised 217 participants, of whom 174 were PD patients and 43 were HCs.

Table 1

Structural MRI studies in PDRBD

Authors	Compared Groups	N (number)	Neuroimaging method	Diagnosis of RBD	Outcome
Morphometry Methods
Boucetta et al. (2016) [11]	PDRBD+ (60.93±9.16) vs. PDRBD–(61.62±9.84)	69 vs. 240	DBM	RBDQ	In PDRBD+, reduced volume in:
					–pontomesencephalic tegmentum
					–medullary reticular formation
					–hypothalamus
					–thalamus
					–putamen
					–amygdala
					–anterior cingulate cortex
	PDRBD+ (60.93±9.16) vs. HC (59.92±10.83)	69 vs. 138	In PDRBD+, reduced volume in:
					–pontomesencephalic tegmentum,
					–medullary reticular formation,
					–hypothalamus,
					–thalamus,
					–putamen
					–amygdala
					–anterior cingulate cortex
Ford et al. (2013) [12]	PDRBD+ (66.4±9.9) vs. PDRBD–(65.8±10.9)	46 vs. 78	VBM	RBDQ	No statistically significant differences among PDRBD+ and PDRBD–after adjustment for multiple comparisons in VBM
García-Lorenzo et al. (2013) [13]	PDRBD+ (62.4±8.4) vs. PDRBD–(56.3±11.5)	24 vs. 12	VBM	PSG	VBM didn’t show any significant difference in white and grey matter among PDRBD+, PDRBD–and HC
	PDRBD+ (62.4±8.4) vs. HC (60.2±8.3)	24 vs. 19
Guo et al. (2018) [15]	PDRBD+ (61.9±9.5) vs. PDRBD–(60.5±9.7)	51 vs. 140	SCN	RBDQ	In PDRBD+, increased nodal measures mainly in:
					–limbic regions
					–frontal-temporal regions,
					–occipital lobe regions
					And decreased nodal measures in:
					–bilateral cerebellum hemisphere
					–left pallidum
	PDRBD+ (61.9±9.5) vs. HC (60.3±10.6)	51 vs. 76			In PDRBD+, increased nodal measures in:
					–frontal-temporal regions (e.g., right pars orbitalis superior frontal gyrus, left fusiform, and left superior temporal gyrus)
					–parietal-occipital regions (right angular and left cuneus)
					–right caudate
					AND decreased nodal measures predominantly in:
					–cerebellum
					–fusiform gyrus
					–inferior frontal gyrus
					–superior frontal gyrus
Kamps et al. (2019) [16]	PDRBD+ (61.1±10.72) vs. PDRBD–(61.08±9.32)	40 vs. 127	VBM	RBDQ	In PDRBD+, smaller volume in:
					–Right putamen
	PDRBD+ (61.1±10.72) vs. HC (59.41±10.76)	40 vs. 68			In PDRBD+, smaller volume in:
					–Right putamen
Lim et al. (2016) [17]	PDRBD+ (69.8±6.4) vs. PDRBD–(69.7±7.2)	24 vs. 14	VBM	PSG	In PDRBD+, a decreased volume in:
					–left posterior cingulate
					–hippocampus
	PDRBD+ (69.8±6.4) vs. HC (68.5±6.6)	24 vs. 25			In PDRBD+, a decreased volume in:
					–precuneus, cuneus, medial frontal gyrus
					–postcentral gyrus
					–both inferior parietal lobule
Salsone et al. (2014) [19]	PDRBD+ (66.6±7.4) vs. PDRBD–(66.9±7.9)	11 vs. 11	VBM	PSG	In PDRBD–, a significant decrease of grey matter volume in:
					–right thalamus
					–left thalamus (when automated volumetry was used)
					AND grey matter abnormalities in:
					–right medial temporal cortex.
	PDRBD+ (66.6±7.4) vs. HC (65.1±7.8)	11 vs. 18			In PDRBD+, a decrease of grey matter in:
					–right thalamus
					–left thalamus (when automated volumetry was used)
Diffusion MRI studies
Ansari et al. (2017) [10]	PDRBD+ (59.43±10.97) vs. PDRBD–(60.64±8.65)	23 vs. 31	DTI (QA)	RBDQ	In PDRBD+, a significantly reduced QA in:
					–Bilateral cingulum pathways
					–All parts of corpus callosum
					–Inferior fronto-occipital fasciculi in both hemispheres
					–Both corticospinal tracts
					–Middle cerebellar peduncles
Ford et al. (2013) [12]	PDRBD+ (66.4±9.9) vs. PDRBD–(65.8±10.9)	46 vs. 78	DTI (FA+MD)	RBDQ	PDRBD+ showed only slight differences with PDRBD–which were not significant after adjustment for multiple comparisons.
García-Lorenzo et al. (2013) [13]	PDRBD+ (62.4±8.4) vs. PDRBD–(56.3±11.5)	24 vs. 12	DTI (FA)	PSG	No difference was found between patients with and without RBD.
	PDRBD+ (62.4±8.4) vs. HC (60.2±8.3)	24 vs. 19			In PDRBD+, significant increases in FA in the left hemisphere in:
					–Tegmentum of the midbrain
					–Rostral pons
					AND significant increases in apparent diffusion coefficient in the right hemisphere in:
					–pontine tegmentum
					–midbrain (cerebral peduncles and substantia nigra)
Ghazi Sherbaf et al. (2018) [14]	PDRBD+ with depression (58.28±8.37) vs. PDRBD+ without depression (59.42±11.3)	14 vs. 18	DMRIc (QA)	RBDQ	In PDRBD+ with depression, decreased connectivity in:
					–fornices
					–left inferior longitudinal fasciculus
					–right corticospinal tract
					–right cingulum
					–genu of corpus callosum
					–left middle cerebellar peduncle
Lim et al. (2016) [17]	PDRBD+ (69.8±6.4) vs. PDRBD–(69.7±7.2)	24 vs. 14	DTI (FA+MD)	PSG	No significant differences found between PDRBD+ and PDRBD–
	PDRBD+ (69.8±6.4) vs HC (68.5±6.6)	24 vs. 25			In PDRBD+, significantly reduced FA in:
					–Frontal areas on both sides
					AND a widespread MD
Rahmani et al. (2016) [18]	PDRBD+ (61±8.15) vs. PDRBD–(64±6.6	10 vs. 7	DTI (QA)	RBDQ	In PDRBD+, reduced QA in:
					–both sides of cingulum
					–Inferior fronto-occipital fasciculus
Neuromelanin-sensitive MRI
García-Lorenzo et al. (2013) [13]	PDRBD+ (62.4±8.4) vs. PDRBD–(56.3±11.5)	24 vs. 12	NM-MRI	PSG	In PDRBD+, a reduced signal intensity in:
					–coeruleus/subcoeruleus complex
	PDRBD+ (62.4±8.4) vs. HC (60.2±8.3)	24 vs. 19			In PDRBD+, a reduced signal intensity in:
					–coeruleus/subcoeruleus complex
Sommerauer et al. (2018) [20]	PDRBD+ (67.7±9.3) vs. PDRBD–(65.4±9)	16 vs. 14	NM-MRI	RBDQ	In PDRBD+, a decreased ratio of:
					–locus coeruleus/pons
	PDRBD+ (67.7±9.3) vs. HC (67.3±6.3)	16 vs. 12			In PDRBD+, a decreased ratio of:
					–locus coeruleus/pons

