ABSTRACT
Background
Treatment response in PD is important clinically and for research diagnostic criteria, but few objective data show treatment‐responsiveness of PD motor features.
Objectives
To evaluate the treatment response of motor features to moderate treatment doses in a “real‐world” PD cohort.
Methods
We analyzed data from a community‐based incident cohort of PD in North‐East Scotland (PINE study). We assessed change in the UPDRS motor scale and its individual items over a period of up to 13 months comparing (1) patients with an increase of at least 300 mg of levodopa‐equivalent dose (LED) and (2) patients without treatment change, matched for age, sex, and disease duration.
Results
We identified 101 matched pairs of patients with and without a treatment increase. LED increases were mostly 300 to 375 mg/day. Forty‐two percent with treatment increase had ≥30% improvement in overall UPDRS motor score, a further 35% had substantial subjective improvement, but only 1 had an objective excellent (>70%) treatment response. Women responded better than men by 5.4 points (95% confidence interval [CI]: 2.7–8.1). All motor features improved with treatment, but after adjustment for age, sex, and initial score, only rest tremor (P < 0.001), rigidity (P = 0.01), bradykinesia (<0.001), posture (P = 0.01), and gait (P = 0.03) had significant improvements, compared to those with no treatment change. Dopa‐less‐responsive motor items, taken together, had small statistically significant relative improvements (1.1‐point difference [95% CI: 0.4–1.8]; P = 0.004).
Conclusions
Motor items sometimes previously considered dopa unresponsive have small improvements with moderate LED increases. Women respond better than men. Excellent treatment responses are uncommon. These data can inform clinical decisions about treatment.
Keywords: Parkinson's disease, treatment response, motor features, levodopa
Dopaminergic replacement therapy (DRT), principally with levodopa or dopamine agonists, is the mainstay of symptomatic treatment for Parkinson's disease (PD),1 but no treatments have been demonstrated to slow its progression.2 There are few objective data to describe which individual clinical features respond to treatment or the degree of response which can be expected. This is important not only for informing patients how they may respond to treatment, but also for research. For instance, in longitudinal epidemiological studies or in neuroprotective trials, dopamine–less‐responsive features may be less likely to be confounded by treatment effects and therefore a better index of disease progression or a disease‐modifying treatment response. Previous attempts have categorised UPDRS3 motor items as treatment responsive (facial expression, tremor, rigidity, and bradykinesia) or treatment unresponsive (speech, arising from chair, posture, postural stability, and gait).4, 5, 6 To the best of our knowledge, this categorization has not been validated. Furthermore, such data would be useful diagnostically in PD: Lack of treatment response to large doses of DRT is an absolute exclusion, and an excellent treatment response is a supportive criterion in the UK PD Brain Bank diagnostic criteria7 and substantial and sustained DRT response are part of the Gelb criteria,8 but none of these has been formally defined. The recently published International Parkinson and Movement Disorder Society (MDS) diagnostic criteria include a 30% objective improvement as a supportive criterion for the diagnosis of PD,9 but it is unclear how frequently this occurs in PD.
We hypothesized that defining a set of dopamine‐unresponsive motor features would generate a useful measure of disease progression. Therefore, we aimed to evaluate the degree of treatment response of particular motor features in PD and the degree of overall motor response to moderate treatment doses in a “real‐world” cohort of PD.
Patients and Methods
PINE Cohort
We analyzed data from PD patients in the PINE study, a prospective, community‐based incident cohort of parkinsonism with ongoing long‐term follow‐up in Aberdeen, UK. We attempted identification of all new patients with a previously undiagnosed parkinsonian syndrome during two incidence periods (over 18 months in a population area of 148,600 from November 2002 and over 36 months in a population area of 317,357 people, from April 2006). Detailed methods were previously published.10, 11, 12 We used multiple, overlapping strategies for case ascertainment in both general practice and hospitals. All new patients with suspected parkinsonism identified by our ascertainment strategy were seen by a study neurologist with a special interest in movement disorders (or supervised trainee) and were invited to consent to long‐term annual follow‐up. At each study visit, the precise diagnosis of the parkinsonian syndrome was reviewed in the light of all existing clinical information. The diagnosis of PD was guided by the UK PD Brain Bank criteria,7 insofar as follow‐up duration permitted the supportive criteria to be applied. Postmortem diagnoses were used where available (those with a clinical diagnosis of PD in life, but an alternative diagnosis at postmortem were excluded from this analysis).
