Article

Endothelial changes in muscle and skin biopsies in patients with CADASIL

February 1998
Neuropathology and Applied Neurobiology 24(1):60-5

February 1998
24(1):60-5

DOI:10.1046/j.1365-2990.1998.00087.x

Source
PubMed

Authors:

Marie-Magdeleine Ruchoux

The Methodist Hospital System

Ruchoux M.-M. & Maurage C.-A. (1998) Neuropathology and Applied Neurobiology24, 60–65 Endothelial changes in muscle and skin biopsies in patients with CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is characterized by the deposition of granular osmiophilic material in association with vascular smooth muscle cells in many different organs. However, the cause of the subsequent destruction of smooth muscle cells that are surrounded by granular osmiophilic material is unclear. In the present study, the ultrastructural changes that occur in endothelial cells in CADASIL have been evaluated by examining blood vessels in six skin biopsies and seven muscle biopsies belonging to three different CADASIL pedigrees. The appearances have been compared with five skin biopsies and five muscle biopsies from age-matched controls without vascular disease. The most striking features observed in vessels in the skin of CADASIL patients were attenuation of endothelial cells and increased density of endothelial cytoplasm, accompanied by the presence of compact bundles of microfilaments within the cytoplasm of endothelial cells. Endothelial cells in muscle biopsies from CADASIL patients, on the other hand, were swollen until destruction of tight junctions were observed. These findings suggest that impaired permeability of vascular endothelium may play a role in the destruction of vascular smooth muscle cells in CADASIL. Furthermore, the results of this study suggest that further fine structural investigation of blood vessel endothelium and underlying smooth muscle may lead to a better understanding of the pathophysiology of CADASIL.

Utilidad de la biopsia de piel en el diagnóstico de enfermedades neurológicas

Article

Full-text available

Aug 2008
REV MED CHILE

Skin biopsy is a powerful diagnostic tool in Dermatology. Its use has been extended to other medical specialties, aüowing the diagnosis of several diseases that previously required complex and high risk diagnostic procedures. Skin contains numerous cell types, including blood vessels and peripheral nerves and represents a window to the systemic circulation and nervous system. In this review we discuss the use of skin biopsy to diagnose nervous system diseases in which patients do not exhibit any clinical cutaneous manifestations. We review the usefulness of skin biopsy in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopaty (CADASIL), some lysosomal storage diseases, Lafora disease and in peripheral neuropathies.

Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment

Article

Full-text available

Mar 2021

CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the EGF-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, being executive function characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. A genome-wide transcriptome study (four cases paired with three healthy siblings) was carried out, in addition to a qRT-PCR for validation purposes (ten new cases and eight new controls). To study the expression profile by cell type of the significant mRNAs found, we performed an in situ hybridization (ISH) (nine cases and eight controls) and a research in the Single-nuclei Brain RNA-seq expression browser (SNBREB). Pathway analysis enrichment was carried out with Gene Ontology and Reactome. Neuropsychological tests were performed in five of the qRT-PCR cases. The two most significant differentially expressed mRNAs ( BANP, p-value = 7.23 × 10 –4 and PDCD6IP, p-value = 8.36 × 10 –4 ) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs ( CAMK2G, p-value = 4.52 × 10 –3 and E2F4, p-value = 4.77 × 10 –3 ) due to their association with ischemic neuronal death. E2F4 showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p = 1.23 × 10 –3 ), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p = 2.04 × 10 –2 ) and attention and information processing speed (IPS) (p = 8.73 × 10 –2 ). In situ hibridization showed E2F4 expression in endothelial and vascular smooth vessel cells. In silico studies indicated that E2F4 is also expressed in brain endothelial cells. Among the most significant pathways analyzed, there was an enrichment of vascular development, cell adhesion and vesicular machinery terms and autophagy process. E2F4 is more highly expressed in the skin biopsy of CADASIL patients compared to controls, and its expression is present in endothelial cells and VSMCs. Further studies are needed to understand whether E2F4 could be useful as a biomarker, to monitor the disease or be used as a therapeutic target.

Genome-wide Transcriptome Study in Skin Biopsies Reveals an Association of E2F4 With Cadasil and Cognitive Impairment

Preprint

Full-text available

May 2020

Background:CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the receptor, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, as executive function is characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. Methods:Agenome-wide transcriptome study(four casespaired with three healthysiblings)was carried out,in addition toa qRT-PCR for validation purposes(ten new cases and eight new controls).Neuropsychological tests were performedto evaluateverbal memory, attention and information processing speed (IPS), motor speed and dexterity, executive function and visuoconstructional skills. The Single-nuclei Brain RNA-seq expression browser (SNBREB) and the GTExPortalwere used to study brain expressionof the significant mRNAs found. Results: The two most significant differentially expressed mRNAs (BANP,p-value=7.23x10⁻⁴ and PDCD6IP, p-value=8.36x10⁻⁴) were selected for the validation study by qRT-PCR. Additionally, we selectedtwo more mRNAs(CAMK2G,p-value=4.52x10-3 and E2F4, p-value=4.77x10⁻³) due to their association with ischemic neuronal death. E2F4showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p=1.23x10⁻³), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expressionwas associated with worseexecutive function (p=2.04x10⁻²) and attention and IPS (p=8.73x10⁻²).In silico studies indicated that E2F4 is expressed in brain endothelial cells. Conclusions:Skin biopsies of CADASIL patients presented higher mRNA levels of E2F4and these higher levels have a significant correlation with worseexecutive function and IPS.

Stem Cell Factor in Combination with Granulocyte Colony-Stimulating Factor reduces Cerebral Capillary Thrombosis in a Mouse Model of CADASIL

Article

Full-text available

Apr 2018
CELL TRANSPLANT

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 mutation-induced vascular smooth muscle cell (VSMC) degeneration, leading to ischemic stroke and vascular dementia. Our previous study has demonstrated that repeated treatment with a combination of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces VSMC degeneration and cerebral endothelial cell (EC) damage and improves cognitive function in a mouse model of CADASIL (TgNotch3R90C). This study aimed to determine whether cerebral thrombosis occurs in TgNotch3R90C mice and whether repeated SCF+G-CSF treatment reduces cerebral thrombosis in TgNotch3R90C mice. Using the approaches of bone marrow transplantation to track bone marrow-derived cells and confocal imaging, we observed bone marrow-derived blood cell occlusion in cerebral small vessels and capillaries (thrombosis). Most thrombosis occurred in the cerebral capillaries (93% of total occluded vessels), and the thrombosis showed an increased frequency in the regions of capillary bifurcation. Degenerated capillary ECs were seen inside and surrounding the thrombosis, and the bone marrow-derived ECs were also found next to the thrombosis. IgG extravasation was seen in and next to the areas of thrombosis. SCF+G-CSF treatment significantly reduced cerebral capillary thrombosis and IgG extravasation. These data suggest that the EC damage is associated with thrombosis and blood-brain barrier leakage in the cerebral capillaries under the CADASIL-like condition, whereas SCF+G-CSF treatment diminishes these pathological alterations. This study provides new insight into the involvement of cerebral capillary thrombosis in the development of CADASIL and potential approaches to reduce the thrombosis, which may restrict the pathological progression of CADASIL.