PDRBD+, Parkinson’s disease’s patients with RBD; PDRBD–, Parkinson’s disease’s patients without RBD; HC, healthy controls; RBDQ, REM Sleep Behavior Disorder Questionnaire; PSG, polysomnography; DBM, deformation-based morphometry; VBM, voxel-based morphometry; SCN, structural correlation network; DTI, diffusion tensor imaging; QA, quantitative anisotropic; FA, fractional anisotropy; MD, mean diffusivity; DMRIc, diffusion MRI connectometry; NM-MRI, neuromelanin-sensitive MRI.

Morphometry studies

The 7 morphometry studies [11–13 , 19] comprised 1,231 participants, of whom 265 were PDRBD+ patients, 622 were PDRBD–patients and 344 were HCs (Table 1).

Six studies used VBM, and one study used defor-mation-based morphometry (DBM) to perform volumetric analyse grey matter analysis.

All studies reported on regional measures and 2 studies [15, 16] reported on global network measures or whole-brain analyses as well. One study reported on the correlation between RBD severity and structural changes [16].

In VBM studies comparing PDRBD+ and PDRBD–groups, RBD was associated with de-creased grey matter volume in thalamus, medial temporal cortex, left posterior cingulate, hippocampus and putamen.

In VBM studies comparing PDRBD+ groups and HC, the PDRBD+ patients exhibited increased grey matter volume in thalamus, precuneus, cuneus, medial frontal gyrus, postcentral gyrus, inferior parietal lobule, right pars orbitalis superior frontal gyrus, left fusiform, superior temporal gyrus, angular cuneus and caudate and decreased grey matter volume in cerebellum, fusiform gyrus, inferior frontal gyrus, superior frontal gyrus and putamen.

There was a negative correlation between RBD symptom severity and volume of putamen, thalamus and hippocampus [16].

Two VBM studies found no significant differences between PDRBD+ and PDRBD–groups [12] or among PDRBD+, PDRBD–and HC groups [13].

The only deformation-based morphometry study reported significantly smaller volume in pontomesencephalic tegmentum, medullary reticular formation, hypothalamus, thalamus, putamen, amygdala and anterior cingulate cortex in PD patients with probable RBD compared to PD patients without RBD and to HC [11].

Diffusion MRI studies

The 4 fMRI studies comprised 217 participants, of whom 174 were PD patients and 43 were HCs.

The 6 diffusion MRI studies [10 , 18] comprised 345 participants, of whom 159 were PDRBD+ patients, 142 were PDRBD–patients and 44 were HC (Table 1).

