Journal of Parkinson's Disease - Volume 10, issue 2

Authors: Helmich, Rick C. | Bloem, Bastiaan R.

Article Type: Article Commentary

DOI: 10.3233/JPD-202038

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 351-354, 2020

Authors: McFarthing, Kevin | Larson, Danielle | Simuni, Tanya

Article Type: Other

DOI: 10.3233/JPD-200002

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 355-368, 2020

Authors: De Mattos, Eduardo P. | Wentink, Anne | Nussbaum-Krammer, Carmen | Hansen, Christian | Bergink, Steven | Melki, Ronald | Kampinga, Harm H.

Article Type: Review Article

Abstract: The pathophysiology of Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and many others converge at alpha-synuclein (α -Syn) aggregation. Although it is still not entirely clear what precise biophysical processes act as triggers, cumulative evidence points towards a crucial role for protein quality control (PQC) systems in modulating α -Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating α -Syn levels. Here, we review the main aspects of α -Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone …α -Syn assemblies: molecular chaperones and the ubiquitin-proteasome system and autophagy-lysosome pathway, respectively. A deeper understanding of these basic protein homeostasis mechanisms might contribute to the development of new therapeutic strategies envisioning the prevention and/or enhanced degradation of α -Syn aggregates. Show more

Keywords: Alpha-synuclein, synucleinopathies, protein homeostasis, protein aggregation, molecular chaperones, ubiquitin-proteasome system, autophagy

DOI: 10.3233/JPD-191790

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 369-382, 2020

Authors: Anastasopoulos, Dimitri

Article Type: Review Article

Abstract: It is commonly believed that tremor, one of the cardinal signs of Parkinson’s disease, is associated with cerebello-thalamo-cortical oscillations set off by the dopamine-depleted basal ganglia networks. The triggering mechanism has been, however, not entirely delineated. Several reports have pointed to the relevance of interactions with peripheral/spinal mechanisms to tremor generation. Investigations of motor unit synchronization and discharge patterns suggested that exaggerated beta-band oscillations may intermittently reach alpha-motoneurons and modulate low-amplitude membrane oscillations due to spinal loop transmission delays. As a result, the spinal reflex loop will oscillate more vigorously and at a lower frequency and, in turn, entrain larger …transcortical loops. Motoneurons may thus represent the specific generator “node” in a tremor network encompassing both cerebral and peripheral/spinal recurrent circuits. Show more

Keywords: Parkinsonian tremor, motor unit synchrony, spike doublets, beta oscillations

DOI: 10.3233/JPD-191715

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 383-392, 2020

Authors: Zuzuárregui, José Rafael P. | Ostrem, Jill L.

Article Type: Review Article

Abstract: Background: Parkinson’s disease (PD) can have a significant impact on sleep. Deep brain stimulation (DBS) is an effective treatment for motor features of PD, but less is understood about the impact DBS may have on sleep architecture and various sleep issues commonly seen in PD. Objective: To review the impact of DBS on various sleep issues in PD. Methods: We reviewed the literature regarding the impact of DBS on sleep patterns, nocturnal motor and non-motor symptoms, and sleep disorders in PD. Results: Objective sleep measures on polysomnography (PSG), including sleep latency and wake after …sleep onset improve after subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS. Subjective sleep measures, nocturnal motor symptoms, and some non-motor symptoms (nocturia) also may improve. Current evidence suggests STN DBS has no impact on Rapid Eye Movement Behavior Disorder (RBD), while STN DBS may improve symptoms of Restless Legs Syndrome (RLS). There are no studies that have evaluated the impact of GPi DBS on RBD, while it is unclear if GPi has an effect on RLS in PD. Conclusion: DBS therapy at either site appears to improve objective and subjective sleep parameters in patients with PD. Most likely, the improvement of motor and some non-motor nocturnal symptoms leads to an increase in total sleep time by up to an hour, as well as reduction of sleep fragmentation. DBS most likely has no impact on RBD, while there is evidence that STN DBS appears to help reduce RLS severity. Further studies are needed. Show more

Keywords: Deep brain stimulation, Parkinson’s disease, sleep, rapid eye movement behavior disorder, restless legs syndrome

DOI: 10.3233/JPD-191862

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 393-404, 2020

Authors: von Linstow, Christian U. | DeLano-Taylor, Merritt | Kordower, Jeffrey H. | Brundin, Patrik

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is a slowly progressing neurodegenerative disorder that is coupled to both widespread protein aggregation and to loss of substantia nigra dopamine (DA) neurons, resulting in a wide variety of motor and non-motor signs and symptoms. Recent findings suggest that the PD process is triggered several years before there is sufficient degeneration of DA neurons to cause onset of overt motor symptoms. According to this concept, the number of DA neurons present in the substantia nigra at birth could influence the time from the molecular triggering event until the clinical diagnosis with lower number of neurons at birth …increasing the risk to develop the disease. Conversely, the risk for diagnosis would be reduced if the number of DA neurons is high at birth. In this commentary, we discuss the genetic and epigenetic factors that might influence the number of nigral DA neurons that each individual is born with and how these may be linked to PD risk. Show more

