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. Author manuscript; available in PMC: 2016 Nov 1.
Published in final edited form as: Mov Disord. 2015 Sep 14;30(13):1834–1839. doi: 10.1002/mds.26413

REM Sleep Behavior Disorder, as assessed by the RBDSQ, in G2019S LRRK2 mutation PD and unaffected carriers

Rachel Saunders-Pullman 1,2,*, Roy N Alcalay 3,4, Anat Mirelman 5, Cuiling Wang 6, Marta San Luciano 7, Roberto A Ortega 1, Amanda Glickman 1, Deborah Raymond 1, Helen Mejia-Santana 3, Nancy Doan 1, Brooke Johannes 1, Kira Yasinovsky 5, Laurie Ozelius 2,8, Lorraine Clark 4,9, Avi Orr-Utreger 10, Karen Marder 3,4,11,12, Nir Giladi 5, Susan B Bressman 1,2; the AJ LRRK2 Consortium
PMCID: PMC4715645  NIHMSID: NIHMS714389  PMID: 26366513

Abstract

Background

Rapid eye movement sleep Behavior Disorder occurs with idiopathic Parkinson disease (PD), and often precedes PD. Its frequency in LRRK2-PD and utility as a pre-clinical marker has not been established.

Methods

144 idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related non-carriers, and 40 controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire.

Results

30.6% idiopathic PD, 19.7% LRRK2-PD, 6% non-manifesting carriers, 20.4% related non-carriers, and 15% controls met cut-scores. The likelihood of abnormal scores was decreased in LRRK2-PD vs. idiopathic PD (OR=0.55, p=0.03), non-manifesting carriers vs. related non-carriers (OR=0.25, p<0.01), and PD <3 years duration, 1/19 LRRK2-PD vs. 14/41 idiopathic PD (p<0.05).

Conclusions

There is a lower frequency of abnormal Questionnaire scores in LRRK2-PD, especially in early LRRK2-PD, and in non-manifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a pre-clinical marker for phenoconversion to PD.

Keywords: Parkinson’s disease, LRRK2, REM Behavior Disorder, RBDSQ, pre-clinical

INTRODUCTION

In the search for markers of pre-clinical parkinsonism, REM sleep behavior disorder (RBD) holds promise, as it is highly specific for phenoconversion to parkinsonism. As many as 90% of RBD cases develop a synucleinopathy, either idiopathic PD (IPD), Parkinson disease with dementia, dementia with Lewy bodies, or multiple system atrophy1–4. The time course to motor phenoconversion may exceed 10 years3, 5, suggesting a long at-risk “pre-clinical” period during which potential therapeutics might be applied to lessen pathologic burden before development of full-fledged clinical disease6, 7. The gold-standard assessment for RBD is polysomnography (PSG). However, questionnaires regarding sleep behavior have good correlation with cases diagnosed in sleep laboratories,8 and are more practical as screening tools. Harboring the G2019S LRRK2 mutation is also a marker of pre-clinical disease, but only a third of carriers develop PD in their lifetimes 9, 10. Therefore, combining a questionnaire marker for RBD with carriage of the LRRK2 mutation might detect individuals who are at higher risk for phenoconversion. The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ)8 is one such questionnaire. In a smaller group of LRRK2-PD, there was a trend for RBDSQ abnormalities to be less frequent in LRRK2-PD than IPD32. Further, in a subset of the population evaluated here, continuous RBDSQ scores did not differ between carriers without PD (non-manifesting carriers (NMC)) and family members without PD (non-carrier family members, NCF)15. Herein we report the largest group of G2019S mutation LRRK2-PD assessed with RBDSQ, and because of the sample size, are able to report on a subgroup with early disease.

METHODS

536 participants from the LRRK2 Ashkenazi Jewish Consortium centers in Tel Aviv (Tel Aviv Medical Center, TA n=249,) and New York (Mount Sinai Beth Israel, MSBI n=155, and Columbia University Medical Center, CU n=155), self-administered the RBDSQ, a questionnaire that evaluates frequency of dreams and nocturnal behavior, self and bed partner injurious behavior, specific movements and activities during sleep, nocturnal awakenings and overall sleep quality. Subjects included 144 PD without G2019S or any of the eight major Ashkenazi Jewish GBA1 mutations (IPD), 142 G2019S mutation carriers with PD (LRRK2-PD), 117 G2019S mutation carriers without PD (NMC), 93 non-PD, non-mutation-carrying family members (NC-F), and 40 unrelated controls. Continuous scores from a subset of the RBDSQ data comparing NMC to NC-F were previously reported.15

Univariate demographic and RBDSQ comparisons were performed using Wilcoxon rank sum and Fisher’s exact or Chi-squared tests both for the groups overall and evaluating factors that might be related to RBD. Generalized estimating equation (GEE) logistic regression models evaluated likelihood of RBD by the RBDSQ cutoff-scores (defined as ≥6 for PD37 and ≥5 for non-PD8), and adjusted for age, gender, UPDRS-III, and site (NY or TA), accounting for correlation between family members.