Pericytes as a new target for pathological processes in CADASIL

Article

Jan 2012
NEUROPATHOLOGY

CADASIL is a generalized angiopathy caused by mutations in NOTCH 3 gene leading to degeneration and loss of vascular smooth muscle cells (VSMC) in small arteries and arterioles. Since the receptor protein encoded by NOTCH 3 gene is expressed not only on VSMC but also on pericytes, pericytes and capillary vessels can be damaged by CADASIL. To check this hypothesis we examined microvessels in autopsy brains and skin-muscle biopsies of CADASIL patients. We found degeneration and loss of pericytes in capillary vessels. Pericytes were shrunken and their cytoplasm contained numerous vacuoles, big vesicular structures and complexes of enlarged pathological mitochondria. Degenerative changes were also observed within endothelial-pericytic connections, especially within peg-and-socket junctions. Nearby pericyte cell membranes or inside infoldings, deposits of granular osmiophilic material (GOM) were usually seen. In the affected capillaries endothelial cells revealed features of degeneration, selective death or swelling, leading to narrowing or occlusion of the capillary lumen. Our findings indicate that in CADASIL not only VSMC but also pericytes are severely damaged. Pericyte involvement in CADASIL can result in increased permeability of capillary vessels and disturbances in cerebral microcirculation, leading to white matter injury. Since in capillaries pericytes regulate vessel contractility, their degeneration can also cause defective vasomotor reactivity, the phenomenon observed very early in CADASIL, before development of histopathological changes in vessel walls.

The pericyte: A critical cell in the pathogenesis of CADASIL

Article

Full-text available

Oct 2021

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease. This may affect critical pericyte-endothelial interactions causing stroke injury and vasomotor disturbances. Changes in microvascular permeability due to perhaps localized blood-brain barrier alterations and pericyte secretory dysfunction likely contribute to delayed neuronal as well as glial cell death. Moreover, pericyte-mediated cerebral venous insufficiency may explain white matter lesions and the dilatation of Virchow-Robin perivascular spaces typical of CADASIL. The postulated central role of the pericyte offers some novel approaches to the study and treatment of CADASIL and enable elucidation of other forms of cerebral small vessel diseases and subcortical vascular dementia.

Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

Article

Full-text available

Jul 2021
INT J MOL SCI

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL

Article

Full-text available

Jan 2021

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.

Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

Article

Full-text available

Feb 2019

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient’s iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease. Electronic supplementary material The online version of this article (10.1007/s13238-019-0608-1) contains supplementary material, which is available to authorized users.

Circulating Biomarkers in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Patients

Article

Nov 2016

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy presenting with variable features, including migraine, psychiatric disorders, stroke, and cognitive decline and variable disability. On neuroimaging, CADASIL is characterized by leukoencephalopathy, multiple lacunar infarcts, and microbleeds. Previous studies suggest a possible role of endothelial impairment in the pathogenesis of the disease. Methods: We assessed plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) and the blood levels of endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) in 49 CADASIL patients and 49 age-matched controls and their association with clinical/functional and neuroimaging features. Results: In multivariate analysis, CADASIL patients had significantly higher vWF and lower EPC levels. TM levels were similar in the 2 groups. CADASIL patients with a more severe clinical phenotype (history of stroke or dementia) presented lower CPC levels in comparison with patients with a milder phenotype. On correlation analysis, lower CPC levels were associated with worse performances on neuropsychological, motor and functional tests, and with higher lesion load on brain magnetic resonance imaging (degree of leukoencephalopathy and number of lacunar infarcts). Conclusions: This is the first CADASIL series in which multiple circulating biomarkers have been studied. Our findings support previous studies on the presence and the possible modulating effect of endothelial impairment in the disease. Furthermore, our research data suggest that blood CPCs may be markers of disease severity.

Genetics and ischemic stroke

Article

Sep 2000

Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

Article

Full-text available

Sep 2014
BRAIN PATHOL

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL A Randomized Controlled Trial

Article

Sep 2014

Background and purpose: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods: In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results: The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions: Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. Clinical trial registration url: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.

Role of Electron Microscopy in the Diagnosis of Cadasil Syndrome: A Study of 32 Patients

Article

Full-text available

Jun 2013
PLOS ONE

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations that result in vascular smooth muscle cell (VSMC) degeneration. Its distinctive feature by electron microscopy (EM) is granular osmiophilic material (GOM) detected in VSMC indentations and/or the extracellular space close to VSMCs. Reports of the sensitivity of EM in detecting GOM in biopsies from CADASIL patients are contradictory. We present data from 32 patients clinically suspected to have CADASIL and discuss the role of EM in its diagnosis in this retrospective study. Skin, skeletal muscle, kidney and pericardial biopsies were examined by EM; the NOTCH3 gene was screened for mutations. Skin and muscle biopsies from 12 patients without neurological symptoms served as controls. All GOM-positive patients exhibited NOTCH3 mutations and vice versa. This study i) confirms that EM is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of GOM distribution in tissues where it has never been described, e.g. pericardium; iii) documents a novel NOTCH3 mutation in exon 3; and iv) shows that EM analysis is critical to highlight the need for comprehensive NOTCH3 analysis. Our findings also confirm the genetic heterogeneity of CADASIL in a small Italian subpopulation and emphasize the difficulties in designing algorithms for molecular diagnosis.

THE EXPRESSION PROFILE OF A GWAS DETECTED GENE (NINJ2) IN THE BRAIN OF A MOUSE MODEL OF ISCHEMIC STROKE

Thesis

Full-text available

Dec 2011

Antonio Tito

Stroke is the third leading cause of death and a major debilitating disease in the United States. Multiple factors, including genetic factors, contribute to the development of the disease. Genome-wide association studies (GWAS) have contributed to the identification of genetic loci influencing risk for complex diseases, such as stroke. In 2010, a GWAS of incident stroke was performed in four large prospective cohorts from the USA and Europe and identified an association of two Single Nucleotide Polymorphisms (SNPs) on chromosome 12p13 with a greater risk of ischemic stroke in individuals of European and African-American ancestry. These SNPs are located 11 Kb upstream of the nerve injury-induced gene 2, Ninjurin2 (NINJ2), suggesting that this gene may be involved in stroke pathogenesis. NINJ2 is a cell adhesion molecule induced in the distal glial cells from a sciatic-nerve injury at 7-days after injury. In an effort to ascribe a possible role of NINJ2 in stroke, we have assessed changes in the level of gene and protein expression of NINJ2 following a time-course from a transiently induced middle cerebral artery ischemic stroke in mice brains. We report an increase in the gene expression of NINJ2 in the ischemic and peri-infarct (ipsilateral) cortical tissues at 7 and 14-days after stroke. We also report an increase in the protein expression of NINJ2 in the cortex of both the ipsilateral and contralateral cortical tissues at the same time-points. We conclude that the expression of NINJ2 is regulated by an ischemic stroke in the cortex and is consistent with NINJ2 being involved in the recovery time-points of stroke.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Article

Full-text available

Mar 2013

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy is an autosomal dominant disease affecting small vessels and often resulting in subcortical infarcts. A skin biopsy may facilitate its diagnosis as the cutaneous surface is much easier to sample than the central nervous system's tissue. Unfortunately, there is no effective treatment available today.

Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): Report of a case with a six-year follow-up

Article

Full-text available

Oct 2012

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disorder of the cerebral small blood vessels caused by a mutation in the NOTCH3 gene, which encodes a large transmembrane receptor NOTCH3. It is associated with systemic arteriopathy involving small arteries, besides the brain, in skin, spleen, liver, muscle, aorta and in the kidney. The key pathological finding is the accumulation of granular osmiophilic material (GOM) on degenerating vascular smooth muscle cells. In the kidney GOMs have been described only in a very limited number of CADASIL patients. We describe a genetically confirmed CADASIL patient with mild renal dysfunction and GOMs in the interlobular and juxtaglomerular arteries and, for the first time, also within the glomerulus, whose nephrology conditions remained stable, whereas the neurological manifestations markedly worsened over a six-year follow-up period. The reasons for this discrepancy are probably related to differences in the structure and function of brain and kidney blood vessels.

Genetic Animal Models of Cerebral Vasculopathies

Article

Dec 2012

Cerebral amyloid angiopathy (CAA) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are genetic cerebrovasculopathies associated with neurodegeneration and vascular cognitive impairment. Linked to autosomal dominant mutations in diverse genes that encode cell-surface receptors (i.e., amyloid precursor protein in CAA and NOTCH3 in CADASIL), both diseases are associated with accumulation of abnormal material around cerebral vessels, such as amyloid in CAA or granular osmiophilic material in CADASIL. Both CAA and CADASIL share clinical features of white matter degeneration and infarcts, and vascular dementia in the human adult; microbleeds occur in both CADASIL and CAA, but large intracerebral hemorrhages are more characteristic for the latter. While the mechanisms are poorly understood, wall thickening, luminal narrowing, and eventual loss of vascular smooth muscle cells are overlapping pathologies involving leptomeningeal, and pial or penetrating small arteries and arterioles in CAA and CADASIL. Dysregulation of cerebral blood flow and eventual hypoperfusion are believed to be the key pathophysiological steps in neurodegeneration and cognitive impairment. Although animal models expressing CAA or CADASIL mutations have partially reproduced the human pathology, there has been marked heterogeneity in the phenotypic spectrum, possibly due to genetic background differences among mouse models, and obvious species differences between mouse and man. Here, we provide an overview of animal models of CAA and CADASIL and the insight on molecular and physiological mechanisms of disease gained from these models.

The genetics of ischemic stroke

Article

Feb 2010
J INTERN MED

Matarin M, Singleton A, Hardy J, Meschia J (Laboratory of Neurogenetics, Bethesda, MD, USA; UCL Institute of Neurology, London, UK; Mayo Clinic, Jacksonville, FL, USA). The genetics of ischaemic stroke (Review). J Intern Med 2010; 267: 139–155. In this review, we discuss the genetic factors in both the aetiology and treatment of ischaemic stroke. We discuss candidate gene association studies, family linkage studies and the more recent whole genome association studies and whole genome expression studies. We also briefly discuss genetic testing for stroke risk and genetic analysis of treatment complications.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Chapter

Apr 2024

Hugues Chabriat

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most frequent hereditary cerebral small vessel disease and the first cause of stroke of hereditary origin. The disease is caused by cysteine mutations of the NOTCH3 gene on chromosome 19 and is observed worldwide. The diagnosis can be confirmed by genetic testing or, in difficult cases, by skin biopsy showing the accumulation of extracellular EGFr domains of the NOTCH3 receptor in the vessel wall. This accumulation is observed using immunostaining and leads to large aggregates described as Granular Osmiophilic Material visible (GOM) visible in arterioles and capillaries by electron microscopy. Accumulation of the NOTCH3 protein presumably disrupts protein homeostasis in the vascular wall, aggregates other matrix proteins and finally leads to loss of smooth muscle cells and fibrosis. The clinical spectrum of the disease of usual onset during midadulthood, and which evolves over several decades, includes migraine with aura, transient ischemic attacks or stroke, cognitive and motor decline, neuropsychiatric manifestations, apathy, gait disturbances and at end-stage severe dementia associated with bedridden status. However, the clinical expression of the disease appears largely variable among affected families and individuals. Vascular risk factors and the location of the NOTCH3 mutation along EGFr domains partly modulate the severity of the disease. Additional factors of this variability remain to be identified.

Correction of a CADASIL point mutation using adenine base editors in hiPSCs and blood vessel organoids

Article

May 2023
J GENET GENOMICS

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPSCs) generated from the peripheral blood mononuclear cells (PBMCs) of a patient with CADASIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VSMCs) differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPSC-derived VSMCs. Furthermore, CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.

CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches

Article

Full-text available

Jun 2021
MOL NEUROBIOL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

Cerebral Small Vessel Disease and Cerebral Amyloid Angiopathy: Neuroimaging markers, cognitive features and rehabilitative issues

Book

Full-text available

Mar 2019

Raffaella Valenti

Sporadic cerebral small vessel disease (SVD) is considered to be among the most commonly known neuropathological processes in the brain, hosting a crucial role in stroke, cognitive impairment, and functional loss in elderly subjects. We investigated clinical (neuroimaging and cognitive) biomarkers in the SVD, through a series of analyses from our five studies. Sporadic cerebral SVD is a complex ‘micro-world’ to be globally considered. All the relevant lesion types and SVD neuroimaging burden should be taken into account. The cumulative effects of microangiopathy burden in the brain of patients affected by SVD are crucial. Cognitive rehabilitation could represent a promising approach to prevent vascular dementia or to improve cognitive performances in patients with cerebral SVD. Longitudinal studies may provide more robust information about the progression and prognostic significance of our findings.

CADASIL: A genetic model of arteriolar degeneration, white matter injury, and dementia in later life

Chapter

Nov 2016

This new edition of The Behavioral Neurology of Dementia provides clinicians and researchers with the latest research findings written by the leading dementia experts. With chapters ranging from cognitive evaluation to imaging, and genetics and pathology to treatment, the detailed clinical descriptions of diseases and symptoms serve not only as an educational tool for trainees, but also as an opportunity for experienced clinicians to deepen their knowledge and better serve their patients. After years of little progress, the pace of discovery has been speeding up in the last decade, and the authors distil the most valuable discoveries into clear, insightful chapters with applicable information. All the chapters from the first edition have been refreshed with new text and figures. There are new chapters on autoimmune antibody-associated encephalopathy; chronic traumatic encephalopathy; and sleep issues in dementia.

Cerebrovascular Diseases

Chapter

Jan 2002

Michael Daffertshofer

Stroke is the third leading cause of death in the western world. Each year, approximately 500,000 people in the United States experience a stroke; for 150,000 of them the outcome is fatal. The US National Health Interview Survey indicates that the prevalence of stroke in the United States is 720/100,000 among the white population and 910/100,000 in the nonwhite population [1].

Introduction to Stroke Genomics

Chapter

Oct 2004

Translation of the explosion in knowledge of acute ischemic stroke into satisfactory treatment regimens has yet to happen. At present tPA, intra-arterial prourokinase and low-molecular-weight heparin form the vanguard for therapeutic intervention, yet these treatments have a limited therapeutic window. Part of this expansion in understanding has been driven by the contribution of stroke genetics and genomics. However, despite the enormous preclinical and clinical information of receptors, enzymes, second messenger systems, and so forth, that are implicated in stroke pathophysiology, delivery of novel drug treatment has been slow. This introductory chapter discusses the multiple sources of clinical and preclinical genetic information. It will describe the importance of integrating expression information into multiple preclinical models with temporal and spatial roles in lesion pathology and, furthermore developing an understanding of function in the clinic before claiming a role in ischemic stroke. The goal of such a holistic integration of information is to increase the yield from current datasets of gene expression and ultimately to help expand the choice of treatment available to the physician and patient.

