Background Our understanding of the natural history of idiopathic Parkinson's disease (PD) remains limited. In the era of potential disease modifying therapies, there is an urgent need for studies assessing the natural evolution of treated PD from onset so that relevant outcome measures can be identified for clinical trials. No previous studies have charted progression in unselected patients followed from the point of diagnosis.
Methods A representative cohort of 132 PD patients was followed from diagnosis for up to 7.9 years (mean 5.2 years). Comprehensive clinical and neuropsychological evaluations were performed every 18 months. Disease progression was evaluated using well validated clinical measures (motor progression and development of dyskinesia on the Unified PD Rating Scale and Hoehn–Yahr scale, dementia onset according to DSM-IV criteria). Multi-level linear modelling was used to chart the nature and rate of progression in parkinsonian symptoms and signs over time. The prognostic importance of baseline demogr`aphic, clinical and genetic variables was evaluated using survival analysis.
Results Axial (gait and postural) symptoms evolve more rapidly than other motor features of PD and appear to be the best index of disease progression. Conversely, conventional outcome measures are relatively insensitive to change over time. Earlier onset of postural instability (Hoehn–Yahr stage 3) is strongly associated with increased age at disease onset and has a significant impact on quality of life.
Conclusions Dementia risk is associated with increased age, impaired baseline semantic fluency and the MAPT H1/H1 genotype. The efficacy of disease modifying therapies may be more meaningfully assessed in terms of their effects in delaying the major milestones of PD, such as postural instability and dementia, since it is these that have the greatest impact on patients.
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Funding This work was supported by a National Institute of Health research award to Addenbrooke's Hospital and the University of Cambridge; the Cure Parkinson's Trust; and Parkinson's UK. JRE is supported by the Van Geest Foundation through a Gussy Marlowe Clinician Fellowship, and is in receipt of a Raymond and Beverley Sackler Studentship.
Competing interests None.
Ethics approval This study was conducted with the approval of the Cambridge 2 Local Research Ethics Committee.
Contributors JRE wrote the article, which was reviewed by all the listed authors. All authors contributed to the design of the study. SLM, CHW-G and TF collected the data. JRE performed the statistical analysis. Statistical methods were reviewed by RA Barker.
Provenance and peer review Not commissioned; externally peer reviewed.