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Background and Purpose— Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. Methods— In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models’ fits were compared using the likelihood ratio test. Results— The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps ( P Conclusions— Our results support a dynamic susceptibility contrast magnetic resonance imaging–based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.

We read with interest the meta-analysis of Ziganshina et al1 and the accompanying Editorial by Bereczki et al2 and value the opinion of our colleagues; however, we disagree with the conclusions in the Editorial and the 2 underlying meta-analyses1,3 about effects of Cerebrolysin in acute ischemic stroke. Most common outcome measures to assess clinical benefit of pharmacological treatment after acute ischemic stroke are modified Rankin Scale and National Institutes of Health Stroke Scale. The meta-analysis of Ziganshina et al1 provided results only on all-cause deaths to assess benefits of Cerebrolysin. Importantly, the death rate in the selected trials was very low (6.4% for Cerebrolysin versus 6.7% for placebo), which severely limits statistical sensitivity. Furthermore, the analysis ignored the clinical benefit of the survivors, that is, of >93% of the study patients. The International Consortium for Health Outcomes Measurement explicitly warns …

Background and Purpose— Cognitive impairment occurs in ≤30% of all stroke survivors. However, effective therapies aimed at preventing poststroke cognitive decline are lacking. We assessed the efficacy of a multidomain intervention on preventing cognitive decline after stroke. Methods— In this randomized, observer-blind trial patients were recruited within 3 months after an acute stroke in 5 Austrian neurological centers. Patients were assigned to a 24-month lifestyle-based multidomain intervention or standard stroke care. Primary outcomes were the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) and occurrence of cognitive decline in the composite scores of at least 2 of 5 cognitive domains at 24 months. Results— A total of 101 patients were randomized into multi-intervention and 101 into standard care during June 2010 and November 2012. Of them, 76 patients in the intervention group and 83 in the control group were included in the final intention-to-treat analysis. At 24 months, 8 of 76 (10.5%) patients in the intervention group and 10 of 83 (12.0%) patients in the control group showed cognitive decline corresponding to a relative risk reduction of 0.874 (95% confidence interval, 0.364–2.098). The change in ADAS-cog from baseline to 24 months was not different either (median 0 [IQR, −1 to 2] in both groups; P =0.808). Conclusions— This trial found no benefit of 24-month multidomain intervention with focus on improvement in lifestyle and vascular risk factors on the incidence of poststroke cognitive decline in comparison with standard stroke care. Studies with a larger sample size are needed. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT01109836.

Advances in cardiopulmonary resuscitation and critical care management of acute severe traumatic, anoxic, or toxic brain injury, have resulted in the survival of many patients who would previously have died. Often patients who had severe brain damage fall into a coma characterized by complete absence of wakefulness and awareness. If not resulting in death, this coma might develop into an acute vegetative state/unresponsive wakefulness syndrome (VS/UWS), when the patient seems awake but unaware, uncommunicative, and unresponsive to the environment.1 If recovery continues, patients regain minimal responsiveness to external stimuli but remain unable to communicate (the so-called minimally conscious state [MCS]).2 Otherwise, patients may remain for a long time in a persistent vegetative state (PVS). Accurate differential diagnosis is essential for the clinical management of patients with disorders of consciousness, but difficult and often leading to diagnostic errors. As a consequence, consensus diagnosis of VS was incorrect in >40% of patients.3 The reliable assessment of the individual patient’s prognosis on the sole basis of clinical findings is even more difficult and in the early stages of the disorder often impossible. However, clinical signs, laboratory, or functional tests (eg, electroencephalography and evoked potentials), as well as conventional neuroimaging methods (eg, computed tomography and MRI) only permit an estimation of the extent of structural brain damage but render only an indirect and incomplete estimation of the functional level that may be relevant for the loss of consciousness.4–7 One may consequently search for more functional measures, such as positron emission tomography (PET) and functional MRI (fMRI) that may specifically target the neural correlates of the (decreased) level of consciousness rather than the underlying structural damage. Our article aims to review the more recent results from functional brain imaging, such as …

Introduction: Perfusion imaging by DSC-MRI (dynamic susceptibility contrast MRI) is the clinical method of choice for identification of penumbral flow (PF) in acute stroke. To date, the tissue at risk is estimated by a single predefined perfusion map. However, integration of various perfusion parameters may amplify the pathophysiological information and yield better estimation of PF. We therefore combined the common perfusion maps in a generalized linear model (GLM) to predict PF as defined by positron emission tomography (PET). Methods: In 18 patients with (sub)acute stroke, consecutive DSC-MRI and O15-water PET was performed (median age/NIHSS: 58 y , 12). PF was defined as cerebral-blood-flow (CBF) < 20 mL/100g/min on PET. MRI perfusion maps included: CBF, CBV, MTT, Tmax, TTP (cerebral-blood-volume, mean-transit-time, time-to-maximum and time-to-peak respectively). Probability maps for PF prediction were generated by a) single maps and b) multi-parametric maps (GLM) and underwent cross validation. ROC analysis assessed performance for PF prediction as area-under the curve (AUC). Results: Single maps showed AUC values between 0.57 and 0.72 (Tmax and CFB showing best performance). The GLM approach yielded an AUC of 0.75. Comparison by the Wilcoxon signed rank test showed that while the absolute difference was moderate, it was significant (p Conclusions: Our results suggest that a multi-parameter perfusion model yields the highest accuracy for PF prediction. This finding, while preliminary, suggest a straight-forward model that can be easily integrated in clinical routine for improved stroke stratification based on the mismatch paradigm. Figure 1: Performance in penumbral flow prediction The graph shows performance in PF prediction for perfusion parameters and GLM. The error-bars represent standard-error. (*) marks significance for p value

One in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and half without. After recurrent stroke, more than a third will become demented.1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms contribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets. Clinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia,3 and experimental studies with animals have addressed the relationship between stroke and AD.4–9 Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ1–42) accumulate in patients with multi-infarct dementia,10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilin-knockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity.9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arterial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in transgenic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute to the higher ischemia …

Stroke is a leading cause of long-term adult disability worldwide. Only a small proportion of stroke survivors (≈14%) achieve full recovery of activities of daily living, whereas 25% to 50% require some assistance and approximately half experience long-term dependency.1 Prediction of outcome after ischemic stroke, therefore, is important for setting realistic and attainable treatment goals, informing patients and their relatives properly, facilitating discharge planning, and anticipating possible consequences for home adjustments and community support.2 Moreover, knowledge of the expected recovery pattern is necessary to assess the effectiveness of new therapeutic interventions and their contribution to recovery and should be applied to select comparable patients populations for treatment trials.3 Several standardized measures assess various aspects of stroke outcome and recovery, including quantification of neurological deficits, functional outcome measures, and quality of life measures. Activities of daily living, including dressing, mobility, and bathing, are assessed most frequently by the Barthel Index4 and by the modified Rankin Scale (mRS)5 but also by the Glasgow Outcome Scale,6 the Functional Independence Measure,7 or other activities of daily living assessment tools.8 Frequently used measures of quality of life include the Stroke Impact Scale and European Quality of Life Scale (EQ-5D).9,10 A considerable number of prognostic stroke studies used the Barthel Index and the mRS as the primary outcome measure reached after 3 to 6 months and found that scores on scales assessing severity of neurological deficits such as the National Institutes of Healt Stroke Scale (NIHSS)11–13 and Canadian Neurological Scale14 in acute stroke (ie, within 72 hours) are strongly associated with outcome beyond 3 months.2,15 A systemic review of prognostic studies8 indicated that age and motor weakness were important predictive variables of outcome in addition to stroke …

Background and Purpose— Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. Methods— Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15-water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. Results— The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group ( t test, P =0.003). Increases were largest for subtest naming ( P =0.002) and tended to be higher for comprehension, token test, and writing ( P t test, P =0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change ( r 2 =0.25; P =0.015). Conclusions— Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks.

In the history of stroke research the term letzte Wiese (English last meadow or last field) was introduced in the early fifties of the past century to describe the risk of low blood perfusion in the periphery of a vascular territory. The term appears 1952 in the discussion of a colloquium held by the German Society of Physiological Chemistry in the small city Mosbach, located close to the scenic river Neckar in the north of the federal state Baden-Wurttemberg.1 The symposium entitled Chemie und Stoffwechsel des Nervengewebes (chemistry and metabolism of nervous tissue) comprised 5 presentations on various aspects of brain function and metabolism. One of these was given by Erich Opitz, Chair of the Physiological Institute of the University Kiel. In his presentation Energieumsatz des Gehirns in situ unter aeroben und anaeroben Bedingungen (energy metabolism of the brain under aerobic and anaerobic conditions), he addressed the magnitude of metabolic activity required to maintain the structural integrity of the brain (Strukturumsatz). In the discussion after his presentation, Max Schneider, Chair of the Physiological Institute of the University of Cologne, remarked that a differentiation between structural and functional activity of the brain can be obtained by gradually reducing the blood perfusion of an isolated head preparation and recording the suppression and recovery of the electroencephalogram. The lowest flow rate down to which spontaneous electroencephalogram activity persists is the amount required to maintain functional activity, and the lowest flow rate which is tolerated for some time without causing irreversible suppression of the electroencephalogram corresponds to the amount required to preserve structural integrity. This approach anticipated the latter differentiation between core and penumbra of evolving brain infarction introduced by Astrup et al2 after occlusion of the middle cerebral artery. However, as pointed out by Schneider,3 global measurements of blood flow …

Introduction: Patients with unknown time from stroke onset, e.g. in wake-up stroke, are not eligible for thrombolyic treatment. Relative signal intensities (rSI) of DWI and FLAIR MRI are biomarkers for eligibility for thrombolysis, but have shown heterogeneous results to date. We investigated if the addition of available clinical parameters improves the prediction of the thrombolysis time window in patients with acute stroke. Hypothesis: Inclusion of clinical parameters improves the prediction of the thrombolysis time window by quantitative MRI biomarkers Methods: Patients from two centers with proven stroke and stroke-onset Results: 82 patients were included. In the unadjusted analysis, DWI-mean and -std (AUC: 0.86, 0.87) performed best. Adjustment for clinical parameters significantly improved the performance of FLAIR-mean (0.87) and DWI-std (0.91). The best performance was found for the final stratified and adjusted models of DWI-std (0.94) and FLAIR-mean (0.96). ADC-rSIs showed no clinically acceptable performance in all models. Conclusion: rSIs of DWI and FLAIR MRI predict eligibility for thrombolysis in acute stroke with high precision, when easily available clinical parameters are included in the prediction.

Translational research has the aim to transform scientific discoveries into clinical applications. Molecular concepts are analyzed in in vitro experiments, tested in vivo in animal preparations, and then explored in human studies by which the applicability for clinical disease management—diagnosis, treatment, prevention—is tested. Pathophysiological studies in animal models traditionally applied invasive methods that could not be used in humans. On the other hand, the resolution capacity of modalities for functional and metabolic imaging in humans in the past did not allow detecting regional abnormalities in small experimental animals. With the advance of high-resolution tomographic devices, comparative studies of metabolic and molecular changes in pathological states could be performed noninvasively and repeatedly in animal models and in humans. Because positron emission tomography (PET) permits the quantitative determination of a large number of physiological, metabolic, and molecular variables, it was in the past and still is an appropriate tool for comparative pathophysiological studies in animal models and human disease. In the following, some examples of the role of PET for translational research in stroke are reviewed. ### The Concept of the Ischemic Penumbra and Identification by Imaging Experimental work on the ischemic flow thresholds of brain tissue demonstrated the existence of 2 critical levels of decreased perfusion: first, a level representing the flow threshold for reversible functional failure (functional threshold); and second, a lower threshold below which irreversible membrane failure and morphological damage occur. The range of perfusion values between those limits was called the “ischemic penumbra,”1 which was characterized by the potential for functional recovery without morphological damage provided that local blood flow can be re-established at a sufficient level. Whereas neuronal function is impaired immediately when blood flow drops below the threshold, the development of irreversible morphological damage is time-dependent. This interaction of severity and duration of ischemia in the development of irreversible cell damage was established in simultaneous recordings …

Background and Purpose— Cerebrolysin showed neuroprotective and neurotrophic properties in various preclinical models of ischemia and small clinical trials. The aim of this large double-blind, placebo-controlled randomized clinical trial was to test its efficacy and safety in patients with acute ischemic stroke. Methods— Patients with acute ischemic hemispheric stroke were randomized within 12 hours of symptoms onset to active treatment (30 mL Cerebrolysin daily) or placebo (saline solution) given as intravenous infusion for 10 days in addition to aspirin (100 mg daily). The patients were followed up to 90 days. The primary end point was the result of a combined global directional test of modified Rankin Scale, Barthel Index, and National Institutes of Health Stroke Scale. Adverse events were documented to assess safety. Results— A total of 1070 patients were enrolled in this study. Five hundred twenty-nine patients were assigned to Cerebrolysin and 541 to placebo. The confirmatory end point showed no significant difference between the treatment groups. When stratified by severity however, a post hoc analysis of National Institutes of Health Stroke Scale and modified Rankin Scale showed a trend in favor of Cerebrolysin in patients with National Institutes of Health Stroke Scale >12 (National Institutes of Health Stroke Scale: OR, 1.27; CI lower bound, 0.97; modified Rankin Scale: OR, 1.27; CI lower bound, 0.90). In this subgroup, the cumulative mortality by 90 days was 20.2% in the placebo and 10.5% in the Cerebrolysin group (hazard ratio, 1.9661; CI lower bound, 1.0013). Conclusions— In this study, the confirmatory end point showed neutral results between the treatment groups. However, a favorable outcome trend was seen in the severely affected patients with ischemic stroke treated with Cerebrolysin. This observation should be confirmed by a further clinical trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00868283.

