HLA allele frequencies and susceptibility to COVID-19 in a group of 99 Italian patients

With the aim to individuate alleles that may reflect a higher susceptibility to the disease, in the present study we analyzed the HLA allele frequency distribution in a group of 99 Italian patients affected by a severe or extremely severe form of COVID-19. After the application of Bonferroni's correction for multiple tests, a significant association was found for HLA-DRB1*15:01, -DQB1*06:02 and -B*27:07, after comparing the results to a reference group of 1017 Italian individuals, previously typed in our laboratory. The increased frequencies observed may contribute to identify potential markers of susceptibility to the disease, although controversial results on the role of single HLA alleles in COVID-19 patients have been recently reported

Will GWAS eventually allow the identification of genomic biomarkers for COVID-19 severity and mortality?

: GWAS involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases, including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multicenter consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this Commentary, we evaluate the advantages and limitations of this approach

COVID-19 annual update: a narrative review

Three and a half years after the pandemic outbreak, now that WHO has formally declared that the emergency is over, COVID-19 is still a significant global issue. Here, we focus on recent developments in genetic and genomic research on COVID-19, and we give an outlook on state-of-the-art therapeutical approaches, as the pandemic is gradually transitioning to an endemic situation. The sequencing and characterization of rare alleles in different populations has made it possible to identify numerous genes that affect either susceptibility to COVID-19 or the severity of the disease. These findings provide a beginning to new avenues and pan-ethnic therapeutic approaches, as well as to potential genetic screening protocols. The causative virus, SARS-CoV-2, is still in the spotlight, but novel threatening virus could appear anywhere at any time. Therefore, continued vigilance and further research is warranted. We also note emphatically that to prevent future pandemics and other world-wide health crises, it is imperative to capitalize on what we have learnt from COVID-19: specifically, regarding its origins, the world's response, and insufficient preparedness. This requires unprecedented international collaboration and timely data sharing for the coordination of effective response and the rapid implementation of containment measures

Amyloid-β42/Neurogranin Ratio as a Potential Index for Cognitive Impairment in Parkinson's Disease

Background: Synaptopathy is critical in pathophysiology of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-β42 (Aβ42) are considered markers of synaptic dysfunction in neurodegenerative diseases. Objective: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aβ42/NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. Methods: Levels of NG, Aβ42, amyloid-β40, total and phosphorylated tau, and Aβ42/NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was determined. Results: NG and Aβ42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aβ42/NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. Conclusions: The novel Aβ42/NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD

Dietary Vitamin E as a protective factor for Parkinson's disease: Clinical and experimental evidence

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

Ischemic injury precipitates neuronal vulnerability in Parkinson's disease: Insights from PINK1 mouse model study and clinical retrospective data

Introduction: Increasing evidence demonstrates the relevant association between Parkinson's disease (PD) and vascular diseases/risk factors, as well as a worse clinico-pathological progression in those patients with vascular comorbidity. The mechanisms underlying this relationship have not been clarified yet, although their comprehension is critical in a perspective of disease-modifying treatments development or prevention. Methods: We performed an experimental protocol of ischemic injury (glucose-oxygen deprivation, OGD) on PTEN-induced kinase 1 knockout (PINK1−/−) mice, a well-established PD model, looking at both electrophysiological and morphological changes in basal ganglia. In addition, 253 PD patients were retrospectively analysed, to estimate the prevalence of vascular risk factors. Results: In PINK1−/− mice, the OGD protocol induced electrophysiological (prolonged depolarization) and morphological alterations (picnotic cells, cellular loss and swelling, thickening of nuclear chromatin) in striatal medium spiny neurons and nigral dopaminergic neurons. Vascular comorbidity occurred in 75% of PD patients. Conclusions: The ischemic injury precipitates neuronal vulnerability in basal ganglia of PINK1−/− mice, probably through an impairment of mitochondrial metabolism and higher oxidative stress. These experimental data may provide a potential mechanistic explanation for both the association between vascular diseases and PD and their reciprocal interactions in determining the clinico-pathological burden of PD patients

Ischemic injury precipitates neuronal vulnerability in Parkinson{'}s disease: Insights from PINK1 mouse model study and clinical retrospective data

Introduction: Increasing evidence demonstrates the relevant association between Parkinson's disease (PD) and vascular diseases/risk factors, as well as a worse clinico-pathological progression in those patients with vascular comorbidity. The mechanisms underlying this relationship have not been clarified yet, although their comprehension is critical in a perspective of disease-modifying treatments development or prevention.Methods: We performed an experimental protocol of ischemic injury (glucose-oxygen deprivation, OGD) on PTEN-induced kinase 1 knockout (PINK1(-/-)) mice, a well-established PD model, looking at both electrophysiological and morphological changes in basal ganglia. In addition, 253 PD patients were retrospectively analysed, to estimate the prevalence of vascular risk factors.Results: In PINK1(-/-) mice, the OGD protocol induced electrophysiological (prolonged depolarization) and morphological alterations (picnotic cells, cellular loss and swelling, thickening of nuclear chromatin) in striatal medium spiny neurons and nigral dopaminergic neurons. Vascular comorbidity occurred in 75% of PD patients.Conclusions: The ischemic injury precipitates neuronal vulnerability in basal ganglia of PINK1(-/-) mice, prob- ably through an impairment of mitochondrial metabolism and higher oxidative stress. These experimental data may provide a potential mechanistic explanation for both the association between vascular diseases and PD and their reciprocal interactions in determining the clinico-pathological burden of PD patients