Publications by authors named "K Ray Chaudhuri"

581 Publications

Editorial: Prodromal Parkinson's Disease.

Front Neurol 2020 12;11:634490. Epub 2021 Jan 12.

Parkinson Foundation International Centre of Excellence, King's College Hospital and King's College, London, United Kingdom.

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http://dx.doi.org/10.3389/fneur.2020.634490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873967PMC
January 2021

Rotigotine Transdermal Patch for Motor and Non-motor Parkinson's Disease: A Review of 12 Years' Clinical Experience.

CNS Drugs 2021 Feb 9;35(2):215-231. Epub 2021 Feb 9.

Parkinson's Foundation Centre of Excellence, King's College Hospital, London, UK.

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1-4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.
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http://dx.doi.org/10.1007/s40263-020-00788-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871129PMC
February 2021

Prevalence of Non-Motor Symptoms and Non-Motor Fluctuations in Parkinson's Disease Using the MDS-NMS.

Mov Disord Clin Pract 2021 Feb 21;8(2):231-239. Epub 2020 Dec 21.

Department of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia Department of Veterans Affairs Parkinson's Disease Research, Education and Clinical Center (PADRECC) Philadelphia Pennsylvania USA.

Background: Non-motor symptoms (NMS) are frequent in Parkinson's disease (PD).

Objectives: To estimate the prevalence of NMS and of non-motor fluctuations (NMF) using the Movement Disorders Society-Non-Motor Rating Scale (MDS-NMS) and other scales assessing NMS, and their relationship with sex and PD severity.

Methods: Cross-sectional study with a sample of 402 PD patients. The Hoehn and Yahr staging system (HY), Clinical Impression of Severity Index for PD (CISI-PD), MDS-NMS (including NMF- subscale), Non-Motor Symptoms scale (NMSS), and MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) were applied. A NMS was considered present when scored ≥1. Differences in scores by sex and HY, CISI-PD, and MDS-UPDRS severity levels were calculated using Fisher's exact and chi-squared tests.

Results: Using the MDS-NMS, NMS were present in 99.7% of patients and the mean number of NMS was 16.13 (SD: 9.36). The most prevalent NMS was muscle, joint or back pain (67.4% of the sample) and the least prevalent was dopamine dysregulation syndrome (2.2%). Feeling sad or depressed was significantly more prevalent in women. Using the MDS-NMS revealed more NMS than the other scales assessing NMS. NMF were present in 41% of the sample, with fatigue being the most prevalent symptom (68.5% patients with NMF), and no differences by sex. Patients with greater PD severity had higher prevalence of NMS than patients with lower severity.

Conclusions: Almost all patients with PD experience NMS, and many experience NMF. Prevalence rates for NMS using the MDS-NMS are higher than on other scales used and increase with higher disease severity.
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http://dx.doi.org/10.1002/mdc3.13122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853195PMC
February 2021

How Time Rules: Diurnal Motor Patterns in de novo Parkinson's Disease.

J Parkinsons Dis 2021 Jan 23. Epub 2021 Jan 23.

King's College London, Department of Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, United Kingdom.

Background: Several smaller-scale studies have shown that motor performance in Parkinson's disease (PD) fluctuates throughout the day. Studies focusing on de novo patients are, however, lacking.

Objective: To evaluate the effect of clock time on motor performance in de novo drug-naïve patients with PD.

Methods: We retrieved MDS-UPDRS III scores for 421 de novo PD patients from the PPMI cohort and stratified them into three groups based on time of assessment: group 1) 7:00-10:00; group 2) 10:00-13:00, and group 3) 13:00-18:00. Groups were compared using Kruskal-Wallis test and results corrected for multiple testing. In addition, we obtained 27 wearable sensor reports, objectively capturing bradykinesia scores in a home setting over a 6-day continuous period, in 12 drug-naïve patients from the Parkinson's Kinetigraph Registry held at King's College Hospital London. Time spent in severe bradykinesia scores were broken down into five daytime (06:00-21:00) three-hourly epochs and scores compared using the Friedman test.

Results: There were no group differences in demographic or other clinical variables for the cross-sectional analysis. MDS-UPDRS III total scores worsened significantly during the course of the day (median 18 (group 1); 20 (group 2); and 23 (group 3); p = 0.001). In the longitudinal wearable sensor cohort, diurnal variations were present in percentage of time spent in severe bradykinesia (p <  0.001) with the lowest percentage during the 09:00-12:00 epoch (69.56±16.68%), when most patients are awake and start daily activity, and the highest percentage during the 18:00-21:00 epoch (73.58±16.35%).

