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In order to promote the clinical diagnosis, management and treatment of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in China, it is necessary to construct evidence - based guidelines. The "Chinese guideline for the diagnosis and management of CADASIL (2022 edition)" will be written by using the World Health Organization (WHO) Guidelines Development Manual" and "Principles for Developing/Revising Clinical Diagnosis and Treatment Guidelines in China (2022 Edition)", and follow the evidence - based guidance development process to develop and publish formal guidance. This guide plan mainly describes the background, initiation and planning of the guide, as well as a concise development method to lay the foundation for the successful release of the subsequent guide. [ABSTRACT FROM AUTHOR]

Introduction: Proteolytic processing of amyloid protein precursor by b-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction. Methods: In this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach. Results: Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), representedmainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL. Conclusion: Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids. [ABSTRACT FROM AUTHOR]

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary vascular disorder inherited in an autosomal dominant manner. MRI plays a crucial role in the diagnosis and follow-up of patients. Characteristic MRI lesions include symmetric and bilateral white matter periventricular hyperintensities, lacunar infarcts and cerebral microbleeds. In our case report, we demonstrate a male patient with genetically confirmed CADASIL syndrome and the progression of symptoms with corresponding imaging findings throughout the years. [ABSTRACT FROM AUTHOR]

Background & Objective: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare disease with a prevalence estimation of, 5 per, 100,000 individuals. Besides, it can highly be misdi - agnosed with other psychiatric disorders. Case Presentation: We report a case of CADASIL in a 32-year-old Asian female presenting with schizophrenia symptoms such as auditory hallucination ،loosening of associations، persecutory delusions، referential delusions، decreased function, and complex hepatic hallucinations that the patient had said sometimes someone has intercourse with me since 2 years ago. After brain Magnetic Resonance Imaging (MRI) and gene checking, she showed up with NOTCH3 gene, besides Brain Magnetic resonance imaging confirmed the presence of CADASIL. Supportive treatments have been done and two years of following up showed a significant increase in patient life quality . Conclusion: This case report demonstrates the challenges of CADASIL diagnosis in a patient with schizophrenia symptoms. The diagnosis should be considered in patients with schizophrenia symptoms. Hence, there is a need for timely diagnosis and management of this disorder. [ABSTRACT FROM AUTHOR]

Objectives: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) show various clinical symptoms, including migraine, recurrent stroke, and cognitive impairment. We investigated the associations between magnetic resonance imaging (MRI) markers of small vessel disease and neuropsychological tests and identified the MRI characteristics for predicting cognitive impairment in patients with CADASIL. Methods: Subjects included 60 CADASIL patients diagnosed with genetic tests and registered in the Japanese CADASIL REDCap database between June 2016 and December 2020. Patient information including clinical data, modified Rankin Scale (mRS); MRI findings of small vessel disease including periventricular and deep white matter lesions (WML), lacunar infarcts, and cerebral microbleeds (CMBs); and neuropsychological tests, including the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), and the Frontal Assessment Battery (FAB), were evaluated. Results: Data from 44 CADASIL patients were eligible for this study, compared between patients with and without dementia. Regarding the neuroimaging findings, the Fazekas score of periventricular and deep WML was higher in patients with dementia (periventricular, p = 0.003; deep, p = 0.009). The number of lacunar infarcts was higher in patients with dementia (p = 0.001). The standardized partial regression coefficient (SPRC) in MoCA-J was 0.826 (95% CI, 0.723–0.942; p = 0.005) for the number of CMBs. The SPRC in MMSE was 0.826 (95% CI, 0.719–0.949; p = 0.007) for the number of CMBs. The SPRC for FAB decreased significantly to 0.728 (95% CI, 0.551–0.960; p = 0.024) for the number of lacunar infarcts. Receiver operating characteristic (ROC) curves for dementia showed that in the number of lacunar infarcts, a cut-off score of 5.5 showed 90.9% sensitivity and 61.1% specificity. For the number of CMBs, a cut-off score of 18.5 showed 45.5% sensitivity and 100% specificity. Conclusion: The characteristic MRI findings were that CADASIL patients with dementia had severe WML, both periventricular and deep, and a larger number of lacunar infarcts than those without dementia. The risk of dementia may be associated with ≥ 6 lacunar infarcts, ≥19 CMBs, or a Fazekas scale score of 3 in periventricular and deep WML. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a congenital small vessel disease of the brain due to NOTCH3 gene mutations. Although adult-onset CADASIL is well documented, more cases are being described within the pediatric population. We describe three siblings with NOTCH3 mutations with various symptomatic presentations of early-onset CADASIL and one sibling with concurrent moyamoya syndrome.Methods: Review of electronic medical records of identified patients.Results: A 19-year-old male who has experienced behavioral dysregulation, hallucinations, and memory loss along with a hyperintense signal abnormality in his temporal lobe; his 15-year-old sister who has the mildest presentation in terms of normal imaging results but experiences severe headaches, anxiety, and depression; and the youngest sibling, a 13-year-old with first reported case of a NOTCH3 mutation associated with moyamoya syndrome and a TREX1 gene mutation of uncertain clinical significance. She had multiple strokes before age five years.Conclusion: Our set of siblings share many similarities with other reported pediatric cases of CADASIL, all with NOTCH3 gene mutations and with early-onset symptoms that range from abnormalities in the cognitive/behavioral/psychiatric field to neurological deficits, migraines, and strokes. Gene testing and imaging studies in symptomatic children with a family history suggestive of CADASIL might aid in early diagnosis, even though there is no effective therapy. We believe that the correlation of clinical presentations and gene mutations together with increased research into the molecular mechanisms underlying CADASIL (and related arteriopathies such as moyamoya syndrome) are critical to the eventual development of targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear.Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL.Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro. The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis.Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G > A, p. A564T) in two pedigrees. In vitro, the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis.Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations. [ABSTRACT FROM AUTHOR]

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary disease of cerebral microvessels with autosomal dominant inheritance due to the NOTCH3 gene mutation. Epileptic seizures were observed in 5-11% of CADASIL cases. Observation of seizures as an initial clinical observation is a rare condition in patients with CADASIL patients. In this report, we present a patient with temporal lobe seizure, whose condition was diagnosed through gene analysis as CADASIL. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a inherited cerebral small vessel disease caused by Notch3 gene mutation. The molecular-genetic mechanisms of CADASIL have been still unclear. This review includes the physiopathology and gene mutation of CADASIL. We will focus on the underlying pathogenesis based on worldwide researches and literatures in recent years, including abnormal signaling of Notch3 protein and downstream targets, endoplasmic reticulum stress and activation of RhoA/Rho kinases, abnormal contraction, proliferation and differentiation of vascular smooth muscle cell, and autophagy defect of vascular smooth muscle cell. [ABSTRACT FROM AUTHOR]

Objective: Most lacunar strokes are sporadic, and hypertension, diabetes, smoking, and cardiovascular diseases are among its main risk factors. Strokes caused by small vessel diseases are generally associated with single-gene disorders with familial dominant and recessive inheritance. The most common condition is cerebral autosomal dominant arteriopathy, with subcortical infarcts and leukoencephalopathy (CADASIL), associated with the NOTCH3 gene. An infrequent form of this disease is the cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), revealed with pathogenic HTRA1 gene variants related to distinct molecular pathways. The neurological and cranial magnetic resonance imaging (MRI) findings are very similar to CADASIL; however, earlier than expected onset of common alopecia in man, low back pain, and more severe memory impairment are the differences in terms of clinical presentations. Clinical findings of 22 patients from 16 families with widespread white matter lesions in the periventricular field in the brain were investigated with molecular genetic findings. Materials and Methods: Clinical examination results and cranial MRI findings are reported, and NOTCH3 and HTRA1 genes are sequenced stepwise by Sanger and next-generation sequencing techniques. Results: Missense changes in epidermal growth factor (EGF)- like domain in the NOTCH3 are found in 18 cases from 14 families. Two different homozygous pathogenic missense and non-sense variants, in the HTRA1 gene, were detected in four patients from two families. The disease onset age was approximately 16 years earlier in cases carrying pathogenic variants located in the encoding region of EGF- like domains 1-6 of NOTCH3. Conclusion: In the NOTCH3 gene with c.382T>C (p.C128R), c.555T>G (p.C185W), and c.1903C>T (p.R635C) and in the HTRA1 gene c.235C>T (p.Q79*) are presented for the first time in this study. Molecular genetic investigation of CADASIL and CARASIL is important to support the clinical diagnosis, determine the inheritance model, provide patient and family counseling, manage disease process, and evaluate possible treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Cysteine-altering NOTCH3 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 NOTCH3 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. MRIs from those with variants were visually rated, each matched with three controls.Results: Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001).Conclusions: Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL. [ABSTRACT FROM AUTHOR]

A case study of a 38‑year‑old gentleman presented with two episodes of sudden onset right hemiparesis in the past 3 years with good recovery along with progressively increasing cognitive impairment. Topics include Cognitive functions were impaired with the pronounced impairment of frontal and temporal lobes on detailed assessment; and computed tomographic (CT) angiography showed multiple fusiform aneurysms in the bilateral distal cervical internal carotid artery.

Introduction CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an inherited disease caused by mutations in the Notch3 gene in chromosome 19.The clinical features are primarily neurological, which include recurrent transient ischaemic attacks, strokes, and migraines.However, psychiatric manifestations such as severe depression, psychosis, changes in behavior and personality have also been reported in CADASIL. Symptoms and disease onset vary widely, with signs typically appearing in the mid-30s.Some individuals may not show signs of the disease until later in life. Objectives In this case report, we present a possible case of CADASIL, a 67-year old female patient diagnosed with schizophrenia fifteen years ago to discuss the co-occurrence of these conditions in the light of the literature. Methods Hospitalization records of the patient viewed. Results Our patient suffered from sleep disturbances, hearing religious voices and in psychiatric examination resistant to treatment psychotic symptoms such as blunted affect, mystic, persecutory delusions, auditory hallucinations were present.Cranial magnetic resonance imaging scan was performed and revealed leukoencephalopathy, high-signal intensity lesions in the periventricular white matter consistent with a diagnosis of CADASIL.Atypical antipsychotics found to be effective in treating psychotic symptoms in our case. Conclusions Persistent psychotic symptoms despite adequate antipsychotic treatment in patients diagnosed with schizophrenia, also with pathological findings in MRI an organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients. Disclosure No significant relationships.

