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Hugues Chabriat - One of the best experts on this subject based on the ideXlab platform.
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the effect of notch3 pathogenic variant position on CADASIL disease severity notch3 egfr 1 6 pathogenic variant are associated with a more severe phenotype and lower survival compared with egfr 7 34 pathogenic variant
Genetics in Medicine, 2019Co-Authors: Julie W Rutten, Hugh S. Markus, Martin Dichgans, L. Pantoni, Antonio Federico, Bastian J Van Eijsden, Marco Duering, Eric Jouvent, Christian Opherk, Hugues ChabriatAbstract:CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7–34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7–34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1–6 pathogenic variant or an EGFr 7–34 pathogenic variant. The frequencies of NOTCH3 EGFr 1–6 and EGFr 7–34 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. CADASIL patients with an EGFr 1–6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7–34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1–6 pathogenic variant, whereas EGFr 7–34 pathogenic variant strongly predominate in the population. NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7–34 pathogenic variant predisposing to a later onset of stroke and longer survival.
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migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL
JAMA Neurology, 2004Co-Authors: Katayoun Vahedi, Anne Joutel, Hugues Chabriat, C Levy, Elisabeth Tournierlasserve, M G BousserAbstract:Background Migraine with aura (MA) is one of the clinical hallmarks of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease of the brain caused by mutations in the NOTCH3 gene, but its exact mechanisms are unknown. Objectives To describe the patterns of MA in CADASIL and to compare brain magnetic resonance signal abnormalities between CADASIL patients with and without MA. Design Comparison of brain magnetic resonance signal abnormalities between cases and controls. Setting Patients with CADASIL seen at Lariboisiere Hospital. Patients Forty-one CADASIL patients with MA and 31 age-matched CADASIL controls without MA. Results The mean age at onset of MA was significantly younger in women compared with men and occurred a mean of 15 years prior to stroke onset. A majority of patients (56%) reported at least 1 migraine attack with atypical aura. All CADASIL patients either with or without MA had white matter signal abnormalities on T2-weighted imaging. There was no difference in the frequency and distribution of brain signal abnormalities between CADASIL patients with and without MA. Conclusions In CADASIL, MA is characterized by an unusually high frequency of attacks of migraine with atypical aura. The distribution and extent of magnetic resonance signal abnormalities did not differ according to migraine phenotype.
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skin biopsy immunostaining with a notch3 monoclonal antibody for CADASIL diagnosis
The Lancet, 2001Co-Authors: Anne Joutel, Frédéric Andreux, Valérie Domenga, Michaelle Cecillon, Hugues Chabriat, Pascal Favrole, Pierre Labauge, Christelle Lescoat, K Vahedi, Anne DucrosAbstract:CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a small-artery disease of the brain caused by NOTCH3 mutations that lead to an abnormal accumulation of NOTCH3 within the vasculature. We aimed to establish whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients). In the retrospective series skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, seven of the 42 patients had a positive skin biopsy whereas only four had a mutation detected by limited NOTCH3 scanning. Our immunostaining technique is highly sensitive (96%) and specific (100%) for diagnosis of CADASIL.
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notch3 mutations in CADASIL a hereditary adult onset condition causing stroke and dementia
Nature, 1996Co-Authors: Anne Joutel, Valérie Domenga, Hugues Chabriat, Katayoun Vahedi, Christophe Corpechot, Anne Ducros, Philippe Mouton, Sonia Alamowitch, Michaelle Cecillion, Emmanuelle MarechalAbstract:Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.
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new phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19 migraine as the prominent clinical feature
Journal of Neurology Neurosurgery and Psychiatry, 1995Co-Authors: Marc Verin, Y Rolland, F Landgraf, Hugues Chabriat, B Bompais, A Michel, Katayoun Vahedi, J P Martinet, E Tournierlasserve, M H LemaitreAbstract:A survey was carried out on a large family presenting the symptoms of familial arteriopathy (CADASIL) recently mapped to chromosome 19. This is characterised clinically by recurrent subcortical infarcts developing into pseudobulbar palsy and subcortical dementia, and radiologically by early MRI abnormalities. To characterise this familial condition, 43 members older than 20 years and spreading over four generations were studied clinically (31 living, 12 deceased), genetically, and radiologically by MRI (n = 31). Twenty out of 43 were found to be clinically symptomatic and of these 13 out of 31 had MRI abnormalities. Genetic studies mapped this condition to the locus of CADASIL (lod score > 3). The natural history suggests a chronological clinicoradiological staging of this phenotype of CADASIL: stage I between 20 and 40 years with frequent migraine-like episodes and well delineated lesions of the white matter; stage II between 40 and 60 years with stroke-like episodes, bipolar or monopolar-like psychotic disorders, coalescent lesions of the white matter, and well delineated lesions of the basal ganglia; and stage III over 60 years with subcortical dementia, pseudobulbar palsy, diffuse leukoencephalopathy, and multiple well delineated lesions of the basal ganglia. This phenotype differs from the other two previously described by high frequency of migraine, frequency of psychotic disorders, and early neurological manifestations. The new acronym "cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and migraine" (CADASILM) is proposed to better describe this particular subvariety of CADASIL.
