Susanne Wegener

Transient Ischemic Attacks Before Ischemic Stroke: Preconditioning the Human Brain? A Multicenter Magnetic Resonance Imaging Study

Background and Purpose— We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. Methods— Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. Results— Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P =0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. Conclusions— The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.

Use of magnetic resonance imaging to predict outcome after stroke: a review of experimental and clinical evidence.

Despite promising results in preclinical stroke research, translation of experimental data into clinical therapy has been difficult. One reason is the heterogeneity of the disease with outcomes ranging from complete recovery to continued decline. A successful treatment in one situation may be ineffective, or even harmful, in another. To overcome this, treatment must be tailored according to the individual based on identification of the risk of damage and estimation of potential recovery. Neuroimaging, particularly magnetic resonance imaging (MRI), could be the tool for a rapid comprehensive assessment in acute stroke with the potential to guide treatment decisions for a better clinical outcome. This review describes current MRI techniques used to characterize stroke in a preclinical research setting, as well as in the clinic. Furthermore, we will discuss current developments and the future potential of neuroimaging for stroke outcome prediction.

Deletion of the ageing gene p66Shc reduces early stroke size following ischaemia/reperfusion brain injury

AIMS Stroke is a leading cause of morbidity and mortality, and its incidence increases with age. Both in animals and in humans, oxidative stress appears to play an important role in ischaemic stroke, with or without reperfusion. The adaptor protein p66(Shc) is a key regulator of reactive oxygen species (ROS) production and a mediator of ischaemia/reperfusion damage in ex vivo hearts. Hence, we hypothesized that p66(Shc) may be involved in ischaemia/reperfusion brain damage. To this end, we investigated whether genetic deletion of p66(Shc) protects from ischaemia/reperfusion brain injury. METHODS AND RESULTS Transient middle cerebral artery occlusion (MCAO) was performed to induce ischaemia/reperfusion brain injury in wild-type (Wt) and p66(Shc) knockout mice (p66(Shc-/-)), followed by 24 h of reperfusion. Cerebral blood flow and blood pressure measurements revealed comparable haemodynamics in both experimental groups. Neuronal nuclear antigen immunohistochemical staining showed a significantly reduced stroke size in p66(Shc-/-) when compared with Wt mice (P < 0.05, n = 7-8). In line with this, p66(Shc-/-) mice exhibited a less impaired neurological function and a decreased production of free radicals locally and systemically (P < 0.05, n = 4-5). Following MCAO, protein levels of gp91phox nicotinamide adenine dinucleotide phosphate oxidase subunit were increased in brain homogenates of Wt (P < 0.05, n = 4), but not of p66(Shc-/-) mice. Further, reperfusion injury in Wt mice induced p66(Shc) protein in the basilar and middle cerebral artery, but not in brain tissue, suggesting a predominant involvement of vascular p66(Shc). CONCLUSION In the present study, we show that the deletion of the ageing gene p66(Shc) protects mice from ischaemia/reperfusion brain injury through a blunted production of free radicals. The ROS mediator p66(Shc) may represent a novel therapeutical target for the treatment of ischaemic stroke.

Quantification of rodent cerebral blood flow (CBF) in normal and high flow states using pulsed arterial spin labeling magnetic resonance imaging

To implement a pulsed arterial spin labeling (ASL) technique in rats that accounts for cerebral blood flow (CBF) quantification errors due to arterial transit times (dt)—the time that tagged blood takes to reach the imaging slice—and outflow of the tag.

A Generative Probabilistic Model and Discriminative Extensions for Brain Lesion Segmentation— With Application to Tumor and Stroke

We introduce a generative probabilistic model for segmentation of brain lesions in multi-dimensional images that generalizes the EM segmenter, a common approach for modelling brain images using Gaussian mixtures and a probabilistic tissue atlas that employs expectation-maximization (EM), to estimate the label map for a new image. Our model augments the probabilistic atlas of the healthy tissues with a latent atlas of the lesion. We derive an estimation algorithm with closed-form EM update equations. The method extracts a latent atlas prior distribution and the lesion posterior distributions jointly from the image data. It delineates lesion areas individually in each channel, allowing for differences in lesion appearance across modalities, an important feature of many brain tumor imaging sequences. We also propose discriminative model extensions to map the output of the generative model to arbitrary labels with semantic and biological meaning, such as “tumor core” or “fluid-filled structure”, but without a one-to-one correspondence to the hypo- or hyper-intense lesion areas identified by the generative model. We test the approach in two image sets: the publicly available BRATS set of glioma patient scans, and multimodal brain images of patients with acute and subacute ischemic stroke. We find the generative model that has been designed for tumor lesions to generalize well to stroke images, and the extended discriminative -discriminative model to be one of the top ranking methods in the BRATS evaluation.

Clinically Isolated Neurosarcoidosis: A Recommended Diagnostic Path

The involvement of the central nervous system in sarcoidosis can manifest with a variety of neurological symptoms, most of them nonspecific. We identified 13 patients with neurosarcoidosis diagnosed at our clinic. Six of 13 patients presented with clinically isolated neurosarcoidosis (CINS) without signs or symptoms of systemic disease. CINS patients were not different with respect to age, as well as imaging and spinal fluid findings, or disease course. However, we found spinal cord involvement in neurosarcoidosis patients much more common than previously described (in 8 out of 13 patients). Spinal cord affection was associated with older age at diagnosis and a less favorable response to therapy. Based on our findings, we propose a diagnostic path for neurosarcoidosis, including spinal magnetic resonance imaging (MRI) as a mandatory and early step during diagnostic workup. i 2014 S. Karger AG, Basel

3-Nitropropionic Acid-Induced Ischemia Tolerance in the Rat Brain is Mediated by Reduced Metabolic Activity and Cerebral Blood Flow

Tissue tolerance to ischemia can be achieved by noxious stimuli that are below a threshold to cause irreversible damage (‘preconditioning’). Understanding the mechanisms underlying preconditioning may lead to the identification of novel therapeutic targets for diseases such as stroke. We here used the oxidative chain inhibitor 3-nitropropionic acid (NPA) to induce ischemia tolerance in a rat middle cerebral artery occlusion (MCAO) stroke model. Cerebral blood flow (CBF) and structural integrity were characterized by longitudinal magnetic resonance imaging (MRI) in combination with behavioral, histologic, and biochemical assessment of NPA-preconditioned animals and controls. Using this approach we show that the ischemia-tolerant state is characterized by a lower energy charge potential and lower CBF, indicating a reduced baseline metabolic demand, and therefore a cellular mechanism of neural protection. Blood vessel density and structural integrity were not altered by NPA treatment. When subjected to MCAO, preconditioned animals had a characteristic MRI signature consisting of enhanced CBF maintenance within the ischemic territory and intraischemic reversal of the initial cytotoxic edema, resulting in reduced infarct volumes. Thus, our data show that tissue protection through preconditioning occurs early during ischemia and indicate that a reduced cellular metabolism is associated with tissue tolerance to ischemia.

The Time of Maximum Post-Ischemic Hyperperfusion Indicates Infarct Growth Following Transient Experimental Ischemia

After recanalization, cerebral blood flow (CBF) can increase above baseline in cerebral ischemia. However, the significance of post-ischemic hyperperfusion for tissue recovery remains unclear. To analyze the course of post-ischemic hyperperfusion and its impact on vascular function, we used magnetic resonance imaging (MRI) with pulsed arterial spin labeling (pASL) and measured CBF quantitatively during and after a 60 minute transient middle cerebral artery occlusion (MCAO) in adult rats. We added a 5% CO2 - challenge to analyze vasoreactivity in the same animals. Results from MRI were compared to histological correlates of angiogenesis. We found that CBF in the ischemic area recovered within one day and reached values significantly above contralateral thereafter. The extent of hyperperfusion changed over time, which was related to final infarct size: early (day 1) maximal hyperperfusion was associated with smaller lesions, whereas a later (day 4) maximum indicated large lesions. Furthermore, after initial vasoparalysis within the ischemic area, vasoreactivity on day 14 was above baseline in a fraction of animals, along with a higher density of blood vessels in the ischemic border zone. These data provide further evidence that late post-ischemic hyperperfusion is a sequel of ischemic damage in regions that are likely to undergo infarction. However, it is transient and its resolution coincides with re-gaining of vascular structure and function.

Challenges in the diagnosis and treatment of neurosarcoidosis

Abstract The diagnosis and treatment of neurosarcoidosis can be very challenging for several reasons. It affects clinically 5%–10% of sarcoidosis patients, but can be found in up to 25% of autopsies. These data reveal that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. Clinical and imaging findings are often non-specific since they can be found in a large number of neurological disorders. Histopathology can also be confounding if not performed by an expert pathologist and not placed in an appropriate clinical context. In this review, we discuss clinical features, laboratory findings, imaging, and histology of neurosarcoidosis, and we report current evidence regarding drug therapy. We conclude that a correct diagnostic approach should include a multidisciplinary evaluation involving clinicians, radiologists, and pathologists and that future studies should evaluate the genetic signature of neurosarcoidosis as they could be helpful in the assessment of this uncommon disease. With head-to-head comparisons of medical treatment for neurosarcoidosis still lacking due to the rarity of the disease and an increasing number of immunomodulating therapies at hand, novel therapeutic approaches are to be expected within the next few years. Key Messages Neurosarcoidosis is a rare disorder that affects clinically 5%–10% of sarcoidosis patients, but can be found in up to 25% of autopsies, revealing that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. A multidisciplinary evaluation is useful to achieve a correct diagnosis because clinical and imaging findings are often non-specific. Corticosteroids are the first-line treatment for neurosarcoidosis, followed by steroid-sparing immune-modulating agents if prednisone therapy is insufficient.

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage.

Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.