Search

Background: The early identification of patients who are unlikely to respond to intravenous recombinant tissue plasminogen activator (IV-tPA) could help select candidates for additional intra-arterial therapy or add-on antithrombotic drugs during the acute stage of stroke. Given that very early neurological improvement (VENI) is a reliable surrogate of early recanalization, we assessed the clinical and magnetic resonance imaging predictors of lack of VENI., Methods and Results: We reviewed consecutive ischemic stroke patients with middle cerebral artery occlusion and treated within 4.5 hours by IV-tPA between 2003 and 2012 in our center, where magnetic resonance imaging is systematically implemented as first-line diagnostic workup. Lack of VENI was defined as a <40% decrease in baseline National Institutes of Health Stroke Scale (NIHSS) score 1 hour after start of IV-tPA. Poor outcome was defined as a 3-month modified Rankin scale ≥2. Associations between lack of VENI and potential determinants were assessed in logistic regression models. In all, 186 patients were included (median baseline NIHSS score, 16; median onset to treatment time, 155 minutes). One hundred forty-three patients (77%) had no VENI. The variables significantly associated with lack of VENI in multivariable analysis were baseline NIHSS (OR, 1.08; 95% CI, 1.01 to 1.16 per 1-point increase; P=0.03), onset to treatment time >120 minutes (OR, 2.94; 95% CI, 1.31 to 6.63; P=0.009) and diffusion weighted imaging--Alberta Stroke Programme Early CT Score ≤5 (OR, 3.60; 95% CI, 1.14 to 11.35; P=0.03). Patients without VENI were more likely to have a modified Rankin Scale ≥2 than those without VENI (68% versus 24%; OR, 5.01; 95% CI, 2.12 to 11.82) and less likely to have recanalization after 24 hours (OR, 0.41; 95% CI, 0.19 to 0.88)., Conclusions: Lack of VENI provides an early estimate of 3-month outcome and recanalization after IV-tPA. Baseline NIHSS, onset to treatment time, and diffusion weighted imaging--Alberta Stroke Programme Early CT Score could help to predict lack of VENI and, in turn, might help early selection of candidates for complementary reperfusion strategies.

Background and Purpose: The extent of diffusion lesion on pretreatment imaging is a risk factor for poor outcome and hemorrhagic transformation after thrombolysis, and volumes of 70 to 100 mL have been advocated as cut-offs. However, estimating diffusion-weighted imaging (DWI) lesion volume (VolDWI) in the acute setting may be cumbersome. We aimed to determine whether the DWI-Alberta Stroke Program Early CT Score (DWI-ASPECTS) can substitute for VolDWI., Methods: DWI-ASPECTS and VolDWI were measured retrospectively on pretreatment MRI (median onset-to-MRI delay=122 minutes) in 330 consecutively treated patients with middle cerebral artery stroke., Results: DWI-ASPECTS and VolDWI were strongly correlated (ρ=-0.82), but each DWI-ASPECTS point corresponded to a wide range of VolDWI. All patients with DWI-ASPECTS≥7 (n=207) had VolDWI<70 mL, whereas 32 of the 34 patients with DWI-ASPECTS<4 had VolDWI>100 mL. However, intermediate DWI-ASPECTS (4-6; n=89) corresponded to highly variable VolDWI (median, 66 mL; interquartile range, 40-98)., Conclusions: Although each DWI-ASPECTS point corresponds to a wide range of volumes, DWI-ASPECTS<4 or ≥7 may be used as reliable surrogates of VolDWI>100 or <70 mL, respectively.

Objective: To investigate whether cortical superficial siderosis (cSS) on MRI, especially if disseminated (involving more than 3 sulci), increases the risk of future symptomatic lobar intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA)., Methods: European multicenter cohort study of 118 patients with CAA (104 with baseline symptomatic lobar ICH) diagnosed according to the Boston criteria. We obtained baseline clinical, MRI, and follow-up data on symptomatic lobar ICH. Using Kaplan-Meier and Cox regression analyses, we investigated cSS and ICH risk, adjusting for known confounders., Results: During a median follow-up time of 24 months (interquartile range 9-44 months), 23 of 118 patients (19.5%, 95% confidence interval [CI]: 12.8%-27.8%) experienced symptomatic lobar ICH. Any cSS and disseminated cSS were predictors of time until first or recurrent ICH (log-rank test: p = 0.0045 and p = 0.0009, respectively). ICH risk at 4 years was 25% (95% CI: 7.6%-28.3%) for patients without siderosis; 28.9% (95% CI: 7.7%-76.7%) for patients with focal siderosis; and 74% (95% CI: 44.1%-95.7%) for patients with disseminated cSS (log-rank test: p = 0.0031). In Cox regression models, any cSS and disseminated cSS were both independently associated with increased lobar ICH risk, after adjusting for ≥ 2 microbleeds and age (hazard ratio: 2.53; 95% CI: 1.05-6.15; p = 0.040 and hazard ratio: 3.16; 95% CI: 1.35-7.43; p = 0.008, respectively). These results remained consistent in sensitivity analyses including only patients with symptomatic lobar ICH at baseline., Conclusions: Our findings indicate that cSS, particularly if disseminated, is associated with an increased risk of symptomatic lobar ICH in CAA. cSS may help stratify future bleeding risk in CAA, with implications for prognosis and treatment.

Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

Introduction: Motor imagery (MI) is the mental rehearsal of a motor first person action-representation. There is interest in using MI to access the motor network after stroke. Conventional fMRI modeling has shown that MI and executed movement (EM) activate similar cortical areas but it remains unknown whether they share cortical networks. Proving this is central to using MI to access the motor network and as a form of motor training. Here we use multivariate analysis (tensor independent component analysis-TICA) to map the array of neural networks involved during MI and EM., Methods: Fifteen right-handed healthy volunteers (mean-age 28.4 years) were recruited and screened for their ability to carry out MI (Chaotic MI Assessment). fMRI consisted of an auditory-paced (1 Hz) right hand finger-thumb opposition sequence (2,3,4,5; 2…) with two separate runs acquired (MI & rest and EM & rest: block design). No distinction was made between MI and EM until the final stage of processing. This allowed TICA to identify independent-components (IC) that are common or distinct to both tasks with no prior assumptions., Results: TICA defined 52 ICs. Non-significant ICs and those representing artifact were excluded. Components in which the subject scores were significantly different to zero (for either EM or MI) were included. Seven IC remained. There were IC's shared between EM and MI involving the contralateral BA4, PMd, parietal areas and SMA. IC's exclusive to EM involved the contralateral BA4, S1 and ipsilateral cerebellum whereas the IC related exclusively to MI involved ipsilateral BA4 and PMd., Conclusion: In addition to networks specific to each task indicating a degree of independence, we formally demonstrate here for the first time that MI and EM share cortical networks. This significantly strengthens the rationale for using MI to access the motor networks, but the results also highlight important differences.