Further secondary analyses were performed within groups to determine whether features segregated with RBD in the LRRK2-PD and IPD groups, including duration of disease, UPDRS-III, motor subtype (postural instability gait predominant, PIGD)16, Montreal Cognitive Assessment (MoCA) and hyposmia (defined as <15th percentile for age and gender with the 40-item University of Pennsylvania Smell Identification Test (UPSIT)).

RESULTS

Demographics (Table 1)

Table 1.

Demographics and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) Scores

IPDa LRRK2-PDb NMCc NC-Fd Controle
n 144 142 117 93 40
Women % 35.4%cde 45.8%ce 59.8%ab 50.5%ae 72.5%abd
Age years 64.9 ± 11.3cde 67.2 ± 9.8cd 53.3 ± 15.9 abe 52.8 ± 18.5 abe 69.8 ± 10.6acd
UPDRS-III 20.1 ± 11.8cde 21.1 ± 13.1cde 2.5 ± 3.5ab 2.5 ± 3.5ab 2.1 ± 3.4ab
Age onset 58.0 ± 10.9 57.4 ± 11.0 - - -
PD Duration years 7.4 ± 7.5b 10.0 ± 7.1a - - -
RBDSQ score median (IQR) 4.0 (2.0–7.0)cde 3.0 (2.0–5.0)cde 2.0 (1.0–3.0)ab 2.0 (1.0–4.0)ab 2.0 (1.0–4.0)ab
RBD+ % 30.6%bcde 19.7%ac 6.0%abd 20.4%ac 15.0%a
Odds Ratios for Abnormal RBDSQ Scores Among
All Groups **
n = 536 OR 95% CI P
Age 1.01 .99–1.02 0.56
Sex (Women) 0.64 .41–1.01 0.06
Site (NY) 1.57 .97–2.54 0.07
Group:
 Control (ref) --- --- ---
 IPD 2.75 .03–7.35 0.04
 LRRK2-PD 1.50 .56–4.04 0.42
 NMC 0.46 .14–1.54 0.21
 NC-F 1.89 .65–5.51 0.25
Further group comparisons*
IPD vs. LRRK2-PD 1.83 .05–3.18 0.03
NMC vs. LRRK2-PD 0.31 .13–0.75 0.01
NC-F vs. LRRK2-PD 0.80 .40–1.59 0.52
NMC vs. NC-F 0.25 .10–0.61 <0.01
Odds Ratios for RBDSQ Restricted to PD Groups
n = 275 OR 95% CI P
IPD vs. LRRK2-PD 2.38 .29–4.38 <0.01
Age 1.01 .99–1.04 0.34
Sex (Women) 0.54 .29–1.00 0.05
Site (NY) 1.37 .75–2.52 0.31
Duration 1.08 .03–1.14 <0.01
UPDRS-III 0.99 .97–1.02 0.20
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*

Additional group comparisons were deduced from the main model; Values provided are number (%) or mean ± SD, as appropriate, unless otherwise stated; Superscripts denote significant differences from the superscripted group (p<0.05); ORs from GEE models adjusted for age, site (NY vs. Israel), gender and family membership Definitions: LRRK2-PD=LRRK2 G2019S mutation carriers with PD; IPD=idiopathic PD; NMC=LRRK2 mutation carriers without PD; NC-F=non-carrier family members; UPDRS-III=Unified Parkinson Disease Rating Scale Motor Score; RBDSQ=REM Sleep Behavior Disorder Screening Questionnaire; RBD+=total RBDSQ score ≥ 5 (non-PD) and total RBDSQ score ≥ 6 (PD).

**

In post-hoc analysis using the main GEE model to assess site differences, all differences from the main model were maintained when limited to participants from either NY or TA, except that NMC from NY were not different from LRRK2-PD (OR=0.34, p=0.07) or NC-F (OR=0.30, p=0.06) and, although the magnitude of the OR was maintained, in TA the odds of RBD was not significantly reduced in LRRK2-PD vs. IPD (OR=0.73, p=0.49).

