[Show abstract][Hide abstract] ABSTRACT: Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1-6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD.
PLoS ONE 10/2015; 10(10):e0139926. DOI:10.1371/journal.pone.0139926 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Language reorganisation following stroke has been studied widely. However, while studies of brain activation and grey matter examined both hemispheres, studies of white matter changes have mostly focused on the left hemisphere. Here we examined the relationship between bilateral hemispheric white matter and aphasia symptoms. 15 chronic stroke patients with aphasia and 18 healthy adults were studied using Diffusion Weighted Imaging data. By applying histogram analysis, Tract-Based Spatial Statistics, tractography and lesion-tract overlap methods, it was found that damage to the left hemisphere in general, and to the arcuate fasciculus in particular, correlated with impairments on word repetition, object naming, sentence comprehension and homophone and rhyme judgement. However, no such relationship was found in the right hemisphere. It is suggested that while some language function in aphasia can be explained by damage to the left arcuate fasciculus, it cannot be explained by looking at the contra-lesional tract.
Brain and Language 09/2015; 150:117-128. DOI:10.1016/j.bandl.2015.09.001 · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using 18F-sodium fluoride (18F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. However, the precise molecular mechanism of 18F-NaF vascular uptake is still unknown. Here we use electron microscopy, autoradiography, histology and preclinical and clinical PET/CT to analyse 18F-NaF binding. We show that 18F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific. 18F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification. This is the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis. The use of 18F-NaF may foster new approaches to developing treatments for vascular calcification.
[Show abstract][Hide abstract] ABSTRACT: This is the accepted manuscript of a paper published in QJM (Evans NR, Harper V, Scoffings DJ, Warburton EA, QJM, 2015, doi:10.1093/qjmed/hcv089). The final version is available at http://dx.doi.org/10.1093/qjmed/hcv089
QJM: monthly journal of the Association of Physicians 05/2015; DOI:10.1093/qjmed/hcv089 · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CT-based perfusion and collateral imaging is increasingly used in the assessment of patients with acute stroke. Time of stroke onset is a critical factor in determining eligibility for and benefit from thrombolysis. Animal studies predict that the volume of ischemic penumbra decreases with time. Here, we evaluate if CT is able to detect a relationship between perfusion or collateral status, as assessed by CT, and time since stroke onset.
We studied 53 consecutive patients with proximal vessel occlusions, mean (SD) age of 71.3 (14.9) years, at a mean (SD) of 125.2 (55.3) minutes from onset, using whole-brain CT perfusion (CTp) imaging. Penumbra was defined using voxel-based thresholds for cerebral blood flow (CBF) and mean transit time (MTT); core was defined by cerebral blood volume (CBV). Normalized penumbra fraction was calculated as Penumbra volume/(Penumbra volume + Core volume) for both CBF and MTT (PenCBF and PenMTT, respectively). Collaterals were assessed on CT angiography (CTA). CTp ASPECTS score was applied visually, lower scores indicating larger lesions. ASPECTS ratios were calculated corresponding to penumbra fractions.
Both PenCBF and PenMTT showed decremental trends with increasing time since onset (Kendall's tau-b = -0.196, p = 0.055, and -0.187, p = 0.068, respectively). The CBF/CBV ASPECTS ratio, which showed a relationship to PenCBF (Kendall's tau-b = 0.190, p = 0.070), decreased with increasing time since onset (Kendall's tau-b = -0.265, p = 0.006). Collateral response did not relate to time (Kendall's tau-b = -0.039, p = 0.724).
Even within 4.5 h since stroke onset, a decremental relationship between penumbra and time, but not between collateral status and time, may be detected using perfusion CT imaging. The trends that we demonstrate merit evaluation in larger datasets to confirm our results, which may have potential wider applications, e.g., in the setting of strokes of unknown onset time.
Frontiers in Neurology 04/2015; 6. DOI:10.3389/fneur.2015.00070
[Show abstract][Hide abstract] ABSTRACT: Background:
Shock index (SI) (ratio between heart rate and systolic blood pressure) has been shown to be associated with poor mortality outcomes in trauma and pneumonia; however it has yet to be examined in stroke. We aimed to examine the relationship between SI and acute outcomes of inpatient, 3-day and 7-day mortality in stroke. Secondly, we aimed to compare SI and systolic blood pressure (SBP) alone in predicting above outcomes.
Data from a multicentre prospective cohort study conducted between October 2009 and September 2012 in eight NHS trusts in East of England were analysed. The relationships between SI, SBP and study outcomes were assessed using multivariable logistic regression models using mid-quintile groups as the reference category. Receiver operating characteristic (ROC) curves assessed the discriminating ability between the SI and SBP models.
A total of 2121 stroke patients were included (47.4% men; mean age 77.10 (sd) 12.40) years. The lowest quintile of the SI, had an increased odds of 3-day and 7-day mortality, adjusted odds ratio (AOR) 2.45 (95% CI:1.16-5.17) and 1.88 (1.01-3.49), respectively. Patients with the highest quintile of SI also had increased odds of in-patient, 3-day and 7-day mortality, AORs 1.85 (1.17-2.92), 2.18 (1.03-4.63) and 2.45 (1.34-4.49), respectively. Similarly, SBP had a U-shape relationship with mortality. All measures had an ROC area under the curve >0.8 but there was no difference in the discriminating ability between SI and SBP.
SI at extremely high and low values appeared to predict stroke mortality and appears to be particularly useful in predicting very early (3-day) mortality.
International Journal of Cardiology 03/2015; 182:523-527. DOI:10.1016/j.ijcard.2014.12.175 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimsThe objective of this study is to externally validate the SOAR stroke score (Stroke subtype, Oxfordshire Community Stroke Project Classification, Age and prestroke modified Rankin score) in predicting hospital length of stay (LOS) following an admission for acute stroke.Methods
We conducted a multi-centre observational study in eight National Health Service hospital trusts in the Anglia Stroke & Heart Clinical Network between September 2008 and April 2011. The usefulness of the SOAR stroke score in predicting hospital LOS in the acute settings was examined for all stroke and then stratified by discharge status (discharged alive or died during the admission).ResultsA total of 3596 patients (mean age 77 years) with first-ever or recurrent stroke (92% ischaemic) were included. Increasing LOS was observed with increasing SOAR stroke score (p < 0.001 for both mean and median) and the SOAR stroke score of 0 had the shortest mean LOS (12 ± 20 days) while the SOAR stroke score of 6 had the longest mean LOS (26 ± 28 days). Among patients who were discharged alive, increasing SOAR stroke score had a significantly higher mean and median LOS (p < 0.001 for both mean and median) and the LOS peaked among patients with score value of 6 [mean (SD) 35 ± 31 days, median (IQR) 23 (14–48) days]. For patients who died as in-patient, there was no significant difference in mean or median LOS with increasing SOAR stroke score (p = 0.68 and p = 0.79, respectively).Conclusion
This external validation study confirms the usefulness of the SOAR stroke score in predicting LOS in patients with acute stroke especially in those who are likely to survive to discharge. This provides a simple prognostic score useful for clinicians, patients and service providers.
International Journal of Clinical Practice 02/2015; 69(6). DOI:10.1111/ijcp.12577 · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The majority of established telestroke services are based on "hub-and-spoke" models for providing acute clinical assessment and thrombolysis. We report results from the first year of the successful implementation of a locally based telemedicine network, without the need of 1 or more hub hospitals, across a largely rural landscape.
Following a successful pilot phase that demonstrated safety and feasibility, the East of England telestroke project was rolled out across 7 regional hospitals, covering an area of 7500 square miles and a population of 5.6 million to enable out-of-hours access to thrombolysis. Between November 2010 and November 2011, 142 telemedicine consultations were recorded out-of-hours. Seventy-four (52.11%) cases received thrombolysis. Median (IQR) onset-to-needle and door-to-needle times were 169 (141.5 to 201.5) minutes and 94 (72 to 113.5) minutes, respectively. Symptomatic hemorrhage rate was 7.3% and stroke mimic rate was 10.6%.
We demonstrate the safety and effectiveness of a horizontal networking approach for stroke telemedicine, which may be applicable to areas where traditional "hub-and-spoke" models may not be geographically feasible.
Journal of the American Heart Association 12/2014; 3(1):e000408. DOI:10.1161/JAHA.113.000408 · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: By detecting β-amyloid (Aβ) in the wall of cortical arterioles, amyloid positron emission tomography (PET) imaging might help diagnose cerebral amyloid angiopathy (CAA) in patients with lobar intracerebral hemorrhage (l-ICH). No previous study has directly assessed the diagnostic value of (11)C-Pittsburgh compound B (PiB) PET in probable CAA-related l-ICH against healthy controls (HCs). (11)C-PiB-PET and magnetic resonance imaging (MRI) including T2* were obtained in 11 nondemented patients fulfilling the Boston criteria for probable CAA-related symptomatic l-ICH (sl-ICH) and 20 HCs without cognitive complaints or impairment. After optimal spatial normalization, cerebral spinal fluid (CSF)-corrected PiB distribution volume ratios (DVRs) were obtained. There was no significant difference in whole cortex or regional DVRs between CAA patients and age-matched HCs. The whole cortex DVR was above the 95% confidence limit in 4/9 HCs and 10/11 CAA patients (sensitivity=91%, specificity=55%). Region/frontal or occipital ratios did not have better discriminative value. Similar but less accurate results were found using visual analysis. In patients with sl-ICH, (11)C-PiB-PET has low specificity for CAA due to the frequent occurrence of high (11)C-PiB uptake in the healthy elderly reflecting incipient Alzheimer's disease (AD), which might also be present in suspected CAA. However, a negative PiB scan rules out CAA with excellent sensitivity, which has clinical implications for prognostication and selection of candidates for drug trials.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 March 2014; doi:10.1038/jcbfm.2014.43.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2014; 34(5). DOI:10.1038/jcbfm.2014.43 · 5.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age has a differential effect on cognition, with word retrieval being one of the cognitive domains most affected by aging. This study examined the functional and structural neural correlates of phonological word retrieval in younger and older adults using word and picture rhyme judgment tasks. Although the behavioral performance in the fMRI task was similar for the two age groups, the older adults had increased activation in the right pars triangularis across tasks and in the right pars orbitalis for the word task only. Increased activation together with preserved performance in the older participants would suggest that increased activation was related to compensatory processing. We validated this hypothesis by showing that right pars triangularis activation during correct rhyme judgments was highest in participants who made overall more errors, therefore being most error-prone. Our findings demonstrate that the effect of aging differ in adjacent but distinct right inferior frontal regions. The differential effect of age on word and picture tasks also provides new clues to the level of processing that is most affected by age in speech production tasks. Specifically, we suggest that right inferior frontal activation in older participants is needed to inhibit errors.
[Show abstract][Hide abstract] ABSTRACT: Background:
Homonymous visual field defects (VFD) are common following stroke, and often recover, partially or fully, by unknown mechanisms. In clinical practice, visual field recovered on perimetry is often considered perceptually normal. However, studies have shown contrast sensitivity (CS) deficits in patients with stroke and homonymous VFD. This study investigated the origin of visual CS loss in patients with VFD due to stroke. We hypothesised that CS deficits would be found in visual field areas appearing normal on perimetry, in patients with ischaemic stroke affecting the retrochiasmal visual system, and that the spatiotemporal properties of this CS loss would be consistent with those of 'blindsight', perhaps suggesting similar underlying mechanisms.
CS measurements were made in 20 healthy participants, and in 7 patients with stroke causing homonymous VFD sparing foveal vision, measured using Humphrey static perimetry (SITA-Fast 24-2 procedure). Importantly, patients with concomitant visuospatial neglect were excluded. CS measurements were made using a modification of the method of increasing contrast, corrected for reaction time. Three spatial stimuli were used, at several spatial frequencies: (1) large sinusoidal gratings; (2) foveal Gabor patches; and (3) Gabor patches presenting in the putatively recovered visual field, near VFD. Stimuli with different temporal profiles were used to selectively stimulate transient and sustained visual channels, to provide insight into mechanisms of visual loss and/or recovery. Analysis of variance (ANOVA) was used in the analysis of the measurements, allowing for correction for age and stimulus eccentricity.
ANOVA for sustained grating stimuli showed orientation-selective (horizontal) CS loss (p = 0.025); no such loss was apparent in the central visual field (foveal Gabor stimuli). Localised CS close to VFD was reduced in stroke-affected hemifields compared with unaffected hemifields (p ≤ 0.005), though these areas appeared normal on perimetry. In these areas, CS was relatively preserved for transient compared with sustained stimuli (Wilcoxon signed rank tests).
The finding of specific CS deficits in the normal-appearing visual field of patients with homonymous VFD due to stroke suggests that static perimetry provides an inadequate assessment of visual function in these patients, with clear implications for testing of vision in clinical practice. The results are consistent with relative sparing of the transient/magnocellular visual channel. These findings demand further investigation. If confirmed in larger, longitudinal studies, this will have important implications for the mechanisms of recovery, and may provide a target for visual rehabilitation - for example, using repeated detection practice ('perceptual learning').
[Show abstract][Hide abstract] ABSTRACT: Mapping the ischaemic penumbra in acute stroke is of considerable clinical interest. For this purpose, mapping tissue hypoxia with (18)F-misonidazole (FMISO) PET is attractive, and is straightforward compared to (15)O PET. Given the current emphasis on penumbra imaging using diffusion/perfusion MR or CT perfusion, investigating the relationships between FMISO uptake and abnormalities with these modalities is important.
According to a prospective design, three patients (age 54-81 years; admission NIH stroke scale scores 16-22) with an anterior circulation stroke and extensive penumbra on CT- or MR-based perfusion imaging successfully completed FMISO PET, diffusion-weighted imaging and MR angiography 6-26 h after stroke onset, and follow-up FLAIR to map the final infarction. All had persistent proximal occlusion and a poor outcome despite thrombolysis. Significant FMISO trapping was defined voxel-wise relative to ten age-matched controls and mapped onto coregistered maps of the penumbra and irreversibly damaged ischaemic core.
FMISO trapping was present in all patients (volume range 18-119 ml) and overlapped mainly with the penumbra but also with the core in each patient. There was a significant (p ≤ 0.001) correlation in the expected direction between FMISO uptake and perfusion, with a sharp FMISO uptake bend around the expected penumbra threshold.
FMISO uptake had the expected overlap with the penumbra and relationship with local perfusion. However, consistent with recent animal data, our study suggests FMISO trapping may not be specific to the penumbra. If confirmed in larger samples, this preliminary finding would have potential implications for the clinical application of FMISO PET in acute ischaemic stroke.
European Journal of Nuclear Medicine 10/2013; 41(4). DOI:10.1007/s00259-013-2581-x · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
An accurate prognosis is useful for patients, family, and service providers after acute stroke.
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.
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.
A simple score based on 4 easily obtainable variables at the point of care may potentially help predict early stroke mortality.
[Show abstract][Hide abstract] ABSTRACT: After stroke, penumbral salvage determines clinical recovery. However, the rescued penumbra may be affected by selective neuronal loss, as documented both histopathologically in animals and using the validated in vivo positron emission tomography marker (11)C-flumazenil in humans. However, whether the non-infarcted penumbra is capable of neuronal activation, and how selective neuronal loss may interfere, is unknown. Here we prospectively mapped the topographical relationships between functional magnetic resonance imaging responses and non-infarcted penumbra, and tested the hypothesis that the former do take place in the latter, but only in its subsets spared selective neuronal loss. Seven patients (mean age 74 years; three thrombolysed) with first-ever acute anterior circulation stroke, presence of penumbra on computed tomography perfusion performed within 6 h of onset, and substantial deficit on admission but good outcome at 1-3 months (National Institute of Health Stroke Score range 6-13 and 0-1, respectively, P = 0.001), were studied. At follow-up, patients underwent structural magnetic resonance imaging to map the infarct, functional magnetic resonance imaging (three tasks selected to probe the right or left hemisphere), and (11)C-flumazenil positron emission tomography generating binding potential maps. Patients with significant carotid or middle-cerebral artery disease or impaired vasoreactivity were excluded. Following image coregistration, the non-infarcted penumbra comprised all acutely ischaemic voxels (identified on acute computed tomography perfusion using previously validated thresholds) not part of the final infarct. To test our hypotheses, the overlap between functional magnetic resonance imaging activation clusters and non-infarcted penumbra was mapped, and binding potential values then computed both within and outside this overlap. In addition, the overlap between functional magnetic resonance imaging activation clusters and areas of significantly reduced binding potential (determined using Statistical Parametric Mapping against 16 age-matched control subjects) was assessed in each patient. An overlap between non-infarcted penumbra and functional magnetic resonance imaging clusters was present in seven of seven patients, substantial in four. Binding potential was significantly reduced in the whole non-infarcted penumbra (P < 0.01) but not within the functional magnetic resonance imaging overlap. Clusters with significantly reduced binding potential showed virtually no overlap with functional magnetic resonance imaging activation compared with 12 age-matched controls (P = 0.04).The results from this proof of principle study suggest that 1-3 months after stroke the non-infarcted penumbra is capable of neuronal activation, consistent with its established role in recovery of neurological functions. However, although the non-infarcted penumbra as a whole was affected by selective neuronal loss, activations tended to occur within portions spared selective neuronal loss, suggesting the latter impedes neuronal activation. Although its clinical correlates are still elusive, selective neuronal loss may represent a novel therapeutic target in the aftermath of ischaemic stroke.