Objective: We investigated the prevalence and clinical-radiologic associations of cortical superficial siderosis (cSS) in patients with probable cerebral amyloid angiopathy (CAA) compared to those with intracerebral hemorrhage (ICH) not attributed to CAA., Methods: We conducted a retrospective multicenter cohort study of 120 patients with probable CAA and 2 comparison groups: 67 patients with either single lobar ICH or mixed (deep and lobar) hemorrhages; and 22 patients with strictly deep hemorrhages. We rated cSS, ICH, white matter changes, and cerebral microbleeds., Results: cSS was detected in 48 of 120 (40%; 95% confidence interval [CI]: 31.2%-49.3%) patients with probable CAA, 10 of 67 (14.9%; 95% CI: 7.4%-25.7%) with single lobar ICH or mixed hemorrhages, and 1 of 22 (4.6%; 95% CI: 0.1%-22.8%) patients with strictly deep hemorrhages (p < 0.001 for trend). Disseminated cSS was present in 29 of 120 (24%; 95% CI: 16.8%-32.8%) patients with probable CAA, but none of the other patients with ICH (p < 0.001). In probable CAA, age (odds ratio [OR]: 1.09; 95% CI: 1.03-1.15; p = 0.002), chronic lobar ICH (OR: 3.94; 95% CI: 1.54-10.08; p = 0.004), and a history of transient focal neurologic episodes (OR: 11.08; 95% CI: 3.49-35.19; p < 0.001) were independently associated with cSS. However, cSS occurred in 17 of 48 patients with probable CAA (35.4%; 95% CI: 22.2%-50.5%) without chronic lobar ICH., Conclusions: cSS (particularly if disseminated) is a common and characteristic feature of CAA. Chronic lobar ICH is an independent risk factor for cSS, but the causal direction and mechanism of association are uncertain. Hemorrhage into the subarachnoid space, independent of previous (chronic) lobar ICH, must also contribute to cSS in CAA. Transient focal neurologic episodes are the strongest clinical marker of cSS.

Background and Purpose: Parenchymal hematoma (PH) may worsen the outcome of patients with stroke. The aim of our study was to confirm the relationship between the volume of very low cerebral blood volume (CBV) and PH using a European multicenter database (I-KNOW). A secondary objective was to explore the impact of early reperfusion and recanalization., Methods: The volume of cerebral tissue with CBV≤2.5th percentile of the normal hemisphere was calculated within the acute diffusion-weighted imaging lesion. Hemorrhagic transformation was assessed on day 2 MRI according to the European Cooperative Acute Stroke Study II criteria. Recanalization and reperfusion were assessed on 3-hour follow-up MRI., Results: Of the 110 patients, hemorrhagic transformation occurred in 59 patients, including 7 PH. In univariate analysis, the acute National Institutes of Health Stroke Scale score (P=0.002), acute diffusion-weighted imaging lesion volume (P=0.02), and thrombolysis (P=0.03), but not very low CBV (P=0.52), were associated with hemorrhagic transformation. The volume of very low CBV was the only predictor of PH (P=0.007). Early reperfusion and recanalization had no influence on either hemorrhagic transformation or PH., Conclusion: Very low CBV was the only independent predictor of PH in patients with acute stroke.

Background and Purpose: Our aim was to estimate the prevalence of negative diffusion-weighted imaging (DWI) with total perfusion-diffusion mismatch in a large series of anterior circulation stroke patients treated with thrombolysis and to describe the characteristics of these patients., Materials and Methods: From January 2006 to December 2010, a retrospective search was made for total perfusion-diffusion (PWI-DWI) mismatch patterns on pretreatment 1.5-T MRI scans of 166 consecutive thrombolyzed patients taken<4.5 h after onset of anterior stroke. A total mismatch profile corresponded to an absence of initial DWI signal changes with hypoperfusion (T(max)>6 s) on PWI. Clinical and MRI characteristics were compared between DWI+ and DWI- patients., Results: Five (3%) patients had a normal initial DWI. All had stable substantial clinical deficits (NIHSS scores ≥ 6) and large perfusion abnormalities - in other words, 'total mismatch' - and infarcts in the acutely hypoperfused area on follow-up imaging. While DWI- and DWI+ patients did not significantly differ in any of the pretreatment imaging or clinical variables except for the extent of PWI-DWI mismatch, DWI- patients had lower NIHSS scores at 24 h, and were more likely to show early neurological improvement (Δ0-24 h NIHSS ≥ 8) and good outcomes (mRS ≤ 2) at the time of hospital discharge., Conclusion: Total mismatch i.e. failure of DWI to reveal any ischemic tissue despite a large perfusion defect, can be observed before thrombolysis even in stroke patients with stable substantial neurological deficits. However, this rare MRI profile is associated with a favorable outcome after thrombolysis., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: To propose a T2*-MR adaptation of the computed tomography angiography-clot burden score (CBS), and assess its value as predictor of 24-hour recanalization and clinical outcome in anterior circulation stroke treated by intravenous thrombolysis ≤4.5 hours from onset., Methods: Two independent observers retrospectively analyzed pretreatment T2* images for evaluation of clot burden, using a 10-point scale T2*-CBS. Three points are subtracted for susceptibility vessel sign in the supraclinoid internal carotid artery, 2 points each for susceptibility vessel sign in the proximal and distal part of middle cerebral artery, and 1 point each for susceptibility vessel sign in middle cerebral artery branches (with a maximum of 2 points) and for susceptibility vessel sign in anterior cerebral artery. Associations with 24-hour recanalization and favorable outcome (3-month modified Rankin Scale score, ≤2) were assessed in multivariate analyses., Results: We analyzed 184 consecutive patients (mean age, 67 years) with median (interquartile range) admission National Institutes of Health Stroke Scale score and onset-to-treatment time of 15 (9-19) and 151 (120-185) minutes, respectively. The intraclass correlation for T2*-CBS between observers was 0.97 (95% confidence interval, 0.97-0.98). In multivariate analyses, T2*-CBS >6 was significantly associated with 24-hour recanalization (adjusted odds ratio, 5.1 [1.9-13.5]; P=0.001) or with favorable outcome (adjusted odds ratio, 4.2 [1.7-10.8]; P=0.003)., Conclusions: T2*-CBS, a new reproducible semiquantitative score adapted from the computed tomography angiography-CBS, is associated with 24-hour recanalization and 3-month outcome after intravenous thrombolysis. This score needs external validation and could be useful to identify poor responders to intravenous thrombolysis.

