Parkinson's disease age at onset genome-wide association study : Defining heritability, genetic loci, and α-synuclein mechanisms

Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe

Investigation of autosomal genetic sex differences in Parkinson's disease

Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner.Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (similar to 20%).Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients.Neurological Motor Disorder

Clinical, radiological, and functional evaluation following acute stroke

1. There are currently no proven treatments for cerebral infarction or intracerebral haematoma. Drug testing is at an exciting phase, however, and thrombolytic and neuroprotective agents appear to have the potential to rescue ischaemic cerebral tissue. The heterogeneous nature of stroke demands adequate patient assessment by clinical and radiological study, with standardised approaches to the measurement of recovery. 2. Previous studies have not fulfilled these stringent criteria, impairing interpretation and inter‐study comparison. The needs of drug studies in the acute phase following stroke are discussed in this review

Pulmonary arteriovenous fistulas are at high neurologic risk

No abstract available

Inhaled dry powder apomorphine (VR040) for 'off ' periods in Parkinson's disease: an in-clinic double-blind dose ranging study

Background: ‘Off’ periods increase as Parkinson's disease (PD) progresses and the benefits of standard therapy wane. Subcutaneous apomorphine rescues ‘off’ periods, but patient self‐injection and adverse cutaneous effects are sometimes problematic. Methods: We assessed safety, tolerability and efficacy of inhaled dry powder apomorphine (VR040) in a double‐blind clinic‐based Phase II study. Of 48 patients recruited at nine sites, 47 were randomized 2:1 inhaled apomorphine/placebo. Respirable doses (drug predicted to reach the lung), ascending through 1.5, 2.3, 3.0 and 4.0 mg until efficacy was achieved, were administered to patients in a practically defined ‘off’ state. The primary endpoint was the response in unified PD rating scale Part 3 (UPDRS 3), at the highest dose received by the patient. Secondary endpoints included time to ‘on’, the proportion of patients converting from ‘off’ to ‘on’, and duration of ‘on’. Results: In the 47 intent‐to‐treat patients with PD, mean age 60.6 years, the mean UPDRS 3 improvement was significantly greater for VR040 at 26.8 points (standard deviation 12.0), vs 14.9 (16.3) for placebo (treatment difference 11.6, 95% confidence interval 2.3–20.9, P = 0.016). Rapid apomorphine absorption (2–7 min) translated to rapid (mean 10 min) reversal from the ‘off’ state. Adverse effects did not differ between VR040 and placebo; no patient discontinued due to an adverse event; one serious adverse event (constipation) in the VR040 group was considered unrelated to trial medication. Conclusions: Inhaled apomorphine shows significant promise as a replacement for intermittent subcutaneous injections; further studies are appropriate to optimize efficacy and tolerability

Brain parenchyma sonography discriminates Parkinson's disease and atypical parkinsonian syndromes

No abstract available

Benefits of L-dopa in the treatment of early Parkinson's disease

The introduction of levodopa (L-dopa) in the late 1960s revolutionized the management of Parkinson's disease (PD). Previously, the only class of medication available for its treatment was anticholinergic therapy. The discovery was highly significant, but controversial in its day regarding the central role of dopamine (rather than other neurotransmitters) in relation to the motor features of PD. Initially, reversal of akinesia in a catecholamine-depleted model was achieved by a mixture of D- and L-dopa. Subsequently, dopamine deficiency was shown at autopsy in the human striatum in 2 cases of PD, and reduced urine dopamine excretion was found in patients. Dopamine replacement therapy was introduced, initially using very high L-dopa doses before the discovery of dopamine decarboxylase inhibitors, which avoid peripheral degradation of L-dopa before passing the blood-brain barrier, and which - as carbidopa or benserazide - are now routinely used in combination with L-dopa

Phase IIa randomized double-blind, placebo-controlled study of inhaled apomorphine as acute challenge for rescuing 'off' periods in patients with established Parkinson's disease

Background and purpose: In this first study of inhaled apomorphine (VR040) in patients with Parkinson's disease, the primary objective was to find the minimum efficacious dose of apomorphine that was useful in rescuing patients during ‘off’ periods. Safety, tolerability and pharmacokinetics of inhaled apomorphine were assessed during the study. Methods: A double‐blind, placebo‐controlled, randomized trial of three escalating single doses of inhaled apomorphine (0.2, 0.5 and 0.8 mg fine particle dose) versus placebo (3 : 1 active:placebo) was performed. Parkinson's motor severity assessments by a clinician, and disease state assessment by the patient, were performed at baseline during an ‘off’ state, and at specified times after test drug administration. Safety assessments (including vital signs, electrocardiogram and forced expiratory volume) were performed, and plasma apomorphine levels measured. Results: All 24 patients completed the study, and considering the three dose levels together, inhaled apomorphine did not significantly increase the proportion of patients switching from ‘off’ to ‘on’ (0/6 at 0.2 mg, 3/6 at 0.5 mg and 2/6 at 0.8 mg vs. 1/6 for placebo), or decrease the time from ‘off’ to ‘on’ post‐treatment (10 min for 0.5 mg, 40 min for 0.8 mg, vs. 20 min for placebo). However, there was a suggestion of benefit at the higher doses (5/12 switched ‘on’ at the 0.5 or 0.8 mg doses, vs. 1/6 for placebo). There were no serious adverse events and treatment was well tolerated. Peak plasma concentration was 1–3 min post‐dose, and plasma level dose proportionality was observed. Conclusions: Inhaled apomorphine was safe and well tolerated at the doses tested for an acute challenge to rescue ‘off’ periods, but efficacy at these doses was limited. A follow‐up study at higher doses is appropriate given these initial findings