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Background: Recovery from stroke is presumed to be a function of a widespread cerebral network. Chronic white matter lesions (WML) have been proposed to be a predictor of poor outcome after acute stroke. We tested the hypothesis that the extent of WML has an effect on functional recovery in acute pontine stroke by disrupting the integrity of the supratentorial cerebral network., Methods: Seventeen patients with acute unilateral pontine stroke who had received a standardized stroke workup and additional diffusion tensor imaging (DTI) were studied. After grading the extent of WML according to the Fazekas scale and semiautomated lesion volume calculation, we compared patients with acute pontine infarction and advanced WML to those with absent or minimal WML regarding baseline characteristics, stroke subtype and clinical outcome. In addition, we used tract-based spatial statistics for voxel-wise analysis of the DTI-derived parameter fractional anisotropy in the white matter tracts., Results: The volume of WML ranged between 0.1 and 42.1 cm³ (mean = 15.9) and was graded as follows: 0 in 5.9%, 1 in 35.3%, 2 in 41.2% and 3 in 17.6%. Both patients with Fazekas grades 2-3 (p = 0.014) as well as those with larger WML volumes (p = 0.037) had severer functional deficits at the 3-month follow-up. White matter tracts displaying a significant decrease in fractional anisotropy values were the corpus callosum, the anterior thalamic radiation and the inferior fronto-occipital fasciculus., Conclusions: Chronic WML contribute to a less favorable clinical outcome after pontine stroke depending on (1) the extent of pre-existing WML and (2) the degree of disruption of cerebral connectivity as indicated by reduced tissue integrity in the white matter not affected by WML as detected by DTI and tract-based spatial statistics., (Copyright © 2011 S. Karger AG, Basel.)

Background: In large territorial stroke of the anterior and the posterior circulation, the extent of affected tissue can be characterized by the demonstration of vessel occlusion on MR angiography (MRA), while the extent of hypoperfusion can be shown on dynamic susceptibility contrast perfusion-weighted MRI (PWI). The ability of MRA and conventional MRI sequences to demonstrate branches of the basilar artery (BA) is very limited. This study analyzes the value of the combined use of diffusion-weighted MRI (DWI), MRA and PWI in acute pontine stroke., Methods: A series of 24 consecutive patients with acute pontine stroke received an extensive MRI stroke workup including DWI, PWI and MRA., Results: In 11/24 patients visual analysis of PWI demonstrated persisting hypoperfusion, and in 1/24 patients indication of hyperperfusion was found. Vessel abnormalities were seen in 19/24 patients (15/24 hypoplastic vertebral artery, 9/24 stenosis or occlusion of the BA, 1/20 ectatic BA). Persistent pontine hypoperfusion was more frequently associated with BA pathology (9/11 vs. 1/13, p = 0.001), large-vessel disease (8/11 vs. 1/13; p = 0.001) and a more pronounced clinical deficit (NIHSS score on day 1: 7 vs. 3, p = 0.01)., Conclusions: In pontine ischemia areas of hypoperfusion can be identified due to the strong contrast induced by ischemia on PWI and can be easily related to DWI lesion size. This is of use particularly as small vessels are frequently missed by MRA and occlusion of the BA can be better characterized with the help of PWI., ((c) 2010 S. Karger AG, Basel.)

Transient global amnesia (TGA) is characterized by the abrupt onset of severe amnesia without concomitant focal neurological symptoms. Recent studies revealed that small and punctate MR-signal diffusion-weighted imaging (DWI) lesions can be found within the hippocampus of TGA patients during the post-acute phase. On the basis of dual-process models of recognition memory, the present study examined the hypothesis that hippocampal dysfunction as suggested by these DWI lesions disrupts hippocampus-mediated recollection in patients with TGA, whereas familiarity-based recognition memory that is assumed to be supported by extra-hippocampal brain regions should be unaffected. We administered a recognition memory task for faces and words to eleven TGA patients during the post-acute phase and to eleven matched controls. Receiver operating characteristics (ROCs) were obtained in order to derive estimates of familiarity and recollection by applying a formal dual-process model of recognition memory. Analyses of ROC curves revealed a disruption of recollection in TGA patients' memory for words [t(20)=2.70, p<.05], but no difference in familiarity-based recognition memory between patients and controls [t(20)=-1.10, p=.284]. Post hoc analyses indicated that the deficit in recollection is more pronounced in TGA patients who show visible hippocampal lesions on diffusion-weighted MR imaging compared to those without detectable hippocampal lesions. In conclusion, consistent with recent neuroanatomical dual-process models of recognition memory, hippocampal dysfunction in patients with TGA is associated with a selective effect on specific recognition memory subprocesses.

Background: Both ischemic stroke and intracerebral hemorrhage are associated with altered expression and activation of matrix metalloproteinases (MMPs). Particularly relevant are MMP-2 and MMP-9. This proteolytic effect is dampened by tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 is an important endogenous inhibitor of MMP-2. Alterations in the TIMP-2 gene expression may contribute to the incidence of ischemic stroke and intracerebral hemorrhage., Methods: TIMP-2 gene SNP -261G/A was genotyped from sequentially recruited stroke patients (n = 356, f/m 151/205, mean age 68.2 years, range 19-100 years) and gender and age matched controls (n = 253, f/m 114/139, mean age 68.5 years, range 32-92 years). The SNP -261G/A was detected after gene sequencing of 95 patients and controls. Furthermore, in a subgroup of 93 patients the serum levels of TIMP-2 were measured during the first 7 days after stroke onset and compared to the genotype., Results: SNP -261G/A in the TIMP-2 gene shows an allele frequency of approximately 39.14%. Homozygosity for allele A is associated significantly with the development of ICH (p = 0.025, OR = 2.020, CI = 1.115-3.661) as compared to heterozygosity and homozygosity for allele G (recessive genotypic model). Concordantly, the serum levels of TIMP-2 showed a nonsignificant decreases, depending on the genotype (p = 0.111)., Conclusion: We investigated a SNP 261 base pairs upstream of the start codon in exon 1 of TIMP-2. Our data suggest that carriers of homozygosity for allele A are at increased risk of developing intracerebral hemorrhage., (Copyright (c) 2009 S. Karger AG, Basel.)

Stem cell therapy seems promising in reducing deficits after focal cerebral ischemia. As stroke may result from intracerebral hemorrhage (ICH) in up to 20% we investigated whether human processed lipoaspirate mesenchymal stem cells (PLA-MSC) influence the functional outcome, migration behavior and the activation of endogenous progenitor cells. Experimental ICH was induced by stereotactic administration of collagenase in rats randomly assigned to the control or treatment group. The latter received 3 x 10(6) PLA-MSC by intravenous (i.v.) injection 24h after ICH induction. The outcome was continuously monitored using the RotaRod test over a period of 4 weeks. Morphometric analysis of ICH was performed consecutively by magnetic resonance imaging (MRI) studies and immunohistochemical analysis. The RotaRod test revealed a significant 1.5-fold improvement (p<0.005) in functional outcome for the PLA-MSC treated group after 4 weeks compared to controls. Histological and MRI assessment of lesion size showed no difference between the two groups. Although i.v. injected human cells could not be detected in the post mortem brain, evaluation of the number of endogenous progenitor cells revealed a twofold increase in the treated animals compared to controls. Treatment with PLA-MSC improved the functional outcome significantly in an experimental ICH model. This effect was achieved by stimulation of endogenous progenitor cells rather than integration and differentiation of the infused PLA-MSC.

Background and Purpose: Occlusion of the internal carotid artery (ICA) and stroke may be the consequence of either local thrombosis due to atherosclerosis or massive embolism. Up to date, there are only few reports of subsequent recanalization., Methods: We report 12/76 cases of acute ICA occlusion leading to ischemic stroke, in which early recanalization was identified. Ultrasound and stroke MRI findings, therapeutic options, and outcome are described., Results: 10/12 patients showed an- or hypoechogenic morphology of occlusion. While in 7/12 cases complete recanalization was seen, in 5/12 patients partial recanalization with filiform flow (4) or residual high-grade stenosis (1) was detected. 10/12 patients had territorial or subcortical infarction, while two showed small cortical lesions only. In 7/12 cases, a potential cardiac source of embolism was found. Five patients received tPA; four patients underwent early carotid endarterectomy of the partially recanalized ICA within 48 hours. In the 10-day follow-up examination 10/12 patients showed clinical improvement as measured by the NIHSS., Conclusions: Spontaneous recanalization after occlusion of the ICA may occur and might be more frequent than hitherto assumed. Echogenicity analysis and serial examinations of symptomatic ICA occlusion is useful for identifying a patient subgroup that might benefit from further therapy.

Background: Matrix metalloproteinases (MMP) are expressed after ischemic stroke. These proteases are responsible for a higher incidence of hemorrhages, are correlated to size of infarction and influence the effects of recombinant tissue plasminogen activator treatment. We therefore evaluated single nucleotide polymorphisms (SNP) of MMP-2 in different subtypes of stroke patients in an association study using a case-control design., Methods: 197 stroke patients were divided according to modified TOAST criteria (small vessel disease, large vessel disease, hemorrhagic stroke and asymptomatic carotid artery stenosis) and compared to 143 controls. Clinical data like age, sex, risk factors and diagnostic results including MRI or cranial CT scans and ultrasound evaluations of intra- and extracranial arteries were obtained. Genotypes of MMP-2 (12 SNP) were compared to controls and DNA samples were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Logistic regression analysis was performed for small vessel disease to test for interactions between markers and defined clinical risk factors. Additionally, MMP-2 serum levels obtained in the first 24 h after stroke were measured., Results: From the MMP-2 gene, 5 markers (rs1030868, rs2241145, rs2287074, rs2287076, rs7201) showed a significant association with small vessel infarcts (p < 0.05) and rs7201:g.C was identified as an independent risk factor by multivariable logistic regression analysis. MMP-2 protein levels were significantly lower in this group (174 +/- 48 ng/dl) versus controls (214 +/- 56 ng/dl). For other stroke subtypes, no significant association with MMP-2 SNP could be found., Conclusion: Our study demonstrates an association of the MMP-2 gene with the development of lacunar stroke, and no association of MMP-2 with other stroke subtypes., ((c) 2008 S. Karger AG, Basel.)

Biological markers play an evolving role in the diagnosis of Alzheimer disease (AD). We compare conventional measurements of cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) proteins to a novel approach - Fourier transformed infrared (FT-IR) spectroscopy - a simple technique derived from chemical and physical sciences that characterizes intramolecular bonds. For automatic diagnostic analysis, we developed an artificial neural network (ANN). We examined 71 patients with a clinical diagnosis of AD and 66 controls. beta-Amyloid(1-42) was decreased (sensitivity 80% and specificity 78%); tau was elevated (sensitivity 76% and specificity 88%) in CSF of AD patients. The combined tau/beta-amyloid(1-42) quotient was able to distinguish healthy from diseased subjects with 99% sensitivity and 86% specificity. The ANN could separate FT-IR spectroscopy data with 88.5% sensitivity and 80% specificity. FT-IR spectroscopy proved to be cost-effective and simple to perform. Diagnostic sensitivity and specificity is in the range of CSF tau and beta-amyloid(1-42) protein analysis. Larger sample numbers for ANN training and validation could increase diagnostic accuracy and thus prove to be a useful screening tool.

Background and Purpose: Molecular imaging of therapeutic interventions with targeted agents that simultaneously carry drugs or genes for local delivery is appealing. We investigated the ability of a novel microbubble carrier (immunobubble) for abciximab, a glycoprotein IIb/IIIa receptor inhibitor, for ultrasonographic molecular imaging of human clots., Methods: Human thrombi were incubated with immunobubbles conjugated with abciximab. Control clots were incubated in either saline or with immunobubbles conjugated with nonspecific antibody. We evaluated immunobubble suspensions with variable concentrations of encapsulated gas and measured mean acoustic intensity of the incubated clots. In vivo molecular imaging of human thrombi with abciximab immunobubbles was evaluated in a rat model of carotid artery occlusion., Results: Mean acoustic intensity was significantly higher for abciximab immunobubbles as compared with control immunobubbles under all conditions tested with maximum difference in intensity at a gas volume of 0.2 microL (P=0.0013 for mechanical index 0.05, P=0.0001 for mechanical index 0.7). Binding of abciximab immunobubbles to clots in vitro led to enhanced echogenicity dependent on bubble concentration. In vivo ultrasonic detectability of carotid thrombi was significantly higher for clots targeted with abciximab immunobubbles (P<0.05). Quantification of in vivo contrast enhancement displayed a highly significant increment for abciximab immunobubble-targeted clots compared with nonspecific immunobubble-targeted clots (P<0.0001) and to native clots (P<0.0001)., Conclusions: This study demonstrates the feasibility of using a therapeutic agent for selective targeting in vascular imaging. Abciximab immunobubbles improve visualization of human clots both in vitro and in an in vivo model of acute arterial thrombotic occlusion.

Objectives: Cell tracking using ultrasmall iron particles is well established in magnetic resonance imaging (MRI). However, in experimental models, intrinsic iron signals derived from erythrocytes mask the labeled cells. Therefore, we evaluated Gadofluorine M with other gadolinium chelates for a T1-weighted positive enhancement for cell tracking in vitro. In addition, Gadofluorine M was tested in vivo., Material and Methods: Gadofluorine M and other gadolinium chelates were used to label stem cells with and without uptake-mediating agents in vitro and in vivo using a 1.5 T MRI. In addition, histology and molecular modeling was investigated., Results: Gadofluorine M revealed comparable properties to an uptake mediating agent in molecular modeling. Without an uptake-mediating agent Gadofluorine M-labeled cells were detected as a T1-weighted positive contrast in vitro and in vivo. Histology confirmed a 100% success rate for intracellular labeling., Conclusion: This study describes a novel contrast agent with the capability of intracellular accumulation without an uptake mediator providing a T1-positive MRI signal at 1.5 T and may be suitable for cell tracking in animal models with intraparenchymal hemorrhages such as stroke or malignant tumors.

Microbubble-enhanced sonothrombolysis (MEST) may be an alternative therapeutic option in ischemic stroke. Clinical study of the efficacy of MEST as an adjunct stroke therapy, before imaging with CT or MRI, requires experimental data on the safety of this approach in the presence of hemorrhagic stroke. We, therefore, investigated the effect of diagnostic transcranial ultrasound combined with microbubbles (US + MB) in an experimental animal model of intracerebral hemorrhage (ICH). ICH was induced in anesthetized rats by intracerebral collagenase injection. Transcranial ultrasound (2 MHz, mechanical index 1.3, 1051 kPa) was applied 3 h after ICH induction to rat brains for 30 min during a continuous IV infusion of sulfur hexafluoride microbubbles (SonoVue). The size of cerebral hemorrhage, the extent of brain edema, and the amount of apoptosis were compared with those from control rats with ICH but without US + MB. Results showed no significant effect of US + MB on hemorrhage size (control 23.3 +/- 10.7 mm(3), US + MB 20.3 +/- 5.8 mm(3)), on the extent of brain edema (control 3.3 +/- 2.0%, US +MB 3.5 +/- 1.9%), or on the rate of apoptosis (control 5.2 +/- 1.5%, US + MB 5.2 +/- 1.0%). We conclude that diagnostic ultrasound in combination with microbubbles does not cause additional damage to the rat brain during ICH in our experimental set-up. This finding provides support for the use of MEST as an early stroke therapy.

Objective: The aim of this study was to evaluate number and kind of neurological patients in comparison with other patients on a medical ICU., Methods: Over a period of one year, all neurological intensive care patients on a medical ICU were evaluated according to age, sex, diagnosis, mortality, diagnostic methods, ventilation and referral to other hospitals and general wards., Results: Comparable to a specialist neurological ICU a wide spectrum of neurological diseases could be observed on an interdisciplinary ICU. In comparison to other patient groups, patients with neurological disease had a higher rate of ventilation, a longer hospital stay and a higher mortality., Conclusion: Our data also demonstrate the relevant amount of neurological patients (19 % measured by bed assignment) in comparison to all patients, and the specific neurological procedures were applicable on a medical/interdisciplinary ICU. A higher interest for neurological patient on a medical ICU would therefore be essential.

Neuroendocrine (NE) tumor cells in prostatic carcinoma (PCa) may influence tumor proliferation by a paracrine stimulus. The role of NE tumor cells is discussed controversially. This study investigates the influence of NE tumor differentiation on proliferation in PCa. Neuroendocrine differentiation, Ki-67, and Polo-like kinase 1 were studied immunohistochemically in 73 consecutive prostatectomies. Polo-like kinase 1 (PLK1) expression was also studied by Western and Northern blot analysis. Tumors were classified as high NE (HNE) and low NE differentiated (LNE), and depending on the growth pattern, with solitary and clusters of NE tumor cells. Low NE differentiated tumors were defined as less than 30 and HNE as 30 or more NE tumor cells per hot spot. Patients were followed by serum prostate-specific antigen (PSA) analysis. Neuroendocrine differentiation was present at least focally in 70% of tumors; 57% were HNE and 43% LNE. Solitary NE tumor cells were more often found in low-grade PCa, whereas clusters of NE tumor cells were more frequent in high-grade PCa. PLK1 messenger RNA and protein as well as Ki-67 were overexpressed in tumor tissue compared with tumor-free tissue. A stronger proliferation as determined by Ki-67 and PLK1 expression was present in HNE tumors compared with LNE tumors and in tumors with clusters in contrast to tumors with solitary NE tumor cells. Analysis for PSA relapse-free survival showed an earlier progression in HNE than in LNE tumors and in PCa with clusters of NE tumor cells. A significant and clustered NE differentiation in PCa may lead to an increased proliferation and earlier tumor progression, whereas few and solitary NE tumor cells have no prognostic impact.

Matrix metalloproteinases are important factors for tissue remodelling and are activated during several physiological and pathological conditions, including cerebrovascular diseases. We give an overview of the structure, production and physiological effects of these widely distributed proteases and describe the genetic background and regulation pathways. In particular, we discuss the role of matrix metalloproteinases in vascular remodelling concerning ischaemic stroke, brain haemorrhage, vascular dementia, carotid artery plaques and cerebral aneurysms., (Copyright (c) 2005 S. Karger AG, Basel.)