Background and Purpose: Small vessel disease (mainly hypertensive arteriopathy and cerebral amyloid angiopathy (CAA)) is an important cause of spontaneous intracerebral haemorrhage (ICH), a devastating and still poorly understood stroke type. Enlarged perivascular spaces (EPVS) are a promising neuroimaging marker of small vessel disease. Based on the underlying arteriopathy distributions, we hypothesised that severe centrum semiovale EPVS are more common in lobar ICH attributed to CAA than other ICH. We evaluated EPVS prevalence, severity and distribution, and their clinical-radiological associations., Methods: Retrospective multicentre cohort study of 121 ICH patients. Clinical information was obtained using standardised forms. Basal ganglia and centrum semiovale EPVS on T2-weighted MRI (graded 0-4 (>40 EPVS)), white-matter changes, cerebral microbleeds (CMBs) and lacunes were rated using validated scales., Results: Patients with probable or possible CAA (n=76) had a higher prevalence of severe (>40) centrum semiovale EPVS compared with other ICH patients (35.5% vs 17.8%; p=0.041). In logistic regression age (OR: 1.43; 95% CI 1.01 to 2.02; p=0.045), deep CMBs (OR: 3.27; 95% CI 1.27 to 8.45; p=0.014) and mean white-matter changes score (OR: 1.29; 95% CI 1.17 to 1.43; p<0.0001) were independently associated with increased basal ganglia EPVS severity; only age was associated with increased centrum semiovale EPVS severity (OR: 1.50; 95% CI 1.08 to 2.10; p=0.017)., Conclusions: EPVS are common in ICH. Different mechanisms may account for EPVS according to their anatomical distribution. Severe centrum semiovale EPVS may be secondary to, and indicative of, CAA with value as a new neuroimaging marker. By contrast, basal ganglia EPVS severity is associated with markers of hypertensive arteriopathy.

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.

Background and Purpose: The DRAGON score, which includes clinical and computed tomographic scan parameters, showed a high specificity to predict 3-month outcome in patients with acute ischemic stroke treated by intravenous tissue plasminogen activator. We adapted the score for patients undergoing MRI as the first-line diagnostic tool., Methods: We reviewed patients with consecutive anterior circulation ischemic stroke treated ≤ 4.5 hour by intravenous tissue plasminogen activator between 2003 and 2012 in our center, where MRI is systematically implemented as first-line diagnostic work-up. We derived the MRI-DRAGON score keeping all clinical parameters of computed tomography-DRAGON (age, initial National Institutes of Health Stroke Scale and glucose level, prestroke handicap, onset to treatment time), and considering the following radiological variables: proximal middle cerebral artery occlusion on MR angiography instead of hyperdense middle cerebral artery sign, and diffusion-weighted imaging Alberta Stroke Program Early Computed Tomography Score (DWI ASPECTS) ≤ 5 instead of early infarct signs on computed tomography. Poor 3-month outcome was defined as modified Rankin scale >2. We calculated c-statistics as a measure of predictive ability and performed an internal cross-validation., Results: Two hundred twenty-eight patients were included. Poor outcome was observed in 98 (43%) patients and was significantly associated with all parameters of the MRI-DRAGON score in multivariate analysis, except for onset to treatment time (nonsignificant trend). The c-statistic was 0.83 (95% confidence interval, 0.78-0.88) for poor outcome prediction. All patients with a MRI-DRAGON score ≤ 2 (n=22) had a good outcome, whereas all patients with a score ≥ 8 (n=11) had a poor outcome., Conclusions: The MRI-DRAGON score is a simple tool to predict 3-month outcome in acute stroke patients screened by MRI then treated by intravenous tissue plasminogen activator and may help for therapeutic decision.

Introduction: Severe brain hypoxia in the territory of the occluded artery is a key feature of ischemic stroke. This region can be imaged using positron emission tomography (PET) and the standard hypoxia radiotracer (18)F-fluoromisonidazole ((18)F-FMISO). However, the utility of (18)F-FMISO is limited by its slow accumulation in the lesion. Therefore, this study investigated three hypoxia-sensitive radiotracers, namely the nitroimidazole (18)F-fluoroazomycin arabinoside ((18)F-FAZA) and two (64)Cu bis(thiosemicarbazone) complexes ((64)Cu-ATSM and (64)Cu-ATSE), expected to have improved pharmacokinetic profiles relative to (18)F-FMISO, in a rodent model of ischemic stroke., Methods: In anaesthetised Wistar rats, the distal middle cerebral artery was permanently occluded by electrocoagulation, the radiotracers administered intravenously and animals PET scanned for up to 3hours, followed by T2-weighted magnetic resonance imaging to map the infarct., Results: As expected, late and prominent (18)F-FMISO retention was observed despite lower tracer delivery into the affected region. Time-activity curves revealed that both (64)Cu-ATSM and (64)Cu-ATSE showed rapid entry and efflux from the brain, but did not show significant accumulation in the lesion. (18)F-FAZA showed limited brain penetration, and accumulation in the lesion was inconsistent, low and as slow as (18)F-FMISO., Conclusions: This study suggests further development of these radiotracers as hypoxia markers for ischemic stroke may not be warranted., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: Increasing age is the single largest non-modifiable risk factor for ischaemic stroke. Animal models have substantiated the view that age related neuron vulnerability to ischaemia plays a role in stroke and other age related neurological diseases. Given the key role of the ischaemic penumbra in stroke pathophysiology, we hypothesised that age has an impact on penumbral tissue and its acute determinants., Methods: We studied a prospective cohort of patients (n=39) at a mean time of 154.7 min from stroke onset, using state of the art whole brain perfusion CT and CT angiography. Penumbral and core were defined using quantitative voxel based thresholds for mean transit time and cerebral blood volume (CBV). Collateral vessel scores were assessed and haemodynamic variables (ie, cerebral blood flow and CBV) were measured in affected and unaffected tissues., Results: While age correlated negatively with normalised penumbral volume (Kendall's τ b=-0.234, p=0.048) and lesion volume (Kendall's τ b=0.238, p=0.045), core volume remained unchanged, accompanied by an incremental collateral response with age (Kendall's τ b=0.496, p<0.0001). Haemodynamic variables remained unaffected by age in our cohort., Conclusions: These findings, described for the first time in a clinical cohort using whole brain CT perfusion and concomitant vascular imaging, suggest that age has a differential effect on acute tissue compartments in the wake of a preserved collateral vascular response and haemodynamic parameters. In agreement with the preclinical literature, the results point to a distinct tissue response to acute ischaemia in the ageing brain and merit validation studies in larger cohorts, particularly in relation to clinical outcomes.

