Abstract
Background:
The asymmetry of motor manifestations present in Parkinson’s disease (PD) suggests the existence of differences between both hemispheres. As a consequence, this asymmetry might contribute to different PD clinical phenotypes.
Objective:
To study the relationship between motor symptom laterality with motor, non-motor symptoms (NMS), freezing of gait (FOG), and quality of life (QoL) impairment in PD.
Methods:
In this cross-sectional study, we measured motor symptoms severity and complications with the Unified Parkinsons’ disease Rating Scale (UPDRS), FOG with the FOG questionnaire, QoL with the 39-item PD Quality of Life Questionnaire Summary Index, and NMS with the NMS, Visual Analogue Scales for Pain and Fatigue, Beck Depression Inventory-II, Impulsive-Compulsive Disorders, and PD Sleep and Cognitive Rating scales. We defined left and right motor laterality using the UPDRS part III. We used comparative, regression, and effect size analyses to evaluate the impact of asymmetry on motor and NMS, FOG, and QoL.
Results:
342 left (LPD) and 310 right (RPD) patients, with a mean age of 62.0±8.8 years, were included. In multivariate regression analysis, LPD was associated with a greater motor (OR = 1,50, 95% CI 1.02–2.21), FOG (OR = 1.56, 95% CI 1.01–2.41), and overall NMS impairment (OR = 1.43, 95% CI 1.001–2.06), and better QoL (OR = 0.52 95% CI 0.32–0.85). Overall, only a mild effect size was found for all comparisons in which significant differences were present.
Conclusion:
In this large multicenter study, motor symptom laterality seems to carry a mild but significant impact on PD clinical manifestations, and QoL.
INTRODUCTION
Asymmetry is an inherent characteristic of the human brain that has been confirmed in both structure and function [1]. This lateralization process is believed to reflect evolutionary, developmental, hereditary, and pathological mechanisms [1]. In the context of neurodegeneration, several conditions have been associated with brain asymmetries, including Alzheimer’s disease [2], Wilson’s disease [3], and Huntington’s disease [4]. This lateralization is especially evident in Parkinson’s disease (PD), which typically presents with asymmetric tremor, rigidity, and bradykinesia. The typical symptom lateralization at disease onset is observed not only in the common sporadic presentation of PD but also in monogenic subtypes of the disease [5]. Moreover, the symmetric onset of symptoms is considered as a red flag against the diagnosis of PD [6], and has been associated with lower survival in patients with PD [7].
Previous studies using brain imaging and neuropathological data have confirmed asymmetry in PD [8]. However, the mechanisms involved in PD asymmetry have not yet been elucidated. Plausible explanations include inborn variations in the number of nigral dopaminergic neurons of each hemisphere, leading to an asymmetric dopamine distribution, with higher levels of dopamine in the left striatum [9], and differences in degeneration susceptibility of each substantia nigra [10]. Other possible mechanisms include handedness, with left hemisphere predilection for neurodegeneration as observed in neuroimaging studies [11], or asymmetric injury of the blood-brain barrier [10].
The intriguing asymmetry of motor manifestations present in PD suggests the existence of functional, anatomic, or neurochemical differences between both hemispheres. Besides, an asymmetric dopaminergic pathway to the limbic, and the neuroendocrine system, might hypothetically condition the severity of extra-nigrostriatal non-motor symptoms (NMS) manifestations [12]. In contrast, there is some evidence that debates against this concept. In rest-tremor predominant PD, neuroimaging studies have shown a significantly lower uptake in the striatum ipsilateral to the rest-tremor compared to akinetic-rigid PD patients, suggesting damage of crossed dopaminergic fibers from the substantia nigra to thalamus [13].
