Published Ahead of Print on January 7, 2015 as 10.1212/WNL.0000000000001215

Reduced striatal dopamine transmission in REM sleep behavior disorder comorbid with depression Yun Kwok Wing, FRCPsych Siu Ping Lam, FHKAM (Psych) Jihui Zhang, PhD, MD Eric Leung, FHKAM (Radiology) Chi Lai Ho, MD Sirong Chen, PhD Man Ki Cheung, PhD, FRSC (CChem) Shirley Xin Li, PhD, RPSGT Joey Wing Yan Chan, FHKAM (Psych) Vincent Mok, MD, FRCP Joshua Tsoh, FHKAM (Psych) Anne Chan, FRCP Crover Kwok Wah Ho, RPSGT

Correspondence to Dr. Wing: [email protected]

ABSTRACT

Objective: To investigate dopamine transmission in patients with comorbid REM sleep behavior disorder (RBD) and major depressive disorder (MDD).

Methods: This is a case-control study including 11 medicated patients with comorbid RBD and MDD (mean age 47.5 6 8.2), 8 medicated patients with MDD only (mean age 47.9 6 8.4), and 10 healthy participants (mean age 46.5 6 10.6 years). They underwent clinical assessment, video-polysomnography, olfactory tests, and neuroimaging studies (18F-DOPA, 11C-raclopride, and 18F-FDG PET neuroimaging). Results: Compared with the 2 control groups, patients with comorbid RBD and MDD had significantly lower 18F-DOPA uptake at 60 minutes in the putamen and caudate after controlling for age and sex effect (p , 0.05). There were no significant differences for the 11C-raclopride and 18 F-FDG-PET. The 18F-DOPA uptake in putamens had significant inverse correlation with severity of RBD symptoms (p , 0.01) and REM-related tonic muscle activity (p , 0.01). The comorbid RBD and MDD group had more impairment in olfactory function. Conclusion: Patients with comorbid RBD and MDD had presynaptic dopamine dysfunction and impaired olfactory function. There is a distinct possibility that the development of RBD symptoms among patients with MDD may represent an early phase of a-synucleinopathy neurodegeneration instead of a merely antidepressant-induced condition. Neurology® 2015;84:1–7 GLOSSARY BDI 5 Beck Depression Inventory; hControl 5 healthy participants; ICSD-3 5 International Classification of Sleep Disorders–III; MDD 5 major depressive disorder; pControl 5 psychiatric controls; PSG 5 polysomnographic; PD 5 Parkinson disease; RBD 5 REM sleep behavior disorder; RBDQ-HK 5 REM sleep behavior disorder screening questionnaire–Hong Kong; REMREEA 5 REM-related EMG activity measured from polysomnographic study; ROI 5 region of interest; SC ratio 5 ratio of substriatal (putamen and caudate) region of interest to cerebellar hemisphere; SCID 5 the SemiStructured Clinical Interview for DSM-IV; SSRI 5 selective serotonin reuptake inhibitor; TA 5 time-dependent activity; UPDRS 5 Unified Parkinson’s Disease Rating Scale; vPSG 5 video polysomnography.

REM sleep behavior disorder (RBD) is regarded as an early precursor of a-synucleinopathyrelated neurodegenerative diseases.1 Typically, RBD affects older people (age .60 years),2,3 but it is being increasingly recognized among younger age groups (age ,50 years), especially among individuals with psychiatric disorders and usage of psychotropics.4–9 A clinical epidemiologic study in a psychiatric outpatient clinic found that the lifetime prevalence of RBD features was 5.8%,4 10 times more common than that of the typical RBD found in the general population.10 Although it is regarded as a drug-induced side effect (particularly of selective serotonin reuptake inhibitors [SSRIs]) by the recent International Classification of Sleep Disorders–III (ICSD-3) diagnostic criteria,11 the risk of developing RBD symptoms among those taking antidepressants was only about 1 out of 20,4 and further naturalistic follow-up studies suggested that RBD symptoms and polysomnographic (PSG) abnormalities persisted despite discontinuing or switching antidepressants.9 Another prospective cohort study also reported that patients with RBD taking antidepressants experienced more olfactory and color vision dysfunction, which could be early signs of neurodegeneration.12 These findings suggested that the development of From the Department of Psychiatry (Y.K.W., S.P.L., J.Z., S.X.L., J.W.Y.C., J.T., C.K.W.H.) and the Department of Medicine and Therapeutics (V.M., A.C.), Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR; and Nuclear Medicine & PET (E.L., C.L.H., S.C., M.K.C.), Hong Kong Sanatorium & Hospital. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2015 American Academy of Neurology