All studies reported on anisotropy (fractional anisotropy (FA) or quantitative anisotropic) and 2 studies [12, 17] reported on mean diffusivity (MD) as well. None of the studies reported on the correlation between RBD severity and structural changes.

In DTi studies comparing PDRBD+ and PDRBD–groups, RBD was associated with reduced connectivity (either FA or MD) in fornices, cingulum pathways, corpus callosum, inferior longitudinal fasciculus, inferior fronto-occipital fasciculi, corticospinal tracts, and the middle cerebellar peduncles in three other studies [10 , 18].

In DTi studies comparing PDRBD+ groups and HC, PDRBD+ patients exhibited reduced FA mainly in frontal areas and widespread reduced mean diffusivity [17], increased FA in the tegmentum of the midbrain and rostral pons [13] and increased apparent diffusion coefficient in the midbrain (cerebral pendunculus and substantia nigra) [13].

Three DTi studies found no significant differences between PDRBD+ and PDRBD [12 , 17].

None reported on the correlation between RBD symptom severity and FA or other DTi parameter.

Neuromelanin-sensitive MRI

The 2 neuromelanin-sensitive MRI studies [13, 20] comprised 97 participants, of whom 40 were PDRBD+ patients, 26 were PDRBD–patients and 31 were HC. Both studies reported reduced signal intensity in the coerueleus/pons region in the PDRBD+ group compared to the PDRBD–and HC groups [13, 20]. In one study, the reduction of the perceived signal correlated with the degree of REM atonia loss in polysomnography [13] (Table 1).

Functional MRI studies

Two resting state functional MRI (rs-fMRI) studies [21, 22] comprised 130 participants, of whom 56 were PDRBD+ patients, 30 were PDRBD–patients and 44 were HC (Table 2).

Table 2

Functional MRI studies in PDRBD

Authors	Compared groups	N (number)	Neuroimaging method	Diagnosis of RBD	Outcome
Gallea et al. (2017) [21]	PDRBD+ with postural instability (61.9±9.4) vs. PDRBD+ without postural instability (62.4±6.4)	16 vs. 22	RS-fMRI	PSG	In PDRBD+ with postural instability, defective connectivity between:
					–PPN and the SMA
					–PPN and the MPFC
	PDRBD+ with postural instability (61.9±9.4) vs. PDRBD–without postural instability (57.9±8.8)	16 vs. 14			In PDRBD+ with postural instability, defective connectivity between:
					–PPN and the SMA
					–PPN and the MPFC
					–PPN and the ACC
	PDRBD+ with postural instability (61.9±9.4) vs. HC (59.8±8)	16 vs. 25			In PDRBD+ with postural instability, defective connectivity between:
					–PPN and the SMA
					–PPN and the MPFC
					–PPN and the ACC
	PDRBD+ without postural instability (62.4±6.4) vs. PDRBD–without postural instability (57.9±8.8)	22 vs. 14			In PDRBD+ without postural instability, defective connectivity between: –PPN and ACC
	PDRBD+ without postural instability (62.4±6.4) vs. HC (59.8±8)	22 vs. 25			In PDRBD+ without postural instability, defective connectivity between:
					–PPN and the ACC
Li et al. (2017) [22]	PDRBD+ (63.9±8.2) vs. PDRBD–(62.8±6.6)	18 vs. 16	ALFF	PSG	In PDRBD+, decreased ALFF in:
					–primary motor cortex extending to premotor cortex
	PDRBD+ (63.9±8.2) vs. HC (62.7±8.1)	18 vs. 19			In PDRBD+, decreased ALFF in:
					–caudate
					–putamen
					AND increased ALFF in:
					–prefrontal cortex

PDRBD+, Parkinson’s disease’s patients with RBD; PDRBD–, Parkinson’s disease’s patients without RBD; HC, healthy controls; PSG, polysomnography; RS-fMRI, resting state-functional MRI; ALFF, amplitude of low frequency fluctuations; PPN, pedunculopontine nucleus; SMA, supplementary motor area; MPFC, medial prefrontal cortices; ACC, anterior cingulate cortices.

Table 3

Magnetic Resonance Spectroscopy studies in PDRBD

Authors	Compared groups	N (number)	Neuroimaging method	Diagnosis of RBD	Outcome
Hanoglu et al. (2006) [23]	PDRBD+ (66.58±7.97) vs. PDRBD–(67.18±7.35)	12 vs. 12	brainstem¹ H-MRS values (long TE NAA/Cr, Ch/Cr and short TE NAA/Cr, Ch/Cr, MI/Cr values)	PSG	There were no statistically important differences in brainstem 1 H-MRS values

PDRBD+, Parkinson’s disease’s patients with RBD; PDRBD–, Parkinson’s disease’s patients without RBD; PSG, polysomnography; ¹H-MRS, ¹H-MR Spectroscopy.

Gallea et al. studied the functional connectivity and found reduced connectivity between the pedunculopontine nucleus (PPN) with the anterior cingulate cortices (ACC) in both PDRPD+ patient groups compared with the PDRBD–patients and HCs. In addition, the presence of postural instability in PDRBD+ patients was associated with defective connectivity between the PPN and the supplementary motor area (SMA) and medial prefrontal cortices areas [21].

