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Neurology 2020 Jun 25. Epub 2020 Jun 25.

Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Objective: To assess the relationship between iron accumulation, blood-brain barrier (BBB) damage, and cognitive function in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Methods: We enrolled 21 patients with mutations and 21 age-matched healthy controls in this cross-sectional study. All participants underwent global physical and cognitive assessments and brain MRI, using voxel-based quantitative susceptibility mapping (QSM; iron deposition measure) and dynamic contrast enhanced MRI (DCE-MRI; BBB permeability measure). Read More

Neurol Genet 2020 Jun 11;6(3):e434. Epub 2020 May 11.

Department of Neurology (G.X., C.M., D.G., A.P., M.S., G.M.H.), University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece; Second Department of Neurology (C.Z., A.T., P.Z., A.B., K.V., G.T.), "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece; Department of Neurology (G.M.H.), Medical School, University of Cyprus, Nicosia, Cyprus; Department of Hygiene and Epidemiology (K.D., C.H.), Faculty of Medicine, University of Thessaly, Larissa, Greece; Department of Medical Oncology (P.N.), University Hospital of Ioannina, Ioannina, Greece; Department of Neurology (P.S.), Mediterraneo Hospital, Glyfada, Athens, Greece; Histopathological Department (C.N., S.S.), Hippokration General Hospital Thessaloniki; and Department of Neurology (G.P.P.), School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece.

Objective: The aim of this study was to evaluate the correlation between the various mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.

Methods: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. Read More

J Neurol Sci 2020 Jun 9;416:116980. Epub 2020 Jun 9.

Department of Neurology, King's College Hospital, London, UK.

Mov Disord 2020 Jun 23. Epub 2020 Jun 23.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

Background: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease.

Methods: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. Read More

PLoS One 2020 18;15(6):e0234797. Epub 2020 Jun 18.

Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: Characteristics of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cysteine-sparing NOTCH3 mutations are relatively unknown. This study compared clinical and imaging characteristics between patients with CADASIL and cysteine-sparing NOTCH3 mutations and those with CADASIL and cysteine-involving NOTCH3 mutations.

Methods: We retrospectively reviewed medical records of patients with CADASIL admitted to the Asan Medical Center between September 1999 and September 2017. Read More

J Am Heart Assoc 2020 Jun 17:e016233. Epub 2020 Jun 17.

Department of Neurology Neurological Institute Taipei Veterans General Hospital Taipei Taiwan.

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by mutations, is characterized by recurrent ischemic strokes and progressive cognitive decline. It remains unclear whether cerebral microbleeds (CMBs) can serve as a surrogate marker for disease progression in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. We aimed to investigate the CMB burdens in mutation carriers at different disease stages and test their associations with cognitive performance. Read More

J Headache Pain 2020 Jun 5;21(1):64. Epub 2020 Jun 5.

Department of Neurology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.

Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Read More

J Int Neuropsychol Soc 2020 Jun 3:1-13. Epub 2020 Jun 3.

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114, USA.

Objectives: Executive dysfunction is a predominant cognitive symptom in cerebral small vessel disease (SVD). The Institute of Cognitive Neurology Frontal Screening (IFS) is a well-validated screening tool allowing the rapid assessment of multiple components of executive function in Spanish-speaking individuals. In this study, we examined performance on the IFS in subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited condition leading to the early onset of SVD. Read More

Front Aging Neurosci 2020 14;12:130. Epub 2020 May 14.

Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of gene mutations in the patients at highest risk who were admitted for lacunar infarctions. Read More

J Neurol Sci 2020 May 21;415:116931. Epub 2020 May 21.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Department of Amyloidosis Research, Nagasaki International University, Sasebo 859-3298, Japan.

To detect vascular Notch3 extracellular domain aggregates in CADASIL, we developed a novel dot-blot assay with both autopsy and biopsy skin samples. We obtained samples from 11 patients with CADASIL and 12 control patients, and we performed dot-blot analyses by using sequential biochemical tissue extractions with three different antibodies against specific regions of the Notch3 extracellular domain. We also analyzed clinical features and vascular accumulations of Notch3 by immunohistochemistry. Read More

Front Aging Neurosci 2020 7;12:91. Epub 2020 May 7.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease caused by mutations in , is characterized by recurrent stroke without vascular risk factors, mood disturbances, and dementia. MRI imaging shows cerebral white matter (WM) hyperintensity, particularly in the external capsule and temporal pole. Missense mutations related to a cysteine residue in the 34 EGFr on the NOTCH3 extracellular domain (N3ECD) are a typical mutation of CADASIL. Read More

Neurology 2020 Jun 19;94(23):1040-1041. Epub 2020 May 19.

From the Departments of Neurology (E.D.G., J.J.M.) and Neuroradiology (S.M.), University of Utah, Salt Lake City.

J Stroke Cerebrovasc Dis 2020 Jul 13;29(7):104832. Epub 2020 May 13.

Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; OMIM #125310) is the most common cause of monogenic familial cerebral small vessel disease. It typically manifests at middle adulthood with highly variable clinical features including migraine with aura, recurrent transient ischemic attacks or ischemic strokes, mood disorders, and progressive cognitive decline. It is caused by mutations in the NOTCH3 gene, which maps to the short arm of chromosome 19 and encode for epidermal growth factor-like repeats. Read More

Stroke 2020 Jun 13;51(6):1750-1757. Epub 2020 May 13.

From the Department of Neurology, Peking University First Hospital, Beijing, China (C.S., C.L., Z.X., Y.S., W.Z., Z.W., Y.Y.).

Background and Purpose- Distribution patterns of iron deposition in deep gray matter and their association with clinical characteristics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) remain unclear. We aimed to evaluate iron deposition in deep gray matter in patients with CADASIL using 7.0-T susceptibility-weighted imaging and mapping and to explore its correlations with clinical characteristics. Read More

J Stroke Cerebrovasc Dis 2020 Jul 6;29(7):104803. Epub 2020 May 6.

Neurology Service, Hospital San Bernardo, Salta Capital, Argentina.

Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), is a genetic disease caused by mutations in the Notch3 gene. More than 170 monogenic mutations leading to the development of CADASIL have been reported. We describe a case of a patient and her family with compatible symptoms of CADASIL disease, in which a variable not yet described in the Notch3 gene was detected, that generates a probably pathogenic change in the protein. Read More

Eur J Neurol 2020 Apr 29. Epub 2020 Apr 29.

Department of Neurology and CERVCO, Reference Center for Rare Vascular Diseases of the Eye and Brain, Hôpital Lariboisiére, APHP, Paris, France.

Background And Purpose: In 2019, the Brain Prize crowned the discovery of CADASIL in the 1990s and research efforts on this archetypal small vessel disease of the brain over 40 years.

Methods And Results: The hereditary origin of this arteriolopathy was discovered from a first clinical case and detailed observation of the patient's family. Thereafter, the role of causative mutations within the NOTCH3 gene were identified, allowing the development of a genetic test and then of an animal model of the disease. Read More

Stem Cell Res 2020 May 22;45:101821. Epub 2020 Apr 22.

Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, United States.

We have successfully generated induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells of five patients with Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These cells carry the genetic NOTCH3 mutation present in their parental cells. These iPSC cells exhibited normal karyotype and phenotype, which were sustained through propagation. Read More

Folia Neuropathol 2020 ;58(1):83-92

Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland.

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, progressive ischemic disease of small vessels of the brain characterized by migraine with aura (MA), recurrent subcortical ischemic episodes, cognitive decline and psychiatric disorders. CADASIL is caused by mutations in the NOTCH3 gene. We identified the NOTCH3 Y189C mutation as a genetic cause of CADASIL in a Polish family and provided its first clinical manifestation. Read More

Radiol Bras 2020 Mar-Apr;53(2):129-136

Hospital Universitário Cassiano Antônio de Moraes da Universidade Federal do Espírito Santo (HUCAM/UFES), Vitória, ES, Brazil.

Various neuropathologies produce hyperintense signals on T2-weighted or fluid-attenuated inversion recovery sequences of the temporal lobes. Recognition of the distribution pattern and associated findings may narrow the spectrum of differential diagnoses or suggest a specific disease. This pictorial essay aims to illustrate the relatively common diseases that affect the temporal lobe, such as herpes simplex encephalitis, neurosyphilis, limbic encephalitis, postictal edema, neoplasia, and multiple sclerosis, as well as those that are less common, such as myotonic dystrophy type 1, CADASIL, and CARASIL, together with the particularities of each entity. Read More

J Neuroinflammation 2020 Apr 22;17(1):124. Epub 2020 Apr 22.

