Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker.

Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y(685), a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p ≤ 0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology.

Hidden dysfunctioning in subacute stroke.

BACKGROUND AND PURPOSE: Determining cognitive dysfunctioning (CDF) after stroke is an important issue because it influences choices for management in terms of return to previous activities. Because previous research in subacute stroke has shown important variations in CDF rates, we aimed to describe the frequency and neuropsychological profile of CDF in subacute stroke outside dementia. We used a large battery of tests to screen any potentially hidden CDF. METHODS: Patients with Mini-Mental State Examination scores >or=23 were prospectively and consecutively included 2 weeks after a first-ever ischemic brain infarct. Stroke features were based on MRI. Four domains were evaluated: instrumental and executive functions, episodic memory, and working memory (WM). Patients were scored using means and compared with education- and age-matched control subjects. Then we attributed Z-scores for each test and each domain. The most relevant cognitive tests characterizing CDF were determined using logistic regression. RESULTS: Among 177 patients (mean age, 50.6 years), 91.5% failed in at least one cognitive domain. WM was the most impaired domain (87.6%) with executive functions (64.4%), episodic memory (64.4%), and instrumental functions (24.9%) being relatively preserved. CDF was associated with age, education, depression, neurological deficit, and leukoaraiosis in bivariate analysis. Using logistic regression, WM tests and age predicted CDF (Modified Paced Auditorial Serial Addition Test: OR=0.96 CI=0.93 to 0.98; Owen-spatial-WM: OR=1.07 CI=1.02 to 1.12; age: OR=0.96 CI=0.93 to 0.98). CONCLUSIONS: CDF appears to be almost constant, although underestimated, in subacute stroke. WM could reflect some hidden dysfunctioning, which may interfere with rehabilitation and return to work. Clinical routine may include WM tests in young patients with mild stroke.

Pretargeting for the implantation of stimulation electrodes into the subthalamic nucleus: a comparative study of magnetic resonance imaging and ventriculography.

OBJECTIVE: The optimal imaging modality for preoperative targeting of the subthalamic nucleus (STN) for high-frequency stimulation is controversially discussed. Commonly used methods were stereotactic magnetic resonance imaging (MRI), stereotactic ventriculography, and fusion between MRI and stereotactic computer tomography. All of these techniques not only have their own advantages but also specific limitations and drawbacks. The purpose of this study was to evaluate the accuracy of the preoperative MRI targeting as compared with ventriculography in terms of both the STN target as well as the internal landmarks. METHODS: Thirty patients with Parkinson's disease who underwent bilateral surgery for STN-high-frequency stimulation received both stereotactic ventriculography and stereotactic MRI. The theoretical target was determined by each of these two imaging modalities. The final electrode placement was performed after extensive electrophysiological evaluation using microrecording and microstimulation. The real target was assumed to be given by the electrode contact with the best clinical result assessed by the United Parkinson's Disease Rating Scale in the postoperative follow-up. In addition, the coordinates of the two landmarks, anterior commissure and posterior commissure, were determined using both imaging methods. RESULTS: The mean targeting error was 4.1 +/- 1.7 mm (mean +/- standard deviation) for MRI and 2.4 +/- 1.1 mm for ventriculography (P< 0.0001). The mean target mismatch between the two imaging methods was 2.9 +/- 1.2 mm. The length of the anterior commissure-posterior commissure distance differed significantly (P < 0.0001) between MRI (27.6 +/- 1.6 mm) and ventriculography (25.0 +/- 1.3 mm). The mismatch was mainly induced by an anterior displacement of the anterior commissure by 1.9 +/- 2.2 mm (P < 0.0001) in MRI determination, as compared with ventriculography. CONCLUSION: Our findings show that the indirect targeting of the STN using coordinates based on radiological landmarks is more accurate than the direct targeting using anatomic visualization of the target structure. Regardless of the imaging procedure, electrophysiological mapping is required for optimal electrode placement, although in 20% of cases, the target determined by MRI falls out of the radius explored by electrophysiology.

Glutamate measurement in Parkinson's disease using MRS at 3 T field strength.

Loss of nigral dopamine neurons in Parkinson's disease induces abnormal activation of glutamate systems in the basal ganglia. The purpose of this study was to assess these changes in the lentiform nucleus using MRS with optimized glutamate sensitivity (TE-averaged method). Ten patients with Parkinson's disease and 10 healthy controls were examined. Compared with healthy controls, no significant differences in glutamate were measured in patients, but a trend to lower total creatine was observed.

Pretargeting for the implantation of stimulation electrodes into the subthalamic nucleus: a comparative study of magnetic resonance imaging and ventriculography.

OBJECTIVE: The optimal imaging modality for preoperative targeting of the subthalamic nucleus (STN) for high-frequency stimulation is controversially discussed. Commonly used methods were stereotactic magnetic resonance imaging (MRI), stereotactic ventriculography, and fusion between MRI and stereotactic computer tomography. All of these techniques not only have their own advantages but also specific limitations and drawbacks. The purpose of this study was to evaluate the accuracy of the preoperative MRI targeting as compared with ventriculography in terms of both the STN target as well as the internal landmarks. METHODS: Thirty patients with Parkinson's disease who underwent bilateral surgery for STN-high-frequency stimulation received both stereotactic ventriculography and stereotactic MRI. The theoretical target was determined by each of these two imaging modalities. The final electrode placement was performed after extensive electrophysiological evaluation using microrecording and microstimulation. The real target was assumed to be given by the electrode contact with the best clinical result assessed by the United Parkinson's Disease Rating Scale in the postoperative follow-up. In addition, the coordinates of the two landmarks, anterior commissure and posterior commissure, were determined using both imaging methods. RESULTS: The mean targeting error was 4.1 +/- 1.7 mm (mean +/- standard deviation) for MRI and 2.4 +/- 1.1 mm for ventriculography (P < 0.0001). The mean target mismatch between the two imaging methods was 2.9 +/- 1.2 mm. The length of the anterior commissure-posterior commissure distance differed significantly (P < 0.0001) between MRI (27.6 +/- 1.6 mm) and ventriculography (25.0 +/- 1.3 mm). The mismatch was mainly induced by an anterior diplacement of the anterior commissure by 1.9 +/- 2.2 mm (P < 0.0001) in MRI determination, as compared with ventriculography. CONCLUSION: Our findings show that the indirect targeting of the STN using coordinates based on radiological landmarks is more accurate than the direct targeting using anatomic visualization of the target structure. Regardless of the imaging procedure, electrophysiological mapping is required for optimal electrode placement, although in 20% of cases, the target determined by MRI falls out of the radius explored by electrophysiology.

Focal brain ischemia in rat: acute changes in brain tissue T1 reflect acute increase in brain tissue water content.

Several recent studies have reported changes of brain tissue T(1) in ischemic models during the first minutes after occlusion of the middle cerebral artery (MCA). In order to assess whether these tissue T(1) changes are related to an increase in tissue water content, we performed T(1) (7 T) and tissue water content measurements in a rat model (n = 10, Sprague-Dawley) of focal cerebral ischemia (intraluminal occlusion model). The tissue water content was determined using a gravimetric technique. The animals were divided into two groups: an ischemic group, with an effective MCA occlusion (n = 6) and a control group, with animals having undergone sham surgery but no MCA occlusion (n = 4). In the ipsilateral cortex, the tissue water content was 81.1 +/- 0.7% at 2 h 15 min following ischemic insult (contralateral value: 79.3 +/- 0.5%). Concomitantly, the tissue T(1) in the ipsilateral cortex was 2062 +/- 60 ms at ischemia onset + 1 h (contralateral 1811 +/- 28 ms) and 2100 +/- 38 ms at ischemia onset + 2 h (contralateral 1807 +/- 18 ms). The tissue T(1) and tissue water content values measured in the contralateral area do not differ from the values obtained in the control group. A significant T(1) increase is observed at ischemia onset + 1 h (+ 14%) and ischemia onset (+ 2 h) + 16%, together with a significant increase in tissue water content (+ 2.3%). This suggests that there is an increase in tissue water content concomitant with cell swelling during the first hours of ischemia.