The other rs-fMRI study by Li et al. investigated baseline brain activity and reported amplitude of low frequency fluctuations (ALFF). In PD patients, the presence of RBD was associated with significantly reduced amplitude of ALFF values in primary motor and in the premotor cortex. In addition, RBDPD+patients had decreased ALFF values in caudate and putamen and increased ALFF values in prefrontal cortex compared to HC [22].

No studies reported on the correlation between RBD symptom severity and rs-fMRI parameters.

Magnetic resonance spectroscopy

We found only one study using magnetic resonance spectroscopy. The study did not show any statistical significance in respect to proton magnetic resonance spectroscopy (1H-MRS) parameters (mainly the ratios of metabolites relative to creatinine in brainstem were calculated: N-acetylaspartate/creatinine, choline/creatinine, myo-inositol/creatinine) between 12 PDRBD+ and 12 PDRBD–(Table 3).

Nuclear medicine imaging

Single photon emission computed tomography (SPECT)

The nine SPECT studies [19 , 24–31] comprised 1,194 participants, of whom 336 were PDRBD+ patients, 707 were PDRBD–patients, 48 were HC and 103 were iRBD (Table 4).

Table 4

SPECT studies in PDRBD

Authors	Compared groups	N (number)	Neuroimaging method	Diagnosis of RBD	Outcome
Arnaldi et al. (2015) [24]	PDRBD+ (69.4±6) vs. PDRBD–(67.2±7.2)	24 vs. 12	¹²³I-FP-CIT-SPECT	RBDQ	In PDRBD+ SBR was lower in:
					–Caudate
	PDRBD+ (69.4±6) vs. iRBD (66.4±7.5)	24 vs. 16			In PDRBD+, SBR was decreased in:
					–putamen
Arnaldi et al. (2016) [25]	PDRBD+ (72.8±6.2) vs. PDRBD–(70.6±7.1)	24 vs. 14	¹²³I-FP-CIT-SPECT	RBDQ	In PDRBD+, stronger dopaminergic impairment in:
					–caudate of the less affected hemisphere
Cao et al. (2020) [26]	PDRBD+ (61.5±10.1) vs. PDRBD–(61.2±9.5)	98 vs. 135	¹²³I-FP-CIT-SPECT	PSG	In PDRBD+, DAT loss in:
					–caudate (faster reduction of ¹²³I-FP-CIT binding)
					–putamen
					WITH less profound interhemispheric asymmetry in DAT binding with the progression of the disease
Iranzo et al. (2011) [27]	iRBD (70.55±6.02) vs. HC (69.5±6.77)	20 vs. 20	¹²³I-FP-CIT-SPECT	PSG	The patients who developed PD (N = 3) had reduced ¹²³I-FP-CIT uptake at baseline and after 3 years a decrease in:
					–left putamen (32%.
					–right putamen (30%.
					–left caudate nucleus (27%.
					–right caudate nucleus (24%.
					They had also the poorest uptake at all 3 scans conducted (baseline, 1.5 year and 3 years)
Liu et al. (2020) [28]	PD patients (60.9±9.6)	225	¹²³I-FP-CIT-SPECT	RBDQ	Striatal SBR decreased by 0.083 for each one unit increase in the z score of RBDSQ across a 28-month follow-up
Maškov $\overset{´}{a}$ et al. (2020) [29]	PDRBD+ (PD group: 56.3±12.4) vs. PDRBD–(PD group:56.3±12.4)	11 vs. 33	¹²³I-FP-CIT-SPECT	PSG	In PDRBD+, SBR was low in: –caudate
	PDRBD+ (PD group: 56.3±12.4) vs. iRBD (66.4±8.1)	11 vs. 61			In PDRBD+, SBR was lower in the most affected hemisphere in:
					–putamen
					–caudate
Pagano et al. (2018) [30]	PDRBD+ (61.8±9.68) vs. PDRBD–(61.47±9.78)	158 vs. 263	¹²³I-FP-CIT-SPECT	RBDQ	No significant difference in ¹²³I-FP-CIT binding in the striatum, putamen or caudate between PDRBD+ and PDRBD–patients.
Salsone et al. (2014) [19]	PDRBD+ (66.6±7.4) vs. PDRBD–(66.9±7.9)	11 vs. 11	DAT-SPECT	PSG	No significant differences in tracer uptake between PDRBD+ and PDRBD–patients
	PDRBD+ (66.6±7.4) vs. HC (65.1±7.8)	11 vs. 18			In PDRBD+ reduced tracer uptake in:
					–putamen
					–caudate
Zoetmulder et al. (2016) [31]	PDRBD+ (66.6±3.44) vs. PDRBD–(66.8±8.72)	10 vs. 10	¹²³I-FP-CIT-SPECT	PSG	No significant differences between PDRBD+ and PDRBD–
	PDRBD+ (66.6±3.44) vs. iRBD (61.2±9.27)	10 vs. 10			In PDRBD+, lower ¹²³I-FP-CIT uptake especially in:
					–left putamen
	PDRBD+ (66.6±3.44) vs. HC (56.2±8.28)	10 vs. 10			In PDRBD+, lower ¹²³I-FP-CIT uptake especially in:
					–left putamen