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1

RBD features in patients with MDD may not be simply an antidepressants-induced condition.13,14 While dopamine dysfunction has been reported in typical RBD of the older age group and was found to be a sensitive marker for detecting early neurodegeneration,15,16 the possibility of dopamine dysfunction in middleaged patients with MDD comorbid with RBD has never been investigated. Thus, we performed this PET neuroimaging study to examine the presynaptic and postsynaptic nigrostriatal dopaminergic transmission. METHODS Participants. A total of 29 participants were included in this study, including 11 medicated participants with MDD comorbid with RBD (MDD 1 RBD), 8 medicated participants with MDD without RBD (psychiatric controls [pControl]), and 10 healthy participants (hControl) recruited from the community. These participants were recruited from a casecontrol study established since 2006.11 Due to the limited resources, only 29 study participants were selected from the cohorts based on the following criteria. Recruitment criteria for comorbid MDD 1 RBD included the following: (1) a diagnosis of RBD ascertained by both clinical and video PSG (vPSG) assessment according to the diagnostic criteria of ICSD-2; and (2) a comorbid diagnosis of MDD ascertained by the SemiStructured Clinical Interview for DSM-IV (SCID). The pControl consisted of 8 age-, sex-, diagnosis-, and medicationmatched patients with MDD and the psychiatric diagnosis was also ascertained by SCID. Age- and sex-matched hControl were recruited from a local community-based epidemiologic study. They had no current or lifetime history of psychiatric disorders as ascertained by SCID interview. To rule out a diagnosis of RBD, all control participants (pControl and hControl) completed a RBD screening questionnaire–Hong Kong (RBDQ-HK) and underwent clinical interviews and vPSG.17 Exclusion criteria included (1) any known lifetime or current diagnosis of bipolar affective disorder, schizophrenia, or substance abuse; and (2) any known neurologic diseases including stroke, Parkinson disease (PD), multiple system atrophy, dementia, or other neurologic conditions that may cause RBD symptoms. To ascertain the absence of clinically established a-synucleinopathyrelated neurodegeneration, all participants were examined by neurologists who were blind to the clinical status of the participants with a thorough neurologic evaluation, including history taking and physical examination with the aid of the Unified Parkinson’s Disease Rating Scale (UPDRS).

Procedures. All participants underwent clinical interview, neurologic examination, vPSG, olfactory test, and PET imaging. To ascertain the time correlation of the neuroimaging and clinical parameters, the above listed assessments were completed within 3 months of the PET imaging. vPSG. Overnight vPSG was conducted to document REM-related EMG activities and any dream-enacting behaviors. Our previous study suggested that a single night vPSG was mostly adequate in establishing a diagnosis of RBD.18 The vPSG monitoring included electro-oculogram, EEG, EMG (monitoring over chin and bilateral anterior tibialis muscles), ECG, nasal-oral airflow, and respiratory movements. The PSG was scored according to American Academy of Sleep Medicine 2007 scoring manual with 2

Neurology 84

modification of the criteria on REM-related EMG activities (REMREEA).18 The REMREEA was quantified as the percentage of total EMG activities (including both tonic and phasic EMG of the mentalis muscle) during REM sleep.18 Quantification was conducted manually by the technicians who were blind to the clinical diagnosis of the participants. The following criteria were adopted: (1) tonic EMG activity was measured as the percentage of 30-second epochs having more than 50% of sustained tonic EMG activity; (2) phasic EMG activity was defined as any burst of EMG activity that lasted for 0.1–5 seconds with the amplitude of 4 times of the baseline EMG tone. It was evaluated in every miniepoch of 3 seconds during REM sleep. The tonic and phasic EMG that increased concurrently with respiratory events, periodic leg movement, spontaneous arousals, or snoring signal artefacts were excluded from the analysis.

PET/CT imaging. All patients underwent a 2-day triple-tracer PET/CT imaging protocol including 18F-DOPA, 11C-raclopride, and 18F-FDG images. The presynaptic dopaminergic function was assessed by 18F-DOPA while the quantitative measurement of dopamine at receptor level (postsynaptic dopamine-D2 receptors) was assessed by 11C-raclopride. The 18F-FDG PET combined with 18 F-DOPA and 11C-raclopride PET was conducted to differentiate typical parkinsonism from atypical cases such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Patients fasted for at least 6 hours and blood glucose concentration was determined before the injection of PET radiopharmaceuticals. Patients rested in a dimmed room before and after the tracer injection. The brain was scanned with an integrated in-line PET/CT (Biograph 40) in the 3D mode. Data acquisition began with CT (with no contrast) at 130 kV, 110–115 mA, 2-mm pitch, and 1-second tube rotation, followed by PET of 148 axial image planes simultaneously at a 21.6 cm axial field of view. First day protocol. A dose of ;15 mCi 11C-raclopride was administered IV and the brain was imaged at 30 minutes after injection with a 10-minute emission acquisition. Twenty minutes after the completion of 11C-raclopride PET/CT (;60 minutes post 11C-raclopride injection), a dose of ;10 mCi 18F-FDG was injected IV and the brain was scanned at 30 minutes after 18 F-FDG administration with a 10-minute acquisition. Second day protocol. A dose of ;10 mCi 18F-dopa was administered IV and 18F-dopa imaging of the brain started at 30, 60, and 90 minutes after injection, each with a 10-minute emission acquisition. Olfactory function. Impaired olfactory function had been reported among RBD and could be one of the potential markers for early neurodegeneration. In this study, olfactory function was assessed with a locally validated Olfactory Identification Test, which consists of 6 common household odors, and the participants are requested to identify the odor among 20 pictures.19 Standard protocol approvals, registrations, and patient consents. The study was approved by the joint ethics committee of the cluster hospitals and university. All participants provided written informed consent for the study. Participants of MDD 1 RBD and pControl arms were instructed to continue their psychotropic medications during vPSG and neuroimaging studies.