Background and Purpose: Current models dictate that, depending on occurrence of early reperfusion, the ischemic penumbra either undergoes or escapes infarction (i.e., "pan-necrosis"). However, tissue outcome following temporary middle-cerebral artery occlusion (tMCAo) in rodents can also include selective neuronal loss (SNL), which even if subtle may impede functional recovery. In order to explore the pathophysiology of ischemic stroke, determine potential therapeutic targets and monitor effects of therapy, in vivo imaging surrogates of these varied histopathological outcomes applicable in the clinical setting would be useful. Although hyperintense signal on T(2)-weighted MRI in the chronic post-stroke stage is considered a reliable surrogate of tissue infarction, SNL is not associated with T(2)W abnormal signal. In the clinical setting, the neuron-specific PET ligand (11)C-flumazenil (FMZ) has been used to identify both pan-necrosis and peri-infarct SNL, but this inference has not been histopathological confirmed so far. Here we investigated the late tissue sequelae of tMCAo in the rodent using in vivo T(2)W MRI and FMZ-PET against post mortem immunohistochemistry as gold standard., Methods: Adult spontaneously hypertensive rats (SHRs) underwent 45 min distal-clip middle-cerebral artery occlusion and, 28 days later, FMZ-PET and T(2)W-MRI, immediately followed by immunohistochemistry for neuronal loss (NeuN), activated microglia and astrocytosis. Based on standard histopathological definitions, ischemic lesions were classified into pan-necrosis, partial infarction or SNL. NeuN changes and FMZ binding across the whole hemisphere were quantified in the same set of 44 regions-of-interest according to previously validated protocols; linear regressions between these two measures were carried out both within and across subjects., Results: Both cortical pan-necrosis/partial infarction and SNL were present in all rats except one, where SNL was isolated and extensive. Infarction/partial infarction, but not SNL, was associated with T(2)W hyperintense signals and cortical atrophy. In contrast, FMZ binding was decreased in all types of lesions including SNL, in proportion with NeuN staining intensity both within (p<0.05 to <0.001) and across (p<0.001) subjects, including the subject that showed pure SNL (p=0.01)., Conclusion: This novel study revealed three main facts: i) long-term histopathological cortical changes following 45 min tMCAo in SHRs included all three of SNL, partial infarction and frank infarction; ii) T2W MRI showed conspicuous high signal lesions for complete or partial infarction, but no changes for SNL; and iii) FMZ-PET was sensitive to all three types of tMCAo-induced histopathological changes, including isolated SNL, suggesting it is a valid surrogate for the histological sequelae of focal cerebral ischemia. In addition, the finding of almost universal completed cortical infarction at 28 days differed from our previous findings at 14-day survival using the same model and rat strain, where SNL was the almost exclusive outcome, possibly representing delayed infarct maturation. Prospective studies are needed to investigate this interesting possibility., (Copyright © 2012 Elsevier Inc. All rights reserved.)

When most doctors encounter older patients with transient focal neurological symptoms, they usually suspect a diagnosis of transient ischemic attacks or some of their known mimics (including migraine auras or focal seizures). This article emphasizes new observations on transient focal neurological episodes in the context of cerebral amyloid angiopathy, a common but under-recognized small vessel disease most often encountered as a cause of symptomatic lobar intracerebral hemorrhage. Transient focal neurological episodes in cerebral amyloid angiopathy are of clinical and pathophysiological interest because they can mimic transient ischemic attacks, but are probably more often related to bleeding (especially superficial cortical siderosis or focal convexity sub-arachnoid hemorrhage) rather than ischemia. Importantly, such episodes may also herald a very high future risk of symptomatic intracerebral hemorrhage. The article highlights scenarios encountered in clinical practice and discusses implications for patient care including: (a) the value of blood-sensitive magnetic resonance imaging sequences in investigating transient focal neurological episodes; and (b) treatment implications, as giving antiplatelet or anticoagulant drugs for these episodes could increase the risk of serious intracerebral hemorrhage., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

A wide range of experimental studies have provided evidence that a night of sleep contributes to memory consolidation. Mental rotation (MR) skill is characterized by fundamental aspect of both cognitive and motor abilities which can be improved within practice sessions, but little is known about the effect of consolidation after MR practice. In the present study, we investigated the effect of MR training and the following corresponding day- and sleep-related time consolidations in taking into account the well-established gender difference in MR. Forty participants (20 women) practiced a computerized version of the Vandenberg and Kuse MR task. Performance was evaluated before MR training, as well as prior to, and after a night of sleep or a similar daytime interval. Data showed that while men outperformed women during the pre-training test, brief MR practice was sufficient for women to achieve equivalent performance. Only participants subjected to a night of sleep were found to enhance MR performance during the retest, independently of gender. These results provide first evidence that a night of sleep facilitates MR performance compared with spending a similar daytime interval, regardless gender of the participants. Since MR is known to involve motor processes, the present data might contribute to schedule relevant mental practice interventions for fruitful applications in rehabilitation and motor learning processes.

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., Methods: 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., Results: 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)., Conclusions: 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').

Stroke and cerebrovascular diseases are major causes of mortality, morbidity, and disability. Nuclear Medicine, primarily via tomographic methods, has made significant contributions to the understanding of the hemodynamic and metabolic consequences of cerebrovascular diseases. In this review, the findings in acute, subacute, and chronic cerebrovascular diseases are described. Many of the pathophysiologic processes and consequences that follow stroke, including completed infarct core, adjacent penumbra, and diaschisis, have been investigated with Nuclear Medicine, and stroke outcome may be related to these phenomena. Additional topics included in this review are cerebrovascular reserve tests and multi-infarct dementia. Finally, Nuclear Medicine investigations of stroke recovery and cerebral plasticity appear to indicate that enhanced activity of preexisting networks, rather than substitution of function, represents the most important mechanism of improvement in chronic stroke rehabilitation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Purpose: In acute stroke, diffusion-weighted imaging (DWI) lesions are commonly considered markers of irreversible ischemia yet can occasionally reverse. However, the extent and clinical correlates of DWI reversal in thrombolyzed patients remain unclear. We assessed the extent of reversible acute DWI lesions (RADs) and their relationships with clinical outcome in patients thrombolyzed≤4.5 hours from onset., Methods: Data were retrospectively analyzed. RAD was defined as an acute DWI lesion not part of a 24-hour DWI lesion as determined voxelwise. Associations with an early neurological improvement (early neurological improvement=ΔNational Institutes of Health Stroke Scale≥8 or National Institutes of Health Stroke Scale≤2 at 24 hours) or an excellent outcome (modified Rankin Scale≤1) were assessed in multivariate analyses., Results: One hundred seventy-six patients were included. The median (interquartile range) time to treatment from onset was 150 minutes (120-194). Eighty-nine patients (50%) exhibited visually-detectable RAD irrespective of its extent. Over the whole population, the median percentage and volume of RAD were 11% (4-36) and 2.4 mL (0.5-8). Subtracting RAD from initial DWI altered perfusion-weighted imaging-DWI classification in 5 of 100 patients (shift from "no mismatch" to "mismatch" profile in all). Percent RAD was significantly greater in patients treated≤3 hours (P=0.049), without proximal occlusion (P=0.003), and in 24-hour recanalizers (P<0.001). Early neurological improvement was independently associated with percent RAD. This association increased with percent RAD split in quartiles in a "dose-dependent" manner (P for trend=0.01). Excellent outcome was independently associated with percent RAD (P for trend<0.001)., Conclusions: DWI reversal was often sizeable in patients treated≤4.5 hours. It was strongly associated with, albeit not necessarily causal for, early neurological improvement.

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.

