Review

Authors: Toshiki Mizuno, Ikuko Mizuta, Akiko Watanabe-Hosomi...

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. On the other hand, atypical mutations including cysteine sparing mutation, null mutation, homozygous mutation, and other associate genes are also reported. From the viewpoint of gain of function apart from Notch signaling or loss of function of Notch signaling, we review the research article about CADASIL and summarized the pathogenesis of small vessel, stroke, and dementia in this disease.

PubMed: 32457593
DOI: 10.3389/fnagi.2020.00091

Review

Authors: Rocco J Cannistraro, Mohammed Badi, Benjamin H Eidelman...

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.

Topics: Antihypertensive Agents; CADASIL; Cerebral Amyloid Angiopathy; Cerebral Small Vessel Diseases; Dementia; Diffusion Magnetic Resonance Imaging; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnetic Resonance Imaging; Platelet Aggregation Inhibitors; Stroke, Lacunar

PubMed: 31142635
DOI: 10.1212/WNL.0000000000007654

Review

Authors: Lamei Yuan, Xiangyu Chen, Joseph Jankovic...

BACKGROUND

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive.

AIM OF REVIEW

This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted.

KEY SCIENTIFIC CONCEPTS OF REVIEW

In this review, CADASIL is revisited as a NOTCH3-associated CSVD along with other hereditary CSVDs.

Topics: Humans; CADASIL; Receptor, Notch3; Cerebral Small Vessel Diseases; Mutation

PubMed: 38176524
DOI: 10.1016/j.jare.2024.01.001

Review

Authors: Elisa A Ferrante, Cornelia D Cudrici, Manfred Boehm...

PURPOSE OF REVIEW

Recent advances in genetic evaluation improved the identification of several variants in the NOTCH3 gene causing Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Despite improved diagnosis, the disease mechanism remains an elusive target and an increasing number of scientific/clinical groups are investigating CADASIL to better understand it. The purpose of this review is to summarize the current knowledge in CADASIL.

RECENT FINDINGS

CADASIL is a genotypically and phenotypically diverse condition involving multiple molecular systems affecting small blood vessels. Cerebral white matter changes observed by MRI are a key CADASIL characteristic in young adult patients often before severe symptoms and trigger NOTCH3 genetic testing. NOTCH3 mutation locations are highly variable, correlate to disease severity and consistently affect the cysteine balance within extracellular Notch3. Granular osmiophilic material deposits around blood vessels are also a unique CADASIL feature and appear to have a role in sequestering proteins that are essential for blood vessel homeostasis. As potential biomarkers and therapeutic targets are being actively investigated, neurofilament light chain can be detected in patient serum and may be a promising circulating biomarker.

SUMMARY

CADASIL is a complex, devastating disease with unknown mechanism and no treatment options. As we increase our understanding of CADASIL, translational research bridging basic science and clinical findings needs to drive biomarker and therapeutic target discovery.

Topics: Animals; Blood Vessels; CADASIL; Genetic Testing; Humans; Receptor, Notch3; Translational Research, Biomedical

PubMed: 30855338
DOI: 10.1097/MOH.0000000000000497

Authors: Yingying Li, Yunqing Ying, Tingyan Yao...

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood-brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (kw). Correlation and multiple linear regression analyses were used to examine the association between kw and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, kw in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased kw in the whole brain (β = -0.634, P = 0.001), normal-appearing white matter (β = -0.599, P = 0.002) and temporal lobe (β = -0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced kw in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (β = 0.458, P = 0.001; β = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of kw for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.

Topics: Humans; Blood-Brain Barrier; CADASIL; Brain; Cerebral Small Vessel Diseases; Cerebral Infarction

PubMed: 36625892
DOI: 10.1093/brain/awac500

Authors: Sheng Liu, Xuejiao Men, Yang Guo...

BACKGROUND

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome.

RESULTS

We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3 mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages.

CONCLUSION

These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL. Video Abstract.

Topics: Animals; Mice; CADASIL; Gastrointestinal Microbiome; Mental Disorders; Cytokines; gamma-Aminobutyric Acid

PubMed: 37684694
DOI: 10.1186/s40168-023-01638-3

Review

Authors: Saara Tikka, Marc Baumann, Maija Siitonen...

