Search Our Scientific Publications & Authors

Aging Dis 2021 Jun 1;12(3):801-811. Epub 2021 Jun 1.

1Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangdong 510282, China.

The relationship between fibrinogen and white matter hyperintensities (WMHs) are inconsistent. Whether there are different relationships between WMHs and fibrinogen in disparate subtypes of cerebral small vessel disease (CSVD) remains unknown. Here, we investigated the roles of plasma fibrinogen in sporadic CSVD (sCSVD) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients. Read More

Front Aging Neurosci 2021 21;13:617733. Epub 2021 May 21.

German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.

We and others have reported that Notch3 is a regulator of adult hippocampal neurogenesis. (CADASIL), the most common genetic form of vascular dementia, is caused by mutations in . The present study intended to investigate whether there is a correlation between altered adult hippocampal neurogenesis and spatial memory performance in CADASIL transgenic mice. Read More

J Alzheimers Dis 2021 Jun 3. Epub 2021 Jun 3.

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

Background: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia.

Objective: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia.

Methods: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). Read More

Neurologia 2021 May 29. Epub 2021 May 29.

Estudante de Medicina, UNAERP, Ribeirão Preto, Brazil.

Front Cell Neurosci 2021 6;15:656832. Epub 2021 May 6.

Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Cellular and Molecular Neurobiology Area, Medellin, Colombia.

Dysfunction in the neurovascular unit (NVU) is a key component in the progressive deterioration of Alzheimer's disease (AD) and is critical in vascular dementia. Recent studies have shown that inflammation plays early and perhaps causal roles in the pathogenesis of AD related to NVU damage, possibly in part by overactivating the aspartic acid protease activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which until now has almost solely been studied in the context of the β-amyloid cascade. In this study, we analyzed the relationship of BACE1 with astrocytes and blood vessels in human brains with sporadic and familial dementia [Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), sporadic Alzheimer's disease (SAD), and familial Alzheimer's disease (FAD)] and how BACE1 inhibition affects astrocytes and endothelial cells under conditions of glutamate toxicity. Read More

Clin Sci (Lond) 2021 May;135(10):1209-1212

British Heart Foundation Centre of Research Excellence, King's College London, School of Cardiovascular Medicine and Science, London, United Kingdom.

Vascular smooth muscle biology is increasingly exploited as an interventional target in vascular disease. Vascular smooth muscle Notch3-Rho kinase-cGMP interaction has been implicated in brain and peripheral arteriopathy in CADASIL. In the present commentary, we discuss the potential implications for other, more common non-atherosclerotic microvascular diseases: INOCA and HFpEF. Read More

Eur Neurol 2021 May 18:1-9. Epub 2021 May 18.

Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background And Purpose: Studies have shown characteristics of genotypes and phenotypes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to describe the clinical and genetic characteristics of and correlations between the genotypes and phenotypes observed in CADASIL in China on the basis of exon classification.

Methods: Consecutive Chinese patients with CADASIL were evaluated. Read More

Brain 2021 May 17. Epub 2021 May 17.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying pathogenesis is poorly understood, but both neuroinflammation and increased blood-brain barrier permeability have been hypothesized to play a role, and preclinical studies suggest the two processes may be linked. We used PET magnetic resonance to simultaneously measure microglial activation using the translocator protein radioligand 11C-PK11195, and blood-brain barrier permeability using dynamic contrast enhanced MRI. Read More

Brain Connect 2021 May 12. Epub 2021 May 12.

Harvard Medical School, 1811, Psychiatry and Neurology, 100 1st Avenue, suite 101, Charlestown, Boston, Massachusetts, United States, 02129;

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, prior to the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. Read More

CNS Neurosci Ther 2021 May 4. Epub 2021 May 4.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Aims: NOTCH3 gene mutations predominantly cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a common etiology of subcortical vascular dementia (SVaD). Besides, there may be a pathogenic link between NOTCH3 variants and Alzheimer's disease (AD). We aimed to study the role of NOTCH3 variants in AD and SVaD patients. Read More

Transl Stroke Res 2021 May 3. Epub 2021 May 3.

Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA.

Small vessel disease is a prevalent age-related condition linked to increased risk of dementia and stroke. We investigate the most commonly inherited form, CADASIL, caused by cysteine-involving mutations in NOTCH3. Recent studies highlight accumulation of NOTCH3 N-terminal fragmentation product (NTF) in disease. Read More

Neurol Genet 2021 Jun 22;7(3):e584. Epub 2021 Apr 22.

Division of Neurology (S.A., S.K., C.S.), Department of Clinical Neuroscience, Karolinska Institutet; Department of Cell and Molecular Biology (F.D.G., E.-B.B., A.A.L., S.J., U.L.), Karolinska Institutet; and Department of Neurobiology, Care Sciences and Society (D.O., H.K., U.L.), Karolinska Institutet, Stockholm, Sweden.

Objective: To conduct a clinical study of a family with neurologic symptoms and findings carrying a novel mutation and to analyze the molecular consequences of the mutation.

Methods: We analyzed a family with complex neurologic symptoms by MRI and neurologic examinations. Exome sequencing of the locus was conducted, and whole-genome sequencing was performed to identify , , and mutations. Read More

Am J Pathol 2021 Apr 22. Epub 2021 Apr 22.