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. [ABSTRACT FROM AUTHOR]

Aim: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited form of cerebral small-vessel disease. The gene that causes CADASIL is the NOTCH3 gene located on the 19th chromosome. The prevalence of the disease which can present with many different neurological and psychiatric symptoms is higher than detected. We wanted to increase awareness of this disease with our publication. Materials and Methods: Total of 20 people, 12 males and 8 females, between the ages of 26-64 were included in our study. Age of onset, initial symptoms and diagnostic processes were evaluated. Results: The most common initial symptoms of the patients were muscle weakness. In addition, there were symptoms of sensory loss and headache. Although it was rare, there was also a history of seizures and behavioral disorders. Depending on these symptoms, patients were mostly followed up with a long-term Multiple Sclerosis pre-diagnosis. Conclusion: CADASIL is a genetic disease that presents symptoms with very different clinical findings and is more common than expected. The genetic disorder that causes the disease can be diagnosed faster with new technologies. With family screening, asymptomatic individuals can be screened and early awareness can be created. Also the transmission of the disease to the next generations can be prevented. [ABSTRACT FROM AUTHOR]

Background: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition.Objective: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL.Methods: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared.Results: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity.Conclusion: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies. [ABSTRACT FROM AUTHOR]

Purpose: Due to the variety of clinical symptoms that occur in rare neurodegenerative diseases and difficulties in the correct diagnosis, there is a need to learn their characteristic imaging findings by using conventional MRI. That knowledge helps to determine the appropriate differential diagnosis and avoid misdiagnosis. The aim of this review is to present the typical neuroimaging signs of the selected neurodegenerative disorders and to create a practical approach to imaging findings useful in everyday clinical practice. Images: Images of progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), Creutzfeldt-Jakob disease (CJD), Wilson's disease (WD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are provided to visualize and distinguish the typical features of those diseases and therefore to assist neurologists and neuroradiologists in decision-making process. Conclusions: It is important to know the characteristic MRI features of rare neurodegenerative diseases and to use them in everyday clinical practice. MRI is a valuable tool when considering the initial diagnosis because it is proven to be very useful in the differentiation of more advanced stages of the rare neurodegenerative diseases but also from other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Small-vessel diseases (SVDs) of the brain are involved in about one-fourth of ischemic strokes and a vast majority of intracerebral hemorrhages and are responsible for nearly half of dementia cases in the elderly. SVDs are a heavy burden for society, a burden that is expected to increase further in the absence of significant therapeutic advances, given the aging population. Here, we provide a critical appraisal of currently available therapeutic approaches for nonamyloid sporadic SVDs that are largely based on targeting modifiable risk factors. We review what is known about the pathogenic mechanisms of vascular risk factor–related SVDs and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most frequent hereditary SVD, and elaborate on two mechanism-based therapeutic approaches worth exploring in sporadic SVD and CADASIL. We conclude by discussing opportunities and challenges that need to be tackled if efforts to achieve significant therapeutic advances for these diseases are to be successful. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifests principally as a suite of cognitive impairments, particularly in the executive domain. Executive functioning requires the dynamic coordination of neural activity over large-scale networks. It remains unclear whether changes in resting-state brain functional network connectivity and regional homogeneities (ReHos) underly the mechanisms of executive dysfunction evident in CADASIL patients. Methods: In this study, 22 CADASIL patients and 44 matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI). Independent component analysis (ICA) was used to measure functional brain network connectivity, and ReHos were calculated to evaluate local brain activities. We used seed-based functional connectivity (FC) analyses to determine whether dysfunctional areas (as defined by ReHos) exhibited abnormal FC with other brain areas. Relationships among the mean intra-network connectivity z-scores of dysfunctional areas within functional networks, and cognitive scores were evaluated using Pearson correlation analyses. Results: Compared to the controls, CADASIL patients exhibited decreased intra-network connectivity within the bilateral lingual gyrus (LG) and the right cuneus (CU) (thus within the visual network [VIN)], and within the right precuneus (Pcu), inferior frontal gyrus (IFG), and precentral gyrus (thus within the frontal network [FRN]). Compared to the controls, patients also exhibited significantly lower ReHos in the right precuneus and cuneus (Pcu/CU), visual association cortex, calcarine gyri, posterior cingulate, limbic lobe, and weaker FC between the right Pcu/CU and the bilateral parahippocampal gyrus (PHG), and between the right Pcu/CU and the right postcentral gyrus. Notably, the mean connectivity z-scores of the bilateral LG and the right CU within the VIN were positively associated with compromised attention, calculation and delayed recall as revealed by tests of the various cognitive domains explored by the Mini-Mental State Examination. Conclusions: The decreases in intra-network connectivity within the VIN and FRN and reduced local brain activity in the posterior parietal area suggest that patients with CADASIL may exhibit dysfunctional visuomotor behaviors (a hallmark of executive function), and that all visual information processing, visuomotor planning, and movement execution may be affected. [ABSTRACT FROM AUTHOR]

Objective To discuss the cognitive function and the clinical characteristics of hereditary cerebral small vessel disease (cSVD). Methods Clinical data, imaging and neuropsychological score of 8 patients with monogenic hereditary cSVD were included from January 2015 to January 2018. The cognitive characteristics of the patients were analyzed during the first diagnosis, follow-up for 6-month and 12 - month. Results Among 8 patients, 6 patients met the diagnostic criteria of cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) and 2 patients met the diagnostic criteria of cerebral autosomal recessive arteriopathy with subcortical infarct and leukoencephalopathy (CARASIL). The main manifestations of CADASIL patients were acute cerebral infarction (2 cases), dizziness and headache (1 case) and cognitive impairment (3 cases), and CARASIL patients showed dizziness (1 case) or cognitive impairment (1 case) during the first diagnosis. Head MRI showed subcortical white matter lesions in different parts and degrees. Three patients had decreased activity of daily living and four patients had different degrees of neuropsychiatric and behavioral disorders, one case might have anxiety and mild depression. All patients had different degrees of neuropsychiatric and behavioral disorders at 6 - month follow - up. Patients with CADASIL suffered from impairment of delayed recall, visuospatial and executive function, abstract ability, language, attention and computational ability, as well as neuropsychiatric behavior disorders such as irritability, emotional apathy, agitation and abnormal motor behavior. Patients with CARASIL suffered from impairment of executive function, orientation (time, place) and short term memory. In addition to irritability, apathy, agitation and abnormal motor behavior, there were delusions, depression and sleep disorders. Conclusions The progress and changes of cognitive function in patients with CARASIL and CADASIL have different characteristics, and there are differences among individuals. [ABSTRACT FROM AUTHOR]

Background: It remains unclear whether the degree of white matter tract damage or cerebral hypoperfusion can better predict global cognitive impairment in CADASIL. We sought to determine the independent effects of cerebral perfusion status and white matter integrity on the cognition. Methods: We reviewed prospectively collected clinical and imaging data from genetically-confirmed CADASIL patients who underwent both arterial spin labeling (ASL) perfusion MRI and diffusion tensor imaging (DTI). We analyzed the cerebral blood flow (CBF), mean diffusion (MD), and fractional anisotropy (FA) by dividing the brain tissue into white matter hyperintensity (WMH) and normal-appearing white matter (NAWM). Global cognitive function was evaluated by using Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Results: Of the included 29 CADASIL patients, the mean age was 48.4 ± 7.9 years, and 17 (58.6%) were women. MD was significantly correlated with CBF in both WMH (r = −0.407, P = 0.035) and NAWM (r = −0.437, P = 0.023) after adjusting for age and WMH volume. A MoCA score was obtained in 13 patients and was significantly correlated with CBF in both WMH (r = 0.742, P = 0.004) and NAWM (r = 0.659, P = 0.014). Both CBF in WMH (area under the curve, 0.767; 95% CI, 0.586-0.947, P = 0.015) and MD in WMH (area under the curve, 0.740; 95% CI, 0.557–0.924, P = 0.028) were good predictors for cognitive impairment (MMSE score < 27). However, multiple linear regression analysis revealed that global cognitive function was independently associated with CBF in WMH only (standardized β = 0.485, P = 0.015), after adjusting for age, gender, WMH volume, the presence of subcortical infarcts and DTI metrics. Conclusions: Our findings suggested that cerebral hypoperfusion was more strongly associated with global cognitive dysfunction than the severity of brain microstructural damage, supporting that CBF assessed by ASL could serve as a candidate imaging indicator for monitoring alterations of global cognitive function in CADASIL. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL.Methods: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities.Results: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity.Conclusions: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield. [ABSTRACT FROM AUTHOR]

Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a stroke and dementia syndrome with degeneration and loss of vascular smooth muscle cells (VSMCs). The disease is due to mutations in NOTCH3 playing an important role in VSMC differentiation, proliferation and apoptosis. Searching for a possible cause of VSMC dysfunction in CADASIL, we investigated morphology and proliferative activity the affected myocytes. In material from autopsy brains and skin‐muscle biopsies of patients with CADASIL diagnosis, assessment of VSMCs in arterial vessels at the level of light and electron microscopy was performed. Proliferative activity of VSMCs was evaluated in immune reactions to proliferative markers: proliferating cell nuclear antigen, and cyclins B1 and D. In CADASIL, abnormal morphology of VSMC nuclei was observed in 18.1%, 11.5%, and 6.9% of the cerebral, skin, and skeletal muscle vessels, respectively. The affected myocytes showed variability in nuclear size, irregularity in nuclear shape, and abnormal chromatin appearance. Frequently, double nuclei of equal size or micronuclei were observed. Sometimes, even multinuclear myocytes were found. In some of the nuclei immune reactions to the examined proliferative markers were positive. Aberrant structure and number of VSCM nuclei, and their immunoreactivity to proliferative markers suggest mitotic instability of vascular myocytes in CADASIL. We speculate that mutant NOTCH3 which is unable to control properly VSMC proliferation, and may be responsible for their premature or inappropriate entry into mitosis, irreversible arrest of the cell cycle, senescence or degeneration and loss. [ABSTRACT FROM AUTHOR]

The article presents a case study related to 45-year-old lady has presented to our hospital with recurrent episodes of tingling in the right hand for the last 3 years. Topics inlcude the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) being an autosomal dominant, and the case of CADASIL presenting with recurrent seizures evidence of cerebral cavernous malformations (CCMs) put forward a common pathophysiological association.

The article presents a case study related to 23-year-old male patient has presented with a history of low backache and difficulty in walking for past 5 years. Topics include the cerebral autosomal‑recessive arteriopathy with subcortical infarcts and leukoencephalopathy being rare single‑gene disorder also known as Nemoto disease or Maeda syndrome, the transmitted through autosomal recessive mode, and the heterozygous single‑gene mutation in the high‑temperature requirement serine peptidase A1.

