J Neurol DOI 10.1007/s00415-015-7745-0
ORIGINAL COMMUNICATION
Brainstem raphe and substantia nigra echogenicity in idiopathic REM sleep behavior disorder with comorbid depression Dolores Vilas1 • Alex Iranzo1 • Claustre Pont-Sunyer1 • Mo´nica Serradell1 Carles Gaig1 • Joan Santamaria1 • Eduardo Tolosa1
•
Received: 17 February 2015 / Revised: 31 March 2015 / Accepted: 9 April 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia nigra (SN?) and hypoechogenicity of the brainstem raphe (BR?) are frequent in PD, particularly when depression is associated. Combined SN? and BR? identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN? and BR? may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sexmatched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). BR? was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %; p = 0.050). Sensitivity of BR? to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN? to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR? and SN? to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the & Alex Iranzo [email protected] 1
Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, C/Villarroel 170, 08036 Barcelona, Spain
serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD. Keywords REM sleep behavior disorder Transcranial sonography Brainstem raphe Substantia nigra Parkinson disease Parkinson disease (PD) has a prodromal period of several years where neuropathologic changes outside the substantia nigra may occur before parkinsonism becomes manifest [1]. A variety of nonmotor symptoms including REM sleep behavior disorder (RBD) and depression may occur during this period [2, 3]. RBD is a parasomnia characterized by nightmares and dream-enacting behaviors during REM sleep. Available data indicate that the idiopathic form of RBD (IRBD) represents premotor PD. About 20–30 % of the PD patients report that RBD symptoms antedated the onset of parkinsonism [4–6]. Longitudinal follow-up of subjects with IRBD showed that the preponderance eventually develop a Lewy body disease such as PD [7–9]. Depression may also be predictive of future development of PD. Case-register studies have shown that depressed patients around the age of 60 years have an increased risk of developing PD [10, 11]. In addition, depressive symptoms precede parkinsonism in 30 % of PD patients [6, 12, 13]. Transcranial sonography (TCS) is a noninvasive imaging tool able to identify the echogenic presence and size of several subcortical areas in the brain such as the substantia nigra (SN) and the brainstem raphe (BR) [14]. Hyperechogenicity of the substantia nigra (SN?) has been proposed as a vulnerability marker for PD [14]. SN? occurs in approximately 90 % of the PD patients [14], and in the healthy population is associated with an increased risk of
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developing this disease [15]. SN? can be detected in subjects at risk for PD such as those with IRBD [16] and in people with depression [17]. In subjects already diagnosed with PD, SN? is related to the coexistence of depression [18]. Besides, several studies showed that hypoechogenicity of the brainstem raphe (BR?) is a frequent feature in people with depression [17, 18] and in PD, particularly in those patients with coexistent depression [17, 19–21]. In subjects with PD, the combination of BR? and SN? is associated with a history of depression prior to parkinsonism onset [17]. Echogenicity of the BR has not been evaluated in IRBD. Since IRBD may represent prodromal PD, it can be speculated that BR?, particularly when combined with SN?, may support the clinical diagnosis of comorbid depression in subjects with this parasomnia. The aim of our study was to evaluate the substantia nigra and brainstem raphe echogenicity and their ability to predict comorbid depression in IRBD.
Methods Participants The current study was conducted between April 2013 and May 2014. All the 86 IRBD patients that were followed in our Multidisciplinary Sleep Unit of the Hospital Clı´nic de Barcelona, Barcelona, Spain, were invited to participate. Ten patients were not able to participate and four were excluded because they had comorbid restless legs syndrome, a condition that is associated with hypoechogenicity of the substantia nigra [22]. The remaining 72 IRBD patients who had no restless legs syndrome agreed to participate and were included in this study. Diagnosis of IRBD required a chronic history of dreamenacting behaviors, video-polysomnographic detection of increased electromyographic activity during REM sleep associated with abnormal behaviors, no motor or cognitive complaints, normal neurological examination, and no temporal association between the introduction or withdrawal of a medication or substance and the start of RBD symptoms [23]. In particular, RBD patients that reported a temporal association between the introduction of an antidepressant and the onset of RBD symptoms were excluded from this study. At the time of the study 54 (75 %) IRDB patients received clonazepam (n = 49) or melatonin (n = 5) for RBD symptomatology (dream-enacting behaviors and nightmares) and this treatment was considered completely successful in 32 patients and partially successful in 22. Seventy-one age and sex-matched controls were recruited for comparisons. All controls were free of neurological diseases, and reported no motor, cognitive or sleep
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complaints at the time of this study. Fifty-two controls were non-blood relatives of the IRBD patients. The remaining 19 controls were asymptomatic individuals followed for years in our sleep unit who were free of sleep symptoms at the time of the study. In all of them polysomnography had previously excluded RBD showing REM sleep with atonia; 16 of them had obstructive sleep apnea successfully treated with continuous positive airway pressure for several years, one had received effective psychological treatment for psychophysiological insomnia, and two had isolated nightmares in the past where polysomnography ruled out RBD and other sleep disorders. Clinical assessment Demographic data, past medical history, RBD data, past and current history of depression, and current medication including antidepressants were obtained from all participants. Neurological evaluation was assessed by means of the motor part of the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRSIII) [24]. Neurological evaluation was performed by two experienced movement disorder specialists (DV and CPS) who were blinded to the status of the patient (IRBD patient or control, depressed or nondepressed). Diagnosis of depression was made according to DSMIV criteria [25]. Following the Structured Clinical Interview for DSM-IV Axis-I Disorders, patients were classified as having major depressive disorder, adjustment disorder with depressed mood, and absence of an affective disorder [25]. The Hospital Anxiety and Depression scale (HADS) [26] and the Beck depression inventory (BDI) [27] were also administered. Transcranial sonography Transcranial sonography (TCS) was performed in all participants using a 2.5-MHz transducer (Phillips, Bothell, WA, USA) by an experienced ultrasound examiner (DV) who was blinded to clinical data and to participant category (IRBD patient or control, depressed or nondepressed). The penetration depth was 14 cm and the dynamic range was 45–55 db. The examination was done from both sides using the temporal approach. The following parameters were assessed: BR echogenicity, SN echogenicity, lenticular nucleus echogenicity, third ventricle width, and size of the frontal horn of the lateral ventricles. Echogenicity of the BR was rated as reduced (BR?) when this midline structure in the midbrain was interrupted or not visible [17, 20]. Visible midbrain raphe was labeled as normoechogenic (BR-). Area of echogenicity in the SN was manually encircled and measured on digitally stored images. The side of greater SN echogenicity was used for statistical analysis.