At each visit (annual review and any interim visits), dopaminergic drug use and dosage were documented (including medication changes between visits), and clinical examination was performed, including the motor UPDRS. Patients were also asked to rate their subjective response to treatment as none, slight (<25% improvement), modest (25–49%), good (50–74%), or excellent (≥75%). The date patients began or changed their treatment was estimated as 14 days after the clinic visit at which the treatment changes were recommended. l‐dopa equivalent doses (LEDs) were calculated for each visit.13 Treatment changes were made according to clinical need and were not influenced by participation in the study.
Inclusion Criteria for Current Analyses
Within the PINE cohort, we nested an internal case‐control study, with pairs of PD patients with increases of DRT (hereafter “patients with treatment increase”) and PD patients with no increase in DRT (hereafter “patients without treatment increase”) matched on age, sex, and disease duration in order to make a valid comparison. Patients with treatment increase were included if they (1) had an initiation of DRT with dose of at least 300‐mg daily LED or increase in DRT by at least 300‐mg LED daily; (2) had a UPDRS motor score documented before and after the treatment increase; (3) both examinations were within 13 months; and (4) the second UPDRS score was measured at least 2 months after the treatment increase date to allow a treatment effect to have occurred. We identified patients without treatment increase from those with (1) two UPDRS motor scores documented within 13 months and the first occurring at same follow‐up time (i.e., years from diagnosis) as a patient with a treatment increase; (2) and with no change in DRT between these two assessments. From those, we randomly selected from a patient of the same age (±2.5 years) and sex for each patient with treatment increase, where possible. Patients with treatment increase could also be selected as internal controls matched to other patients at times where they did not change LED and patients could be selected as internal controls more than once.14 Patients were never their own control.
Statistical Analysis
We described change in overall motor score in patients with treatment increase. We described the proportion with 30% improvement (as used in the MDS diagnostic criteria)9 and 70% improvement (described as “excellent” response in one of the UK PD brain bank papers).15 We assessed potential factors predicting treatment response (age, sex, UPDRS motor score before treatment increase, daily LED increase, and disease duration) using multivariable linear regression. We compared change in overall UPDRS motor score and “dopa‐responsive” and “dopa‐unresponsive” items (as classified by Levy et al.)4 and individual UPDRS motor items between matched pairs of patients with treatment increase and patients without treatment increase. We plotted histograms of change in “dopa‐responsive” items and “dopa‐unresponsive” items in those with treatment increase and those without treatment increase. We compared change in UPDRS motor scores between patients with treatment increase and patients without treatment increase using linear regression, with adjustment for age, time between UPDRS assessments, and initial score of the particular motor item(s) being compared. We also performed a sensitivity analysis by restricting the analyses to pairs where the patient with treatment increase was initiating treatment given that those starting dopaminergic treatment may have been more homogeneous than those with a later increase in dopaminergic treatment.
Results
Of 377 patients with suspected degenerative or vascular parkinsonism in the incidence period, 355 (94%) consented to follow‐up and 198 of these had a latest diagnosis of idiopathic PD after mean 6.1 years’ follow‐up. Only 8 PD patients (4%) were lost to follow‐up. Of the 42 patients with a clinical diagnosis of PD in life who had an autopsy after their death, 37 (88%) had pathologically proven PD. One hundred one matched pairs of patients with and without a treatment increase were identified. Twenty patients were used as controls more than once. Characteristics of the whole cohort and the matched pairs are given in Table 1. The cohort was predominantly elderly because it was derived from an incidence study.
Table 1.