CADASIL and CARASIL are hereditary small vessel diseases leading to vascular dementia. CADASIL commonly begins with migraine followed by minor strokes in mid-adulthood. Dominantly inherited CADASIL is caused by mutations (n > 230) in NOTCH3 gene, which encodes Notch3 receptor expressed in vascular smooth muscle cells (VSMC). Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by VSMC degeneration and subsequent fibrosis and stenosis of arterioles, predominantly in cerebral white matter, where characteristic ischemic MRI changes and lacunar infarcts emerge. The likely pathogenesis of CADASIL is toxic gain of function related to mutation-induced unpaired cysteine in N3ECD. Definite diagnosis is made by molecular genetics but is also possible by electron microscopic demonstration of pathognomonic granular osmiophilic material at VSMCs or by positive immunohistochemistry for N3ECD in dermal arteries. In rare, recessively inherited CARASIL the clinical picture and white matter changes are similar as in CADASIL, but cognitive decline begins earlier. In addition, gait disturbance, low back pain and alopecia are characteristic features. CARASIL is caused by mutations (presently n = 10) in high-temperature requirement. A serine peptidase 1 (HTRA1) gene, which result in reduced function of HTRA1 as repressor of transforming growth factor-β (TGF β) -signaling. Cerebral arteries show loss of VSMCs and marked hyalinosis, but not stenosis.

Topics: Alopecia; Brain; CADASIL; Cerebral Infarction; Humans; Leukoencephalopathies; Spinal Diseases

PubMed: 25323668
DOI: 10.1111/bpa.12181

Authors: Yunqing Ying, Yingying Li, Tingyan Yao...

INTRODUCTION

We explored how blood-brain barrier (BBB) leakage rate of gadolinium chelates (K) and BBB water exchange rate (k) varied in cerebral small vessel disease (cSVD) subtypes.

METHODS

Thirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high-temperature requirement factor A serine peptidase 1 (HTRA) -related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment.

RESULTS

In CADASIL, no difference in K, but lower k was observed in multiple brain regions. In sporadic cSVD, no difference in k, but higher K was found in the whole brain and normal-appearing white matter. In HTRA1-related cSVD, both higher K in the whole brain and lower k in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity.

DISCUSSION

In cSVD subtypes, distinct alterations of k and K were observed. The combination of K and k can depict the heterogeneous BBB dysfunction.

HIGHLIGHTS

We measured BBB leakage to gadolinium-based contrast agent (K) and water exchange rate (k) across BBB in three subtypes of cSVD. CADASIL is characterized by lower k, HTRA1-related cSVD exhibits both higher K and lower k, while sporadic cSVD is distinguished by higher K. There are distinct alterations in k and K among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction.

Topics: Humans; Blood-Brain Barrier; Cerebral Small Vessel Diseases; Male; Female; Middle Aged; Magnetic Resonance Imaging; Brain; Aged; CADASIL; High-Temperature Requirement A Serine Peptidase 1; Gadolinium; Contrast Media; Adult

PubMed: 38787758
DOI: 10.1002/alz.13874

Review

Authors: Yerim Kim, Jong Seok Bae, Ju-Young Lee...

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small-vessel disease caused by mutations in the NOTCH3 gene. Classical pathogenic mechanisms are associated with cysteine gain or loss, but recent studies suggest that cysteine-sparing mutations might have a potential role as a pathogen. In comparison with CADASIL patients in Western countries, there are several differences in Asian patients: (1) prevalent locus of NOTCH3 mutations (exons 2-6 [particularly exon 4] vs. exon 11), (2) age at symptom onset, (3) prevalence of cerebral microbleeds and hemorrhagic stroke, (4) clinical symptoms, and (5) severity of white matter hyperintensities and typical involvement of the anterior temporal pole in magnetic resonance imaging. Both ethnicity and founder effects contribute to these differences in the clinical NOTCH3 spectrum in different cohorts. More functional investigations from diverse races are needed to clarify unknown but novel variants of NOTCH3 mutations. This review may broaden the spectrum of NOTCH3 variants from an Asian perspective and draw attention to the hidden pathogenic roles of NOTCH3 variants.

Topics: CADASIL; Cysteine; Exons; Genotype; Humans; Magnetic Resonance Imaging; Mutation; Phenotype; Receptor, Notch3; Receptors, Notch

PubMed: 36232798
DOI: 10.3390/ijms231911506