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In accordance to previously reported cut-off values, hyperechogenicity of the SN (SN?) was defined as an area of echogenic signal equal or greater than 0.20 cm2 [14, 16]. Areas of echogeniticy of less than 0.20 cm2 were classified as normoechogenic (SN-). If one or both sides of the SN were hyperechogenic, the structure was classified as SN?. Echogenicity of lenticular nuclei was classified as hyperechogenic when it was more intense than the surrounding white matter [14, 17]. The maximal transverse diameter in the axial scanning plane of the third ventricle, and the right and left frontal horn of the lateral ventricles were measured in the thalamic plane [14, 17]. In each patient, clinical assessment and TCS were performed on the same day. The study was approved by the Ethics Committee of Hospital Clı´nic de Barcelona and written informed consent was obtained from all paricipants. Statistical analysis Demographical, clinical and TCS data are reported in mean, standard deviation, number and percentage. Quantitative variables were analyzed using Student’s t test for comparisons of two independent groups. Qualitative variables were analyzed by Chi-square test. Spearman’s correlation coefficients were used to examine association between BR? and SN? with age, gender, UPDRS-III score, estimated RBD duration (interval between estimated reported onset of RBD symptoms and the time of TCS), RBD follow-up duration (interval between diagnosis of IRBD at our sleep center with videopolysomnography to the time of TCS). Sensitivity, specificity, positive predictive value, negative predictive value and relative risk, along with 95 % confidence intervals (CIs), were estimated for BR?, SN?, and combined BR? and SN? as markers to predict depression in IRBD. P values less than 0.05 were considered to be significant. Statistical analyses were performed with SPSS version 20.0 (IBM).
Results Demographic and clinical findings (Tables 1, 2) Patients were 53 (73.6 %) men and 19 (26.4 %) women with a mean age of 71.39 ± 6.68 years. None of the patients reported motor complaints, cognitive decline or showed clinical evidence of psychosis. No differences were found in age, gender and UPDRS-III score between patients and controls. At the time of this study, nine (12.5 %) patients and six (8.5 %) controls had a previous diagnosis of depression
and were receiving antidepressants. However, when during this study participants were interviewed about depressive symptomatology, 23 additional IRBD patients and seven controls were diagnosed with depression, according to DSM-IV diagnostic criteria. Thus, depression was found in 32 (44.4 %) IRBD subjects (RBDD?); 18 with major depressive disorder and 14 with adjustment disorder with depressed mood. In 21 (65.6 %) RBDD? patients, depressive symptomatology preceded the onset of RBD. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). Total HADS score and depression HADS score were both higher in the IRBD group than in the control group, indicating that patients had more depressive symptoms. No differences were found in the BDI score between patients and controls. When compared with IRBD patients without depression (RBDD-), RBDD? subjects had similar age, estimated RBD duration, RBD follow-up duration, and UPDRS-III score. Women were more frequent in the RBDD? group than in the RBDD- group. TCS assessment Twelve (16.6 %) IRBD patients and 14 (21.1 %) controls had insufficient temporal acoustic bone window to assess BR echogenicity. Thirteen (18.1 %) IRBD patients and 12 (16.9 %) controls had insufficient temporal acoustic bone window to assess SN echogenicity. Twenty-three (16.1 %) study subjects had inadequate bone window for both SN and BR assessments. Of the individuals without adequate bone window, seven (9.7 %) patients and five (7.0 %) controls had depression. Therefore, BR echogenicity could be examined in 60 IRBD patients (25 RBDD? and 35 RBDD-) and 57 controls, and SN echogenicity in 59 patients (25 RBDD? and 34 RBDD-) and 59 controls. Brainstem raphe echogenicity (Table 3; Fig. 1) No differences were found in the proportion of individuals with BR? between patients and controls (20.0 vs. 17.5 %; p = 0.734). The lack of significance was also found when controls with comorbid depression were excluded from the analysis (20.0 vs. 20.0 %, p = 0.769). Of 25 RBDD?, eight (32.0 %) had BR? and the remaining 17 (68.0 %) had BR-. Of the seven controls with depression, one (14.3 %) had BR? and six (85.7 %) had BR-. BR? was more frequent in RBDD? than in RBDD- (32.0 vs. 11.4 %; p = 0.050). This difference was not found in the control group when comparing individuals with and without depression (14.3 vs. 18.0 %; p = 0.809). The frequency of BR? was similar between RBDDand controls, and also between RBDD? and controls. The frequency of BR? was not different between subjects with
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J Neurol Table 1 Demographic, clinical and transcranial sonography data of idiopathic REM sleep behavior patients and controls
IRBD n = 72
Controls n = 71
p value
Age (years)
71.39 ± 6.68
70.70 ± 6.10
0.523
Male [n (%)]
53 (76.3)
49 (69.0)
0.367
Estimated RBD duration (years)
10.2 ± 7.09
NA
RBD follow-up duration (years)
3.71 ± 3.41
NA
UPDRS-III score (n)
7.67 ± 5.45
5.80 ± 6.39
0.062
Depression [n (%)]
32 (44.4)
13 (18.3)
0.001
Major depressive disorder [n (%)]
18 (56.2)
7 (53.8)
0.456
Adjustment disorder with depressed mood [n (%)]
14 (43.8)
6 (46.2)
0.546
HADS total score (n)
9.86 ± 7.72
7.04 ± 6.10
0.018
HADS anxiety score (n)
5.58 ± 4.72
4.10 ± 3.51
0.032
HADS depression score (n) Beck depression inventory (n)
4.28 ± 3.84 7.96 ± 6.83
2.91 ± 3.34 6.56 ± 6.99
0.026 0.231
BR? [n (%)]*
12 (20.0)
10 (17.5)
0.734
SN? [n (%)]*
37 (62.7)
17 (28.8)
0.001
Maximal SN (cm2)*
0.238 ± 0.095
0.176 ± 0.108
0.001
Left SN (cm2)*
0.219 ± 0.090
0.162 ± 0.101
0.003
Right SN (cm2)*
0.187 ± 0.091
0.153 ± 0.101
0.073
Third ventricle (cm)*
0.599 ± 0.200
0.565 ± 0.219
0.373
Right frontal horn (cm)*
1.704 ± 0.334
1.684 ± 0.294
0.735
Left frontal horn (cm)*
1.786 ± 0.316
1.777 ± 0.308
0.885
LN? [n (%)]*
3 (5.3)
2 (3.7)
0.692
p values equal or less than 0.05 are indicated in bold Values are expressed as mean, standard deviation, number and percentage RBD REM sleep behavior disorder, IRBD idiopathic REM sleep behavior disorder, UPDRS-III unified Parkinson’s disease rating scale, part III, HADS Hamilton anxiety and depression scale, BR? brainstem raphe hypoechogenicity, SN? substantia nigra hyperechogenicity, SN substantia nigra, LN? lenticular nucleus hyperechogenicity * Echogenicity was evaluated in patients and controls with adequate bone windows
Table 2 Demographic and clinical data of idiopathic REM sleep behavior patients with and without depression
RBDD? n = 32
RBDDn = 40
p value
Age (years)
70.91 ± 7.30
71.78 ± 6.20
0.485
Female [n (%)]
13 (40.6)
6 (15.0)
0.001
Estimated RBD duration (years)
10.00 ± 7.55
10.35 ± 6.80
0.618
RBD follow-up duration (years)
3.30 ± 2.56
4.05 ± 3.97
0.851
UPDRS-III score (n)
8.25 ± 5.94
7.20 ± 5.06
0.506
HADS total score (n)
13.97 ± 7.80
6.68 ± 6.02
0.001
HADS depression score (n)
6.16 ± 4.02
2.83 ± 3.00
0.001
Beck depression inventory (n)
11.32 ± 7.75
5.35 ± 4.64
0.001
BR? [n (%)]*
8 (32.0)
4 (11.4)
0.050
SN? [n (%)]*
18 (72.0)
19 (55.9)
0.206
p values equal or less than 0.05 are indicated in bold Values are expressed as mean, standard deviation, number and percentage RBDD? IRBD patients with clinical DSM-IV depression, RBDD- IRBD patients without clinical DSM-IV depression, UPDRS-III Unified Parkinson’s Disease Rating Scale, part III, HADS Hamilton Anxiety and Depression Scale, BR? brainstem raphe hypoechogenicity, SN? substantia nigra hyperechogenicity * Echogenicity was evaluated in patients and controls with adequate bone windows
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J Neurol Table 3 Brainstem raphe echogenicity in IRBD, IRBD patients with and without depression and controls IRBD
RBDD?
