More Than Rapid Eye Movement Sleep Behavior Disorder: Sleep Differences in Parkinson’s Disease LRRK2 and GBA Genotypes

Article information

J Sleep Med. 2025;22(2):82-90

Publication date (electronic) : 2025 August 27

doi : https://doi.org/10.13078/jsm.250016

Adina Wise¹, Deborah Raymond¹, Mengxi Yang^,1, Amy Astefanous¹, Abby Cohen¹, Melba Beltre¹, Casey Young¹, Barbara Plitnick², Susan B. Bressman¹, Mariana G. Figueiro², Rachel Saunders-Pullman^,1

¹Department of Neurology, Icahn School of Medicine at Mount Sinai and Mount Sinai Beth Israel, New York, NY, USA

²Light and Health Research Center, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Address for correspondence Rachel Saunders-Pullman, MD, MPH Department of Neurology, Icahn School of Medicine at Mount Sinai and Mount Sinai Beth Israel, 10 Union Square East, Suite 5J, New York, NY 10003, USA Tel: +1-212-844-8719 Fax: +1-212-844-8710 E-mail: Rachel.Saunders-Pullman@mountsinai.org

Mengxi Yang, MPH Department of Neurology, Icahn School of Medicine at Mount Sinai and Mount Sinai Beth Israel, 10 Union Square East, Suite 5J, New York, NY 10003, USA Tel: +1-212-844-8719 Fax: +1-212-844-8710 E-mail: Mengxi.Yang@mountsinai.org

Received 2025 May 1; Revised 2025 July 22; Accepted 2025 August 7.

Abstract

INTRODUCTION

Sleep disturbances may affect over 80% of patients with Parkinson’s disease (PD) [1]. They include insomnia, sleep fragmentation, excessive daytime somnolence, circadian rhythm disorders, restless leg syndrome, periodic leg movements and rapid eye movement (REM) sleep behavior disorder (RBD) [1,2]. While PD is characterized by the loss of nigral dopaminergic neurons in all cases, there is some heterogeneity among those with PD with regard to accompanying Lewy body/Lewy neurite accumulation [3]. The identification of genetic etiologies has helped to better understand genetic PD subtypes, particularly as these are related to the underlying pathophysiology.

Variants in glucosylceramidase beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic contributors to PD, and represent relative extremes on a pathologic spectrum: PD associated with GBA1 mutations (GBA PD) has a higher burden of cortical Lewy body/Lewy neurites; in contrast, LRRK2 PD demonstrates isolated nigral degeneration without Lewy body accumulation in approximately one third of cases, and both nigral degeneration and Lewy bodies in the remaining [3]. Thus, evaluation of these two genetic cohorts may improve our understanding of the mechanistic underpinnings of sleep disorders in PD, particularly those that may be related to Lewy body disease. RBD has been extensively studied in PD and is more frequent in GBA PD than LRRK2 PD, as would be expected given its association with a high degree of alpha-synuclein aggregation and Lewy body deposition [4]. However, other sleep features, including sleep duration, wake after sleep onset (WASO) and time of sleep onset, are less well studied in these cohorts. As an early step in characterizing non-REM sleep-related features, we evaluated ambulatory actigraphy and sleep questionnaires in our unique LRRK2 PD and GBA PD cohorts. Understanding these may lend clues that will lead to the better development of effective and personalized interventions.

METHODS

RESULTS

Demographics and clinical features

Thirty-three women and 46 men with PD enrolled in the study, including: 18 LRRK2 PD (44% women), 22 GBA PD (45.4% women), 37 iPD (37.8% women), and 2 LRRK2 GBA PD (50% women). The mean disease duration among participants was 10.56±5.15 years. Participants with LRRK2 PD were significantly older, later age at disease onset, and better MoCA scores (Table 1). Compared to GBA PD and iPD, individuals with LRRK2 PD were also less likely to be hyposmic and similarly less likely to score below the fifteenth percentile on the UPSIT (LRRK2 PD 44%, GBA PD 95%, iPD 95%; p<0.001) (Table 1).

Table 1.

Summary of demographic and clinical characteristics among genetic PD groups

Actigraphy data

All groups had median sleep start times that began after 11:00 PM, with start times across all groups at 11:44 PM (Table 2, Fig. 1). LRRK2 PD median sleep start time was 11:45 PM, with a range from 9:41 PM to 2:59 AM; GBA PD median sleep start time was 11:26 PM, with a range from 9:48 PM to 2:09 AM; and the iPD median sleep start time was 11:47 PM, with a range from 8:04 PM to 4:21 AM (Table 2).