PD, Parkinson’s disease; PDRBD+, Parkinson’s disease’s patients with RBD; PDRBD–, Parkinson’s disease’s patients without RBD; HC, healthy controls; iRBD, idiopathic REM Sleep Behavior Disorder; RBDQ, REM Sleep Behavior Disorder Questionnaire; RBDSQ, REM Sleep Behavior Disorder Screening Questionnaire; PSG, polysomnography; SBR, specific binding ration; ¹²³I-FP-CIT, ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane; SPECT, single-photon emission computed tomography; DAT, dopamine transporter

Seven studies compared PDRBD+ (N = 375) vs. PDRBD–(N = 540) patients [19 , 29–31], two studies compared PDRBD+ vs. HC, one study followed the phenoconversion from iRBD to PDRBD+ [27] and one study reported in a non-controlled study on dopaminergic transporter (DAT) binding changes related to the presence of RBD in PD patients [28]. All studies reported on DAT binding using ¹²³I-FP-CIT-SPECT.

In ¹²³I-FP-CIT-SPECT studies comparing PDRBD+ and PDRBD–groups, RBD was associated with low specific binding ratio (SBR) at caudate [24–26 , 29], in putamen [26, 29] and in ventral putamen [32].

One study reduced DAT uptake was more prominent in the less affected side [25] Interestingly the interhemispheric asymmetry in DAT binding is less profound as disease progresses [26].

In ¹²³I-FP-CIT-SPECT studies comparing PDRBD+ and iRBD groups, PDRBD+ patients exhibited lower DAT uptake in the putamen [24 , 31]. In ¹²³I-FP-CIT-SPECT studies comparing PDRBD+ groups and HC, PDRBD+ patients exhibited lower DAT uptake, especially in the putamen [19, 31] and caudate [19]. Two ¹²³I-FP-CIT-SPECT study found no significant differences between PDRBD+ and PDRBD–.

One study [27] examined 20 iRBD patients at baseline and in two intervals of 1.5 years to examine the association between the development of PD in iRBD with ¹²³I-FP-CIT uptake. The patients who developed PD (N = 3) had generally the poorest ¹²³I-FP-CIT uptake at baseline and a decrease in the left putamen(32%., the right putamen (30%., the left caudate nucleus (27%., and in the right caudate nucleus (24%. after 3 years compared with HCs [27].

One study reported a significant negative correlation between RBD symptoms (assessed by RBDSQ) and striatal SBR in ¹²³I-FP-CIT-SPECT [28].

Positron emission tomography studies

The nine PET studies [20 , 32–38] comprised 401 participants, of whom 213 were PDRBD+ patients, 185 were PDRBD–patients, 224 were HC and 131were iRBD (Table 5).