Stroke Center and Department of Neurology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10055, Taiwan.

Background: Stroke remains the most cumbersome disease burden in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to investigate whether plasma biomarkers can reflect disease severity and predict stroke recurrence in CADASIL patients.

Methods: Sixty-three CADASIL patients (mean age 58. Read More

J Neurol 2020 Apr 21. Epub 2020 Apr 21.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. Read More

Rev Neurol (Paris) 2020 Apr 17. Epub 2020 Apr 17.

AP-HP, Neurology Department, Pitié-Salpêtrière hospital, 47-83 Boulevard de l'Hôpital, 75013 Paris, France. Electronic address:

Biochim Biophys Acta Mol Basis Dis 2020 Aug 14;1866(8):165797. Epub 2020 Apr 14.

Cellular and Molecular Neurobiology Area, Group of Neuroscience, SIU, Faculty of Medicine, University of Antioquia UdeA, Calle 70 No. 52 - 21, Medellín, Colombia. Electronic address:

Sporadic Alzheimer's disease (SAD) is the most common form of dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary ischemic small vessel disease of the brain. Relevant biomarkers or specific metabolic signatures could provide powerful tools to manage these diseases. Therefore, the main goal of this study was to compare the postmortem frontal cortex gray matter, white matter and cerebrospinal fluid (CSF) between a cognitively healthy group and CADASIL and SAD groups. Read More

J Hum Genet 2020 Aug 10;65(8):637-646. Epub 2020 Apr 10.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. Read More

Front Pharmacol 2020 13;11:321. Epub 2020 Mar 13.

Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy caused by mutations in the NOTCH 3 gene, located on chromosome 19, usually affecting middle-ages adults, whose clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability. In this review, we provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. The hypothesis that CADASIL is an appropriate model to explore the pathogenesis of sporadic cerebral small vessel disease is also reviewed. Read More

Biomolecules 2020 Mar 23;10(3). Epub 2020 Mar 23.

University of Manchester, Faculty of Biology, Medicine and Health, School of Biological Sciences, Michael Smith Building, Oxford Rd. Manchester M13 9PY, UK.

Notch3 is one of four mammalian Notch proteins, which act as signalling receptors to control cell fate in many developmental and adult tissue contexts. Notch signalling continues to be important in the adult organism for tissue maintenance and renewal and mis-regulation of Notch is involved in many diseases. Genetic studies have shown that gene knockouts are viable and have limited developmental defects, focussed mostly on defects in the arterial smooth muscle cell lineage. Read More

Eur J Neurol 2020 Jun 20;27(6):909-927. Epub 2020 Mar 20.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background And Purpose: Guidelines on monogenic cerebral small-vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. Read More

Mol Brain 2020 03 19;13(1):38. Epub 2020 Mar 19.

Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary cerebral small vessel diseases and is caused by mutations in NOTCH3. Our group has previously reported incorporation of NOTCH3 extracellular domain (N3ECD) in the CADASIL-specific granular osmiophilic materials and increase of PDGFRβ immunoreactivity in CADASIL postmortem brains. Here, we aimed to establish an in vitro model of CADASIL, which can recapitulate those CADASIL phenotypes, using induced pluripotent stem cells (iPSCs). Read More

Case Rep Neurol Med 2020 17;2020:4980847. Epub 2020 Feb 17.

American University of Beirut Medical Center, Department of Neurology, Beirut, Lebanon.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited disorder caused by a mutation in the NOTCH 3 gene, characterized by early onset of subcortical lacunar infarcts in the absence of vascular risk factors and cerebral microbleeds. Homozygosity for the factor Methylenetetrahydrofolate Reductase (MTHFR) is also associated with lacunar stroke risk and cerebral small-vessel disease regardless of the homocysteine level. The coexistence of MTHFR C677T homozygosity and NOTCH 3 mutation has never been reported in the literature previously, and that brings up the challenge of antithrombotic treatment in the presence of cerebral microbleeds. Read More

BMC Neurol 2020 Mar 2;20(1):72. Epub 2020 Mar 2.

Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations. Read More

Exp Neurol 2020 Jun 28;328:113261. Epub 2020 Feb 28.