Over the last decades, there is a growing interest in the analysis of variability in clinical presentation reflecting the existence of several subtypes of and heterogeneous progression in PD. The identification of subgroups of patients within PD has important implications for generating hypotheses on defining PD heterogeneity, etiopathogenic mechanisms, and treatments. The aim of this study is then to assess the relationship between motor symptom laterality with clinical variability in terms of motor, freezing of gait (FOG), NMS, and quality of life (QoL) impairment in a large, clinically well-characterized cohort of PD patients belonging to the Spanish COPPADIS-2015 study [14]. We hypothesize that the burden of motor and NMS would be higher in LPD compared to RPD.
METHODS
Design and sample characteristics
COPPADIS-2015 (Cohort of Patients with idiopathic Parkinson’s Disease in Spain, 2015) is an ongoing prospective, multicenter, non-interventional, 5-year follow-up study designed to analyze disease progression in a Spanish population of idiopathic PD patients [15]. In this study, clinical evaluations, serum biomarkers, genetic studies, and neuroimaging data are prospectively obtained. We present a cross-sectional study in which clinical data was obtained from the baseline evaluation of PD patients participating in the COPPADIS cohort, performed between January 2016 and October 2017. The methodology, including the inclusion and exclusion criteria used in COPPADIS-2015, has been previously published [15]. Briefly, in this study, we included non-demented patients diagnosed with idiopathic PD, according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria [16], aged between 30 and 75 years. We excluded patients with other severe and disabling concomitant non-neurological conditions, and receiving active treatment with continuous infusion of levodopa or apomorphine, and patients with deep brain stimulation at baseline.
Standard protocol approvals, registrations, and patient consents
For this study, approval was obtained from the appropriate Local and National Ethics Standard Committees. We obtained signed informed consent forms from all participants in the study before initiating the study. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios), as a post-authorization prospective follow-up study with the reference code COH-PAK-2014-01.
Outcome measures
PD sample and clinical characteristics
We collected information on sociodemographic aspects, factors related to PD, including disease duration from symptoms onset, and treatment. The levodopa (L-dopa) equivalent daily dosage (LEDD) was calculated using a standardized formula [17]. Patients’ evaluations included assessments of PD severity using the Hoehn & Yahr (HY) stage [18], off-state Unified Parkinson’s Disease Rating Scale (UPDRS) parts III (motor examination) and part IV (therapy complications) [19], and Freezing of Gait questionnaire (FOG-Q) [20]. We assessed NMS with the following rating scales: Non-motor symptoms Scale (NMSS) [21], Parkinson’s Disease Sleep Scale (PDSS) [22], Visual Analog Scale-Pain (VAS-Pain) [23], Visual Analog Fatigue Scale (VAFS) including physical and mental fatigue [24], mood and neuropsychiatric symptoms with the Beck Depression Inventory-II (BDI-II) [25], and the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS) [26]. Cognitive status was assessed with the Parkinson’s Disease Cognitive Rating Scale (PDCRS) [27], which included two sub-domains: frontal-subcortical PD-CRS (attention, working memory, Stroop test, phonemic, semantic, alternating, and verbal action fluencies, immediate and delayed verbal memory, clock drawing), and the posterior cortical PD-CRS (naming and copy of a clock). QoL life was measured using the 39-item Parkinson’s disease Quality of Life Questionnaire Summary Index (PDQ-39) [28].
Response to levodopa was defined as the percentage improvement in UPDRS motor scores with levodopa as [(OFF – ON motor UPDRS-III scores)/OFF UPDRS-III scores] x 100 [29], and PD motor subtype calculation [tremor vs. postural instability and gait difficulty (PIGD)] based on previous DATATOP studies [30].
Motor symptoms laterality definition
For this study, PD motor laterality was defined as having the predominant right (left hemisphere) or left (right hemisphere) motor symptoms using a formula based on the off UPDRS-III motor items at baseline visit [31]. To include the clinical spectrum of asymmetric PD patients, we considered two groups of patients, based on the following published definition: (1) Mild/Moderate right asymmetry (RPD) defined as having a quotient >1 and <3, by dividing the total score of right bradykinesia, tremor, and rigidity over the total score of the left side. The same formula, but for the left motor scores, was used to define mild/moderate left asymmetry (LPD); (2) Extreme right or left asymmetry, defined as having a quotient ≥3 by dividing the total score of right or left bradykinesia, tremor, and rigidity over the total score of the left or right side, respectively [30]. To avoid confusion, we excluded PD patients with an asymmetry quotient = 1 indicating symmetric impairment of motor symptoms.
