Stephanie M. van Rooden

The Identification of Parkinson's Disease Subtypes Using Cluster Analysis: A Systematic Review

The clinical variability between patients with Parkinsons disease (PD) may point at the existence of subtypes of the disease. Identification of subtypes is important, since a focus on homogeneous groups may enhance the chance of success of research on mechanisms of disease and may also lead to tailored treatment strategies. Cluster analysis (CA) is an objective method to classify patients into subtypes. We systematically reviewed the methodology and results of CA studies in PD to gain a better understanding of the robustness of identified subtypes. We found seven studies that fulfilled the inclusion criteria. Studies were limited by incomplete reporting and methodological limitations. Differences between studies rendered comparisons of the results difficult. However, it appeared that studies which applied a comparable design identified similar subtypes. The cluster profiles “old age‐at‐onset and rapid disease progression” and “young age‐at‐onset and slow disease progression” emerged from the majority of studies. Other cluster profiles were less consistent across studies. Future studies with a rigorous study design that is standardized with respect to the included variables, data processing, and CA technique may advance the knowledge on subtypes in PD.© 2010 Movement Disorder Society

Nighttime sleep problems and daytime sleepiness in Parkinson's disease.

Our objective is to evaluate nighttime sleep problems (NSP) and daytime sleepiness (DS) in patients with Parkinsons disease (PD) compared to controls, and to assess relations with demographic, disease‐related, and clinical characteristics in patients. NSP and DS were evaluated with the SCOPA‐SLEEP questionnaire in PD patients and controls. In patients, other disease‐related and clinical characteristics were also evaluated. Four hundred twenty PD patients [mean (SD) age 61.1 (11.5) years] and 150 controls [mean (SD) age 60.9 (9.9) years] participated in the study. Compared to controls, a significantly greater proportion of patients had excessive DS (EDS) (43 vs. 10%), excessive NSP (ENSP) (27 vs. 9%), or used sleep medication (17 vs. 12%). Difficulties with falling asleep were similar in both groups. In both patients and controls, women experienced more NSP than men. In patients, depressive symptoms accounted for 21% of NSP variance and was the major contributor to the total explained variance (30%). Furthermore, NSP were related to dopamine‐agonist and levodopa dose, whereas DS was related to age, dopamine‐agonist dose, and disease severity. NSP and DS occur frequently in PD, with EDS being reported more commonly than ENSP. No strong relations were found between DS and demographic or clinical variables. The strong relation between NSP and depressive symptoms in PD calls for future studies to explore the nature of this relation.

Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease†

Early onset Parkinsons disease (EOPD) has been associated with mutations in the Parkin, DJ‐1, PINK1, LRRK2, and SNCA genes. The aim of this study is to assess the contribution of these genes in a Dutch EOPD cohort and the phenotypic characteristics of the mutation carriers. A total of 187 unrelated Dutch EOPD patients (age at onset ≤ 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ‐1, and PINK1 by direct sequencing and gene dosage analysis. Additionally, analysis of the A30P mutation and exon dosage of SNCA and sequencing of exons 19,31,35,38,41, and 48 of LRRK2 was performed. Pathogenic variations could explain disease in 4% (7 of 187) of the patients including five patients carrying homozygous or compound heterozygous mutations in Parkin, one with a novel homozygous deletion in DJ‐1 (P158Del) and one with a heterozygous mutation in LRRK2 (T2356I). We found seven novel mutations. The phenotypic characteristics of mutation carriers varied widely, comparable to the variability seen in sporadic EOPD. Parkin is the most frequently mutated gene in this EOPD cohort, followed by DJ‐1, PINK1 and LRRK2. The low overall mutation frequency indicates that the extrapolation of mutation frequencies from other populations should be applied with caution.

Assessment of psychiatric complications in Parkinson's disease: The SCOPA-PC

The objective of this study was to develop a clinimetric sound scale that addresses both psychotic and compulsive complications in Parkinsons disease (PD). The SCales for Outcomes in PArkinsons disease‐Psychiatric Complications (SCOPA‐PC) was developed by modifying the items of the Parkinson Psychosis Rating Scale (PPRS) and including an item on compulsive behavior in PD. To evaluate the validity of the SCOPA‐PC, 106 PD patients were assessed. A subsample of 43 patients was assessed for interrater and test–retest reliability. Construct validity was evaluated using the Neuropsychiatric Inventory (NPI) and the South Oaks Gambling Scale (SOGS). Interrater and test–retest reliability for the total score was 0.95 and 0.91 (intraclass correlation coefficient), respectively. For the items, the interrater reliability ranged from 0.62 to 0.96 (weighted kappa) and the test–retest reliability ranged from 0.54 to 0.88 (weighted kappa). Cronbachs alpha was 0.68. The correlation between the SCOPA‐PC total score and the NPI was 0.41. The correlation between SCOPA‐PC items and NPI items that addressed similar constructs ranged from 0.34 to 0.68, whereas the correlation between the item on compulsive behavior and the SOGS was 0.49. In conclusion, the SCOPA‐PC is a reliable, valid, and easily‐administered semistructured questionnaire for both psychotic and compulsive complications in PD.

