30 results on '"Whone AL"'
Search Results
2. Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study.
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Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, Brooks DJ, and REAL-PET Study Group
- Published
- 2003
3. Slower rates of prism adaptation but intact aftereffects in patients with early to mid-stage Parkinson's disease.
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Swainson A, Woodward KM, Boca M, Rolinski M, Collard P, Cerminara NL, Apps R, Whone AL, and Gilchrist ID
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- Humans, Psychomotor Performance, Adaptation, Physiological, Parkinson Disease psychology
- Abstract
There is currently mixed evidence on the effect of Parkinson's disease on motor adaptation. Some studies report that patients display adaptation comparable to age-matched controls, while others report a complete inability to adapt to novel sensory perturbations. Here, early to mid-stage Parkinson's patients were recruited to perform a prism adaptation task. When compared to controls, patients showed slower rates of initial adaptation but intact aftereffects. These results support the suggestion that patients with early to mid-stage Parkinson's disease display intact adaptation driven by sensory prediction errors, as shown by the intact aftereffect. But impaired facilitation of performance through cognitive strategies informed by task error, as shown by the impaired initial adaptation. These results support recent studies that suggest that patients with Parkinson's disease retain the ability to perform visuomotor adaptation, but display altered use of cognitive strategies to aid performance and generalises these previous findings to the classical prism adaptation task., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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4. Acceptability of an In-home Multimodal Sensor Platform for Parkinson Disease: Nonrandomized Qualitative Study.
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Morgan C, Tonkin EL, Craddock I, and Whone AL
- Abstract
Background: Parkinson disease (PD) symptoms are complex, gradually progressive, and fluctuate hour by hour. Home-based technological sensors are being investigated to measure symptoms and track disease progression. A smart home sensor platform, with cameras and wearable devices, could be a useful tool to use to get a fuller picture of what someone's symptoms are like. High-resolution video can capture the ground truth of symptoms and activities. There is a paucity of information about the acceptability of such sensors in PD., Objective: The primary objective of our study was to explore the acceptability of living with a multimodal sensor platform in a naturalistic setting in PD. Two subobjectives are to identify any suggested limitations and to explore the sensors' impact on participant behaviors., Methods: A qualitative study was conducted with an inductive approach using semistructured interviews with a cohort of PD and control participants who lived freely for several days in a home-like environment while continuously being sensed., Results: This study of 24 participants (12 with PD) found that it is broadly acceptable to use multimodal sensors including wrist-worn wearables, cameras, and other ambient sensors passively in free-living in PD. The sensor that was found to be the least acceptable was the wearable device. Suggested limitations on the platform for home deployment included camera-free time and space. Behavior changes were noted by the study participants, which may have related to being passively sensed. Recording high-resolution video in the home setting for limited periods of time was felt to be acceptable to all participants., Conclusions: The results broaden the knowledge of what types of sensors are acceptable for use in research in PD and what potential limitations on these sensors should be considered in future work. The participants' reported behavior change in this study should inform future similar research design to take this factor into account. Collaborative research study design, involving people living with PD at every stage, is important to ensure that the technology is acceptable and that the data outcomes produced are ecologically valid and accurate., International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2020-041303., (©Catherine Morgan, Emma L Tonkin, Ian Craddock, Alan L Whone. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 07.07.2022.)
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- 2022
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5. An Automatic Gait Analysis Pipeline for Wearable Sensors: A Pilot Study in Parkinson's Disease.
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Peraza LR, Kinnunen KM, McNaney R, Craddock IJ, Whone AL, Morgan C, Joules R, and Wolz R
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- Gait, Gait Analysis, Humans, Pilot Projects, Parkinson Disease diagnosis, Wearable Electronic Devices
- Abstract
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.
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- 2021
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6. Multimodal Classification of Parkinson's Disease in Home Environments with Resiliency to Missing Modalities.
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Heidarivincheh F, McConville R, Morgan C, McNaney R, Masullo A, Mirmehdi M, Whone AL, and Craddock I
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- Humans, Machine Learning, Monitoring, Physiologic, Parkinson Disease
- Abstract
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., Competing Interests: The authors declare no conflict of interest.
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- 2021
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7. Protocol for PD SENSORS: Parkinson's Disease Symptom Evaluation in a Naturalistic Setting producing Outcome measuRes using SPHERE technology. An observational feasibility study of multi-modal multi-sensor technology to measure symptoms and activities of daily living in Parkinson's disease.