Statistical analysis. Descriptive data were reported as means and SDs, or frequency and percentages. Kolmogorov-Smirnov test was used to assess normality of the distribution of the variables. Univariate analysis of categorical data was performed by x2 test. For continuous data, one-way analysis of variance

February 3, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

followed by the contrast analysis. Correlations of the PET data with other parameters were examined by Spearman test.

followed by Tukey honestly significant difference post hoc analysis and Kruskal-Wallis test were used for parametric and nonparametric data, respectively. All analyses were performed with the statistical software package SPSS 17.0 for Windows (Chicago, IL, SPSS). PET data analysis. The following regions of interest (ROIs), including right and left putamen, caudate, and cerebellar hemisphere, were automatically drawn on 18F-FDG PET using MIMNeuro4.2. The contours from 18F-FDG PET were copied to 18F-dopa and 11C-raclopride brain PET images for all the above-mentioned ROIs. The standardized uptake value (SUVmean) ratio of substriatal (putamen and caudate) ROI to cerebellar hemisphere (SC ratio) was generated for 18F-dopa PET and 11C-raclopride PET. To account for the 18F-DOPA timedependent activity (TA) in individual cerebral blood space, 3 sets of 18F-DOPA images at 30, 60, and 90 minutes were further analyzed by calculation of 18F-DOPA influx constant Ki (minute21) of the substriatal ROIs with 18F-DOPA TA in occipital lobe as the input, a multiple time graphical analysis approach by Patlak and Blasberg20 that was considered having more distinguishing power for the identification of PD but more complicated than ratio analysis. For analysis of PET data, as age and sex could have significant effects, analysis of covariance adjusted for age and sex was used for 3-group comparison

Table 1

RESULTS Demographic

and

clinical

parameters.

Demographic and clinical data of the case and control participants are presented in table 1. The 3 groups had similar demography in terms of age, sex, smoking status, and educational level. Both depressed groups (MDD 1 RBD and pControl) had a comparable mean age at diagnosis of MDD at around late 30s to early 40s. The MDD 1 RBD group had a longer duration of use of antidepressants but the group differences were not statistically significant. The pattern of psychotropic prescription is presented in tables e-1 and e-2 (on the Neurology® Web site at neurology.org). The 2 groups are mostly prescribed antidepressants (predominantly SSRIs) with comparable dosages, which are all within the therapeutic range. Regarding the clinical symptoms, the MDD 1 RBD group scored slightly higher on the Beck Depression Inventory (BDI) and

Demographic, clinical, and polysomnographic variables MDD 1 RBD (a) (n 5 11)

pControl (b) (n 5 8)

hControl (c) (n 5 10)

p Value

Post hoc analysis

Age, y, mean (SD)

47.5 (8.2)

47.9 (8.4)

46.5 (10.6)

NS

—

Sex, male (%)

8 (72.7)

5 (62.5)

7 (70)

NS

—

Primary

1 (9.1)

2 (25)

0

Secondary

7 (63.6)

4 (50)

6 (60)

Education (%)

NS

Tertiary

3 (27.3)

2 (25)

4 (40)

Smoking (%)

4 (36.4)

0

2 (20)

NS

Age MDD diagnosed, y, mean (SD)

39.6 (9.4)

42.9 (7.9)

—

NS

Duration of antidepressant usage, y, mean (SD)

6.9 (4.2)

4.6 (3.3)

—

NS (by Student t test)

BDI, mean (SD)

10.6 (5.6)

9.4 (4.3)

3.2 (3.2)

,0.01

a . b; b . c

45.2 (14.6)

10.9 (11.3)

11.0 (7.9)

,0.01

a . b; a . c

RBDQ-HK, mean (SD) Total Factor 1

15.7 (4.6)

5.9 (5.6)

7.6 (4.2)

,0.01

a . b; a.c

Factor 2

29.5 (11.5)

5.0 (6.0)

2.2 (3.0)

,0.01

a . b; a . c

UPDRS motor score, mean (SD)

1.82 (1.08)

1.13 (1.0)

1.0 (0.8)

NS

OIT

3.0 (1.8)

4.8 (1.0)

4.2 (0.92)

NS