Anne Joutel - One of the best experts on this subject based on the ideXlab platform.
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characterisation of early ultrastructural changes in the cerebral white matter of CADASIL small vessel disease using high pressure freezing freeze substitution
Neuropathology and Applied Neurobiology, 2021Co-Authors: Rikesh M Rajani, Anne Joutel, Valerie Domengadenier, Nicolas Dupre, Guillaume Van Niel, Xavier HeiligensteinAbstract:Aims The objective of this study was to elucidate the early white matter changes in CADASIL small vessel disease. Methods We used high pressure freezing and freeze substitution (HPF/FS) in combination with high resolution electron microscopy (EM), immunohistochemistry and confocal microscopy of brain specimens from control and CADASIL (TgNotch3R169C ) mice aged 4 to 15 months to study white matter lesions in the corpus callosum. Results We first optimized the HPF/FS protocol in which samples were chemically prefixed, frozen in a sample carrier filled with 20% polyvinylpyrrolidone and freeze-substituted in a cocktail of tannic acid, osmium tetroxide and uranyl acetate dissolved in acetone. EM analysis showed that CADASIL mice exhibit significant splitting of myelin layers and enlargement of the inner tongue of small calibre axons from the age of 6 months, then vesiculation of the inner tongue and myelin sheath thinning at 15 months of age. Immunohistochemistry revealed an increased number of oligodendrocyte precursor cells, although only in older mice, but no reduction in the number of mature oligodendrocytes at any age. The number of Iba1 positive microglial cells was increased in older but not in younger CADASIL mice, but the number of activated microglial cells (Iba1 and CD68 positive) was unchanged at any age. Conclusion We conclude that early WM lesions in CADASIL affect first and foremost the myelin sheath and the inner tongue, suggestive of a primary myelin injury. We propose that those defects are consistent with a hypoxic/ischaemic mechanism.
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Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL
Acta Neuropathologica Communications, 2019Co-Authors: Rikesh Rajani, Hannu Kalimo, Julien Ratelade, Valérie Domenga-denier, Yoshiki Hase, Raj Kalaria, Anne JoutelAbstract:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology ("pure" WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.
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A JOURNAL OF NEUROLOGY Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients
2016Co-Authors: Saara Tikka, Anne Joutel, Matti Viitanen, Marie-magdeleine Ruchoux, Robert Bergholm, Maija Junna, Marc Baumann, Hannu KalimoAbstract:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients ’ skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patient
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contribution of voltage gated potassium channels in cerebrovascular dysfunction associated with a genetic model of ischemic small vessel disease 1068 1
The FASEB Journal, 2014Co-Authors: Fabrice Dabertrand, Anne Joutel, Christel Kroigaard, Adrian D Bonev, Joseph E Brayden, Mark NelsonAbstract:Dominant mutations in the NOTCH3 gene induce the most common heritable cause of stroke and vascular dementia, referred to as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Using a recently developed mouse model of CADASIL (Joutel, JCI, 2010), we examined the consequences of this mutation on the function of intracerebral arterioles. Elevation of intravascular pressure to 20 mm Hg constricted isolated arterioles from control and CADASIL mice to a similar extent. However, above 30 mm Hg, CADASIL arterioles displayed impaired vascular reactivity. At 40 mm Hg, CADASIL arterioles were 38% less constricted, and their smooth muscle membrane potential was 10 mV more hyperpolarized than control. A pharmacologic approach revealed an unchanged activity of small-, intermediate-, large-conductance calcium-sensitive potassium channels. However the voltage-gated potassium (Kv) channel blocker 4-AP enhanced pressure-induced constriction to a greater extent in both par...