Highlights • CADASIL is an inherited disease of cerebral vascular cells. • Increased intracellular domain of NOTCH3 in VSMCR133C. • Increased amount of lysosomes co-localized with NOTCH3 in VSMCR133C. • Decreased co-localization of NOTCH3 with LC3 and LAMP2 indicating a defect in the autophagy-lysosomal pathway. • Dysregulation of autophagy-lysosomal signalling pathway in VSMCR133C. Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial progressive degenerative disorder and is caused by mutations in NOTCH3 gene. Previous study reported that mutant NOTCH3 is more prone to form aggregates than wild-type NOTCH3 and the mutant aggregates are resistant to degradation. We hypothesized that aggregation or accumulation of NOTCH3 could be due to impaired lysosomal-autophagy machinery in VSMC. Here, we investigated the possible cause of accumulation/aggregation of NOTCH3 in CADASIL using cerebral VSMCs derived from control and CADASIL patients carrying NOTCH3R133C mutation. Thioflavin-S-staining confirmed the increased accumulation of aggregated NOTCH3 in VSMCR133C compared to VSMCWT. Increased levels of the lysosomal marker, Lamp2, were detected in VSMCR133C, which also showed co-localization with NOTCH3 using double-immunohistochemistry. Increased level of LC3-II/LC3-I ratio was observed in VSMCR133C suggesting an accumulation of autophagosomes. This was coupled with the decreased co-localization of NOTCH3 with LC3, and Lamp2 and, further, increase of p62/SQSTM1 levels in VSMCR133C compared to the VSMCWT. In addition, Western blot analysis indicated phosphorylation of p-ERK, p-S6RP, and p-P70 S6K. Altogether, these results suggested a dysfunction in the autophagy-lysosomal pathway in VSMCR133C. The present study provides an interesting avenue of the research investigating the molecular mechanism of CADASIL. [ABSTRACT FROM AUTHOR]

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts, and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects. Methods: We evaluated post‐mortem brains from CADASIL, cerebral small vessel disease, similar age cognitively normal and older control subjects. Standard immunohistochemical, immunofluorescent, and unbiased stereological methods were used to evaluate the distribution of astrocytes, microvessels, and autophagy markers in five different brain regions. Results: Compared to the controls, the deep WM of CADASIL subjects overall showed increased numbers of glial fibrillary acidic protein (GFAP)‐positive clasmatodendritic astrocytes (P=0.037) and a decrease in the percentage of normal appearing astrocytes (P=0.025). In accord with confluent WM hyperintensities, the anterior temporal pole contained abundant clasmatodendritic astrocytes with displaced aquaporin 4 immunoreactivity. Remarkably, we also found strong evidence for the immunolocalization of autophagy markers including microtubule‐associated protein 1, light chain 3 (LC3), and sequestosome 1/p62 and Caspase‐3 in GFAP‐positive clasmatodendritic cells, particularly within perivascular regions of the deep WM. LC3 was co‐localized in more than 90% of the GFAP‐positive clasmatodendrocytes. Conclusions: Our novel findings show astrocytes undergo autophagy‐like cell death in CADASIL, with the anterior temporal pole being highly vulnerable. We propose astrocytes transform from normal appearing type A to hypertrophic type B and eventually to clasmatodendritic type C cells. These observations also suggest the gliovascular unit of the deep WM is severely impaired in CADASIL. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3ECD) and the formation of protein deposits of insufficiently determined composition in vessel walls. To identify key molecules and pathways involved in this process, we quantitatively determined the brain vessel proteome from CADASIL patient and control autopsy samples (n = 6 for each group), obtaining 95 proteins with significantly increased abundance. Intriguingly, high-temperature requirement protein A1 (HTRA1), the extracellular protease mutated in CARASIL, was found to be strongly enriched (4.9-fold, p = 1.6 × 10−3) and to colocalize with Notch3ECD deposits in patient vessels suggesting a sequestration process. Furthermore, the presence of increased levels of several HTRA1 substrates in the CADASIL proteome was compatible with their reduced degradation as consequence of a loss of HTRA1 activity. Indeed, a comparison with the brain vessel proteome of HTRA1 knockout mice (n = 5) revealed a highly significant overlap of 18 enriched proteins (p = 2.2 × 10−16), primarily representing secreted and extracellular matrix factors. Several of them were shown to be processed by HTRA1 in an in vitro proteolysis assay identifying them as novel substrates. Our study provides evidence for a loss of HTRA1 function as a critical step in the development of CADASIL pathology linking the molecular mechanisms of two distinct SVD forms. [ABSTRACT FROM AUTHOR]