Background and Purpose: Transient focal neurological episodes (TFNE) are recognized in cerebral amyloid angiopathy (CAA) and may herald a high risk of intracerebral hemorrhage (ICH). We aimed to determine their prevalence, clinical neuroimaging spectrum, and future ICH risk., Methods: This was a multicenter retrospective cohort study of 172 CAA patients. Clinical, imaging, and follow-up data were collected. We classified TFNE into: predominantly positive symptoms ("aura-like" spreading paraesthesias/positive visual phenomena or limb jerking) and predominantly negative symptoms ("transient ischemic attack-like" sudden-onset limb weakness, dysphasia, or visual loss). We pooled our results with all published cases identified in a systematic review., Results: In our multicenter cohort, 25 patients (14.5%; 95% confidence interval, 9.6%-20.7%) had TFNE. Positive and negative symptoms were equally common (52% vs 48%, respectively). The commonest neuroimaging features were leukoaraiosis (84%), lobar ICH (76%), multiple lobar cerebral microbleeds (58%), and superficial cortical siderosis/convexity subarachnoid hemorrhage (54%). The CAA patients with TFNE more often had superficial cortical siderosis/convexity subarachnoid hemorrhage (but not other magnetic resonance imaging features) compared with those without TFNE (50% vs 19%; P=0.001). Over a median period of 14 months, 50% of TFNE patients had symptomatic lobar ICH. The meta-analysis showed a risk of symptomatic ICH after TFNE of 24.5% (95% confidence interval, 15.8%-36.9%) at 8 weeks, related neither to clinical features nor to previous symptomatic ICH., Conclusions: TFNE are common in CAA, include both positive and negative neurological symptoms, and may be caused by superficial cortical siderosis/convexity subarachnoid hemorrhage. TFNE predict a high early risk of symptomatic ICH (which may be amenable to prevention). Blood-sensitive magnetic resonance imaging sequences are important in the investigation of such episodes.

Studies attempting to map post-stroke cognitive or motor symptoms to lesion location have been available in the literature for over 150 years. In the last two decades, two computational techniques have been developed to identify the lesion sites associated with behavioural impairments. Voxel Based Morphometry (VBM) has now been used extensively for this purpose in many different patient populations. More recently, Voxel-based Lesion Symptom Mapping (VLSM) was developed specifically for the purpose of identifying lesion-symptom relationships in stroke patients, and has been used extensively to study, among others functions, language, motor abilities and attention. However, no studies have compared the results of these two techniques so far. In this study we compared VLSM and VBM in a cohort of 20 patients with chronic post-stroke aphasia. Comparison of the two techniques showed overlap in regions previously found to be relevant for the tasks used, suggesting that using both techniques and looking for overlaps between them can increase the reliability of the results obtained. However, overall VBM and VLSM provided only partially concordant results and the differences between the two techniques are discussed.

Oxygen utilization is central to the human brain's high metabolic rate. Measurement of this fundamental process, in both disease and health, has been a focus of research attention over the last 35 years. This review plots the course of the use of oxygen-15 to study regional cerebral oxygen extraction and metabolism using Positron Emission Tomography (PET) in disease and in health. The scientific discoveries and resulting conceptual changes to both basic and clinical neuroscience, as well as the new methodological approaches brought about by this area of research, are also summarized. We conclude with a brief overview of the current status of oxygen-15 PET in neuroscience, along with our visions for future developments and applications., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Evidence supporting the widespread use of GreenLight High Performance System (HPS) 120-W photoselective vaporization of the prostate (PVP) is lacking., Objective: To assess the noninferiority of PVP compared with transurethral resection of the prostate (TURP) on urinary symptoms and the superiority of PVP over TURP on length of hospital stay., Design, Setting, and Participants: A multicenter randomized controlled trial was conducted., Intervention: Patients underwent monopolar TURP or PVP with the GreenLight HPS 120-W laser., Measurements: International Prostate Symptom Score (IPSS), Euro-QOL questionnaire, uroflowmetry, Danish Prostate Symptom Score Sexual Function Questionnaire, sexual satisfaction, and adverse events were collected at 1, 3, 6, and 12 mo. The two groups were compared using the 95% confidence interval (CI) of median difference for testing noninferiority of the IPSS at 12 mo and the student t test for testing the difference in length of hospital stay., Results and Limitations: A total of 139 patients (70 vs 69 men in each group) were randomized. Median IPSS scores at 12-mo follow-up were 5 (interquartile range [IQR]: 3-8) for TURP versus 6 (IQR: 3-9) for PVP, and the 95% CI of the difference of the median was equal to -2 to 3. Because the upper limit of the 95% CI was >2 (the noninferiority margin), the hypothesis of noninferiority could not be considered demonstrated. Median length of stay was significantly shorter in the PVP group than in the TURP group, with a median of 1 (IQR: 1-2) versus 2.5 (IQR: 2-3.5), respectively (p<0.0001). Uroflowmetry parameters and complications were comparable in both groups. Sexual outcomes were slightly better in the PVP group without reaching statistical significance., Conclusions: The present study failed to demonstrate the noninferiority of 120-W GreenLight PVP versus TURP on prostate symptoms at 1 yr but showed that PVP was associated with a shorter length of stay in the hospital., Trial Registration: NCT01043588., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Identifying the specific substrates of memory deficits in early Alzheimer's disease would help to develop clinically-relevant therapies. The present study assesses the relationships between encoding versus retrieval deficits in patients with amnestic Mild Cognitive Impairment (aMCI) and atrophy specifically within the hippocampus and throughout the white matter. Twenty-two aMCI patients underwent T1-weighted MRI scans and neuropsychological testing. Grey matter and white matter segments obtained from the MRI images were each entered in correlation analyses, assessed only in the hippocampus for grey matter segments, with encoding and retrieval memory performances. For the grey matter segments, the resulting spmT correlation maps were then superimposed onto a 3D surface view of the hippocampus to identify the relative involvement of the different subfields, a method already used and validated elsewhere. Memory encoding deficits specifically correlated with CA1 subfield atrophy, while no relationship was found with white matter atrophy. In contrast, retrieval deficits were weakly related to hippocampal atrophy and did not involve a particular subfield, while they strongly correlated with loss of white matter, specifically in medial parietal and frontal areas. In aMCI patients, encoding impairment appears specifically related to atrophy of the CA1 hippocampal subfield, consistent with the predominance of encoding deficits and CA1 atrophy in aMCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Post-stroke microglial activation (MA) may have both neurotoxic and pro-repair effects, particularly in the salvaged penumbra. Mapping MA in vivo is therefore an important goal. 11C-PK11195, a ligand for the 18 kDa translocator protein, is the reference radioligand for MA imaging, but a correlation between the regional distributions of in vivo tracer binding and post mortem MA after stroke, as assessed with PET and immunohistochemistry, respectively, has not been demonstrated so far. Here we performed 11C-PK11195 microPET in a rat model previously shown to induce extensive cortical MA, and determined the correlation between 11C-PK11195 and immunostaining with the CD11 antibody OX42, so as to verify the presence of activated microglia, in a template of PET-resolution size regions-of-interest (ROIs) spanning the whole affected hemisphere., Methods: Adult spontaneously hypertensive rats underwent 45 min distal middle cerebral artery occlusion and 11C-PK11195 PET at Days 2 and 14 after stroke according to a longitudinal design. Following perfusion-fixation at Day 14, brains were removed and coronally cut for OX42 staining. 11C-PK11195 binding potential (BPND) parametric maps were generated, and in each rat both BP(ND) and OX42 (intensity×extent score) were obtained in the same set of 44 ROIs extracted from a cytoarchitectonic atlas to cover the whole hemisphere. Correlations were computed across the 44 ROIs both within and across subjects., Results: Significant BPND increases were observed in both the infarct and surrounding areas in all rats at day 14; less strong but still significant increases were present at day 2. There were highly significant (all p<0.001) positive correlations, both within- and across-subjects, between day 14 BPND values and OX42 scores., Conclusions: The correlation between Day 14 11C-PK11195 and OX42 across the affected hemisphere from the same brain regions and animals further supports the validity of 11C-PK11195 as an in vivo imaging marker of MA following stroke. The finding of statistically significant increases in 11C-PK11195 as early as 48 h after stroke is novel. These results have implications for mapping MA after stroke, with potential therapeutic applications., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Rationale: An ankle-foot cast may enable people to repeatedly practice walking with a more normal movement pattern early after stroke., Aims: To evaluate the clinical efficacy of using an ankle-foot cast [soft scotch ankle-foot (SWIFT) Cast] to enhance walking recovery and to find whether site of stroke lesion and/or baseline biomechanical characteristics predict response to a SWIFT Cast., Design: Randomized, controlled, observer-blind trial., Study: Participants (n = 120), 3-42 days after stroke with walking difficulty. All will receive conventional physical therapy. Those allocated to the experimental group will also receive a SWIFT Cast for up to six-weeks. During therapy sessions, the SWIFT Cast will be worn for retraining of walking as clinically appropriate. Outside therapy sessions, participants will initially wear the SWIFT Cast for the whole of their waking day, and this will be adjusted as clinically appropriate., Outcomes: Measures will be undertaken before randomization, six-weeks thereafter and six-months after stroke. Primary outcome will be walking speed. Secondary outcomes will include the Functional Ambulation Category and efficiency of gait (e.g. step-time symmetry). Structural brain imaging using magnetic resonance imaging (standard fluid attenuated inversion recovery and T1-weighted high-resolution 'volume' spoiled gradient) will be undertaken at baseline. The clinical efficacy analysis will use analysis of covariance. The relationship between clinical response to therapy and biomechanical data will use correlation and multivariate regression techniques as required. For neuroimaging data, the relationship to clinical response to therapy will be computed using voxel-based lesion-symptom mapping. An interaction test across groups will identify which voxels are associated with different mean levels of treatment efficacy., (© 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.)

