Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation

Jun Takei; Yujiro Higuchi; Masahiro Ando; Akiko Yoshimura; Jun-Hui Yuan; Natsumi Fujisaki; Takashi Tokashiki; Naomi Kanzato; Manabu Jonosono; Takeshi Sueyoshi; Naoaki Kanda; Hideki Matsuoka; Ryuichi Okubo; Masahito Suehara; Eiji Matsuura; Hiroshi Takashima

doi:10.3389/fneur.2023.1241678

Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation

Front Neurol. 2023 Aug 23:14:1241678. doi: 10.3389/fneur.2023.1241678. eCollection 2023.

Authors

Affiliations

¹ Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
² Department of Neurology, National Hospital Organization Okinawa Hospital, Okinawa, Japan.
³ Department of Neurology, Okinawa Prefectural Southern Medical Center & Children's Medical Center, Okinawa, Japan.
⁴ Department of Neurology, Okinawa Chubu Hospital, Okinawa, Japan.
⁵ Department of Radiology, Minei Daiichi Hospital, Okinawa, Japan.
⁶ Department of Neurology, Imamura General Hospital, Kagoshima, Japan.
⁷ Department of Cerebrovascular Medicine, Stroke Center, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.
⁸ Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.

Abstract

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan.

Methods: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images.

Results: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign).

Conclusion: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

Keywords: CADASIL; CMBs; MCT sign; NOTCH3; R75P; thalamus.

Grants and funding

This study was supported by grants-in-aid from the Research Committee of Ataxia, Health Labour Sciences Research Grant, the Ministry of Health, Labour, and Welfare, Japan (20317603 and 201610002B). This research was also supported by the Research program for conquering intractable disease from the Japan Agency for Medical Research and Development (AMED) (201442014A and 201442071A) and JSPS KAKENHI Grants (JP18H02742, JP20K16604, JP21K15702, JP21H02842, JP22K15713, JP22K07495, and JP23K06931).