RBDD-
Controls
n
60
25
35
57
BR? [n (%)]
12 (20.0)
8 (32.0)
4 (11.4)
10 (17.54)
p value (IRBD vs. controls)
p value (RBDD? vs. controls)
p value (RBDD- vs. controls)
p value (RBDD? vs. RBDD-)
0.734
0.148
0.125
0.050
IRBD idiopathic REM sleep behavior disorder, RBDD? IRBD patients with clinical DSM-IV depression, RBDD- IRBD patients without clinical DSM-IV depression, BR? brainstem raphe hypoechogenicity
Fig. 1 Sonographic images of corresponding midbrain axial sections in four subjects. The butterfly-shaped midbrain was encircled for better visualization. Arrows indicate the brainstem raphe. The area encircled inside the midbrain represents the substantia nigra. a Subject with normal echogenicity of the brainstem raphe and with normal substantia nigra size. b Subject with hyperechogenicity of the substantia nigra but normal, highly echogenic brainstem raphe. c Subject with abnormal (interrupted) echogenicity of the brainstem raphe and normal echogenicity of the substantia nigra. d Subject with hypoechogenicity of the brainstem raphe and normal echogenicity of the substantia nigra
major depressive disorder and those with adjustment disorder with depressed mood (38.5 vs. 25.0 %; p = 0.148). No correlation was found between BR? and age (r = -0.040, p = 0.763), sex (r = 0.112, p = 0.395), estimated duration of RBD (r = 0.083, p = 0.532), duration of RBD follow-up (r = -0160, p = 0.227) and UPDRS-III score (r = 0.113, p = 0.388). Substantia nigra echogenicity (Tables 1, 4) The mean echogenic size of SN was larger in the IRBD group when compared with the control group. The
frequency of individuals with SN? was greater in IRBD patients than in controls. SN? was more frequent in RBDD? than in controls, and in RBDD- than in controls. The frequency of SN? was not different between RBDD? and RBDD-, and it was also similar between subjects with major depressive disorder and with adjustment disorder with depressed mood (61.5 vs. 83.3 %; p = 0.225). No correlation was found between SN? and age (r = -0.105, p = 0.427), estimated duration of RBD (r = -0.062, p = 0.646), duration of RBD follow-up (r = 0.004, p = 0.972) and UPDRS-III score (r = 0.148, p = 0.265).
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J Neurol Table 4 Substantia nigra echogenicity in IRBD patients, IRBD patients with and without depression, and controls IRBD
RBDD?
RBDD-
Controls
n
59
25
34
59
SN? [n (%)]
37 (62.7)
18 (72.0)
19 (55.9)
17 (28.8)
p value (IRBD vs. controls)
p value (RBDD? vs. controls)
p value (RBDD- vs. controls)
p value (RBDD? vs. RBDD-)
0.001
0.001
0.010
0.206
IRBD idiopathic REM sleep behavior disorder, RBDD? IRBD patients with clinical DSM-IV depression, RBDD- IRBD patients without clinical DSM-IV depression, SN? substantia nigra hyperchogenicity
Combined BR1 and SN1
Discussion
In IRBD patients, combined BR? and SN? had a higher frequency of depression than those without this echogenic combination (85.7 vs. 14.3 %, p = 0.014). In the RBDD? group, combined BR? and SN? was not associated with age (p = 0.464), sex (p = 0.527), estimated RBD duration (p = 1.00), RBD follow-up duration (p = 0.733) and UPDRS-III score (p = 0.427).
To the best of our knowledge, this is the first study assessing the brainstem raphe echogenicity in IRBD. The current work also represents the first attempt to examine the association of BR? and SN? with comorbid depression in IRBD. We found that depression is a common feature in IRBD and that isolated BR? distinguished depressed from non-depressed patients with high specificity but with low sensitivity. For the detection of depression, sensitivity of SN? was high, and its combination with BR? increased the specificity to 97 % with a relative risk of 2.3. Thus, in IRBD subjects with SN?, the combination with BR? is indicative of the presence of depression. Besides clinical history, our study shows that TCS may be useful to detect coexistent depression in IRBD. We found that depression was common in IRBD. This was somewhat predictable since IRBD frequently heralds PD, and depression in the general population may also be predictive of future development of PD [13, 28]. Depression is a major health problem with a lifetime prevalence in the general population of 15–20 % where an important number of subjects remain underdiagnosed [29, 30]. Identification of individuals with depression is important because adequate therapy may result in complete remission [30]. We found that depression in IRBD was overlooked since 72 % of our RBD? patients were not previously diagnosed. Our study showed that the evaluation of BR and SN echogenicity with TCS may constitute an optimal noninvasive approach to support the clinical diagnosis of depression. We found that BR? occurred in 20 % of the patients with IRBD, particularly in those with comorbid depression (32 %). BR? alone was a marker of depression in IRBD with a specificity of 89 % that was not linked to age, sex, UPDRS score or duration of RBD. The frequency of BR? was similar between IRBD patients and controls probably because the majority of the IRBD subjects were not depressed (56 %) and most of the RBD? had normoechogenicity of the BR (68 %).
