Thuy Vu

Progression of motor and nonmotor features of Parkinson's disease and their response to treatment.

AIMS (i) To describe the progression of the cardinal features of Parkinsons disease (PD); (ii) to investigate whether baseline PD subtypes explain disease progression; and (iii) to quantify the symptomatic and disease-modifying effects of anti-parkinsonian treatments. METHODS Data were available for 795 PD subjects, initially untreated, followed for up to 8 years. Cardinal features [tremor, rigidity, bradykinesia, and postural instability and gait disorder (PIGD)] were derived from the total unified Parkinsons disease rating scale (total UPDRS), cognitive status from the mini-mental status exam score (MMSE) and depression status from the Hamilton depression scale (HAM-D). Analysis was performed using a nonlinear mixed effects approach with an asymptotic model for natural disease progression. Treatment effects (i.e. symptomatic and disease modifying) were evaluated by describing changes in the natural history model parameters. RESULTS Tremor progressed more slowly (half-time of 3.9 years) than all other motor features (half-time 2-3 years). The MMSE progression was negligible, while HAM-D progressed with a half-time of 5 years. Levodopa had marked symptomatic effects on all features, but low potency for effect on PIGD (ED₅₀ of 1237 mg day⁻¹ compared with 7-24 mg day⁻¹ for other motor and nonmotor features). Other anti-parkinsonian treatments had much smaller symptomatic effects. All treatments had disease-modifying effects on the cardinal features of PD. Baseline PD subtypes only explained small differences in disease progression. CONCLUSIONS This analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment responsive in early PD patients. There was no evidence of baseline PD subtypes as a clinically useful predictor of disease progression rate. Anti-parkinsonian treatments have symptomatic and disease-modifying effects on all major features of PD.

Dexmedetomidine hemodynamics in children after cardiac surgery.

Background:  Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration–response profile for these hemodynamic effects in children after cardiac surgery.

Disease progress and response to treatment as predictors of survival, disability, cognitive impairment and depression in Parkinson's disease

AIM To describe the time to clinical events (death, disability, cognitive impairment and depression) in Parkinsons disease using the time course of disease status and treatment as explanatory variables. METHODS Disease status based on the Unified Parkinsons Disease Rating Scale (UPDRS) and the time to clinical outcome events were obtained from 800 patients who initially had early Parkinsons disease. Parametric hazard models were used to describe the time to the events of interest. RESULTS Time course of disease status (severity) was an important predictor of clinical outcome events. There was an increased hazard ratio for death 1.4 (95% CI 1.31, 149), disability 2.75 (95% CI 2.30, 3.28), cognitive impairment 4.35 (95% CI 1.94, 9.74), and depressive state 1.43 (95% CI 1.26, 1.63) with each 10 unit increase of UPDRS. Age at study entry increased the hazard with hazard ratios of 49.1 (95% CI 8.7, 278) for death, 4.76 (95% CI 1.10, 20.6) for disability and 90.0 (95% CI 63.3-128) for cognitive impairment at age 60 years. Selegiline treatment had independent effects as a predictor of death at 8 year follow-up with a hazard ratio of 2.54 (95% CI 1.51, 4.25) but had beneficial effects on disability with a hazard ratio of 0.363 (95% CI 0.132, 0.533) and depression with a hazard ratio of 0.372 (95% CI 0.12, 0.552). CONCLUSIONS Our findings show that the time course of disease status based on UPDRS is a much better predictor of future clinical events than any baseline disease characteristic. Continued selegiline treatment appears to increase the hazard of death.

Review: Efficient Rehabilitation Trial Designs Using Disease Progress Modeling: A Pediatric Traumatic Brain Injury Example

Background. The identification of possible treatment effects against a background of spontaneous recovery is a major challenge to the successful completion of randomized clinical trials (RCTs) in rehabilitation research. Conventional trial outcomes such as the differences between group means of an outcome measure at a fixed time point are inefficient to an extent that is a major problem, particularly for exploratory studies seeking preliminary evidence of efficacy. Objective . To quantitate gains in study power over conventional fixed-end-point designs by using parametric end points derived from the modeling of the time course of recovery after brain injury. Methods. Nonlinear mixed effects (NLME) modeling of the recovery trajectories of 103 children rehabilitating after traumatic brain injury (TBI) as reflected in serial WeeFIM scores was performed. Pseudoreplicate data sets were generated replicating the statistical characteristics of the original data set, and these formed the basis of clinical trial simulations to derive robust estimates of study power. Results. Parametric end points derived from modeling of recovery improve study power (and reduce necessary sample size) by up to 5 times in this example. Conclusions. Parametric end points derived from models of recovery trajectories offer an efficient alternative design for exploratory clinical studies of rehabilitation interventions.

Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple-dose Studies of Erenumab in Healthy Subjects and Patients With Migraine

Monoclonal antibodies (mAbs) targeting calcitonin gene‐related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin‐induced dermal blood flow, with no apparent dose‐dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention.

Authors' response to Marras and Oakes, ‘piecing together the puzzle of progression and mortality in Parkinson's disease’

Marras and Oakes [1] have suggested that our conclusions that selegiline is associated with increased mortality may be an artifact of our modelling assumptions [2]. The crux of their argument is that an observed Unified Parkinsons Disease Rating Scale (UPDRS) score measured while taking selegiline does not reflect the disease severity because of ‘symptomatic’ effects that improve the UPDRS but do not change the underlying risk of death. They conclude, therefore, that an increase in hazard of death associated with selegiline is an artifact due to inclusion of the symptomatic benefit when adjusting the hazard for disease severity based on UPDRS. This supposition is a straw man. Marras and Oakes provide no evidence that UPDRS scores in the presence of selegiline do not reflect disease severity. In contrast, we have confirmed [3] the original observation reported by Oakes and his colleagues that selegiline slows the rate of progression of Parkinsons disease measured with UPDRS [4]. This slowing of progression of UPDRS has been shown to reduce the hazard of death, disability, dementia and depression [3]. One can consider an even larger straw man. Levodopa has a much larger symptomatic effect than selegiline, e.g. 12 UPDRS units for levodopa at 300 mg day−1 and 1.2 units for selegiline at 10 mg day−1 [5]. According to Marras and Oakes, this would mean that levodopa should be associated with an even larger increase in the hazard of mortality because the symptomatic benefit of levodopa lowers the UPDRS but does not change the risk of death. If the estimate of levodopa-associated hazard of death was conditional on the UPDRS score, there would be an excess of deaths predicted in the levodopa group at any given observed UPDRS. In fact, there is no evidence that levodopa increases the risk of death. Our own analysis of the risk of death, using the same model that we used for selegiline, showed no increase in hazard with levodopa after adjusting for the UPDRS. This provides strong evidence against the symptomatic straw man conjecture. Marras [6] previously reported that selegiline was not associated with increased risk of mortality. That analysis was based on an intention-to-treat analysis that ignored the treatment with selegiline, which was stopped and restarted several times in the various add-on trials in the DATATOP cohort. We found that selegiline use without adjusting for UPDRS was associated with a nonsignificant decrease in hazard ratio (0.71, with 95% confidence interval 0.48–1.07). A decrease in hazard is not unexpected, because the beneficial effects on hazard reflected in UPDRS are not taken into account. In contrast, adjusting for UPDRS revealed an increased hazard ratio for death (2.54, with 95% confidence interval 1.51–4.25). Our finding that selegiline is associated with increased mortality is in agreement with the only prospective large controlled trial comparing treatment with and without selegiline [7]. In conclusion, we thank Marras and Oakes for identifying a possible criticism of our work, which has led us to understand even better that both the symptomatic and the disease-modifying changes in UPDRS caused by selegiline and levodopa contribute to understanding disease severity and its association with increased hazard of death. This story is not finished because of the increasing use of rasagiline, the pharmacological brother of selegiline. It is hoped that those involved with evaluating the safety of rasagiline will look carefully for a similar increased hazard of death.