Neurol Sci (2013) 34:935–940 DOI 10.1007/s10072-012-1164-0
ORIGINAL ARTICLE
Comparison study of olfactory function and substantia nigra hyperechogenicity in idiopathic REM sleep behavior disorder, Parkinson’s disease and normal control Hee Young Shin • Eun Youn Joo • Seong Tae Kim Hun-Jong Dhong • Jin Whan Cho
•
Received: 18 December 2011 / Accepted: 26 March 2012 / Published online: 28 July 2012 Ó Springer-Verlag 2012
Abstract Rapid eye movement (REM) sleep behavior disorder (RBD) is a preclinical feature of synucleinopathies, such as Parkinson’s disease (PD).This study aimed to investigate the presence of potential early manifestations of parkinsonism, such as olfactory dysfunction and substantia nigra (SN) hyperechogenicity, in idiopathic RBD (iRBD) patients, PD patients and normal controls. We performed an olfactory function test using the cross-cultural smell identification test (CC-SIT) and midbrain transcranial sonography (TCS) in 15 patients with iRBD as confirmed by polysomnography, 30 patients with PD, and 30 normal controls. The CC-SIT scores of the iRBD patients and PD patients were significantly lower than those of the normal controls and similar between iRBD and PD (mean ± SD, 7.1 ± 2.2 and 7.6 ± 2.4 vs. 10.4 ± 1.2, respectively, p \ 0.01). The sum of bilateral SN echosignals in the iRBD patients was greater than that of the normal controls but lower than that of the PD patients (0.29 ± 0.47, 0.11 ± 0.17 and 0.72 ± 0.41 cm2, respectively, p \ 0.01). H. Y. Shin Department of Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea E. Y. Joo J. W. Cho (&) Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-Dong Gangnam-Gu, Seoul 135-710, Korea e-mail:
[email protected] S. T. Kim Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea H.-J. Dhong Department of Otolaryngology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
In conclusion, we found that the concomitant abnormality of olfaction and increased SN echogenicity was more frequent in iRBD compared with normal control. Olfactory dysfunction and SN hyperechogenicity could be preclinical manifestations of parkinsonism in iRBD patients. Keywords REM sleep behavior disorder Parkinson’s disease Olfaction CC-SIT Transcranial sonography
Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by loss of atonia during REM sleep with prominent motor activity and dreaming [1, 2]. RBD is frequently associated with neurodegenerative disorders characterized by a-synuclein deposition, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy body (DLB) [3–5]. Recent dopamine transporter SPECT and PET studies have demonstrated decreased striatal dopaminergic innervations in idiopathic RBD (iRBD) [6, 7]. Furthermore, a study using cardiac 123 I-metaiodobenzylguanidine (MIBG) scintigraphy revealed that the cardiac MIBG uptake was reduced in iRBD patients in comparison to patients with other neurodegenerative disorders, such as MSA, DLB, and progressive supranuclear palsy (PSP). Marked reduction in cardiac uptake of 123I-MIBG seems to be a specific marker of Lewy body disease [8, 9]. The results of these studies suggest that iRBD occurs prior to the development of clinically evident parkinsonism and that iRBD may be an early warning sign of PD though not all PD patients are afflicted by RBD. Several potential early markers of PD have recently emerged, and they will be useful in determining the
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preclinical stages of PD. Olfactory deficits have been recognized as a prominent clinical finding in patients with PD, and they are thought to occur frequently even in the early stages of the disease [10–12]. Midbrain substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) is also reported to be a potential early marker of PD [13–15]. This study aimed to investigate the presence of potential early manifestations of PD, such as olfactory dysfunction and SN hyperechogenicity, in iRBD patients. Patients and methods We prospectively enrolled 15 iRBD patients whose clinical and polysomnographic features met the criteria for iRBD [16, 17], 30 patients with early stage PD who met the United Kingdom PD Society Brain Bank criteria [18], and 30 healthy controls. All the patients provided written informed consent to use their clinical data for research purposes, and this study was approved by the Institutional Review Boards. All iRBD patients showed typical polysomnographic findings of loss of atonia during REM sleep and were diagnosed with iRBD due to the absence of other possible other causes of RBD. Neurologist trained and experienced in Movement disorders performed the neurological examination including Unified Parkinson’s Disease Rating Scale (UPDRS) [19] part III in all patients with iRBD patients, PD patients and normal controls. The PD patients showed no atypical features, such as gaze palsy, cerebellar ataxia, or pyramidal signs, and none of the PD patients had a history of neuroleptic intake or other identifiable possible causes of secondary parkinsonism. We excluded the presence of RBD in normal controls and PD patients with no history of symptom like dream-enacting behaviors, sleeprelated injury, or behaviors causing sleep disruption, and using the revised international classification of sleep disorder (ICSD) diagnostic criteria [20]. Early stage of PD patients without motor fluctuations were enrolled, and the severity of parkinsonism was evaluated based on UPDRS
Fig. 1 a Transcranial sonography (TCS) image of the midbrain of a patient with PD. We identified the hypoechogenic midbrain (encircled by dotted line) surrounded by the hyperechogenic basal cisterns, and we manually encircled the interior hyperechogenic area of substantia
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part III score and Hoehn and Yahr (H-Y) stage [21]. Mean value of L-dopa equivalent dose was 215 ± 10.7 mg/day, and all PD patients had no history of hypnotics or sedatives intake. All these subjects were performed an olfactory test with cross-cultural smell identification test (CC-SIT) and examined for SN echosignal with midbrain TCS. Rhinologist examined all patients for other causes of olfactory dysfunction such as rhinitis, sinusitis or other structural lesions. In the present study, the 12-item CC-SIT (Sensonics, Inc, Haddon Heights, NJ) was used to evaluate olfactory function. The CC-SIT is a standardized, fouralternative forced-choice test in which twelve different odorants are given in the form of ‘‘scratch and sniff’’ microcapsules fixed and positioned on strips attached to a testing booklet [22, 23]. The raw scores were calculated, and the results were categorized as normosmia, hyposmia, or anosmia based on the number of correctly identified odorants. The results were considered indicative of normosmia if one or none of the 12 items were incorrectly identified (score of 11 or 12). Scores of 6–10 were considered indicative of hyposmia, and scores of 5 and under were considered indicative of anosmia. The threshold for odor detection was the lowest concentration of olfactory stimulus required for the perception of a smell. Butanol was administered in increasing dilutions in our study. A trained technician who was blinded to the clinical information of the subjects working in the department of otorhinolaryngology administered both olfactometric tests. An examination SN echogenicity was performed through the preauricular acoustic bone window by S.T. Kim who was blinded to the clinical information of the subjects, an expert in the use of TCS, using a 2.5 MHz sonographic device (HDI 5000, Sono CT; Philips) with a depth of 16 cm and a dynamic range of 45 dB, as described previously [24]. The SN was scanned from both temporal bone windows in the axial plane. After identifying the butterfly shaped hypoechogenic midbrain surrounded by the hyperechogenic basal cistern, the clearest image of the hyperechogenic signals in the SN region was stored in the Ultrasonic device (Fig. 1a). The transverse areas of the midbrain and the size
nigra (thick solid line). b Transcranial sonography (TCS) images of the midbrain in a normal control, an iRBD patient, and a PD patient. Cerebral aqueduct (asterisk), substantia nigra (arrowheads)
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Table 1 Demography and data of CC-SIT and midbrain TCS in iRBD patients, PD patients and normal controls iRBD
PD
Controls
p
Number
15
30
30
Gender (male/female)
8/7
21/9
17/13
0.379d
Age (mean ± SD years)
65.2 ± 8.7
62.3 ± 6.3
61.6 ± 5.1
0.219§
Disease duration of RBD, PD
67.0
34.0
NA
Hyposmia (6 B CC-SIT score B 10)
12 (80.0)
22 (73.3)
16 (53.3)
0.149d
Anosmia (5 \ CC-SIT score)
2 (13.3)
4 (13.3)
0
0.118d
CC-SIT score (mean ± SD)
7.1 ± 2.2
7.6 ± 2.4
10.4 ± 1.2
<0.01§*
Threshold (mean ± SD)
4.2 ± 0.7
4.4 ± 0.8
5.2 ± 0.5
<0.01§*
12 6 (50.0)
24 21 (87.5)
25 4 (16.0)
<0.01d*
0.29 ± 0.47
0.72 ± 0.41
0.11 ± 0.17
<0.01§*
Patients
Olfactory test
N of successful TCS Hyperechogenicity 2
Sum of bilateral SN echosignals (mean ± SD cm )
iRBD idiopathic REM sleep behavior disorder, PD Parkinson’s disease, OSA obstructive sleep apnea, PLMD periodic limb movement disorder, NA not assessed, H-Y stage Hoehn and Yahr stage, UPDRS unified PD rating scale §
Calculated by one-way ANOVA test
d
Calculated by Kruskal–Wallis test (parenthesis value means percentages; hyperechogenicity represents SN echogenicity size of 0.2 cm2 and more; * means p \ 0.05)
of SN echosignals were determined by averaging both measured areas obtained from the right and left temporal windows. To evaluate the degree of hyperechogenicity, we calculated the sum of the SN hyperechogenic areas and its ratio to the whole area of the midbrain at the same level. For a criterion for abnormal increased SN echogenicity, we used a cut-off value of 0.2 cm2 for the size of SN echosignals on at least one side of the midbrain. This had been introduced as the classification criteria for normal echogenicity in previous studies [14, 24–26]. Statistical analysis was performed using SPSS software package version 13.0 (SPSS Inc., Chicago, IL). Normal distribution of data was tested using the Kolmogorov– Smirnov test. In case of normal distribution, one-way ANOVA test was applied for quantitative variables in three groups. For the non-normal distribution, Kruskal–Wallis test was applied. Chi-square test was used to evaluate differences of qualitative variables between groups. The results with significant differences among the three groups were then analyzed using multiple comparison analysis between each two groups. Multiple comparison analysis was performed between each two groups by the least significant difference (LSD) test for continuous variables (CC-SIT score, Threshold, Sum of bilateral SN hyperechogenicity) and v2 test corrected by Bonferroni’s correction for categorical variable (hyperechogenicity). Correlation analysis was performed between duration of symptom RBD and PD, and CC-SIT score and the sum of bilateral size of SN echosignals, and correlation between CC-SIT score and the bilateral size of SN echosignal with Spearman’s
correlation coefficient. A probability value of \0.05 was used as the criterion for statistical significance.
Results The clinical characteristics of the subjects are summarized in Table 1. The mean H-Y stage of the PD patients was 1.6 ± 0.5, and their mean UPDRS part III score was 8.4 ± 2.4. Patients with iRBD showed minimal feature of parkinsonism (UPDRS part III mean score 1.7). There were no specific other causes of olfaction such as sinusitis, rhinitis or structural lesions upon examination by rhinologist. The frequency of olfactory deficits, including hyposmia or anosmia, was higher in the iRBD patients than in the normal controls but similar to that in the PD patients (93.3 vs. 53.3 %, 86.7 % respectively). Only one patient in the iRBD group was able to differentiate between odors normally. On the other hand, none of the normal controls were categorized as anosmia (Table 1). The CC-SIT scores of the iRBD patients were significantly lower than those of the normal controls (7.1 ± 2.2 vs. 10.4 ± 1.2), but similar to those of the PD patients (7.6 ± 2.4). The odor detection sensitivity was significantly lower in the iRBD patients than in the normal controls (4.2 ± 0.7 vs. 5.2 ± 0.5, p \ 0.01) (Table 1). There was no specific odor item on the CC-SIT that was more frequently misidentified by the iRBD and PD patients. TCS failed in 3 of the 15 (20.0 %) iRBD patients, 6 of the 30 (20.0 %) PD patients, and 5 of the 30 (16.7 %)
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normal controls due to insufficient acoustic temporal bone windows. The frequency of abnormal increased SN echogenicity in the iRBD patients was greater than that of normal controls (50.0 vs. 16.0 %, p = 0.42), but lower in the PD patients (50.0 vs. 87.5 %, p \ 0.05). In the iRBD group, six patients showed abnormal increased SN echogenicity, four patients showed unilateral hyperechogenicity, and two patients showed bilateral hyperechogenicity (example in Fig. 1b). The sum of bilateral SN echosignals in the iRBD patients was greater than that in the normal controls but lower than that in PD patients (0.29 ± 0.47 vs. 0.11 ± 0.17, p = 0.025, and 0.29 ± 0.47 vs. 0.72 ± 0.41 cm2, p = 0.01, respectively) (Table 1). Concomitant abnormality of olfaction and SN hyperechogenicity was frequently observed in PD and iRBD patients (75 vs. 50 %) when compared with normal control (3 %) (Fig. 2). CC-SIT scores were not correlated with duration of iRBD or PD (r = 0.067, p = 0.812 and r = -0.203, p = 0.283, respectively). In addition, the sum of the bilateral size of SN echosignals were not correlated with duration of iRBD or PD (r = -0.279, p = 0.381 and r = 0.344, p = 0.100, respectively). There was no correlation between CC-SIT score and the bilateral size of SN echosignal
Fig. 2 The proportion of concomitant abnormality of olfaction and SN hyperechogenicity in PD, iRBD and normal controls
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in iRBD and PD patients. (r = 0.327, p = 0.106 and r = 0.418, p = 0.235, respectively).
Discussion We compared the concomitant abnormality of olfaction and SN echogenicity in iRBD, early stage of PD and normal controls. Our study showed the possibility that iRBD would be the transitional stage of PD according to olfactory dysfunction and SN hyperechogenic changes. There is an increasing evidence of the link between iRBD and PD. A longitudinal study showed that of patients [ 50 years old, diagnosed iRBD, at least twothirds will develop PD and related disorders, the mean interval to PD onset was [10 years [27]. Olfactory dysfunction and SN echogenicity changes supported the common pathophysiological manifestation in the patients of iRBD and PD. Olfactory deficits have been thought to occur frequently in neurodegenerative disease, even in the early stage of PD [10–12]. Neuropathological staging of PD proposed by Braak [28], who described lesions of lower brainstem areas known to be responsible for REM sleep—in very early PD, that is, before the degeneration of the dopaminergic nigrostriatal pathway. The progression of degeneration from the subceruleus region to the midbrain would be responsible for PD following RBD. Lai and his colleagues suggested that neuronal degeneration could be generated in either part of the ventral brainstem, the rostral ventral midbrain, and the ventral mesopontine junction (VMPJ), and then progressively extend to the caudal or rostral part of the brainstem. PD would develop first if the lesion starts in the rostral ventral midbrain, whereas RBD would be seen first if neuronal degeneration begins in the VMPJ [29]. Postuma and his colleagues [30] reported impairment of olfaction, color vision, and motor speed in iRBD patients. They showed that olfactory dysfunction was closely related to decrease in motor speed and nigrostriatal degeneration in patients with chronic iRBD. SN echogenicity changes also have been thought to occur frequently in PD [13–15]. In addition, a recent study which demonstrated that some of the patients with iRBD showed reduced striatal uptake in FP-CIT SPECT, and SN hyperechogenicity on TCS [4]. These previous studies suggested that olfactory dysfunction and SN hyperechogenicity on TCS could be biomarker of developing PD in iRBD. This study showed that CC-SIT scores and detection threshold demonstrated that patients with iRBD have moderate olfactory deficits in comparison to normal controls, and similar with PD patients. The size of SN echosignals in the iRBD patients was greater than that in the normal controls, but less than that in the PD patients. These
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results were consistent with those of recent studies [7, 31]. However, few study investigated the concomitant olfactory dysfunction and TCS in iRBD patients. In this study, we showed that the concomitant abnormality of olfaction and SN echogenicity was more prevalent in iRBD patients compared with normal control, and less frequent than in PD patients (40 vs. 3 % and 60 %, respectively). Thus, these results further support that iRBD could be preclinical features of PD, as suggested in previous studies [4, 30]. It was hard to assume that combined abnormality of olfactory function and SN echogenicity was the contributing factors to develop PD in iRBD patients. To overcome this challenge, longitudinal study in our subjects of iRBD will be needed; the olfactory dysfunction and SN hyperechogenicity could be an early noninvasive biomarker of PD in iRBD patients. There were some inherent weaknesses in this study. There could be selection bias in normal control and early PD patients with subclinical RBD without symptomatic history. We performed polysomnography (PSG) in all iRBD patients, but we excluded the presence of RBD in normal controls and PD patients with history taking and using the revised international classification of sleep disorder (ICSD) diagnostic criteria. Relatively high rate of failure with poor echo-window (16–20 %) was observed. However, there was a similar result with previous study conducted on Asian population, which was higher rate when compared with Western population [24]. The duration of iRBD was relatively long (67 months) compared with PD symptom duration (34 months), the effect of disease duration could make a difference in SN hyperechogenicity of TCD result. In this study, even though the number of patients was relatively insufficient to evaluate the correlation between the size of SN echosignals and the duration of RBD, the size of SN echosignals seemed not to be correlated with the duration of iRBD or PD (r = -0.279, p = 0.381 and r = 0.344, p = 0.100, respectively). In conclusion, we found that the concomitant abnormality of olfaction and increased SN echogenicity were more frequent in PD and iRBD. Olfactory dysfunction and SN hyperechogenicity could be preclinical manifestations of parkinsonism in iRBD patients. Acknowledgments This study was supported by Samsung Medical Center Clinical Research Development Program Grant (#CRS10615-1).
