Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a common sleep related movement disorder that can be idiopathic or occurs in comorbidity with other medical conditions such as polyneuropathy, iron deficiency anemia, multiple sclerosis, hypertension and cardiovascular diseases. In recent years, a growing body of literature investigated the association between RLS/WED and Parkinson's Disease (PD). Several questions regarding the comorbidity between these two disorders are still unanswered. If the insurgence of RLS/WED may precede the onset of PD, or if RLS/WED could represent a secondary condition of PD and if impaired dopaminergic pathway may represent a bridge between these two conditions are still debatable issues. In this review, we critically discuss the relationship between RLS/WED and PD by reviewing cross sectional and longitudinal studies, as well as the role of dopamine in these disorders. A twofold interpretation have to be taken into account: dopaminergic therapy may have a crucial role in the development of RLS/WED in PD patients or RLS/WED can be conceived as an early manifestation of PD rather than a risk factor. Several studies showed a high prevalence of RLS/WED in PD patients and several findings related to dopaminergic and iron alterations in both disorders, however up to now it is difficult to find a point of agreement between studies. A greater number of systematic and strongly controlled longitudinal studies as well as basic pathophysiological investigations particularly in RLS/WED are needed to clarify this complex relationship.

Purpose We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. Methods Twenty-six patients with neurological symptoms (neuro-COVID-19) and [ 18 F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo-and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo-and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. ResultsThe "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. Conclusion Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes. KeywordsNeuro-COVID • [ 18 F]FDG • Hypometabolism • Hypermetabolism • Recovery This article is part of the Topical Collection on Neurology.

A BS TRACT: Background: Glucosylceramidase (GBA) mutations are considered the most common genetic risk factors for developing Parkinson's disease (PD). Objectives: We aimed to assess, at different time points, the integrity of brain striatal and extra-striatal dopamine pathways and clinical phenotype of a group of PD subjects bearing heterozygous GBA mutations (GBA-PD), compared with a group of idiopathic PD patients (iPD) stratified by age at disease onset. A longitudinal approach was adopted to evaluate the progression over time for clinical and 123 I-FP-CIT SPECT imaging features. Methods: We considered 46 GBA-PD patients and 339 iPD patients, subdivided into two groups according to age at PD onset (n = 58 < 50 years and n = 281 > 50 years). We measured differences in the occurrence/severity/progression of motor and non-motor features, 123 I-FP-CIT standard uptake value ratios (SUVr) in striatal and extra-striatal regions, and global cognitive deterioration over time in a subset of 168 cases with available follow-up.Results: At baseline, the GBA-PD cohort showed more severe motor and cognitive deficits than the early-iPD cohort. The 123 I-FP-CIT SUVr reduction in the striatal and the extra-striatal regions was more marked in the GBA-PD than the early-and late-iPD cohorts. Both GBA-PD and late-iPD patients had a significant annual deterioration in their global cognitive performance, while the early-iPD group showed global cognitive stability over time. At follow-up, the iPD cohorts became similar to the GBA-PD group in 123 I-FP-CIT SUVr reduction. Conclusion: These new findings support the hypothesis of a biological role of GBA mutations in accelerating the early neurodegenerative processes in PD, leading to the malignant clinical phenotype.