Microvascular Pathology in Familial Multiinfarct Dementia or CADASIL: Implications for Cerebral Blood Flow

Chapter

Jan 2001

Recent reports suggest the existence of several forms of hereditary cerebrovascular disease leading to multiinfarct dementia or vascular dementia. The most common form of familial vascular dementia appears to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which has also been called a familial form of Binswanger’s disease. CADASIL is a disease of the arteries that has been linked to single missense mutations in the NOTCH 3 gene on chromosome 19. The pathogenesis of the disorder or how the mutations lead to brain infarcts and dementia is not known. Elucidation of the microvascular pathology associated with such genetic disorders not necessarily involving physiological risk factors for cardiovascular disease or stroke can bear much light on the primary vascular mechanisms that lead to ischemic blood flow and neuronal vulnerability. The investigation of vascular changes found in CADASIL may be one way of delineating direct gene effects in brain vascular and neuronal cells from peripheral influences.

Neurogene Muskelveränderungen und -erkrankungen

Chapter

Jan 2002

J. Michael Schröder

Die Einflüsse des Nervensystems auf den Skelettmuskel sind vielfältig. Heredodegenerative Erkrankungen des peripheren und motorischen Neurons mit progressiver „spinaler“ oder „neuraler“ Muskelatrophie sind zu unterscheiden von nichthereditären, traumatischen, entzündlichen und anderen Schädigungen des peripheren motorischen Neurons. Auch Schädigungen des peripheren und zentralen Neurons oder nur des zentralen motorischen Neurons sowie des extrapyramidalmotorischen Systems bzw. übergeordneter Zentren der Tonusregulation bewirken Veränderungen im Muskel. Außerdem bleiben Störungen der sensorischen Afferenz, d.h. der peripheren und zentralen reflektorischen Kontrollmechanismen, nicht ohne Auswirkungen. Umgekehrt führen Muskelfasernekrosen und andere Veränderungen an den Muskelfasern selbst zu Rückwirkungen auf das Nervensystem, insbesondere auf die Nervenendigungen und die sog. terminale und ultraterminale Innervation. Schließlich kommt es bei Regenerations- und Reinnervationsvorgängen zu komplexen funktionellen und strukturellen Wechselwirkungen zwischen Nervensystem und Muskel, die noch nicht in allen Details aufgeklärt sind.

Developmental anomalies and hereditary diseases of vessels

Article

Jan 2002

Congenital vascular anomalies can be divided into three groups: those developing during intra-uterine life, those associated with karyotype aberrations, and those arising from the effects of single genes or complex polygenic mutations. There are no good data on the incidence of these lesions; a recent Finnish study on 4346 new-borns showed a 3.8% rate of vascular lesions excluding salmon patches on the head and neck, in general agreement with other studies [1]. Seventy to 80% of lesions are said to regress spontaneously by the age of seven years. In most instances of this type of lesion both blood and lymphatic vessels may be affected.

Electron Microscopy

Chapter

Jan 2008

Transmission electron microscopy

Chapter

Jan 2013

CADASIL: A genetic model of arteriolar degeneration, white matter injury and dementia in later life

Article

May 2009

Introduction Cerebral microvascular disease, as seen on magnetic resonance imaging (MRI) is common in the elderly (de Leeuw et al., 2000) and there is growing evidence that it makes a major contribution to cognitive impairment and dementia in the elderly, especially in the presence of fibrillar amyloid and tau pathology (Bennett et al., 1992, 1994; Snowdon, 1997; Snowdon et al., 2000; White et al., 2002) Understanding the unique impact of cerebral microvascular disease on cognition in the elderly is challenging because the base rate of Alzheimer's disease (AD) is high in this age group (Alzheimer's Association, 2007) making it difficult to reliably exclude patients with concomitant AD (Jellinger, 2002). The CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) provides a valuable model for studying the pathogenesis of microvascular disease and the specific impact of subcortical vascular white matter injury on cognitive function. CADASIL is a genetic disorder characterized by progression of subcortical arteriolar degeneration and white matter lesions, with the development of white matter changes and clinical symptoms in early to mid adulthood, well before the onset of significant Alzheimer's pathology. Subcortical vascular dementia occurs in later stages of the illness, with a general correspondence between the severity of white matter lesions on MRI and the extent of cognitive deficits (Amberla et al., 2004). Moreover, the cognitive profile of CADASIL overlaps considerably with that of sporadic ischemic vascular disease in the elderly but differs from that of patients with AD (Charlton et al., 2006).

Markers of endothelial dysfunction, oxidative stress, and inflammation in cerebral small vessel disease

Article

Jan 2011

Introduction: The hallmarks of cerebral small vessel disease (CSVD) are widespread lesions in the white matter (white matter lesions [WMLs]) and lacunar infarcts identified on neuroimaging. In the vast majority of patients, CSVD is related to aging and vascular risk factors, such as hypertension and diabetes mellitus (sporadic CSVD) [1]. Less frequently, inherited diseases can cause similar neuroimaging alterations, and among these the most studied is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is considered the model of pure vascular dementia due to small vessel pathology [2]. It has been hypothesized that the brain damage is induced primarily by a chronic ischemia caused by cerebral hypoperfusion and impaired autoregulation related to the structural alterations of parenchymal small vessel walls (tunica media thickening and hyaline degeneration in the cases due to arterial hypertension [1], and genetically determined smooth muscle cell degeneration in CADASIL [3]). Several studies using different methods, including brain positron emission tomography (PET) and magnetic resonance imaging (MRI), have shown cerebral hypoperfusion in sporadic CSVD. In particular, reduced perfusion was found within the cerebral white matter not only in conjunction with WMLs but also in MRI normal-appearing white matter [4]. This result would support a causal role of hypoperfusion in determining brain lesions, contrasting with the hypothesis that it could be a consequence of reduced demand from damaged tissue. Also, reduced resting perfusion was found in CADASIL patients [5].

Electron Microscopy as a Useful Tool in the Diagnosis of Lysosomal Storage Diseases

Article

Jul 2013

Introduction Morphological Findings Conclusion References

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephaloapthy (CADASIL)

Article

Apr 2005
AM J DERMATOPATH

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by recurrent subcortical ischemic strokes starting in the third or fourth decade as a result of mutations in the Notch3 gene. Granular osmiophilic material (GOM) deposition around the vascular smooth muscle cells is a specific feature and electron microscopic observations of skin biopsies are useful for this diagnosis. A 39-year-old female with dizziness, abnormal visual fields, and hemiplegia, and a 42-year-old male with tinnitus and dizziness, were suspected of suffering from CADASIL based on MRI findings. Both cases were shown to have characteristic deposits of GOM, 200 to 800 nm in diameter, around the vascular smooth muscle cells of small arteries in the deep dermis, and thus the diagnoses of CADASIL were made, although there was no family history of cerebrovascular disorders or dementia. Dermatologists should be aware of these ultra-structural findings because this disease may occur sporadically and might be more common than initially thought.

