Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA, SDMA and hArg paradoxes

Abstract NG-Methylation of l-arginine (Arg) residues in certain proteins by protein arginine methyltransferases and subsequent proteolysis yields NG-monomethyl-l-arginine (MMA), NG,NG-dimethyl-l-arginine (asymmetric dimethylarginine, ADMA) and NG,N′G-dimethyl-l-arginine (symmetric dimethylarginine, SDMA). Biological MMA, ADMA and SDMA occur as free acids in the nM-range and as residues of proteins of largely unknown quantity. Arginine:glycine amidinotransferase (AGAT) catalyzes the synthesis of L-homoarginine (hArg) from free Arg and l-lysine. Biological hArg is considered to occur exclusively as free acid in the lower µM-range. Nitric oxide synthase (NOS) catalyzes the conversion of Arg (high affinity) and hArg (low affinity) to nitric oxide (NO) which is a pleiotropic signaling molecule. MMA, ADMA and SDMA are inhibitors (MMA > ADMA ≫ SDMA) of NOS activity. Slightly elevated ADMA and SDMA concentrations and slightly reduced hArg concentrations in the circulation are associated with many diseases including diabetes mellitus. Yet, this is paradox: (1) free ADMA and SDMA are weak inhibitors of endothelial NOS (eNOS) which is primarily responsible for NO-related effects in the cardiovascular system, with free hArg being a poor substrate for eNOS; (2) free ADMA, SDMA and hArg are not associated with oxidative stress which is considered to induce NO-related endothelial dysfunction. This ADMA/SDMA/hArg paradox may be solved by the assumption that not the free acids but their precursor proteins exert biological effects in the vasculature, with hArg antagonizing the effects of NG-methylated proteins

Enhanced Nitric Oxide (NO) and Decreased ADMA Synthesis in Pediatric ADHD and Selective Potentiation of NO Synthesis by Methylphenidate

Attention deficit hyperactivity disorder (ADHD) is a common pediatric psychiatric disorder, frequently treated with methylphenidate (MPH). Recently, MPH’s cardiovascular safety has been questioned by observational studies describing an increased cardiovascular risk in adults and blood pressure alterations in children. We considered members of the L-arginine (Arg)/nitric oxide (NO) pathway as possible early cardiovascular risk factors in pediatric ADHD children. They include the NO metabolites, nitrite and nitrate, the NO precursor Arg, and asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor and a cardiovascular risk factor in adults. We conducted a prospective clinical trial with 42 ADHD children (aged 6–16 years) with (n = 19) and without (n = 23) MPH treatment. Age-matched children without ADHD (n = 43) served as controls. All plasma and urine metabolites were determined by gas chromatography-mass spectrometry. We observed higher plasma nitrite and lower plasma ADMA concentrations in the ADHD children. MPH-treated ADHD children had higher plasma nitrite concentrations than MPH-untreated ADHD children. As NOS activity is basally inhibited by ADMA, MPH treatment seems to have decreased the inhibitory potency of ADMA. Percentiles of systolic blood pressure were higher in MPH-treated ADHD children. The underlying mechanisms and their implications in the MPH therapy of pediatric ADHD with MPH remain to be elucidated in larger cohorts

Enhanced nitric oxide (NO) and decreased ADMA synthesis in pediatric ADHD and selective potentiation of NO synthesis by methylphenidate

Attention deficit hyperactivity disorder (ADHD) is a common pediatric psychiatric disorder, frequently treated with methylphenidate (MPH). Recently, MPH’s cardiovascular safety has been questioned by observational studies describing an increased cardiovascular risk in adults and blood pressure alterations in children. We considered members of the L-arginine (Arg)/nitric oxide (NO) pathway as possible early cardiovascular risk factors in pediatric ADHD children. They include the NO metabolites, nitrite and nitrate, the NO precursor Arg, and asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor and a cardiovascular risk factor in adults. We conducted a prospective clinical trial with 42 ADHD children (aged 6–16 years) with ($\it n$ = 19) and without ($\it n$ = 23) MPH treatment. Age-matched children without ADHD ($\it n$ = 43) served as controls. All plasma and urine metabolites were determined by gas chromatography-mass spectrometry. We observed higher plasma nitrite and lower plasma ADMA concentrations in the ADHD children. MPH-treated ADHD children had higher plasma nitrite concentrations than MPH-untreated ADHD children. As NOS activity is basally inhibited by ADMA, MPH treatment seems to have decreased the inhibitory potency of ADMA. Percentiles of systolic blood pressure were higher in MPH-treated ADHD children. The underlying mechanisms and their implications in the MPH therapy of pediatric ADHD with MPH remain to be elucidated in larger cohorts

Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans.

BackgroundAngiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses.Methods and findingsIn this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73-0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86-0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30-5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93-1.38, median follow-up 30 days).ConclusionsThis observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials