Novel Targets for Molecular Imaging of Inflammatory Processes of Carotid Atherosclerosis: A Systematic Review.

Computed tomography angiography (CTA), magnetic resonance angiography (MRA) and 18F-FDG-PET have proven clinical value when evaluating patients with carotid atherosclerosis. In this systematic review, we will focus on the role of novel molecular imaging tracers in that assessment and their potential strengths to stratify stroke risk. We systematically searched PubMed, Embase, the Web of Science Core Collection, and Cochrane Library for articles reporting on molecular imaging to noninvasively detect or characterize inflammation in carotid atherosclerosis. As our focus was on nonclassical novel targets, we omitted reports solely on 18F-FDG and 18F-NaF. We summarized and mapped the selected studies to provide an overview of the current clinical development in molecular imaging in relation to risk factors, imaging and histological findings, diagnostic and prognostic performance. We identified 20 articles in which the utilized tracers to visualize carotid wall inflammation were somatostatin subtype-2- (SST2-) (n = 5), CXC-motif chemokine receptor 4- (CXCR4-) (n = 3), translocator protein- (TSPO-) (n = 2) and aVß3 integrin-ligands (n = 2) and choline-tracers (n = 2). Tracer uptake correlated with traditional cardiovascular risk factors, that is, age, gender, diabetes, hypercholesterolemia, and hypertension as well as prior cardiovascular disease. We identified discrepancies between tracer uptake and grade of stenosis, plaque calcification, and 18F-FDG uptake, suggesting the importance of alternative characterization of atherosclerosis beyond classical neuroimaging features. Immunohistochemical analysis linked tracer uptake to markers of macrophage infiltration and neovascularization. Symptomatic carotid arteries showed higher uptake compared to asymptomatic (including contralateral, nonculprit) arteries. Some studies demonstrated a potential role of these novel molecular imaging as a specific intermediary (bio)marker for outcome. Several novel tracers show promise for identification of high-risk plaque inflammation. Based on the current evidence we cautiously propose the SST2-ligands and the choline radiotracers as viable candidates for larger prospective longitudinal outcome studies to evaluate their predictive use in clinical practice.

Imaging Carotid Plaque Inflammation Using Positron Emission Tomography: Emerging Role in Clinical Stroke Care, Research Applications, and Future Directions.

Atherosclerosis is a chronic systemic inflammatory condition of the vasculature and a leading cause of stroke. Luminal stenosis severity is an important factor in determining vascular risk. Conventional imaging modalities, such as angiography or duplex ultrasonography, are used to quantify stenosis severity and inform clinical care but provide limited information on plaque biology. Inflammatory processes are central to atherosclerotic plaque progression and destabilization. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a validated technique for quantifying plaque inflammation. In this review, we discuss the evolution of FDG-PET as an imaging modality to quantify plaque vulnerability, challenges in standardization of image acquisition and analysis, its potential application to routine clinical care after stroke, and the possible role it will play in future drug discovery.

The contribution of competing mechanisms in stroke despite anticoagulation in patients with atrial fibrillation.

BACKGROUND: For reasons poorly understood, strokes frequently occur in patients with atrial fibrillation (AF) despite oral anticoagulation. Better data are needed to inform randomised trials (RCTs) of new strategies to prevent recurrence in these patients. We investigate the relative contribution of competing stroke mechanisms in patients with AF who have stroke despite anticoagulation (OAC+) compared with those who are anticoagulant naïve (OAC-) at the time of their event. PATIENTS AND METHODS: We performed a cross-sectional study leveraging data from a prospective stroke registry (2015-2022). Eligible patients had ischemic stroke and AF. Stroke classification was performed by a single stroke-specialist blinded to OAC status using TOAST criteria. The presence of atherosclerotic plaque was determined using duplex ultrasonography, computerised tomography (CT) or magnetic resonance (MR) angiography. Imaging was reviewed by a single reader. Logistic regression was used to identify independent predictors of stroke despite anticoagulation. RESULTS: Of 596 patients included, 198 (33.2%) were in the OAC+ group. A competing cause for stroke was more frequent in patients with OAC+ versus OAC- (69/198 (34.8%)) versus 77/398 (19.3%), p < 0.001). After adjustment, both small vessel occlusion (odds ratio (OR): 2.46, 95% CI: 1.20-5.06) and arterial atheroma (⩾50% stenosis) (OR: 1.78, 95% CI: 1.07-2.94) were independently associated with stroke despite anticoagulation. DISCUSSION AND CONCLUSION: Patients with AF-associated stroke despite OAC are much more likely than patients who are OAC-naïve to have competing stroke mechanisms. Rigorous investigation for alternative stroke causes in stroke despite OAC has a high diagnostic yield. These data should be used to guide patient selection for future RCTs in this population.