Sensitivity, specificity, positive predictive value, negative predictive value, and relative risk to detect depression in IRBD with the use of TCS The sensitivity of BR? to predict depression in IRBD was 32.0 % (95 % CI 13.71–50.29 %), the specificity was 88.57 % (95 % CI 78.03–99.11 %), the positive predictive value was 66.67 % (95 % CI 39.9–93.34 %), the negative predictive value was 64.58 % (95 % CI 5105–78.11 %), and the relative risk was 1.88 (95 % CI 1.08–3.27). The sensitivity of SN? to detect depression in IRBD was 72.0 % (95 % CI 54.40–89.60 %), the specificity was 44.12 % (95 % CI 27.43–60.81 %), the positive predictive value was 48.65 % (95 % CI 32.54–64.75 %), the negative predictive value was 68.18 % (95 % CI 48.72–87.65 %), and the relative risk was 1.529 (95 % CI 0.76–3.07). The sensitivity of combined BR? and SN? to predict depression in IRBD was 23.08 % (95 % CI 6.88–39.27 %), the specificity was 97.14 % (95 % CI 91.62–100 %), the positive predictive value was 85.71 % (95 % CI 59.79–100 %), the negative predictive value was 62.96 % (95 % CI 50.08–75.84 %), and the relative risk was 2.314 (95 % CI 1.46–3.67). Echogenicity of other brain structures No differences between patients and controls were found in the widths of the third ventricle and of the frontal horns of lateral ventricles, and in the proportion of individuals with hyperechogenicity of the lentiform nucleus (Table 1).
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Our findings in BR echogenicity resemble those previously reported in major depression and in PD. Reduced BR echogenicity has been described in 50–70 % of subjects with major depression and adjustment disorder with depressed mood, irrespective of severity of the depressive symptoms, age and sex [17, 19]. In the setting of PD, BR? is more frequent in subjects with than without depression. In PD subjects with depression, BR? occurs in about 40 % in both early and advanced stages, and it is not associated with age, gender, UPDRS-III score and parkinsonism duration [17, 21]. In PD, the sensitivity and specificity to detect depression are 34 and 88 %, respectively [31]. BR? visualized by TCS is a structural alteration that is thought to reflect dysfunction of the serotonergic dorsal raphe nucleus. This midbrain structure is interconnected with several regions involved in the pathogenesis of depression in PD such as the noradrenergic locus coeruleus and the dopaminergic ventral tegmental area, the limbic system and the basal ganglia [31]. In PD, damage of the dorsal raphe nucleus is common and is thought to be one of the main neuronal mechanisms underlying depression [31, 32]. The finding that BR? distinguishes depressed from nondepressed IRBD subjects suggests that dysfunction of the dorsal raphe nucleus may also be involved in the pathogenesis of depression in subjects with this parasomnia. As previously reported by our group and others, SN? was more frequent in IRBD patients than in controls [16]. SN? alone was not a specific marker of depression because its proportion was similar between RBDD? and RBDDpatients, and it was higher in RBDD- than in controls. Sensitivity of SN? to predict the presence of depression, though, was high because most of the IRBD patients (62 %) had enlarged size of the substantia nigra. In our study, SN? was not correlated with age, sex, UPDRS score and RBD duration. TCS detects SN? in approximately 90 % PD patients independent of age, disease stage and disease duration [14]. This suggests that SN? may be present in subjects at risk for PD, as it has been shown in IRBD subjects [16]. SN? is also common in depressed subjects from the general population, and it is more frequent in depressed than in nondepressed PD patients [17]. In PD, sensitivity and specificity of SN? alone to predict depression are 87 and 31 %, respectively [31]. These figures are similar to those found in the current study with IRBD where sensitivity and specificity of SN? alone to predict depression were 72 and 44 %, respectively. SN? is thought to reflect increased iron content and microglia activation within the substantia nigra and it is not associated with nigrostriatal dopaminergic deficit [14]. It is unclear why SN? is more common in depressed than in nondepressed PD patients.
In PD, combined BR? and SN? is associated with a history of depression prior to the diagnosis of PD [16]. This finding suggests that depressed individuals with combined BR? and SN? are at increased risk of developing PD. It is possible that in IRBD, the combination of BR? and SN? is not only a high specific marker of depression, but also indicative of developing PD and no other neurodegenerative diseases. IRBD patients may also develop dementia with Lewy bodies and multiple system atrophy, two conditions where combined BR and SN echogenicity has not been examined. Follow-up of our IRBD cohort will elucidate if this speculation is correct. In our study, the width of the third ventricle and frontal horns and the percentage lenticular nucleus hyperechogenicity did not differ between patients and controls. Larger widths of the ventricular system and lenticular nucleus hyperechogenicity have been associated with cognitive decline and psychosis in PD [32], two features that did not occur in our IRBD patients [14]. Our study has some limitations. First, insufficient temporal acoustic bone window prevented assessing BR and SN echogenicity in some patients and controls. Second, although none of our controls reported sleep behaviors suggestive of RBD they did not undergo polysomnography to formally exclude this parasomnia. Third, our results have to be interpreted with caution since according to BDI score RBDD? group had mild level of depression and the overall score was similar between RBD and control groups. Finally, the study was cross-sectional and long-term follow-up was not available. Despite these limitations, our study showed that depression is common in IRBD, and that the combined evaluation of BR and SN echogenicity supports the clinical diagnosis of depression in individuals with IRBD. Our findings suggest that dysfunction of the serotonergic system arising from the dorsal raphe nucleus in the brainstem may be implicated in the pathogenesis of depression in IRBD. BR? may represent a morphological marker of underlying neurodegeneration in depressed IRBD patients taking or not taking antidepressants at the time of TCSs. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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18. Becker G, Struck M, Bogdahn U, Becker T (1994) Echogenicity of the brainstem raphe in patients with major depression. Psychiatry Res 55:75–84 19. Becker T, Becker G, Seufert J, Hofmann E, Lange KW, Naumann M et al (1997) Parkinson’s disease and depression: evidence for an alteration of the basal limbic system detected by transcranial sonography. J Neurol Neurosurg Psychiatry 63:590–596 20. Berg D, Supprian T, Hofmann E, Zeiler B, Jager A, Lange KW et al (1999) Depression in Parkinson’s disease: brainstem midline alteration on transcranial sonography and magnetic resonance imaging. J Neurol 246:1186–1193 21. Cho JW, Baik JS, Lee MS (2011) Mesencephalic midline change on transcranial sonography in early Parkinson disease patients with depression. J Neurol Sci 310:50–52 22. Schmidauer C, Sojer M, Seppi K et al (2005) Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol 58:630–634 23. American Academy of Sleep Medicine (2014) International classification of sleep disorders, 3rd edn. American Academy of Sleep Medicine, Darien 24. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P et al (2008) Movement disorder societysponsored revision of the unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23:2129–2170 25. American Psychiatric Association (1995) Diagnostic and statistical manual of mental disorders 4a. American Psychiatric Association, Washington, DC 26. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370 27. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571 28. Schrag A, Hosrdfall L, Walters K, Noyce A, Petersen I (2014) Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol 14:57–64 29. Kessler RC, Birnbaum H, Bromet E et al (2010) Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R). Psaychol Med 40:225–237 30. Richards D (2011) Prevalence and clinical course of depression: a review. Clin Psycol Rev 31:117–1125 31. Grinberg LT, Rueb U, di Lorenzo AT, Heinsen H (2010) Brainstem pathology and non-motor symptoms of PD. J Neurol Sci 289:81–88 32. Walter U, Skoloduik D, Berg D (2010) Transcranial sonography findings related to non-motor features of Parkinson’s disease. J Neurol Sci 289:123–127
