Introduction: Functional dependency in basic activities of daily living (ADLs) is a key outcome in Parkinson's disease (PD). We aimed to define dependency in PD, using the original and MDS versions of the Unified Parkinson's Disease Rating Scale (UPDRS). Methods: We developed two algorithms to define dependency from items of UPDRS Part 2 and MDS-UPDRS Part 2 relating to basic ADLs (feeding, dressing, hygiene and walking, and getting out of a chair). We validated both algorithms using data from 1110 patients from six community-based PD incidence cohorts, testing concurrent validity, convergent validity, and predictive validity. Results: Our optimal algorithm showed high specificity and moderate to high sensitivity versus Schwab & England < 80% (specificity 95% [95% confidence interval (CI) 93-97] and sensitivity 65% [95% CI 55-73] at baseline; 88% [95% CI 85-91] and 85% [95% CI 79-97] respectively at five-years follow-up). Convergent validity was demonstrated by strong associations between dependency defined by the algorithm and cognition (MMSE), quality of life (PDQ39), and impairment (UPDRS part 3) (all p < 0.001). Algorithm-defined dependency status also predicted mortality: HR for mortality in those dependent vs independent at baseline was 1.6 (95%CI 1.2-2.1) and in those dependent vs independent at five-years' follow-up was 2.2 (1.6-3.0). Discussion: We have demonstrated the concurrent validity, convergent validity, and predictive validity of a UPDRS-OS-UPDRS-based algorithm to define functional dependency in PD. This can be used for studying dependency in any study where UPDRS or MDS-UPDRS part 2 data have been collected.

Background: Disease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer's disease (AD) and Parkinson's disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification.Methods: MEDLINE, Embase and CENTRAL (1980-2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect.Results: 128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified.Conclusion: We currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.

BACKGROUND:Simple, robust, sensitive and clinically meaningful outcome measures are required for neuroprotective trials in Parkinson's disease (PD). We explored the feasibility of a composite binary outcome measure, 'dead or dependent', in such trials using data from a prospective follow-up study of an incident cohort of PD patients. METHODS:Two hundred incident patients had an annual follow-up, including assessment of the Hoehn-Yahr stage (H-Y) and Schwab and England Activities of Daily Living Scale (S&E). Annual scores were converted into binary variables (H-Y <3 vs H-Y ≥3, and S&E ≥80% vs S&E <80%). A new outcome of 'dead or dependent' was also created, with dependence in activities of daily living defined as S&E <80%. Using these data, sample sizes were calculated for a hypothetical three-year randomised trial in which the trial outcome was defined by a binary clinical variable, all-cause mortality, or PD-related mortality. RESULTS:At 3 years, 18.0% of patients were dead and 38.4% were dead or dependent. At 80% power, large sample sizes were required if PD-related mortality (n=1938 per study arm) or all-cause mortality (n=734) were used as the outcome, even for large treatment effects (30% reduction in relative risk). The new outcome of 'death or dependency' required the smallest sample sizes of all the outcome measures (n=277 for 30% reduction in relative risk, 627 for a 20% reduction). CONCLUSIONS:'Death or dependency' is a feasible and potentially useful outcome measure in PD trials of neuroprotective agents, but further work is required to validate its use and define dependency.

Background: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform.Methods: MEDLINE and Embase (1950-2011) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression.Results: Fifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8-1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors.Conclusions: We found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional 'roadmap' to improve the quality of future disease progression biomarker studies is presented.

Objectives To determine which clinical measures of disease progression in Parkinson's disease (PD) can feasibly be measured across the disease spectrum and which are most sensitive to change. Background Understanding the feasibility of measuring clinical outcomes and their sensitivity to change is crucial when choosing outcome measures for trials of putative neuroprotective drugs in PD. Methods People with clinically defined PD were identified from an on–going long–term follow–up study of incident parkinsonian patients. Annual follow–up included a motor UPDRS, MMSE, Schwab and England, and a timed–walk. In cases of advanced consent a full UPDRS, timed hand–taps, MMP, PDQ–39, EuroQol–5Dindex, EQ–VAS and the Barthel index were also completed. Using data from consenting patients who completed each annual follow–up, percentage completion of collection for each measure over five years was examined. In a subset that completed three years of follow–up, linear mixed modelling was used to determine if clinical measures changed significantly over time. Sensitivity to change was assessed by grouping the measures (motor impairment, disability, quality of life, and cognition) and comparing the percentage change in each from baseline. Results Annual percentage completion of all measures (n=203 at baseline) was high (>80%) over five years. Change over time was examined in 176 patients who had completed three–years of follow–up. All measures, except the stigma (P=0.102) and social (P=0.177) subsections of the PDQ–39, demonstrated significant progression over three–years. The PDQ–39 summary index and its subsections were most sensitive to change (motor impairment, PDQ–39 mobility; disability, PDQ–39 ADL; quality of life, PDQ–39 summary index; cognition, PDQ–39 cognition). Conclusions Collection of all examined clinical measures was feasible. The PDQ–39 summary index and subsections were most sensitive to change.

Scope: Using surrogate outcome biomarkers as endpoints in Parkinson's disease (PD) trials may help differentiate symptomatic effects of putative neuroprotective agents from true disease-modification. We undertook a systematic review to assess what biomarkers for disease progression in PD exist.Searc

Objectives Undertake a systematic review to assess what potential surrogate markers for disease progression in Alzheimer9s disease exist, whether any meet the criteria for use in clinical trials, and if not which looks most promising. Methods Literature searches were conducted in MEDLINE (1950 to 2011) and Embase (1980 to 2011). Five separate search strategies were run in each database. The first four were based on free–text words identified through background reading of relevant review articles. These searches included potential1 blood,2 urine or cerebrospinal fluid (CSF),3 imaging and4 neurophysiological biomarkers. A fifth search using generic terms for biomarkers based on index headings was also run in both databases. The electronic searches were limited to human studies. Reference lists of included articles and relevant review articles were checked to identify any studies which the electronic search strategy may have missed. We included studies of participants with a diagnosis of probable Alzheimer9s disease made by applying formal criteria. Studies which included participants with prodromal Alzheimer9s disease or Mild Cognitive Impairment (MCI) were only included if conversion from MCI to Alzheimer9s disease was confirmed in all participants by clinical follow–up. We made no restriction on participant9s age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate design to use when developing a biomarker for disease progression. We included studies of any test used to investigate disease progression in Alzheimer9s disease, including (but not restricted to) imaging, blood, CSF and neurophysiological tests. We looked for associations of the change in the test result over time with the change in any clinical measure of disease progression–impairment, global cognitive function, disability, handicap, and quality of life. Associations to individual symptoms, parts of scoring systems, mood, disease duration, complications related to therapy and treatment status were excluded. Only papers available in full and in English were included. We assessed study quality using criteria we developed after a recent similar systematic review in Parkinson9s disease. Results Fifty–nine studies were finally included. The most commonly examined biomarker was brain MRI, which was examined in 17 (29%) of the included studies. The median follow–up time in the included longitudinal studies was only 1.0 years (IQR 0.8–1.7). Included studies were generally of poor quality with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and inappropriate statistical analyses. Conclusions We found insufficient evidence to recommend the use of any biomarker for disease progression in Alzheimer9s disease clinical trials at present. This finding may reflect the poor quality of most previous studies in this area. We, therefore, present a provisional roadmap for conducting future studies to develop biomarkers for disease progression in Alzheimer9s disease.

Gardener et al. [ [1] Gardener H. Gao X. Chen H. Schwarzschild M.A. Spiegelman D. Ascherio A. Prenatal and early life factors and risk of Parkinson’s disease. Mov Disord. 2010; 25: 1560-1567 Crossref PubMed Scopus (27) Google Scholar ] recently reported a marginally increased risk of Parkinson’s disease (PD) among those born in the spring compared to winter, although this was not statistically significant (P = 0.08). However, they also reported that women born during the summer had an 82% higher risk of PD than those born in winter. We performed a case-control analysis using data from our ongoing longitudinal incidence study of Parkinsonism in the North East of Scotland (PINE study) [ [2] Taylor K.S. Counsell C.E. Harris C.E. Gordon J.C. Smith W.C. Pilot study of the incidence and prognosis of degenerative Parkinsonian disorders in Aberdeen, United Kingdom: methods and preliminary results. Mov Disord. 2006; 21: 976-982 Crossref PubMed Scopus (36) Google Scholar ] to see if we found similar results.

Background A marked response to dopamine replacement therapy is important in supporting a diagnosis of idiopathic Parkinson's disease (PD). The aim of the study was to compare PD patients' subjective rating of improvement with measured improvement on a number of scales.Methods People with clinically defined PD were identified from a prospective long term follow-up study of incident parkinsonian patients. Changes in the Unified Parkinson's Disease Rating Scale (UPDRS) (activities of daily living and motor subsections), timed tests and Parkinson's Disease Questionnaire, full version, between assessments immediately before starting adequate dopamine replacement and the two subsequent follow-up assessments (mean 6 and 12 months after baseline) were calculated. These were compared with the patients' own subjective ratings of improvement (nil, slight, moderate, good, excellent).Results 133 patients were included (mean age 71 years, 56% men). Thirty-eight patients were treated with a dopamine agonist and 95 with L-dopa (median L-dopa equivalent dose 300 mg). Most patients showed improvements in their measured scores but there was no statistically significant association between these scores and the patient subjective response, except for the motor UPDRS at the first follow-up. A third of those who showed no improvement in their motor UPDRS at the first follow-up rated their improvement as moderate or better, while 29% of those whose motor UPDRS improved by over 50% said they had no or slight improvement.Conclusion PD patients' subjective ratings of their degree of improvement often do not accurately reflect the degree of objective change in parkinsonian impairment or disability. Clinicians should record a simple measure of motor impairment before and after treatment to assess treatment response more accurately.