The 5-hydroxytryptamine type 2a (5-HT(2A)) selective radiotracer [(18)F]altanserin has been subjected to a quantitative micro-positron emission tomography study in Lister Hooded rats. Metabolite-corrected plasma input modeling was compared with reference tissue modeling using the cerebellum as reference tissue. [(18)F]altanserin showed sufficient brain uptake in a distribution pattern consistent with the known distribution of 5-HT(2A) receptors. Full binding saturation and displacement was documented, and no significant uptake of radioactive metabolites was detected in the brain. Blood input as well as reference tissue models were equally appropriate to describe the radiotracer kinetics. [(18)F]altanserin is suitable for quantification of 5-HT(2A) receptor availability in rats.

Background and Purpose: To provide guidance regarding the most appropriate voxel-based morphometry (VBM)-derived method for assessing hippocampal atrophy in early Alzheimer's disease (AD)., Methods: T1-MRI volume data were collected in 23 patients with amnestic mild cognitive impairment (aMCI) and 18 controls. Three types of data (unmodulated and 2 types of modulated MRI) and 2 extraction methods (with reference to the hippocampal peak of atrophy identified from a preliminary whole-brain analysis, or using a template region of interest-ROI-approach) were compared to the gold-standard individual ROI (ROI-i) method through 2 statistical approaches (ANOVA and Pearson's R)., Results: First, whole-brain analyses performed on modulated data are as sensitive as the ROI-i approach in detecting aMCI patients' hippocampal atrophy. Second, values extracted from the ROI-template applied to modulated data provide measures of hippocampal volume comparable to those obtained using the ROI-i approach., Conclusions: This study provides guidance on how to extract accurate hippocampal measures from VBM-derived data in early AD, as a time-saving and easy alternative to the reference ROI-i method., (© 2010 by the American Society of Neuroimaging.)

Objective: To investigate the safety, acceptability, and feasibility of positron emission tomography (PET) using carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) to measure cerebral β-amyloid in adults with Down syndrome (DS) and to explore if the technique differentiates between participants with and without Alzheimer disease (AD)., Design: Proof-of-principle case-controlled study of a nonrandomly selected cohort of participants with DS (with or without AD) compared within group and with healthy controls without DS. All had dynamic [(11)C]PiB PET and magnetic resonance imaging. Carbon 11-labeled PiB binding in the regions of interest associated with AD was quantitatively analyzed., Setting: Wolfson Brain Imaging Centre, Cambridge, England., Participants: Nine with DS (aged 25-64 years), of whom 5 had a diagnosis of AD, and 14 healthy controls without DS (aged 33-69 years)., Main Outcome Measure: Positive [(11)C]PiB binding in regions of interest., Results: The scanning process was feasible and acceptable with no adverse events or safety concerns. Maps and regional values of nondisplaceable binding potential were produced using the reference tissue-input Logan plot, with the cerebellum used as the reference tissue. When compared with the healthy control group without DS, only participants with DS older than 45 years had significant [(11)C]PiB binding in regions of interest usually associated with AD, whether or not they had clinical evidence of dementia., Conclusions: Dynamic [(11)C]PiB PET can be used successfully to measure cerebral β-amyloid deposition in DS. A clinical diagnosis of AD and age appear to be predictors of [(11)C]PiB binding in regions of interest, but given the small numbers, we cannot generalize the results.