ORIGINAL COMMUNICATION
Brainstem raphe and substantia nigra echogenicity in idiopathic REM sleep behavior disorder with comorbid depression Dolores Vilas1 • Alex Iranzo1 • Claustre Pont-Sunyer1 • Mo´nica Serradell1 Carles Gaig1 • Joan Santamaria1 • Eduardo Tolosa1
•
Received: 17 February 2015 / Revised: 31 March 2015 / Accepted: 9 April 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia nigra (SN?) and hypoechogenicity of the brainstem raphe (BR?) are frequent in PD, particularly when depression is associated. Combined SN? and BR? identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN? and BR? may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sexmatched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). BR? was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %; p = 0.050). Sensitivity of BR? to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN? to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR? and SN? to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the & Alex Iranzo [email protected] 1
Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, C/Villarroel 170, 08036 Barcelona, Spain
serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD. Keywords REM sleep behavior disorder Transcranial sonography Brainstem raphe Substantia nigra Parkinson disease Parkinson disease (PD) has a prodromal period of several years where neuropathologic changes outside the substantia nigra may occur before parkinsonism becomes manifest [1]. A variety of nonmotor symptoms including REM sleep behavior disorder (RBD) and depression may occur during this period [2, 3]. RBD is a parasomnia characterized by nightmares and dream-enacting behaviors during REM sleep. Available data indicate that the idiopathic form of RBD (IRBD) represents premotor PD. About 20–30 % of the PD patients report that RBD symptoms antedated the onset of parkinsonism [4–6]. Longitudinal follow-up of subjects with IRBD showed that the preponderance eventually develop a Lewy body disease such as PD [7–9]. Depression may also be predictive of future development of PD. Case-register studies have shown that depressed patients around the age of 60 years have an increased risk of developing PD [10, 11]. In addition, depressive symptoms precede parkinsonism in 30 % of PD patients [6, 12, 13]. Transcranial sonography (TCS) is a noninvasive imaging tool able to identify the echogenic presence and size of several subcortical areas in the brain such as the substantia nigra (SN) and the brainstem raphe (BR) [14]. Hyperechogenicity of the substantia nigra (SN?) has been proposed as a vulnerability marker for PD [14]. SN? occurs in approximately 90 % of the PD patients [14], and in the healthy population is associated with an increased risk of
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developing this disease [15]. SN? can be detected in subjects at risk for PD such as those with IRBD [16] and in people with depression [17]. In subjects already diagnosed with PD, SN? is related to the coexistence of depression [18]. Besides, several studies showed that hypoechogenicity of the brainstem raphe (BR?) is a frequent feature in people with depression [17, 18] and in PD, particularly in those patients with coexistent depression [17, 19–21]. In subjects with PD, the combination of BR? and SN? is associated with a history of depression prior to parkinsonism onset [17]. Echogenicity of the BR has not been evaluated in IRBD. Since IRBD may represent prodromal PD, it can be speculated that BR?, particularly when combined with SN?, may support the clinical diagnosis of comorbid depression in subjects with this parasomnia. The aim of our study was to evaluate the substantia nigra and brainstem raphe echogenicity and their ability to predict comorbid depression in IRBD.
Methods Participants The current study was conducted between April 2013 and May 2014. All the 86 IRBD patients that were followed in our Multidisciplinary Sleep Unit of the Hospital Clı´nic de Barcelona, Barcelona, Spain, were invited to participate. Ten patients were not able to participate and four were excluded because they had comorbid restless legs syndrome, a condition that is associated with hypoechogenicity of the substantia nigra [22]. The remaining 72 IRBD patients who had no restless legs syndrome agreed to participate and were included in this study. Diagnosis of IRBD required a chronic history of dreamenacting behaviors, video-polysomnographic detection of increased electromyographic activity during REM sleep associated with abnormal behaviors, no motor or cognitive complaints, normal neurological examination, and no temporal association between the introduction or withdrawal of a medication or substance and the start of RBD symptoms [23]. In particular, RBD patients that reported a temporal association between the introduction of an antidepressant and the onset of RBD symptoms were excluded from this study. At the time of the study 54 (75 %) IRDB patients received clonazepam (n = 49) or melatonin (n = 5) for RBD symptomatology (dream-enacting behaviors and nightmares) and this treatment was considered completely successful in 32 patients and partially successful in 22. Seventy-one age and sex-matched controls were recruited for comparisons. All controls were free of neurological diseases, and reported no motor, cognitive or sleep
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complaints at the time of this study. Fifty-two controls were non-blood relatives of the IRBD patients. The remaining 19 controls were asymptomatic individuals followed for years in our sleep unit who were free of sleep symptoms at the time of the study. In all of them polysomnography had previously excluded RBD showing REM sleep with atonia; 16 of them had obstructive sleep apnea successfully treated with continuous positive airway pressure for several years, one had received effective psychological treatment for psychophysiological insomnia, and two had isolated nightmares in the past where polysomnography ruled out RBD and other sleep disorders. Clinical assessment Demographic data, past medical history, RBD data, past and current history of depression, and current medication including antidepressants were obtained from all participants. Neurological evaluation was assessed by means of the motor part of the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRSIII) [24]. Neurological evaluation was performed by two experienced movement disorder specialists (DV and CPS) who were blinded to the status of the patient (IRBD patient or control, depressed or nondepressed). Diagnosis of depression was made according to DSMIV criteria [25]. Following the Structured Clinical Interview for DSM-IV Axis-I Disorders, patients were classified as having major depressive disorder, adjustment disorder with depressed mood, and absence of an affective disorder [25]. The Hospital Anxiety and Depression scale (HADS) [26] and the Beck depression inventory (BDI) [27] were also administered. Transcranial sonography Transcranial sonography (TCS) was performed in all participants using a 2.5-MHz transducer (Phillips, Bothell, WA, USA) by an experienced ultrasound examiner (DV) who was blinded to clinical data and to participant category (IRBD patient or control, depressed or nondepressed). The penetration depth was 14 cm and the dynamic range was 45–55 db. The examination was done from both sides using the temporal approach. The following parameters were assessed: BR echogenicity, SN echogenicity, lenticular nucleus echogenicity, third ventricle width, and size of the frontal horn of the lateral ventricles. Echogenicity of the BR was rated as reduced (BR?) when this midline structure in the midbrain was interrupted or not visible [17, 20]. Visible midbrain raphe was labeled as normoechogenic (BR-). Area of echogenicity in the SN was manually encircled and measured on digitally stored images. The side of greater SN echogenicity was used for statistical analysis.
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In accordance to previously reported cut-off values, hyperechogenicity of the SN (SN?) was defined as an area of echogenic signal equal or greater than 0.20 cm2 [14, 16]. Areas of echogeniticy of less than 0.20 cm2 were classified as normoechogenic (SN-). If one or both sides of the SN were hyperechogenic, the structure was classified as SN?. Echogenicity of lenticular nuclei was classified as hyperechogenic when it was more intense than the surrounding white matter [14, 17]. The maximal transverse diameter in the axial scanning plane of the third ventricle, and the right and left frontal horn of the lateral ventricles were measured in the thalamic plane [14, 17]. In each patient, clinical assessment and TCS were performed on the same day. The study was approved by the Ethics Committee of Hospital Clı´nic de Barcelona and written informed consent was obtained from all paricipants. Statistical analysis Demographical, clinical and TCS data are reported in mean, standard deviation, number and percentage. Quantitative variables were analyzed using Student’s t test for comparisons of two independent groups. Qualitative variables were analyzed by Chi-square test. Spearman’s correlation coefficients were used to examine association between BR? and SN? with age, gender, UPDRS-III score, estimated RBD duration (interval between estimated reported onset of RBD symptoms and the time of TCS), RBD follow-up duration (interval between diagnosis of IRBD at our sleep center with videopolysomnography to the time of TCS). Sensitivity, specificity, positive predictive value, negative predictive value and relative risk, along with 95 % confidence intervals (CIs), were estimated for BR?, SN?, and combined BR? and SN? as markers to predict depression in IRBD. P values less than 0.05 were considered to be significant. Statistical analyses were performed with SPSS version 20.0 (IBM).
Results Demographic and clinical findings (Tables 1, 2) Patients were 53 (73.6 %) men and 19 (26.4 %) women with a mean age of 71.39 ± 6.68 years. None of the patients reported motor complaints, cognitive decline or showed clinical evidence of psychosis. No differences were found in age, gender and UPDRS-III score between patients and controls. At the time of this study, nine (12.5 %) patients and six (8.5 %) controls had a previous diagnosis of depression
and were receiving antidepressants. However, when during this study participants were interviewed about depressive symptomatology, 23 additional IRBD patients and seven controls were diagnosed with depression, according to DSM-IV diagnostic criteria. Thus, depression was found in 32 (44.4 %) IRBD subjects (RBDD?); 18 with major depressive disorder and 14 with adjustment disorder with depressed mood. In 21 (65.6 %) RBDD? patients, depressive symptomatology preceded the onset of RBD. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). Total HADS score and depression HADS score were both higher in the IRBD group than in the control group, indicating that patients had more depressive symptoms. No differences were found in the BDI score between patients and controls. When compared with IRBD patients without depression (RBDD-), RBDD? subjects had similar age, estimated RBD duration, RBD follow-up duration, and UPDRS-III score. Women were more frequent in the RBDD? group than in the RBDD- group. TCS assessment Twelve (16.6 %) IRBD patients and 14 (21.1 %) controls had insufficient temporal acoustic bone window to assess BR echogenicity. Thirteen (18.1 %) IRBD patients and 12 (16.9 %) controls had insufficient temporal acoustic bone window to assess SN echogenicity. Twenty-three (16.1 %) study subjects had inadequate bone window for both SN and BR assessments. Of the individuals without adequate bone window, seven (9.7 %) patients and five (7.0 %) controls had depression. Therefore, BR echogenicity could be examined in 60 IRBD patients (25 RBDD? and 35 RBDD-) and 57 controls, and SN echogenicity in 59 patients (25 RBDD? and 34 RBDD-) and 59 controls. Brainstem raphe echogenicity (Table 3; Fig. 1) No differences were found in the proportion of individuals with BR? between patients and controls (20.0 vs. 17.5 %; p = 0.734). The lack of significance was also found when controls with comorbid depression were excluded from the analysis (20.0 vs. 20.0 %, p = 0.769). Of 25 RBDD?, eight (32.0 %) had BR? and the remaining 17 (68.0 %) had BR-. Of the seven controls with depression, one (14.3 %) had BR? and six (85.7 %) had BR-. BR? was more frequent in RBDD? than in RBDD- (32.0 vs. 11.4 %; p = 0.050). This difference was not found in the control group when comparing individuals with and without depression (14.3 vs. 18.0 %; p = 0.809). The frequency of BR? was similar between RBDDand controls, and also between RBDD? and controls. The frequency of BR? was not different between subjects with
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J Neurol Table 1 Demographic, clinical and transcranial sonography data of idiopathic REM sleep behavior patients and controls
IRBD n = 72
Controls n = 71
p value
Age (years)
71.39 ± 6.68
70.70 ± 6.10
0.523
Male [n (%)]
53 (76.3)
49 (69.0)
0.367
Estimated RBD duration (years)
10.2 ± 7.09
NA
RBD follow-up duration (years)
3.71 ± 3.41
NA
UPDRS-III score (n)
7.67 ± 5.45
5.80 ± 6.39
0.062
Depression [n (%)]
32 (44.4)
13 (18.3)
0.001
Major depressive disorder [n (%)]
18 (56.2)
7 (53.8)
0.456
Adjustment disorder with depressed mood [n (%)]
14 (43.8)
6 (46.2)
0.546
HADS total score (n)
9.86 ± 7.72
7.04 ± 6.10
0.018
HADS anxiety score (n)