Schepens Eye Research Institute of the Mass Eye and Ear and Department of Ophthalmology of Harvard Medical School, Boston, Massachusetts. Electronic address:

Mutations in the NOTCH3 gene can lead to small-vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations altering the number of cysteine residues in the extracellular domain of Notch3. Growing evidence indicates that other mutations in NOTCH3, including cysteine-sparing missense mutations or frameshift and premature stop codons, can lead to small-vessel disease phenotypes of variable severity or penetrance. There are currently no disease-modifying therapies for small-vessel disease, including those associated with NOTCH3 mutations. Read More

Biochem Biophys Res Commun 2021 Jun 21;557:302-308. Epub 2021 Apr 21.

Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan. Electronic address:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease characterized by NOTCH3 mutation and abnormal aggregation of NOTCH3 mutant proteins around vessel walls. NOTCH3 is a transmembrane receptor that is degraded by JAGGED1 (JAG1) through a process called trans-endocytosis. There are two types of CADASIL-associated NOTCH3 mutations: signal-active (SA) and signal-deficient (SD) mutations. Read More

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405;

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. Read More

Neurobiol Aging 2021 Jul 13;103:128-129. Epub 2021 Mar 13.

Klinik Landstrasse, Messerli Institute, Vienna, Austria. Electronic address:

Sci Rep 2021 Mar 25;11(1):6846. Epub 2021 Mar 25.

Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l`Hospital de la Santa Creu i Sant Pau, C/Sant Antoni María Claret 167, Barcelona, Spain.

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. Read More

J Alzheimers Dis 2021 ;81(1):221-229

Department of Neurology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China.

Background: Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. Read More

Sci Rep 2021 Mar 16;11(1):6072. Epub 2021 Mar 16.

Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. Read More

Front Neurol 2021 25;12:586366. Epub 2021 Feb 25.

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

No study yet has compared the longitudinal course and prognosis between subcortical vascular cognitive impairment patients with and without genetic component. In this study, we compared the longitudinal changes in cerebral small vessel disease markers and cognitive function between subcortical vascular mild cognitive impairment (svMCI) patients with and without variant [(+) svMCI vs. (-) svMCI]. Read More

J Neurol Neurosurg Psychiatry 2021 Mar 12. Epub 2021 Mar 12.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, Cambridgeshire, UK

Background: Cysteine-altering variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear.

Methods: Cysteine-altering variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. Read More

Int J Dermatol 2021 Mar 12. Epub 2021 Mar 12.

Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.

There are several neurological diseases wherein skin biopsy is useful for diagnosis, even in the absence of skin involvement. Skin biopsy is especially relevant in diseases in which the metabolic error is unknown or has no available diagnostic biochemical test. Skin biopsy, being relatively noninvasive, obviates the need for an invasive procedure such as a brain biopsy. Read More

Cochrane Database Syst Rev 2021 02 22;2:CD013306. Epub 2021 Feb 22.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. Read More

Clin Sci (Lond) 2021 Mar;135(6):753-773

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.

Notch3 mutations cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), which predisposes to stroke and dementia. CADASIL is characterised by vascular dysfunction and granular osmiophilic material (GOM) accumulation in cerebral small vessels. Systemic vessels may also be impacted by Notch3 mutations. Read More

Intern Med 2021 Mar 8. Epub 2021 Mar 8.

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

A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. Read More

J Comput Assist Tomogr 2021 Mar-Apr 01;45(2):285-293

From the Department of Radiology, Huashan Hospital, Fudan University, Shanghai, P.R. China.

Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial arteriopathy characterized by recurrent lacunar stroke, migraine, and depression. The mechanism of cognitive dysfunction in CADASIL is still uncertain. The aim of this study was to use tract-based spatial statistics (TBSS) to map voxelwise the spatial distribution of brain microstructural change revealed by DTI-derived indices in patients with CADASIL to further study the underlying neuropsychopathological mechanism of CADASIL. Read More

J Stroke 2021 Jan 31;23(1):132-134. Epub 2021 Jan 31.

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

Front Neurol 2021 1;12:631407. Epub 2021 Feb 1.

Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore, Singapore.

Leukodystrophies are a diverse group of genetic disorders that selectively involve the white matter of the brain and are a frequent cause of young-onset cognitive impairment. Genetic diagnosis is challenging. Data on the utility of incorporating brain magnetic resonance imaging (MRI) diagnostic algorithms with next-generation sequencing (NGS) for diagnosis in a real-life clinical setting is limited. Read More

Stroke 2021 Mar 4;52(3):985-993. Epub 2021 Feb 4.

Department of Neurology, Taipei Veterans General Hospital, Taiwan (Y.-C. Liao., Y.-C.H., C.-P.C., Y.-F.W., Y.-C. Lee.).

Background And Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small vessel disease. The role of intracerebral hemorrhage (ICH) in CADASIL remains elusive. The present study aims to investigate the prevalence, characteristics, and risk factors for ICH in CADASIL. Read More

Neurol Clin Pract 2020 Dec;10(6):488-496

Department of Neurology (PAG, EDG, MKB, TGB, JFM), Mayo Clinic; Mayo Clinic Libraries (TJB), Mayo Clinic; and Department of Biomedical Statistics and Informatics (ERL), Mayo Clinic, Jacksonville, FL.

Background: Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) without consensus guidelines for treatment. Migraine treatment poses a theoretical risk within this unique population with precarious cerebrovascular autoregulation, given the vasomodulatory influence of many antimigraine medications. In this systematic review and meta-analysis, we evaluate the frequency and efficacy of treatments for migraine in individuals with CADASIL. Read More