Characteristics of patients at baseline, description of treatment increases at time points analyzed, and details of UPDRS motor scores before treatment increase
| Matched Analysis | |||
|---|---|---|---|
| All PD Patients in PINE Cohort N = 198 | PD Patients With Treatment Increase N = 101 | Matched PD Patients Without Increase in Treatment N = 101 | |
| Mean age at diagnosis (SD) | 72.5 (10.4) | 72.3 (7.9) | 72.2 (8.0) |
| Male sex, N (%) | 119 (60) | 64 (63) | 64 (63) |
| White ethnicity, N (%) | 197 (99) | 100 (99) | 100 (99) |
| Mean scores at diagnosis, mean (SD) | |||
| H & Y stage (SD) | 2.3 (0.8) | 2.3 (0.8) | 2.0 (0.7) |
| UPDRS motor score (SD) | 25.1 (11.6) | 24.3 (10.9) | 19.0 (10.6) |
| Schwab & England score (SD) | 83.1 (16.5) | 85.1 (14.6) | 89.3 (13.5) |
| Median time in months (IQR) | NA | ||
| From diagnosis to treatment increase of interesta | 12 (0–22) | 12 (0–15) | |
| From most recent examination to increase | 0.5 (0.5–0.8) | NA | |
| From treatment increase to second examination | 5 (4–7) | NA | |
| Between examinationsb | 6 (4–10) | 12 (12–13) | |
| LED before treatment increasea | NA | ||
| Number untreated (%) | 90 (89%) | 64 (63%) | |
| Mean daily LED in mg in those on treatment (SD) | 264 (308) | 354 (151) | |
| Increase in daily LED between examinations of interest | |||
| Median in mg (IQR) | NA | 300 (300–375) | 0 (0–0) |
| N with increase 300 to 375 mg (%) | 79 (78) | ||
| N with increase 400 to 480 mg (%) | 17 (17) | ||
| N with increase 550 to 750 mg (%) | 5 (5) | ||
| Dopaminergic drug increased | NA | NA | |
| l‐dopa | 83 (82%) | ||
| Dopamine agonist | 18 (18%) | ||
| Motor item scores before dose increase, mean (SD) | NA | ||
| Speech score | 1.5 (0.7) | 1.0 (0.8) | |
| Facial expression score | 2.0 (0.6) | 1.4 (0.9) | |
| Rest tremor score | 3.2 (2.9) | 2.3 (2.0) | |
| Postural tremor score | 1.8 (1.4) | 1.6 (1.1) | |
| Rigidity score | 4.6 (2.6) | 2.7 (2.3) | |
| Bradykinesia score | 11.2 (4.0) | 6.8 (3.7) | |
| Arising from chair score | 0.9 (0.9) | 0.4 (0.7) | |
| Posture score | 1.3 (0.8) | 0.8 (0.8) | |
| Gait score | 1.1 (0.8) | 0.5 (0.7) | |
| Postural stability score | 1.0 (0.8) | 0.7 (0.8) | |
| Body bradykinesia score | 2.2 (0.8) | 1.2 (0.9) | |
| Total UPDRS motor score | 30.8 (8.5) | 19.5 (8.3) | |
Treatment increase refers to the patients’ first dose increase of at least 300‐mg LED.
Or matched time point.
Time interval is shorter for those with treatment increase as they whose initiating treatment has a 4‐ or 6‐monthly review to assess treatment response.
IQR, interquartile range; NA, not applicable; SD, standard deviation.
Description of Treatment Response in Patients With Treatment Increase
Most patients improved after treatment increase (n = 81; 80%), but only 42 (42%) had ≥30% improvement in UPDRS motor score. Of the 59 patients with <30% improvement in overall UPDRS motor score, 35 (59%) reported modest or substantial subjective benefit (≥25%). Thus, 77 (76%) patients had evidence of at least modest objective or subjective improvement. Only 1 patient had >70% improvement in overall UPDRS motor score. Factors associated with better (absolute) treatment response included female sex (5.37 points on average [95% confidence interval {CI}: 2.67–8.08] and higher initial UPDRS score (0.48 points on average for every unit increase in initial score [95% CI: 0.32–0.63]). There was no evidence that age or disease duration were associated with treatment responsiveness (Table 2).
Table 2.
Multivariable linear regression model of predictors of change in overall UPDRS part III (motor) score
| Patients With Treatment Increase (N = 101) | Matched Pairs of Patients With and Without Treatment Increase (N = 202) | |||
|---|---|---|---|---|
| Variable | Coefficient (95% CI)a | P Value | Coefficient (95% CI)a | P Value |
| Age at first time pointb (10‐year increase) | –0.04 (–1.89 to 1.80) | 0.96 | 0.26 (–0.97 to 1.49) | 0.68 |
| Sex (male vs. female) | 5.37 (2.67 to 8.08) | <0.001 | 3.28 (1.36–5.20) | 0.001 |
| Initial UPDRS motor score | –0.48 (–0.63 to –0.32) | <0.001 | –0.37 (–0.48 to –0.26) | <0.001 |
| Years from diagnosis to treatment change | –0.64 (–1.64 to 0.35) | 0.20 | NA | |
| Change in daily LED per 100 mg | –0.89 (–2.46 to 0.72) | 0.28 | NA | |
| Treatment increase of 300‐mg daily LED versus no treatment increasec | NA | –5.50 (–7.48 to –3.51) | <0.001 | |
| Months between assessments | NA | 0.31 (–0.01 to 0.62) | 0.06 | |
| Constant | –2.24 (–14.4 to 18.9) | 0.79 | –0.72 (–9.67 to 11.1) | 0.89 |
Negative coefficients indicate lower UPDRS scores at second time point (i.e., better treatment response in those treated).
Before treatment increase in those with treatment increase and at matched disease duration in patients without treatment increase.
Entered as a continuous variable (mg daily LED, equal to zero in all patients without treatment increase), but coefficient displayed for a meaningful 300‐mg increase.
NA, not applicable.
Comparison Between Patients With and Without Treatment Increase
In the matched analysis of PD patients with and without a treatment increase, as expected, those with treatment increases had higher (worse) initial motor scores (i.e., before treatment increase or at matched time point). Unadjusted changes in dopa‐responsive and dopa‐unresponsive items (as defined by Levy) are shown in Figure 1. The multivariable model for change in overall UPDRS motor score in matched pairs is shown in Table 2. A 300‐mg daily LED treatment increase was associated with 5.5 points higher improvement in overall UPDRS motor score, on average, than those without treatment increase.
Figure 1.
Changes in UPDRS motor scores in patients with and without LED increase by dopa responsiveness as defined by Levy et al. Negative numbers indicate improvement in motor score.
In the comparison of individual items, all items had a greater average improvement in patients with a treatment increase than in patients without a treatment increase when adjusted for age, sex, and time interval (Table 3). This was statistically significant for all items except postural tremor and postural instability. With additional adjustment for the value of the particular item before the treatment change (or matched time point), the average improvement was also greater for those with increase in treatment than in those without an increase in treatment. However, the magnitude of the difference was lower, and the differences in changes in score was only significant for rest tremor (P < 0.001), rigidity (P = 0.01), bradykinesia (<0.001), posture (P = 0.01), and gait (P = 0.03). The relative improvement in score (treatment increase vs. no treatment increase) in the “dopa‐unresponsive” items was lower (–1.07 [–1.78 to ‐0.35]) than in the dopa‐responsive symptoms (–5.89 [–7.97 to ‐3.80]), but was still statistically significant. The sensitivity analysis restricted to patients with treatment initiation only did not lead to substantially different results.
Table 3.
Difference in change in score between matched patients with and without treatment increase
| Analyses Adjusted for Age, Sex, and Time Interval Between First and Second UPDRS score | Analyses Also Adjusted for First UPDRS Score (particular item or sum being analyzed; i.e., before change in those with increase in dose) | |||
|---|---|---|---|---|
| Item (dependent variable) | Coefficient (95% CI) | P Value | Coefficient (95% CI) | P Value |
| Overall UPDRS motor score | –10.6 (–13.2 to –8.06) | <0.001 | –7.05 (–9.61 to –4.50) | <0.001 |
| Speech | –0.36 (–0.62 to 0.10 | 0.007 | –0.13 (–0.36 to 0.09) | 0.25 |
| Facial expression | –0.43 (–0.71 to –0.14) | 0.003 | –0.10 (–0.34 to 0.13) | 0.38 |
| Rest tremor | –1.26 (–1.74 to –0.78) | <0.001 | –1.20 (–1.68 to –0.72) | <0.001 |
| Postural tremor | –0.39 (–0.84 to 0.07) | 0.09 | –0.28 (–0.70 to 0.14) | 0.19 |
| Rigidity | –1.71 (–2.50 to –0.93) | <0.001 | –0.92 (–1.63 to –0.20) | 0.01 |
| Bradykinesia | –4.16 (–5.39 to –2.92) | <0.001 | –2.79 (–3.97 to –1.61) | <0.001 |
| Arising from chair | –0.41 (–0.69 to –0.13) | 0.004 | –0.18 (–0.40 to 0.03) | 0.10 |
| Posture | –0.48 (–0.74 to –0.23) | <0.001 | –0.29 (–0.52 to 0.06) | 0.01 |
| Gait | –0.38 (–0.61 to –0.16) | 0.001 | –0.22 (–0.42 to –0.02) | 0.03 |
| Postural instability | –0.27 (–0.55 to 0.01) | 0.06 | –0.14 (–0.38 to 0.09) | 0.23 |
| Body bradykinesia | –0.51 (–0.79 to –0.23) | <0.001 | –0.15 (–0.39 to 0.10) | 0.24 |
| Dopa‐responsive itemsa | –8.46 (–10.6 to –6.37) | <0.001 | –5.89 (–7.97 to –3.80) | <0.001 |
| Dopa‐unresponsive itemsa | –1.89 (–2.71 to –1.07) | <0.001 | –1.07 (–1.78 to –0.35) | 0.004 |
Negative values of coefficients indicate greater improvement in those with treatment increase than those without treatment increase.
As defined by Levy.4
Discussion
This study provides “real‐life” clinically applicable data on the motor response to moderate doses of DRT in a representative cohort of PD. Our main findings are: (1) that a marked objective treatment response is uncommon at such doses; (2) that the UPDRS motor items that have sometimes previously been regarded as treatment unresponsive do respond to DRT, although the magnitude of the average response is small; and (3) women respond better to treatment than men. We were not able to define a set of unresponsive motor features for use as a measure of disease progression. We would caution against making firm conclusions from these data about the treatment responsiveness or otherwise of individual motor items (other than rest tremor and bradykinesia) given lack of power to identify small treatment responses and the risk of type 1 errors with multiple comparisons.
A randomized comparison between l‐dopa and placebo has lower risk of confounding than our observational data, but is less generalizable than our data. Few such trials have been performed. The ELLDOPA study compared different doses of l‐dopa with placebo and demonstrated a 3.8‐point difference in change in motor score over 42 weeks between placebo and 300 mg/day of l‐dopa.16 The recently published LEAP trial demonstrated a 5.1‐point difference in change in total UPDRS score over 44 weeks between placebo and 300 mg/day of l‐dopa.17 Neither of these studies reported individual motor items. Our observational data suggest a higher treatment responsiveness than these trials, perhaps because our data were unblinded, but it may also partly be attributed to substantially higher UPDRS motor scores in patients before the treatment increase in our study than in these trials.
We found lower overall treatment responses than in the UK Brain Bank series of 100 pathologically confirmed cases of PD, in which 94 had at least 30% initial response to l‐dopa, although the treatment doses and method of measuring response were not defined.15 However, this was an autopsy series, so it was, by definition, a highly selected cohort, and the mean age of onset was 10 years younger than in our study. It may be that older, frailer patients (who are often missed from clinical cohorts unless sought out in the community)18, 19 have lower treatment response rates, although we did not find evidence for this in our analyses and we are unaware of other objective data on this. However, the predominant reason may be that the DRT doses used in the autopsy series, which recruited patients who died between 1986 and 1990, were much higher than those used in our study. Our findings, together with the ELLDOPA and LEAP trial results showing smaller average treatment responses than in our study, suggest that a 70% to 100% response in an objective score (as used in the UK Brain Bank supportive criteria)7 is infrequent in PD at the typical dose increments used in current practice. Therefore, 30% improvements in an objective score, as used in the new MDS criteria,9 may be more useful in clinical practice, although the frequency of this improvement in atypical parkinsonian disorders also needs to be established. However, most patients had LED increases of around 300 mg, so it is possible that larger DRT increases are associated with larger improvements in motor impairment.
Our data also cast new light on the degree particular motor features respond to DRT. Many previous researchers have considered the motor features of PD as either “dopa‐responsive” or “dopa‐unresponsive.”4, 5, 20 However, we found that those features they have regarded as nonresponsive to DRT, when taken together, had a statistically significant average improvement of 1.1 points. While it is unclear what is a clinically significant benefit in these items specifically, there is a consistent trend for improvement in all items, and some 1‐point improvements in particular items are likely to lead to clinical benefit (e.g., in gait and postural instability). We therefore suggest that the terms “less dopa responsive” and “more dopa responsive” be used rather than dopa responsive and dopa unresponsive. Given the consistency of the trend for improvement across all the motor features and the overall statistical significance, it is likely that more power would demonstrate statistically significant improvements in each motor item, but this requires confirmation.
Our data showed that women responded better to treatment with, on average, a 5‐point greater improvement in motor UPDRS than men. Although it was not a predefined subgroup, this finding may not be chance given that a similar finding has been reported previously.21 This may be attributable to greater bioavailability of l‐dopa in women, even after adjustment for weight,22 which could be attributed to hormonal differences in l‐dopa metabolism,23 and is in keeping with the observation in some studies that dyskinesias are more frequent in women.24, 25 However, there are sex differences in the incidence,26 symptom frequency,27 and probably survival28 in PD, so there may be pathophysiological differences relating to sex which could explain this finding.
This analysis has several strengths. It is an unselected community‐based incident cohort so is more representative, and thus more generalizable, than specialist‐clinic or trial‐based cohorts.19 The study was prospective; and examinations were performed by clinicians with expertise in movement disorders. Furthermore, a substantial minority of the cohort had postmortem diagnostic confirmation. The high accuracy of clinical diagnosis in those who had postmortem examination demonstrates that this cohort is predominantly PD with diagnostic error similar to those previously reported by movement disorders experts.7 Additionally, the assessments conducted before and after treatment increased were relatively close together (median time apart: 6 months) to try to minimize the confounding effect of disease progression. We used matched internal controls without increase in treatment to minimize the confounding effects of disease progression. By matching on disease duration, we have adjusted for the possibility that treatment response varies with disease duration.29 Last, the data we analyzed were mostly based on clinical signs rather than the patients’ subjective experience, which we found did not always correlate with objective findings as we have reported and discussed previously.30
Nevertheless, there are several limitations relating to these analyses. We did not measure compliance with prescribed treatment. Previous studies using electronic monitoring medication bottles showed that 10% to 20% of patients had suboptimal medication adherence in PD, although these studies were performed later in the disease course, on average, than in our study, so the medication regimens may have been more complex.31 Nonadherence could introduce a bias by underestimating of the true potential improvement attributed to treatment. However, these are “real‐world” data representing the reality of clinical practice. Furthermore, there is potentially nonlinearity in UPDRS items, so that a 1‐point increase from 0 to 1, for instance, may not be equivalent to a 1‐point increase from 1 to 2. If the average improvement in a particular item is different from the average deterioration in that item, the magnitude of the improvement may not be directly comparable with the magnitude of deterioration. This may potentially skew the comparisons between items. Also, the clinical assessments were not blind to treatment status, which may have exaggerated the improvement in those with treatment increase, but again this is the real‐life experience from treating these patients. The patients with treatment increase had higher average scores for each UPDRS motor item, which reflects greater parkinsonian impairment requiring more treatment. Although we adjusted for this difference in the analyses, there may have been some regression to the mean so that a worse score was more likely to have greater improvement, which may also exaggerate the differences between treated and untreated patients. We had insufficient numbers of patients treated with dopamine agonists to investigate whether there are differential treatment responses between l‐dopa and dopamine agonists, but we are unaware of any data to suggest there would be a substantial difference in effectiveness of the equivalent LED of these drugs on the motor features studied. This study did not use the MDS‐UPDRS motor scale32 (this study began before its publication).
In conclusion, these data will be useful for informing discussions with patients about potential benefits of treatment. Excellent overall treatment responses appear to be less common than older data suggest, which has implications for diagnosis. Women had better treatment responses than men. The less‐dopamine‐responsive signs do show some response to treatment and therefore are unlikely to provide a “pure” measure of disease progression, but in combination they may be a better measure of disease progression than an overall UPDRS motor score with less confounding by DRT treatment effect. Further work with longitudinal representative cohorts is warranted to further analyze the utility of such measures for detecting changes over time in PD and to evaluate change using the MDS‐UPDRS scale. Further work to look at the responsiveness of nonmotor features of PD and treatment responsiveness in atypical parkinsonian syndromes would also be valuable.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
A.D.M.: 1A, 1B, 1C, 2A, 2B, 3A
C.E.C.: 1A 1B, 1C, 2C, 3B
Disclosures
Ethical Compliance Statement
The study was approved by the Multi‐centre Research Ethics Committee for Scotland (reference 05/MRE00/94) and conducted with the informed consent of the patients involved. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
This study was supported by Parkinson's UK, the Scottish Chief Scientist Office, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, NHS Grampian endowments, and SPRING. The authors report no conflicts of interest.
Financial Disclosures for previous 12 months
Dr. Macleod was funded by a Clinical Lecturer Fellowship from the Scottish Chief Scientist Office and NHS Education for Scotland (PCL/17/10). He has also received research funding from the Academy of Medical Sciences and NHS Grampian Endowments. Dr. Counsell received research funding from the Scottish Chief Scientist Office and NHS Grampian endowments.
Acknowledgments
We acknowledge funding for the PINE study from Parkinson's UK, the Scottish Chief Scientist Office, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, NHS Grampian endowments, and SPRING. We thank the patients for their participation and the research staff who collected data and supported the study database.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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