Table 5

PET studies in PDRBD

Authors	Compared groups	N (number)	Neuroimaging method	Diagnosis of RBD	Outcome
Andersen et al. (2020) [33]	PDRBD+ (67.7±9.3) vs. PDRBD–(65.4±9)	16 vs. 14	¹¹C-MeNER PET	PSG	In PDRBD+, a profound decrease in mean values of VOIs in:
					–precentral gyri
					–postcentral gyri
	PDRBD+ (67.7±9.3) vs. HC (67±8)	16 vs. 25			In PDRBD+, a profound decrease in mean values of VOIs in:
					–precentral gyri
					–postcentral gyri
	PDRBD+ (67.7±9.3) vs. iRBD (66±8)	16 vs. 17			There was no direct comparison between PDRBD+ and iRBD patients
Arnaldi et al. (2016) [25]	PDRBD+ (72.8±6.2) vs. PDRBD–(70.6±7.1)	24 vs. 14	¹⁸F-FDG-PET	RBDQ	In PDRBD+, increased metabolism in:
					–anterior cortical regions (especially the anterior cingulate and precentral gyrus) of the most affected hemisphere
					AND decreased metabolism in:
					–posterior cortical regions (incl. the parietal, occipital and posterior temporal regions) of the more affected hemisphere
	PDRBD+ (72.8±6.2) vs. HC (67.8±11.6)	24 vs. 49			HC were used as the control group for ¹⁸F-FDG-PET comparison with PD groups to assess brain metabolism differences between the two PD groups and normal subjects. No results for PDRBD+ vs. HC available
Arnaldi et al. (2019) [34]	PDRBD+ (71.8±6.6) vs. PDRBD–(68.4±8.5)	40 vs. 32	¹⁸F-FDG-PET	PSG	The patterns of brain hypometabolism were very similar between PDRBD+ and PDRBD–patients offering only moderate discrimination capability
	PDRBD+ (71.8±6.6) vs. iRBD (64.1±6.5)	40 vs. 36			The patterns of brain hypometabolism were very similar between PDRBD+ and iRBD patients offering only moderate discrimination capability
	PDRBD+ (71.8±6.6) vs. HC (65.6±9.4)	40 vs. 79			In PDRBD+, decreased metabolism was found
Chung et al. (2017) [32]	PDRBD+ (69.3±7.8) vs. PDRBD–(67.5±11.1)	39 vs. 58	¹⁸F-FP-CIT	RBDQ	In PDRBD+, DAT uptake was poorer in:
					–Putamen (mainly ventral putamen)
					WITH the difference being more profound in the less affected side.
Kogan et al. (2020) [35]	iRBD (66.37±5.17)	20	¹⁸F-FDG-PET	PSG	4 patients who developed PD in the 4 years of the follow up, had suprathreshold PDRP (a pattern that characterizes early PD and may differentiate it from MSA and other atypical parkinsonian disorders) z scores at baseline and after ∼3.7 years as well as more rapid change in the PDRP score
	HC (63.1±6.7)	16			HC were used only to z-transform the iRBD PDRP scores
Kotagal et al. (2012) [36]	PDRBD+ (63.7±6.7) vs. PDRBD–(65.3±7.1)	27 vs. 53	[¹¹C]PMP AChE PET DTBZ VMAT2 PET DASB SERT PET	RBDQ	In PDRBD+, ¹¹C-methylpiperidyl propionate acetylcholinesterase showed a reduced cholinergic innervation in:
					–neortical regions
					–limbic cortical regions
					–thalamus
The other serotonin and dopamine transporter tracers did not reveal any significant differences
Lee et al. (2019) [37]	PDRBD+ (69.2±7) vs. iRBD (70.5±5.9)	30 vs. 30	¹⁸F-FP-CIT	PSG	In PDRBD+, profound reduction in DAT density in:
					–caudate nucleus
					–anterior putamen
					–posterior putamen
					–substantia nigra
	PDRBD+ (69.2±7) vs. HC (70.1±4.8)	30 vs. 19			In PDRBD+, profound reduction in DAT density in:
					–caudate nucleus
					–anterior putamen
					–posterior putamen
					–substantia nigra
Sommerauer et al. (2018) [20]	PDRBD+ (67.7±9.3) vs. PDRBD–(65.4±9)	16 vs. 14	¹¹C-MeNER PET	RBDQ	In PDRBD+, the lowest mean values of DVRs in:
					–all imaged brain areas
	PDRBD+ (67.7±9.3) vs. HC (67.3±6.3)	16 vs. 12			In PDRBD+, the lowest mean values of DVRs in:
					–all imaged brain areas
Yoon et al. (2019) [38]	PDRBD+ (69.2±7.8) vs. iRBD (69.8±5.6)	21 vs. 28	¹⁸F-FDG-PET	RBDQ	In PDRBD+, decreased metabolism in:
					–occipital areas
					AND increased metabolism in:
					–Primary motor cortex
					–Supplementary motor area
					–Premotor cortex
					–Rostral and orbital areas of the superior frontal cortex
					–Thalamus
					–Basal ganglia (putamen/globus pallidus)
					–cerebellum
					–pons
					–parahippocampal gyrus
	PDRBD+ (69.2±7.8) vs. HC (69.5±4.3)	21 vs. 24			In PDRBD+, decreased metabolism in:
					–occipital areas
					AND increased metabolism in:
					–Primary motor cortex
					–Supplementary motor area
					–Premotor cortex
					–Rostral and orbital areas of the superior frontal cortex
					–Thalamus
					–Basal ganglia (putamen/globus pallidus)
					–cerebellum
					–pons
					–parahippocampal gyrus

PDRBD+, Parkinson’s disease’s patients with RBD; PDRBD–, Parkinson’s disease’s patients without RBD; HC, healthy controls; iRBD, idiopathic REM sleep behavior disorder; RBDQ, REM Sleep Behavior Disorder Questionnaire; PSG, polysomnography; VOIs, volume of interest; DVRs, distribution volume ratios; PET, positron emission tomography; ¹¹C-MeNER, (S,S)-¹¹C-2-(α-(2-methoxyphenoxy)benzyl)morpholine; ¹⁸F-FDG, 2-deoxy-2-[fluorine-18]fluoro- D-glucose; DAT, dopamine transporter; ¹⁸F-FP-CIT, N-(3-¹⁸F-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane; [¹¹C]PMP AChE, [¹¹C]methylpiperidyl propionate acetylcholinesterase; DTBZ, [¹¹C]dihy-drotetrabenazine; VMAT2, Vesicular Monoamine Transporter type 2; DASB, ¹¹C3-Amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile; SERT, serotonin transporter.

Six PET studies compared PDRBD+ vs. PDRBD–patients [20 , 36] six studies compared PDRBD+ vs. iRBD and HC [20 , 38], one study followed the phenoconversion from iRBD to PDRBD+ [35].

Several tracers/radioligands have been reported including ¹¹C-methylpiperidyl propionate acetylcho-linesterase, dopamine transporter tracers, (S,S)-11C-2-(α-(2-methoxyphenoxy)benzyl)morpholine (¹¹C-MeNER PET), Fluorodeoxyglucose-18F (¹⁸F-FDG) and serotonin tracers.