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Morgan C, Craddock I, Tonkin EL, Kinnunen KM, McNaney R, Whitehouse S, Mirmehdi M, Heidarivincheh F, McConville R, Carey J, Horne A, Rolinski M, Rochester L, Maetzler W, Matthews H, Watson O, Eardley R, and Whone AL
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- Activities of Daily Living, Feasibility Studies, Humans, Outcome Assessment, Health Care, Symptom Assessment, Technology, Parkinson Disease diagnosis
- Abstract
Introduction: The impact of disease-modifying agents on disease progression in Parkinson's disease is largely assessed in clinical trials using clinical rating scales. These scales have drawbacks in terms of their ability to capture the fluctuating nature of symptoms while living in a naturalistic environment. The SPHERE (Sensor Platform for HEalthcare in a Residential Environment) project has designed a multi-sensor platform with multimodal devices designed to allow continuous, relatively inexpensive, unobtrusive sensing of motor, non-motor and activities of daily living metrics in a home or a home-like environment. The aim of this study is to evaluate how the SPHERE technology can measure aspects of Parkinson's disease., Methods and Analysis: This is a small-scale feasibility and acceptability study during which 12 pairs of participants (comprising a person with Parkinson's and a healthy control participant) will stay and live freely for 5 days in a home-like environment embedded with SPHERE technology including environmental, appliance monitoring, wrist-worn accelerometry and camera sensors. These data will be collected alongside clinical rating scales, participant diary entries and expert clinician annotations of colour video images. Machine learning will be used to look for a signal to discriminate between Parkinson's disease and control, and between Parkinson's disease symptoms 'on' and 'off' medications. Additional outcome measures including bradykinesia, activity level, sleep parameters and some activities of daily living will be explored. Acceptability of the technology will be evaluated qualitatively using semi-structured interviews., Ethics and Dissemination: Ethical approval has been given to commence this study; the results will be disseminated as widely as appropriate., Competing Interests: Conflicts of interests: KK is employed by IXICO, that have provided some financial support for the study. Their search may lead to the development of products which may be licensed to IXICO., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2020
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8. A Neurologist's Guide to REM Sleep Behavior Disorder.
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Roguski A, Rayment D, Whone AL, Jones MW, and Rolinski M
- Abstract
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., (Copyright © 2020 Roguski, Rayment, Whone, Jones and Rolinski.)
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- 2020
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9. Freezing of Gait in People with Parkinson's Disease: Nature, Occurrence, and Risk Factors.
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Lord SR, Bindels H, Ketheeswaran M, Brodie MA, Lawrence AD, Close JCT, Whone AL, Ben-Shlomo Y, and Henderson EJ
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- Accelerometry, Aged, Female, Gait Disorders, Neurologic etiology, Humans, Male, Middle Aged, Parkinson Disease complications, Risk Factors, Severity of Illness Index, Time Factors, Executive Function physiology, Gait Disorders, Neurologic physiopathology, Parkinson Disease physiopathology, Parkinson Disease psychology, Postural Balance physiology, Proprioception physiology
- Abstract
Background: Freezing of gait (FOG) is a common symptom of Parkinson's disease (PD) which can result in falls and fall related injuries, poor quality of life and reduced functional independence. It is a heterogeneous phenomenon that is difficult to quantify and eludes a unified pathophysiological framework., Objective: Our aim was to document the occurrence and nature of freezing, cognitive stops and stumbles in people with PD during walks with varying cognitive loads and conditions designed to elicit FOG., Methods: 130 people with PD walked under four conditions (normal walking, walking plus easy and hard dual-tasks, and a FOG elicitation condition. Video and accelerometry recordings were examined to document freezes and other gait disruptions., Results: Participants experienced 391 freezes, 97 cognitive stops and 73 stumbles in the trial walks; with total gait disruptions increasing with task complexity. Most freezes in the FOG elicitation condition occurred during turning and approach destination. People who experienced freezing during the walks were more likely to have Postural Instability and Gait Difficulty (PIGD) subtype, longer disease duration and more severe UPDRS part II and part III sub-scores than people who did not freeze. They also took higher doses of levodopa, reported freezing in the past month, more prior falls, had poorer executive function, poorer proprioception, slower reaction time, poorer standing and leaning balance, more depressive symptoms, lower quality of life and greater fear of falling. PD disease duration, reduced controlled leaning balance and poor proprioception were identified as independent and significant determinants of freezing in logistic regression analysis., Conclusion: The multiple motor and cognitive factors identified as being associated with freezing, including poor proprioception and impaired controlled leaning balance provide new insights into this debilitating PD symptom and may contribute to potential new targets for rehabilitation.
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- 2020
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10. Systematic Review Looking at the Use of Technology to Measure Free-Living Symptom and Activity Outcomes in Parkinson's Disease in the Home or a Home-like Environment.
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Morgan C, Rolinski M, McNaney R, Jones B, Rochester L, Maetzler W, Craddock I, and Whone AL
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- Humans, Activities of Daily Living, Mobile Applications, Monitoring, Ambulatory, Parkinson Disease diagnosis, Patient Outcome Assessment, Psychometrics, Telemedicine, Wearable Electronic Devices
- 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.
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- 2020
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11. Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.
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Whone AL, Boca M, Luz M, Woolley M, Mooney L, Dharia S, Broadfoot J, Cronin D, Schroers C, Barua NU, Longpre L, Barclay CL, Boiko C, Johnson GA, Fibiger HC, Harrison R, Lewis O, Pritchard G, Howell M, Irving C, Johnson D, Kinch S, Marshall C, Lawrence AD, Blinder S, Sossi V, Stoessl AJ, Skinner P, Mohr E, and Gill SS
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- Antiparkinson Agents therapeutic use, Dihydroxyphenylalanine analogs & derivatives, Female, Fluorine Radioisotopes, Humans, Levodopa therapeutic use, Male, Middle Aged, Parkinson Disease diagnostic imaging, Parkinson Disease metabolism, Positron-Emission Tomography, Putamen metabolism, Randomized Controlled Trials as Topic, Glial Cell Line-Derived Neurotrophic Factor therapeutic use, Parkinson Disease drug therapy, Putamen diagnostic imaging
- Abstract
Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen., Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks., Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score., Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified., Conclusions: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.
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- 2019
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12. Deep Brain Stimulation for Parkinson's Disease with Early Motor Complications: A UK Cost-Effectiveness Analysis.