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migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL
JAMA Neurology, 2004Co-Authors: Katayoun Vahedi, Anne Joutel, Hugues Chabriat, C Levy, Elisabeth Tournierlasserve, M G BousserAbstract:Background Migraine with aura (MA) is one of the clinical hallmarks of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease of the brain caused by mutations in the NOTCH3 gene, but its exact mechanisms are unknown. Objectives To describe the patterns of MA in CADASIL and to compare brain magnetic resonance signal abnormalities between CADASIL patients with and without MA. Design Comparison of brain magnetic resonance signal abnormalities between cases and controls. Setting Patients with CADASIL seen at Lariboisiere Hospital. Patients Forty-one CADASIL patients with MA and 31 age-matched CADASIL controls without MA. Results The mean age at onset of MA was significantly younger in women compared with men and occurred a mean of 15 years prior to stroke onset. A majority of patients (56%) reported at least 1 migraine attack with atypical aura. All CADASIL patients either with or without MA had white matter signal abnormalities on T2-weighted imaging. There was no difference in the frequency and distribution of brain signal abnormalities between CADASIL patients with and without MA. Conclusions In CADASIL, MA is characterized by an unusually high frequency of attacks of migraine with atypical aura. The distribution and extent of magnetic resonance signal abnormalities did not differ according to migraine phenotype.
Martin Dichgans - One of the best experts on this subject based on the ideXlab platform.
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the effect of notch3 pathogenic variant position on CADASIL disease severity notch3 egfr 1 6 pathogenic variant are associated with a more severe phenotype and lower survival compared with egfr 7 34 pathogenic variant
Genetics in Medicine, 2019Co-Authors: Julie W Rutten, Hugh S. Markus, Martin Dichgans, L. Pantoni, Antonio Federico, Bastian J Van Eijsden, Marco Duering, Eric Jouvent, Christian Opherk, Hugues ChabriatAbstract:CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7–34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7–34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1–6 pathogenic variant or an EGFr 7–34 pathogenic variant. The frequencies of NOTCH3 EGFr 1–6 and EGFr 7–34 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. CADASIL patients with an EGFr 1–6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7–34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1–6 pathogenic variant, whereas EGFr 7–34 pathogenic variant strongly predominate in the population. NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7–34 pathogenic variant predisposing to a later onset of stroke and longer survival.
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Cognition in CADASIL
2016Co-Authors: Martin DichgansAbstract:Abstract—CADASIL is an early onset small vessel disease and genetic variant of pure subcortical ischemic vascular dementia (SIVD). The condition has been invaluable in defining the profile and neuroimaging correlates of cognitive deficits in pure SIVD. The recent completion of a randomized trial in cognitively impaired CADASIL patients has illustrated the feasibility of targeted therapeutic trials in narrowly defined subtypes of vascular cognitive impairment. This article highlights some of the advances on cognition in CADASIL. (Stroke. 2009;40[suppl 1]:S45-S47.) Key Words: CADASIL syndrome genetics lacunar infarcts vascular cognitive impairment vascular dementia white matter disease stroke Investigating the mechanisms and therapeutic approaches tovascular dementia (VaD) remains a challenge, for several reasons: First, VaD represents a heterogeneous condition encompassing various vascular pathologies and dementia mechanisms, which may coexist. Second, many elderly sub-jects have comorbid neurodegenerative disease, which is difficult to assess particularly during early stages but may nevertheless impact on cognition. Finally, many of the assessment tools, such as cognitive test batteries used i
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cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL an 18f fdg pet study
The Journal of Nuclear Medicine, 2003Co-Authors: Klaus Tatsch, Nils Peters, Walter Koch, Rainer Linke, Gabriele Poepperl, Markus Holtmannspoetter, Martin DichgansAbstract:UNLABELLED Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-vessel disease caused by mutations in the NOTCH3 gene. As in sporadic small-vessel disease, ischemic lesions are largely confined to subcortical structures, whereas the cortex is spared. CADASIL, therefore, may serve as a model to study subcortically induced remote effects. The purpose of this study was to evaluate with (18)F-FDG PET whether regional cerebral metabolic rate of glucose (rCMRglc) is altered in CADASIL patients and, if so, whether there is evidence of subcortically induced disconnection. METHODS Eleven CADASIL patients (7 women, 4 men; mean age, 55.8 +/- 6.7 y) without cortical lesions on brain MR images underwent PET after intravenous injection of 120 MBq (18)F-FDG, with calculation of rCMRglc according to a previously published method. For further processing, patient studies were registered to a template of a healthy control group and region-of-interest-based and voxelwise comparisons were performed. RESULTS In CADASIL patients, mean rCMRglc was significantly reduced in all cortical and subcortical structures, compared with the values in healthy volunteers. In the subcortical gray matter, metabolic rates, given as the percentage of the mean of healthy volunteers, were 49.7%, 65.3%, and 51.6% in the caudate, putamen, and thalamus, respectively. Among cortical structures, the values were 66.9%, 67.9%, 67.2%, and 76.5% for the frontal, parietal, temporal, and occipital lobes, respectively. On an individual level, most patients showed marked asymmetry and inhomogeneities of cortical glucose metabolism. In 6 (55%) CADASIL patients, there was evidence of crossed cerebellar diaschisis. CONCLUSION This study showed that cortical glucose metabolism is significantly lower in CADASIL patients than in healthy volunteers. The observed decrease in rCMRglc may in part be explained by a reduction of cerebral blood flow and neuronal loss. In addition, our data provide evidence of remote effects secondary to the functional disruption of subcortical fiber tracts in this particular type of small-vessel disease.
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cerebral microbleeds in CADASIL a gradient echo magnetic resonance imaging and autopsy study
Stroke, 2002Co-Authors: Martin Dichgans, Markus Holtmannspotter, Jurgen Herzog, Nils Peters, Michael Bergmann, T A YousryAbstract:Background and Purpose: An increased frequency of clinically silent microbleeds (MB) has recently been observed in patients with sporadic small-vessel disease related to vascular amyloid deposition or hypertension. In this study, we searched for cerebral MBs in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a unique type of small-vessel disease caused by mutations in the Notch3 gene. Our purposes were (1) to determine the frequency, extent, and pattern of MBs in CADASIL; (2) to analyze the relationship between MBs and T2-hyperintense lesions; and (3) to evaluate the histopathology of brain tissue affected by MBs. Methods: Gradient-echo, T2/PD-weighted dual-echo, and T1-weighted MRI scans of the brain were obtained from 16 consecutive CADASIL subjects and 16 age-matched control subjects. T2-lesion volume measurements were made with a semiautomated segmentation technique based on local thresholding. Postmortem examinations were performed on the brains of 7 additional CADASIL subjects. Results: Focal areas of signal loss on gradient-echo images suggesting past MBs were found in 11 CADASIL individuals (69%) and no control subjects (P<0.001). The average number of MBs was 5.9±7.3 (range, 0 to 22) in individual CADASIL patients. MBs were associated with age (r=0.71, P=0.002) and total lesion volume (r=0.75, P=0.001). However, after correction for age, the correlation with lesion volume was no longer significant. MBs were located simultaneously in various parts of the brain with a preference for cortical-subcortical regions (38%), white matter (20%), thalamus (13%), and brainstem (14%). Eighty-two percent of the MBs were located outside areas appearing hyperintense on T2-weighted images. Postmortem examination revealed focal accumulations of hemosiderin-containing macrophages in 6 of the 7 brains (86%). They were always found outside ischemic lesions. Conclusions: This study shows a high frequency and multiplicity of MBs in individuals with CADASIL. Our results suggest that MBs and ischemic lesions are largely independent manifestations of the underlying angiopathy. The pattern of MBs shows a significant overlap with that reported in other types of small-vessel disease.
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quantitative mri in CADASIL correlation with disability and cognitive performance
Neurology, 1999Co-Authors: Martin Dichgans, Massimo Filippi, R Bruning, Giuseppe Iannucci, Christian Berchtenbreiter, L Minicucci, I Uttner, A Crispin, H Ludwig, Thomas GasserAbstract:Objective: To study correlations between total lesion load on brain MRI and clinical features, and to evaluate the influence of demographic variables on quantitative MRI variables in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Background: CADASIL is a hereditary form of small-vessel disease caused by mutations within the Notch3 gene. MRI abnormalities have been found both in asymptomatic and symptomatic CADASIL individuals. Methods: Quantitative measurements on cerebral MRI were performed in 64 CADASIL individuals. MRI lesions were quantified using a semi-automated segmentation technique based on local thresholds. Results: MRI total lesion volume correlated significantly with disability (Rankin Scale) on both T1- and proton density (PD)-weighted images. There was a significant inverse correlation between total lesion volume and overall cognitive performance as determined by the Mini-Mental State Examination. Age but not sex was correlated with lesion load both on T1- and PD-weighted images. There was no detectable influence of the Notch3 genotype on quantitative MRI variables. Conclusions: This study demonstrates correlations between MRI lesion volume and clinical characteristics in CADASIL. Longitudinal studies are now warranted to investigate whether quantitative MRI could be used as an adjunct outcome measure in future therapeutic trials in CADASIL.
Muiño Acuña Elena - One of the best experts on this subject based on the ideXlab platform.
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Análisis de la etiopatogenia del CADASIL mediante estudios transcriptómicos y estimación del pronóstico tras el ictus isquémico en el CADASIL
CSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS), 2021Co-Authors: Muiño Acuña ElenaAbstract:Tesis doctoral. Universitat Autònoma de Barcelona. Departament de Medicina.[ES] El CADASIL es una arteriopatía sistémica causada por mutaciones en NOTCH3, que afectan al número de cisteínas del dominio extracelular del receptor, alterando los puentes disulfuro y propiciando un mal plegamiento de este, y su agregación junto con la de otras proteínas; mecanismo que actualmente se considera responsable de la enfermedad. Considerada una enfermedad rara, es la causa más frecuente de ictus y demencia de causa hereditaria. Debido a la variabilidad fenotípica del CADASIL, incluso dentro de una misma familia, se ve dificultada la posibilidad de establecer un pronóstico certero en estos pacientes, en una enfermedad sin tratamiento. El objetivo principal de esta tesis es profundizar en la etiopatogenia de la enfermedad y así encontrar potenciales biomarcadores o dianas terapéuticas. Por una parte, a través del estudio de la patogenicidad de las mutaciones que no afectan a residuos cisteína de Notch3, cuestionando la hipótesis etiopatogénica actual del CADASIL; y por otra, a través del estudio transcriptómico, que permitirá encontrar moléculas relevantes en esta enfermedad. El objetivo secundario, es la creación de un modelo pronóstico que prediga la discapacidad a los tres meses de un paciente con un ictus isquémico y CADASIL. Como resultado del trabajo de la presente tesis, se ha encontrado que existen mutaciones que no afectan al número de cisteínas, y que pueden ser consideradas patogénicas y causantes de CADASIL (p. R61W, p. R75P, p. D80G y p. R213K). Por tanto, mecanismos diferentes y/o adicionales a la alteración producida por la aparición de un número impar de cisteínas, podrían causar el CADASIL. Por otra parte, el estudio transcriptómico ha puesto de manifiesto que E2F4 se encuentra sobreexpresado en pacientes con CADASIL, y que esta sobreexpresión se correlaciona de forma negativa con el rendimiento de las pruebas que valoran la función ejecutiva y la atención y velocidad de procesamiento de la información, dominios cognitivos característicamente afectados en pacientes con esta enfermedad. Por último, el Parsifal Score es un modelo que predice el estado funcional de un paciente con un ictus isquémico, a los tres meses. Este modelo también es eficaz para predecir la discapacidad, en el caso de pacientes con CADASIL y un ictus isquémico.[EN] CADASIL is a systemic artery disease caused by mutations in NOTCH3, which affect the number of cysteines in the extracellular domain of the receptor, altering the disulfide bridges and causing a missfolding of the receptor, and its aggregation along with other proteins; a mechanism currently considered responsible for the disease. Considered a rare disease, it is the most frequent cause of stroke and dementia of hereditary cause. Due to the phenotypic variability of CADASIL, even within the same family, the possibility of establishing an accurate prognosis in these patients, in a disease without treatment, is difficult. The main objective of this thesis is to deepen in the etiopathogenesis of the disease and thus, find potential biomarkers or therapeutic targets. On the one hand, through the study of the pathogenicity of mutations that do not affect Notch3 cysteine residues, questioning the current aetiopathogenic hypothesis of CADASIL; and on the other hand, through the transcriptomical study, which will allow finding relevant molecules in this disease. The secondary objective is the creation of a prognostic model that predicts the disability at three months, of a patient with an ischemic stroke and CADASIL. As a result of the work of this thesis, it has been found that there are mutations that do not affect the number of cysteines, and that can be considered pathogenic and cause CADASIL (p. R61W, p. R75P, p. D80G and p. R213K). Therefore, different and/or additional mechanisms to the alteration produced by the appearance of an odd number of cysteines, could cause CADASIL. On the other hand, the transcriptomic study has shown that E2F4 is over-expressed in patients with CADASIL, and that this over-expression is negatively correlated with the performance of tests that assess executive function and attention and speed of information processing, cognitive domains characteristically affected in patients with this disease. Finally, the Parsifal Score is a model that predicts the functional status of a patient with an ischemic stroke, at three months. This model is also effective in the case of CADASIL patients with ischemic stroke.[CA] El CADASIL és una arteriopatia sistèmica causada per mutacions en NOTCH3, que afecten el nombre de cisteïnes del domini extracel·lular del receptor, alterant els ponts disulfur i propiciant un mal plegament d'aquest, i la seva agregació juntament amb la d'altres proteïnes; mecanisme que actualment es considera responsable de la malaltia. Considerada una malaltia rara, és la causa més freqüent d'ictus i demència de causa hereditària. A causa de la variabilitat fenotípica del CADASIL, fins i tot dins d'una mateixa família, es veu dificultada la possibilitat d'establir un pronòstic precís en aquests pacients, es tracta d'una malaltia sense tractament. L'objectiu principal d'aquesta tesi és aprofundir en l'etiopatogènia de la malaltia a través del estudi de l'expressió diferencial en biòpsies de pell de pacients amb CADASIL respecte a controls sans, a través d'un Genome-Wide Transcriptomic Study (GWTS). Com a objectius secundaris es va voler estudiar si mutacions que no afectessin el nombre de cisteïnes podrien considerar-se patogèniques, mitjançant la revisió sistemàtica en la literatura d'aquest tipus de mutacions; i crear un model per predir el grau de discapacitat en pacients amb ictus isquèmic i testar-ho en pacients amb CADASIL. Com a resultat de la feina de la present tesi, s'ha trobat que hi ha mutacions que no afecten el nombre de cisteïnes, i que poden ser considerades patogèniques i causants de CADASIL (p. R61W, p. R75P, p. D80G i p. R213K) . Per tant, mecanismes diferents i / o addicionals a l'alteració produïda per l'aparició d'un nombre imparell de cisteïnes, podrien causar el CADASIL. D'altra banda, l'estudi transcriptòmic ha posat de manifest que E2F4 es troba sobreexpressat en pacients amb CADASIL, i que aquesta sobreexpressió es correlaciona de manera negativa amb el rendiment de les proves que valoren la funció executiva i l'atenció i velocitat de processament de la informació, dominis cognitius característicament afectats en pacients amb aquesta malaltia. Finalment, el Parsifal Score és un model que prediu l'estat funcional d'un pacient amb un ictus isquèmic, als tres mesos. Aquest model també és eficaç per predir la discapacitat, en el cas de pacients amb CADASIL i un ictus isquèmic
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Análisis de la etiopatogenia del CADASIL mediante estudios transcriptómicos y estimación del pronóstico tras el ictus isquémico en el CADASIL
'Universitat Autonoma de Barcelona', 2020Co-Authors: Muiño Acuña ElenaAbstract:El CADASIL és una arteriopatia sistèmica causada per mutacions en NOTCH3, que afecten el nombre de cisteïnes del domini extracel·lular del receptor, alterant els ponts disulfur i propiciant un mal plegament d’aquest, i la seva agregació juntament amb la d’altres proteïnes; mecanisme que actualment es considera responsable de la malaltia. Considerada una malaltia rara, és la causa més freqüent d’ictus i demència de causa hereditària. A causa de la variabilitat fenotípica del CADASIL, fins i tot dins d’una mateixa família, es veu dificultada la possibilitat d’establir un pronòstic precís en aquests pacients, es tracta d’una malaltia sense tractament. L’objectiu principal d’aquesta tesi és aprofundir en l’etiopatogènia de la malaltia a través del estudi de l’expressió diferencial en biòpsies de pell de pacients amb CADASIL respecte a controls sans, a través d’un Genome-Wide Transcriptomic Study (GWTS). Com a objectius secundaris es va voler estudiar si mutacions que no afectessin el nombre de cisteïnes podrien considerar-se patogèniques, mitjançant la revisió sistemàtica en la literatura d’aquest tipus de mutacions; i crear un model per predir el grau de discapacitat en pacients amb ictus isquèmic i testar-ho en pacients amb CADASIL. Com a resultat de la feina de la present tesi, s’ha trobat que hi ha mutacions que no afecten el nombre de cisteïnes, i que poden ser considerades patogèniques i causants de CADASIL (p.R61W, p.R75P, p.D80G i p.R213K) . Per tant, mecanismes diferents i / o addicionals a l’alteració produïda per l’aparició d’un nombre imparell de cisteïnes, podrien causar el CADASIL. D’altra banda, l’estudi transcriptòmic ha posat de manifest que E2F4 es troba sobreexpressat en pacients amb CADASIL, i que aquesta sobreexpressió es correlaciona de manera negativa amb el rendiment de les proves que valoren la funció executiva i l’atenció i velocitat de processament de la informació, dominis cognitius característicament afectats en pacients amb aquesta malaltia. Finalment, el Parsifal Score és