Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, ...impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system.
Although Parkinson's disease (PD) is the only chronic neurodegenerative disorder for which there are effective symptomatic therapies no treatment has yet been identified that would significantly slow ...its natural progression. Studies into the natural history of Parkinson's disease have been complicated by issues of diagnostic accuracy, heterogeneity of different forms of the disease as well as confounding effects of age related comorbidities. Only recently results from placebo-controlled clinical trials have helped to define the rates of progression of motor dysfunction as assessed by the UPDRS in early PD. Studies in treated patients suggest that there may be different rates of progression in different phases of the disease with faster decline in earlier versus later stages. Measuring progression of motor symptoms, however, alone is insufficient to describe the natural history of PD and may also be inadequate to define clinically meaningful disease modification in intervention trials. Progression of global disability as captured in the Hoehn and Yahr scale is important to consider and progression to stage III with beginning postural impairment defines a major milestone in the natural history of this illness. In addition, non-motor symptoms have major impact on the natural history of PD. Dementia, sleep-wake cycle dysregulation and autonomic failure were present in 50-80% of patients in one recent 15 year-follow up study. Dementia and psychosis are also major risk factors for nursing home placement in PD. A prerequisite for effective interventions that would modify disease progression in Parkinson's disease is the identification of the earliest preclinical stages of illness. This is now become a realistic possibility with screening tests of olfactory function and subsequent functional imaging. Subjects at risk for Parkinson's disease should be the future focus of neuroprotective trials.
Although idiopathic Parkinson disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, there are still major unmet needs regarding its ...long-term management. Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. Current evidence suggests that these are related to mode of administration, whereby multiple oral doses of levodopa generate pulsatile stimulation of striatal dopamine receptors. Current dopamine agonists, while producing more constant plasma levels, fail to match levodopa's efficacy. Strategies to treat levodopa-related motor complications are only partially effective, rarely abolishing motor fluctuations or dyskinesias. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus. Another area of major unmet medical need is related to nondopaminergic and nonmotor symptoms of PD. Targeting transmitter systems beyond the dopamine system is an interesting approach, both for the motor and nonmotor problems of PD. So far, clinical trial evidence regarding 5-HT agonists, glutamate antagonists, adenosine A(2) antagonists and alpha-adrenergic receptor antagonists, has been inconsistent, but trials with cholinesterase inhibitors and atypical antipsychotics to treat dementia and psychosis, have been successful. However, the ultimate goal of PD medical management is modifying disease progression, thereby delaying the evolution of motor and nonmotor complications of advanced disease. As understanding of preclinical markers for PD develops, there is new hope for neuropreventive strategies to target "at risk" populations before clinical onset of disease.
Parkinson's disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity ...or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. In fact, the recently defined MDS research criteria for prodromal PD have included combinations of risk and prodromal markers allowing to define target populations of future disease modification trials.
Summary Background Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment of Parkinson's disease with ergolinic dopamine agonists; however, until now, ...these complications have not substantially affected the routine clinical use of these drugs. The occurrence of restrictive valvular heart disease during treatment with pergolide and cabergoline caused concern about the safety of dopamine agonists in Parkinson's disease. Specifically, there is uncertainty whether fibrotic cardiac valvulopathy is due to exposure to these two ergolinic dopamine agonists or whether the abnormality is reversible. Changes in the heart valves can incur additional disability and worsen the clinical disorders of Parkinson's disease. Recent developments Population studies of patients with Parkinson's disease compared with non-parkinsonian controls have reported that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets. The fibrotic changes cause thickening, retraction, and stiffening of valves, which result in incomplete leaflet coaptation and clinically significant regurgitation, and have necessitated surgical valve replacement in some patients. Pergolide and cabergoline have high affinity for the 5-HT2B serotonin receptors, which are expressed in heart valves and might mediate mitogenesis and, in turn, the proliferation of fibroblasts. When analysed together, current population studies of similar designs and doses report 102 patients on cabergoline, 245 patients on pergolide, 181 patients on non-ergot agonists (pramipexole and ropinirole), and 177 non-parkinsonian controls. The frequency of moderate-to-severe regurgitation in at least one heart valve was higher in patients receiving cabergoline or pergolide than in patients taking non-ergot agonists or controls, and the incidence of new-onset valvulopathy was high in patients taking the ergot-derived drugs. Where next? Because of the routine prescription of pergolide and cabergoline, the switching of patients to different treatment regimens might be difficult. Moreover, whether the fibrotic changes are reversible is unknown. Finally, these adverse events do not occur in all patients, and no susceptibility factors are known. Prospective studies will assess the full effect of these abnormalities and help establish whether and when mitral valve tenting area abnormalities become clinically relevant during chronic treatment. The exact pathway leading to valvulopathy is unknown, although agonism of 5-HT2B receptors in the heart is implicated as a mediator in the process. Other ergolinic dopamine agonists, such as lisuride, and non-ergot dopamine agonists are devoid of 5-HT2B agonistic activity; therefore, their use might not induce fibrotic changes in heart valves. However, further prospective studies are needed. Such studies should also clarify the clinical relevance of mild-to-moderate echocardiographic changes and their natural history. Because of the clinical consequences of the adverse reactions, we suggest that affinity for 5-HT2B receptors is routinely tested in future drugs, in the laboratory or in animals, before they are given to patients.
Summary Background Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa ...compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations. Methods We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30–83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14–15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov , NCT01568073. Findings Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was −56·0 min (SE 13·4; 95% CI −82·3 to −29·7) for placebo, −96·3 min (13·4; −122·6 to −70·0) for entacapone, −91·3 min (13·5; −117·7 to −64·8) for opicapone 5 mg, −85·9 min (13·7; −112·8 to −59·1) for opicapone 25 mg, and −116·8 min (14·0; −144·2 to −89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline −60·8 min, 95% CI −97·2 to −24·4; p=0·0015) and non-inferior to entacapone (−26·2 min, −63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group. Interpretation The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit. Funding BIAL.
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