Levodopa-carbidopa intestinal gel infusion (LCIG) in Parkinson disease with genetic mutations.

BACKGROUND: Levodopa-carbidopa intestinal gel infusion (LCIG) is a therapeutic option for advanced Parkinson disease (PD) patients with troublesome motor complications, unresponsive to conventional oral treatment. There is some evidence to suggest that the genetic background may influence the clinical presentation and rate of progression of PD. Whether the genetic background influences the outcome of device-assisted therapies is currently debated. Some studies have investigated the effectiveness of deep brain stimulation (DBS) in PD patients with different genetic background, while evidence is lacking regarding LCIG. METHODS: A cohort of LCIG patients underwent genetic testing. The motor and neuropsychological outcomes of LCIG were retrospectively analyzed. RESULTS: Fifty-six patients were analyzed, nine of them (15%) had at least one mutation/variant in a PD-associated gene: five GBA1, two SNCA, one LRRK2, one PRKN; 13 (23%) carried the BDNF Val66Met polymorphism. The mean duration of follow-up was 4.9 ± 2.6 years. There were no significant differences in motor or neuropsychological outcomes between patients with and without these gene mutations/variants. No cognitive worsening was observed at follow-up among GBA-PD patients, and they responded well to LCIG in terms of motor symptoms. CONCLUSIONS: Overall, we observed a significant benefit in terms of motor complications in our cohort, including patients carrying genetic mutations/variants. Due to the small sample and limited number of patients carrying genetic mutations/variants, no definitive conclusions can be drawn yet on the genotype impact on LCIG outcome. A careful selection of patients, regardless of the genetic background, is pivotal for an optimal outcome of LCIG.

Parkinson disease.

Parkinson disease (PD) is the most common neurodegenerative movement disorder. In Europe, prevalence and incidence rates for PD are estimated at approximately 108-257/100 000 and 11-19/100 000 per year, respectively. Risk factors include age, male gender and some environmental factors. The aetiology of the disease in most patients is unknown, but different genetic causes have been identified. Although familial forms of PD account for only 5%-15% of cases, studies on these families provided interesting insight on the genetics and the pathogenesis of the disease allowing the identification of genes implicated in its pathogenesis and offering critical insights into the mechanisms of disease. The cardinal motor symptoms of PD are tremor, rigidity, bradykinesia/akinesia and postural instability, but the clinical picture includes other motor and non-motor symptoms. Its diagnosis is principally clinical, although specific investigations can help the differential diagnosis from other forms of parkinsonism. Pathologically, PD is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by accumulation of misfolded α-synuclein, which is found in intra-cytoplasmic inclusions called Lewy bodies. Currently available treatments offer good control of motor symptoms but do not modify the evolution of the disease. This article is intended to provide a comprehensive, general and practical review of PD for the general neurologist.

Neurological effects of glucocerebrosidase gene mutations.

The association between Gaucher disease (GD) and Parkinson disease (PD) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD. Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%-20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD, type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Practical recommendations for the process of proposing, planning and writing a neurological management guideline by EAN task forces.

The European Academy of Neurology (EAN), founded in 2014 after the merging of the two previously active European Neurological Societies, considers the production of neurological guidelines a major obligation, as this is a major tool to improve clinical practice in neurology. This paper updates practical suggestions to develop guidelines about the treatment and diagnosis of neurological diseases within the framework of the EAN. Its aim is to make uniform, traceable and explicit the path from the decision to write an EAN guideline to its publication. We explain the protocol structure, handling of conflicts of interest, format, timeline and process of revision and acceptance. It provides the view of the Scientific Committee and the Board of the EAN. We hope to make easier a larger involvement of the EAN scientific community in producing guidelines.

The timing of deep brain stimulation for Parkinson disease in the UK from 1997 to 2012.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) for Parkinson disease (PD) has traditionally been reserved for the late stages of the disease. There is evidence that DBS is also effective if applied earlier in the disease course. Changes in the frequency of DBS procedures in the UK over a 15-year period were investigated. METHODS: A retrospective review was performed of patient age and disease duration for DBS surgery for PD in UK neurosurgical units from 1997 to 2012 using departmental databases. RESULTS: The number of DBS procedures in the UK increased from three in 1997 to over 80 per year during this period. The mean age at the time of surgery (60 years) and the mean duration of PD at the time of DBS (11 years) remained unchanged over 15 years. CONCLUSIONS: The age and disease duration at which DBS is performed for PD in the UK has been static over a 15-year period and DBS appears to remain a therapy for PD applied late in its course. This may change in the light of clinical evidence suggesting a benefit for earlier DBS.

Early L-dopa, but not pramipexole, restores basal ganglia activity in partially 6-OHDA-lesioned rats.

The most appropriate time for the initiation of dopaminergic symptomatic therapy in Parkinson's disease remains debatable. It has been suggested that early correction of basal ganglia pathophysiological abnormalities may have long-term beneficial effects. To test this hypothesis, we investigated the early and delayed actions of L-dopa and pramipexole, using a delayed-start protocol of treatment. The effects of early and delayed administration of these drugs on motor response, development of dyskinesias, neurogenesis and molecular markers in basal ganglia were studied in rats with a unilateral and partial 6-hydroxydopamine-induced nigrostriatal lesion. Ten days after lesioning, rats received treatment with: a) L-dopa methyl ester (25mg/kg with 6.25mg/kg of benserazide, i.p., twice a day); b) pramipexole (0.5mg/kg, sc, twice a day) or c) saline for 4weeks. Four weeks after treatment initiation, rats from the saline group were distributed in three groups that then received the following treatments: d) L-dopa, e) pramipexole or f) saline, for 4weeks more. Three animals in each treatment arm received 5-bromo-2-deoxyuridine injections (200mg/kg) 3days before starting treatment. When compared with delayed-start L-dopa, early-start L-dopa treatment induced a lower rotational response (p<0.01), an improvement in limb akinesia (p<0.05), a lower level of dyskinesia (p<0.01) and a normalization of lesion-induced molecular changes in basal ganglia. When compared with delayed-start pramipexole, early-start pramipexole induced a higher rotational response (p<0.01), but did not improve limb akinesia, induce dyskinesia nor normalize lesion-induced molecular changes. Neither significant modifications of striatal dopamine D1-D3 receptor heteromerization nor subventricular zone neurogenesis was found after any L-dopa or pramipexole treatments. Our data support a possible restoration of basal ganglia physiological mechanisms by early-start L-dopa therapy.

Long-term safety and sustained efficacy of extended-release pramipexole in early and advanced Parkinson's disease.

BACKGROUND AND PURPOSE: To assess the long-term safety and efficacy of pramipexole as a once-daily (q.d.) extended-release oral formulation in early or advanced Parkinson's disease (PD). METHODS: In two double-blind (DB) studies of early PD and one of advanced PD,active-treatment arms received pramipexole immediate release (IR) or extended release (ER), with exposure lasting up to 33 weeks. In open-label (OL) extensions that followed immediately, subjects took ER q.d. for up to 80 weeks, with dosage adjustment permitted (range 0.375-4.5 mg q.d.). RESULTS: Of 590 subjects completing an early-PD DB study, 511 entered the early-PD OL extension; 408 completed it. Reported adverse events (AEs) with incidence ≥10.0% were somnolence (15.1%), peripheral edema (11.7%) and back pain (10.6%). Of 465 subjects completing the advanced-PD DB study, 391 entered the advanced-PD OL extension; 329 completed it. Reported AEs with incidence ≥10.0%were dyskinesia (27.4%) and somnolence (13.6%). Impulse control disorders were identified by semi-structured interview in 13 subjects (1.4% of 902). In exploratory analyses, adjusted mean Unified Parkinson's Disease Rating Scale (UPDRS) PartsII + III scores (excluding ex-placebo recipients) remained substantially improved from DB baseline scores prior to pramipexole introduction, at -6.6 and -6.3 points amongst ex-DB-ER and ex-DB-IR recipients after 113 weeks of pramipexole (33 DB plus 80 OL) in early PD, and -11.5 and -9.1 after up to 113 weeks (up to 33 DB plus 80 OL) in advanced PD. CONCLUSIONS: These results support the long-term safety and efficacy of pramipexole ER in early and advanced PD. AEs were typical for dopaminergic medications, and UPDRS scores suggested sustained symptomatic benefit.

Patient-reported convenience of once-daily versus three-times-daily dosing during long-term studies of pramipexole in early and advanced Parkinson's disease.

BACKGROUND AND PURPOSE: In chronic diseases including Parkinson's disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less-effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical-trial designs preclude direct comparisons of adherence to various schedules. METHODS: In two double-blind (DB) studies of early PD and one of advanced PD, subjects received three-times-daily (t.i.d.) pramipexole or placebo. In open-label (OL) extensions, subjects took extended-release, once-daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. RESULTS: Of 590 DB-trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it 'very much more convenient' and 27.8%'more convenient'), 2.7% preferred t.i.d., and 2.9% chose 'no difference'. Of 465 DB-trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it 'very much more convenient' and 40.1%'more convenient'), 5.7% preferred t.i.d., and 5.4% chose 'no difference'. Results excluding DB-placebo recipients were highly similar. CONCLUSIONS: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine-agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced-PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.

Success rate, efficacy, and safety/tolerability of overnight switching from immediate- to extended-release pramipexole in advanced Parkinson's disease.

BACKGROUND AND PURPOSE: For Parkinson's disease (PD), an extended-release (ER) pramipexole formulation taken once daily, has shown efficacy, safety, and tolerability resembling those of immediate-release (IR) pramipexole taken three times daily. The present study assessed, in advanced PD, the success of an overnight switch from adjunctive IR to ER. METHODS: Levodopa users experiencing motor fluctuations were randomized to adjunctive double-blind (DB) placebo, IR, or ER. Amongst completers of ≥18 weeks, ER recipients were kept on DB ER, whilst IR recipients were switched overnight to DB ER at unchanged daily dosage. After a DB week, switch success was assessed. During the next 5 weeks, all patients underwent ER titration to optimal open-label maintenance dosage. RESULTS: One week post-switch, 86.2% of 123 IR-to-ER and 83.8% of 105 ER-to-ER patients had ≤15% (or ≤3-point, for pre-switch scores ≤20) increase on UPDRS Parts II + III, and 77.9% (of 122) and 70.2% (of 104) had ≤1-h increase in daily OFF-time. At 32 weeks, the groups showed comparable improvements from DB baseline (pramipexole inception), including, on UPDRS II + III, adjusted mean (SE) changes of -14.8 (1.5) for IR-to-ER and -13.3 (1.6) for ER-to-ER. Rates of premature discontinuation owing to adverse events were 6.5% for IR-to-ER and 4.9% for ER-to-ER. CONCLUSIONS: By OFF-time and UPDRS criteria, majorities of patients with advanced PD were successfully switched overnight from pramipexole IR to ER at unchanged daily dosage. During subsequent maintenance, pramipexole showed sustained efficacy, safety, and tolerability, regardless of formulation (IR or ER) in the preceding DB trial.

Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson's disease.

BACKGROUND AND PURPOSE: Safinamide is an α-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action in Phase III clinical development as a once-daily add-on to dopamine agonist (DA) therapy for early Parkinson's disease (PD). METHODS: Study 017 was a 12-month, randomized, double-blind, placebo-controlled pre-planned extension study to the previously reported Study 015. Patients received safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to 'intervention', defined as increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post hoc analyses were performed on each separate dose group. RESULTS: Of the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled safinamide and placebo groups, respectively (log-rank test; P = 0.3342). In post hoc analyses, patients receiving safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and a delay in median time to intervention of 9 days (P < 0.05; 240- to 540-day analysis). CONCLUSIONS: The pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that safinamide 100 mg/day may be effective as add-on treatment to DA in PD.

Challenges to the development of disease-modifying therapies in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that involves the neurones of multiple transmitter pathways. The dopaminergic neuronal degeneration determines the main early clinical characteristics of the disease. There have been many recent valuable insights into the pathogenesis of PD, driven primarily by research of the genetic causes of the disease. These now provide a clearer view of the pathways that lead to neuronal dysfunction and death. Perhaps surprisingly, the same pathways initiated by gene mutations causing familial PD are those already identified to be involved in idiopathic sporadic PD, namely mitochondrial dysfunction, oxidative stress and protein misfolding and aggregation. Novel therapies designed to slow PD progression are likely to intervene in one or more of these pathways. Some candidates have been tested based upon this hypothesis, albeit with varying results. Significant developments in this area face several challenges including effective disease-modelling systems and clinical trial designs that can enable a true positive result to be obtained in a relatively short period.

Mitochondrial matters of the brain: the role in Huntington's disease.

Even before the discovery of the mutant htt gene as the cause of Huntington's Disease (HD), abnormal energy metabolism and mitochondrial dysfunction had been suggested as a possible pathogenic mechanism in HD. These initial investigations described defects in energy metabolism using Positron Emission Tomography (PET) and Nuclear Magnetic Resonance (NMR) Spectroscopy in symptomatic and pre-symptomatic HD patients. Concurrently, 3-nitroproprionic acid, a mitochondrial complex II inhibitor, was found to replicate many of the pathological and clinical features of HD when administered to animals. Subsequently, reductions in mitochondrial respiratory chain enzyme activities in HD brain and muscle, HD mice models and cellular HD models were discovered and confirmed impaired mitochondrial function as an important component of pathogenesis. A unifying hypothesis linking chronic ATP depletion, oxidative stress and mitochondrial dysfunction culminated in the "slow excitotoxic theory" of HD pathogenesis. More recently, the localization of mutant htt within mitochondria and the association between transcriptional dysregulation caused by impaired PGC-1 alpha activity with abnormal mitochondrial biogenesis and function has provided further links with additional potential pathogenic mechanisms.

Genetic causes of PD: A pathway to disease modification.

The underline neuropathology of Parkinson disease is pleiomorphic and its genetic background diverse. Possibly because of this heterogeneity, no effective disease modifying therapy is available. In this paper we give an overview of the genetics of Parkinson disease and explain how this is relevant for the development of new therapies. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.