A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan

Shindo, Akihiro; Tabei, Ken-ichi; Taniguchi, Akira; Nozaki, Hiroaki; Onodera, Osamu; Ueda, Akihiko; Ando, Yukio; Urabe, Takao; Kimura, Kazumi; Kitagawa, Kazuo; Hanyu, Haruo; Hirano, Teruyuki; Wakita, Hideaki; Fukuyama, Hidenao; Kagimura, Tatsuo; Miyamoto, Yoshihiro; Takegami, Misa; Saitô, Satoshi; Watanabe-Hosomi, Akiko; Mizuta, Ikuko; Ihara, Masafumi; Mizuno, Toshiki; Tomimoto, Hidekazu

doi:10.3389/fnagi.2020.00216

Cited by 15 publications

(13 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Larger studies, including CADASIL patients with variable disease severity cohort. 27 The absence of GOM, therefore, does not exclude a CADASIL diagnosis, which is relevant for clinical practice, as to date GOM are deemed to have very high sensitivity and specificity for CADASIL. 7,[27][28][29] The strengths of this study are the prospective design, the quantitative analysis of both the ultrastructural GOM and the NOTCH3 ECD staining, as well as assessing NOTCH3 ECD aggregation in both skin and brain vasculature.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

Gravesteijn

Hack

Mulder

et al. 2021

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

Aims: CADASIL, the most prevalent hereditary cerebral small vessel disease, is caused by cysteine-altering NOTCH3 variants (NOTCH3 cys ) leading to vascular NOTCH3 protein aggregation. It has recently been shown that variants located in one of NOTCH3 protein epidermal growth-factor like repeat (EGFr) domains 1-6, are associated with a more severe phenotype than variants located in one of the EGFr domains 7-34. The underlying mechanism for this genotype-phenotype correlation is unknown. The aim of this study was to analyse whether NOTCH3 cys variant position is associated with NOTCH3 protein aggregation load.Methods: We quantified vascular NOTCH3 aggregation in skin biopsies (n = 25) and brain tissue (n = 7) of CADASIL patients with a NOTCH3 cys EGFr 1-6 variant or a EGFr 7-34 variant, using NOTCH3 immunohistochemistry (NOTCH3 score) and ultrastructural analysis of granular osmiophilic material (GOM count). Disease severity was assessed by neuroimaging (lacune count and white matter hyperintensity volume) and disability (modified Rankin scale).Results: Patients with NOTCH3 cys EGFr 7-34 variants had lower NOTCH3 scores (P = 1.3Á10 À5 ) and lower GOM counts (P = 8.2Á10 À5 ) than patients with NOTCH3 cys EGFr 1-6 variants in skin vessels. A similar trend was observed in brain vasculature. In the EGFr 7-34 group, NOTCH3 aggregation levels were associated with lacune count (P = 0.03) and white matter hyperintensity volume (P = 0.02), but not with disability.Conclusions: CADASIL patients with an EGFr 7-34 variant have significantly less vascular NOTCH3 aggregation than patients with an EGFr 1-6 variant. This may be one of the factors underlying the difference in disease severity between NOTCH3 cys EGFr 7-34 and EGFr 1-6 variants.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The absence of GOM in skin biopsies has also been recently described in another CADASIL cohort. 27 The absence of GOM, therefore, does not exclude a CADASIL diagnosis, which is relevant for clinical practice, as to date GOM are deemed to have very high sensitivity and specificity for CADASIL. 7 , 27 , 28 , 29 …”

Section: Discussionmentioning

confidence: 99%

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

Gravesteijn

Hack

Mulder

et al. 2021

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

show abstract

“…We constructed the REDCap database for CADASIL patients using a Research Electronic Data Capture (REDCap) system (Harris et al, 2009;Shindo et al, 2020). After obtaining consent and approval from the local institutional review board committee, the physician sent a registration form to the secretariat at the National Cerebral and Cardiovascular Center of Japan.…”

Section: Patientsmentioning

confidence: 99%

“…The diagnosis of CADASIL was based on the genetic criteria that either the patient or a third-degree relative had NOTCH3 mutations (Shindo et al, 2020). Dementia was diagnosed in each hospital, and defined according to the diagnostic criteria found in the fourth or fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV or DSM-V).…”

Section: Patientsmentioning

confidence: 99%

See 1 more Smart Citation

Imaging Characteristics for Predicting Cognitive Impairment in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Taniguchi

Shindo

Tabei

et al. 2022

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

ObjectivesPatients 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.MethodsSubjects 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.ResultsData 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.ConclusionThe 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.

show abstract

Antiplatelet use and CADASIL: a retrospective observational analysis

2023

View full text Add to dashboard Cite

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan

Cited by 15 publications

References 30 publications

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

Imaging Characteristics for Predicting Cognitive Impairment in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Antiplatelet use and CADASIL: a retrospective observational analysis

Contact Info

Product

Resources

About