Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

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

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.

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

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.

How to treat Parkinson's disease in 2013.

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.

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

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.

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.

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.

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

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.

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

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.

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

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.