Statistical analysis
Data were analyzed using the statistical package SPSS v. 25.0 (IBM, San Francisco, CA) for Windows. Statistical significance was set at p-value <0.05. We adopted case-wise deletions to deal with missing values. We performed parametric and non-parametric statistical analyses according to the normal distribution of the variables, verified by a one-sample Kolmogorov-Smirnov test. A descriptive analysis of the participants’ characteristics was performed in terms of frequencies (percentages) for categorical variables, means and standard deviation (SD) (normally distributed continuous variables), or medians and interquartile range (IQR) (non-normally distributed continuous variables). We performed exploratory group comparisons using independent t-tests (normally distributed continuous variables), Mann-Whitney tests (non-normally distributed continuous variables), and the χ2 and Fisher tests (categorical variables). To analyze the magnitude of the difference, we measured the effect size. For normally distributed variables with unequal groups, we used the Hedges’ g values [g = M1–M2)/SDpooled] (M = mean, SD = standard deviation) of 0.20–0.49 (weak), 0.50–0.79 (moderate), and≥80 (strong) [31]. For non-normally distributed variables, we used r-values = z/√ N (z = z value; N = Observation number) of 0.10–0.29 (weak), 0.30–0.49 (moderate), >0.50 (strong) [33].
Assuming that variables of interest like UPDRS-III, NMSS, and PDQ-39 scores did not follow the normal distribution, even after being log-transformed, we used adjusted, multivariate logistic regression analyses, to analyze the impact of PD motor laterality on motor, NMS, and QoL impairment. Dependent variables, including the UPDRS-III, FOG-Q, NMSS, and PDQ-39, were divided into two groups (mild-moderate vs. severe impairment), based on the median distribution of the corresponding rating scale scores, and adjusted for age, gender, LEDD, and PD duration.
RESULTS
PD sample characteristics
From January 2016 to October 2017, 681 PD patients from 35 centers in Spain were included. We excluded 32 (4.7%) subjects due to the presence of symmetric motor signs. Three hundred and ninety males (59.7%) and 263 females (42.7%) were included with a mean age of 62.0±8.8 years, and a PD duration of 5.3±4.2 years. Application of the asymmetry criteria yielded 419 patients in the mild-moderate asymmetric PD group (201 RPD, 218 LPD), and 233 patients in the extreme asymmetric PD group (109 RPD and 124 LPD). Mild-moderate asymmetric PD patients were older compared to the extreme asymmetric group (66.3±8.6 years vs. 60.7±9.4 years, p < 0.0001), had longer PD duration (6.0±4.5 years vs. 4.1±3.3 years, p < 0.0001), presented more frequently with a HY stage ≥3 [304 (84.6%) vs. 133 (63.9%), p < 0.0001)], and PIGD phenotype [168 (43.2%) vs. 70 (31.5%), <0.0001].
Asymmetry and PD motor, non-motor, quality of life, treatment response characteristics and effect size
Overall, the severity of mild-moderate (LPD vs. RPD), and extreme asymmetric patients (LPD vs. RPD), was not significantly different regarding the majority of variables, and both groups showed a similar response to levodopa (Table 1). However, compared to the RPD, the entire cohort of LPD patients scored worse in the UPDRS part III, Physical-VAFS, FOG-Q, and presented with a higher HY (Table 1). Within the NMSS (Table 1), only the scores of the sleep/fatigue domain were greater in the LPD compared to the RPD [RPD: 10.4 (2.08; 20.8) vs. LPD: 14.5 (4.1; 25.0), p = 0.004]. In terms of QoL, the PDQ-39 total score was similar in both groups, except for greater impairment in the activities of the daily living domain in the RPD compared to the LPD group [14.5 (4.1;25.0) vs. 12.5 (0.0;25.0), p = 0.004]. Hedges’ g and r calculations showed that, overall, only a mild effect size was found for all comparisons in which significant differences were present (Table 1).