LRRK2-PD were more likely to be male than controls and NMC but not than IPD or NC-F. Mean age of IPD (64.9 ± 11.3) was not different from LRRK2-PD (67.2 ± 9.8). Both IPD and LRRK2-PD were older than NMC (53.3 ± 15.9) and NC-F (52.8 ± 18.5). IPD were younger than controls (69.8 ± 10.6) but LRRK2-PD were not. Age at onset did not differ between IPD and LRRK2-PD (58.0 ± 10.9 and 57.4 ± 11.0), nor did UPDRS-III, but duration of PD was longer in the LRRK2-PD group (7.36 ± 7.53 vs. 9.98 ± 7.10 years) (p<0.01).17

RBDSQ Scores (Table 1)

30.6% of IPD met criteria for abnormal RBDSQ score vs. 19.7% of LRRK2-PD, 6.0% of NMC, 20.4% of non-carrier family members and 15.0% of controls. In the main GEE model adjusting for age, site (NY vs. TA) and gender, the likelihood of having abnormal RBDSQ was decreased in LRRK2-PD vs. IPD (OR=0.55, p=0.03) and increased in LRRK2-PD vs. NMC (OR=3.24, p=0.01) but not different in LRRK2-PD vs. controls (OR 1.50, p=0.42). It was less in NMC than NC-F (OR=0.25, p<0.01), and did not differ between NMC and controls (OR=2.17, p=0.21). Among subjects with early PD (<3 years duration), abnormal scores were present in only 1/19 cases with LRRK2-PD and in 12/41 cases with IPD (p<0.05). In post hoc univariate comparisons in IPD (Table 2), abnormal RBDSQ scores were associated with worse UPSIT score, PIGD phenotype. In LRRK2-PD, duration of disease and anxiety were significant.

Table 2.

Features associated with RBDSQ Cut-scores in Parkinson disease

RBDSQ+ RBDSQ- P
LRRK2-PD (n=142) 28 (19.7%) 114 (80.3%) ---
Women 9 (32.1%) 56 (49.1%) 0.14
Age 68.2 ± 9.1 67.0 ± 10.0 0.72
Duration 14.6 ± 7.6 8.8 ± 6.5 <0.01
UPSIT Score (125) 20.9 ± 8.6 23.5 ± 8.6 0.19
Hyposmia 15 (60.0%) 53 (53.0%) 0.53
UPDRS-III (135) 24.2 ± 12.9 20.3 ± 13.1 0.07
PIGD phenotype (133) 22 (81.5%) 67 (63.2%) 0.11
MoCA Score (131) 24.8 ± 3.6 25.4 ± 2.8 0.67
STAI (42)
 State 43.4 ± 11.8 33.7 ± 13.4 0.03
 Trait 48.8 ± 14.6 33.4 ± 11.7 <0.01
IPD (n=144) 44 (30.6%) 100 (69.4%) ---
Women 11 (25.0%) 40 (40.0%) 0.08
Age 67.5 ± 10.1 63.8 ± 11.7 0.06
Duration 7.8 ± 6.6 7.2 ± 7.9 0.48
UPSIT Score (117) 17.1 ± 7.6 19.5 ± 6.9 <0.05
Hyposmia 26 (86.7%) 65 (74.1%) 0.21
UPDRS-III (142) 21.2 ± 12.0 19.7 ± 11.8 0.51
PIGD phenotype (141) 31 (70.5%) 45 (46.4%) <0.01
MoCA Score (134) 24.7 ± 3.2 25.1 ± 3.9 0.28
STAI (36)
 State 40.2 ± 7.1 34.6 ± 10.5 0.06
 Trait 38.6 ± 9.8 36.9 ± 12.6 0.48
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Values provided are number (%) or mean ± SD, as appropriate, unless otherwise stated.

RBD+=total RBDSQ score ≥5 (non-PD) and total RBDSQ score ≥6 (PD).; LRRK2-PD = LRRK2 G2019S mutation carriers with PD; IPD = idiopathic PD; UPSIT = University of Pennsylvania Smell Identification Test; Hyposmic = UPSIT percentile score < 15; UPDRS-III = Unified Parkinson Disease Rating Scale Motor Score; PIGD = Postural Instability and Gait Disorder subtype; MoCA = Montreal Cognitive Assessment; STAI = State-Trait Anxiety Inventory

There was no difference between the IPD and LRRK2-PD groups in current use of medications implicated as triggers of RBD, such as MAO-B inhibitor, tricyclic antidepressant (TCA), or selective serotonin reuptake inhibitor (SSRI) (IPD=82.6% vs. LRRK2-PD=73.9%, p=0.07) or those used for treatment of RBD, such as clonazepam (IPD=6.9% vs. LRRK2-PD=7.8%, p=0.80). In a GEE model limited to patients with PD adjusting for reported current use of trigger or treatment medication, age, site, gender, and disease duration, there was no change in the direction or the overall magnitude of the odds ratio for abnormal RBDSQ between LRRK2-PD and IPD.