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Fundament T, Eldridge PR, Green AL, Whone AL, Taylor RS, Williams AC, and Schuepbach WM
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- Humans, Middle Aged, Models, Theoretical, Parkinson Disease physiopathology, Probability, Quality of Life, Quality-Adjusted Life Years, United Kingdom, Cost-Benefit Analysis, Deep Brain Stimulation economics, Deep Brain Stimulation methods, Motor Activity, Parkinson Disease economics, Parkinson Disease therapy
- Abstract
Background: 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., Methods: 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., Results: 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., Conclusion: 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.
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- 2016
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13. Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial.
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Henderson EJ, Lord SR, Brodie MA, Gaunt DM, Lawrence AD, Close JC, Whone AL, and Ben-Shlomo Y
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- Accidental Falls, Aged, Aged, 80 and over, Cholinesterase Inhibitors administration & dosage, Cholinesterase Inhibitors adverse effects, Double-Blind Method, Female, Gait Disorders, Neurologic etiology, Humans, Male, Middle Aged, Parkinson Disease complications, Rivastigmine administration & dosage, Rivastigmine adverse effects, Cholinesterase Inhibitors pharmacology, Gait Disorders, Neurologic drug therapy, Outcome Assessment, Health Care, Parkinson Disease drug therapy, Rivastigmine pharmacology
- Abstract
Background: Falls are a frequent and serious complication of Parkinson's disease and are related partly to an underlying cholinergic deficit that contributes to gait and cognitive dysfunction in these patients. Gait dysfunction can lead to an increased variability of gait from one step to another, raising the likelihood of falls. In the ReSPonD trial we aimed to assess whether ameliorating this cholinergic deficit with the acetylcholinesterase inhibitor rivastigmine would reduce gait variability., Methods: We did this randomised, double-blind, placebo-controlled, phase 2 trial at the North Bristol NHS Trust Hospital, Bristol, UK, in patients with Parkinson's disease recruited from community and hospital settings in the UK. We included patients who had fallen at least once in the year before enrolment, were able to walk 18 m without an aid, had no previous exposure to an acetylcholinesterase inhibitor, and did not have dementia. Our clinical trials unit randomly assigned (1:1) patients to oral rivastigmine or placebo capsules (both taken twice a day) using a computer-generated randomisation sequence and web-based allocation. Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks. Both the trial team and patients were masked to treatment allocation. Masking was achieved with matched placebo capsules and a dummy uptitration schedule. The primary endpoint was difference in step time variability between the two groups at 32 weeks, adjusted for baseline age, cognition, step time variability, and number of falls in the previous year. We measured step time variability with a triaxial accelerometer during an 18 m walking task in three conditions: normal walking, simple dual task with phonemic verbal fluency (walking while naming words beginning with a single letter), and complex dual task switching with phonemic verbal fluency (walking while naming words, alternating between two letters of the alphabet). Analysis was by modified intention to treat; we excluded from the primary analysis patients who withdrew, died, or did not attend the 32 week assessment. This trial is registered with ISRCTN, number 19880883., Findings: Between Oct 4, 2012 and March 28, 2013, we enrolled 130 patients and randomly assigned 65 to the rivastigmine group and 65 to the placebo group. At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had improved step time variability for normal walking (ratio of geometric means 0.72, 95% CI 0.58-0.88; p=0.002) and the simple dual task (0.79; 0.62-0.99; p=0.045). Improvements in step time variability for the complex dual task did not differ between groups (0.81, 0.60-1.09; p=0.17). Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p<0.0001); 20 (31%) patients in the rivastigmine group versus three (5%) in the placebo group had nausea and 15 (17%) versus three (5%) had vomiting., Interpretation: Rivastigmine can improve gait stability and might reduce the frequency of falls. A phase 3 study is needed to confirm these findings and show cost-effectiveness of rivastigmine treatment., Funding: Parkinson's UK., (Copyright © 2016 Henderson et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
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14. Comparison of Test Your Memory and Montreal Cognitive Assessment Measures in Parkinson's Disease.
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Henderson EJ, Chu H, Gaunt DM, Whone AL, Ben-Shlomo Y, and Lyell V
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Background. MoCA is widely used in Parkinson's disease (PD) to assess cognition. The Test Your Memory (TYM) test is a cognitive screening tool that is self-administered. Objectives. We sought to determine (a) the optimal value of TYM to discriminate between PD patients with and without cognitive deficits on MoCA testing, (b) equivalent MoCA and TYM scores, and (c) interrater reliability in TYM testing. Methods. We assessed the discriminant ability of TYM and the equivalence between TYM and MoCA scores and measured the interrater reliability between three raters. Results. Of the 135 subjects that completed both tests, 55% had cognitive impairment according to MoCA. A MoCA score of 25 was equivalent to a TYM score of 43-44. The area under the receiver operator characteristic (ROC) curve for TYM to differentiate between PD-normal and PD-cognitive impairment was 0.82 (95% CI 0.75 to 0.89). The optimal cutoff to distinguish PD-cognitive impairment from PD-normal was ≤45 (sensitivity 90.5%, specificity 59%) thereby correctly classifying 76.3% of patients with PD-cognitive impairment. Interrater agreement was high (0.97) and TYM was completed in under 7 minutes (interquartile range 5.33 to 8.52 minutes). Conclusions. The TYM test is a useful and less resource intensive screening test for cognitive deficits in PD.