No study so far has attempted to map the 3D topography of brain hypoxia in the individual rat in vivo following middle cerebral artery occlusion (MCAo). In a previous microPET study, we reported that (18)F-fluoromisonidazole ((18)F-MISO) trapping in the brain after MCAo was specific for the hypoxic viable tissue. Here, we used (18)F-MISO microPET to map the 3D topography of brain hypoxia in the acute stage of permanent distal MCAo in individual spontaneously hypertensive rats. Normal rats were also studied. (18)F-MISO was intravenously injected approximately 1 h after clip placement and PET data were acquired for 2 hours. Animals were sacrificed and the brains harvested 48 h later for infarct mapping using standard histopathology. As expected, continuous (18)F-MISO trapping was found over the affected relative to unaffected and control MCA cortex. Using single-subject voxel-based statistical mapping, tracer accumulation 90-120 min after injection was consistently significantly higher in the anterior MCA cortex (proximal relative to clip site) and gradually decreased towards posterior areas, a pattern consistent with the classic penumbra concept. The data also suggested that (i) a portion of the significant (18)F-MISO trapping area may sit outside the contours of the final infarct despite the permanent MCAo, suggesting that (18)F-MISO may be a marker not only of severe (penumbral) but also of milder (oligemic) hypoxia, and (ii) small portions of the final infarct may not exhibit early tracer trapping, suggesting that by the time the tracer was administered this tissue had already progressed to irreversible damage. This study shows the feasibility of single-subject mapping of brain hypoxia following MCAo in the rat, which has potential applications in pathophysiological investigations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Depicting the salvageable tissue is increasingly used in the clinical setting following stroke. As absolute cerebral blood flow (CBF) is difficult to measure using perfusion magnetic resonance or computed tomography and has limitations as a penumbral marker, time-based variables, particularly the mean transit time (MTT), are routinely used as surrogates. However, a direct validation of MTT as a predictor of the penumbra threshold using gold-standard positron emission tomography (PET) is lacking. Using (15)O-PET data sets obtained from two independent acute stroke samples (N=7 and N=30, respectively), we derived areas under the curve (AUCs), optimal thresholds (OTs), and 90%-specificity thresholds (90%-Ts) from receiver operating characteristic curves for absolute MTT, MTT delay, and MTT ratio to predict three penumbra thresholds ('classic': CBF <20  mL/100  g per min; 'normalized': CBF ratio <0.5; and 'stringent': both CBF <20  mL/100  g per min and oxygen extraction fraction >0.55). In sample 1, AUCs ranged from 0.79 to 0.92, indicating good validity; OTs ranged from 7.8 to 8.3  seconds, 2.8 to 4.7  seconds, and 151% to 267% for absolute MTT, MTT delay, and MTT ratio, respectively, while as expected, 90%-Ts were longer. There was no significant difference between sample 1 and sample 2 for any of the above measurements, save for a single MTT parameter with a single penumbra threshold. These consistent findings from gold-standard PET obtained in two independent cohorts document that MTT is a very good surrogate to CBF for depicting the penumbra threshold.

In this study, we show a basis function method (BAFPIC) for voxelwise calculation of kinetic parameters (K(1), k(2), k(3), K(i)) and blood volume using an irreversible two-tissue compartment model. BAFPIC was applied to rat ischaemic stroke micro-positron emission tomography data acquired with the hypoxia tracer [(18)F]fluoromisonidazole because irreversible two-tissue compartmental modelling provided good fits to data from both hypoxic and normoxic tissues. Simulated data show that BAFPIC produces kinetic parameters with significantly lower variability and bias than nonlinear least squares (NLLS) modelling in hypoxic tissue. The advantage of BAFPIC over NLLS is less pronounced in normoxic tissue. K(i) determined from BAFPIC has lower variability than that from the Patlak-Gjedde graphical analysis (PGA) by up to 40% and lower bias, except for normoxic tissue at mid-high noise levels. Consistent with the simulation results, BAFPIC parametric maps of real data suffer less noise-induced variability than do NLLS and PGA. Delineation of hypoxia on BAFPIC k(3) maps is aided by low variability in normoxic tissue, which matches that in K(i) maps. BAFPIC produces K(i) values that correlate well with those from PGA (r(2)=0.93 to 0.97; slope 0.99 to 1.05, absolute intercept <0.00002 mL/g per min). BAFPIC is a computationally efficient method of determining parametric maps with low bias and variance.

Background: Despite use in clinical practice and major positive trials of thrombolysis, non-contrast computed tomography (NCCT) is not sensitive for identifying penumbral tissue in acute stroke. This study evaluated how physiological imaging using CT perfusion (CTP) could add to the diagnostic utility of an NCCT and inform clinical decisions regarding thrombolysis., Methods: Forty imaging datasets containing NCCT and CTP were retrospectively identified from a cohort of consecutive acute stroke patients. Two sets of observers (n = 6) and a neuroradiologist evaluated the images without knowledge of clinical symptoms. Inter-observer agreement was calculated using the κ statistic for identifying acute ischaemic change on NCCT: perfusion abnormalities (namely cerebral blood volume, cerebral blood flow and time to peak), and penumbral tissue on perfusion maps obtained by two image processing algorithms., Results: Inter-rater agreement was moderate (κ = 0.54) for early ischaemic change on NCCT. Perfusion maps improved this to substantial for cerebral blood volume (κ = 0.67) and to almost perfect for time to peak (κ = 0.87) and cerebral blood flow (κ = 0.87). The agreement for qualitative assessment of penumbral tissue was substantial to perfect for images obtained using the two different perfusion algorithms. Overall, there was a high rate of decision to thrombolyse based on NCCT (81.25%). CTP strengthened the decision to thrombolyse based on NCCT in 38.3% of cases. It negatively influenced the decision in 14.6% of cases, this being significantly more common in experienced observers (p = 0.02)., Conclusions: We demonstrate that the qualitative evaluation of CTP produces near perfect inter-observer agreement, regardless of the post-processing method used. CTP is a reliable, accessible and practical imaging modality that improves confidence in reaching the appropriate diagnosis. It is particularly useful for less experienced clinicians, to arrive at a physiologically informed treatment decision., (Copyright © 2011 S. Karger AG, Basel.)

Hippocampal atrophy, posterior cingulate and frontal glucose hypometabolism, and white-matter tract disruption are well described early macroscopic events in Alzheimer's disease. The relationships between these three types of alterations have been documented in previous studies, but their chronology still remains to be established. The present study used multi-modal fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging longitudinal data to address this question in patients with amnestic mild cognitive impairment. We found unidirectional, specific sequential relationships between: (i) baseline hippocampal atrophy and both cingulum bundle (r = 0.70; P = 3 × 10⁻³) and uncinate fasciculus (r = 0.75; P = 7 × 10⁻⁴) rate of atrophy; (ii) baseline cingulum bundle atrophy and rate of decline of posterior (r = 0.72; P = 2 × 10⁻³); and anterior (r = 0.74; P = 1 × 10⁻³) cingulate metabolism; and (iii) baseline uncinate white matter atrophy and subgenual metabolism rate of change (r = 0.65; P = 6 × 10⁻³). Baseline local grey matter atrophy was not found to contribute to hypometabolism progression within the posterior and anterior cingulate as well as subgenual cortices. These findings suggest that hippocampal atrophy progressively leads to disruption of the cingulum bundle and uncinate fasciculus, which in turn leads to glucose hypometabolism of the cingulate and subgenual cortices, respectively. This study reinforces the relevance of remote mechanisms above local interactions to account for the pattern of metabolic brain alteration observed in amnestic mild cognitive impairment, and provides new avenues to assess the sequence of events in complex diseases characterized by multiple manifestations.

