The amino acid L-arginine serves as substrate for the nitric oxide synthase which is crucial in vascular function and disease. Derivatives of arginine, such as asymmetric (ADMA) and symmetric ...dimethylarginine (SDMA), are regarded as markers of endothelial dysfunction and have been implicated in vascular disorders. While there is a variety of studies consolidating ADMA as biomarker of cerebrovascular risk, morbidity and mortality, SDMA is currently emerging as an interesting metabolite with distinct characteristics in ischemic stroke. In contrast to dimethylarginines, homoarginine is inversely associated with adverse events and mortality in cerebrovascular diseases and might constitute a modifiable protective risk factor. This review aims to provide an overview of the current evidence for the pathophysiological role of arginine derivatives in cerebrovascular ischemic diseases. We discuss the complex mechanisms of arginine metabolism in health and disease and its potential clinical implications in diverse aspects of ischemic stroke.
Background A substantial proportion of ischemic strokes remain cryptogenic, which has important implications for secondary prevention. Identifying genetic variants related to mechanisms of stroke ...causes may provide a chance to clarify the actual causes of cryptogenic strokes. Methods and Results In a 2-step process, 2 investigators independently and systematically screened studies that reported genetic variants in regard to stroke causes that were published between January 1991 and April 2021. Studies on monogenetic disorders, investigation of vascular risk factors as the primary end point, reviews, meta-analyses, and studies not written in English were excluded. We extracted information on study types, ancestries, corresponding single nucleotide polymorphisms, and sample and effect sizes. There were 937 studies screened, and 233 were eligible. We identified 35 single nucleotide polymorphisms and allele variants that were associated with an overlap between cryptogenic strokes and another defined cause. Conclusions Associations of single variants with an overlap between cryptogenic stroke and another defined cause were limited to a few polymorphisms. A limitation of all studies is a low granularity of clinical data, which is of major importance in a complex disease such as stroke. Deep phenotyping is in supposed contradiction with large sample sizes but needed for genome-wide analyses. Future studies should attempt to address this restriction to advance the promising approach of elucidating the cause of stroke at the genetic level. Especially in a highly heterogenous disease such as ischemic stroke, genetics are promising to establish a personalized approach in diagnostics and treatment in the sense of precision medicine.
Abstract
In patients with left ventricular assist device (LVAD), infections and thrombotic events represent severe complications. We investigated device-specific local and systemic inflammation and ...its impact on cerebrovascular events (CVE) and mortality. In 118 LVAD patients referred for
18
F-FDG-PET/CT, metabolic activity of LVAD components, thoracic aortic wall, lymphoid and hematopoietic organs, was quantified and correlated with clinical characteristics, laboratory findings, and outcome. Driveline infection was detected in 92/118 (78%) patients by
18
F-FDG-PET/CT. Activity at the driveline entry site was associated with increased signals in aortic wall (r = 0.32,
p
< 0.001), spleen (r = 0.20,
p
= 0.03) and bone marrow (r = 0.20,
p
= 0.03), indicating systemic interactions. Multivariable analysis revealed independent associations of aortic wall activity with activity of spleen (β = 0.43, 95% CI 0.18–0.68,
p
< 0.001) and driveline entry site (β = 0.04, 95% CI 0.01–0.06,
p
= 0.001). Twenty-two (19%) patients suffered CVE after PET/CT. In a binary logistic regression analysis metabolic activity at the driveline entry site missed the level of significance as an influencing factor for CVE after adjusting for anticoagulation (OR = 1.16, 95% CI 1–1.33,
p
= 0.05). Metabolic activity of the subcutaneous driveline (OR = 1.13, 95% CI 1.02–1.24,
p
= 0.016) emerged as independent risk factor for mortality. Molecular imaging revealed systemic inflammatory interplay between thoracic aorta, hematopoietic organs, and infected device components in LVAD patients, the latter predicting CVE and mortality.
(1) Background: Patients with acute ischaemic stroke (AIS) are at high risk for stroke-associated infections (SAIs). We hypothesised that increased concentrations of systemic inflammation markers ...predict SAIs and unfavourable outcomes; (2) Methods: In 223 patients with AIS, blood samples were taken at ≤24 h, 3 d and 7d after a stroke, to determine IL-6, IL-10, CRP and LBP. The outcome was assessed using the modified Rankin Scale at 90 d. Patients were thoroughly examined regarding the development of SAIs; (3) Results: 47 patients developed SAIs, including 15 lower respiratory tract infections (LRTIs). IL-6 and LBP at 24 h differed, between patients with and without SAIs (IL-6: p < 0.001; LBP: p = 0.042). However, these associations could not be confirmed after adjustment for age, white blood cell count, reduced consciousness and NIHSS. When considering the subgroup of LRTIs, in patients who presented early (≤12 h after stroke, n = 139), IL-6 was independently associated with LRTIs (OR: 1.073, 95% CI: 1.002−1.148). The ROC-analysis for prediction of LRTIs showed an AUC of 0.918 for the combination of IL-6 and clinical factors; (4) Conclusions: Blood biomarkers were not predictive for total SAIs. At early stages, IL-6 was independently associated with outcome-relevant LRTIs. Further studies need to clarify the use of biochemical markers to identify patients prone to SAIs.
Many ischemic strokes are diagnosed as embolic strokes of undetermined source (ESUS). Recent evidence suggests that nonstenotic carotid plaque (nsCP) may be a substantial contributor to the risk for ...ESUS. We aimed to investigate the risk factor profile associated with nsCP in ESUS and defined stroke etiologies.
In this retrospective case-control study, we investigated consecutive patients with acute ischemic stroke due to ESUS, small-vessel disease, or cardioembolism proven by magnetic resonance imaging. The association of vascular risk factors age, arterial hypertension, diabetes, dyslipoproteinemia, body mass index, alcohol consumption, tobacco use, kidney failure, and history of stroke with the presence of nsCP was investigated using binary logistic regression analysis and further stratified by stroke etiology and sex.
In total, 609 patients (median age, 76 years; 46% women) who were treated from 2018 to 2020 were considered. In patients with ESUS, sex played a more important role for the prevalence of nsCP than in defined etiologies. Female patients with ESUS had lower odds of exhibiting nsCP compared with male patients with ESUS (adjusted odds ratio, 0.36 95% CI, 0.15-0.86). In male patients with ESUS, we observed that age (adjusted odds ratio per 10-year increase, 2.55 95% CI, 1.26-5.17) and hypertension (adjusted odds ratio, 2.49 95% CI, 0.56-11.1) were the main risk factors for nsCP, whereas in female patients with ESUS also tobacco use was particularly relevant (adjusted odds ratio, 3.71 95% CI, 0.61-22.5). These results were in line with a sensitivity analysis in nsCP located ipsilateral to the infarct.
Sex differences play an important role in nsCP prevalence in patients with ESUS. These findings may have important implications for the management in targeted secondary prevention following ESUS.
Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient ...records from our academic centre (2010-2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed.
Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neurological disorders. A growing number of genes, involved in glial and neuronal functions, have been associated with ...different subtypes of CMT leading to improved diagnostics and understanding of pathophysiological mechanisms. However, some patients and families remain genetically unsolved.
We report on a German family including four affected members over three generations with a CMT phenotype accompanied by cognitive deficits, predominantly with regard to visual abilities and episodic memory.
A comprehensive clinical characterization followed by a sequential diagnostic approach disclosed a heterozygous rare SEPT9 missense variant c.1406 T > C, p.(Val469Ala), that segregates with disease. SEPT9 has been linked to various intracellular functions, such as cytokinesis and membrane trafficking. Interestingly, SEPT9-mutations are known to cause hereditary neuralgic amyotrophy (HNA), a recurrent focal peripheral neuropathy.
We, for the first time, present a SEPT9 variant associated to a CMT phenotype and suggest SEPT9 as new sufficient candidate gene in CMT.
Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. ...Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this study we, therefore, aimed to investigate the potential role of monocyte subsets and associated chemokines as clinical biomarkers for vulnerability of CS. Patients with symptomatic and asymptomatic CS (n = 21), patients with cardioembolic ischemic strokes (n = 11), and controls without any cardiovascular disorder (n = 11) were examined. Cardiovascular risk was quantified using the Essen Stroke Risk Score (ESRS). Monocyte subsets in peripheral blood were measured by quantitative flow cytometry. Plaque specimens were histologically analyzed. Furthermore, plasma levels of monocyte chemotactic protein 1 (MCP-1) and fractalkine were measured. Intermediate monocytes (Mon2) were significantly elevated in symptomatic and asymptomatic CS-patients compared to controls. Mon2 counts positively correlated with the ESRS. Moreover, stroke patients showed an elevation of Mon2 compared to controls, independent of the ESRS. MCP-1 levels were significantly higher in patients with symptomatic than in those with asymptomatic CS. Several histological criteria significantly differed between symptomatic and asymptomatic plaques. However, there was no association of monocyte subsets or chemokines with histological features of plaque vulnerability. Due to the multifactorial influence on monocyte subsets, the usability as clinical markers for plaque vulnerability seems to be limited. However, monocyte subsets may be critically involved in the pathology of CS.
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