Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial

Background: High-intensity aerobic exercise might attenuate the symptoms of Parkinson's disease, but high-quality evidence is scarce. Moreover, long-term adherence remains challenging. We aimed to evaluate the effectiveness of aerobic exercise—gamified and delivered at home, to promote adherence—on relieving motor symptoms in patients with Parkinson's disease with mild disease severity who were on common treatment regimes. Methods: In this single-centre, double-blind, randomised controlled trial (Park-in-Shape), we recruited sedentary patients with Parkinson's disease from the outpatient clinic at Radboudumc, Nijmegen, Netherlands. Patients were made aware of the study either by their treating neurologist or via information in the waiting room. Patients could also contact the study team via social media. We included patients aged 30–75 years with a Hoehn and Yahr stage of 2 or lower, who were on stable dopaminergic medication. Patients were randomly assigned (in a 1:1 ratio) to either aerobic exercise done on a stationary home-trainer (aerobic intervention group) or stretching (active control group) by means of a web-based system with minimisation for sex and medication status (treated or untreated) and permuted blocks of varying sizes of more than two (unknown to study personnel). Patients were only aware of the content of their assigned programme. Assessors were unaware of group assignments. Both interventions were home based, requiring 30–45 min training three times per week for 6 months. Both groups received a motivational app and remote supervision. Home trainers were enhanced with virtual reality software and real-life videos providing a so-called exergaming experience (ie, exercise enhanced by gamified elements). The primary outcome was the between-group difference in the Movement Disorders Society—Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor section at 6 months, tested during the off state (≥12 h after last dopaminergic medication). The analysis was done on an intention-to-treat basis in patients who completed the follow-up assessment, regardless of whether they completed the assigned intervention. Patients reported adverse events directly to their coach and also after the 6-month visit retrospectively. A between-group difference of 3·5 points or more was deemed a-priori clinically relevant. The study is concluded and registered with the Dutch Trial Registry, NTR4743. Findings: Between Feb 2, 2015, and Oct 27, 2017, 139 patients were assessed for eligibility in person, of whom 130 were randomly assigned to either the aerobic intervention group (n=65) or the active control group (n=65). Data from 125 (96%) patients were available for the primary analysis; five patients were lost to follow-up (four in the intervention group; one in the control group). 20 patients (ten in each group) did not complete their assigned programme. The off-state MDS-UPDRS motor score revealed a between-group difference of 4·2 points (95% CI 1·6–6·9, p=0·0020) in favour of aerobic exercise (mean 1·3 points [SE 1·8] in the intervention group and 5·6 points [SE 1·9] for the control group). 11 patients had potentially related adverse events (seven [11%] in the intervention group, four [6%] in the control group) and seven had unrelated serious adverse events (three in the intervention group [vestibilar disorder, vasovagal collapse, knee injury during gardening that required surgery; 6%], four in the control group [supraventricular tachycardia, hip fracture, fall related injury, severe dyskinesias after suprathreshold dose levodopa in a patient with deep brain stimulation; 7%]). Interpretation: Aerobic exercise can be done at home by patients with Parkinson's disease with mild disease severity and it attenuates off-state motor signs. Future studies should establish long-term effectiveness and possible disease-modifying effects. Funding: Netherlands Organization for Health Research and Development

Barriers and Motivators to Engage in Exercise for Persons with Parkinson's Disease

Exercise is increasingly being recognized as a key element in the overall management of persons living with Parkinson's disease (PD) but various (disease-specific) barriers may impede even motivated patients to participate in regular exercise. We aimed to provide a comprehensive review of the various barriers and motivators for exercise in persons with PD. We scrutinized data on compliance-related factors published in cross-sectional studies, randomized controlled trials and reviews. We classified the barriers and motivators to exercise from a patient perspective according to the International Classification of Functioning, Disability and Health. We present an overview of the large range of potential motivators and barriers for exercise in persons with PD. Healthcare professionals should consider a wide and comprehensive range of factors, in order to identify which specific determinants matter most for each individual. Only when persons with PD are adequately motivated in a way that appeals to them and after all person-specific barriers have been tackled, we can begin to expect their long-term adherence to exercise. Such long-term compliance will be essential if exercise is to live up to its expectations, including the hope that prolonged engagement in regular exercise might help to modify the otherwise relentlessly progressive course of PD.status: publishe

Massive CA1/2 Neuronal Loss with Intraneuronal and N-Terminal Truncated Aβ(42) Accumulation in a Novel Alzheimer Transgenic Model

Alzheimer’s disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human β-amyloid (Aβ) precursor protein. Aβ(x-42) is the major form of Aβ species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Aβ and thioflavine-S-positive intracellular material but not with extracellular Aβ deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Aβ(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration

Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer's disease.

Item does not contain fulltextHippocampal atrophy and neuron loss are commonly found in Alzheimer's disease (AD). However, the underlying molecular mechanisms and the fate in the AD hippocampus of subpopulations of interneurons that express the calcium-binding proteins parvalbumin (PV) and calretinin (CR) has not yet been properly assessed. Using quantitative stereologic methods, we analyzed the regional pattern of age-related loss of PV- and CR-immunoreactive (ir) neurons in the hippocampus of mice that carry M233T/L235P knocked-in mutations in presenilin-1 (PS1) and overexpress a mutated human beta-amyloid precursor protein (APP), namely, the APP(SL)/PS1 KI mice, as well as in APP(SL) mice and PS1 KI mice. We found a loss of PV-ir neurons (40-50%) in the CA1-2, and a loss of CR-ir neurons (37-52%) in the dentate gyrus and hilus of APP(SL)/PS1 KI mice. Interestingly, comparable PV- and CR-ir neuron losses were observed in the dentate gyrus of postmortem brain specimens obtained from patients with AD. The loss of these interneurons in AD may have substantial functional repercussions on local inhibitory processes in the hippocampus.01 maart 201