Blood vessel ultrastructural picture in a CADASIL patient diagnosed at an advanced age

Article

Jan 2014
FOLIA NEUROPATHOL

We report the case of an 84-year-old male patient afflicted by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) showing minimal symptoms of disease. The patient was diagnosed on the basis of ultrastructural and genetic examinations. Ultrastructurally, a typical vascular pathology was found. However, in abnormal capillary vessel walls no granular osmiophilic material (GOM) was found. In the arteriole there were only a few GOM deposits that revealed various structures, of which only some resembled typical round GOM. The arteriolar walls showed severe damage, including fragmentation, degeneration and loss of vascular smooth muscle cells (VSMCs) with numerous deposits of elastin, mucosubstances, different granular debris, as well as collagen fibres in the basement membrane. Lysosomal inclusions with fingerprint morphology, atypical for CADASIL, were located in some of the VSMCs. Very old age at the onset of the disease may suggest that morphological changes in blood vessels, described in this report, may be due to both the disease and the patient's age. To our best knowledge it is the first description of pathology of blood vessels and GOM morphology in a CADASIL patient diagnosed at an advanced age.

Adult-Onset Genetic Leukoencephalopathies. Focus on the More Recently Defined Forms

Article

Oct 2014
CURR MOL MED

Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brain white matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range of overlapping neurological manifestations possibly associated with variable systemic involvement are found in these disorders making clinical diagnosis challenging. Advances in molecular genetics enabled the identification of the responsible genes of an increasing number of previously undefined forms. This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of which have an autosomal dominant inheritance. The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinal microangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will be detailed because of the vascular based myelin damage and the recent genetic characterization. Other adult onset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD) due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X-associated tremor/ataxia syndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variants of the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally, palliative, curative and experimental treatment options are here summarized.

CADASIL: The most common hereditary subcortical vascular dementia

Article

Nov 2008
Future Neurol

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by the defective NOTCH3 gene, which encodes a transmembrane receptor; over 170 different mutations are known. The main clinical features are migraine with aura (often atypical or isolated), strokes, cognitive decline/dementia and psychiatric symptoms. Executive and organizing cognitive functions are impaired first, memory is affected late. Typical MRI findings are T2 weighted hyperintensities in temporopolar white matter and the capsula externa. Smooth muscle cells in small arteries throughout the body degenerate and vessel walls become fibrotic. In the brain, this results in circulatory disturbances and lacunar infarcts, mainly in cerebral white matter and deep gray matter. The exact pathogenesis is still open: a dominant-negative toxic effect is suggested, possibly related to Notch3 misfolding. Diagnosis is reached either by identifying a pathogenic NOTCH3 mutation or by electron microscopic demonstration of granular osmiophilic material in a (skin) biopsy. Only symptomatic treatment is available at present.

Brain Microvascular Accumulation and Distribution of the NOTCH3 Ectodomain and Granular Osmiophilic Material in CADASIL

Article

Apr 2013
J NEUROPATH EXP NEUR

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial brain arteriopathy, is associated with deposition of granular osmiophilic material (GOM). We used immunohistochemistry and immunogold electron microscopy (EM) to examine the distribution of GOM and NOTCH3 ectodomain (N3ECD) protein in microvasculatureof brain gray matter and white matter in patients with CADASIL, non-CADASIL hereditary small-vessel disease and sporadic age-related degenerative disease, and comparable-age controls. We observed intense immunostaining patterns with 2 different anti-N3ECD antibodies in CADASIL but not in young and older controls or other small-vessel disease patients. In addition, CADASIL samples exhibited immunoreactivity in arterial walls and in most capillaries. Electron microscopy revealed profound and widespread extracellular distribution of 0.2- to 2-μm GOM deposits associated with meningeal vessels and perforating arteries and arterioles. Granular osmiophilic material was adjacent to capillaries even within white matter. Immunogold EM with antibody A1-1 to N3ECD revealed abundant particles in GOM within microvessels, vascular smooth muscle cell membranes, and perivascular cells. Granular osmiophilic material did not exhibit immunogold labeling for smooth muscle α-actin or collagen IV. These results showed the specificity of the antibodies and confirm the predominant localization of N3ECD within GOM deposits. The extensive distribution of N3ECD-GOM complexes within meninges, arteries, arterioles, and particularly capillaries in the brains of CADASIL patients suggests that NOTCH3 fragments are major components of GOM deposits, which may be eliminated via perivascular routes.

Topical Pimecrolimus 1% Cream in the Treatment of Seborrheic Dermatitis

Article

Feb 2013

Seborrheic dermatitis is a multifactorial skin disease characterized by a chronic course with periods of exacerbation and remission. Although topical corticosteroids have been the mainstay of treatment, alternative therapies are often needed to avoid protracted use of topical corticosteroid therapy in order to avert side effects and to sustain control of the disorder. Topical pimecrolimus, a calcinuerin inhibitor, is a safe alternative for seborrheic dermatitis and is more ideal for long-term use. More specifically, topical pimecrolimus not only has an attractive safety profile with no risk of many of the potential side effects seen with topical corticosteroids, but also has favorable efficacy data, including more data on long-term use. This is a review of literature evaluating the efficacy and safety profile of topical pimecrolimus 1% cream for the treatment of seborrheic dermatitis.

CADASIL 2002

Data

Full-text available

Nov 2012

The Handbook of Alzheimer's Disease and Other Dementias

Chapter

Sep 2011

IntroductionVaD Incidence and PrevalenceVaD Diagnosis and Clinical FeaturesNeuropathological Findings in VaDPathophysiology of VaDRisk Factors for VaDTreatment and Intervention of VaDFuture DirectionsAcknowledgmentsReferences

Migraine and Genetic and Acquired Vasculopathies

Article

Sep 2009
CEPHALALGIA

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.

The CADASIL Syndrome and Other Genetic Causes of Stroke and Vascular Dementia

Chapter

Jan 2005

Genetic factors play an important role in the etiology of stroke and vascular dementia (VaD). Genetic influences are primarily polygenic, although several monogenic disorders causing stroke have recently been identified. The clearest example of a monogenic disorder causing small artery stroke and vascular dementia is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. CADASIL is a useful model for studying the pathogenesis of small artery disease and the correlation between imaging changes and the evolution of clinical symptoms in VaD. CADASIL is a nonatherosclerotic, nonamyloid angiopathy caused by mutations in the Notch-3 gene on chromosome 19. Affected individuals develop subcortical strokes, cognitive deficits, migraines with aura, mood disorders, pseudobulbar palsy, and physical disability in their 50s and 60s (1). Brain magnetic resonance imaging (MRI) reveals large areas of leukoencephalopathy and multiple subcortical lacunar infarctions. More than 500 families have been identified worldwide (2), but the disease is underdiagnosed and its prevalence is unknown. The first transgenic model expressing a notch3 mutation has been developed and considerable progress has been made in understanding the physiology of notch3 signaling and the sequence of arterial degeneration in CADASIL. This chapter concludes with a review of the recent advances in identifying gene candidates of other monogenic and polygenic disorders associated with stroke.

Simultaneous Impairment of Intracranial and Peripheral Artery Vasoreactivity in CADASIL Patients

Article

Full-text available

Dec 2011
CEREBROVASC DIS

Reduced cerebrovascular reactivity (CVR) is an important step in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The present study utilized quantitative single photon emission computed tomography (SPECT) with the autoradiographic (ARG) method and reactive hyperemia peripheral arterial tonometry (RH-PAT) to assess vasoreactivity in intracranial arteries and in peripheral arteries in patients with CADASIL. Quantitative SPECT studies were conducted in eight patients with CADASIL, while RH-PAT analysis was conducted in eight CADASIL patients and in eight age-matched normal subjects. Quantitative SPECT studies with the ARG method were performed at baseline and after administration of acetazolamide. Regional cerebral blood flow (rCBF) values were measured using stereotactic extraction estimation (SEE) methods. The rCBF of CADASIL patients was averaged in the bilateral frontal, temporal, parietal, and occipital lobes as well as in the limbic system, cerebellar hemisphere, whole cerebral cortex and basal ganglia. The CVR index from acetazolamide stress of intracranial arteries was calculated in each area. Vasoreactivity of peripheral arteries was estimated by the reactive hyperemia index (RHI) measured with a PAT device before and after interruption of arterial flow. Average RHI after post-deflation was lower in CADASIL patients than in normal subjects. RHI correlated significantly with CVR in all brain areas in CADASIL patients. Vasoreactivity is reduced in peripheral arteries and in intracranial arteries in patients with CADASIL.

CADASIL: Experimental insights from animal models

Article

Oct 2010
STROKE

Cenk Ayata

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited form of small vessel disease, characterized by frequent migraine attacks with aura, recurrent strokes and progressive white matter degeneration. Early vascular cognitive impairment progresses into frank dementia of subcortical type later in life. Linked to mutations in the NOTCH3 gene, CADASIL vasculopathy is associated with accumulation of granular osmiophilic material and NOTCH3 extracellular domain around small caliber arteries and arterioles, and eventual loss of vascular smooth muscle cells. Cerebral blood flow dysregulation has been hypothesized as a major mechanism, largely based on evidence from hemodynamic studies in CADASIL patients. Although animal models expressing CADASIL mutations reproduced the pathology and cerebrovascular dysfunction, the phenotypic spectrum has been quite heterogeneous, possibly due to the choice of genetic constructs and obvious species differences between mouse and man. Nevertheless, these experimental models provide new opportunities to explore the molecular and physiological mechanisms of CADASIL, and address the fundamental question of whether CADASIL phenotype represents loss of NOTCH3 function or gain of a novel and pathological function. Here, I provide an overview of existing animal models of CADASIL and the pathophysiological insights gained from these models.

Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

Article

Nov 2010
NEUROPATH APPL NEURO

Y. Yamamoto, L. Craggs, M. Baumann, H. Kalimo and R. N. Kalaria (2011) Neuropathology and Applied Neurobiology 37, 94–113 Molecular genetics and pathology of hereditary small vessel diseases of the brain Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)‐related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell‐signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor‐β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1 , which encodes an abundant 3′–5′ DNA‐specific exonuclease. TREX1 mutations lead to detrimental gain‐of‐function or insufficient quantities of enzyme. The COL4A1‐related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.

Cognitive impairment of vascular origin: Neuropathology of cognitive impairment of vascular origin

Article

Dec 2010

Isidre Ferrer

The term cognitive impairment of vascular origin is used to designate global cognitive deficits as well as focal neurological deficits such as aphasia, apraxia and agnosia of vascular/circulatory origin. It has been useful for identifying early clinical and neuroradiological alterations that might permit therapeutic strategies geared to curbing the progression of cerebrovascular disease. Multi-infarct encephalopathy, infarcts in strategic areas, lacunae and lacunar status, Binswanger's encephalopathy, hippocampal sclerosis, cortical granular atrophy and watershed infarcts are common lesions. Hypertension and vascular diseases such as arteriosclerosis, small blood vessel disease, inflammatory diseases of the blood vessels, Sneddon syndrome, cerebral amyloid angiopathies, cerebral autosomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Maeda's syndrome are causative of cognitive impairment of vascular origin. Other less common causes are hereditary endotheliopathy with retinopathy, neuropathy and strokes (HERNS), cerebro-retinian vasculopathy (CRV), hereditary vascular retinopathy (HVR) (all three linked to 3p21.1-p21.3), hereditary infantile hemiparesis with arteriolar retinopathy and leukoencephalopathy (HIHRATL) (not linked to 3p21), fibromuscular dysplasia, and moya-moya disease. Lack of uniformity of clinical manifestations, the variety of vascular diseases and circulatory factors, the diverse, but often convergent, neuropathological substrates, and the common association with unrelated neurodegenerative diseases in the elderly, make it hard to assume a single clinical approach in the diagnosis and treatment of cognitive impairment of vascular origin. Rather, environmental and genetic risk factors, underlying vascular diseases, associated systemic, metabolic and neurodegenerative diseases and identification of extent and distribution of lesions with morphological and functional neuroimaging methods should be applied in every individual patient.

Confluent thalamic hyperintensities in CADASIL

Article

Aug 2010
CEREBROVASC DIS

CADASIL is responsible for diffuse hyperintensities in the white matter on FLAIR images. These lesions are often associated with focal lesions in the basal ganglia such as lacunar infarctions. The prevalence and significance of diffuse or confluent thalamic hyperintensities (CTH) remain unknown. The frequency of hyperintensities on FLAIR images in the thalamus was assessed in 147 CADASIL patients, and signal abnormalities on both FLAIR and T(1)-weighted images were categorized as focal/punctuate or diffuse/confluent by the same reader. The areas of increased diffusion were also analyzed on apparent diffusion coefficient maps. The association of CTH with vascular risk factors, the main clinical manifestations of the disease and MRI markers (brain parenchymal fraction, volume of white matter hyperintensities, volume of lacunar infarcts and number of microbleeds) was analyzed with generalized linear regression models. CTH were detected in 12% of the CADASIL subjects in association with hypointensities on T(1)-weighted images. CTH corresponded to areas of increased diffusion on apparent diffusion coefficient maps. CTH were found significantly associated with age and independently related to the volume of white matter hyperintensities but not to that of lacunar infarctions or to cerebral atrophy after adjustment for age and sex. No significant association was found between CTH and global cognitive performances. CTH are observed on FLAIR images in a sizeable proportion of CADASIL patients. They are mainly related to the extent of white matter hyperintensities and do not correlate with cognitive decline. Demyelination and/or loss of glial cells appear to be the most plausible cause of these confluent signal changes in the thalamus.

Pathophysiology of CADASIL disease

Article

Full-text available

Jul 2010

The pathogenic mechanism underlying Cerebral Autosomal Dominant Artheriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) remains elusive although the disease is well characterized at clinical, histological and genetic level. The conservation of the Notch pathway among species allowed the development of several animal and cellular models in order to study it. This review analyzes the reliability of the 7 pathogenic models raised for CADASIL disease: autoimmune origin, mitochondrial dysfunction, loss of Notch3 function, granular osmiophilic material (GOM) toxicity and long term unfolded protein response (UPR) activation. Besides, the relationship between vascular smooth muscle cells (VSMC) degeneration, ischemic lesions and symptoms are discussed. Lastly, some theories are pointed that would explain the exclusiveness of clinical expression to the neural system, being in fact a systemic artheriopathy. Copyright 2009 Elsevier España, S.L. All rights reserved.

Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707-710

Article

Full-text available

Oct 1996

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 sub-cortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuro-imaging1,2. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries3. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis4. We have previously mapped the mutant gene to chromosome 19 (ref. 5). 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.

Role of the endothelial cytoskeleton in blood-brain-barrier permeability to protein

Article

Full-text available

Feb 1995

Sukriti Nag

The role of the cytoskeletal elements, microfilaments and microtubules in cerebral endothelial permeability to protein during steady states was investigated by studies of cerebrovascular permeability to horseradish peroxidase (HRP) in rats pretreated with cytochalasin B or colchicine, agents known to disrupt microfilaments and microtubules, respectively. In addition, the effect of colchicine pretreatment on the alterations in cerebrovascular permeability that occur in acute hypertension were studied. Rats infused with cytochalasin B showed increased cerebrovascular permeability to HRP in multifocal areas of the ipsilateral hemisphere. Most of the permeable vessels were arterioles; however, capillaries and venules also showed increased permeability. Ultrastructural studies of permeable vessels showed HRP in all layers of vessel walls and in endothelial and smooth muscle cell pinocytotic vesicles, which were increased in number. Although segments of interendothelial spaces were labeled by tracer, continuous labeling of interendothelial spaces from the luminal to the abluminal end was not seen and tight junctions were not disrupted. Normotensive rats pretreated with colchicine showed no alteration in cerebrovascular permeability to HRP. Colchicine pretreatment attenuated the permeability alterations that were observed in acutely hypertensive rats. This study demonstrates that integrity of endothelial actin filaments is important for maintenance of the blood-brain barrier to protein during steady states since increased permeability occurred in the presence of an actin disrupting agent. The microtubular network had no demonstrable role during steady states; however, disruption of the microtubular network had a protective effect and prevented the development of alterations in permeability to protein in acute hypertension.

A patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) confirmed by sural nerve biops

Article

Full-text available

Mar 1996

Herditary multi-infarct dementia

Article

May 1977

A family is described in which for three subsequent generations numerous individuals were affected with a progressive neuropsychiatric disease with pyramidal, bulbar and cerebellar symptoms, relapsing course and gradually evolving severe dementia. Post-mortem studies performed on three siblings afflicted with the disease suggest that the remarkably uniform macroscopic picture of the cerebral changes consisting in multiple small cystic infarctions, particularly localized to the central grey and white matter and pons as well as the cortical and central brain atrophy, is caused by an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Collected pertinent information concerning the affected family members shows that the illness begins in early adulthood (at 29–38 years of age), affects both sexes and generally lasts for 10–15 years. The only exception so far noticed was a second generation descendant of one of the siblings. This patient died about 5 months after clinical onset of the disease in masslve cerebral haemorrhage and showed similar vascular changes as the older members of the family. The disease is considered to be genetically caused and transmitted as a dominant autosomal character. For this apparently new nosological entity the eponym “hereditary multi-infarct dementia” is suggested.

Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Article

Jan 1995

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, non-amyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.

Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease

Article

Sep 1977

A family is described in which for three subsequent generations numerous individuals were affected with a progressive neuropsychiatric disease with pyramidal, bulbar and cerebellar symptoms, relapsing course and gradually evolving severe dementia. Post-mortem studies performed on three siblings afflicted with the disease suggest that the remarkably uniform macroscopic picture of the cerebral changes consisting in multiple small cystic infarctions, particularly localized to the central grey and white matter and pons as well as the cortical and central brain atrophy, is caused by an occlusive disease of small intracerebral and leptomeningeal arteries and arterioles. Collected pertinent information concerning the affected family members shows that the illness begins in early adulthood (at 29--38 years of age), affects both sexes and generally lasts for 10--15 years. The only exception so far noticed was a second generation descendant of one of the siblings. This patient died about 5 months after clinical onset of the disease in massive cerebral haemorrhage and showed similar vascular changes as the older members of the family. The disease is considered to be genetically caused and transmitted as a dominant autosomal character. For this apparently new nosological entity the eponym "hereditary multi-infarct dementia" is suggested.

Autosomal dominant syndrome with strokelike episodes and leukoencephalopath

Article

Nov 1991

We conducted a prospective survey of a family presenting a new syndrome characterized mainly by recurrent strokelike episodes and neuroimaging evidence of leukoencephalopathy. Forty-five members of a single family were studied clinically and with magnetic resonance imaging. Nine had strokelike episodes, including transient ischemic attacks, and minor or major strokes starting between the fourth and sixth decades, with neuroimaging evidence of small, deep infarcts and a widespread white matter disorder. Other symptoms included migraine (three), dementia (two), epilepsy (one), and hearing loss (one). In some patients, we found various immunologic anomalies and muscular lipidosis without ragged-red fibers. Eight other family members were clinically normal, but had identical neuroimaging signs of leukoencephalopathy. No abnormality was detected in the 28 other members of the family examined. Extensive investigations failed to reveal any known cause of cerebral ischemia. There appears to be a new syndrome in this family that is characterized by recurrent subcortical strokelike episodes, leukoencephalopathy, immunologic anomalies, muscular lipidosis, and an autosomal dominant pattern of transmission.

Sclerosing Vasculopathy of the Central Nervous System in Nonelderly Demented Patients

Article

Jul 1991
ARCH NEUROL-CHICAGO

Three nonelderly patients without hypertension whose clinical and radiologic features otherwise resembled Binswanger's subcortical arteriosclerotic encephalopathy underwent biopsy of the hyperintense periventricular lesions seen on magnetic resonance imaging. The pathologic findings of the periventricular lesions consisted of gliosis with mild rarefaction and edema of the white matter. All patients had a sclerosing vasculopathy of unknown cause, which involved numerous small vessels within the periventricular lesions. The vessels stained negatively for amyloid, amyloid precursors, desmin, vimentin, keratin, immunoglobulin, and complement. On electron microscopy, small arteries, arterioles, venules, and capillaries were characterized by swollen astrocytic foot processes surrounding the vessels; dense, perivascular collagen packing; crystalline arrays of filaments within basement membrane; giant lipid-laden lysosomes within perivascular cells; and narrowing of the vascular lumina. Similar changes were not seen in a control group of 19 patients. The pathologic features of the vessels in these cases are distinct from the vasculopathy associated with Binswanger's subcortical arteriosclerotic encephalopathy. We suggest that a spectrum of vasculopathies may be associated with dementia and periventricular hyperintense lesions on magnetic resonance imaging.

Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Article

Feb 1995

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL) has recently been identified as a hereditary disorder with characteristic fine structural changes of small intracerebral arteries and arterioles. Electron microscopically there are characteristic perivascular deposits of granular electron-dense material resembling immunoglobulin deposits. The present case from a family with four affected members in three successive generations shows that similar vascular changes as described in the central nervous system are present in blood vessels of the sural nerve, although less pronounced and, therefore, affording electron microscopy for their unequivocal detection. Nevertheless it has been shown for the first time that the diagnosis of CADASIL can be verified by a sural nerve biopsy. Occasional focal accumulation of pinocytotic vesicles opposite the granular deposits suggests exocytosis as one of the possible pathomechanisms for their production.