Keywords: Parkinson’s disease risk, dopamine neuron number, substantia nigra, neural development, motor dysfunction, cis-regulation

DOI: 10.3233/JPD-191877

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 405-411, 2020

Authors: Zeissler, Marie-Louise | Li, Vivien | Parmar, Mahesh K.B. | Carroll, Camille Buchholz

Article Type: Review Article

Abstract: Many potential disease modifying therapies have been identified as suitable for clinical evaluation in Parkinson’s disease (PD). Currently, the evaluation of compounds in phase II and phase III clinical trials in PD are set up in isolation, a process that is lengthy, costly and lacks efficiency. This review will introduce the concept of a multi-arm, multi-stage (MAMS) trial platform which allows for the assessment of several potential therapies at once, transitioning seamlessly from a phase II safety and efficacy study to a phase III trial by means of an interim analysis. At the interim checkpoint, ineffective arms are dropped and …replaced by new treatment arms, thereby allowing for the continuous evaluation of interventions. MAMS trial platforms already exist for prostate, renal and oropharyngeal cancer and are currently being developed for progressive multiple sclerosis (PMS) and motor neuron disease (MND) within the UK. As a MAMS trial will evaluate many potential treatments it is of critical importance that a widely endorsed core protocol is developed which will investigate outcomes and objectives meaningful to patients. This review will discuss the challenges of drug selection, trial design, stratification and outcome measures and will share strategies implemented in the planned MAMS trials for MND and PMS that may be of interest to the PD field. Show more

Keywords: Parkinson’s disease, adaptive clinical trial, outcome measure, clinical trial protocol, multiple sclerosis, motor neuron disease

DOI: 10.3233/JPD-191856

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 413-428, 2020

Authors: Morgan, Catherine | Rolinski, Michal | McNaney, Roisin | Jones, Bennet | Rochester, Lynn | Maetzler, Walter | Craddock, Ian | Whone, Alan L.

Article Type: Review Article

Abstract: Background: 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. Objective: 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. …Methods: 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. Results: 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. Conclusions: Home-based free-living testing in PD is being conducted by multiple groups with diverse approaches, focussing mainly on motor symptoms and sleep. Show more

Keywords: Parkinsonian disorders, basal ganglia diseases, technology, algorithms, patient outcome assessment

DOI: 10.3233/JPD-191781

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 429-454, 2020

Authors: Shirahige, Lívia | Berenguer-Rocha, Marina | Mendonça, Sarah | Rocha, Sérgio | Rodrigues, Marcelo Cairrão | Monte-Silva, Kátia

Article Type: Review Article

Abstract: Background: Individualized treatment guided by biomarkers certainly will play a crucial role in the more effective treatment of various neurological diseases in the near future. Identifying the electroencephalographic biomarkers in the brain of patients with Parkinson’s disease (PD) may help in the decision-making process of health professionals regarding the non-invasive brain stimulation (NIBS) protocols. Objective: To summarize quantitative electroencephalographic (qEEG) characteristics of patients with PD with motor symptoms at rest or during movement to identify potential biomarker associated with motor impairment in PD. Methods: A systematic search was conducted in the databases MEDLINE/PubMed, LILACS/BIREME, CINAHL/EBSCO, Web …of Science, and CENTRAL, performed according to PRISMA-statement guidelines. Two independent authors searched for studies that reported qEEG data related to motor outcomes at rest or during movements in patients with PD and compared the data with control healthy group. The studies’ methodological quality was examined using the Cochrane Handbook. Studies/sample characteristics, qEEG parameters/analyses, and the studies’ results were summarized. Prospero-register: CRD42018085660. Results: Nineteen studies (18 cross-sectional/one cross-over) with 312 PD patients and 277 controls, published between 1994-2018, were included for the qualitative analysis. In comparison to healthy controls, our findings suggest a slowing down of the cortical activity in patients with PD due to an increase of slower band waves activity and a decrease of fast band waves at resting and during complex movement execution mainly in the central and frontal cortex. Conclusion: Slowing down of cortical waves suggest excitatory NIBS for motor impairment in PD. However, qEEG biomarker for motor symptoms of PD cannot be established yet because the studies that related qEEG with motor outcomes presented methodological poor quality. Show more

Keywords: Parkinson’s disease, electroencephalography, biomarker, tremor dominant, postural instability/gait difficulty

DOI: 10.3233/JPD-191840

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 455-470, 2020

Authors: Waninger, Shani | Berka, Chris | Stevanovic Karic, Marija | Korszen, Stephanie | Mozley, P. David | Henchcliffe, Claire | Kang, Yeona | Hesterman, Jacob | Mangoubi, Tomer | Verma, Ajay

Article Type: Research Article

Abstract: Background: There is a need for reliable and robust Parkinson’s disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics. Objective: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison’s disease. Methods: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson’s disease patients off medication and compared against age-matched controls. Results: Qualitative and test/retest analysis of the EEG data demonstrated the reliability …of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson’s patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson’s disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson’s disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET. Conclusion: Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson’s disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson’s disease modification therapy. Show more

Keywords: Biomarkers, dopamine transporter PET, EEG, neurophysiology, Parkinson’s disease

DOI: 10.3233/JPD-191844

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 471-480, 2020