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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) 18 F-fluorodeoxyglucose (FDG) and 18 F-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 (TBR max ) and macrocalcification quantified using Agatston scoring., Results: In 26 individuals, median most diseased segment TBR max (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 TBR max 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 TBR max differed between bifurcations with low macrocalcification ( r s =0.38; P <0.001) versus high macrocalcification ( r s =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.

Background and Purpose: We investigated the relationship between magnetic resonance imaging-visible centrum semiovale perivascular spaces (CSO-PVS), a biomarker of impaired interstitial fluid drainage, and positron emission tomography-based amyloid-β burden across a wide range of cerebrovascular amyloid deposition., Methods: Thirty-one nondemented subjects (11 probable cerebral amyloid angiopathy patients and 10 healthy subjects≥60 years; 10 older individuals, <60 years) had brain magnetic resonance imaging and Pittsburgh compound B-positron emission tomography. CSO-PVS was evaluated on T2-magnetic resonance imaging using a 4-point scale. The association between Pittsburgh compound B and CSO-PVS was assessed in linear regression., Results: In multivariable analyses adjusted for age, microbleeds and white matter hyperintensities, whole cortex Pittsburgh compound B binding was associated with CSO-PVS degree both as continuous (coefficient, 0.11; 95% confidence interval, 0.01-0.22; P=0.040) and as dichotomous variable (coefficient, 0.27; 95% confidence interval, 0.11-0.44; P=0.002). The median Pittsburgh compound B retention was higher in high versus low CSO-PVS degree (P=0.0007)., Conclusions: This pilot study suggests a possible association between cerebrovascular amyloid deposition and CSO-PVS, with potential pathophysiological implications., (© 2015 American Heart Association, Inc.)

Background and Purpose: An accurate prognosis is useful for patients, family, and service providers after acute stroke., Methods: We validated the Stroke subtype, Oxfordshire Community Stroke Project Classification, Age, and prestroke Rankin stroke score in predicting inpatient and 7-day mortality using data from 8 National Health Service hospital trusts in the Anglia Stroke and Heart Clinical Network between September 2008 and April 2011., Results: A total of 3547 stroke patients (ischemic, 92%) were included. An incremental increase of inpatient and 7-day mortality was observed with increase in Stroke subtype, Oxfordshire Community Stroke Project Classification, Age, and prestroke Rankin stroke score. Using a cut-off of ≥3, the area under the receiver operator curves values for inpatient and 7-day mortality were 0.80 and 0.82, respectively., Conclusions: A simple score based on 4 easily obtainable variables at the point of care may potentially help predict early stroke mortality.

Objectives: The usefulness of the implantable loop recorder (ILR) with improved atrial fibrillation (AF) detection capability (Reveal XT) and the factors associated with AF in the setting of unexplained stroke were investigated., Methods: A cohort study is reported of 51 patients in whom ILRs were implanted for the investigation of ischemic stroke for which no cause had been found (cryptogenic) following appropriate vascular and cardiac imaging and at least 24 hours of cardiac rhythm monitoring., Results: The patients were aged from 17 to 73 (median 52) years. Of the 30 patients with a shunt investigation, 22 had a patent foramen ovale (73.3%; 95% confidence interval [CI] 56.5%-90.1%). AF was identified in 13 (25.5%; 95% CI 13.1%-37.9%) cases. AF was associated with increasing age (p = 0.018), interatrial conduction block (p = 0.02), left atrial volume (p = 0.025), and the occurrence of atrial premature contractions on preceding external monitoring (p = 0.004). The median (range) of monitoring prior to AF detection was 48 (0-154) days., Conclusion: In patients with unexplained stroke, AF was detected by ILR in 25.5%. Predictors of AF were identified, which may help to target investigations. ILRs may have a central role in the future in the investigation of patients with unexplained stroke.