Summary of the proceedings of the First International Workshop on CADASIL. Paris, May 19-21, 1993

Article

Apr 1994

Presence of CADASIL ultrastructural arterial lesions in muscle and skin vessels

Article

Dec 1994

Small arterial granular degeneration in familial Binswanger's syndrom

Article

Feb 1994

A 55-year-old mildly hypertensive woman died after having developed a subcortical dementia during the past 9 years, with focal neurological signs. She presented at the age of 46 years with short episodes of dizziness and diplopia, suggesting that transient ischemic attacks involved the posterior fossa structures. Over the next 8 years, she developed difficulty in walking, urinary incontinence and seizures. On examination in 1989, she was severely demented. There was tetraparesis, bilateral arm and leg spasticity with hyperreflexia and bilateral Babinski signs. She showed epilepsia partialis continua involving the eyes, left hemiface and limbs. CT showed hypodensity of the white matter and lacunes in the basal ganglia and centrum semiovale, moderate hydrocephalus with cerebellar and cortical atrophy. Clinical and radiological features were similar to those of Binswanger's disease. Similar cases had occurred in the family affecting the patient's grandfather, father and two brothers, suggesting an autosomal dominant hereditary disease. Postmortem examination disclosed a Binswanger type of leukoencephalopathy caused by a peculiar microangiopathy characterized by a slightly basophilic small arterial granular degeneration of the medial sheath associated with the presence of ballooned smooth muscle cells with clear cytoplasm. Electron microscopic study revealed degenerative changes in the parietal vessels with notable increase of basal-membrane-type material and electron-dense granular deposits. These lesions could correspond to a specific familial pathology of the small arteries of the brain. They are identical to those reported in some patients with autosomal dominant inheritance. For other patients with similar clinical features and the same familial pattern, reported as "hereditary multi-infarct dementia'' and "chronic familial vascular encephalopathy'', there are no sufficient objective pathological facts to consider that they have the same disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Autosomal dominant arteriopathic leuko-encephalopathy and Alzheimer's diseas

Article

Mar 1994

A 49-year-old man suffered from progressive dementia and seizures leading to death after 2 years. CT scans showed severe cortical-subcortical atrophy and hypodensity of the white matter. His father had died at about the same age with similar clinical signs. Two sisters and one brother were also affected. Neuropathological study revealed predominant involvement of the cerebral white matter with myelin loss, gliosis and type I lacunes. The small arteries and arterioles of the white matter and basal ganglia, and, to a lesser extent those of the subarachnoidal space, displayed fibrosis and replacement of the media by an eosinophilic, PAS positive, Congo Red negative, granular substance. Electron microscopy showed swollen myocytes surrounded by collagen, elastin and a compact electron-dense material. Immunofluorescence using antibodies against IgA, IgG, IgM, C1q and C3 stained the abnormal media weakly. In the cortex, there were diffuse senile plaques and neurofibrillary tangles. Immunohistochemistry demonstrated beta/A4 positive material in cortical senile plaques but not in arterial walls. Adventitial macrophages were, however, immunoreactive for gamma-trace. Systemic arterioles were normal. The vascular changes and leukoencephalopathy are comparable to those described in 'Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy' (CADASIL). Similar vascular changes were also observed in nonfamilial cases. An association with Alzheimer changes in the cortex has not been described previously. The relationship between both diseases and the role of each in the causation of the dementia is unclear.

Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor

Article

Aug 1993
CELL

The Notch gene of Drosophila plays an important role in cell fate specification throughout development. To investigate the functions of specific structural domains of the Notch protein in vivo, a series of deletion mutants have been ectopically expressed under the hsp70 heat shock promoter. Two classes of dominant phenotypes are observed, one suggestive of Notch loss-of-function mutations and the other of Notch gain-of-function mutations. Dominant activated phenotypes result from overexpression of a protein lacking most extracellular sequences, while dominant negative phenotypes result from overexpression of a protein lacking most intracellular sequences. These results support the notion that Notch functions as a receptor whose extracellular domain mediates ligand binding, resulting in the transmission of developmental signals by the cytoplasmic domain. Finally, the phenotypes observed suggest that the cdc 10/ankyrin repeat region within the intracellular domain plays an essential role in the postulated signal transduction events.

Autosomal dominant leukoencephalopathy and subcortical ischemic stroke. A clinicopathological study

Article

Feb 1993

We recently described an autosomal dominant syndrome characterized mainly by recurrent strokes and neuroimaging evidence of leukoencephalopathy. We now report the pathological findings in one of the affected subjects. A 40-year-old woman experienced her first grand mal seizure in 1971. From 1983 on she suffered recurrent strokes, seizures, and psychiatric disturbances with depressions, manic episodes, and dementia. In 1988, after her fourth stroke, she became tetraplegic with a severe pseudobulbar palsy, and she died in 1990. Pathological examination disclosed a recent capsulolenticular hematoma, multiple small deep infarcts, a diffuse myelin loss and pallor of the hemispheric white matter, and a widespread vasculopathy of the small arteries penetrating the white matter. The arterial wall was markedly thickened with an extensive nonamyloid eosinophilic deposit in the media and reduplication of the internal elastic lamella. The underlying lesion of this hereditary disorder is located in the small arteries and is of unknown etiology. It differs from arteriosclerotic and amyloid angiopathies but is similar to that described in some cases of hereditary multi-infarct dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12

Article

Apr 1993

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non-arteriosclerotic, non-amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - Confirmation by cerebral biopsy in 2 cases

Article

Jul 1995
CLIN NEUROPATHOL

CADASIL is a recently recognized familial form of subcortical multi-infarct dementia. The pathogenesis of the disease is unknown, but it is characterized pathologically by a novel vasculopathy affecting leptomeningeal and subcortical arteries. We describe 2 cases in which the diagnosis could be made from the cerebral biopsy appearances of affected leptomeningeal vessels. The ultrastructural appearances of the vessel wall deposit are illustrated, and their similarity to those of immune complex deposits discussed.

Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian NOTCH gene

Article

Aug 1996

The int-3 oncogene was identified as a frequent target in Mouse Mammary Tumor Virus (MMTV)-induced mammary carcinomas and encodes the intracellular domain of a novel mouse Notch gene. To investigate the role of the int-3 proto-oncogene in mouse development and carcinogenesis, we isolated cDNA clones corresponding to the entire coding potential of the int-3 proto-oncogene. We propose to name this gene Notch4 and reserve the int-3 nomenclature for references to the oncogenic form. The deduced amino acid sequence of Notch4 contains conserved motifs found in Notch proteins; however Notch4 has fewer epidermal growth factor (EGF)-like repeats and a shorter intracellular domain than other mouse Notch homologues. Comparison of the coding potential of the int-3 gene to that of Notch4 suggests that loss of the extracellular domain of Notch4 leads to constitutive activation of this murine Notch protein. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life. Truncated Notch4 transcripts were detected in post-meiotic male germ cells. The distinct Notch4 protein features and its restricted expression pattern suggests a specific role for Notch4 during development of vertebrate endothelium.

Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy

Article

Sep 1996

We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue.

Notch 3 mutations in CADASIL, a hereditary adult‐onset condition causing stroke and dementia.

Joutel A

Endothelial changes in muscle and skin biopsies in patients with CADASIL

Abstract

No full-text available

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