Abstract: Background and Objective: Neurovascular coupling is the complex biological process that underlies use‐dependent increases in blood flow in response to neural activation. Neurovascular coupling was investigated at the early stage of CADASIL, a genetic paradigm of ischemic small vessel disease. Methods: Functional hyperemia and evoked potentials during 20‐ and 40‐sec visual and motor stimulations were monitored simultaneously using arterial spin labeling‐functional magnetic resonance imaging (ASL‐fMRI) and electroencephalography. Results: Cortical functional hyperemia differed significantly between 19 patients and 19 healthy individuals, whereas evoked potentials were unaltered. Functional hyperemia dynamics, assessed using the difference in the slope of the response curve between 15 and 30 sec, showed a time‐shifted decrease in the response to 40‐sec neural stimulations in CADASIL patients. These results were replicated in a second cohort of 10 patients and 10 controls and confirmed in the whole population. Interpretation: Alterations of neurovascular coupling occur early in CADASIL and can be assessed by ASL‐fMRI using a simple marker of vascular dysfunction. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) represents the most common monogenic cause of adult-onset ischemic stroke and vascular dementia. It is caused by heterozygous missense mutations in the NOTCH3 gene, encoding a transmembrane receptor protein on vascular smooth muscle cells. Classical CADASIL mutations affect conserved cysteine residues of the Notch3 protein. By contrast, the role of non-canonical genetic variation in NOTCH3, in particular of variants causing a hypomorphic Notch3 protein, is subject to an ongoing scientific debate. In this context, we here report a novel NOTCH3 frameshift variant in exon 18 (NM_000435.2: c.2853_2857delTCCCG), causing a frameshift and introducing a premature stop codon, which was detected in a 43-year-old woman and her father. Both carriers of the variant were carefully evaluated, including serial follow-up in the index. Neither clinical nor imaging features provided convincing evidence for a classical CADASIL phenotype, thus reinforcing the concept of hypomorphic NOTCH3 variants most likely not being causative for CADASIL. Our finding, which is discussed in the light of the published literature, has practical implications for interpreting results of NOTCH3 molecular genetic testing as well as patient counseling. [ABSTRACT FROM AUTHOR]

Background and purpose: The frequency, clinical correlates, and risk factors of cerebral microbleeds (CMB) in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) are still poorly known. We aimed at determining the location and number of CMB and their relationship with clinical manifestations, vascular risk factors, drugs, and other neuroimaging features in CADASIL patients. Methods: We collected clinical data by means of a structured proforma and centrally evaluated CMB on magnetic resonance gradient echo sequences applying the Microbleed Anatomical Rating Scale in CADASIL patients seen in 2 referral centers in Italy and United Kingdom. Results: We evaluated 125 patients. CMB were present in 34% of patients and their presence was strongly influenced by the age. Twenty-nine percent of the patients had CMB in deep subcortical location, 22% in a lobar location, and 18% in infratentorial regions. After adjustment for age, factors significantly associated with a higher total number of CMB were hemorrhagic stroke, dementia, urge incontinence, and statins use (this latter not confirmed by multivariate analysis). Infratentorial and deep CMB were associated with dementia and urge incontinence, lobar CMB with hemorrhagic stroke, dementia, and statins use. Unexpectedly, patients with migraine, with or without aura, had a lower total, deep, and lobar number of CMB than patients without migraine. Discussion: CMB formation in CADASIL seems to increase with age. History of hemorrhagic stroke, dementia, urge incontinence, and statins use are associated with a higher number of CMB. However, these findings need to be confirmed by longitudinal studies. [ABSTRACT FROM AUTHOR]

Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL) is an inherited cerebral small vessel disease caused by NOTCH3 gene mutations. CADASIL women are frequently considered at high risk of systemic vascular events during pregnancy and often prescribed with antithrombotic drugs. This decision is not evidence-based considering the lack of data about pregnancy outcome in CADASIL. We describe our experience on pregnancy in CADASIL patients. Materials and methods We reviewed records of 50 CADASIL females followed in our center, and we collected prospective information in six patients for a total of 93 pregnancies. Results No woman had the disease onset or suffered from cerebral vascular ischemic events during pregnancy. Sixteen miscarriages (17.2%) were recorded. There were 72 vaginal births, and five cesarean sections. Considering the six patients followed prospectively (for a total of eight pregnancies), data on fetal growth and newborns weight were in line with those from the general population. Considering gestational complications, we recorded mild proteinuria without hypertension in one patient and hyperinsulinemia and pre-eclampsia in another affected by a known nephropathy. Antithrombotic drugs were used in three patients, in one for an unrelated coexisting prothrombotic condition. Conclusions CADASIL does not seem to be associated with an unfavorable outcome of pregnancy either for women and fetuses. Patients and treating physicians should be reassured that pregnancy can be safely initiated in CADASIL, as there is no evidence to support a specific preventive antithrombotic treatment during pregnancy in CADASIL. Larger studies are needed to definitively confirm these conclusions. [ABSTRACT FROM AUTHOR]

Purpose Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. Subjects and methods All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n = 37, Group 1) or after 2011 (n = 65, Group 2), 67 young stroke patients (≤ 55 years old), and 53 NOTCH3 -negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. Results In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37–74 years old) and bimodal (< 55 and > 55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3 -negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2–8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. Conclusion We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing. [ABSTRACT FROM AUTHOR]

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL. [ABSTRACT FROM AUTHOR]

Aim To characterize clinical features and mutation spectrum in Chinese patients with CADASIL. Methods We collected 261 clinically suspected Chinese CADASIL patients from three hospitals located in different regions of China. Sanger sequencing is performed to screen the exons 2 to 24 of NOTCH3 gene. Clinical and genetic data were retrospectively studied. Haplotype analyses were performed in patients carrying p.Arg544Cys and p.Arg607Cys, respectively. Results A total of 214 patients were finally genetically diagnosed as CADASIL, with 45 known NOTCH3 mutations and a novel c.1817G>T mutation. We found that patients carrying p.Arg607Cys or p.Arg544Cys mutation located in exon 11 occupied nearly 35% in our mutation spectrum. In retrospectively study of clinical data, we found a higher number of patients having cognitive impairment and a lower number of patients having migraine with aura. Furthermore, we identified that patients carrying mutations in exon 11 seemed to experience a later disease onset ( p=6.8×10 −5). Additionally, a common haplotype was found in patients from eastern China carrying p.Arg607Cys, and the patients from Fujian carrying p.Arg544Cys shared the same haplotype with patients from Taiwan carrying p.Arg544Cys. Conclusions These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients. [ABSTRACT FROM AUTHOR]