Protocol for the development of a multidisciplinary clinical practice guideline for the care of patients with chronic subdural haematoma.

Introduction: A common neurosurgical condition, chronic subdural haematoma (cSDH) typically affects older people with other underlying health conditions. The care of this potentially vulnerable cohort is often, however, fragmented and suboptimal. In other complex conditions, multidisciplinary guidelines have transformed patient experience and outcomes, but no such framework exists for cSDH. This paper outlines a protocol to develop the first comprehensive multidisciplinary guideline from diagnosis to long-term recovery with cSDH. Methods: The project will be guided by a steering group of key stakeholders and professional organisations and will feature patient and public involvement. Multidisciplinary thematic working groups will examine key aspects of care to formulate appropriate, patient-centered research questions, targeted with evidence review using the GRADE framework. The working groups will then formulate draft clinical recommendations to be used in a modified Delphi process to build consensus on guideline contents. Conclusions: We present a protocol for the development of a multidisciplinary guideline to inform the care of patients with a cSDH, developed by cross-disciplinary working groups and arrived at through a consensus-building process, including a modified online Delphi.

Frailty and cerebrovascular disease: Concepts and clinical implications for stroke medicine.

Frailty is a distinctive health state in which the ability of older people to cope with acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems. Although closely associated with age, multimorbidity, and disability, frailty is a discrete syndrome that is associated with poorer outcomes across a range of medical conditions. However, its role in cerebrovascular disease and stroke has received limited attention. The estimated rise in the prevalence of frailty associated with changing demographics over the coming decades makes it an important issue for stroke practitioners, cerebrovascular research, clinical service provision, and stroke survivors alike. This review will consider the concept and models of frailty, how frailty is common in cerebrovascular disease, the impact of frailty on stroke risk factors, acute treatments, and rehabilitation, and considerations for future applications in both cerebrovascular clinical and research settings.

Carotid Atheroinflammation Is Associated With Cerebral Small Vessel Disease Severity.

Background: Atherosclerosis is a systemic inflammatory disease, with common inflammatory processes implicated in both atheroma vulnerability and blood-brain barrier disruption. This prospective multimodal imaging study aimed to measure directly the association between systemic atheroma inflammation ("atheroinflammation") and downstream chronic cerebral small vessel disease severity. Methods: Twenty-six individuals with ischemic stroke with ipsilateral carotid artery stenosis of >50% underwent 18fluoride-fluorodeoxyglucose-positron emission tomography within 2 weeks of stroke. Small vessel disease severity and white matter hyperintensity volume were assessed using 3-tesla magnetic resonance imaging also within 2 weeks of stroke. Results: Fluorodeoxyglucose uptake was independently associated with more severe small vessel disease (odds ratio 6.18, 95% confidence interval 2.1-18.2, P < 0.01 for the non-culprit carotid artery) and larger white matter hyperintensity volumes (coefficient = 14.33 mL, P < 0.01 for the non-culprit carotid artery). Conclusion: These proof-of-concept results have important implications for our understanding of the neurovascular interface and potential therapeutic exploitation in the management of systemic atherosclerosis, particularly non-stenotic disease previously considered asymptomatic, in order to reduce the burden of chronic cerebrovascular disease.

Assessing robustness of carotid artery CT angiography radiomics in the identification of culprit lesions in cerebrovascular events.

Radiomics, quantitative feature extraction from radiological images, can improve disease diagnosis and prognostication. However, radiomic features are susceptible to image acquisition and segmentation variability. Ideally, only features robust to these variations would be incorporated into predictive models, for good generalisability. We extracted 93 radiomic features from carotid artery computed tomography angiograms of 41 patients with cerebrovascular events. We tested feature robustness to region-of-interest perturbations, image pre-processing settings and quantisation methods using both single- and multi-slice approaches. We assessed the ability of the most robust features to identify culprit and non-culprit arteries using several machine learning algorithms and report the average area under the curve (AUC) from five-fold cross validation. Multi-slice features were superior to single for producing robust radiomic features (67 vs. 61). The optimal image quantisation method used bin widths of 25 or 30. Incorporating our top 10 non-redundant robust radiomics features into ElasticNet achieved an AUC of 0.73 and accuracy of 69% (compared to carotid calcification alone [AUC: 0.44, accuracy: 46%]). Our results provide key information for introducing carotid CT radiomics into clinical practice. If validated prospectively, our robust carotid radiomic set could improve stroke prediction and target therapies to those at highest risk.

Atherosclerosis imaging using PET: Insights and applications.

PET imaging is able to harness biological processes to characterise high-risk features of atherosclerotic plaque prone to rupture. Current radiotracers are able to track inflammation, microcalcification, hypoxia, and neoangiogenesis within vulnerable plaque. 18 F-fluorodeoxyglucose (18 F-FDG) is the most commonly used radiotracer in vascular studies and is employed as a surrogate marker of plaque inflammation. Increasingly, 18 F-FDG and other PET tracers are also being used to provide imaging endpoints in cardiovascular interventional trials. The evolution of novel PET radiotracers, imaging protocols, and hybrid scanners are likely to enable more efficient and accurate characterisation of high-risk plaque. This review explores the role of PET imaging in atherosclerosis with a focus on PET tracers utilised in clinical research and the applications of PET imaging to cardiovascular drug development.

Impact of stroke on outcomes following cardiac surgery: Propensity matched analysis.

BACKGROUND: Stroke remains a devastating complication of cardiac surgery. The aim of this study was to characterize the incidence of stroke and analyze the impact of stroke on patient outcomes and survival. METHODS: A retrospective analysis was performed of patients with a computed tomography-confirmed stroke diagnosis between 1 January 2015 and 31 March 2019 at a single center. 2:1 propensity matching was performed to identify a control population. RESULTS: Over the period 165 patients suffered a stroke (1.99%), with an incidence ranging from 0.85% for coronary artery bypass grafting to 8.14% for aortic surgery. The mean age was 70.3 years and 58.8% were male. 18% had experienced a previous stroke or transient ischemic attack. Compared to the comparison group, patients experiencing postoperative stroke had a significantly prolonged period of intensive care unit admission (8.0 vs 1.1 days P < .001) and hospital length of stay (12.94 vs 8.0 days P < .001). Patient survival was also inferior. In-hospital mortality was almost three times as high (17.0% vs 5.9%; P < .001). Longer-term survival was also inferior to Kaplan-Meier estimation (P < .001). The 1-year and 3-year survival were 61.5% and 53.8% respectively compared to 89.4% and 86.1% for the comparison group. CONCLUSION: Perioperative stroke is a devastating complication following cardiac surgery. Perioperative stroke is associated with significantly inferior outcomes in terms of both morbidity and mortality. Notably a 28% reduction in 1-year survival. Efforts should focus on identifying strategies aimed at reducing the incidence, morbidity, and mortality of perioperative stroke following cardiac surgery.

Integrated cardiovascular assessment of atherosclerosis using PET/MRI.

Atherosclerosis is a systemic inflammatory disease typified by the development of lipid-rich atheroma (plaques), the rupture of which are a major cause of myocardial infarction and stroke. Anatomical evaluation of the plaque considering only the degree of luminal stenosis overlooks features associated with vulnerable plaques, such as high-risk morphological features or pathophysiology, and hence risks missing vulnerable or ruptured non-stenotic plaques. Consequently, there has been interest in identifying these markers of vulnerability using either MRI for morphology, or positron emission tomography (PET) for physiological processes involved in atherogenesis. The advent of hybrid PET/MRI scanners offers the potential to combine the strengths of PET and MRI to allow comprehensive assessment of the atherosclerotic plaque. This review will discuss the principles and technical aspects of hybrid PET/MRI assessment of atherosclerosis, and consider how combining the complementary modalities of PET and MRI has already furthered our understanding of atherogenesis, advanced drug development, and how it may hold potential for clinical application.

Dual-Tracer Positron-Emission Tomography for Identification of Culprit Carotid Plaques and Pathophysiology In Vivo.

BACKGROUND: Inflammation and microcalcification are interrelated processes contributing to atherosclerotic plaque vulnerability. Positron-emission tomography can quantify these processes in vivo. This study investigates (1) 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) uptake in culprit versus nonculprit carotid atheroma, (2) spatial distributions of uptake, and (3) how macrocalcification affects this relationship. METHODS: Individuals with acute ischemic stroke with ipsilateral carotid stenosis of ≥50% underwent FDG-positron-emission tomography and NaF-positron-emission tomography. Tracer uptake was quantified using maximum tissue-to-background ratios (TBRmax) and macrocalcification quantified using Agatston scoring. RESULTS: In 26 individuals, median most diseased segment TBRmax (interquartile range) was higher in culprit than in nonculprit atheroma for both FDG (2.08 [0.52] versus 1.89 [0.40]; P<0.001) and NaF (2.68 [0.63] versus 2.39 [1.02]; P<0.001). However, whole vessel TBRmax was higher in culprit arteries for FDG (1.92 [0.41] versus 1.71 [0.31]; P<0.001) but not NaF (1.85 [0.28] versus 1.79 [0.60]; P=0.10). NaF uptake was concentrated at carotid bifurcations, while FDG was distributed evenly throughout arteries. Correlations between FDG and NaF TBRmax differed between bifurcations with low macrocalcification (rs=0.38; P<0.001) versus high macrocalcification (rs=0.59; P<0.001). CONCLUSIONS: This is the first study to demonstrate increased uptake of both FDG and NaF in culprit carotid plaques, with discrete distributions of pathophysiology influencing vulnerability in vivo. These findings have implications for our understanding of the natural history of the disease and for the clinical assessment and management of carotid atherosclerosis.

Clinical frailty independently predicts early mortality after ischaemic stroke.

BACKGROUND: Clinical frailty is an important syndrome for clinical care and research, independently predicting mortality and rates of institutionalisation in a range of medical conditions. However, there has been little research into the role of frailty in stroke. OBJECTIVE: This study investigates the effect of frailty on 28-day mortality following ischaemic stroke and outcomes following stroke thrombolysis. METHODS: Frailty was measured using the Clinical Frailty Scale (CFS) for all ischaemic stroke admissions aged ≥75 years. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). 28-day mortality and clinical outcomes were collected retrospectively. Analysis included both dichotomised measures of frailty (non-frail: CFS 1-4, frail: 5-8) and CFS as a continuous ordinal scale. RESULTS: In 433 individuals with ischaemic stroke, 28-day mortality was higher in frail versus non-frail individuals (39 (16.7%) versus 10 (5%), P < 0.01). On multivariable analysis, a one-point increase in CFS was independently associated with 28-day mortality (OR 1.03 (1.01-1.05)). In 63 thrombolysed individuals, median NIHSS reduced significantly in non-frail individuals (12.5 (interquartile range (IQR) 9.25) to 5 (IQR 10.5), P < 0.01) but not in frail individuals (15 (IQR 11.5) to 16 (IQR 16.5), P = 0.23). On multivariable analysis, a one-point increase in CFS was independently associated with a one-point reduction in post-thrombolysis NIHSS improvement (coefficient 1.07, P = 0.03). CONCLUSION: Clinical frailty is independently associated with 28-day mortality after ischaemic stroke and appears independently associated with attenuated improvement in NIHSS following stroke thrombolysis. Further research is needed to elucidate the underlying mechanisms and how frailty may be utilised in clinical decision-making.

Vascular Positron Emission Tomography and Restenosis in Symptomatic Peripheral Arterial Disease: A Prospective Clinical Study.

