Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia.
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Leptomeningeal glioneuronal heterotopias are a focal type of cortical dysplasia in which neural cells migrate aberrantly into superficial layers of the cerebral cortex and meninges. These heterotopias are frequently observed as microscopic abnormalities in the brains of individuals with central nervous system (CNS) malformations and epilepsy. Previous work has demonstrated that the function of Emx2, which encodes a homeodomain transcription factor, is essential for development of the cortical preplate, which gives rise to the marginal zone and subplate. However, transcriptional targets of EMX2 during CNS development are unknown. We report that leptomeningeal glioneuronal heterotopias form in Emx2(-/-) mice that are equivalent to human lesions. Additionally, we observed ectopic expression of Wnt1 in the embryonic roofplate organizer region and dorsal telencephalon. To determine the phenotypic consequences of such Wnt1 misexpression, we deleted a putative EMX2 DNA-binding site from the Wnt1 enhancer and used this to misexpress Wnt1 in the developing murine CNS. Heterotopias were detected in transgenic mice as early as 13.5 days postcoitum, consistent with a defect of preplate development during early phases of radial neuronal migration. Furthermore, we observed diffuse abnormalities of reelin- and calretinin-positive cell populations in the marginal zone and subplate similar to those observed in Emx2-null animals. Taken together, these findings indicate that EMX2 is a direct repressor of Wnt1 expression in the developing mammalian telencephalon. They further suggest that EMX2-Wnt1 interactions are essential for normal development of preplate derivatives in the mammalian cerebral cortex. (+info)
Pre- and post-treatment MR imaging and single photon emission CT in patients with dural arteriovenous fistulas and retrograde leptomeningeal venous drainage.
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BACKGROUND AND PURPOSE: Dural arteriovenous fistulas (DAVFs) with disturbed regional cerebral blood flow (rCBF) include retrograde leptomeningeal venous drainage (RLVD). We examined rCBF disturbances in patients with DAVFs by studying MR imaging and single photon emission CT (SPECT) changes before and after treatment. METHODS: In 22 patients with DAVFs and RLVD, we studied their symptoms, pre- and post-treatment MR imaging and SPECT findings, and treatment results. Patients were assigned to two groups: Type 1 included those with RLVD into more than one venous sinus, and type 2, those with RLVD into a single venous sinus. RESULTS: Eleven patients had type 1 RLVD. In these patients, preoperative T2-weighted MR images showed no hyperintense areas, and angiographic evidence showed flow into more than one venous sinus. The other 11 patients had type 2 RLVD. In these patients, preoperative SPECT demonstrated hypoperfused areas that coincided with hyperintense areas on T2-weighted MR images. After treatment, the hyperintense areas disappeared, and symptoms improved in seven of these patients (type 2a). Their preoperative SPECT studies demonstrated preservation of vasoreactivity after an acetazolamide challenge. In the other four patients (Type 2b), the hyperintense areas and symptoms persisted after treatment. Their preoperative SPECT studies revealed a marked disturbance of vasoreactivity. CONCLUSION: In patients with drainage into a single venous sinus, we consistently observed areas of hyperintensity on MR images. These results and findings of hypoperfusion on SPECT scans apparently reflect venous congestion, whereas unpreserved vasoreactivity after an acetazolamide challenge on SPECT scans reflects venous infarction. The preservation of vasoreactivity after the challenge appears to be a good prognostic indicator. (+info)
Angiographic features of spontaneous intracranial hypotension.
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The imaging characteristics of spontaneous intracranial hypotension have been well described in the clinical and imaging literature. We present a case of spontaneous intracranial hypotension with typical clinical and laboratory features that were thought to be suspicious for a ruptured aneurysm. Blood in the CSF in conjunction with headaches led to cerebral angiography that showed diffuse enlargement of cortical and medullary veins. The angiographic findings were diagnostic of spontaneous intracranial hypotension and consistent with the Monro-Kellie hypothesis. (+info)
Contrast-enhanced fluid-attenuated inversion recovery imaging for leptomeningeal disease in children.
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BACKGROUND AND PURPOSE: To develop an MR imaging method that improves detection of leptomeningeal disease when compared with the current reference standard, contrast-enhanced T1-weighted imaging. METHODS: We investigated the cases of 10 children who were at high risk of intracranial leptomeningeal disease (Sturge-Weber syndrome and medulloblastoma). The cases of Sturge-Weber syndrome were investigated by using one MR imaging examination, and the cases of medulloblastoma were investigated by using four MR imaging examinations performed over 18 months. In all cases, contrast-enhanced fluid-attenuated inversion recovery (FLAIR) images were acquired in addition to the routine sequences. The parameters of the FLAIR sequence were chosen to maximize the T1 component of the signal intensity, to maximize detection of leptomeningeal enhancement. We made subjective and objective assessments of the presence and extent of leptomeningeal disease as shown on contrast-enhanced T1-weighted images and contrast-enhanced FLAIR images. RESULTS: In three of the four cases of Sturge-Weber syndrome, the T1 and FLAIR sequences showed comparable extent of leptomeningeal enhancement. For one child, FLAIR images showed unexpected bilateral disease and more extensive leptomeningeal enhancement on the clinically suspected side. In four of six cases of medulloblastoma, no leptomeningeal enhancement was shown on any examinations during the 18-month period. In two cases, FLAIR images showed more extensive leptomeningeal enhancement when compared with T1-weighted images. CONCLUSION: Contrast-enhanced FLAIR imaging seems to improve detection of leptomeningeal disease when compared with routine contrast-enhanced T1-weighted imaging. This seems to be partly because of suppression of signal intensity from normal vascular structures on the surface of the brain by FLAIR, which allows easier visualization of abnormal leptomeninges. We think that these findings can be extrapolated to the investigation of leptomeningeal disease of all causes and at all ages. (+info)
A 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion.
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Amyloid beta (A beta), the major constituent of the fibrils composing senile plaques and vascular amyloid deposits in Alzheimer's disease (AD) and related disorders, is a 39-42-residue self-aggregating degradation peptide of a larger multidomain membrane glycoprotein designated amyloid precursor protein (APP). An array of biological functions has been assigned to different APP domains, including growth regulation, neurotoxicity, inhibitory activity of serine proteinases and promotion of cell-cell and cell-matrix interactions. A beta is generated through an as-yet-unknown catabolic pathway that by-passes or inhibits the cleavage of APP within the A beta sequence. We have identified a 16 kDa intermediate APP C-terminal fragment containing A beta in leptomeningeal vessels of aged normal individuals and AD patients by means of its immunoreactivity with a panel of four different anti-(APP C-terminal) antibodies, indicating a different pathway of APP processing. Previous studies have indicated that the APP C-terminal domain is the most likely to be involved in cell-matrix interactions. A 109-amino-acid construct C109 with a sequence analogous to the C-terminal of APP (positions 587-695 of APP695), similar in length and immunoreactivity to the 16 kDa fragment, was found to promote cell adhesion. By use of synthetic peptides, this activity was initially located to the extracellular 28 residues of A beta. Inhibition studies demonstrated that the sequence RHDS (amino acids 5-8 of A beta, corresponding to residues 601-604 of APP695 was responsible for the adhesion-promoting activity. The interaction is dependent on bivalent cations and can be blocked either by the tetrapeptides RHDS and RGDS or by an anti-(beta 1 integrin) antibody. Thus, through integrin-like surface receptors, APP or its derivative proteolytic fragments containing the sequence RHDS may modulate cell-cell or cell-matrix interactions. (+info)
The delayed perfusion sign at MRI.
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PURPOSE: Effective collateral blood flow seem to be an important factor associated with a small infarct volume and a good clinical outcome. We aimed to assess leptomeningeal collateral blood flow on source perfusion-weighted images in patients with acute stroke. MATERIALS AND METHODS: 29 patients with proximal middle cerebral artery occlusion (MCA alone, n=17; MCA + internal carotid artery [ICA] occlusion, n=12) were evaluated with MRI at baseline before thrombolytic therapy, and at day 60. Clinical evaluation was performed at days 0 and 60 with the National Institutes of Health Stroke Scale (NIHSS) score, and at day 60 with the modified Rankin score. We assessed (on source images of the dynamic contrast-enhanced T2*-weighted perfusion [PWI] sequence) the presence of a hypointensity consistent with delayed contrast arrival within the global perfusion deficit (delayed perfusion sign). We analyzed the extent of the area demonstrating such delayed perfusion (DP area) on source images of the PWI sequence, and compared it with the global perfusion (GP) abnormality shown by time-to-peak maps. We calculated the Spearman rank correlation coefficient between the DP/GP ratio and: 1. age; 2. clinical scores; 3. site of occlusion [MCA alone versus ICA+MCA occlusion]; 4. DWI lesion size at day 0, and T2WI lesion size at day 60; 5. PWI-derived parameters (time-to-peak [TTP], relative cerebral blood volume [rCBV], relative cerebral blood flow [rCBF], and peak height). All tests were bilateral and a p value<0.05 was considered as significant. RESULTS: Delayed perfusion areas of various size were found within the global perfusion deficit in all patients. High DP/GP ratio values were significantly correlated with: 1. better clinical scores at day 0 and day 60 (all p<=0.04); 2. smaller lesions at day 0 DWI and at day 60 T2WI (all p<=0.004); 3. ICA patency (r=0.49, p=0.01); 4. lower TTP delays, and higher values of rCBV, rCBF, and peak height. CONCLUSION: These preliminary data suggest that a delayed contrast filling observed on native perfusion-weighted images may be a marker of leptomeningeal collateral blood flow, and may lead to better clinical and morphological outcomes in acute ischemic stroke. (+info)
Spontaneous intracranial hypotension in a patient with reversible pachymeningeal enhancement and brain descent.
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A 56-year-old woman presented with severe orthostatic headache in association with nausea and vomiting. Lumbar puncture for the patient revealed significantly low cerebrospinal fluid pressure (CSF) and the clinical diagnosis of intracranial hypotension syndrome was made. An initial gadolinium-enhanced brain magnetic resonance imaging (MRI) disclosed diffuse meningeal enhancement as well as brain sagging. No definite CSF leakage was found using radionuclide cisternography. Her headaches abated with proper usage of analgesics, strict bed rest, and intravenous hydration. Follow-up neuroimaging studies showed partially resolved meningeal enhancement 2 months after treatment and complete resolution 6 months after treatment. The temporal changes found on MRI suggest that the pachymeningeal enhancement is reversible in patients with spontaneous intracranial hypotension. Moreover, proliferation of meninges is likely to be responsible for this type of delayed resolution phenomenon. (+info)
Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease.
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Alzheimer's disease (AD) is characterized by neurofibrillary tangles and by the accumulation of beta-amyloid (Abeta) peptides in senile plaques and in the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA). There also is a significant increase of interstitial fluid (ISF) in cerebral white matter (WM), the pathological basis of which is largely unknown. We hypothesized that the accumulation of ISF in dilated periarterial spaces of the WM in AD correlates with the severity of CAA, with the total Abeta load in the cortex and with Apo E genotype. A total of 24 AD brains and 17 nondemented age-matched control brains were examined. CAA was seen in vessels isolated from brain by using EDTA-SDS lysis stained by Thioflavin-S. Total Abeta in gray matter and WM was quantified by immunoassay, ApoE genotyping by PCR, and dilatation of perivascular spaces in the WM was assessed by quantitative histology. The study showed that the frequency and severity of dilatation of perivascular spaces in the WM in AD were significantly greater than in controls (P< 0.001) and correlated with Abeta load in the cortex, with the severity of CAA, and with ApoE epsilon4 genotype. The results of this study suggest that dilation of perivascular spaces and failure of drainage of ISF from the WM in AD may be associated with the deposition of Abeta in the perivascular fluid drainage pathways of cortical and leptomeningeal arteries. This failure of fluid drainage has implications for therapeutic strategies to treat Alzheimer's disease. (+info)