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- 2016
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15. Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes.
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Wang W, Wang X, Fujioka H, Hoppel C, Whone AL, Caldwell MA, Cullen PJ, Liu J, and Zhu X
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- Aged, Aged, 80 and over, Animals, Blotting, Western, Cell Line, Tumor, Dynamins metabolism, Female, Fluorescence Recovery After Photobleaching, Fluorescent Antibody Technique, Gene Knockdown Techniques, Humans, In Vitro Techniques, Male, Mice, Microscopy, Electron, Transmission, Microscopy, Immunoelectron, Mitochondria pathology, Neurons, Oxidative Stress, Parkinson Disease metabolism, Parkinson Disease pathology, Rats, Substantia Nigra cytology, Time-Lapse Imaging, GTP Phosphohydrolases metabolism, Microtubule-Associated Proteins metabolism, Mitochondria metabolism, Mitochondrial Dynamics genetics, Mitochondrial Proteins metabolism, Parkinson Disease genetics, Vesicular Transport Proteins genetics
- Abstract
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.
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- 2016
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16. Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation.
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McGough IJ, Steinberg F, Jia D, Barbuti PA, McMillan KJ, Heesom KJ, Whone AL, Caldwell MA, Billadeau DD, Rosen MK, and Cullen PJ
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- 2014
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17. Ventral striatal dopamine synthesis capacity predicts financial extravagance in Parkinson's disease.
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Lawrence AD, Brooks DJ, and Whone AL
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Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson's disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait "disinhibition" is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[(18)F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.
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- 2013
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18. Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making.
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Coulthard EJ, Bogacz R, Javed S, Mooney LK, Murphy G, Keeley S, and Whone AL
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- Analysis of Variance, Decision Making drug effects, Deep Brain Stimulation methods, Dopamine Agents therapeutic use, Female, Humans, Learning drug effects, Male, Middle Aged, Neuropsychological Tests, Photic Stimulation, Psychomotor Performance drug effects, Psychomotor Performance physiology, Reaction Time drug effects, Time Factors, Decision Making physiology, Dopamine metabolism, Learning physiology, Parkinson Disease metabolism, Parkinson Disease physiopathology, Parkinson Disease therapy, Probability, Subthalamic Nucleus physiology
- Abstract
Even simple behaviour requires us to make decisions based on combining multiple pieces of learned and new information. Making such decisions requires both learning the optimal response to each given stimulus as well as combining probabilistic information from multiple stimuli before selecting a response. Computational theories of decision making predict that learning individual stimulus-response associations and rapid combination of information from multiple stimuli are dependent on different components of basal ganglia circuitry. In particular, learning and retention of memory, required for optimal response choice, are significantly reliant on dopamine, whereas integrating information probabilistically is critically dependent upon functioning of the glutamatergic subthalamic nucleus (computing the 'normalization term' in Bayes' theorem). Here, we test these theories by investigating 22 patients with Parkinson's disease either treated with deep brain stimulation to the subthalamic nucleus and dopaminergic therapy or managed with dopaminergic therapy alone. We use computerized tasks that probe three cognitive functions-information acquisition (learning), memory over a delay and information integration when multiple pieces of sequentially presented information have to be combined. Patients performed the tasks ON or OFF deep brain stimulation and/or ON or OFF dopaminergic therapy. Consistent with the computational theories, we show that stopping dopaminergic therapy impairs memory for probabilistic information over a delay, whereas deep brain stimulation to the region of the subthalamic nucleus disrupts decision making when multiple pieces of acquired information must be combined. Furthermore, we found that when participants needed to update their decision on the basis of the last piece of information presented in the decision-making task, patients with deep brain stimulation of the subthalamic nucleus region did not slow down appropriately to revise their plan, a pattern of behaviour that mirrors the impulsivity described clinically in some patients with subthalamic nucleus deep brain stimulation. Thus, we demonstrate distinct mechanisms for two important facets of human decision making: first, a role for dopamine in memory consolidation, and second, the critical importance of the subthalamic nucleus in successful decision making when multiple pieces of information must be combined.
- Published
- 2012
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19. Cerebral ischaemia in the context of improving, steroid-treated pneumococcal meningitis.
- Author
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Rice CM, Ramamoorthi M, Renowden SA, Heywood P, Whone AL, and Scolding NJ
- Subjects
- Adult, Anti-Bacterial Agents therapeutic use, Brain Ischemia diagnosis, Ceftriaxone therapeutic use, Dexamethasone therapeutic use, Exotropia etiology, Glucocorticoids therapeutic use, Headache etiology, Humans, Magnetic Resonance Imaging, Male, Meningitis, Pneumococcal drug therapy, Myoclonus etiology, Brain Ischemia etiology, Meningitis, Pneumococcal complications
- Published
- 2012
- Full Text
- View/download PDF
20. Human bone marrow mesenchymal stem cells protect catecholaminergic and serotonergic neuronal perikarya and transporter function from oxidative stress by the secretion of glial-derived neurotrophic factor.
- Author
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Whone AL, Kemp K, Sun M, Wilkins A, and Scolding NJ
- Subjects
- Analysis of Variance, Animals, Cell Survival drug effects, Culture Media, Conditioned pharmacology, Embryo, Mammalian, Female, Glial Cell Line-Derived Neurotrophic Factor pharmacology, Humans, Nerve Growth Factors metabolism, Nerve Tissue Proteins metabolism, Nitric Oxide pharmacology, Oxidative Stress drug effects, Plasma Membrane Neurotransmitter Transport Proteins metabolism, Pregnancy, Rats, Time Factors, Catecholamines metabolism, Glial Cell Line-Derived Neurotrophic Factor metabolism, Mesenchymal Stem Cells metabolism, Neural Stem Cells drug effects, Neural Stem Cells physiology, Serotonin metabolism
- Abstract
In neurodegenerative disorders, including Parkinson's disease (PD), the potential of mesenchymal stem cells (MSCs) to produce neurorestoration via trans-differentiation has garnered much interest. We believe, however, that the paracrine effects of MSCs may have greater utility. MSCs release neurotrophic factors, including glial derived neurotrophic factor (GDNF). The benefits conferred by MSC GDNF release could potentially apply to all degenerating monoaminergic fibre types, throughout the brains of patients with PD, rather than solely affording protection to the dopaminergic neurones of the nigro-striatal pathway alone. Using an in vitro approach, we have investigated the neuroprotective properties of unmodified human MSCs on rat catecholaminergic and serotonergic cell cultures exposed to the damaging effects of nitric oxide. We have shown that post oxidative and inflammatory stress, soluble factors produced by native human MSCs, requiring no direct cell-cell contact or genetic or other manipulation, confer protection not only of cultured monoaminergic perikarya, but also of monoamine neurotransmitter transporter function. Furthermore, we have confirmed that, in part, this MSC mediated neuroprotective effect is due to MSC GDNF release and that such protection is diminished when the action of GDNF is blocked. Trophic factor release may afford a way by which intravenously infused MSCs can offer protection to all of the dopaminergic, noradrenergic and serotonergic fibre types degenerating widely throughout the brains of patients with PD., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
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21. Progression of monoaminergic dysfunction in Parkinson's disease: a longitudinal 18F-dopa PET study.
- Author
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Pavese N, Rivero-Bosch M, Lewis SJ, Whone AL, and Brooks DJ
- Subjects
- Amino Acid Transport Systems, Neutral metabolism, Antiparkinson Agents therapeutic use, Decarboxylation, Dihydroxyphenylalanine analogs & derivatives, Dopamine metabolism, Dopamine physiology, Female, Follow-Up Studies, Humans, Image Processing, Computer-Assisted, Levodopa therapeutic use, Longitudinal Studies, Male, Middle Aged, Norepinephrine metabolism, Norepinephrine physiology, Positron-Emission Tomography, Radiopharmaceuticals, Serotonin metabolism, Serotonin physiology, Biogenic Monoamines physiology, Parkinson Disease diagnostic imaging, Parkinson Disease physiopathology
- Abstract
Post-mortem and neuroimaging studies in Parkinson's disease (PD) have shown involvement of the brain serotoninergic, noradrenergic and cholinergic pathways alongside the characteristic degeneration of nigrostriatal dopamine neurons. The rate of progression of the degenerative process in these extrastriatal areas is still unclear. We used (18)F-dopa PET, a marker of aromatic aminoacid decarboxylase activity in monoaminergic neurons, to assess longitudinal changes in tracer uptake in brain noradrenergic, serotoninergic and extrastriatal dopaminergic structures over a 3-year period in a group of early PD patients. Ten PD patients had (18)F-dopa PET twice: at baseline and again after 37.1±21.5 months follow up. A standard object map was used to extract tracer influx constants (Ki) in 11 striatal and extrastriatal regions. Progressive decreases in (18)F-dopa Ki occurred over the follow-up period in the majority of the investigated areas, the fastest annual declines occurring in putamen (8.1%), locus coeruleus (7.8%), and globus pallidus interna (7.7%). Caudate and hypothalamus showed 6.3% and 6.1% annual Ki declines, respectively. At baseline, some structures showed increased levels of (18)F-dopa uptake in PD compared to controls (internal pallidum, locus coeruleus), indicating possible compensatory upregulation of monoamine turnover. These increased levels had normalised (globus pallidus interna) or become subnormal (locus coeruleus) at follow-up suggesting exhaustion of these mechanisms within the first years of disease. Loss of monoaminergic function in extrastriatal regions, as reflected by(18)F-dopa PET, is delayed and occurs independently from nigrostriatal degeneration. When assessing the efficacy of novel neuroprotective agents on nigrostriatal dysfunction in PD, (18)F-dopa PET could provide supplementary information concerning function of extrastriatal monoaminergic structures., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
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22. Outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with Parkinson's disease.
- Author
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Khan S, Mooney L, Plaha P, Javed S, White P, Whone AL, and Gill SS
- Subjects
- Adult, Antiparkinson Agents therapeutic use, Female, Gait Disorders, Neurologic physiopathology, Humans, Male, Middle Aged, Parkinson Disease physiopathology, Quality of Life, Severity of Illness Index, Treatment Outcome, Deep Brain Stimulation methods, Gait Disorders, Neurologic therapy, Parkinson Disease therapy, Pedunculopontine Tegmental Nucleus physiopathology, Subthalamus physiopathology
- Abstract
Introduction: Axial symptoms including postural instability, falls and failure of gait initiation are some of the most disabling motor symptoms of Parkinson's disease (PD). We performed bilateral deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) in combination with the caudal zona incerta (cZi) in order to determine their efficacy in alleviating these symptoms., Methods: Seven patients with predominant axial symptoms in both the 'on' and 'off' medication states underwent bilateral cZi and PPN DBS. Motor outcomes were assessed using the motor component of the Unified Parkinson's Disease Rating Scale (UPDRS 3) and a composite axial subscore was derived from items 27, 28, 29 and 30 (arising from chair, posture, gait and postural stability). Quality of life was measured using the PDQ39. Comparisons were made between scores obtained at baseline and those at a mean follow-up of 12 months., Results: In both the off and on medication states, a statistically significant improvement in the UPDRS part 3 score was achieved by stimulation of the PPN, cZi and both in combination. In the off medication state, our composite axial subscore of the UPDRS part 3 improved with stimulation of the PPN, cZi and both in combination. The composite axial subscore, in the 'on' medication state, however, only showed a statistically significant improvement when a combination of cZi and PPN stimulation was used., Conclusions: This study provides evidence that a combination of PPN and cZi stimulation can achieve a significant improvement in the hitherto untreatable 'on' medication axial symptoms of PD.
