Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis

Joutel, Anne; Favrole, Pascal; Labauge, Pierre; Chabriat, Hugues; Lescoat, Christelle; Andreux, F.; Domenga, Valérie; Cécillon, Michaelle; Vahedi, Katayoun; Ducros, Anne; Cavé-Riant, Florence; Bousser, Marie Germaine; Tournier‐Lasserve, Elisabeth

doi:10.1016/s0140-6736(01)07142-2

Cited by 218 publications

(143 citation statements)

References 4 publications

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“…In CADASIL patients, an accumulation of the Notch3 protein is detected at the plasma membrane of VSMC, presumably related to altered clearance of the receptor (Joutel et al, 2001;Joutel and TournierLasserve 2002). In the vessel wall, the disease is characterized by a degeneration of VSMC and the presence of a granular osmiophilic material within the basement membrane (Joutel et al, 2000;Kalimo et al, 2002;Ruchoux et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Characteristic Features of in vivo Skin Microvascular Reactivity in CADASIL

Gobron

Vahedi

Vicaut

et al. 2006

J Cereb Blood Flow Metab

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CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is caused by mutations in the Notch3 receptor expressed at the surface of vascular smooth muscle cells. The functional consequences of the disease at the peripheral microcirculation level are incompletely elucidated. In this study, we aimed to assess, in vivo, the endotheliumdependent and independent vasodilation of the skin microvasculature in CADASIL patients. Twentythree affected subjects were compared with 23 gender and age-matched controls. The brachial artery endothelium-dependent and endothelium-independent vasodilation were assessed after forearm cuff occlusion and nitroglycerin administration. Skin vasoreactivity to transcutaneous administration of acetylcholine and sodium nitroprussiate, and after postocclusive hyperemia were measured by Laser Doppler flowmetry. The maximum changes in the diameter of the brachial artery after the cuff release or after nitroglycerin administration did not differ between patients and controls. With iontopheresis, only the peak value of the dose response was found decreased in normocholesterolemic patients after nitroprussiate administration. The postocclusive test revealed a large increase of the time to peak value and whole duration of the hyperemic response in CADASIL patients. The results of this study show that the skin vasoreactivity is altered in CADASIL. Particularly, the kinetics of reactive hyperemia after cuff occlusion is dramatically changed with a lengthened and delayed response. This characteristic pattern may be related to the specific ultrastructural modifications related to Notch3 gene mutations involving smooth muscle cells in the microvasculature.

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Section: Introductionmentioning

confidence: 99%

Characteristic Features of in vivo Skin Microvascular Reactivity in CADASIL

Gobron

Vahedi

Vicaut

et al. 2006

J Cereb Blood Flow Metab

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“…81,85 These findings have directed mechanistic studies to a neomorphic effect ( Figure 2B). A toxic gain-of-function mechanism is supported by the stereotyped nature of CADASIL mutations (see above) and by data showing that CADASIL-mutant NOTCH3 ECD aggregates accumulate in the extracellular space of small arteries, arterioles, and capillaries: First, ultrastructural examination of microvessels from CADASIL patients reveals pathognomonic granular osmiophilic material that locates to the vicinity of vascular smooth muscle cells and is NOTCH3-positive on immunogold labeling; 86 Second, NOTCH3 immunostaining of CADASIL microvessels reveals massive immunoreactivity that is specific for this condition; 87 Third, immunoblotting of brain homogenates as well as homogenates from isolated arteries demonstrates accumulation and aggregation of NOTCH3 ECD ; 86,88 And fourth, aggregation and accumulation of mutant NOTCH3 can be recapitulated in vitro using scanning for intensely fluorescent targets, a confocal method allowing the detection of single-protein particles in solution. When the multimerization behavior of NOTCH3-EGF 1-5 a fragment encompassing the mutational hot spot for disease-associated mutations, was analyzed, mutant NOTCH3 showed a much stronger tendency to self-aggregate than the wild-type protein.…”

Section: Cerebral Autosomal Dominant Arteriopathy With Subcortical Inmentioning

confidence: 90%

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Haffner

Malik

Dichgans

2015

J Cereb Blood Flow Metab

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Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

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“…Joutel et al (2001) introduced IHC as a diagnostic tool in CADASIL. In that study they showed in a cohort of 39 patients (23 patients, 16 controls) that sensitivity of N3ECD staining was 96% and specificity 100%.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Another study with a cohort of 41 NOTCH3 mutation carriers, 21 controls and 10 hereditary cerebral hemorrhage with amyloidosis-Dutch (HCHWA-D) patients reported sensitivity of 85.4-90.2% and specificity of 95.2-100% (Lesnik Oberstein et al, 2003). Both studies reported false negatives which were associated with mutations in exon 11 (Joutel et al, 2001, Lesnik Oberstein et al, 2003. In addition, nonspecific staining is an inherent caveat of IHC producing false positives (Lesnik Oberstein et al, 2003).…”

Section: Immunohistochemistrymentioning

confidence: 99%