Departments of Neurology, University of Michigan, Ann Arbor, MI 48109-5622, USA; Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA. Electronic address:

Cerebral small vessel disease is a common condition linked to dementia and stroke. As an age-dependent brain pathology, cerebral SVD may share molecular processes with core neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Many neurodegenerative diseases feature abnormal protein accumulation and aberrant protein folding, resulting in multimerization of specific proteins. Read More

Mult Scler Relat Disord 2020 Jun 19;41:102014. Epub 2020 Feb 19.

Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a common cause of inherited stroke in young adults. CADASIL causes extensive white matter T2 hyperintensities at brain MRI, in particular involving anterior-temporal lobes and external capsules; usually, there is no spinal cord involvement. Since CADASIL clinical spectrum is heterogeneous and MRI findings are sometimes not specific, Multiple Sclerosis (MS) represents a frequent CADASIL misdiagnosis. Read More

J Stroke Cerebrovasc Dis 2020 May 24;29(5):104701. Epub 2020 Feb 24.

Department of Neurology, Tosei General Hospital, Seto, Aichi, Japan.

Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can develop multiple border-zone infarcts due to hypotension, hypovolemia, or surgery. We report the case of a 41-year-old woman with CADASIL who developed multiple border-zone infarcts due to influenza A virus infection. The patient had no apparent history or episode of stroke or altered consciousness following the onset of respiratory symptoms, which were due to the influenza A infection. Read More

Hum Brain Mapp 2020 Jul 22;41(10):2629-2641. Epub 2020 Feb 22.

Institute for Stroke and Dementia Research (ISD), University Hospital, Munich, Germany.

While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL, n = 41) and sporadic SVD (n = 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test-retest reliability of functional network measures in sporadic SVD patients participating in a high-frequency (monthly) serial imaging study (RUN DMC-InTENse, median: 8 MRIs per participant). Read More

Adv Exp Med Biol 2020 ;1218:159-187

Department of Dermatology, The Saarland University Hospital, Homburg, Germany.

The evolutionary highly conserved Notch pathway governs many cellular core processes including cell fate decisions. Although it is characterized by a simple molecular design, Notch signaling, which first developed in metazoans, represents one of the most important pathways that govern embryonic development. Consequently, a broad variety of independent inherited diseases linked to defective Notch signaling has now been identified, including Alagille, Adams-Oliver, and Hajdu-Cheney syndromes, CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), early-onset arteriopathy with cavitating leukodystrophy, lateral meningocele syndrome, and infantile myofibromatosis. Read More

Adv Exp Med Biol 2020 ;1218:1-7

Department of Dermatology, The Saarland University Hospital, Homburg, Germany.

The attention of science first turned to the gene that later earned the name Notch over a century ago, when the American scientist John S. Dexter discovered in his laboratory at Olivet College the characteristic notched-wing phenotype (a nick or notch in the wingtip) in mutant fruit flies Drosophila melanogaster. At present, it is generally accepted that the Notch pathway governs tissue patterning and many key cell fate decisions and other core processes during embryonic development and in adult tissues. Read More

Ann Transl Med 2020 Jan;8(1):10

Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130000, China.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular disease caused by mutations in , that are primarily localized in exons 4, 3, and 11. The Arg332Cys mutation in exon 6 has been rarely reported in patients with CADASIL.

Methods: A case study and the results of a comprehensive systemic search of the PubMed database, using the keywords "CADASIL", "Arg332Cys", "R332C", and "exon 6", are reported. Read More

Clin Case Rep 2020 Jan 8;8(1):47-50. Epub 2019 Dec 8.

Weill Cornell Medical College New York Presbyterian Hospital New York NY USA.

The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) should be considered in patients with late-onset personality change and mania. However, neuropsychological deficits precipitated by the disorder pose significant challenges to recognition and appropriate management of CADASIL in susceptible patients. Read More

Hum Mol Genet 2020 Jan 21. Epub 2020 Jan 21.

Department of Clinical Genetics, Leiden University Medical Center, Leiden.

CADASIL is a vascular protein aggregation disorder caused by cysteine altering NOTCH3 variants, leading to mid-adult onset stroke and dementia. Here, we report individuals with a cysteine altering NOTCH3 variant that induces exon 9 skipping, mimicking therapeutic NOTCH3 cysteine correction. The index came to our attention after a coincidental finding on a commercial screening MRI, revealing white matter hyperintensities. Read More

J Clin Neurosci 2020 Mar 11;73:179-182. Epub 2020 Jan 11.

Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cause of vascular dementia in adults. Migraine is a major symptom of the disease. We aimed to identify clinical and demographical features of the headache associated with increased cerebral lesion burden in a cohort of CADASIL patients. Read More

Zh Nevrol Psikhiatr Im S S Korsakova 2019 ;119(10. Vyp. 2):128-136

Vagner Perm State Medical University, Perm, Russia.

Two cases of clinical and MRI manifestations of genetically verified CADASIL syndrome in female patients under 40 years of age are presented. The primary misinterpretation of clinical data and the neuroimaging results within multiple sclerosis indicates a lack of awareness of radiologists and neurologists about this disease. The article reviewed the current literature on the problems of diagnosis and treatment of CADASIL. Read More

Psychosomatics 2020 Jul - Aug;61(4):395-399. Epub 2019 Nov 20.

Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Neurologic Institute, Cleveland, OH.

Front Neurol 2019 17;10:1321. Epub 2019 Dec 17.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

The white matter disease spectrum is associated with many genetic diseases, including , and others. In this study, to determine the novel mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. Read More

Hum Genomics 2020 Jan 8;14(1). Epub 2020 Jan 8.

Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Our laboratory has been undertaking genetic diagnostic testing for CADASIL since 1997. Work originally utilised Sanger sequencing methods targeting specific NOTCH3 exons. Read More

J Biol Chem 2020 Feb 4;295(7):1960-1972. Epub 2020 Jan 4.

Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5622

The small-vessel disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) arises from mutations in the human gene encoding NOTCH3 and results in vascular smooth muscle cell degeneration, stroke, and dementia. However, the structural changes in NOTCH3 involved in CADASIL etiology are unclear. Here, we discovered site-specific fragmentation of NOTCH3 protein in pathologically affected vessels of human CADASIL-affected brains. Read More

Headache 2020 Feb 26;60(2):396-404. Epub 2019 Dec 26.

Department of Neurological Sciences, The University of Vermont, Burlington, VT, USA.

Objective: To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients.

Background: There is considerable evidence supporting the comorbidity of gastrointestinal dysmotility and migraine. Gastrointestinal motility, however, has never been investigated in transgenic mouse models of migraine. Read More

Expert Rev Neurother 2020 Jan 12;20(1):65-84. Epub 2019 Dec 12.

Myelin Disorders Clinic, Department of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.

: Leukodystrophies constitute heterogenous group of rare heritable disorders primarily affecting the white matter of central nervous system. These conditions are often under-appreciated among physicians. The first clinical manifestations of leukodystrophies are often nonspecific and can occur in different ages from neonatal to late adulthood periods. Read More

J Stroke Cerebrovasc Dis 2020 Feb 6;29(2):104530. Epub 2019 Dec 6.

Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago, Chile; Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile. Electronic address:

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke disorder caused by mutations in the NOTCH3 gene. We report the first Chilean CADASIL family with complete radiological and histological studies.

Methods: The family tree was constructed from an autopsy-confirmed confirmed patient, and includes 3 generations. Read More

Maedica (Buchar) 2019 Sep;14(3):305-309

Department of Radiology and Medical Imaging, Fundeni Clinical Institute, Bucharest, Romania.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease caused by mutations in NOTCH3 gene, characterized by accumulation of a toxic protein in the small and medium size arterioles. Clinical manifestations of CADASIL include lacunar infarcts or, less frequently, large artery ischemic strokes, transient ischemic attacks, dementia, migraine and psychiatric disorders. Brain magnetic resonance imaging (MRI) usually shows multiple lacunar infarcts, diffuse leukoencephalopathy and cerebral microbleeds. Read More

Front Neurosci 2019 15;13:1142. Epub 2019 Nov 15.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.

Maintaining the homeostasis of proteins (proteostasis) by controlling their synthesis, folding and degradation is a central task of cells and tissues. The gradual decline of the capacity of the various proteostasis machineries, frequently in combination with their overload through mutated, aggregation-prone proteins, is increasingly recognized as an important catalyst of age-dependent pathologies in the brain, most prominently neurodegenerative disorders. A dysfunctional proteostasis might also contribute to neurovascular disease as indicated by the occurrence of excessive protein accumulation or massive extracellular matrix expansion within vessel walls in conditions such as cerebral small vessel disease (SVD), a major cause of ischemic stroke, and cerebral amyloid angiopathy. Read More