Parkinson’s disease characteristics based on RPD vs. LPD motor laterality
Cases do not sum up due to missing cases in some variables. LPD, Left Parkinson’s disease; RPD, Right Parkinson’s disease. Values are expressed in means±standard deviation otherwise specified. *Values are expressed in medians (interquartile range). **Levodopa response was calculated in 126 LPD vs. 99 RPD (total group), 100 LPD vs. 82 RPD (mild-moderate group), and 26 LPD vs.17 RPD (extreme group). LEDD, L-dopa equivalent daily dosage; HY, Hoenh & Yahr; UPDRS, Unified Parkinson’s Disease Rating Scale parts II, III and part IV; FOG-Q, Freezing of Gait questionnaire; NMSS, non-motor symptoms, Non-Motor Symptoms Scale; PDSS, Parkinson’s Disease Sleep Scale; VAS-Pain, Visual Analog Scale-Pain; VAFS, Visual Analog Fatigue Scale including physical and mental fatigue, mood and neuropsychiatric symptoms; BDI-II, Beck Depression Inventory-II; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; PDCRS, Parkinson’s Disease Cognitive Rating Scale; PDQ-39, 39-item Parkinson’s disease Quality of Life Questionnaire Summary Index.
Multivariate regression analysis
According to the adjusted multivariate logistic regression analysis, LPD was associated with higher scores in the UPDRS-III (OR = 1.50, 95% CI 1.02–2.21), FOG-Q (OR = 1.56 (1.01–2.41), NMSS (OR = 1.43, 95% CI 1.001–2.06), and lower scores in the PDQ-39 (OR = 0.52, 95% 0.32–0.85) (Table 2).
Multivariate Logistic Regression
OR, odds ratio; CI, confidence interval; LPD, Left Parkinson’s disease; PD, Parkinson’s disease; LEED, levodopa equivalent daily dosage; UPDRS, Unified Parkinson’s disease Rating Scale; NMSS, Non-motor symptoms severity scale; B-value, Betta coefficient. aDependent variable: Unified Parkinson’s Disease Rating Scale, motor score (UPDRS-III) Off state (severe impairment). Model fitness (Hosmer & Lemeshow test p = 0.05; Nagelkerke R2 test p = 0.28). This model classified 69.9 % of the sample. bDependent variable Freezing of gait (FOG) (severe impairment). Model fitness (Hosmer & Lemeshow test p = 0.57; Nagelkerke R2 test p = 0.46). This model classified 75.7% of the sample. cDependent variable: Non-Motor Symptoms (NMS) (severe impairment). Model fitness (Hosmer & Lemeshow test p = 0.27; Nagelkerke R2 test p = 0.12). This model classified 63.3 % of the sample. dDependent variable: 39-item Parkinson’s disease Quality of Life Questionnaire Summary Index (PDQ-39) (severe impairment). Model fitness (Hosmer & Lemeshow test p = 0.36; Nagelkerke R2 test p = 0.57). This model classified 79.3 % of the sample.
DISCUSSION
In this large multicenter study, compared to the RPD group, patients with LPD presented with a mild but significant higher motor and overall NMS impairment, but on the other hand, better QoL. These results are in concordance with previous studies [34], in which LPD has exhibited a correlation with motor, NMS, and QoL, suggesting that the side of motor symptom onset may have prognostic implications.
Analyses of large sample studies [35] have shown that patients with PD present a marked motor laterality predominance on the UPDRS III scores, and this laterality persists over time [36]. However, the degree of laterality seems to decrease over time, most likely due to progressive neurodegeneration of both hemispheres [37]. Supporting the former hypotheses, we observed a lower degree of motor symptom asymmetry in older patients and with higher PD duration.