Background and Purpose— Perfusion-weighted imaging maps are used to identify critical hypoperfusion in acute stroke. However, quantification of perfusion may depend on the choice of the arterial input function (AIF). Using quantitative positron emission tomography we evaluated the influence of the AIF location on maps of absolute and relative perfusion-weighted imaging to detect penumbral flow (PF; CBF ) in acute stroke. Methods— In 22 patients with acute stroke the AIF was placed at 7 sites (M1, M2, M3 ipsi- and contralateral and internal carotid artery–M1 contralateral to the infarct). Comparative 15 O-water positron emission tomography and AIF-dependent perfusion-weighted imaging (cerebral blood flow, cerebral blood volume, mean transit time, and time to maximum) were performed. A receiver operating characteristic curve analysis described the threshold independent performance (area under the curve) of the perfusion-weighted maps for all 7 AIF locations and identified the best AIF-dependent absolute and relative thresholds to identify PF. These results were compared with AIF-independent time-to-peak maps. Results— Quantitative perfusion-weighted imaging maps of cerebral blood flow and time to maximum performed best. For PF detection, AIF placement did significantly influence absolute PF thresholds. However, AIF placement did not influence (1) the threshold independent performance; and (2) the relative PF thresholds. AIF placement in the proximal segment of the contralateral middle cerebral artery (cM1) was preferable for quantification. Conclusions— AIF-based maps of cerebral blood flow and time to maximum were most accurate to detect the PF threshold. The AIF placement significantly altered absolute PF thresholds and showed best agreement with positron emission tomography for the cM1 segment. The performance of relative PF thresholds, however, was not AIF location-dependent and might be along with AIF-independent time-to-peak maps, more suitable than absolute PF thresholds in acute stroke if detailed postprocessing is not feasible.

Background and Purpose— Although functional imaging studies suggest that recruitment of contralesional areas hinders optimal functional reorganization in patients with aphasic stroke, only limited evidence is available on the efficacy of noninvasive brain stimulation such as repetitive transcranial magnetic stimulation aimed at suppression of contralateral overactivation. Methods— In this randomized, controlled, blinded pilot study, the effect of 1-Hz repetitive transcranial magnetic stimulation over right-hemispheric Broca homolog in subjects with poststroke aphasia in the subacute stage was examined. According to their group allocation, patients received, in addition to conventional speech and language therapy, multiple sessions of repetitive transcranial magnetic stimulation either over the right-hemispheric inferior frontal gyrus (intervention group) or over the vertex (control group). The primary outcome parameter was the change in laterality indices as quantified by activation positron emission tomography before and after the 2-week intervention period. The clinical efficacy was evaluated with the Aachen Aphasia Test. Results— At baseline, no group differences were discovered for age, laterality indices, or mean Aachen Aphasia Test scores. Four patients were lost to follow-up, but none due to side effects of the transcranial magnetic stimulation. Positron emission tomography revealed an activation shift toward the right hemisphere in the control group ( P =0.0165), which was absent in the intervention group. Furthermore, the latter improved significantly clinically by a mean of 19.8 points in the Aachen Aphasia Test total score ( P =0.002), whereas the control group did not. There was however no clear linear relationship between the extent of laterality shift and clinical improvement ( r =0.193, P =nonsignificant). Conclusions— Repetitive transcranial magnetic stimulation might be an effective, safe, and feasible complementary therapy for poststroke aphasia.

Background and Purpose— Perfusion-weighted imaging maps are used to identify hypoperfusion in acute ischemic stroke. We evaluated maps of cerebral blood flow (CBF), cerebral blood volume, mean transit time, and time to peak (TTP) in acute stroke by comparison with positron emission tomography. Methods— Perfusion-weighted imaging and positron emission tomography were performed in 26 patients with acute ischemic stroke (median 18.5 hours after stroke onset, 65 minutes between MRI and positron emission tomography). The perfusion-weighted imaging-derived maps of CBF, cerebral blood volume, mean transit time, and TTP delay were compared with quantitative positron emission tomography CBF. A receiver-operating characteristic curve analysis identified the best perfusion-weighted imaging map and threshold to identify hypoperfusion Results— Individual regression analysis of positron emission tomography CBF and perfusion-weighted imaging values were strong for CBF and TTP delay and weaker for mean transit time and cerebral blood volume, but the pooled analysis showed a large variance. Receiver-operating characteristic curve analysis identified TTP and CBF maps as most predictive (median area under the curve=0.94 and 0.93). Penumbral flow thresholds were 5.3 seconds (mean transit time), and >4.2 seconds (TTP). TTP and CBF maps reached sensitivity/specificity values of 91%/82% and 89%/87%. Conclusion— In our sample, maps of CBF, TTP, and mean transit time yielded a good estimate of penumbral flow. The performance of TTP maps was equivalent to deconvolution techniques using an arterial input function. For all maps, the application of a predefined threshold is mandatory and calibration studies will enhance their use in acute stroke therapy as well as in clinical stroke trials.