- Published
- 2011
- Full Text
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23. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis.
- Author
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Rice CM, Mallam EA, Whone AL, Walsh P, Brooks DJ, Kane N, Butler SR, Marks DI, and Scolding NJ
- Subjects
- Adult, Bone Marrow Transplantation adverse effects, Disability Evaluation, Feasibility Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Transplantation, Autologous, Bone Marrow Transplantation methods, Evoked Potentials, Magnetic Resonance Imaging methods, Multiple Sclerosis, Relapsing-Remitting surgery
- Abstract
In this phase I study, we assessed the safety and feasibility of intravenous, autologous bone marrow (BM) cell therapy, without immunosuppressive preconditioning, in six patients with clinically definite, relapsing-progressive multiple sclerosis (MS). Assessment of efficacy was a secondary objective and employed clinical disability rating scales, multimodal evoked potential (MMEP) recordings, and magnetic resonance imaging (MRI) scans. Cells were harvested, filtered and infused intravenously in a day-case procedure that was well tolerated by patients and was not associated with any serious adverse events (AEs). Over a period of 12 months after the therapy, clinical disability scores showed either no change (Extended Disability Status Score, EDSS) or improvement (MS impact scale-29, MSIS-29), and MMEPs showed neurophysiological improvement. MRI scans did not show any significant changes over a post-therapy period of 3 months. The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous BM in patients with MS.
- Published
- 2010
- Full Text
- View/download PDF
24. Extrastriatal monoamine neuron function in Parkinson's disease: an 18F-dopa PET study.
- Author
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Moore RY, Whone AL, and Brooks DJ
- Subjects
- Adult, Biogenic Monoamines metabolism, Cerebral Cortex diagnostic imaging, Cerebral Cortex metabolism, Cross-Sectional Studies, Fluorine Radioisotopes, Humans, Middle Aged, Neurons physiology, Dihydroxyphenylalanine metabolism, Dopamine metabolism, Neurons diagnostic imaging, Parkinson Disease diagnostic imaging, Parkinson Disease metabolism, Positron-Emission Tomography methods
- Abstract
The early motor manifestations of Parkinson's disease (PD) reflect degeneration of nigrostriatal dopamine neurons projecting to the caudal putamen. However, extrastriatal dopamine and other monoamine systems are also involved, particularly in later disease. We used (18)F-dopa PET in a cross-sectional study to characterize extrastriatal monoamine neuronal dysfunction in PD. 16 Controls and 41 patients underwent investigation. We found that (18)F-dopa uptake was decreased in cortical motor areas, particularly the motor cortex, even in early disease. Frontal association areas were also affected in later disease but limbic areas were spared except for hypothalamus. The substantia nigra, midbrain raphe and locus coeruleus showed normal or increased (18)F-dopa uptake until PD was advanced, indicating compensatory responses in intact monoamine neuron perikarya. The red nucleus, subthalamus, ventral thalamus and pineal gland were also eventually involved. These findings provide a further basis for understanding the complex pathophysiology of PD in vivo and complement pathological studies.
- Published
- 2008
- Full Text
- View/download PDF
25. The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study.
- Author
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von Spiczak S, Whone AL, Hammers A, Asselin MC, Turkheimer F, Tings T, Happe S, Paulus W, Trenkwalder C, and Brooks DJ
- Subjects
- Adult, Aged, Carbon Radioisotopes, Case-Control Studies, Diprenorphine, Female, Humans, Image Processing, Computer-Assisted methods, Male, Middle Aged, Narcotic Antagonists, Pain Measurement, Positron-Emission Tomography methods, Restless Legs Syndrome diagnostic imaging, Severity of Illness Index, Opioid Peptides physiology, Restless Legs Syndrome physiopathology
- Abstract
Opioids have been shown to provide symptomatic relief from dysaesthesias and motor symptoms in restless legs syndrome (RLS). However, the mechanisms by which endogenous opioids contribute to the pathophysiology of RLS remain unknown. We have studied opioid receptor availability in 15 patients with primary RLS and 12 age-matched healthy volunteers using PET and [11C]diprenorphine, a non-selective opioid receptor radioligand. Ligand binding was quantified by generating parametric images of volume of distribution (V(d)) using a plasma-derived input function. Statistical parametric mapping (SPM) was used to localize mean group differences between patients and controls and to correlate ligand binding with clinical scores of disease severity. There were no mean group differences in opioid receptor binding between patients and controls. However, we found regional negative correlations between ligand binding and RLS severity (international restless legs scale, IRLS) in areas serving the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex and orbitofrontal cortex). Pain scores (affective component of the McGill Pain Questionnaire) correlated inversely with opioid receptor binding in orbitofrontal cortex and anterior cingulate gyrus. Our findings suggest that, the more severe the RLS, the greater the release of endogenous opioids within the medial pain system. We therefore discuss a possible role for opioids in the pathophysiology of RLS with respect to sensory and motor symptoms.
- Published
- 2005
- Full Text
- View/download PDF
26. Opioid binding in DYT1 primary torsion dystonia: an 11C-diprenorphine PET study.
- Author
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Whone AL, Von Spiczak S, Edwards M, Valente EM, Hammers A, Bhatia KP, and Brooks DJ
- Subjects
- Adult, Aged, Basal Ganglia metabolism, Binding Sites, Corpus Striatum metabolism, Diprenorphine administration & dosage, Female, Gene Deletion, Humans, Male, Middle Aged, Severity of Illness Index, Diprenorphine pharmacokinetics, Dystonia Musculorum Deformans genetics, Dystonia Musculorum Deformans metabolism, Enkephalins metabolism, Molecular Chaperones genetics, Positron-Emission Tomography
- Abstract
The opioid transmitters enkephalin and dynorphin are known to regulate pallidal output and consequently cortical excitability. Indeed, abnormal basal ganglia opioid transmission has been reported in several involuntary movement disorders, including levodopa-induced dyskinesias in Parkinson's disease (PD), tardive dyskinesias/dystonia, Huntington's disease, and Tourette's syndrome. Moreover, a previous 11C-diprenorphine PET study investigating levodopa-induced dyskinesias found reduced opioid receptor availability in PD with but not without dyskinesias. We wished to investigate if a similar alteration in basal ganglia opioid binding was present in DYT1 primary torsion dystonia (PTD). Regional cerebral 11C-diprenorphine binding was investigated in 7 manifesting carriers of the DYT1 gene and 15 age-matched normal controls using a region-of-interest (ROI) approach and statistical parametric mapping (SPM). No difference in regional mean 11C-diprenorphine binding was found between DYT1-PTD and controls, and no correlation between the severity of dystonia and opioid binding was seen. We conclude that aberrant opioid transmission is unlikely to be present in DYT1-PTD and altered opioid transmission is not a common mechanism underlying all disorders of involuntary movement., (2004 Movement Disorder Society.)
- Published
- 2004
- Full Text
- View/download PDF
27. A technique for standardized central analysis of 6-(18)F-fluoro-L-DOPA PET data from a multicenter study.
- Author
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Whone AL, Bailey DL, Remy P, Pavese N, and Brooks DJ
- Subjects
- Algorithms, Antiparkinson Agents therapeutic use, Canada, Dopamine Agents therapeutic use, France, Germany, Humans, Radiopharmaceuticals, Reproducibility of Results, Sensitivity and Specificity, Tomography, Emission-Computed methods, Treatment Outcome, United Kingdom, Dihydroxyphenylalanine analogs & derivatives, Image Interpretation, Computer-Assisted methods, Indoles therapeutic use, Levodopa therapeutic use, Parkinson Disease diagnostic imaging, Parkinson Disease drug therapy
- Abstract
Unlabelled: We have recently completed a large 6-(18)F-fluoro-L-DOPA ((18)F-DOPA) PET study comparing rates of loss of dopamine terminal function in Parkinson's disease (PD) patients taking either the dopamine agonist ropinirole or L-DOPA. This trial involved a "distributed acquisition/centralized analysis" method, in which (18)F-DOPA images were acquired at 6 different PET centers around the world and then analyzed at a single site. To our knowledge, this is the first time such a centralized approach has been employed with (18)F-DOPA PET and this descriptive basic science article outlines the methods used., Methods: One hundred eighty-six PD patients were randomized (1:1) to ropinirole or L-DOPA therapy, and (18)F-DOPA PET was performed at baseline and again at 2 y. The primary outcome measure was the percentage change in putamen (18)F-DOPA influx rate constant (K(i)) from Patlak graphical analysis. Dynamic images were acquired and reconstructed using each center's individual protocols before being transferred to the site performing the central analysis. Once there, individual parametric K(i) images were created using a single analysis program without file formats being transformed from the original. Parametric images were then normalized to standard space and K(i) values extracted with a region of interest analysis. Significant K(i) changes were also localized at a voxel level with statistical parametric mapping. These processes required numerous checks to ensure the integrity of each dataset., Results: Three hundred twenty-five (170 baseline, 155 follow-up) dynamic PET datasets were acquired, of which 12 were considered uninterpretable due to missing time frames, radiopharmaceutical problems, lack of measured attenuation correction, or excessive head movement. In those datasets suitable for central analysis, after quality control and spatial normalization of the images had been applied, putamen (18)F-DOPA signal decline was found to be significantly (one third) slower in the ropinirole group compared with that of the L-DOPA group., Conclusion: Paired (18)F-DOPA-PET images acquired from multiple sites can be successfully analyzed centrally to assess the efficacy of potential disease-modifying therapies in PD. However, numerous options must be considered and data checks put in place before adopting such an approach. Centralized analysis offers the potential for improved detection of outcomes due to the standardization of the analytic approach and allows the analysis of large numbers of PET studies.