Prevalence and clinical profile of restless legs syndrome in Parkinson's disease†

Parkinsons disease (PD) and restless legs syndrome (RLS) have a dopaminergic link. More insight in the clinical profile of RLS in patients with PD may benefit our understanding of this link. The aims of this study were to evaluate the frequency and clinical profile of RLS in a large cohort of PD patients. In 269 nondemented Caucasian PD patients, the four diagnostic criteria for RLS were administered by a RLS trained researcher. In patients with definite RLS, the severity of these symptoms was assessed. Furthermore, in all patients, relevant motor and nonmotor symptoms in PD were evaluated. Definite RLS was present in 11% of the patients. RLS patients were more often female (69% vs. 32%, P < 0.001), but no other significant differences existed between PD patients with and without RLS. Within the PD patients with RLS, severity of RLS correlated positively with PD severity, motor fluctuations, depressive symptoms, daytime sleepiness, cognitive problems, autonomic symptoms, and psychotic symptoms. This study in a large PD cohort shows that prevalence of RLS is similar to that in the general population, which might be caused by underestimation of RLS due to dopaminergic treatment. No relations were found between the presence of RLS and PD symptoms, but the severity of RLS was related to the severity of PD‐related, mainly nondopaminergic, symptoms. It is hypothesized that, nondopaminergic systems, such as the noradrenergic system may play a role in the possible link between PD and RLS.

SCOPA-Cognition Cutoff Value for Detection of Parkinson's Disease Dementia

The SCOPA‐Cognition is a reliable and valid test to evaluate cognitive functioning in Parkinsons disease and is widely used in clinical and research settings. Recently, the Movement Disorder Society introduced criteria for Parkinsons disease dementia. The objective of the present study was to use these criteria to determine SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinsons disease dementia. A total of 282 patients with Parkinsons disease were assessed with the SCOPA‐Cognition and the Movement Disorder Societys Parkinsons disease dementia criteria. From the 275 patients with a complete assessment of the dementia criteria, 12% (n = 32) fulfilled the criteria. Data from 268 patients with complete assessments of both the dementia criteria and the SCOPA‐Cognition were used to determine cutoffs for maximum accuracy, screening, and diagnosing of Parkinsons disease dementia. The area under the curve was 0.91 (95% confidence interval, 0.85–0.97), showing a strong association between the dementia criteria and the SCOPA‐Cognition. The cutoff for maximum accuracy was 22/23, based on the highest sum of sensitivity (0.80) and specificity (0.87), with positive and negative predictive values of 0.43 and 0.97, respectively. The optimal screening cutoff was 24/25, and the optimal diagnostic cutoff was 17/18. Using the recently published Parkinsons disease dementia criteria as a reference, the current study presents SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinsons disease dementia. The availability of SCOPA‐Cognition cutoffs for Parkinsons disease dementia may contribute to the scales usefulness and promote its further use in both clinical and research settings.

Motor patterns in Parkinson's disease: a data-driven approach.

To identify patterns of motor disturbances in Parkinsons disease (PD) and evaluate their relation with other PD domains. A cohort of 399 PD patients was randomly divided into two samples. Factors within the motor section of the SPES/SCOPA were identified by exploratory factor analysis on data from the first sample and next tested by confirmatory factor analysis in the second sample. Relations with other PD domains were evaluated by regression analyses. A four factor model was found to be valid. This included a tremor, a bradykinetic‐rigid, and two axial factors. One axial factor (“rise”, “gait”, “postural instability”) was associated with age and cognition, while the other axial factor (“freezing”, “speech”, “swallowing”) was related to dopaminergic medication and complications of therapy. Both other factors showed no relevant associations with demographic and clinical characteristics. The identification of motor factors and their relation with other domains of the disease may help to elucidate the mechanisms responsible for these associations and provide an objective base for further research on subtypes in PD.

Psychotic and compulsive symptoms in Parkinson's disease†

The objective of this study is to evaluate psychiatric symptoms in Parkinsons disease (PD) patients and to assess their relation with other clinical aspects of PD. Psychotic symptoms (PS) and compulsive symptoms (CS) as well as other nonmotor and motor features were evaluated in 353 PD patients. Psychotic and compulsive symptom scores did not correlate significantly. PS occurred in 65% of patients, with item frequencies ranging from 10% (paranoid ideation) to 55% (altered dream phenomena). Regression analysis showed that autonomic impairment accounted for 20% of the 32% explained variance of PS, whereas cognitive problems, depression, daytime sleepiness, and dopamine agonist (DA) dose explained the rest. CS occurred in 19%, with item frequencies of 10% for both sexual preoccupation and compulsive shopping/gambling. Patients with more severe CS (score ≥ 2 on one or both items) were significantly more often men, had a younger age at onset, a higher DA dose and experienced more motor fluctuations compared to the other patients. PS and CS are common but unrelated psychiatric symptoms in PD. The relations found between PS and cognitive problems, depression, daytime sleepiness, and autonomic impairment suggests a resemblance with Dementia with Lewy Bodies. The prominent association between PS and autonomic impairment may be explained by a shared underlying mechanism. Our results confirm previous reports on the profile of patients developing CS, and mechanisms underlying motor fluctuations may also play a role in the development of CS in PD.