5.58 ± 4.72
4.10 ± 3.51
0.032
HADS depression score (n) Beck depression inventory (n)
4.28 ± 3.84 7.96 ± 6.83
2.91 ± 3.34 6.56 ± 6.99
0.026 0.231
BR? [n (%)]*
12 (20.0)
10 (17.5)
0.734
SN? [n (%)]*
37 (62.7)
17 (28.8)
0.001
Maximal SN (cm2)*
0.238 ± 0.095
0.176 ± 0.108
0.001
Left SN (cm2)*
0.219 ± 0.090
0.162 ± 0.101
0.003
Right SN (cm2)*
0.187 ± 0.091
0.153 ± 0.101
0.073
Third ventricle (cm)*
0.599 ± 0.200
0.565 ± 0.219
0.373
Right frontal horn (cm)*
1.704 ± 0.334
1.684 ± 0.294
0.735
Left frontal horn (cm)*
1.786 ± 0.316
1.777 ± 0.308
0.885
LN? [n (%)]*
3 (5.3)
2 (3.7)
0.692
p values equal or less than 0.05 are indicated in bold Values are expressed as mean, standard deviation, number and percentage RBD REM sleep behavior disorder, IRBD idiopathic REM sleep behavior disorder, UPDRS-III unified Parkinson’s disease rating scale, part III, HADS Hamilton anxiety and depression scale, BR? brainstem raphe hypoechogenicity, SN? substantia nigra hyperechogenicity, SN substantia nigra, LN? lenticular nucleus hyperechogenicity * Echogenicity was evaluated in patients and controls with adequate bone windows
Table 2 Demographic and clinical data of idiopathic REM sleep behavior patients with and without depression
RBDD? n = 32
RBDDn = 40
p value
Age (years)
70.91 ± 7.30
71.78 ± 6.20
0.485
Female [n (%)]
13 (40.6)
6 (15.0)
0.001
Estimated RBD duration (years)
10.00 ± 7.55
10.35 ± 6.80
0.618
RBD follow-up duration (years)
3.30 ± 2.56
4.05 ± 3.97
0.851
UPDRS-III score (n)
8.25 ± 5.94
7.20 ± 5.06
0.506
HADS total score (n)
13.97 ± 7.80
6.68 ± 6.02
0.001
HADS depression score (n)
6.16 ± 4.02
2.83 ± 3.00
0.001
Beck depression inventory (n)
11.32 ± 7.75
5.35 ± 4.64
0.001
BR? [n (%)]*
8 (32.0)
4 (11.4)
0.050
SN? [n (%)]*
18 (72.0)
19 (55.9)
0.206
p values equal or less than 0.05 are indicated in bold Values are expressed as mean, standard deviation, number and percentage RBDD? IRBD patients with clinical DSM-IV depression, RBDD- IRBD patients without clinical DSM-IV depression, UPDRS-III Unified Parkinson’s Disease Rating Scale, part III, HADS Hamilton Anxiety and Depression Scale, BR? brainstem raphe hypoechogenicity, SN? substantia nigra hyperechogenicity * Echogenicity was evaluated in patients and controls with adequate bone windows
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J Neurol Table 3 Brainstem raphe echogenicity in IRBD, IRBD patients with and without depression and controls IRBD
RBDD?
RBDD-
Controls
n
60
25
35
57
BR? [n (%)]
12 (20.0)
8 (32.0)
4 (11.4)
10 (17.54)
p value (IRBD vs. controls)
p value (RBDD? vs. controls)
p value (RBDD- vs. controls)
p value (RBDD? vs. RBDD-)
0.734
0.148
0.125
0.050
IRBD idiopathic REM sleep behavior disorder, RBDD? IRBD patients with clinical DSM-IV depression, RBDD- IRBD patients without clinical DSM-IV depression, BR? brainstem raphe hypoechogenicity
Fig. 1 Sonographic images of corresponding midbrain axial sections in four subjects. The butterfly-shaped midbrain was encircled for better visualization. Arrows indicate the brainstem raphe. The area encircled inside the midbrain represents the substantia nigra. a Subject with normal echogenicity of the brainstem raphe and with normal substantia nigra size. b Subject with hyperechogenicity of the substantia nigra but normal, highly echogenic brainstem raphe. c Subject with abnormal (interrupted) echogenicity of the brainstem raphe and normal echogenicity of the substantia nigra. d Subject with hypoechogenicity of the brainstem raphe and normal echogenicity of the substantia nigra
major depressive disorder and those with adjustment disorder with depressed mood (38.5 vs. 25.0 %; p = 0.148). No correlation was found between BR? and age (r = -0.040, p = 0.763), sex (r = 0.112, p = 0.395), estimated duration of RBD (r = 0.083, p = 0.532), duration of RBD follow-up (r = -0160, p = 0.227) and UPDRS-III score (r = 0.113, p = 0.388). Substantia nigra echogenicity (Tables 1, 4) The mean echogenic size of SN was larger in the IRBD group when compared with the control group. The
frequency of individuals with SN? was greater in IRBD patients than in controls. SN? was more frequent in RBDD? than in controls, and in RBDD- than in controls. The frequency of SN? was not different between RBDD? and RBDD-, and it was also similar between subjects with major depressive disorder and with adjustment disorder with depressed mood (61.5 vs. 83.3 %; p = 0.225). No correlation was found between SN? and age (r = -0.105, p = 0.427), estimated duration of RBD (r = -0.062, p = 0.646), duration of RBD follow-up (r = 0.004, p = 0.972) and UPDRS-III score (r = 0.148, p = 0.265).
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J Neurol Table 4 Substantia nigra echogenicity in IRBD patients, IRBD patients with and without depression, and controls IRBD
RBDD?
RBDD-
Controls
n
59
25
34
59
SN? [n (%)]
37 (62.7)
18 (72.0)
19 (55.9)
17 (28.8)
p value (IRBD vs. controls)
p value (RBDD? vs. controls)
p value (RBDD- vs. controls)
p value (RBDD? vs. RBDD-)
0.001
0.001
0.010
0.206
IRBD idiopathic REM sleep behavior disorder, RBDD? IRBD patients with clinical DSM-IV depression, RBDD- IRBD patients without clinical DSM-IV depression, SN? substantia nigra hyperchogenicity
Combined BR1 and SN1
Discussion
In IRBD patients, combined BR? and SN? had a higher frequency of depression than those without this echogenic combination (85.7 vs. 14.3 %, p = 0.014). In the RBDD? group, combined BR? and SN? was not associated with age (p = 0.464), sex (p = 0.527), estimated RBD duration (p = 1.00), RBD follow-up duration (p = 0.733) and UPDRS-III score (p = 0.427).
