Abstract
Background
We recently showed that by employing an enhanced drug-delivery approach, repeated administration of glial cell line–derived neurotrophic factor (GDNF) can produce a spatially distributed increased 18F-DOPA positron emission tomography (PET) uptake, suggesting sprouting of dopaminergic terminals throughout the putamen structure. Despite this, we failed to prove a significant measurable clinical response. Since, however, we have identified a subject demonstrating a temporal relationship between repeated GDNF infusions and dyskinesia arising in the practically defined off (pracoff) state.
Objectives
To describe the development of pracoff dyskinesia across our study population and consider its utility as an indicator that trophic factor–induced terminal sprouting can affect enhanced endogenous dopamine levels.
Methods
This was a blinded retrospective analysis of videotaped motor assessments at eight weekly study visits. Dyskinesia in the pracoff and supramaximal on state were rated using the Clinical Dyskinesia Rating Scale. Logistic regression was employed to explore the predictors of pracoff dyskinesia. Generalized estimated equations were used to estimate the cumulative effect of repeated GDNF infusions.
Results
Mild–moderate choreiform dyskinesia in the pracoff state were seen in 47 assessments in 17 (n = 41) subjects. During the 18-month timeframe, each subsequent 8-week period of receiving GDNF increased the risk of demonstrating pracoff state dyskinesia by 34% (odds ratio [OR], 1.34 (95% confidence interval [CI], 1.20, 1.50); P
Conclusions
We report the first description of increasingly prevalent pracoff-state dyskinesia developing during the course of a trophic factor study. This may provide a surrogate marker that GDNF can enable recovery of endogenous dopamine release even in advanced Parkinson's disease.
We recently showed that by employing an enhanced drug-delivery approach, repeated administration of glial cell line–derived neurotrophic factor (GDNF) can produce a spatially distributed increased 18F-DOPA positron emission tomography (PET) uptake, suggesting sprouting of dopaminergic terminals throughout the putamen structure. Despite this, we failed to prove a significant measurable clinical response. Since, however, we have identified a subject demonstrating a temporal relationship between repeated GDNF infusions and dyskinesia arising in the practically defined off (pracoff) state.
Objectives
To describe the development of pracoff dyskinesia across our study population and consider its utility as an indicator that trophic factor–induced terminal sprouting can affect enhanced endogenous dopamine levels.
Methods
This was a blinded retrospective analysis of videotaped motor assessments at eight weekly study visits. Dyskinesia in the pracoff and supramaximal on state were rated using the Clinical Dyskinesia Rating Scale. Logistic regression was employed to explore the predictors of pracoff dyskinesia. Generalized estimated equations were used to estimate the cumulative effect of repeated GDNF infusions.
Results
Mild–moderate choreiform dyskinesia in the pracoff state were seen in 47 assessments in 17 (n = 41) subjects. During the 18-month timeframe, each subsequent 8-week period of receiving GDNF increased the risk of demonstrating pracoff state dyskinesia by 34% (odds ratio [OR], 1.34 (95% confidence interval [CI], 1.20, 1.50); P
Conclusions
We report the first description of increasingly prevalent pracoff-state dyskinesia developing during the course of a trophic factor study. This may provide a surrogate marker that GDNF can enable recovery of endogenous dopamine release even in advanced Parkinson's disease.
| Original language | English |
|---|---|
| Pages (from-to) | 104-112 |
| Number of pages | 9 |
| Journal | Movement Disorders |
| Volume | 38 |
| Issue number | 1 |
| Early online date | 29 Nov 2022 |
| DOIs | |
| Publication status | Published - 19 Jan 2023 |
Bibliographical note
Funding Information:K.L. is funded by a National Institute for Health and Care Research Academic Clinical Fellowship. M.L. is employed by the University of Bristol and worked on two observational cohort studies funded by Parkinson's UK. A.W. is employed by the University of Bristol and has no further financial disclosures for the past 12 months.
Funding Information:
The support for the statistical analyses reported in this article were funded from a donation by David Medlock toward Parkinson's research at North Bristol NHS Trust. The underlying phase II glial cell line–derived neurotrophic factor and extension studies were funded by Parkinson's UK (J‐1102), with financial support from The Cure Parkinson's Trust, and were was sponsored by North Bristol NHS Trust. Study drug, additional project resources, and supplementary funding were provided by MedGenesis Therapeutix, which in turn received program funding support from The Michael J. Fox Foundation for Parkinson's Research. Renishaw plc manufactured the drug delivery device on behalf of North Bristol NHS Trust and provided additional technical and analytical support. Funding agencies:
Publisher Copyright:
© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Research Groups and Themes
- Ageing and Movement Research Group