Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD – to modulate disease progression – still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.

Effective disease-modifying treatments are an urgent need for Parkinson's disease (PD). A putative successful strategy is to counteract oxidative stress, not only with synthetic compounds, but also with natural agents or dietary choices. Vitamin E, in particular, is a powerful antioxidant, commonly found in vegetables and other components of the diet. In this work, we performed a questionnaire based case-control study on 100 PD patients and 100 healthy controls. The analysis showed that a higher dietary intake of Vitamin E was inversely associated with PD occurrence independently from age and gender (OR = 1.022; 95% CI = 0.999–1.045; p < 0.05), though unrelated to clinical severity. Then, in order to provide a mechanistic explanation for such observation, we tested the effects of Vitamin E and other alimentary antioxidants in vitro, by utilizing the homozygous PTEN-induced kinase 1 knockout (PINK1^−/−) mouse model of PD. PINK1^−/− mice exhibit peculiar alterations of synaptic plasticity at corticostriatal synapses, consisting in the loss of both long-term potentiation (LTP) and long-term depression (LTD), in the absence of overt neurodegeneration. Chronic administration of Vitamin E (alpha-tocopherol and the water-soluble analog trolox) fully restored corticostriatal synaptic plasticity in PINK1^−/− mice, suggestive of a specific protective action. Vitamin E might indeed compensate PINK1 haploinsufficiency and mitochondrial impairment, reverting some central steps of the pathogenic process. Altogether, both clinical and experimental findings suggest that Vitamin E could be a potential, useful agent for PD patients. These data, although preliminary, may encourage future confirmatory trials.

Objective: The complex nature of Parkinson's disease (PD) makes difficult to rate its severity, mainly based on visual inspection of motor impairments. Wearable sensors have been demonstrated to help overcoming such a difficulty, by providing objective measures of motor abnormalities. However, up to now those sensors have been used on advanced PD patients with evident motor impairment. As a novelty, here we report the impact of wearable sensors in the evaluation of motor abnormalities in newly diagnosed, untreated, namely de novo, patients. Methods: A network of wearable sensors was used to measure motor capabilities, in 30 de novo PD patients and 30 healthy subjects, while performing five motor tasks. Measurement data were used to determine motor features useful to highlight impairments and were compared with the corresponding clinical scores. Three classifiers were used to differentiate PD from healthy subjects. Results: Motor features gathered from wearable sensors showed a high degree of significance in discriminating the early untreated de novo PD patients from the healthy subjects, with 95% in accuracy. The rates of severity obtained from the measured features are partially in agreement with the clinical scores, with some highlighted, though justified, exceptions. Conclusion: Our findings support the feasibility of adopting wearable sensors in the detection of motor anomalies in early, untreated, PD patients. Significance: This work demonstrates that subtle motor impairments, occurring in de novo patients, can be evidenced by means of wearable sensors, providing clinicians with instrumental tools as suitable supports for early diagnosis, and subsequent management.

Background: Complex parkinsonism is the commonest phenotype in late‐onset PLA2G6‐associated 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, which may explain the phenotypic heterogeneity of childhood‐ and late‐onset PLA2G6‐associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology.Conclusions: Biallelic PLA2G6 mutations cause early‐onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell‐tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society