OBJECTIVES: This study determined whether in vivo positron emission tomography (PET) of arterial inflammation (18F-fluorodeoxyglucose [18F-FDG]) or microcalcification (18F-sodium fluoride [18F-NaF]) could predict restenosis following PTA. BACKGROUND: Restenosis following lower limb percutaneous transluminal angioplasty (PTA) is common, unpredictable, and challenging to treat. Currently, it is impossible to predict which patient will suffer from restenosis following angioplasty. METHODS: In this prospective observational cohort study, 50 patients with symptomatic peripheral arterial disease underwent 18F-FDG and 18F-NaF PET/computed tomography (CT) imaging of the superficial femoral artery before and 6 weeks after angioplasty. The primary outcome was arterial restenosis at 12 months. RESULTS: Forty subjects completed the study protocol with 14 patients (35%) reaching the primary outcome of restenosis. The baseline activities of femoral arterial inflammation (18F-FDG tissue-to-background ratio [TBR] 2.43 [interquartile range (IQR): 2.29 to 2.61] vs. 1.63 [IQR: 1.52 to 1.78]; p < 0.001) and microcalcification (18F-NaF TBR 2.61 [IQR: 2.50 to 2.77] vs. 1.69 [IQR: 1.54 to 1.77]; p < 0.001) were higher in patients who developed restenosis. The predictive value of both 18F-FDG (cut-off TBRmax value of 1.98) and 18F-NaF (cut-off TBRmax value of 2.11) uptake demonstrated excellent discrimination in predicting 1-year restenosis (Kaplan Meier estimator, log-rank p < 0.001). CONCLUSIONS: Baseline and persistent femoral arterial inflammation and micro-calcification are associated with restenosis following lower limb PTA. For the first time, we describe a method of identifying complex metabolically active plaques and patients at risk of restenosis that has the potential to select patients for intervention and to serve as a biomarker to test novel interventions to prevent restenosis.

18F-FDG Uptake on PET/CT in Symptomatic versus Asymptomatic Carotid Disease: a Meta-Analysis.

INTRODUCTION: The role of positron emission tomography (PET)/computed tomography (CT) in the determination of inflammation in arterial disease is not well defined. This can provide information about arterial wall inflammation in atherosclerotic disease, and may give insight into plaque stability. The aim of this review was to perform a meta-analysis of PET/CT with 18F-FDG (fluorodeoxyglucose) uptake in symptomatic and asymptomatic carotid artery disease. METHODS: This was a systematic review, following PRISMA guidelines, which interrogated the MEDLINE database from January 2001 to May 2017. The search combined the terms, "inflammation", "FDG", and "stroke". The search criteria included all types of studies, with a primary outcome of the degree of arterial vascular inflammation determined by 18F-FDG uptake. Analysis involved an inverse weighted variance estimate of pooled data, using a random effects model. RESULTS: A total of 14 articles (539 patients) were included in the meta-analysis. Comparing carotid artery 18F-FDG uptake in symptomatic versus asymptomatic disease yielded a standard mean difference of 0.94 (95% CI 0.58-1.130; p < .0001; I2 = 65%). CONCLUSIONS: PET/CT using 18F-FDG can demonstrate carotid plaque inflammation, and is a marker of symptomatic disease. Further studies are required to understand the clinical implication of PET/CT as a risk prediction tool.

PET imaging of the neurovascular interface in cerebrovascular disease.

This corrects the article DOI: 10.1038/nrneurol.2017.129.

PET imaging of the neurovascular interface in cerebrovascular disease.

Cerebrovascular disease encompasses a range of pathologies that affect different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate altered metabolic processes that are key to their pathogenesis. Although structural imaging techniques such as MRI are the mainstay of clinical care and research in cerebrovascular disease, they have limited ability to detect these pathophysiological processes in vivo. By contrast, PET can detect and quantify metabolic processes that are relevant to each facet of cerebrovascular disease. Information obtained from PET studies has helped to shape the understanding of key concepts in cerebrovascular medicine, including vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult. PET has also helped to elucidate the relationships between chronic hypoxia, neuroinflammation, and amyloid-ß deposition in cerebral small vessel disease. This Review describes how PET-based imaging of metabolic processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease.