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A BS TRACT: Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6associated neurodegeneration. Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. Results: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/ dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating,

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled crossover trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson’s disease (PD) patients. In a subgroup of patients, we measured selected neurotrophin levels and markers of inflammation and oxidative stress in serum, before and after the experimental intervention. Thirty-three PD patients with associated freezing of gait were randomised to either nVNS or sham. After baseline assessments, patients were instructed to deliver 6 two-minute stimulations (total 12 min/day) of the nVNS/sham device (electroCore, Inc. USA) for one month at home. Patients were then re-assessed. After a washout period of one month, the same patients were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters were observed with nVNS, including walking speed, stance time and step length, compared to sham. Similarly, overall motor function (MDS-UPDRS III) also improved significantly following nVNS stimulation. Serum Tumor Necrosis Factor (TNF)-α and glutathione levels decreased and brain-derived neurotrophic factor (BDNF) levels increased significantly (p < 0.05) after treatment with nVNS. Here we present the first double-blind sham-controlled trial evidence of the efficacy and safety of nVNS in the treatment of gait and motor function in patients with PD.