Vicarious function within the human primary motor cortex? A longitudinal fMRI stroke study.

While experimental studies in the monkey have shown that motor recovery after partial destruction of the hand motor cortex was based on adjacent motor reorganization, functional MRI (fMRI) studies with isolated primary motor cortical stroke have not yet been reported in humans. Based on experimental data, we designed a study to test if recovery after stroke within primary motor cortex (M1) was associated with reorganization within the surrounding motor cortex, i.e. the motor cortex was able to vicariate. Since motor recovery is time-dependent and might be inflected according to the tested task, the delay after stroke and two motor tasks were included in our design. We examined four patients with one ischaemic stroke limited to M1, and four sex- and age-matched healthy controls in a temporally balanced prospective longitudinal fMRI study over three sessions: <20 days, 4 months and 2 years after stroke. The paradigm included two motor tasks, finger tapping (FT) and finger extension (FE). Distinct patterns of motor activation were observed with time for FT and FE. At the first session, FT-related activation was lateralized in the ipsilateral hemisphere while FE-related activation was contralateral, involving bilateral cerebellar regions for both tasks. From 4 months, skilled motor recovery was associated with contralateral dorsal premotor and sensorimotor cortex and ipsilateral cerebellum motor-related activations, leading to lateralized motor patterns for both tasks. For the left recovered hand, FT and FE-related activations within M1 were more dorsal in patients than in controls. This dorsal shift progressively increased over 2 years, reflecting functional reorganization in the motor cortex adjacent to the lesion. In addition, patients showed a reverse representation of FT and FE within M1, corresponding to a greater dorsal shift for FT than for FE. This functional dissociation might reflect the structural subdivision of M1 with two distinct finger motor representations within M1. Recovery of FT, located within the lesioned depth of the rolandic sulcus in controls, might be related to the re-emergence of a new representation in the intact dorsal M1, while FE, located more dorsally, underwent minor reorganization. This is the first fMRI study of humans presenting with isolated M1 stroke comparable with experimental lesions in animals. Despite the small number of patients, our findings showing the re-emergence of a fingers motor task in the intact dorsal M1 instead of in ventral M1 are consistent with 'vicariation' models of stroke recovery.

Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease.

BACKGROUND: Although the short-term benefits of bilateral stimulation of the subthalamic nucleus in patients with advanced Parkinson's disease have been well documented, the long-term outcomes of the procedure are unknown. METHODS: We conducted a five-year prospective study of the first 49 consecutive patients whom we treated with bilateral stimulation of the subthalamic nucleus. Patients were assessed at one, three, and five years with levodopa (on medication) and without levodopa (off medication), with use of the Unified Parkinson's Disease Rating Scale. Seven patients did not complete the study: three died, and four were lost to follow-up. RESULTS: As compared with base line, the patients' scores at five years for motor function while off medication improved by 54 percent (P<0.001) and those for activities of daily living improved by 49 percent (P<0.001). Speech was the only motor function for which off-medication scores did not improve. The scores for motor function on medication did not improve one year after surgery, except for the dyskinesia scores. On-medication akinesia, speech, postural stability, and freezing of gait worsened between year 1 and year 5 (P<0.001 for all comparisons). At five years, the dose of dopaminergic treatment and the duration and severity of levodopa-induced dyskinesia were reduced, as compared with base line (P<0.001 for each comparison). The average scores for cognitive performance remained unchanged, but dementia developed in three patients after three years. Mean depression scores remained unchanged. Severe adverse events included a large intracerebral hemorrhage in one patient. One patient committed suicide. CONCLUSIONS: Patients with advanced Parkinson's disease who were treated with bilateral stimulation of the subthalamic nucleus had marked improvements over five years in motor function while off medication and in dyskinesia while on medication. There was no control group, but worsening of akinesia, speech, postural stability, freezing of gait, and cognitive function between the first and the fifth year is consistent with the natural history of Parkinson's disease.