Publications by authors named "Paul Worth"

11 Publications

  • Page 1 of 1

Taking the 'Disease' out of 'Parkinson's': has the disease had its day?

Authors:
Paul F Worth

Pract Neurol 2019 02 21;19(1):2-4. Epub 2018 Nov 21.

Addenbrooke's Hospital, Cambridge CB2 0QQ, UK

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http://dx.doi.org/10.1136/practneurol-2018-002066DOI Listing
February 2019

Results of the early stage PD MED study: revelation or recapitulation?

Authors:
Paul Worth

Pract Neurol 2015 Dec 10;15(6):408-10. Epub 2015 Aug 10.

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http://dx.doi.org/10.1136/practneurol-2015-001149DOI Listing
December 2015

Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.

Brain 2013 Oct 11;136(Pt 10):3106-18. Epub 2013 Sep 11.

1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.

Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. All cases had been tested for spinocerebellar ataxia 1-3, 6, 7 and Friedrich's ataxia and had multiple other biochemical, genetic and invasive tests. In those cases where we identified the genetic mutation, we determined the time to diagnosis. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. The highest detection rate was in those with an adolescent onset and a family history (75%). The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. In the cases where we made an eventual diagnosis, the delay was 3-35 years (mean 18.1 years). Alignment and coverage metrics indicated that the capture and sequencing was highly efficient and the consumable cost was ∼£400 (€460 or US$620). Our pathogenicity interpretation pathway predicted 13 different mutations in eight different genes: PRKCG, TTBK2, SETX, SPTBN2, SACS, MRE11, KCNC3 and DARS2 of which nine were novel including one causing a newly described recessive ataxia syndrome. Genetic testing using targeted capture followed by next-generation sequencing was efficient, cost-effective, and enabled a molecular diagnosis in many refractory cases. A specific challenge of next-generation sequencing data is pathogenicity interpretation, but functional analysis confirmed the pathogenicity of novel variants showing that the pipeline was robust. Our results have broad implications for clinical neurology practice and the approach to diagnostic testing.
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http://dx.doi.org/10.1093/brain/awt236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784284PMC
October 2013

Managing impulse control behaviours in Parkinson's disease: practical guidelines.

Br J Hosp Med (Lond) 2013 Mar;74(3):160-6

Southern General Hospital, Glasgow, UK.

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http://dx.doi.org/10.12968/hmed.2013.74.3.160DOI Listing
March 2013

When the going gets tough: how to select patients with Parkinson's disease for advanced therapies.

Authors:
Paul F Worth

Pract Neurol 2013 Jun 13;13(3):140-52. Epub 2013 Mar 13.

Department of Neurology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK.

Levodopa-induced motor complications of Parkinson's disease, including motor fluctuations and dyskinesias, become increasingly frequent as the disease progresses, and are often disabling. Oral and transdermal therapies have limited efficacy in controlling these problems. Advanced device-aided therapies, including continuous infusion of apomorphine, deep brain stimulation and levodopa-carbidopa intestinal gel can all ameliorate these complications. This review summarises the principles of each of these therapies, their modes of action, efficacy and adverse effects, and gives advice on timely identification of suitable patients and how to decide on the most appropriate therapy for a given patient.
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http://dx.doi.org/10.1136/practneurol-2012-000463DOI Listing
June 2013

How to treat Parkinson's disease in 2013.

Authors:
Paul F Worth

Clin Med (Lond) 2013 Feb;13(1):93-6

Department of Neurology, Norfolk and Norwich University Hospital NHS Trust.

Parkinson's disease is a common, progressive, debilitating disease with substantial physical, psychological and social implications. Pharmacological management is complex and should be individualised according to the needs of the patient. In early disease, treatment is generally highly effective, but medication becomes increasingly inadequate in controlling motor fluctuations and dyskinesias as the disease progresses. Non-motor symptoms, especially depression and dementia, require a holistic, multidisciplinary approach to maximise quality of life for patients and their carers. For the future, the ideal solution remains neuroprotection and restoration. Progress has been hampered by the lack of animal models that reflect the widespread brain pathology presumed to cause both motor and non-motor symptoms of PD in humans. Currently, agents are undergoing clinical trials in early, mildly affected patients, such as the plant-derived substance PYM50028 (Cogane), which promotes expression of endogenous neural growth factors and has shown promise in vitro and in animal models. Gene-therapy trials in progress rely on the viral vectors used to deliver the enzymatic machinery required for dopamine synthesis to the striatum. As PD progresses, adequate control of motor symptoms depends increasingly on continuous drug delivery, and greater physiological stimulation of dopamine receptors may help to prevent the development of LIDs and motor fluctuations. Efforts thus are afoot to develop better delivery systems for levodopa, and a new sustained-release formulation is in development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873719PMC
http://dx.doi.org/10.7861/clinmedicine.13-1-93DOI Listing
February 2013

Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia.

Mov Disord 2013 Apr 9;28(4):524-8. Epub 2012 Nov 9.

Department of Neurology, Norfolk and Norwich University Hospital, Norwich, United Kingdom.

Background: The major clinical feature of ataxia telangiectasia (A-T) is severe progressive neurodegeneration with onset in infancy. This classical A-T phenotype is caused by biallelic null mutations in the ATM gene, leading to the absence of ATM protein and increased cellular radiosensitivity. We report an unusual case of A-T in a 41-year-old mother, A-T210, who had very mild neurological symptoms despite complete loss of ATM protein.

Methods: A neurological examination was performed, cellular radiosensitivity was assessed, and the ATM gene was sequenced. Skin fibroblasts and a lymphoblastoid cell line (LCL) were assayed for ATM protein expression and kinase activity.

Results: Patient A-T210 showed mild chorea, dystonia, and gait ataxia, walked independently, and drove a car. LCL and skin fibroblasts were radiosensitive and did not express ATM protein. Two ATM-null mutations were identified.

Conclusions: The severe neurodegeneration resulting from loss of ATM can be mitigated in some circumstances.
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http://dx.doi.org/10.1002/mds.25236DOI Listing
April 2013

The use of carer assisted adherence therapy for people with Parkinson's disease and their carers (CAAT-PARK): study protocol for a randomised controlled trial.

Trials 2011 Nov 28;12:251. Epub 2011 Nov 28.

Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk, NR4 7TJ, UK.

Background: Pharmacological intervention is essential for managing the symptoms of Parkinson's disease. Adherence to medication regimens however is a major problem. Poor adherence leads to significant motor deterioration and inadequate symptom control. This results in poor quality of life. Whilst interventions to improve medication adherence have shown considerable benefit in other chronic conditions, the efficacy of such treatments in Parkinson's disease is less well researched. Many people with Parkinson's disease require substantial support from spouse/caregivers. This often extends to medication taking. Consequently, spouse/caregiver's support for timely medication management is paramount. We aim to investigate the benefit of a novel intervention, Carer Assisted Adherence Therapy, for improving medication adherence and quality of life in people with Parkinson's disease. Adherence therapy may help to optimise the efficacy of anti-parkinsonian agents, subsequently improving clinical outcomes.

Methods/design: A parallel, randomised controlled trial will be conducted to investigate whether carer assisted adherence therapy is effective for improving medication adherence and quality of life. We aim to recruit 40 patient/carer pairs into each group. Participants will be randomly assigned by the Clinical Research Trials Unit at the University of East Anglia. Adherence therapy is a brief cognitive-behavioural approach aimed at facilitating a process of shared decision making. The central theory is that when patients make shared choices with a professional they are more likely to continue with those choices because they are personally owned and meaningful. Outcomes will be rates of adherence and quality of life, determined by the Morisky Medication Adherence Scale-4 and the Parkinson's disease Questionnaire-39 respectively. Assessments will take place post randomisation, immediately post intervention and 12-weeks post randomisation. Primary outcomes are adherence and quality of life at 12-week follow-up. Efficacy will be determined using intention-to-treat analysis. Independent samples t-tests will compare mean changes between groups from baseline to follow-up. Per protocol analysis will be conducted based on individuals with no major protocol deviation. Where imbalances in baseline characteristics are identified, an adjusted analysis will be performed using a regression model. Analysis will be masked to treatment allocation.

Trial Registration: ISRCTN: ISRCTN07830951.
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http://dx.doi.org/10.1186/1745-6215-12-251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235063PMC
November 2011

Systematic review of apomorphine infusion, levodopa infusion and deep brain stimulation in advanced Parkinson's disease.

Parkinsonism Relat Disord 2009 Dec 4;15(10):728-41. Epub 2009 Oct 4.

Department of Neurology, City Hospital, Birmingham, UK.

The effectiveness of oral levodopa in complex Parkinson's disease (PD) is limited by its short half-life, and the resulting pulsatile dopaminergic stimulation leads to complex motor fluctuations and dyskinesia. Several treatments provide more continuous/less pulsatile dopaminergic stimulation by modifying the pharmacokinetics of levodopa or dopamine; however, patients with advanced disease can be refractory to these treatments. In such cases infusion therapies (apomorphine and intraduodenal levodopa) and neurosurgery (deep brain stimulation [DBS]) may be used. The purpose of this systematic review is to assess, as far as possible, the relative effectiveness of these therapies. There were no randomised controlled trials comparing the three treatment modalities or any directly comparable studies, therefore a descriptive analysis of the data was performed. Studies identified for levodopa infusion and DBS supported a significant benefit compared with best medical management in terms of improvements in the proportion of the waking day in a functional "on" state, activities of daily living and motor score. This finding was supported in observational studies for all three therapies. Adverse events were not adequately reported in the majority of included studies and it was therefore not possible to obtain a reliable tolerability profile of the different treatment options. The absence of direct comparative data means that, for the immediate future at least, treatment choices for advanced PD will be determined by clinical judgement and patient preference. There is an urgent need for well-designed clinical trials to generate reliable data to inform the clinical management of this difficult-to-treat subgroup of PD patients.
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http://dx.doi.org/10.1016/j.parkreldis.2009.09.005DOI Listing
December 2009

Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11.

Nat Genet 2007 Dec 25;39(12):1434-6. Epub 2007 Nov 25.

Department of Molecular Neuroscience, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.
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http://dx.doi.org/10.1038/ng.2007.43DOI Listing
December 2007

A perspective on the current issues in the diagnosis of Parkinson's disease.

Authors:
Paul F Worth

Br J Hosp Med (Lond) 2007 May;68(5):S6, S8-11, S14-5

Department of Neurology, Norfolk and Norwich University Hospital NHS Trust, Norwich NR4 7UY.

The National Institute for Health and Clinical Excellence published guidelines for the management of Parkinson's disease in 2006. This article summarizes the key diagnostic recommendations of the guidelines, and gives a personal view of current barriers to their implementation and how these might be overcome.
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http://dx.doi.org/10.12968/hmed.2007.68.5.23348DOI Listing
May 2007