References 1. Mahowald MWSC (1994) REM sleep behavior disorder. Saunders, Philadelphia, pp 574–588 2. Lapierre O, Montplaisir J (1992) Polysomnographic features of REM sleep behavior disorder: development of a scoring method. Neurology 42:1371–1374
939 3. Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE (2001) Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 16:622–630 4. Stiasny-Kolster K, Doerr Y, Moller JC, Hoffken H, Behr TM, Oertel WH, Mayer G (2005) Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128:126–137 5. Uchiyama M, Isse K, Tanaka K, Yokota N, Hamamoto M, Aida S, Ito Y, Yoshimura M, Okawa M (1995) Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 45:709–712 6. Albin RL, Koeppe RA, Chervin RD, Consens FB, Wernette K, Frey KA, Aldrich MS (2000) Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 55:1410– 1412 7. Eisensehr I, Linke R, Noachtar S, Schwarz J, Gildehaus FJ, Tatsch K (2000) Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain 123 (Pt 6):1155– 1160 8. Miyamoto T, Miyamoto M, Inoue Y, Usui Y, Suzuki K, Hirata K (2006) Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder. Neurology 67:2236–2238 9. Miyamoto T, Miyamoto M, Suzuki K, Nishibayashi M, Iwanami M, Hirata K (2008) 123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder. Sleep 31:717–723 10. Doty RL, Deems DA, Stellar S (1988) Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38:1237–1244 11. Hawkes CH, Shephard BC, Daniel SE (1997) Olfactory dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry 62:436–446 12. Double KL, Rowe DB, Hayes M, Chan DK, Blackie J, Corbett A, Joffe R, Fung VS, Morris J, Halliday GM (2003) Identifying the pattern of olfactory deficits in Parkinson disease using the brief smell identification test. Arch Neurol 60:545–549 13. Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K (1995) Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology 45:182–184 14. Walter U, Wittstock M, Benecke R, Dressler D (2002) Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson’s disease. J Neural Transm 109:191–196 15. Spiegel J, Hellwig D, Mollers MO, Behnke S, Jost W, Fassbender K, Samnick S, Dillmann U, Becker G, Kirsch CM (2006) Transcranial sonography and [123I]FP-CIT SPECT disclose complementary aspects of Parkinson’s disease. Brain 129:1188– 1193 16. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW (1987) Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. JAMA 257:1786–1789 17. Olson EJ, Boeve BF, Silber MH (2000) Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 123(Pt 2):331–339 18. Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56:33–39 19. Fahn SER (1987) The unified Parkinson’s disease rating scale. Macmillan Health Care Information, Florham Park 20. American Academy of Sleep Medicine (2001) International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. American Academy of Sleep Medicine, Rochester
123
940 21. Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17:427–442 22. Kim JY, Lee WY, Chung EJ, Dhong HJ (2007) Analysis of olfactory function and the depth of olfactory sulcus in patients with Parkinson’s disease. Mov Disord 22:1563–1566 23. Doty RL, Marcus A, Lee WW (1996) Development of the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Laryngoscope 106:353–356 24. Kim JY, Kim ST, Jeon SH, Lee WY (2007) Midbrain transcranial sonography in Korean patients with Parkinson’s disease. Mov Disord 22:1922–1926 25. Berg D, Siefker C, Becker G (2001) Echogenicity of the substantia nigra in Parkinson’s disease and its relation to clinical findings. J Neurol 248:684–689 26. Walter U, Niehaus L, Probst T, Benecke R, Meyer BU, Dressler D (2003) Brain parenchyma sonography discriminates Parkinson’s disease and atypical parkinsonian syndromes. Neurology 60:74–77 27. Iranzo A, Santamaria J, Tolosa E (2009) The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases. Sleep Med Rev 13:385–401
123
Neurol Sci (2013) 34:935–940 28. Claassen DO, Josephs KA, Ahlskog JE, Silber MH, TippmannPeikert M, Boeve BF (2010) REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 75:494–499 29. Lai YY, Hsieh KC, Nguyen D, Peever J, Siegel JM (2008) Neurotoxic lesions at the ventral mesopontine junction change sleep time and muscle activity during sleep: an animal model of motor disorders in sleep. Neuroscience 154:431–443 30. Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J (2006) Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 66:845–851 31. Unger MM, Moller JC, Stiasny-Kolster K, Mankel K, Berg D, Walter U, Hoeffken H, Mayer G, Oertel WH (2008) Assessment of idiopathic rapid-eye-movement sleep behavior disorder by transcranial sonography, olfactory function test, and FP-CITSPECT. Mov Disord 23:596–599