- Published
- 2004
28. Cognitive and motor effects of dopaminergic medication withdrawal in Parkinson's disease.
- Author
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Fern-Pollak L, Whone AL, Brooks DJ, and Mehta MA
- Subjects
- Aged, Analysis of Variance, Association Learning drug effects, Dopamine Agents therapeutic use, Female, Humans, Male, Memory, Short-Term drug effects, Middle Aged, Neuropsychological Tests, Parkinson Disease drug therapy, Reaction Time drug effects, Spatial Behavior drug effects, Cognition drug effects, Dopamine Agents adverse effects, Motor Activity drug effects, Substance Withdrawal Syndrome etiology
- Abstract
Aims: Recent evidence points towards dissociable effects of dopaminergic medication on motor function and cognitive function mediated by different fronto-striatal neural circuits. This study aimed to clarify the role of dopaminergic medication in spatial working memory, and reinforcement-based associative learning in relation to clinical changes in motor function in early Parkinson's disease (PD)., Method: We tested 14 patients with mild to moderate PD on and off dopaminergic medication, on a spatial delayed-response working memory task, and on spatial and non-spatial (visual) trial-and-error learning tasks based on reinforcement, carefully matched for motor requirements. In addition, we explored relationships between the effects of withdrawal on motor symptom expression and performance on the cognitive tasks., Results: Withdrawal from dopaminergic medication significantly exacerbated motor symptoms. This was related to spatial learning, but not visual learning, or delayed response accuracy. Moreover, medication withdrawal led to dissociable effects of response latency on the spatial learning and spatial delayed response tasks, with patients becoming faster after spatial learning, but relatively slower on the delayed response task. These changes in response latency were unrelated to motor symptom impairment., Conclusion: Our findings suggest dissociable effects of dopamine medication withdrawal on cognitive processes putatively mediated by dorsal and ventral striatal regions.
- Published
- 2004
- Full Text
- View/download PDF
29. Monoamine neuron innervation of the normal human brain: an 18F-DOPA PET study.
- Author
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Moore RY, Whone AL, McGowan S, and Brooks DJ
- Subjects
- Adult, Brain diagnostic imaging, Fluorine Radioisotopes metabolism, Humans, Middle Aged, Neurons diagnostic imaging, Biogenic Monoamines metabolism, Brain metabolism, Dihydroxyphenylalanine metabolism, Neurons metabolism, Tomography, Emission-Computed methods
- Abstract
18F-DOPA positron emission tomography (PET) has been used for two decades to study the organization and pathology of the striatal dopamine system in the human brain, particularly in Parkinson's disease. High resolution 3D PET allows a more detailed analysis than previously available and was employed in this study to determine the regional uptake of 18F-DOPA in control brain. Eleven healthy volunteers underwent 18F-DOPA PET with a region of interest (ROI) study performed using individual volumetric MRI's coregistered to the PET ADD image. A Patlak linear graphical analysis was undertaken to obtain influx constant (Ki) values. The highest Ki values were from neostriatal areas, with a rostrocaudal gradient of increasing Ki values from head of caudate nucleus to rostral putamen to caudal putamen. However, Ki values for transaxial slices from dorsal to ventral through the caudate and putamen were uniform. Ventral striatum Ki was 81% with red nucleus and globus pallidus Ki values of approximately 40% of neostriatum. In limbic areas, highest values were obtained from amygdala (35% neostriatal Ki). Neocortical Ki values varied from 22% in temporal pole to 6% in occipital cortex of neostriatal values. Hypothalamic Ki was high (45%) in comparison to thalamus (17%) and retina (17%). 18F-DOPA is taken up by serotonin (raphe, 51%), and noradrenaline (locus coeruleus, 37%) as well as dopamine neurons. These data indicate that 18F-DOPA PET can be used with detailed, anatomically based ROIs as a tool for in vivo analysis of regional changes in monoamine neuron systems throughout the brain in Parkinson's disease and other disorders.
- Published
- 2003
- Full Text
- View/download PDF
30. Plasticity of the nigropallidal pathway in Parkinson's disease.
- Author
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Whone AL, Moore RY, Piccini PP, and Brooks DJ
- Subjects
- Adult, Aged, Brain Mapping, Globus Pallidus physiology, Humans, Magnetic Resonance Imaging, Middle Aged, Neural Pathways, Substantia Nigra physiology, Globus Pallidus pathology, Neuronal Plasticity physiology, Parkinson Disease pathology, Parkinson Disease physiopathology, Substantia Nigra pathology
- Abstract
The degeneration of nigrostriatal dopamine neurons in early Parkinson's disease (PD) is compensated in part by increased transmitter turnover in surviving neurons of the pathway. In this (18)F-dopa positron emission tomography study, we demonstrate compensatory changes in PD in another midbrain dopamine projection to the basal ganglia, the nigropallidal projection to the internal segment of the globus pallidus (GPi). Increased (18)F-dopa uptake in the GPi is seen in early PD which then is lost in advanced PD. Our early PD cases show an absence of significant clinical progression in the face of a continuing loss of nigrostriatal projections. This indicates a compensatory neuronal plasticity that we now show to involve the nigropallidal dopamine pathway to the GPi but not to the external segment of the globus pallidus (GPe). Enhanced function of the dopamine projection to the GPi serves, we propose, to maintain a more normal pattern of pallidal output to ventral thalamus and motor cortex in early PD, whereas loss of this adaptive pathway in advanced disease may be a pivotal step in the progression of the disease.
- Published
- 2003
- Full Text
- View/download PDF
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