DISCUSSION

RBD should meet several criteria to serve as a marker to detect a highly at-risk LRRK2-PD subset: it should 1) have easily applied and relevant instruments that discern the marker and these should 2) be abnormal in at least a subset of affected individuals in the disease of interest (LRRK2-PD), 3) be abnormal early in disease, and 4) be present in at least a subset of NMC prior to phenoconversion. While PSG is the gold-standard, the RBDSQ is readily applied and inexpensive and, in our study, the proportion of IPD with RBD was similar to another study18. However, while present in LRRK2 carriers, abnormal RBDSQ scores occurred in only one of the 19 LRRK2-PD with early disease, compared with 14/41 IPD (p=0.05). This supports that even in a cross-sectional LRRK2 study, abnormal RBDSQ is not a frequent feature in early LRRK2-PD. Further, the paucity of NMC who meet criteria for RBDSQ does not allow for assessment of a subcluster, which might be present in a small subgroup of NMC close to phenoconversion.19

The decreased frequency of abnormal RBDSQ scores in LRRK2-PD compared with IPD is consistent with its infrequency in certain genetic forms of PD. RBD is more common in IPD with neuropsychological deficits,20–24 akinetic-rigid disease,25–27 orthostatic changes,3, 28 and greater heart-rate variability29. With the exception of MoCA, which did not correlate with abnormal RBDSQ scores in this cohort, we observed similar trends suggesting possible subgroups relating RBD and non-motor features in both IPD and LRRK2-PD. In the IPD group, RBDSQ was associated with worse olfaction and PIGD phenotype. In the LRRK2-PD group, RBD was associated with more prominent trait (p<0.01) and state (p=0.03) anxiety. 30,31,19

There are several limitations to our study. Measurement of RBD by questionnaire does not capture RBD in the same manner as the gold standard polysomnography, and the RBDSQ is just one of several validated questionnaires, each with their respective strengths. Additionally, we did not require sleep partners to participate in all questionnaires, and the information regarding whether a bed partner participated in the questionnaire was not consistently noted, so that a proportion of cases might be underestimated or mis-classified. However, in support of our methodology and findings, our results are consistent with the trends seen using other assessment methods, where the rates of RBD were lower in LRRK2-PD (range: 11.1–21.2%) compared to IPD (range: 29 to 42%)32–34. Further, the RBDSQ performs well overall, particularly with normal volunteer controls, with 96% sensitivity and 92% specificity8. This group is more similar to NMC, NC-F and controls than a symptomatic RBD group would be. Only one study reports the gold standard for RBD, PSG, and reports six cases of LRRK2-PD with RBD14. However rates were not compared between LRRK2-PD and IPD. Further, PSG is time-intensive and expensive. We cannot exclude that rates might differ were PSG utilized, as clinical reports may underreport as many as half of the cases36, 37.

In summary, RBD, as measured by RBDSQ, is not a common feature of early LRRK2 PD and LRRK2 gene carrier status overall. Longitudinal study with PSG will facilitate a more precise assessment of the association between RBD and LRRK2 expression over time.

Acknowledgments

Funding: This study was funded by the Michael J Fox Foundation for Parkinson’s Research, the National Institute of Health (through Grant Numbers K02-NS073836, R56NS036630, K02NS080915, NS050487, NS060113, UL1 TR000040, UL1 RR024156 and NINDS 10628097) as well as by grants from the Tel Aviv Sourasky Medical Center Grant of Excellence, Khan Foundation, and the Israel Science Foundation Heritage Legacy. The funding sources had no involvement in the design, interpretation or writing of this manuscript.