Table 2.

Sleep start times by genetic PD group

Fig. 1.

Histogram of sleep onset categorized by genetic group. Time of sleep onset at baseline according to genetic status; X axis: time in minutes; Y axis: individual participants. Mean sleep start time was after 11:00 PM for all groups with a mean start time across all groups of 11:44 PM. LRRK2 median sleep start time was 11:45 PM, with a range from 9:42 PM to 2:59 AM; GBA1 median sleep start time was 11:26 PM, with a range from 9:48 PM to 2:09 AM; and the iPD median sleep start time was 11:47 PM, with a range from 8:05 PM to 4:21 AM. GBA, GBA gene encoding glucocerebrosidase; LRRK2, leucine-rich repeat kinase 2 gene; PD, Parkinson’s disease.

In univariate analyses (excluding the LRRK2 GBA PD group), participants with LRRK2 PD variant had fewer minutes of WASO than those with iPD and GBA PD (p=0.037) (Table 3). Although the LRRK2 PD group also had longer sleep time, longer sleep duration, shorter sleep latency, and less nap time, these results were not statistically significant. There were no differences in the WASO, sleep time and duration, nap time or sleep start time between the iPD and GBA PD groups.

Table 3.

Sleep actigraphy measures by genetic PD group (unadjusted)

In the regression analyses adjusting for age, disease duration and gender with iPD as the reference group, LRRK2 PD status was associated with higher percent sleep (5.4%; 95% CI: 1.6 to 9.2; p=0.006), higher sleep efficiency (6.3%, 95% CI: 0.66 to 12; p=0.029) and reduced WASO (-25 minutes; 95% CI: -41 to -9.8; p=0.002) (Table 4). GBA PD did not differ from iPD in these measurements. No significant differences were noted between the genetic groups in sleep duration, sleep time or onset latency.

Table 4.

Regression results modeling relationship between genetic status and actigraphic sleep measures

In the analyses assessing factors related to sleep features, continuous MoCA scores were associated with WASO and percent sleep. Specifically, a 1-point increase in MoCA was associated with a 1.8-minute (95% CI: -3.3 to -0.26) decline in WASO and a 0.37-percent (95% CI: 0.031 to 0.74) increase in sleep percentage. A higher LEDD was also associated with a decline in sleep duration (b=-0.05, 95% CI: -0.09 to -0.01), with 1 mg of LEDD associated with a -0.05 minute decline in sleep duration, unadjusted for other variables (Supplementary Table 1 in the online-only Data Supplement).

Subjective sleep questionnaires

Individuals with iPD were most likely to endorse question 1 on the Mayo Sleep Questionnaire and report acting out their dreams (71%), followed by those with GBA (55%) and those with LRRK2 PD (18%) (p<0.001) (Table 5). No other statistically significant differences were identified in subjectively reported measures of mood and sleep (Table 5).

Table 5.

Questionnaire measures of sleep outcomes and mood

DISCUSSION

Our study of baseline sleep characteristics in GBA PD, LRRK2 PD and iPD identified significant differences in baseline sleep features among genetic subgroups, as well as important trends in overall sleep patterns. Notably, none of the genetic cohorts demonstrated an overall phase advance, which has been previously reported in patients with PD on dopaminergic therapy [19].

Furthermore, individuals with LRRK2 PD had better sleep overall, as evidenced by less time awake after falling asleep and a higher percentage of time asleep relative to the iPD and GBA PD groups. In regression analyses, after adjusting for age, age at onset, and gender, LRRK2 PD status was also associated with higher sleep efficiency. Together, these results suggest that individuals with LRRK2 PD experience less fragmented overnight sleep than those with iPD or GBA PD and that therapies aimed at sleep improvement may target these groups differently.

Exploration of the most common genetic subtypes of PD, those associated with variants in GBA1 and those with LRRK2 variants, revealed differences in phenotypes with regard to both motor and non-motor symptoms [20,21]. While GBA PD is associated with an earlier age of onset, greater cognitive dysfunction and more rapid motor progression than iPD, LRRK2 PD is associated with an older age of onset, largely preserved cognition and overall slower disease progression [21,22].

Fragmented sleep has previously been cited as the most common nocturnal sleep disorder in PD, with estimates suggesting that approximately 50%–75% of the PD population is affected by interrupted sleep patterns [23]. Our study is the first to reveal differences in the prevalence of sleep fragmentation among genetic PD subgroups.

Sleep fragmentation is associated with a wide range of poor health outcomes, including decreased insulin sensitivity, cognitive decline, mood symptoms, inattention, cerebral arteriolosclerosis, and subcortical stroke [24]. In mice, sleep fragmentation has additionally been associated with glucose intolerance and an increase in inflammatory markers, as well as impaired endothelial dysfunction and morphological vessel changes [25]. The biological mechanisms underlying the fragmentation of sleep remain incompletely understood; however, Lim et al. [26] showed that, in older adults, sleep fragmentation is associated with a loss of galanin-producing neurons in the intermediate nucleus of the hypothalamus.

Recognizing that certain genetic subgroups of patients with PD are more susceptible to sleep fragmentation has important implications for the management and prevention of active clinical diseases. Our data suggest that people with PD and known GBA variants, as well as those with iPD, should be actively monitored for sleep disorders, including sleep fragmentation, and interventions aimed at improving sleep quality and quality of life should be offered. Light therapy is a low-cost, low-risk method for improving sleep among patients with PD and has been shown to improve sleep fragmentation [27,28].

A greater burden of actigraphically measured sleep fragmentation has also been found to be correlated with an increased burden of Lewy bodies and substantia nigra neuron loss in postmortem neuropathology in individuals who were not diagnosed with PD at the time of death [29]. These findings suggest that sleep fragmentation may contribute to PD pathology and/or may be a useful marker of prodromal disease [30].

Most previous studies of sleep differences among genetic PD subgroups have focused on the presence and/or severity of RBD. In a quantitative meta-analysis, Huang et al. [4] analyzed 40 reports of sleep disturbance in genetic PD subtypes, including 17 studies focused on GBA, 25 on LRRK2 and 7 on PRKN (some overlapping). RBD was the only evaluated sleep-disorder outcome in 21 of the examined studies. Using random-effects meta-analysis, they found that the risk of RBD was higher among GBA carriers with PD and lower in LRRK2 G2019S carriers with PD (but not in those with LRRK2 G2385R variants). While in our present study, a significantly higher percentage of participants in the iPD group reported RBD-like symptoms relative to the GBA PD group, we did not perform polysomnography (PSG), which would better assess RBD.

As individuals with LRRK2 PD generally experience a milder course and slower disease progression than those with GBA PD and iPD [22,30], it is not surprising that this group may also have more continuous, and therefore more restful, sleep. Impaired sleep has been proposed as a causative mechanism in neurodegenerative diseases, and in PD, difficulties with sleep may predate the onset of motor symptoms [31-33]. This raises the question of whether the relative preservation of high-quality sleep in LRRK2 PD may contribute to the less severe cognitive and motor phenotypes associated with this genetic subgroup [20,22].

In addition, these findings indicate a relationship between alpha-synuclein, genetic PD subgroups and sleep. As noted, the burden of alpha-synuclein is generally lower in individuals with LRRK2 PD and the relationship between alpha-synuclein aggregation phenotypes and RBD is well-established [34,35]. Though associations between alpha-synuclein and other sleep disorders commonly seen in PD have been less extensively explored, it has been theorized that that the build-up of alpha-synuclein may lead to dysfunction among “sleep-control neurons” of the laterodorsal tegmentum and the pedunculopontine tegmentum, thereby resulting in sleep disorders that may manifest years to decades before bradykinesia and tremors and/or rigidity [36]. Since RBD has not been demonstrated in prodromal LRRK2 disease, it is postulated that these mechanisms are less prevalent in this group. Additional studies, which did not identify correlations between alpha-synuclein levels and clinical symptoms, have also found that excessive daytime sleepiness (EDS) [33] and restless leg syndrome [37] are not only prevalent in PD, but may precede motor symptoms, further emphasizing the need for at-risk individuals to be monitored and treated for sleep disorders.

While we did not collect cerebrospinal fluid (CSF) samples in the present study and were thus unable to directly evaluate synuclein seeding, olfactory performance may serve as a surrogate for the absence of Lewy body pathology [38]. Indeed, clusters of olfactory performance have been demonstrated in LRRK2 [39] and their relative distribution is correlated with the overall frequency of isolated nigral degeneration and nigral degeneration and Lewy bodies [3]. Thus, we performed post hoc analyses within the LRRK2 PD group. Although an overall association between hyposmia and sleep time was not demonstrated (Supplementary Table 2 in the online-only Data Supplement), a sizeable cluster of those who were normosmic had longer sleep times and sleep durations than all LRRK2 PD participants with impaired olfaction. Specifically, among LRRK2 PD participants, half who were normosmic (Supplementary Fig. 1 in the online-only Data Supplement) had sleep durations greater than 480 minutes and sleep times greater than 450 minutes. None of the LRRK2 PD participants with hyposmia had sleep durations greater than 480 minutes or sleep times greater than 465 minutes.

Similar to recently published data from the Parkinson’s Progression Markers Initiative [40], we found no significant differences in scores on the EDS among those with LRRK2 PD, GBA PD or iPD. Of interest, in our study and others [41], there are discrepancies between subjective reports of sleep quality on sleep-related measures and objective data obtained through actigraphy and/or PSG. Although individuals with LRRK2 PD performed better on many objective measures of sleep, 55% had high scores on the PDSS and 75% had high scores on the FACIT-F. These results are consistent with another study that reported high levels of subjectively reported sleep impairment in the LRRK2 PD population [42]. Since a relationship between LRRK2 variants and mood disorders has been previously identified [43], the influence of depression, anxiety, and other psychiatric conditions on subjective reports of poor sleep is worthy of further consideration.

Notably, in contrast to other reports, the mean sleep start time for all groups was 11:00 PM. This is particularly noteworthy, as a prior study exploring the relationship between sleep and PD found that PD patients on dopaminergic therapy exhibit a significantly earlier nocturnal melatonin peak than medication-naïve PD patients [19]. These results have previously been used to justify the administration of lighting therapy for PD patients in the evening; however, our results suggest that morning light exposure may be preferable. It should be noted that we did not measure the circadian phase in our study, but only sleep onset times, which can be influenced by social activities. Furthermore, Bordet et al. [19] measured melatonin acrophase, but not dim light melatonin onset. It is possible that the phase angle of entrainment between sleep onset times and the melatonin acrophase is shortened in PD patients [44,45]. Future studies should investigate this hypothesis further. In addition, a recent study by Obayashi et al. [2] found that patients with PD who experienced greater daytime light exposure and lower nighttime light exposure had better objective measures of sleep, including higher sleep efficiency and shorter WASO.

The present study has a number of limitations. Firstly, the relatively small sample size, particularly within genetic subgroups, limits the statistical power and generalizability of the findings. Larger cohorts, which are difficult to construct, are needed to confirm these results and to detect subtle differences in sleep characteristics among genetic PD subgroups. Another potential limitation was that the groups were not matched for mean age or disease duration. In our study cohort, the mean age of iPD patients (59.70 years) was between that of GBA PD (60.18 years) and LRRK2 PD (73.17 years). As anticipated, iPD patients were significantly older than those with GBA PD (p<0.001) but, although younger than LRRK2 PD patients, this difference was not significant (p=0.29). Similarly, while between that of LRRK2 PD and GBA PD, mean disease duration in iPD (10.74 years) was not significantly different from LRRK2 PD (11.65 years, p=0.56) nor GBA PD (8.85 years, p=0.15).

An additional limitation is that the evaluation of CSF synuclein seeding may help disentangle the contribution of alpha-synuclein pathology to the non-RBD sleep abnormalities that we have described. Alternatively, the assessment of actigraphy measures in LRRK2 cohorts, in combination with CSF seeding data, could further address this question.

There were also limitations in the sleep assessments. While actigraphy provides reliable objective data on sleep patterns, it is less precise than PSG in diagnosing specific sleep disorders, including RBD, and in evaluating the characteristics of sleep and sleep-disordered breathing. The absence of PSG in the present study limited our ability to identify these disorders and their underlying mechanisms. Another limitation was that we did not formally assess obstructive sleep apnea (OSA). The groups did not differ in body mass index (BMI), which is associated with a higher rate of OSA; however, OSA may also be associated with a normal BMI. Therefore, we could not determine the extent to which WASO was influenced by OSA without specific measurements. Subjective assessments of sleep quality and mood symptoms were obtained through validated questionnaires but may be subject to recall bias. The observed discrepancies between subjective and objective sleep measures underscore the need for multimodal evaluation in future research.

Our study highlights significant differences in sleep fragmentation and baseline sleep characteristics among genetic subgroups of PD, specifically in individuals with LRRK2 PD, GBA PD, and iPD. Participants with LRRK2 PD demonstrated better overall sleep quality, with higher sleep efficiency, reduced WASO and a greater percentage of time asleep than the GBA PD and iPD groups. These findings suggest that LRRK2 PD is associated with less fragmented and more restorative sleep, which aligns with the milder disease course observed in this genetic subgroup. Importantly, our results support the need for tailored clinical approaches to address sleep disturbances in genetic subtypes of PD.

Supplementary Materials

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