Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson’s Disease

Abstract

BackgroundIdiopathic Parkinson’s disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined.ObjectiveTo evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients.MethodsThe presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated.ResultsUniversity of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination.ConclusionNeuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.

REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers

“…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 misclassified. 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 with IPD (range, 29%‐42%) . Furthermore, the RBDSQ performs well overall, particularly with normal volunteer controls, with 96% sensitivity and 92% specificity .…”

“…The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) is one such questionnaire. In a smaller group of LRRK2‐PD, a trend was seen for RBDSQ abnormalities to be less frequent in LRRK2‐PD than IPD . Furthermore, in a subset of the population evaluated here, continuous RBDSQ scores did not differ between carriers without PD (nonmanifesting carriers [NMC]) and family members without PD (noncarrier family members) .…”

Motor and nonmotor heterogeneity of LRRK2‐related and idiopathic Parkinson's disease

“…However, the accuracy of the RBDSQ for RBD is not 100%, and it is possible that using polysomnography, the gold standard diagnostic tool for RBD, might have led to different results. A number of previous studies have noted that olfactory function is better in LRRK2-associated PD than iPD 1,4,6,[10][11][12][13] and we have found the same.…”

“…1 Establishing differences between LRRK2-associated PD and idiopathic PD (iPD) may provide clues to the molecular pathogenesis of specific features of Parkinson's disease in that those that differ may relate to the function of the LRRK2. The phenotype of LRRK2-related PD has been described as broadly consistent with idiopathic Parkinson's disease, but the phenotype of LRRK2-associated PD has been described as more slowly progressive from the motor perspective, 1 with less autonomic, 2-6 cognitive, [1][2][3][7][8][9] and olfactory 1,4,6,[10][11][12][13] dysfunction. On the other hand, a high frequency of anxiety and depressive symptoms has been noted.…”

Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease

“…On the one hand, hyposmia has been shown to be approximately 30% less frequent in LRRK2-PD than in idiopathic PD. 3,16 On the other hand, asymptomatic carriers of the LRRK2 G2019S mutation are not more hyposmic than their relative noncarriers and healthy controls. 3,17 Our data, coming from a longitudinal study, also suggest that olfaction loss is not common at the earliest stages of LRRK2 G2019S-associated PD and therefore is not a good predictor of phenoconversion to PD at the premotor stage.…”