Conclusion: This exploratory study shows the existence of a diurnal pattern of motor function in patients with de novo PD. The results obtained were corroborated by objective measurements in a small longitudinal cohort confirming a similar diurnal motor score variation.
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http://dx.doi.org/10.3233/JPD-202352DOI Listing
January 2021

Non-motor complications in late stage Parkinson's disease: recognition, management and unmet needs.

Expert Rev Neurother 2021 Feb 16:1-18. Epub 2021 Feb 16.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience at King's College and King's College Hospital NHS Foundation Trust , London, UK.

: The burden of non-motor symptoms (NMS) is a major determinant of health-related quality of life in Parkinson's disease (PD), particularly at its late stage. : The late stage is usually defined as the period from unstable advanced to the palliative stage, characterized by a combination of emerging treatment-resistant axial motor symptoms (freezing of gait, postural instability, falls and dysphagia), as well as both non-dopaminergic and dopaminergic NMS: cognitive decline, neuropsychiatric symptoms, aspects of dysautonomia, pain and sleep disturbances (insomnia and excessive day-time sleepiness). Here, the authors summarize the current knowledge on NMS dominating the late stage of PD and propose a pragmatic and clinically focused approach for their recognition and treatment. : The NMS progression pattern is complex and remains under-researched. While dopamine-dependent NMS may improve with dopamine replacement therapy, non-dopamine dependent NMS worsen progressively and culminate at the late stages of PD. Furthermore, some PD specific features could interact negatively with other comorbidities, multiple medication use and frailty - the evaluation of these aspects is important in the creation of personalized management plans in the late stage of PD.
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http://dx.doi.org/10.1080/14737175.2021.1883428DOI Listing
February 2021

Thirty years of research on autonomic dysfunction, non-motor features, and endophenotypes in Parkinson disease.

Authors:
K Ray Chaudhuri

Clin Auton Res 2021 Feb 30;31(1):37-39. Epub 2021 Jan 30.

Department of Basic and Clinical Neuroscience, Parkinson Foundation International Centre of Excellence, Kings College Hospital and Kings College London, Cutcombe Road, London, SE5 9RT, England, UK.

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http://dx.doi.org/10.1007/s10286-021-00771-zDOI Listing
February 2021

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study.

Parkinsonism Relat Disord 2021 Feb 12;83:79-85. Epub 2021 Jan 12.

University College London Institute of Neurology, Queen Square, London, UK. Electronic address:

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).

Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.

Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515).

Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.
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http://dx.doi.org/10.1016/j.parkreldis.2020.12.024DOI Listing
February 2021

Assessment of real life eating difficulties in Parkinson's disease patients by measuring plate to mouth movement elongation with inertial sensors.

Sci Rep 2021 Jan 15;11(1):1632. Epub 2021 Jan 15.

Multimedia Understanding Group, Information Processing Laboratory, Department of Electrical and Computer Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Parkinson's disease (PD) is a neurodegenerative disorder with both motor and non-motor symptoms. Despite the progressive nature of PD, early diagnosis, tracking the disease's natural history and measuring the drug response are factors that play a major role in determining the quality of life of the affected individual. Apart from the common motor symptoms, i.e., tremor at rest, rigidity and bradykinesia, studies suggest that PD is associated with disturbances in eating behavior and energy intake. Specifically, PD is associated with drug-induced impulsive eating disorders such as binge eating, appetite-related non-motor issues such as weight loss and/or gain as well as dysphagia-factors that correlate with difficulties in completing day-to-day eating-related tasks. In this work we introduce Plate-to-Mouth (PtM), an indicator that relates with the time spent for the hand operating the utensil to transfer a quantity of food from the plate into the mouth during the course of a meal. We propose a two-step approach towards the objective calculation of PtM. Initially, we use the 3D acceleration and orientation velocity signals from an off-the-shelf smartwatch to detect the bite moments and upwards wrist micromovements that occur during a meal session. Afterwards, we process the upwards hand micromovements that appear prior to every detected bite during the meal in order to estimate the bite's PtM duration. Finally, we use a density-based scheme to estimate the PtM durations distribution and form the in-meal eating behavior profile of the subject. In the results section, we provide validation for every step of the process independently, as well as showcase our findings using a total of three datasets, one collected in a controlled clinical setting using standardized meals (with a total of 28 meal sessions from 7 Healthy Controls (HC) and 21 PD patients) and two collected in-the-wild under free living conditions (37 meals from 4 HC/10 PD patients and 629 meals from 3 HC/3 PD patients, respectively). Experimental results reveal an Area Under the Curve (AUC) of 0.748 for the clinical dataset and 0.775/1.000 for the in-the-wild datasets towards the classification of in-meal eating behavior profiles to the PD or HC group. This is the first work that attempts to use wearable Inertial Measurement Unit (IMU) sensor data, collected both in clinical and in-the-wild settings, towards the extraction of an objective eating behavior indicator for PD.
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http://dx.doi.org/10.1038/s41598-020-80394-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810687PMC
January 2021

