Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as ...important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.
Retromer is a protein assembly that plays a central role in orchestrating export of transmembrane-spanning cargo proteins from endosomes into retrieval pathways destined for the Golgi apparatus and ...the plasma membrane 1. Recently, a specific mutation in the retromer component VPS35, VPS35(D620N), has linked retromer dysfunction to familial autosomal dominant and sporadic Parkinson disease 2, 3. However, the effect of this mutation on retromer function remains poorly characterized. Here we established that in cells expressing VPS35(D620N) there is a perturbation in endosome-to-TGN transport but not endosome-to-plasma membrane recycling, which we confirm in patient cells harboring the VPS35(D620N) mutation. Through comparative stable isotope labeling by amino acids in cell culture (SILAC)-based analysis of wild-type VPS35 versus the VPS35(D620N) mutant interactomes, we establish that the major defect of the D620N mutation lies in the association to the actin-nucleating Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex. Moreover, using isothermal calorimetry, we establish that the primary defect of the VPS35(D620N) mutant is a 2.2 ± 0.5-fold decrease in affinity for the WASH complex component FAM21. These data define the primary molecular defect in retromer assembly that arises from the VPS35(D620N) mutation and, by revealing functional effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in Parkinson disease.
•VPS35(D620N) mutation leads to a defect in endosome-to-TGN transport•Mutant has a perturbed association with the actin-polymerizing WASH complex•Primary defect is a reduced affinity for binding WASH component FAM21•Provides new molecular insight into retromer deregulation in Parkinson disease
Using quantitative proteomics and functional analysis in patient-derived fibroblasts, McGough et al. define the primary molecular defect associated with the Parkinson disease-linked retromer VPS35(D620N) mutation and, by revealing effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in this disease.
Parkinson’s disease is increasing in incidence at a faster rate than any other serious neurologic condition.
1
Despite multiple agents putatively showing preclinical promise, there is no ...disease-modifying therapy available for clinical use in this disorder. Indeed, no potential treatment has survived scrutiny in a clinical trial to reach approval by a regulatory body. Several target mechanisms have been identified by which to achieve neuroprotection or neurorestoration of dopaminergic neurons that are at the nexus of Parkinson’s disease. One approach, which engendered much hope, has been the targeting of the pathologically aggregated form of the protein α-synuclein.
2
Studies of active immunotherapy . . .
Trials of GDNF in Parkinson's disease have yielded inconsistent results. In a randomised controlled trial, Whone et al. administer GDNF using a paradigm designed to optimize delivery to the putamen. ...18FDOPA PET reveals putamen-wide uptake, but GDNF does not differ from placebo in its effects on motor function.
Abstract
We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45 and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: −4.9%, 95% CI: −16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.
Parkinson’s disease (PD) is a chronic neurodegenerative condition that affects a patient’s everyday life. Authors have proposed that a machine learning and sensor-based approach that continuously ...monitors patients in naturalistic settings can provide constant evaluation of PD and objectively analyse its progression. In this paper, we make progress toward such PD evaluation by presenting a multimodal deep learning approach for discriminating between people with PD and without PD. Specifically, our proposed architecture, named MCPD-Net, uses two data modalities, acquired from vision and accelerometer sensors in a home environment to train variational autoencoder (VAE) models. These are modality-specific VAEs that predict effective representations of human movements to be fused and given to a classification module. During our end-to-end training, we minimise the difference between the latent spaces corresponding to the two data modalities. This makes our method capable of dealing with missing modalities during inference. We show that our proposed multimodal method outperforms unimodal and other multimodal approaches by an average increase in F1-score of 0.25 and 0.09, respectively, on a data set with real patients. We also show that our method still outperforms other approaches by an average increase in F1-score of 0.17 when a modality is missing during inference, demonstrating the benefit of training on multiple modalities.
Parkinson's disease (PD) is a debilitating illness associated with considerable impairment of quality of life and substantial costs to health care systems. Deep brain stimulation (DBS) is an ...established surgical treatment option for some patients with advanced PD. The EARLYSTIM trial has recently demonstrated its clinical benefit also in patients with early motor complications. We sought to evaluate the cost-effectiveness of DBS, compared to best medical therapy (BMT), among PD patients with early onset of motor complications, from a United Kingdom (UK) payer perspective.
We developed a Markov model to represent the progression of PD as rated using the Unified Parkinson's Disease Rating Scale (UPDRS) over time in patients with early PD. Evidence sources were a systematic review of clinical evidence; data from the EARLYSTIM study; and a UK Clinical Practice Research Datalink (CPRD) dataset including DBS patients. A mapping algorithm was developed to generate utility values based on UPDRS data for each intervention. The cost-effectiveness was expressed as the incremental cost per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were undertaken to explore the effect of parameter uncertainty.
Over a 15-year time horizon, DBS was predicted to lead to additional mean cost per patient of £26,799 compared with BMT (£73,077/patient versus £46,278/patient) and an additional mean 1.35 QALYs (6.69 QALYs versus 5.35 QALYs), resulting in an incremental cost-effectiveness ratio of £19,887 per QALY gained with a 99% probability of DBS being cost-effective at a threshold of £30,000/QALY. One-way sensitivity analyses suggested that the results were not significantly impacted by plausible changes in the input parameter values.
These results indicate that DBS is a cost-effective intervention in PD patients with early motor complications when compared with existing interventions, offering additional health benefits at acceptable incremental cost. This supports the extended use of DBS among patients with early onset of motor complications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of wearable sensors allows continuous recordings of physical activity from participants in free-living or at-home clinical studies. The large amount of data collected demands automatic ...analysis pipelines to extract gait parameters that can be used as clinical endpoints. We introduce a deep learning-based automatic pipeline for wearables that processes tri-axial accelerometry data and extracts gait events-bout segmentation, initial contact (IC), and final contact (FC)-from a single sensor located at either the lower back (near L5), shin or wrist. The gait events detected are posteriorly used for gait parameter estimation, such as step time, length, and symmetry. We report results from a leave-one-subject-out (LOSO) validation on a pilot study dataset of five participants clinically diagnosed with Parkinson's disease (PD) and six healthy controls (HC). Participants wore sensors at three body locations and walked on a pressure-sensing walkway to obtain reference gait data. Mean absolute errors (MAE) for the IC events ranged from 22.82 to 33.09 milliseconds (msecs) for the lower back sensor while for the shin and wrist sensors, MAE ranges were 28.56-64.66 and 40.19-72.50 msecs, respectively. For the FC-event detection, MAE ranges were 29.06-48.42, 40.19-72.70 and 36.06-60.18 msecs for the lumbar, wrist and shin sensors, respectively. Intraclass correlation coefficients, ICC(2,k), between the estimated parameters and the reference data resulted in good-to-excellent agreement (ICC ≥ 0.84) for the lumbar and shin sensors, excluding the double support time (ICC = 0.37 lumbar and 0.38 shin) and swing time (ICC = 0.55 lumbar and 0.59 shin). The wrist sensor also showed good agreements, but the ICCs were lower overall than for the other two sensors. Our proposed analysis pipeline has the potential to extract up to 100 gait-related parameters, and we expect our contribution will further support developments in the fields of wearable sensors, digital health, and remote monitoring in clinical trials.
The emergence of new technologies measuring outcomes in Parkinson's disease (PD) to complement the existing clinical rating scales has introduced the possibility of measurement occurring in patients' ...own homes whilst they freely live and carry out normal day-to-day activities.
This systematic review seeks to provide an overview of what technology is being used to test which outcomes in PD from free-living participant activity in the setting of the home environment. Additionally, this review seeks to form an impression of the nature of validation and clinimetric testing carried out on the technological device(s) being used.
Five databases (Medline, Embase, PsycInfo, Cochrane and Web of Science) were systematically searched for papers dating from 2000. Study eligibility criteria included: adults with a PD diagnosis; the use of technology; the setting of a home or home-like environment; outcomes measuring any motor and non-motor aspect relevant to PD, as well as activities of daily living; unrestricted/unscripted activities undertaken by participants.
65 studies were selected for data extraction. There were wide varieties of participant sample sizes (<10 up to hundreds) and study durations (<2 weeks up to a year). The metrics evaluated by technology, largely using inertial measurement units in wearable devices, included gait, tremor, physical activity, bradykinesia, dyskinesia and motor fluctuations, posture, falls, typing, sleep and activities of daily living.
Home-based free-living testing in PD is being conducted by multiple groups with diverse approaches, focussing mainly on motor symptoms and sleep.
REM Sleep Behavior Disorder (RBD) is a chronic sleep condition characterized by dream enactment and loss of REM atonia. Individuals often present to clinic with complaints of injury to themselves or ...their bed-partner due to violent movements during sleep. RBD patients have a high risk of developing one of the neurodegenerative α-synucleinopathy diseases: over 70% will develop parkinsonism or dementia within 12 years of their diagnosis. RBD patients also exhibit accelerated disease progression and a more severe phenotype than α-synucleinopathy sufferers without RBD. The disease's low prevalence and the relatively limited awareness of the condition amongst medical professionals makes the diagnosis and treatment of RBD challenging. Uncertainty in patient management is further exacerbated by a lack of clinical guidelines for RBD patient care. There are no binary prognostic markers for RBD disease course and there are no clinical guidelines for neurodegeneration scaling or tracking in these patients. Both clinicians and patients are therefore forced to deal with uncertain outcomes. In this review, we summarize RBD pathology and differential diagnoses, diagnostic, and treatment guidelines as well as prognostic recommendations with a look to current research in the scientific field. We aim to raise awareness and develop a framework for best practice for RBD patient management.
PDF