Interestingly, although LPD and RPD showed a similar levodopa response, LPD was associated with higher motor impairment, especially in patients with mild-moderate asymmetry. Although we do not have a compelling explanation for this observation, possible mechanisms could be: 1) RPD patients might have a higher dopaminergic neural reserve in the dominant hemisphere, allowing them to better cope with PD-related pathological changes, early in the disease, and therefore minimizing motor manifestations [38]; 2) the serotonin neural reserve in both hemispheres might compensate and contribute to the similar response to levodopa [39]; and 3) right-handed patients with LPD may be aware of their motor defects in the non-dominant hand later in the course of the disease, leading to delayed diagnosis and greater disease severity compared to RPD.
The design of our study allowed the measurement of NMS exhaustively in a large cohort of PD patients at different stages of the disease. Whereas we observed worse NMSS scores among LPD patients, especially in the sleep/fatigue domain compared to RPD, other studies have shown that RPD has a higher risk for hallucinations and sleep behavior disorder compared to the LPD [31, 41]. The reason for these contradictory results is still unclear, as well as the clinical relevance of the impact of motor laterality on NMS. The existence of contradictory and sparse literature definitions on NMS asymmetry highlights the difficulty of comparing the burden of NMS asymmetry without the presence of established biological markers.
In agreement with other studies [42], when LPD was compared to RPD, QoL was better preserved in the LPD group despite the higher motor and NMS burden in this group. In this regard, a better QoL in the LPD group could be related that the majority of the population is right-handed, and subsequently, they can perform better some aspects of the daily living activities with the dominant hand. A second explanation could be that in LPD, there is a decreased awareness of motor disturbances due to predominant right hemisphere impairment [41].
In this study, we recognize several limitations. Firstly, the limited interpretation of the clinical results of a heterogeneous disorder such as PD in a cross-sectional study; secondly, the difficulty in comparing our results with previous studies due to the use of different methodologies; and thirdly, the lack of correlation of motor laterality with neuroimaging and other biological markers, and post-mortem brain data. In PD studies analyzing the motor laterality, one of the most relevant issues is the definition of motor asymmetry. We recognize that by using UPDRS motor scores, there is a risk of misclassification, especially among PD patients presenting with mild asymmetry. Although we have applied a definition of asymmetry previously published [31], and followed a mathematical concept similarly used to define other motor phenotypes like PIGD, wearable technology will ideally help to define motor asymmetry more accurately. We are also aware of the lack of data on handedness in our study. The controversial relationship of the dominant hand with daily living activities impairment and motor disability in PD is still unclear. However, although it is still under debate, handedness is not associated with asymmetric dopaminergic function in healthy subjects [43], suggesting that handedness has a low impact on PD neurodegeneration.
Nevertheless, and despite the limitations mentioned above, this study presents the clinical profile of the motor laterality of one of the largest multicenter cohorts of PD patients at different stages of the disease. We included extensive, exploratory comparative and multivariate analysis in a database without any pre-specified hypotheses at the time of data collection, thus reducing sample selection bias. Finally, the longitudinal nature of this cohort study will allow us to analyze soon the impact and causality of PD motor symptom laterality on motor, NMS, and QoL over time.
In conclusion, the variability in phenotype presentation suggests the existence of several PD subtypes within this heterogeneous disorder. In the present study, we have observed that motor symptom laterality seems to carry a mild but significant impact on PD clinical manifestations and QoL. However, a validated definition of PD motor and non-motor symptoms asymmetry correlated with biological data in independent cohorts of patients, is still required to confirm these results.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
E. Cubo: has received honoraria for educational presentations by Abbvie, and travel grants from Allergan, Boston, Abbvie.
P. Martínez-Martín has received Honoraria for educational/advise presentations by Editorial Viguera; International Parkinson and Movement Disorder Society; Air Liquide, Abbvie, and HM Hospitales Madrid. License fee payments for the King’s Parkinson’s Disease Pain scale.
D. Santos-García D. has received honoraria for educational presentations and/or advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva.