We thank the participants of this project for their invaluable participation and the staff of the AJ LRRK2 consortium for their contribution:

Mount Sinai Beth Israel Medical Center, New York, NY : Vicki Lynn Shanker, MD; Mark Groves, MD; Christine Palmese, PhD; Erin Deegan, MD; Adam Drobnis, MD; Jeffrey Ratliff, MD; Lawrence Severt, MD; Naomi Lubarr, MD; Rivka Sachdev, MD; Amanda Pomerantz, BA

Columbia University, Columbia Presbyterian Medical Center, New-York, NY: Stanley Fahn, MD; Lucien Cote, MD; Paul Greene, MD; Cheryl Waters, MD; Pietro Mazzoni, MD, PhD; Blair Ford, MD; Elan Louis, MD MSc; Oren Levy, MD PhD; Ming Xin Tang, MD; Brian Rakitin, PhD; Ernest Roos, MD; Martha Orbe Riley, MD; Llency Rosado, MD; Carol Moskowitz, RNC; Tsvyatko Dorovski; Xinmin Liu, PhD; Sergey Kisselev, MS; Itsik Peer, PhD; Vladimir Vacic, PhD

Tel Aviv Sourasky Medical Center, Tel Aviv, Israel: Yaacov Balash, MD; Shabtai Hertzel, MD; Ariella Hillel, RN; Ziv Gan Or, PhD; Hila Kobo, MSc; Noa Bregman, MD; Meir Kestenbaum, MD; Talma Hendler, MD, PhD; Hedva Lehrman, MD; Einat Even Sapir, MD, PhD; Maayan Zelis, DMD; Michal Shtaigman, RN; Eti Shimony; Michaela Victor; Marina Grumberg; Ora Assais

Footnotes

Disclosures: The authors report no conflicts of interest relating to this study

Authors’ roles: 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique

R.S-P. 1A, 1B, 1C, 2A, 2C, 3A, 3B

R.N.A. 1A, 1B, 3B

A.M. 1C, 3B

C.W. 2A, 2B, 2C, 3B

M.S. 2A, 2B, 2C, 3B

R.O. 1C, 2B, 2C, 3B

A.G. 1C, 2B, 3B

D.R. 1B, 1C, 3B

H.M-S. 1B, 1C

N.D. 1B, 1C

B.J. 1B, 1C

K.Y. 1B, 1C

L.O. 1B, 1C, 3B

L.C. 1B, 1C, 3B

A.O-U. 1A, 1B, 1C, 3B

K.M. 1A, 3B

N.G. 1A, 1B, 1C, 3B

S.B.B. 1A, 1B, 1C, 3B

Disclosure: The authors report no conflicts of interest. Dr. Saunders-Pullman, Dr. Alcalay, Dr. Mirelman, Dr. Wang, Dr. San Luciano, Mr. Ortega, Ms. Glickman, Ms. Raymond, Ms. Mejia-Santana, Ms. Doan, Ms. Johannes, Ms. Yasinovsky, Dr. Ozelius, Dr. Clark, Dr. Orr-Urtreger, Dr. Marder, Dr. Giladi and Dr. Bressman have nothing to disclose.

Dr. Saunders-Pullman served on the Scientific Advisory Board of the Dystonia Medical Research Foundation. She receives research support from the NIH (K02 NS073836), the Michael J Fox Foundation for Parkinson’s Research, the Bachmann-Strauss Dystonia and Parkinson’s Foundation, the Marcled Foundation, and the Genzyme Generations Program.

Dr. Alcalay receives research support from the NIH (K02NS080915), the Parkinson’s disease Foundation, the Smart Foundation and the Michael J Fox foundation.

Dr. Ozelius receives salary support from NIH [NS037409, NS075881, DC011805]. She is a current member of the scientific advisory boards of the National Spasmodic Dysphonia Association, the Benign Essential Blepharospasm Research Foundation and Tourette Syndrome Association, Inc. Dr. Ozelius receives royalty payments from Athena Diagnostics related to patents.

Dr. Clark receives research support from the NIH [NINDS #R01 NS060113 (principal investigator), NINDS #R01 NS073872 (Co-principal investigator), NIA #5P50AG008702(Project 3, principal investigator), and NINDS #NS36630 (coinvestigator) and 2P50NS038370-11 (Co-Investigator)], and the Parkinson’s Disease Foundation (principal investigator) and the Michael J Fox Foundation (co-investigator).

Dr. Bressman serves on the advisory boards of the Michael J. Fox Foundation, the Dystonia Medical Research Foundation, the Bachmann Strauss Dystonia and Parkinson’s Foundation, and the Board of We Move. She has consulted for Bristol Meyer Squibb. She has received research support from the Michael J. Fox Foundation, National Institutes of Health (NIH), and Dystonia Medical Research Foundation.

Dr. Marder receives research support from the NIH [#NS036630 (PI), 1UL1 RR024156-01(Director PCIR), PO412196- G (Co-I), and PO412196-G (Co-I)]. She received compensation for participating on the steering committee for U01NS052592 and from the Parkinson Disease Foundation, Huntington’s Disease Society of America, the Parkinson Study Group, CHDI, and the Michael J Fox foundation.

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