β-Amyloid deposition is one of the main hallmarks of Alzheimer's disease thought to eventually cause neuronal death. Post-mortem and neuroimaging studies have consistently reported cases with documented normal cognition despite high β-amyloid burden. It is of great interest to understand what differentiates these particular subjects from those without β-amyloid deposition or with both β-amyloid deposition and cognitive deficits, i.e. what allows these subjects to resist the damage of the pathological lesions. [¹¹C]Pittsburgh compound B positron emission tomography and magnetic resonance brain scans were obtained in 149 participants including healthy controls and patients with subjective cognitive impairment, mild cognitive impairment and Alzheimer's disease. Magnetic resonance data were compared between high versus low-[11C]Pittsburgh compound B cases, and between high-[¹¹C]Pittsburgh compound B cases with versus those without cognitive deficits. Larger temporal (including hippocampal) grey matter volume, associated with better episodic memory performance, was found in high- versus low-[¹¹C]Pittsburgh compound B healthy controls. The same finding was obtained using different [¹¹C]Pittsburgh compound B thresholds, correcting [¹¹C]Pittsburgh compound B data for partial averaging, using age, education, Mini-Mental State Examination, apolipoprotein E4 and sex-matched subsamples, and using manual hippocampal delineation instead of voxel-based analysis. By contrast, in participants with subjective cognitive impairment, significant grey matter atrophy was found in high-[¹¹C]Pittsburgh compound B cases compared to low-[¹¹C]Pittsburgh compound B cases, as well as in high-[¹¹C]Pittsburgh compound B cases with subjective cognitive impairment, mild cognitive impairment and Alzheimer's disease compared to high-[¹¹C]Pittsburgh compound B healthy controls. Larger grey matter volume in high-[¹¹C]Pittsburgh compound B healthy controls may reflect either a tissue reactive response to β-amyloid or a combination of higher 'brain reserve' and under-representation of subjects with standard/low temporal volume in the high-[¹¹C]Pittsburgh compound B healthy controls. Our complementary analyses tend to support the latter hypotheses. Overall, our findings suggest that the deleterious effects of β-amyloid on cognition may be delayed in those subjects with larger brain (temporal) volume.

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.

Not only finger tapping speed, but also tapping regularity can be impaired after stroke, contributing to reduced dexterity. The neural substrates of impaired tapping regularity after stroke are unknown. Previous work suggests damage to the dorsal premotor cortex (PMd) and prefrontal cortex (PFCx) affects externally-cued hand movement. We tested the hypothesis that these two areas are involved in impaired post-stroke tapping regularity. In 19 right-handed patients (15 men/4 women; age 45-80 years; purely subcortical in 16) partially to fully recovered from hemiparetic stroke, tri-axial accelerometric quantitative assessment of tapping regularity and BOLD fMRI were obtained during fixed-rate auditory-cued index-thumb tapping, in a single session 10-230 days after stroke. A strong random-effect correlation between tapping regularity index and fMRI signal was found in contralesional PMd such that the worse the regularity the stronger the activation. A significant correlation in the opposite direction was also present within contralesional PFCx. Both correlations were maintained if maximal index tapping speed, degree of paresis and time since stroke were added as potential confounds. Thus, the contralesional PMd and PFCx appear to be involved in the impaired ability of stroke patients to fingertap in pace with external cues. The findings for PMd are consistent with repetitive TMS investigations in stroke suggesting a role for this area in affected-hand movement timing. The inverse relationship with tapping regularity observed for the PFCx and the PMd suggests these two anatomically-connected areas negatively co-operate. These findings have implications for understanding the disruption and reorganization of the motor systems after stroke., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Accurately tracing the optic radiations in living humans has important implications for studying the relationship between tract structure or integrity and visual function, in health and disease. Probabilistic tractography is an established method for tracing white matter tracts in humans. Prior studies have used this method to trace the optic radiations, but operator-dependent factors, particularly variability in seed voxel placement and choice of connectivity threshold to select between tract and non-tract voxels, remain potential causes of significant variability. Methods using prior information to modify tract images risk introducing error by underestimating individual variability, particularly in subjects with abnormal anatomy. Finally, existing methods lack thorough validation against a histological standard, causing difficulty in evaluating individual methods, and quantitatively comparing methods. Here we describe a method for producing binary optic radiation images using an existing, well-validated tractography method. All stages are automated, including mask image generation, and thresholds are objectively selected by comparing tract images with existing probabilistic histological data in stereotaxic space. Data from two subject groups are presented; the first used to derive analysis parameters, and the second to test these parameters in an independent sample. Validation utilised a novel variant of receiver operating characteristic analysis, providing both justification for this method and a metric by which tractography methods might be compared generally. The resulting tracts match the histological data well; images generated in individuals matched the histological group data about as well as did images derived in individuals from that histological data set, with a low false positive rate., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

The GABA(A) receptor alpha2/alpha3 subtype-selective compound 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023; also known as MK-0777) is a triazolopyridazine that has similar, subnanomolar affinity for the benzodiazepine binding site of alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors and has partial agonist efficacy at the alpha2 and alpha3 but not the alpha1 or alpha5 subtypes. The purpose of the present study was to define the relationship between plasma TPA023 concentrations and benzodiazepine binding site occupancy across species measured using various methods. Thus, occupancy was measured using either in vivo [(3)H]flumazenil binding or [(11)C]flumazenil small-animal positron emission tomography (microPET) in rats, [(123)I]iomazenil gamma-scintigraphy in rhesus monkeys, and [(11)C]flumazenil PET in baboons and humans. For each study, plasma-occupancy curves were derived, and the plasma concentration of TPA023 required to produce 50% occupancy (EC(50)) was calculated. The EC(50) values for rats, rhesus monkeys, and baboons were all similar and ranged from 19 to 30 ng/ml, although in humans, the EC(50) was slightly lower at 9 ng/ml. In humans, a single 2-mg dose of TPA023 produced in the region of 50 to 60% occupancy in the absence of overt sedative-like effects. Considering that nonselective full agonists are associated with sedation at occupancies of less than 30%, these data emphasize the relatively nonsedating nature of TPA023.

Rescuing the ischemic penumbra from infarction is the mainstay of acute stroke therapy. However, the rescued penumbra may be affected by selective neuronal loss (SNL) and microglial activation (MA), which may hinder functional recovery and hence represent potential new therapeutic targets. Imaging them in vivo is currently attracting considerable interest, but relevant rat models are needed to underpin methods development and validation. Although striatal SNL/MA is well described following proximal MCA occlusion (MCAo), neocortical SNL/MA is still poorly characterized, yet has greater clinical relevance. This study aimed to assess the distribution and intensity of neocortical SNL and MA in a distal clip MCAo model known to cause severe neocortical ischemia. Spontaneously hypertensive rats were subjected to 45 min distal MCAo with ipsilateral common carotid artery occlusion. At day 14, post mortem SNL and MA were mapped using NeuN and OX42 immunohistochemistry, respectively. In a separate group, cerebral blood flow (CBF) was mapped during MCAo using (14)C-iodoantipyrine autoradiography. Values for SNL, MA, and CBF were obtained in the same set of anatomical ROIs covering the cortical MCA territory. Extensive SNL and MA affected the non-infarcted MCA cortex, adopting a well-defined regional distribution and a striking patchy/pseudo-columnar pattern. Regional intensities of SNL and MA were strongly inter-correlated, and also strikingly related to occlusion CBF, showing sharp rises for CBF <40%, i.e. the penumbra threshold. This rat model may be useful in providing in vitro reference for studies aiming to validate novel imaging tracers of SNL and MA in vivo.

Background: Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS). Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies., Methodology/principal Findings: Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and (18)F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients., Conclusions/significance: These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker.