Background Prognosis in Parkinson's disease (PD) remains poorly understood due to a lack of unbiased data on the natural history of treated PD. The CamPaIGN study has been the first to prospectively track disease evolution from diagnosis in an unselected population-representative incident cohort. We now report the 10-year follow-up data, focusing on three key irreversible milestones: postural instability (Hoehn and Yahr 3), dementia and death. Methods The cohort was collected between December 2000 and 2002. Those meeting diagnostic criteria (n=142) were followed-up until 1 January 2012. Clinical, neuropsychological and genetic testing were performed. Progression to key milestones was evaluated using Kaplan–Meier and Cox regression survival analyses. Results At 10 years, 55% had died, 68% had postural instability and 46% dementia. 23% had a good outcome at 10 years (surviving free of dementia/postural instability). Death rate was comparable with the UK population (standardised mortality ratio 1.29 (0.97–1.61)). Death certificates indicated PD was a substantial contributor in only 20%, with pneumonia being the commonest cause of death. Age, non-tremor-dominant motor phenotype and comorbidity predicted earlier postural instability. Baseline predictors of dementia were age, motor impairment, ‘posterior-cortical’ cognitive deficits and MAPT genotype. Conclusions (1) outlook in PD is heterogeneous, with most dying or developing dementia or postural instability by 10 years from diagnosis, but a quarter still doing well, with preserved mobility and intact cognition; (2) death is not directly related to PD in the majority; (3) baseline clinical and genetic variables are predictive of outcome and may be helpful in selecting patients for clinical trials.

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Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's disease. The frequency of GBA mutations in unselected Parkinson's disease populations has not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson's disease using prospective follow-up. We studied DNA from 262 cases who had been recruited at diagnosis into one of two independent community-based incidence studies of Parkinson's disease. In 121 cases, longitudinal data regarding progression of motor disability and cognitive function were derived from follow-up assessments conducted every 18 months for a median of 71 months. Sequencing of the GBA was performed after two-stage polymerase chain reaction amplification. The carrier frequency of genetic variants in GBA was determined. Baseline demographic and clinical variables were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-type homozygotes. Cox regression analysis was used to model progression to major motor (Hoehn and Yahr stage 3), and cognitive (dementia) end-points in cases followed longitudinally. We show that in a representative, unselected UK Parkinson's disease population, GBA mutations are present at a frequency of 3.5%. This is higher than the prevalence of other genetic mutations currently associated with Parkinson's disease and indicates that GBA mutations make an important contribution to Parkinson's disease encountered in the community setting. Baseline clinical characteristics did not differ significantly between cases with and without GBA sequence variants. However, the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers. We also show that carriers of polymorphisms in GBA which are not generally considered to increase Parkinson's disease risk are at significantly increased risk of progression to Hoehn and Yahr stage 3 (3.2, P = 0.004). Our results indicate that genetic variation in GBA has an important impact on the natural history of Parkinson's disease. To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson's disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson's disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.

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ObjectiveWe hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates.MethodsA total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.ResultsOverall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.InterpretationMutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685

BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

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 HoehneYahr 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 (HoehneYahr 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.

Taken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications.