Partial characterization of apoptotic factor in Alzheimer plasma.
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We have previously demonstrated that a plasma natriuretic factor is present in Alzheimer's disease (AD), but not in multi-infarct dementia (MID) or normal controls (C). We postulated that the natriuretic factor might induce the increased cytosolic calcium reported in AD by inhibiting the sodium-calcium antiporter, thereby activating the apoptotic pathway. To test for a factor in AD plasma that induces apoptosis, we exposed nonconfluent cultured LLC-PK1 cells to plasma from AD, MID, and C for 2 h and performed a terminal transferase-dUTP-nick-end labeling (TUNEL) assay. The plasma from AD increased apoptosis nearly fourfold compared with MID and C. The effect was dose dependent and the peak effect was attained after a 2-h exposure. Additionally, apoptotic morphology was detected by electron microscopy, and internucleosomal DNA cleavage was found. We inhibited apoptosis by removing calcium from the medium, inhibiting protein synthesis with cycloheximide, alternately boiling or freezing and thawing the plasma, and digesting a partially purified fraction with trypsin. Heating AD plasma to 56 degrees C did not deactivate the apoptotic factor. These results demonstrate the presence of an apoptotic factor in the plasma of patients with AD. (+info)
Should computed tomography appearance of lacunar stroke influence patient management?
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Patients with a lacunar stroke syndrome may have cortical infarcts on brain imaging rather than lacunar infarcts, and patients with the clinical features of a small cortical stroke (partial anterior circulation syndrome, PACS) may have lacunar infarcts on imaging. The aim was to compare risk factors and outcome in lacunar syndrome (LACS) with cortical infarct, LACS with lacunar infarct, PACS with cortical infarct, and PACS with lacunar infarct to determine whether the clinical syndrome should be modified according to brain imaging. As part of a hospital stroke registry, patients with first ever stroke from 1990 to 1998 were assessed by a stroke physician who assigned a clinical classification using clinical features only. A neuroradiologist classified recent clinically relevant infarcts on brain imaging as cortical, posterior cerebral artery territory or lacunar. Of 1772 first ever strokes, there were 637 patients with PACS and 377 patients with LACS who had CT or MRI. Recent infarcts were seen in 395 PACS and 180 LACS. Atrial fibrillation was more common in PACS with cortical than lacunar infarcts (OR 2.3, 95% confidence interval (95% CI) 0.9-5.5), and in LACS with cortical than lacunar infarcts (OR 3.9, 1.2-12). Severe ipsilateral carotid stenosis or occlusion was more common in PACS with cortical than lacunar infarcts (OR 3.5, 1.3-9.5); and in LACS with cortical than lacunar infarcts (OR 3.7, 1.1-12). In conclusion, patients with cortical infarcts are more likely to have severe ipsilateral carotid stenosis or atrial fibrillation than those with lacunar infarcts irrespective of the presenting clinical syndrome. Brain imaging should modify the clinical classification and influence patient investigation. (+info)
Distinguishing primary angiitis of the central nervous system from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: the importance of family history.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetically linked neurologic disease characterized by recurrent strokes and progressive or stepwise dementia, with or without migraine-like headaches, seizures, and pseudobulbar palsy. We describe a patient referred with a diagnosis of treatment-refractory primary angiitis of the central nervous system. Meningocortical and skin biopsies confirmed that the patient had CADASIL. Clinical and radiographic differences in these disorders may be subtle, but awareness of them is crucial if the patient is to avoid unnecessary exposure to potentially deleterious immunosuppressive therapy. (+info)
Clinical severity in CADASIL related to ultrastructural damage in white matter: in vivo study with diffusion tensor MRI.
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BACKGROUND AND PURPOSE: CADASIL is a newly recognized cause of subcortical ischemic strokes that progressively leads to dementia associated with pseudobulbar palsy and severe motor disability. This deleterious progression and the severity of clinical presentation are widely variable among affected subjects. The exact role played by MRI white-matter abnormalities, a hallmark of the disease, in the severity of the clinical phenotype remains poorly understood. METHODS: To address this issue, we used diffusion tensor imaging (DTI), a new MRI technique highly sensitive to white-matter microstructural changes, in 16 symptomatic patients and 10 age-matched controls. Mean diffusivity and anisotropy of diffusion were measured within hyperintensities identified on T2-weighted images (T2WI) and outside these lesions on 4 slices at the level of centrum semiovale. RESULTS: We found a 60% increase of water mean diffusivity and a parallel loss of diffusion anisotropy in hyperintensities identified on T2WI. The same pattern of diffusion changes, but of lesser intensity, was found in the normal-appearing white matter on T2WI. Mean diffusivity in regions with increased signal on T2WI was higher in patients with severe clinical disability compared with those with no or mild deficit (1.33+/-0.11 versus 1.13+/-0.11 10(-3) mm(2)/s, P<0.01). Furthermore, diffusion measured within T2 hyperintensities correlated with both the Mini-Mental State Examination and Rankin scale scores. In patients with a severe clinical status, the increase of water diffusion in these regions exceeded 70% in comparison with values obtained in the normal white matter in control subjects. CONCLUSIONS: These results indicate that DTI is able to detect important ultrastructural changes in regions with increased signal on T2WI and within the normal-appearing white matter in CADASIL. The diffusion changes might be related to both neuronal loss and demyelination. The degree of the underlying ultrastructural alterations is related to the severity of the clinical status with a possible threshold level of white-matter damage above which severe neurological impairment may occur in this disease. DTI appears to be a promising technique for monitoring disease progression in CADASIL. (+info)
The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients.