Besides its well known function on bone metabolism, vitamin D role in cerebrovascular pathologies including cerebral small vessel disease has been confirmed by recent meta-analysis. In this study, we measured vitamin D levels in 56 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients (mean age 49.9) with no or minimal disability (modified Ranking Score, mRS ≤2) and in 56 age, sex and seasonality matched healthy controls. History of ischemic events was recorded and cognitive functions were assessed using the Mini-Mental State Examination. White matter hyperintensities on brain T2-weighted magnetic resonance images were classified according to a modified Fazekas scale. Comparison of vitamin D levels between patients and controls showed significant lower values (p < 0.05) in no-to-mild CADASIL patients and a higher number of subjects with severe deficiency [25(OH)D <10 ng/ml]. Vitamin D levels did not correlate with vascular risk factors, clinical data or Fazekas score. The role of vitamin D is worth to be further explored in prospective studies. [ABSTRACT FROM AUTHOR]

Background: Fatal familial insomnia (FFI) is a rare autosomal dominant disease caused by the PRNP D178N/129 M mutation. Routine brain CT and MRI usually reveal non-specific features. We report a patient with FFI presenting with diffuse abnormal signals on MRI, later confirmed as combined with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).Case Presentation: The patient was a 58-year-old female, whose main clinical manifestations were insomnia, movement disorders, autonomic hyperactivity and mental deterioration. The patient also suffered a typical episode of transient global amnesia. MRI indicated a diffuse white matter abnormality and microbleeding on the susceptibility-weighted imaging. On biopsy, the brain tissue sections showed spongiform changes with gliosis, neuronal degeneration, and prion protein deposition in a portion of the neurons. In addition, arteriosclerosis was prominent. Transmission electron microscopy showed osmiophilic particle deposition in the matrix of medial smooth muscle cells. Gene sequencing confirmed a diagnosis of FFI with CADASIL.Conclusions: This case is a compelling example that even with evidence of leukoencephalopathy, prion disease should be an important differential diagnosis of rapidly progressive dementia and related diseases. In cases of genetic diseases with atypical manifestations, the coexistence of two or even more diseases should be considered as a possible explanation. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of stroke. In addition to ischemic stroke, CADASIL predisposes to development of cerebral microbleeds (CMB). CMB and hypertension are known to be associated with intracerebral hemorrhage (ICH). The purpose of this study was to analyze the relationships among CMB, hypertension, and ICH in CADASIL. Materials and methods: We enrolled 94 genetically confirmed CADASIL patients from 76 unrelated families at Jeju National University Hospital (Korea) between March 2012 and February 2015. We analyzed CMB presence, number, and distribution on susceptibility-weighted imaging MRI using the microbleed anatomical rating scale. Multiple logistic regression was used to determine factors associated with the presence of CMB and ICH. results: CMB were observed in 62 patients (66%), median number of CMB per patient was 4 (range 0-121). Twenty-two ICHs were found in 16 patients (17%). There was incongruence between the most common site of CMB (thalamus) and that of ICH (basal ganglia). Hypertension was independently associated with the presence of CMB (multi- ple regression OR, 2.71; 95% CI 1.02-7.18, p < 0.05), and CMB ≥ 9 (highest third) was significantly associated with the presence of ICH (multiple regression OR = 9.50, 95% CI 1.08-83.71, p < 0.05). conclusion: In this CADASIL sample, presence of hypertension was independently associated with CMB presence, and CMB burden was independently associated with ICH. Incongruence of sites for CMB and ICH is currently unexplained and requires further study. [ABSTRACT FROM AUTHOR]

CADASIL is Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [corrected]. (CADASIL) is sometimes misdiagnosed as multiple sclerosis (MS). MS and CADASIL are not known to co-occur and brain magnetic resonance imagining (MRI) findings can help with differential diagnosis. Despite the availability of this information, a case report is presented of a 61-year-old woman who was misdiagnosed with MS at age 50, tested positive for CADASIL at age 56, described incorrectly as having both conditions simultaneously, and continued on MS disease-modifying medications, resulting in financial and physical hardship. Neuropsychological consultation helped initiate removal of the MS diagnosis and treatment. Better understanding is needed among clinicians that MS and CADASIL are not known to co-exist, that no association has been found between MS and the NOTCH3 mutations that cause CADASIL, and that neuroimaging and clinical features can help distinguish between the two conditions in addition to genetic testing. This case study highlights how neuropsychological consultation involves more than testing, can help improve diagnostic decision making, and can improve outcomes by reducing costs to the patient and the healthcare system. [ABSTRACT FROM AUTHOR]

Though rare, monogenic causes of stroke are recognizable by key clinical and radiographic features. A lack of epidemiological data leaves their true incidence unknown, but the most common monogenetic causes of stroke are sickle cell disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Fabry's disease, and cerebral cavernous malformations. In this article, the author covers the epidemiology, clinical features, and treatment of those diseases as well as other well-described monogenic causes of ischemic and hemorrhagic stroke. A "shotgun" approach to genetic testing should be avoided in favor of targeted testing that can provide a higher yield. Neurologists caring for stroke patients should be familiar with these monogenic causes of stroke, as heightened awareness and an armamentarium of additional diagnostic techniques will allow neurologists to diagnose correctly, implement individual distinct treatment paradigms, and provide future risk assessment. [ABSTRACT FROM AUTHOR]

