L-dopa responsiveness in early Parkinson's disease is associated with the rate of motor progression

https://doi.org/10.1016/j.parkreldis.2019.05.022Get rights and content

Highlights

  • L-Dopa responsiveness in Parkinson's disease varies with age.

  • L-Dopa responsiveness in early Parkinson's disease is associated with the rate of motor progression.

  • L-Dopa responsiveness in early disease is unaffected by gender.

  • Response to L-Dopa in early disease is unaffected by acute challenge test dose.

Abstract

Background

L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined.

Methods

Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (<24.5%).

Results

1007 cases, mean age 66.1 years (SD 9.1) at diagnosis, were assessed 3.4 (SD 0.9) years after diagnosis. The L-dopa response was definite in 614 cases (61.0%), median reduction in MDS UPDRS 3 scores was 42.0%, (IQR 33.3, 53.1), and was limited in 393 cases (39.0%), median reduction in MDS UPDRS 3 scores 11.5% (IQR 4.3, 18.2). Definite responders were younger (66.3 years at study entry, SD 9.3) than limited responders (69.2 years, SD 8.4, p < 0.001). The MDS UPDRS 3 score at study entry in definite responders (21.0, SD 10.5) was significantly lower than in limited responders (24.7, SD 13.4, p < 0.001). The MDS UPDRS 3 increase over 18 months was less in definite responders at 3.0 (SD 10.4), compared to limited responders (6.4, SD 11.0, p < 0.001). The levodopa equivalent daily dose (LEDD) was not significantly different at study entry (definite responders 317 mg, SD 199, vs limited responders 305 mg, SD 191, p = 0.53). However, LEDD was significantly higher at the time of the L-dopa challenge test in definite responders (541 mg, SD 293) compared to limited responders (485 mg, SD 215, p = 0.01). Responsiveness to L-dopa was unaffected by the challenge test dose (p = 0.54).

Conclusions

The main determinants of variation in the L-dopa response in early PD are age and motor severity. A limited L-dopa response is associated with faster motor progression.

Introduction

The phenotypic heterogeneity of Parkinson's disease (PD) is well recognized [1], and includes variability in L-dopa responsiveness [2,3]. While an excellent [4] or clear and dramatic [5] response to L-dopa is a supportive feature in the diagnostic criteria for idiopathic PD, a less marked response does not rule out the diagnosis of PD [4,5]. A number of studies have shown variation in the response to either an acute L-dopa challenge dose [[6], [7], [8]], or chronic L-dopa therapy [2,4,6,8] both in clinically diagnosed PD [2,4,6,8], and in pathologically confirmed cases [4]. However, the clinical correlates and significance of this variation in response are not clearly defined. We wished to explore in detail, in a large cohort of recently diagnosed PD patients, which clinical characteristics are associated with the level of motor responsiveness to L-dopa. We hypothesised that a limited motor response to L-dopa was a likely contributor to variation in the motor progression rate, which could be measured by prospective observation. We also set out to examine whether comorbidities (e.g. cerebrovascular disease) influenced the L-dopa motor response.

Section snippets

Methods

Tracking Parkinson's is a prospective observational multicentre study that has recruited from 72 centres in the United Kingdom (UK). Patients were recruited with a clinical diagnosis of PD made by a clinician if they fulfilled UK Brain Bank criteria [4]. This was supported by structural and/or functional neuroimaging when the diagnosis was not firmly established clinically. Both drug-naïve and treated patients, aged 18–90 years were eligible. Recent onset cases (diagnosed in the preceding 3.5

Results

There were 2006 patients recruited, of whom 37 were excluded either due to disease duration over 3.5 years (n = 6) or change in diagnosis after recruitment (n = 31). A further 429 did not have data for the 2-year visit, leaving 1540 cases, of whom 228 were not prescribed L-dopa at the time of the visit, and 305 in whom data collection was incomplete. Accordingly, complete data were available for the L-dopa challenge in 1007 cases (Table 1).

These cases had a mean age of 67.5 years (SD 9.1) at

Discussion

Our main finding is that, in a large cohort of prospectively recruited recent onset PD patients, there is a substantial variation in the degree of motor response to L-dopa. These results are consistent with variation in L-dopa responsiveness in clinical trials and pathological case series [[2], [3], [4]]. In the ELLDOPA study in 260 L-dopa treated patients, the average improvement in UPDRS 3 was 27.4% (SD 30.6) at 9 weeks, and 26.2% (SD 36.4) at 24 weeks [2,3]. Because of the known differences

Financial disclosures

N Malek, KA Grosset, MA Lawton, N Williams, Y Ben-Shlomo: No conflicts of interest.

N Bajaj has received payment for advisory board attendance from UCB, Teva Lundbeck, Britannia, GSK, Boehringer, and honoraria from UCB Pharma, GE Healthcare, Lily Pharma, Medtronic, and BIAL Pharma.

He has received research grant support from GE Healthcare, Wellcome Trust, Medical Research Council, Parkinson's UK and National Institute for Health Research.

RA Barker has received grants from Parkinson's UK, NIHR,

Author contributions

NM: Data collection, analysis, manuscript writing and editing.

MAL, SK, VP: Data analysis, manuscript writing and editing.

NB, TF: Data collection, manuscript editing.

JH, NMW, NW: Study design.

DJB, RAB, HRM: Study design, data collection, manuscript editing.

YBS: Study design, data analysis plan, manuscript editing.

KAG, DGG: Study design, data collection, analysis, manuscript writing and editing.

Acknowledgements

The research was funded by Parkinson's UK and supported by the National Institute for Health Research (NIHR) DeNDRoN network, the NIHR Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and the NIHR funded Biomedical Research Centre in Cambridge. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. RAB is an NIHR Senior Investigator.

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