More than 95% completeness of reported procedures in the population-based Dutch Arthroplasty Register

Background and purpose — A complete and correct national arthroplasty register is indispensable for the quality of arthroplasty outcome studies. We evaluated the coverage, completeness, and validity of the Dutch Arthroplasty Register (LROI) for hip and knee arthroplasty. Patients and methods — The LROI is a nationwide population-based registry with information on joint arthroplasties in the Netherlands. Completeness of entered procedures was validated in 2 ways: (1) by comparison with the number of reimbursements for arthroplasty surgeries (Vektis database), and (2) by comparison with data from hospital information systems (HISs). The validity was examined by conducting checks on missing or incorrectly coded values in the LROI. Results — The LROI contains over 300,000 hip and knee arthroplasties performed since 2007. Coverage of all Dutch hospitals (n = 100) was reached in 2012. Completeness of registered procedures was 98% for hip arthroplasty and 96% for knee arthroplasty in 2012, based on Vektis data. Based on comparison with data from the HIS, completeness of registered procedures was 97% for primary total hip arthroplasty and 96% for primary knee arthroplasty in 2013. Completeness of revision arthroplasty was 88% for hips and 90% for knees in 2013. The proportion of missing or incorrectly coded values of variables was generally less than 0.5%, except for encrypted personal identity numbers (17% of which were missing) and ASA scores (10% of which were missing). Interpretation — The LROI now contains over 300,000 hip and knee arthroplasty procedures, with coverage of all hospitals. It has a good level of completeness (i.e. more than 95% for primary hip and knee arthroplasty procedures in 2012 and 2013) and the database has high validity.

Relation of clinical subtypes in Parkinson's disease with survival

It is increasingly recognized that Parkinson’s disease (PD) is a clinically heterogeneous disease, with wide variation in presence and severity of motor and non-motor symptoms and disease course. Overall, PD is associated with an increased mortality rate compared with the general population, but survival after disease onset differs considerably across patients. One might hypothesize that certain subgroups of PD patients have a worse prognosis in terms of mortality risk than others. It has been suggested that there are several clinical subtypes of PD. A data-driven cluster analysis, which was performed on baseline data from the “Profiling Parkinson’s Disease” (PROPARK) study and validated in an independent Spanish cohort, previously revealed four distinct clinical subtypes of PD (denoted as subtypes 1, 2, 3, and 4). Patients who have subtype 1 PD are characterized by an overall mild severity in all clinical domains, subtype 2 is predominantly characterized by severe and frequent motor complications, patients with subtype 3 are affected mainly on nondopaminergic domains (postural instability/gait disturbance, cognitive impairment, autonomic dysfunction, depression, and psychosis) without prominent motor complications, and those with subtype 4 are severely affected on all domains. 6 We compared survival in these clinical subtypes using follow-up data from the PROPARK study. The PROPARK study is a longitudinal cohort study of 414 patients with PD who undergo extensive annual evaluation of a large number of motor and non-motor symptoms. The recruitment procedure has been described in detail elsewhere. The medical ethical committee of the Leiden University Medical Center approved the study, and written informed consent was obtained from all patients. At baseline (May 2003 to September 2005) and at five annual follow-up visits, all patients received a standardized assessment of different clinical domains (all assessments were described previously in detail). Classification according to the four clinical subtypes was available for 343 patients (83%) in the cohort. The remaining patients were excluded from the cluster analyses because of stereotactic surgery (n 5 18) or missing data (n 5 53). When patients did not respond to their yearly invitation for the follow-up assessments, the patient’s general practitioner was contacted to verify the vital status. In case the patient had died, the general practitioner provided the exact mortality date. Unadjusted survival in four clinical subtypes was examined using Kaplan-Meier analysis and was compared using the log-rank test. The association of individual subtypes with mortality was evaluated by means of Cox proportional hazards regression analyses that were adjusted for age, sex, and disease duration, using the most common subtype (subtype 1) as the reference category. During the follow-up period, 37 patients (10.8%) died. Unadjusted survival differed significantly across the four clinical subtypes (log-rank test; P 5 0.000). Subtype 3 and 4 were associated with a significantly increased risk of mortality compared with subtype 1 (Table 1). Our finding that mortality rates differed significantly across clinical subtypes lends support to the concept of distinct subgroups of PD patients displaying differences in clinical profile, disease course, and prognosis. Survival was most strongly reduced in subtypes 3 and 4, both of which were characterized TABLE 1. Association between clinical subtypes of PD and mortality