un model que prediu l’estat funcional d’un pacient amb un ictus isquèmic, als tres mesos. Aquest model també és eficaç per predir la discapacitat, en el cas de pacients amb CADASIL i un ictus isquèmic.El CADASIL es una arteriopatía sistémica causada por mutaciones en NOTCH3, que afectan al número de cisteínas del dominio extracelular del receptor, alterando los puentes disulfuro y propiciando un mal plegamiento de este, y su agregación junto con la de otras proteínas; mecanismo que actualmente se considera responsable de la enfermedad. Considerada una enfermedad rara, es la causa más frecuente de ictus y demencia de causa hereditaria. Debido a la variabilidad fenotípica del CADASIL, incluso dentro de una misma familia, se ve dificultada la posibilidad de establecer un pronóstico certero en estos pacientes, en una enfermedad sin tratamiento. El objetivo principal de esta tesis es profundizar en la etiopatogenia de la enfermedad y así encontrar potenciales biomarcadores o dianas terapéuticas. Por una parte, a través del estudio de la patogenicidad de las mutaciones que no afectan a residuos cisteína de Notch3, cuestionando la hipótesis etiopatogénica actual del CADASIL; y por otra, a través del estudio transcriptómico, que permitirá encontrar moléculas relevantes en esta enfermedad. El objetivo secundario, es la creación de un modelo pronóstico que prediga la discapacidad a los tres meses de un paciente con un ictus isquémico y CADASIL. Como resultado del trabajo de la presente tesis, se ha encontrado que existen mutaciones que no afectan al número de cisteínas, y que pueden ser consideradas patogénicas y causantes de CADASIL (p.R61W, p.R75P, p.D80G y p.R213K). Por tanto, mecanismos diferentes y/o adicionales a la alteración producida por la aparición de un número impar de cisteínas, podrían causar el CADASIL. Por otra parte, el estudio transcriptómico ha puesto de manifiesto que E2F4 se encuentra sobreexpresado en pacientes con CADASIL, y que esta sobreexpresión se correlaciona de forma negativa con el rendimiento de las pruebas que valoran la función ejecutiva y la atención y velocidad de procesamiento de la información, dominios cognitivos característicamente afectados en pacientes con esta enfermedad. Por último, el Parsifal Score es un modelo que predice el estado funcional de un paciente con un ictus isquémico, a los tres meses. Este modelo también es eficaz para predecir la discapacidad, en el caso de pacientes con CADASIL y un ictus isquémico.CADASIL is a systemic artery disease caused by mutations in NOTCH3, which affect the number of cysteines in the extracellular domain of the receptor, altering the disulfide bridges and causing a missfolding of the receptor, and its aggregation along with other proteins; a mechanism currently considered responsible for the disease. Considered a rare disease, it is the most frequent cause of stroke and dementia of hereditary cause. Due to the phenotypic variability of CADASIL, even within the same family, the possibility of establishing an accurate prognosis in these patients, in a disease without treatment, is difficult. The main objective of this thesis is to deepen in the etiopathogenesis of the disease and thus, find potential biomarkers or therapeutic targets. On the one hand, through the study of the pathogenicity of mutations that do not affect Notch3 cysteine residues, questioning the current aetiopathogenic hypothesis of CADASIL; and on the other hand, through the transcriptomical study, which will allow finding relevant molecules in this disease. The secondary objective is the creation of a prognostic model that predicts the disability at three months, of a patient with an ischemic stroke and CADASIL. As a result of the work of this thesis, it has been found that there are mutations that do not affect the number of cysteines, and that can be considered pathogenic and cause CADASIL (p.R61W, p.R75P, p.D80G and p.R213K). Therefore, different and/or additional mechanisms to the alteration produced by the appearance of an odd number of cysteines, could cause CADASIL. On the other hand, the transcriptomic study has shown that E2F4 is over-expressed in patients with CADASIL, and that this over-expression is negatively correlated with the performance of tests that assess executive function and attention and speed of information processing, cognitive domains characteristically affected in patients with this disease. Finally, the Parsifal Score is a model that predicts the functional status of a patient with an ischemic stroke, at three months. This model is also effective in the case of CADASIL patients with ischemic stroke
Hugh S. Markus - One of the best experts on this subject based on the ideXlab platform.
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the effect of notch3 pathogenic variant position on CADASIL disease severity notch3 egfr 1 6 pathogenic variant are associated with a more severe phenotype and lower survival compared with egfr 7 34 pathogenic variant
Genetics in Medicine, 2019Co-Authors: Julie W Rutten, Hugh S. Markus, Martin Dichgans, L. Pantoni, Antonio Federico, Bastian J Van Eijsden, Marco Duering, Eric Jouvent, Christian Opherk, Hugues ChabriatAbstract:CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7–34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7–34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1–6 pathogenic variant or an EGFr 7–34 pathogenic variant. The frequencies of NOTCH3 EGFr 1–6 and EGFr 7–34 pathogenic variant were compared between individuals in the genome Aggregation Database and CADASIL patients. CADASIL patients with an EGFr 1–6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7–34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1–6 pathogenic variant, whereas EGFr 7–34 pathogenic variant strongly predominate in the population. NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7–34 pathogenic variant predisposing to a later onset of stroke and longer survival.
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abstract 26 prevalence of CADASIL and fabry disease in a large cohort of mri defined younger onset lacunar stroke
Stroke, 2015Co-Authors: Loes C A Ruttenjacobs, Steve Bevan, Laura L Kilarski, R J Baker, Derralynn Hughes, Hugh S. MarkusAbstract:Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, most likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence of CADASIL and FD in a well-defined, MRI verified cohort of patients with lacunar infarct. Methods: Caucasian patients with lacunar infarction, aged Results: Of 1,049 subjects four had pathogenic NOTCH3 mutations (R169C, R207C, R587C and C1222G) all resulting in loss of gain of a cysteine in the NOTCH3 protein. All four patients had confluent leukoaraiosis (Fazekas grade ≥2), and three had multiple infarcts. CADASIL prevalence overall was 0.4 (95% CI 0.1%-0.9%) and among cases with confluent leukoaraiosis 1.2% (95% CI 0.4%-2.8%). One additional patient had a missense mutation in the GLA gene (R118C) of uncertain significance; conflicting data exists pathogenicity of this mutation. Conclusions: CADASIL cases can be detected in younger onset apparently sporadic lacunar stroke, but are rare. FD screening in this patient group has a minimal pick-up.
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mri hyperintensities of the temporal lobe and external capsule in patients with CADASIL
Neurology, 2001Co-Authors: Michael Osullivan, Jozef Jarosz, R J Martin, N Deasy, John Powell, Hugh S. MarkusAbstract:Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited, autosomal dominant condition caused by mutations of the Notch3 gene. Affected individuals have migraine, mood disturbance, and recurrent strokes, often progressing to subcortical dementia and premature death. MRI findings include focal lacunar infarcts and diffuse T2-weighted hyperintensity, or leukoaraiosis. However, such findings are seen much more commonly in patients with cardiovascular risk factors, particularly hypertension, where they are believed to represent cerebral small vessel disease. No previous study has sought to identify specific radiologic markers of CADASIL. Methods: MRI scans from 20 consecutive patients with CADASIL and 20 patients with sporadic leukoaraiosis due to presumed small-vessel disease were compared using the previously validated semiquantitative MRI rating scale devised by Scheltens et al. Analysis was blinded to clinical category. Results: Scores for hyperintensities of the temporal white matter and external capsule–insula region were significantly higher in patients with CADASIL. Hyperintensity confined to the pole of the temporal lobe was a characteristic finding in CADASIL, occurring in 19 patients with CADASIL but no patients with ischemic leukoaraiosis. Involvement of the external capsule, though less specific, was seen early in the disease course. In a few patients with CADASIL, involvement of the corpus callosum was observed. Conclusions: Temporal pole hyperintensity is a radiologic marker of CADASIL. Involvement of the external capsule and corpus callosum are also characteristic findings that may help to distinguish the disease.