To the best of our knowledge, this is the first study assessing the brainstem raphe echogenicity in IRBD. The current work also represents the first attempt to examine the association of BR? and SN? with comorbid depression in IRBD. We found that depression is a common feature in IRBD and that isolated BR? distinguished depressed from non-depressed patients with high specificity but with low sensitivity. For the detection of depression, sensitivity of SN? was high, and its combination with BR? increased the specificity to 97 % with a relative risk of 2.3. Thus, in IRBD subjects with SN?, the combination with BR? is indicative of the presence of depression. Besides clinical history, our study shows that TCS may be useful to detect coexistent depression in IRBD. We found that depression was common in IRBD. This was somewhat predictable since IRBD frequently heralds PD, and depression in the general population may also be predictive of future development of PD [13, 28]. Depression is a major health problem with a lifetime prevalence in the general population of 15–20 % where an important number of subjects remain underdiagnosed [29, 30]. Identification of individuals with depression is important because adequate therapy may result in complete remission [30]. We found that depression in IRBD was overlooked since 72 % of our RBD? patients were not previously diagnosed. Our study showed that the evaluation of BR and SN echogenicity with TCS may constitute an optimal noninvasive approach to support the clinical diagnosis of depression. We found that BR? occurred in 20 % of the patients with IRBD, particularly in those with comorbid depression (32 %). BR? alone was a marker of depression in IRBD with a specificity of 89 % that was not linked to age, sex, UPDRS score or duration of RBD. The frequency of BR? was similar between IRBD patients and controls probably because the majority of the IRBD subjects were not depressed (56 %) and most of the RBD? had normoechogenicity of the BR (68 %).
Sensitivity, specificity, positive predictive value, negative predictive value, and relative risk to detect depression in IRBD with the use of TCS The sensitivity of BR? to predict depression in IRBD was 32.0 % (95 % CI 13.71–50.29 %), the specificity was 88.57 % (95 % CI 78.03–99.11 %), the positive predictive value was 66.67 % (95 % CI 39.9–93.34 %), the negative predictive value was 64.58 % (95 % CI 5105–78.11 %), and the relative risk was 1.88 (95 % CI 1.08–3.27). The sensitivity of SN? to detect depression in IRBD was 72.0 % (95 % CI 54.40–89.60 %), the specificity was 44.12 % (95 % CI 27.43–60.81 %), the positive predictive value was 48.65 % (95 % CI 32.54–64.75 %), the negative predictive value was 68.18 % (95 % CI 48.72–87.65 %), and the relative risk was 1.529 (95 % CI 0.76–3.07). The sensitivity of combined BR? and SN? to predict depression in IRBD was 23.08 % (95 % CI 6.88–39.27 %), the specificity was 97.14 % (95 % CI 91.62–100 %), the positive predictive value was 85.71 % (95 % CI 59.79–100 %), the negative predictive value was 62.96 % (95 % CI 50.08–75.84 %), and the relative risk was 2.314 (95 % CI 1.46–3.67). Echogenicity of other brain structures No differences between patients and controls were found in the widths of the third ventricle and of the frontal horns of lateral ventricles, and in the proportion of individuals with hyperechogenicity of the lentiform nucleus (Table 1).
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Our findings in BR echogenicity resemble those previously reported in major depression and in PD. Reduced BR echogenicity has been described in 50–70 % of subjects with major depression and adjustment disorder with depressed mood, irrespective of severity of the depressive symptoms, age and sex [17, 19]. In the setting of PD, BR? is more frequent in subjects with than without depression. In PD subjects with depression, BR? occurs in about 40 % in both early and advanced stages, and it is not associated with age, gender, UPDRS-III score and parkinsonism duration [17, 21]. In PD, the sensitivity and specificity to detect depression are 34 and 88 %, respectively [31]. BR? visualized by TCS is a structural alteration that is thought to reflect dysfunction of the serotonergic dorsal raphe nucleus. This midbrain structure is interconnected with several regions involved in the pathogenesis of depression in PD such as the noradrenergic locus coeruleus and the dopaminergic ventral tegmental area, the limbic system and the basal ganglia [31]. In PD, damage of the dorsal raphe nucleus is common and is thought to be one of the main neuronal mechanisms underlying depression [31, 32]. The finding that BR? distinguishes depressed from nondepressed IRBD subjects suggests that dysfunction of the dorsal raphe nucleus may also be involved in the pathogenesis of depression in subjects with this parasomnia. As previously reported by our group and others, SN? was more frequent in IRBD patients than in controls [16]. SN? alone was not a specific marker of depression because its proportion was similar between RBDD? and RBDDpatients, and it was higher in RBDD- than in controls. Sensitivity of SN? to predict the presence of depression, though, was high because most of the IRBD patients (62 %) had enlarged size of the substantia nigra. In our study, SN? was not correlated with age, sex, UPDRS score and RBD duration. TCS detects SN? in approximately 90 % PD patients independent of age, disease stage and disease duration [14]. This suggests that SN? may be present in subjects at risk for PD, as it has been shown in IRBD subjects [16]. SN? is also common in depressed subjects from the general population, and it is more frequent in depressed than in nondepressed PD patients [17]. In PD, sensitivity and specificity of SN? alone to predict depression are 87 and 31 %, respectively [31]. These figures are similar to those found in the current study with IRBD where sensitivity and specificity of SN? alone to predict depression were 72 and 44 %, respectively. SN? is thought to reflect increased iron content and microglia activation within the substantia nigra and it is not associated with nigrostriatal dopaminergic deficit [14]. It is unclear why SN? is more common in depressed than in nondepressed PD patients.
In PD, combined BR? and SN? is associated with a history of depression prior to the diagnosis of PD [16]. This finding suggests that depressed individuals with combined BR? and SN? are at increased risk of developing PD. It is possible that in IRBD, the combination of BR? and SN? is not only a high specific marker of depression, but also indicative of developing PD and no other neurodegenerative diseases. IRBD patients may also develop dementia with Lewy bodies and multiple system atrophy, two conditions where combined BR and SN echogenicity has not been examined. Follow-up of our IRBD cohort will elucidate if this speculation is correct. In our study, the width of the third ventricle and frontal horns and the percentage lenticular nucleus hyperechogenicity did not differ between patients and controls. Larger widths of the ventricular system and lenticular nucleus hyperechogenicity have been associated with cognitive decline and psychosis in PD [32], two features that did not occur in our IRBD patients [14]. Our study has some limitations. First, insufficient temporal acoustic bone window prevented assessing BR and SN echogenicity in some patients and controls. Second, although none of our controls reported sleep behaviors suggestive of RBD they did not undergo polysomnography to formally exclude this parasomnia. Third, our results have to be interpreted with caution since according to BDI score RBDD? group had mild level of depression and the overall score was similar between RBD and control groups. Finally, the study was cross-sectional and long-term follow-up was not available. Despite these limitations, our study showed that depression is common in IRBD, and that the combined evaluation of BR and SN echogenicity supports the clinical diagnosis of depression in individuals with IRBD. Our findings suggest that dysfunction of the serotonergic system arising from the dorsal raphe nucleus in the brainstem may be implicated in the pathogenesis of depression in IRBD. BR? may represent a morphological marker of underlying neurodegeneration in depressed IRBD patients taking or not taking antidepressants at the time of TCSs. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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