In PET studies comparing PDRBD+ and PDRBD–groups, RBD was associated with several findings. First, a reduced neocortical, limbic cortical and thalamic cholinergic innervation in ¹¹C-methylpiperidyl propionate acetylcholinesterase tracer [36]. Second, lower mean values of distribution volume ratios (SVR) in all imaged brain areas, especially in brainstem [20], and a profound decrease in mean values of the volume of interest in the precentral and postcentral gyri [33] in the ¹¹C-MeNER PET. Finally, an increased metabolism in anterior cortical regions, a decreased metabolism in posterior cortical regions in ¹⁸F-FDG-PET [25], and a poorer DAT uptake in the putamen (mainly ventral putamen) in ¹⁸ FP-CIT-PET [32].

In PET studies comparing PDRBD+ groups and HC, PDRBD+ patients exhibited lower mean values of distribution volume ratios (SVR) in all imaged brain areas, especially in brainstem [20] in the ¹¹C-MeNER PET. In addition, several studies reported a decreased metabolism in the occipital areas and increased metabolism in the primary motor cortex, SMA, premotor cortex, thalamus, basal ganglia (putamen and globus pallidus), cerebellum, pons, parahippocampal gyrus, rostral and orbital areas of the superior frontal cortex [25, 38]. Finally, one study showed a profound reduction in the DAT density in caudate nucleus, anterior putamen, posterior putamen and substantia nigra [37] in ¹⁸F-FDG-PET.

Similar findings were reported in PET studies when PDRBD+ patients were compared with iRBD patients [34 , 38]. In addition, one ¹⁸F-FDG-PET study [35] followed 20 iRBD patients showing the 4 patients who developed PD in the 4 years of the follow up, had suprathreshold Parkinson’s Disease Related Pattern (PDRP), a pattern that characterizes early PD and may differentiate it from MSA and other atypical parkinsonian disorders, and also a more rapid change in the PDRP score [35].

One ¹¹C-MeNER PET study found no significant differences between PDRBD+ and PDRBD–in respect to cortical thickness [33].

DISCUSSION

To our knowledge, this is the first systematic review that examines and critically discusses available literature on brain neuroimaging findings in PD with RBD. We included studies that used both structural and functional MRI techniques as well as nuclear medicine techniques including SPECT and PET.

Fig. 2

The association of RBD with multiple brain imaging alterations and a more malignant motor and non-motor subtype in PD. Orange area (RSWA): RBD in the early phases of PD is directly related to metabolic alterations (reduced NAT binding) and neurodegenerative processes (lower neuromelanin signal) in several brainstem nuclei which are implicated in the regulation of REM sleep and REM atonia. Green area (psychiatric symptoms): Structural (affecting both grey and white matter) and functional alterations in key limbic regions, including thalamus, hypothalamus, amygdala, cingulate gyrus, and related structures (i.e., ILF) are thought to possibly underlie the increased non-motor profile, in particular psychiatric disturbances, more intense dreaming and dream enactment, that characterizes PD patients with RBD. Blue area (neurocognitive symptoms): RBD-specific structural (lower neuromelanin signal), degenerative (reduced DAT binding in SPECT) and functional (FDG hypermetabolism) cortical changes, in particular in frontoparietal regions, might underly the unique and specific impaired cognitive profile in PD patients with RBD. Yellow area (motor symptoms): Neurodegeneration (reduced DAT binding) and atrophy (reduced grey matter volume) in basal ganglia might be the neural substrate for the increased motor symptoms in PD patients with RBD compared to those without RBD. DAT, dopamine transporter; FDG, Fluorodeoxyglucose (18F); GM, grey matter; ILF, inferior longitudinal fasciculus; NAT, noradrenaline transporter; PD, Parkinson’s disease; RBD, REM sleep behavior disorder; REM, rapid eye movement; RSWA, REM sleep without atonia; WM, white matter. Up arrow for increase, Down arrow for decrease.

MRI studies assessing structural changes in grey matter, report abnormalities and atrophy in limbic structures, such as the thalamus, hypothalamus, cingulate gyrus, amygdala, hippocampus and in basal ganglia mainly the putamen, in PDRBD patients compared to PDRBD–or HC. Similarly, the presence of RBD in PD is associated with white matter abnormalities in limbic connectivity but also in midbrain, brainstem and corticospinal connectivity which are closely involved in locomotion and muscle tone regulation.

In consistence with structural MRI findings, functional MRI studies report abnormal functional activation and connectivity in the motor/premotor cortex, in brainstem regions and in basal ganglia associated with RBD in PD.

Lastly, SPECT and PET studies show functional changes in dopaminergic, noradrenergic, and cholinergic transmission as well as metabolic changes in the fronto-limbic neural circuitry, in brainstem and in basal ganglia in PDRBD compared to PDRBD–and HC.