Background: Cerebral infarcts distal to carotid stenoses are thought to be caused by emboli from inflamed, destabilized plaques. We hypothesized that microembolic signals (MES) on transcranial Doppler will be associated with carotid plaque inflammation on (18)F fluorodeoxyglucose positron-emission tomography (FDG PET) in recently symptomatic patients., Methods and Results: Sixteen patients presenting with recent (47 ± 31 days) anterior circulation transient ischemic attack or minor stroke and 50% to 99% stenosis of the ipsilateral carotid bifurcation underwent FDG PET, high-resolution black-blood carotid MRI, and transcranial Doppler for detection of MES. Patients with potential cardiac sources of emboli or contralateral MES were excluded. Regions of interest defined on the coregistered MRI were used to measure FDG standardized uptake values (with Rousset partial volume correction) from the index and contralateral carotid plaques and artery. Ipsilateral MES were detected in 7 patients (MES+ group) and absent in 8 (MES- group). There was a significant difference in index-to-contralateral plaque standardized uptake value ratio between MES+ (median, 1.05; first to third quartile, 0.96 to 1.32) and MES- (median, 0.76; first to third quartile, 0.62 to 0.94) patients (P=0.005). The interval from symptom onset to PET and percent index carotid stenosis were not different between the 2 groups (P=0.68 and P=0.48, respectively)., Conclusions: In this sample of recently symptomatic patients with carotid stenosis, an association was found between in vivo measures of plaque inflammation detected by FDG PET and the presence of transcranial Doppler MES. These findings strengthen the notion that embolic events distal to carotid stenoses are related to plaque inflammation, and FDG PET may be useful in the investigation of culprit carotid lesions.

Background and Purpose: Stroke is a major risk factor for hip fracture. Patients with intermediate rather than severe or mild stroke deficits at the time of hospital discharge have the most fractures. This proof-of-concept study evaluated the efficacy of a single infusion of zoledronate, an intravenous bisphosphonate, in preserving hip bone density after stroke., Methods: In a 1-year randomized, double-blind, placebo-controlled, clinical trial, 27 newly hemiplegic patients (6 females, 21 males) with acute stroke were assigned to receive 4 mg of the intravenous zoledronate (n=14) or placebo (n=13) within 35 days. Strict inclusion criteria were followed-up to ensure recruited patients were likely to have residual functional impairment. Both groups received calcium and vitamin D supplementation. The primary outcome measure was the change in bone mineral density (BMD; Lunar Prodigy) at the hemiplegic hip during the year of investigation., Results: The treatment was generally well tolerated. Mean total hip BMD was unchanged in the hemiplegic hip of the zoledronate group (mean 0.0% change), whereas in the placebo group the total hip BMD changed by -5.5%, with the greatest bone loss observed in the trochanteric subregion (mean, -8.1%). On the unaffected side the mean change in total hip BMD was +1.0% with zoledronate versus a mean change of -2.7% without. Repeated measures ANOVA confirmed the significance of the differences between groups at both hips (hemiplegic, P<0.001; unaffected, P=0.002)., Conclusions: Stroke patients were protected from the deleterious effects of hemiplegia on hip bone density for at least 1 year after a single infusion of zoledronate.

Background and Purpose: Evidence now exists for a pathogenic role for neutrophils in acute cerebral ischemia. We have studied the patterns and temporal profile of cerebral neutrophil recruitment to areas of acute ischemic stroke (IS) and have attempted to correlate this with neurological status and outcome., Methods: Patients with cortical middle cerebral artery (MCA) IS were recruited within 24 hours of clinical onset. Neutrophil recruitment was studied using indium-111 (111In) troponolate-labeled neutrophils, planar imaging, and single-photon emission computed tomography (SPECT). Volume of brain infarction was calculated from concurrent computed tomography (CT). Hematoxylin and eosin sections were obtained postmortem (n=2). Outcome was measured using Barthel, Rankin, and National Institute of Health Stroke (NIHSS) scales., Results: Fifteen patients were studied. Significant 111In-neutrophil recruitment to ipsilateral hemisphere, as measured by asymmetry index (AI), was demonstrated within 24 hours of onset in 9 patients; this response was heterogenous between patients and on repeated measurement attenuated over time. Histologically, recruitment was confirmed within intravascular, intramural, and intraparenchymal compartments. Interindividual heterogeneity in neutrophil response did not correlate with infarct volume or outcome. In an exploratory analysis, neutrophil accumulation appeared to correlate significantly with infarct expansion (Spearman rho=0.66; P=0.03, n=12)., Conclusions: Neutrophils recruit to areas of ischemic brain within 24 hours of symptom onset. This recruitment attenuates over time and is confirmed histologically. While neutrophil accumulation may be associated with either the magnitude or the rate of infarct growth, these results require confirmation in future studies.

Objective: To compare contrast-enhanced MR angiography (CEMRA) with intra-arterial digital subtraction angiography (DSA) for evaluating carotid stenosis., Methods: A total of 167 consecutive symptomatic patients, scheduled for DSA following screening duplex ultrasound (DUS), were prospectively recruited to have CEMRA. Three independent readers reported on each examination in a blinded and random manner. Agreement was assessed using the Bland-Altman method. Diagnostic and potential clinical impact of CEMRA was evaluated, singly and in combination with DUS., Results: CEMRA tended to overestimate stenosis by a mean bias ranging from 2.4 to 3.8%. A significant part of the disagreement between CEMRA and DSA was directly caused by interobserver variability. For detection of severe stenosis, CEMRA alone had a sensitivity of 93.0% and specificity of 80.6%, with a diagnostic misclassification rate of 15.0% (n = 30). More importantly, clinical decision-making would, however, have been potentially altered only in 6.0% of cases (n = 12). The combination of concordant DUS and CEMRA reduced diagnostic misclassification rate to 10.1% (n = 19) at the expense of 47 (24.9%) discordant cases needing to proceed to DSA. An intermediate approach of selective DUS review resulted in a marginally worse diagnostic misclassification rate of 11.6% (n = 22) but with only 6.8% of discordant cases (n = 13)., Conclusions: DSA remains the gold standard for carotid imaging. The clinical misclassification rate with CEMRA, however, is acceptably low to support its safe use instead of DSA. The appropriateness of combination strategies depends on institutional choice and cost-effectiveness issues.

Background: Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques., Methods and Results: Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque., Conclusions: This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.

Background and Purpose: The increase in fractional anisotropy (FA) in acute stroke has yet to be explained. Using an engineering methodology known as pq diagrams, we sought to explain the increase in FA by describing changes in the total magnitude of the diffusion tensor (L) as well as the isotropic (p) and anisotropic (q) components., Methods: Diffusion tensor imaging was performed in 10 patients with stroke <27 hours old. The diffusion tensor was decomposed into the p and q components and plotted to describe the diffusion trajectories. FA was also calculated and compared., Results: There was significant and consistent reduction in p, q, and L (p: mean, -50.0%; range, -36.6% to -64.5%; q: mean, -50.8%; range, -30.8% to -72.8%; L: mean, -50.3%; range, -37.0% to -65.1%). There were inconsistent changes in FA (mean, -0.5%; range, -44.9% to +45.0%). Five patients had elevated FA due to proportionately higher loss of L than q., Conclusions: Changes in FA only occur when there is a change in the ratio of q/L. Acute elevation of FA occurred in the context of a larger reduction in L than q. The elevation in FA occurs in the context of a reduction in the anisotropic tensor and therefore is a consequence of ratio-metric measurement. This appears to clarify the reported increase in FA in terms of alterations in the shape of the apparent diffusion tensor. pq diagrams appear to offer improved resolution of acute diffusion changes in ischemia.

Background: Osteoporosis is a significant complication of stroke. The clinical course of hemiplegic stroke predisposes patients to disturbed bone physiology. Sudden immobility and unilateral loss of function unload the skeleton at key areas such as the affected hip. This is manifest by an early reduction in bone density at this site. Stroke patients may also have motor, sensory, and visual/perceptual deficits that predispose them to falls. These factors result in an early but sustained increase in hip fractures after stroke., Summary of Comment: Potential bone loss is often overlooked in stroke treatment. Morbidity and mortality from hip fractures might be reduced by preventing bone loss at an early stage. In the crucial first year after stroke, bone loss seems to be due to accelerated resorption. Bisphosphonates are the drugs of choice in preventing osteoclastic bone resorption, but oral administration soon after stroke may be impractical. Potent new intravenous bisphosphonates have been used in postmenopausal women with osteoporosis with good preliminary results. Effective dosing regimens for osteoporosis have included a single annual or semiannual injection of bisphosphonate as well as weekly oral dosing. This article reviews the current literature on osteoporosis and hip fractures after stroke, making a case for a trial of intravenous bisphosphonates early after stroke., Conclusions: Hip fracture after stroke is an increasingly recognized problem. Measures to prevent bone loss and preserve bone architecture have not been part of stroke management thus far. Because rapid bone loss is a risk factor for fracture, we believe that a randomized, placebo-controlled trial of intravenous bisphosphonates given in the early phase of stroke rehabilitation is indicated.