Striatal Dopaminergic Deficit and Sleep in Idiopathic Rapid Eye Movement Behaviour Disorder: An Explorative Study.

Nat Sci Sleep 2021 6;13:1-9. Epub 2021 Jan 6.

Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.

Introduction: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is increasingly recognised as an important precursor disease state of alpha-synucleinopathies. This parasomnia is characterized by a history of recurrent nocturnal dream enactment behaviour, loss of skeletal muscle atonia, and increased phasic muscle activity during REM sleep. Neuroimaging studies of striatal dopamine transporter uptake tracer signaling suggest increasing dopaminergic deficit across the continuum of the alpha-synucleinopathies, with early sleep dysfunction suggestive of early caudate dysfunction. Henceforth, we set out to investigate the relationship between early sleep changes and the striatal dopaminergic availability in iRBD.

Methods: Twelve patients with iRBD, who had undergone a video polysomnography and a neuroimaging assessment of striatal dopamine transporter (DaT) uptake tracer signaling, and 22 matched controls who had similarly undergone a video polysomnography were retrospectively identified. Data were statistically analyzed to identify altered sleep parameters and correlate them with striatal dopamine transporter uptake tracer signaling.

Results: The iRBD patients exhibited an increased number of periodic limb movements during sleep (=0.001), compared to 22 age-matched healthy subjects. In addition, several significant links were found between regional DaT-uptakes and sleep architecture. Correlational analyses suggested a strong positive association between sleep fragmentation and dopamine deficiency in left caudate (r=-0.630, =0.028), whilst an increased uptake in the whole striatum was strongly linked to the sleep efficiency, and to a lesser degree to the length of sleep duration.

Discussion: To the best of our knowledge, this is the first demonstration of a close relationship between dopaminergic availability in striatum and the quality of sleep in iRBD. Taken together, our exploratory findings suggest that subtle but functionally significant striatal changes in early stages of iRBD may contribute to the further shaping of sleep architecture.
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http://dx.doi.org/10.2147/NSS.S267037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802085PMC
January 2021

Nature and dimensions of the systemic hyper-inflammation and its attenuation by convalescent plasma in severe COVID-19.

J Infect Dis 2021 Jan 12. Epub 2021 Jan 12.

IICB-Translational Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, India.

Novel coronavirus SARS-CoV2, causing coronavirus disease 2019 or COVID-19, led to significant morbidity and mortality. While most suffer from mild symptoms, some patients progress to a severe disease with acute respiratory distress syndrome (ARDS) and an associated systemic hyper-inflammation. First to characterize key cytokines and their dynamics in this hyper-inflammatory condition, we assessed abundance and correlative expression of a panel of forty eight cytokines in patients progressing to ARDS, as compared to patients with mild disease. Then in an ongoing randomized control trial of convalescent plasma therapy (CPT), we analyzed rapid effects of CPT on the systemic cytokine dynamics, as a correlate for the level of hypoxia experienced by the patients. We identified an anti-inflammatory role of CPT independent of its neutralizing antibody content. Neutralizing antibodies as well as reductions in circulating interleukin-6 and interferon gamma induced protein 10, contributed to marked rapid reductions in hypoxia in response to CPT.
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http://dx.doi.org/10.1093/infdis/jiab010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928875PMC
January 2021

A Preliminary Investigation of the Views of People With Parkinson's (With and Without Psychosis) and Caregivers on Participating in Clinical Trials During the Covid-19 Pandemic: An Online Survey.

Front Psychiatry 2020 23;11:602480. Epub 2020 Dec 23.

Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

The coronavirus pandemic is having a profound impact on non-COVID-19 related research, including the delivery of clinical trials for patients with Parkinson's disease. A preliminary investigation to explore the views of Parkinson's disease (PD) patients, with and without experience of psychosis symptoms, and carers on the resumption of clinical research and adaptations to trials in light of COVID-19. An anonymous self-administered online survey was completed by 30 PD patients and six family members/carers via the Parkinson's UK Research Support Network to explore current perceptions on taking part in PD research and how a planned clinical trial for psychosis in PD may be adapted so participants feel safe. Ninety-one percent of respondents were enthusiastic about the continuation of non-COVID-19 related research as long as certain safety measures were in place. Ninety-four percent stated that they would be happy to complete assessments virtually. However, they noted that care should be taken to ensure that this does not exclude participants, particularly those with more advanced PD who may require assistance using portable electronic devices. Regular and supportive communication from the research team was also seen as important for maintaining the psychological well-being of participants while taking part in the trial. In the era of COVID-19 pandemic, standard approaches will have to be modified and rapid adoption of virtual assessments will be critical for the continuation of clinical research. It is important that alongside the traditional methods, new tools are developed, and older ones validated for virtual assessments, to allow safe and comprehensive assessments vital for ongoing research in people with Parkinson's.
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http://dx.doi.org/10.3389/fpsyt.2020.602480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785792PMC
December 2020

Cost-Effectiveness of Device-Aided Therapies in Parkinson's Disease: A Structured Review.

J Parkinsons Dis 2020 Dec 27. Epub 2020 Dec 27.

Institute of Psychiatry, Psychology & Neuroscience, Department of Basic & Clinical Neuroscience, King's College London, London, United Kingdom.

Background: Despite optimal dopaminergic treatment most patients in moderate to advanced stages of Parkinson's disease (PD) experience progressively increasing disabilities, necessitating a shift from oral medication to device-aided therapies, including deep brain stimulation (DBS), intrajejunal levodopa-carbidopa infusion (IJLI), and continuous subcutaneous apomorphine infusion (CSAI). However, these therapies are costly, limiting their implementation.

Objectives: To perform a systematic review on cost-effectiveness analyses for device-aided therapies in PD.

Methods: References were identified by performing a systematic search in the PubMed and Web of Science databases in accordance with the PRISMA statement. In the absence of universal cost-effectiveness definitions, the gross domestic product per capita (GDP) in the country where a study was performed was used as a cut-off for cost-effectiveness based on cost per quality adjusted life year (QALY) gained.

Results: In total 30 studies were retrieved. All device-aided therapies improved quality of life compared to best medical treatment, with improvements in QALYs between 0.88 and 1.26 in the studies with long temporal horizons. For DBS, nearly all studies showed that cost per QALY was below the GDP threshold. For infusion therapies only three studies showed a cost per QALY below this threshold, with several studies with long temporal horizons showing costs below or near the GDP threshold.

Conclusion: Of the device-aided therapies, DBS can be considered cost-effective, but the majority of infusion therapy studies showed that these were less cost-effective. However, long-term use of the infusion therapies appears to improve their cost-effectiveness and in addition, several strategies are underway to reduce these high costs.
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http://dx.doi.org/10.3233/JPD-202348DOI Listing
December 2020

Scaling-up Health-Arts Programmes: the largest study in the world bringing arts-based mental health interventions into a national health service.

BJPsych Bull 2021 Feb;45(1):32-39

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

The Scaling-up Health-Arts Programme: Implementation and Effectiveness Research (SHAPER) project is the world's largest hybrid study on the impact of the arts on mental health embedded into a national healthcare system. This programme, funded by the Wellcome Trust, aims to study the impact and the scalability of the arts as an intervention for mental health. The programme will be delivered by a team of clinicians, research scientists, charities, artists, patients and healthcare professionals in the UK's National Health Service (NHS) and the community, spanning academia, the NHS and the charity sector. SHAPER consists of three studies - Melodies for Mums, Dance for Parkinson's, and Stroke Odysseys - which will recruit over 800 participants, deliver the interventions and draw conclusions on their clinical impact, implementation effectiveness and cost-effectiveness. We hope that this work will inspire organisations and commissioners in the NHS and around the world to expand the remit of social prescribing to include evidence-based arts interventions.
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http://dx.doi.org/10.1192/bjb.2020.122DOI Listing
February 2021

Unmet needs in Parkinson disease: Motor and non-motor.

Parkinsonism Relat Disord 2020 11 19;80 Suppl 1:S7-S12. Epub 2020 Dec 19.

King's College London and Parkinson's Foundation Centre of Excellence, King's College Hospital, London, United Kingdom.

Compared to other neurodegenerative diseases, Parkinson's disease (PD) is distinctive in terms of marked symptomatic variability and prognosis, as well as for the wide variety of symptomatic treatment options. Despite several decades of advances in medications and neurosurgical approaches, there remains an unmet need for symptomatic motor control. Better control of tremor, gait and balance, posture, dexterity, and communication skills are major challenges for better therapeutics of the PD movement disorder. Non-motor symptoms (NMS), which often precede motor impairments, add complexity to the burden of PD and its management. Recognized by James Parkinson MD two centuries ago, and despite 21st century neurological advances, a range of NMS plague the patient's journey, from prodromal to palliative stages. Characterizing the clinical phenotype of the entire non-motor profile of PD is challenging. Further research and understanding are needed for discovering biomarkers of certain NMS, such as dementia, fatigue, pain, sleep, and apathy. More work is needed to gather a robust evidence base for guiding treatment of troubling NMS, which exert a major impact on quality of life for people with PD and their caregivers.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.024DOI Listing
November 2020

Unobtrusive detection of Parkinson's disease from multi-modal and in-the-wild sensor data using deep learning techniques.

Sci Rep 2020 12 7;10(1):21370. Epub 2020 Dec 7.

Multimedia Understanding Group, Information Processing Laboratory, Department of Electrical and Computer Engineering, Aristotle University of Thessaloniki, Thessaloníki , Greece.

Parkinson's Disease (PD) is the second most common neurodegenerative disorder, affecting more than 1% of the population above 60 years old with both motor and non-motor symptoms of escalating severity as it progresses. Since it cannot be cured, treatment options focus on the improvement of PD symptoms. In fact, evidence suggests that early PD intervention has the potential to slow down symptom progression and improve the general quality of life in the long term. However, the initial motor symptoms are usually very subtle and, as a result, patients seek medical assistance only when their condition has substantially deteriorated; thus, missing the opportunity for an improved clinical outcome. This situation highlights the need for accessible tools that can screen for early motor PD symptoms and alert individuals to act accordingly. Here we show that PD and its motor symptoms can unobtrusively be detected from the combination of accelerometer and touchscreen typing data that are passively captured during natural user-smartphone interaction. To this end, we introduce a deep learning framework that analyses such data to simultaneously predict tremor, fine-motor impairment and PD. In a validation dataset from 22 clinically-assessed subjects (8 Healthy Controls (HC)/14 PD patients with a total data contribution of 18.305 accelerometer and 2.922 typing sessions), the proposed approach achieved 0.86/0.93 sensitivity/specificity for the binary classification task of HC versus PD. Additional validation on data from 157 subjects (131 HC/26 PD with a total contribution of 76.528 accelerometer and 18.069 typing sessions) with self-reported health status (HC or PD), resulted in area under curve of 0.87, with sensitivity/specificity of 0.92/0.69 and 0.60/0.92 at the operating points of highest sensitivity or specificity, respectively. Our findings suggest that the proposed method can be used as a stepping stone towards the development of an accessible PD screening tool that will passively monitor the subject-smartphone interaction for signs of PD and which could be used to reduce the critical gap between disease onset and start of treatment.
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http://dx.doi.org/10.1038/s41598-020-78418-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721908PMC
December 2020

Successful Convalescent Plasma Therapy in a Child With Severe Coronavirus Disease.

Indian Pediatr 2021 Jan 1;58(1):89-90. Epub 2020 Dec 1.

Department of Transfusion Medicine, Apollo Gleneagles Hospitals, Kolkata 700 054, India.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840383PMC
January 2021

Non-Motor Symptoms in Cervical Dystonia: A Concept in Evolution.

Ann Indian Acad Neurol 2020 Jul-Aug;23(4):428. Epub 2020 Jul 16.

King's College London, Department of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, United Kingdom.

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http://dx.doi.org/10.4103/aian.AIAN_287_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657303PMC
July 2020

Improving the Delivery of Levodopa in Parkinson's Disease: A Review of Approved and Emerging Therapies.

CNS Drugs 2020 11 4;34(11):1149-1163. Epub 2020 Nov 4.

Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK.

Levodopa is the most effective drug for the treatment of Parkinson's disease, but its use as an oral medication is complicated by its erratic absorption, extensive metabolism and short plasma half-life. On long-term use and with disease progression, there is a high incidence of motor and non-motor complications, which remain a major clinical and research challenge. It is widely accepted that levodopa needs to be administered using formulations that result in good and consistent bioavailability and the physiologically relevant and continuous formation of dopamine in the brain to maximise its efficacy while avoiding and reversing 'wearing off' and dyskinesia. However, the physicochemical properties of levodopa along with its pharmacokinetic and pharmacodynamic profile make it difficult to deliver the drug in a manner that fulfils these criteria. In this review, we examine the problems associated with the administration of levodopa in Parkinson's disease and how the use of novel technologies and delivery devices is leading to a more consistent and sustained levodopa delivery with the aim of controlling motor function as well as non-motor symptoms.
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http://dx.doi.org/10.1007/s40263-020-00769-7DOI Listing
November 2020

Emotional well-being and pain could be a greater determinant of quality of life compared to motor severity in cervical dystonia.

J Neural Transm (Vienna) 2020 Nov 4. Epub 2020 Nov 4.

Department of Neurology, Technische Universität Dresden, Fetscherstraße 74, Dresden, Germany.

Non-motor symptoms (NMS) occur in patients with cervical dystonia (CD) but with variable frequencies and impact on health-related quality of life (HRQoL). To define non-motor and motor profiles and their respective impact on HRQoL in CD patients using the newly validated Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest). In an observational prospective multicentre case-control study, we enrolled 61 patients with CD and 61 age- and sex-matched healthy controls (HC) comparing demographic data, motor and non-motor symptoms and HRQoL measurements. 95% CD patients reported at least one NMS. Mean total NMS score was significantly higher in CD patients (5.62 ± 3.33) than in HC (1.74 ± 1.52; p < 0.001). Pain, insomnia and stigma were the most prevalent NMS and HRQoL was significantly impaired in CD patients compared to HC. There was strong correlation of NMS burden with HRQoL (CDQ-24: r = 0.72, EQ-5D: r = - 0.59; p < 0.001) in CD patients. Regression analysis between HRQoL and NMS suggested that emotional well-being (standardized beta = - 0.352) and pain (standardized beta = - 0.291) had a major impact on HRQoL while, in contrast motor severity had no significant impact in this model. Most NMS with the exception of pain, stigma and ADL did not correlate with motor severity. NMS are highly prevalent in CD patients and occur independent of age, sex, disease duration, duration of botulinum neurotoxin therapy and socio-economic status. Specific NMS such as emotional well-being and pain have a major impact on HRQoL and are more relevant than motor severity.
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http://dx.doi.org/10.1007/s00702-020-02274-zDOI Listing
November 2020

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

Brief Bioinform 2020 10 20. Epub 2020 Oct 20.

Head of Department of Neurology, Zhujiang Hospital, Southern Medical University, China.

Objective: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC).

Methods: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS.

Results: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS.

Conclusions: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.
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http://dx.doi.org/10.1093/bib/bbaa244DOI Listing
October 2020

The Parkinson's disease pain classification system (PDPCS): results from an international mechanism-based classification approach.

Pain 2020 Oct 8. Epub 2020 Oct 8.

Pain Center, LIM-62, Departamento de Neurologia da Faculdade de Medicina da Universidade de Sao Paulo, Hospital das Clínicas, Sao Paulo, Brazil.

Pain is a common non-motor symptom in patients with Parkinson's disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into three groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory (BPI) and McGill pain questionnaire (MPQ), PDQ-8 quality of life score, MDS-UPDRS scores, and non-motor symptoms). 159 non-demented PD patients (disease duration 10.2±7.6 years) and 37 healthy controls were recruited in four centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's BPI and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression and anxiety measures. Moderate intra- and inter-rater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.
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http://dx.doi.org/10.1097/j.pain.0000000000002107DOI Listing
October 2020

Application of the '5-2-1' screening criteria in advanced Parkinson's disease: interim analysis of DUOGLOBE.

Neurodegener Dis Manag 2020 10 2;10(5):309-323. Epub 2020 Sep 2.

Parkinson Foundation International Centre of Excellence, King's College & King's College Hospital, Denmark Hill, London, UK.

A Delphi expert consensus panel proposed that fulfilling ≥1 of the '5-2-1 criteria' (≥five-times daily oral levodopa use, ≥two daily hours with 'Off' symptoms or ≥one daily hour with troublesome dyskinesia) suggests advanced Parkinson's disease (PD). DUOdopa/Duopa in Patients with Advanced PD - a GLobal OBservational Study Evaluating Long-Term Effectiveness (DUOGLOBE) - is a single-arm, postmarketing, observational, long-term effectiveness study of levodopa-carbidopa intestinal gel (LCIG) for advanced PD. This 6-month interim analysis (n = 139) affirms that most (98%) enrolled patients fulfill ≥1 of the 5-2-1 criteria. These patients responded favorably to LCIG treatment. Safety was consistent with other LCIG studies. In advanced PD patients, the 5-2-1 criteria generally aligns with clinician assessment. Clinical Trial Registration: NCT02611713 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/nmt-2020-0021DOI Listing
October 2020

Effect of Short-term Integrated Palliative Care on Patient-Reported Outcomes Among Patients Severely Affected With Long-term Neurological Conditions: A Randomized Clinical Trial.

JAMA Netw Open 2020 08 3;3(8):e2015061. Epub 2020 Aug 3.

Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, King's College London, London, United Kingdom.

Importance: Palliative care has shown benefits in reducing symptom intensity and quality of life in patients with advanced cancer. However, high-quality evidence to support palliative care policy and service developments for patients with long-term neurological conditions (LTNCs) is lacking.

Objective: To determine the effectiveness of a short-term integrated palliative care (SIPC) intervention for people with LTNCs.

Design, Setting, And Participants: Multicenter, phase 3, randomized clinical trial conducted from April 1, 2015, to November 30, 2017, with a last follow-up date of May 31, 2018, in 7 UK hospitals with both neurology and palliative care services. A total of 535 patients with LTNC were assessed for eligibility and 350 were randomized. Inclusion criteria were patients 18 years or older with any advanced stage of multiple sclerosis, motor neuron disease, idiopathic Parkinson disease multiple system atrophy, or progressive supranuclear palsy. Data were analyzed from November 2018 to March 2019.

Interventions: Patients were randomized 1:1 using minimization method to receive SIPC (intervention, n = 176) or standard care (control, n = 174).

Main Outcomes And Measures: Primary outcome was change in 8 key palliative care symptoms from baseline to 12-weeks, measured by the Integrated Palliative care Outcome Scale for neurological conditions. Secondary outcomes included change in the burden of other symptoms, health-related quality of life, caregiver burden, and costs. Data were collected and analyzed blindly by intention to treat.

Results: A total of 350 patients (mean [SD] age 67 [12] years; years since diagnosis, 12 [range, 0-56]; 51% men; 49% requiring considerable assistance) with an advanced stage of LTNC were recruited, along with informal caregivers (n = 229). There were no between-group differences in primary outcome (effect size, -0.16; 95% CI, -0.37 to 0.05), any other patient-reported outcomes, adverse events, or survival. Although there was more symptom reduction in the SIPC group in relation to mean change in primary outcome, the difference between the groups was not statistically significant (-0.78; 95% CI, -1.29 to -0.26 vs -0.28; 95% CI, -0.82 to 0.26; P = .14). There was a decrease in mean health and social care costs from baseline to 12 weeks -$1367 (95% CI, -$2450 to -$282) in the SIPC group and -653 (95% CI, -$1839 to -$532) in the control group, but this difference was not statistically significant (P = .12). SIPC was perceived by patients and caregivers as building resilience, attending to function and deficits, and enabling caregivers.

Conclusions And Relevance: In this study, SIPC was not statistically significantly different from standard care for the patient-reported outcomes. However, SIPC was associated with lower cost, and in qualitative analysis was well-received by patients and caregivers, and there were no safety concerns. Further research is warranted.

Trial Registration: isrctn.org Identifier: ISRCTN18337380.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.15061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455856PMC
August 2020

Progression of sleep disturbances in Parkinson's disease: a 5-year longitudinal study.

J Neurol 2021 Jan 17;268(1):312-320. Epub 2020 Aug 17.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Background: Sleep disorders can occur in early Parkinson's disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not been fully explored.

Objective: To describe the frequency, coexistence, and longitudinal change in excessive daytime sleepiness (EDS), insomnia, and probable REM sleep behavior disorder (pRBD) in early PD.

Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI). EDS, insomnia, and pRBD were defined using the Epworth Sleepiness Scale, MDS-UPDRS Part I sub-item 1.7, and RBD screening questionnaire.

Results: 218 PD subjects and 102 controls completed 5 years of follow-up. At baseline, 69 (31.7%) PD subjects reported one type of sleep disturbance, 25 (11.5%) reported two types of sleep disturbances, and three (1.4%) reported all three types of sleep disturbances. At 5 years, the number of PD subjects reporting one, two, and three types of sleep disturbances was 85 (39.0%), 51 (23.4%), and 16 (7.3%), respectively. Only 41(18.8%) patients were taking sleep medications. The largest increase in frequency was seen in insomnia (44.5%), followed by EDS (32.1%) and pRBD (31.2%). Insomnia was the most common sleep problem at any time over the 5-year follow-up. The frequency of sleep disturbances in HCs remained stable.

Conclusions: There is a progressive increase in the frequency of sleep disturbances in PD, with the number of subjects reporting multiple sleep disturbances increasing over time. Relatively a few patients reported multiple sleep disturbances, suggesting that they can have different pathogenesis. A large number of patients were not treated for their sleep disturbances.
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http://dx.doi.org/10.1007/s00415-020-10140-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815601PMC
January 2021

'Dopamine agonist Phobia' in Parkinson's disease: when does it matter? Implications for non-motor symptoms and personalized medicine.

Expert Rev Neurother 2020 09 15;20(9):953-965. Epub 2020 Sep 15.

Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London , London, UK.

Introduction: Dopamine agonists have been widely used to treat patients with Parkinson's disease, but concerns related to their well-known side effects might prevent their use even when indicated. In this review, the authors describe for the first time the concept of 'Dopamine Agonist Phobia', a pharmacophobia that the authors believe might affect clinicians, and they provide evidence of the benefits of dopamine agonists, focusing on non-motor symptoms.

Areas Covered: The authors performed an extensive literature research, including studies exploring the use of dopamine agonists for the treatment of non-motor symptoms. The authors indicate the highest level of evidence in each section.

Expert Opinion: 'Dopamine Agonist Phobia' may preclude valid therapeutic options in selected cases, specifically for the treatment of non-motor symptoms. Thus, the authors propose a personalized approach in Parkinson's disease treatment, and encourage a thoughtful use of dopamine agonists, rather than an overall nihilism.
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http://dx.doi.org/10.1080/14737175.2020.1806059DOI Listing
September 2020

Therapy of Parkinson's Disease Subtypes.

Neurotherapeutics 2020 10;17(4):1366-1377

The Ottawa Hospital Research Institute and University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada.

Early descriptions of subtypes of Parkinson's disease (PD) are dominated by the approach of predetermined groups. Experts defined, from clinical observation, groups based on clinical or demographic features that appeared to divide PD into clinically distinct subsets. Common bases on which to define subtypes have been motor phenotype (tremor dominant vs akinetic-rigid or postural instability gait disorder types), age, nonmotor dominant symptoms, and genetic forms. Recently, data-driven approaches have been used to define PD subtypes, taking an unbiased statistical approach to the identification of PD subgroups. The vast majority of data-driven subtyping has been done based on clinical features. Biomarker-based subtyping is an emerging but still quite undeveloped field. Not all of the subtyping methods have established therapeutic implications. This may not be surprising given that they were born largely from clinical observations of phenotype and not in observations regarding treatment response or biological hypotheses. The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies. Therapies for GBA-PD and LRRK2-PD are already under development. This review discusses each of the major subtyping systems/methods in terms of its applicability to therapy in PD, and the opportunities and challenges designing clinical trials to develop the evidence base for personalized medicine based on subtypes.
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http://dx.doi.org/10.1007/s13311-020-00894-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851253PMC
October 2020

Screening of Parkinsonian subtle fine-motor impairment from touchscreen typing via deep learning.

Sci Rep 2020 07 28;10(1):12623. Epub 2020 Jul 28.

Department of Electrical and Computer Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Fine-motor impairment (FMI) is progressively expressed in early Parkinson's Disease (PD) patients and is now known to be evident in the immediate prodromal stage of the condition. The clinical techniques for detecting FMI may not be robust enough and here, we show that the subtle FMI of early PD patients can be effectively estimated from the analysis of natural smartphone touchscreen typing via deep learning networks, trained in stages of initialization and fine-tuning. In a validation dataset of 36,000 typing sessions from 39 subjects (17 healthy/22 PD patients with medically validated UPDRS Part III single-item scores), the proposed approach achieved values of area under the receiver operating characteristic curve (AUC) of 0.89 (95% confidence interval: 0.80-0.96) with sensitivity/specificity: 0.90/0.83. The derived estimations result in statistically significant ([Formula: see text]) correlation of 0.66/0.73/0.58 with the clinical standard UPDRS Part III items 22/23/31, respectively. Further validation analysis on 9 de novo PD patients vs. 17 healthy controls classification resulted in AUC of 0.97 (0.93-1.00) with 0.93/0.90. For 253 remote study participants, with self-reported health status providing 252.000 typing sessions via a touchscreen typing data acquisition mobile app (iPrognosis), the proposed approach predicted 0.79 AUC (0.66-0.91) with 0.76/0.71. Remote and unobtrusive screening of subtle FMI via natural smartphone usage, may assist in consolidating early and accurate diagnosis of PD.
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http://dx.doi.org/10.1038/s41598-020-69369-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387517PMC
July 2020