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Mutations in Notch3 cause CADASIL (cerebral autosomal dominant adult onset arteriopathy), which leads to stroke and dementia in humans. CADASIL arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits. Patients carry highly stereotyped mutations that lead to an odd number of cysteine residues within EGF-like repeats of the Notch3 receptor extracellular domain. Such mutations may alter the processing or the trafficking of this receptor, or may favor its oligomerization. In this study, we examined the Notch3 expression pattern in normal tissues and investigated the consequences of mutations on Notch3 expression in transfected cells and CADASIL brains. In normal tissues, Notch3 expression is restricted to vascular smooth muscle cells. Notch3 undergoes a proteolytic cleavage leading to a 210-kDa extracellular fragment and a 97-kDa intracellular fragment. In CADASIL brains, we found evidence of a dramatic and selective accumulation of the 210-kDa Notch3 cleavage product. Notch3 accumulates at the cytoplasmic membrane of vascular smooth muscle cells, in close vicinity to but not within the granular osmiophilic material. These results strongly suggest that CADASIL mutations specifically impair the clearance of the Notch3 ectodomain, but not the cytosolic domain, from the cell surface. (+info)
Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains.
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CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations. (+info)
Corpus callosum atrophy in patients with leukoaraiosis may indicate global cognitive impairment.
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BACKGROUND AND PURPOSE: The extent of white matter high-intensity lesions (WMLs) on T2-weighted MR images may be an indicator of cognitive impairment, especially impairment related to frontal lobe dysfunction. However, it is unclear whether the extent of WMLs is an independent predictor of cognitive impairment. In patients with extensive WMLs, atrophy of the corpus callosum may be an important predictor of global cognitive impairment. The purpose of this study was to investigate the relation of the extent of WMLs and callosal size with cognitive functions in a patient population with a wide range of extent of WMLs. METHODS: We studied 62 patients, aged 49 to 86 years, who underwent MRI because of neurological symptoms and were diagnosed as having lacunar stroke or no specific neurological disease: 28 with lacunar infarcts and 34 without. Multivariate analysis was used to test the independent predictive value of patient age, sex, educational level, other medical illness, lacunar infarct, corpus callosum area, and extent of WMLs with respect to scores of Mini-Mental State Examination or verbal fluency task. RESULTS: Only callosal size and age were significant independent predictors of the scores of the Mini-Mental State Examination, while only the extent of WMLs was an independent predictor of the score of the verbal fluency task. CONCLUSIONS: Callosal atrophy may be an important predictor of global cognitive impairment in patients with WMLs, whereas the extent of WMLs per se may be related to impairment of frontal lobe function independent of callosal atrophy. (+info)
Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking.
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BACKGROUND: White matter lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are underlaid by severe ultrastructural changes of the arteriolar wall. Although chronic ischemia is presumed to cause the tissue lesions, the pattern of perfusion abnormalities and hemodynamic reserve in CADASIL, particularly within the white matter, remains unknown. METHODS: We used the MRI bolus tracking method in 15 symptomatic patients with CADASIL (5 with dementia) and 10 age-matched control subjects before and 20 minutes after the intravenous injection of acetazolamide (ACZ, 17 mg/kg). Cerebral blood flow (CBF), blood volume (CBV), and mean transit time (MTT) were calculated both in the cortex and in the white matter according to the singular value decomposition technique. Perfusion parameters were obtained in regions of hyperintensities and within the normal-appearing white matter as observed on T2-weighted images. Analysis was performed with both absolute and relative (region/whole brain) values. RESULTS: A significant reduction in absolute and relative CBF and CBV was found within areas of T2 hyperintensities in white matter in the absence of significant variations of MTT. This reduction was more severe in demented than in nondemented patients. No significant change in absolute CBF and CBV values was observed in the cortex of patients with CADASIL. A decrease in relative CBF and CBV values was detected in the occipital cortex. After ACZ administration, CBF and CBV increased significantly in both the cortex and white matter of affected subjects, but the increase in absolute CBF was lower within areas of increased signal on T2-weighted images in patients than in the white matter of control subjects. CONCLUSIONS: In CADASIL, both basal perfusion and hemodynamic reserve are decreased in areas of T2 hyperintensities in the white matter. This hypoperfusion appears to be related to the clinical severity. The significant effect of ACZ on CBF and CBV suggests that cerebral perfusion might be increased using pharmacological vasodilation in CADASIL. (+info)