Objectives The magnitude of the blood oxygen dependent level (BOLD) functional MRI (fMRI) response to visual stimulation is reduced in the small vessel disease cerebral amyloid angiopathy (CAA), reflecting impaired vascular reactivity. We determined whether BOLD responses were reduced in another small vessel disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods BOLD fMRI data were collected using a visual stimulus (contrast-reversing checkerboard) and motor task (finger-tapping). The amplitude of BOLD responses in the visual cortex (visual stimulus) and motor cortex (motor task) were compared between 5 CADASIL, 18 CAA and 18 control subjects, controlling for age and hypertension. Results BOLD response varied by group for the visual stimulus ( p < 0.001) but not the motor task ( p = 0.47). After adjusting for age and hypertension, the estimated mean visual cortex BOLD amplitude response was 3.95% in CADASIL (95% confidence interval, CI 3.15–4.75%), 1.73% in CAA (95% CI 1.19–2.27%), and 2.88% (95% CI 2.39–3.37%) in controls. In CADASIL, the visual BOLD response was greater than in CAA ( p < 0.001) and controls ( p = 0.04). Conclusions We observed increased and unchanged BOLD amplitude responses in the visual and motor cortices of CADASIL patients, respectively. This suggests that cortical blood flow regulation by neuronal activity may be relatively preserved in CADASIL, in contrast to CAA where occipital vascular reactivity is impaired. Cortical vascular reactivity in CADASIL may be preserved because the disease-related injury is primarily subcortical, whereas increased activation may reflect compensatory mechanisms for subcortical injury. [ABSTRACT FROM AUTHOR]

Whether cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL) is a risk factor for spontaneous intracerebral hemorrhage ( ICH) and influences outcomes remains unclear. In this study, we report two cases of CADASIL presenting with cerebral hemorrhages. These cases suggest that a CADASIL vasculopathy by itself mainly results in ICH, as indicated by slight vascular risk factors and prominent neuroimaging abnormalities, suggesting that CADASIL should be considered a risk factor for ICH. Interestingly, decreased perihematomal edema was noted in ICH patients with CADASIL in this study. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD. [ABSTRACT FROM AUTHOR]

Purpose Of Review: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an important disease to consider in the differential diagnosis of migraine with aura. This review examines current literature regarding migraine in CADASIL, as well as diagnostic and treatment modalities.Recent Findings: Recent studies have shown that smoking is a modifiable risk factor for progression of CADASIL (Chabriat et al. in Stroke 47:4-11, 2015). Specific imaging changes and findings on clinical exam can predict disease progression. However, migraine symptoms often precede MRI changes (Guey et al. in Cephalalgia 36:1038-47, 2015). A recent paper on migraine treatment in CADASIL reevaluates the prevailing belief that vasoconstrictive abortive medications are contraindicated in these patients (Tan and Markus in PLoS ONE 11:e0157613, 2016). CADASIL is an autosomal dominantly inherited vasculopathy causing ischemic pathology in younger individuals due to a mutation in the NOTCH3 gene. The mutation results in impaired arterial contractility due to accumulation of granular osmiophilic extracellular material (GOM) in vascular smooth muscle cells (VSMCs). Clinical manifestations include migraine with and without aura, cognitive decline, ischemic events, and mood disorders. The presenting symptom is often migraine with aura. Characteristic MRI changes are often present. Genetic screening is available to confirm NOTCH3 mutation and pathognomic changes are often seen in skin biopsy. Treatment of migraine is similar to the general population, but with some notable and specific differences. Further studies in CADASIL, other small vessel arteriopathies, and migraine may help us understand more about the pathophysiology of these conditions and help with treatment development. [ABSTRACT FROM AUTHOR]

Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL) is a hereditary systemic vascular disorder. Granular osmiophilic material ( GOM) is its ultrastructural marker. We reviewed tissue biopsies from CADASIL patients to establish whether ultrastructural observations help clarify the pathogenic mechanism of CADASIL. Given the resemblance of the GOM deposits to the immunoglobulin deposits seen in glomerulonephritis and focal segmental glomerulosclerosis ( FSGS), their morphologies were investigated and compared. Methods Skin, skeletal muscle, kidney, and pericardium tissue biopsies from 13 patients with a clinical and molecular diagnosis of CADASIL, and kidney biopsies from five patients with IgA nephropathy and five patients with primary FSGS were subjected to ultrastructural examination. Results In CADASIL patients, several GOM deposits from all sites were partially or totally surrounded by an electron-lucent halo. The deposits frequently had a more electron-dense portion with a regular outline on the inner side and a less osmiophilic, looser outer side displaying a less regular profile. The uniformly dense deposits tended to be more osmiophilic if located close to the cell membrane and less osmiophilic if laid farther away from it. The immunoglobulin deposits from the glomerulonephritis and FSGS patients lacked both the granular pattern and the halo. Conclusions This study demonstrates that GOM deposits may have a nonuniform morphology and describes in detail an electron-lucent halo surrounding several of them. It is conceivable that the halo is the morphological evidence and possibly the cause of an aberrant NOTCH3 processing, already suspected to be involved in CADASIL. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients. [ABSTRACT FROM AUTHOR]