These neuroimaging findings are consistent with the hypothesis that RBD in PD is not simply the result of a brainstem pathology affecting the REM sleep regulating nuclei but may represent a certain subtype of PD, with unique progression and prognosis and strongly related to specific mechanisms, patterns and localization of PD-related pathology [39] (Fig. 2). Indeed, according to the Braak’s hypothesis, abnormal a-synuclein accumulation in PD follows a specific pattern, from neurons of the nasal cavity and in the gut to the brainstem and pontine regions (Stage 1–2), to limbic structures and later to substantia nigra and basal ganglia (Stage 3–4), and finally to the neocortex and frontoparietal lobes (Stages 5–6) [40]. In agreement with this a-synuclein pathology staging scheme [40], it has been suggested that RBD in the prodromal and early phases of PD is directly related to neurodegeneration in several brainstem nuclei, including the cholinergic PPN, the noradrenergic locus coeruleus and the serotonergic raphe nuclei, which are implicated in the regulation of wakefulness, the generation of REM-sleep circuit, the sleep staging and the generation of REM atonia [41]. As degeneration progresses, damage to key limbic regions, such as hypothalamus, amygdala, thalamus, is thought to possibly underlie the increased psychiatric/emotional disturbances and a more severe non-motor parkinsonian phenotype of PDRBD compared to PDRBD–as well as dreaming and dream enactment that PDRBD patients experience already from the early stages of the disease [41 –43]. Lastly, RBD-specific cortical changes, in particular in frontoparietal regions, might underly the unique and specific impaired cognitive profile in PD patients with RBD [44].

Further support for the hypothesis that the presence of RBD might define a specific PD subtype and that PDRBD progresses along a disease continuum from iRBD, derives from increasing number of neuroimaging studies showing specific structural and functional brain abnormalities in the group of iRBD patients that convert to PDRBD [45]. Indeed, iRBD patients that developed PD, showed poor ¹²³I-FP-CIT uptake in basal ganglia areas [27] and hypometabolism in parieto-occipital and premotor cortices concomitant with metabolic preservation or hypermetabolism in cerebellum, pons, thalamus and lentiform nucleus in FDG-PET [35] (the PDRP), all consisting early neuroimaging markers of PD. These observations are consistent with clinical studies demonstrating that patients with iRBD present non-motor symptoms and signs also found in PD. However, further appropriate studies following a greater number of patients are needed to decipher this hypothesis.

Limitations

With the exception of some morphometry and very few nuclear medicine studies, the majority of studies included small sample sizes. Furthermore, studies often have included patients with different types of PD, in various disease and treatment stages (i.e., newly diagnosed/drug naïve vs. medically treated), therefore the results between the studies were not always comparable. The lack of a HC group in some of the included studies presents another limitation. 15 studies used RBD questionnaires instead of polysomnography, thus compromising the diagnostic accuracy of RBD. The presence of RBD in PD is associated with more severe non-motor symptoms which might consist important confounders for several neuroimaging findings (i.e., depression or apathy for abnormalities associated with limbic regions or cognitive deficits for abnormalities associated with cortical regions). The majority of studies assessed clinical/neuropsychological/neurocognitive symptoms in the comparison groups; however, only 4 studies [13 , 28] performed a clinico-radiological correlation analysis and only two studies grouped PD patients based on a second clinical characteristic (depression [14] and postural instability [21]), apart from RBD, in order to identify clinical confounders in their neuroimaging findings. Finally, most of the studies were cross-sectional, which implies difficulties in concluding about temporal or causal relations. In the studies with a longitudinal follow-up design a very small number of PDRBD patients has been included.

Another limitation of our systematic approach was that the period over which the reviewed studies were published spanned 20 years. During this time, the precision of the performed techniques and the diagnostic criteria for RBD have changed. Finally, there is a possibility of selection bias based on language criteria due to the exclusion of articles that were not written in English and of publication bias since we only included papers published on PubMed.

CONCLUSIONS

In this systematic review, we showed that RBD was associated with a widespread structural and functional brain impairment mainly involving limbic, brainstem and basal ganglia neural circuits. This could be attributed to a unique pattern of neurodegeneration of an ongoing condition in different stages including iRBD, iRBD with non-motor symptoms and PDRBD. This is consistent with the increasing evidence that, apart from the characteristic nocturnal behaviors, PD patients with RBD experience more non-motor symptoms than PD patients without RBD. Further studies are needed to better elucidate the pathophysiology and neuroanatomical substrate of RBD in PD.

Footnotes

ACKNOWLEDGMENTS

We thank Domenic Kaderli for assisting in the literature search.

CONFLICT OF INTEREST

There was no financial or material support for this work. All authors declare no conflicts of interests.

The supplementary material is available in the electronic version of this article: .

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Brain Neuroimaging of Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s Disease: A Systematic Review

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

INTRODUCTION

METHODS

Quality assessment

RESULTS

Magnetic resonance imaging

Structural MRI studies

Morphometry studies

Diffusion MRI studies

Neuromelanin-sensitive MRI

Functional MRI studies

Magnetic resonance spectroscopy

Nuclear medicine imaging

Single photon emission computed tomography (SPECT)

Positron emission tomography studies

DISCUSSION

Limitations

CONCLUSIONS

Footnotes

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

References