Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054.

Prevalence of massively diluted bone marrow cell samples aspirated from patients with myelodysplastic syndromes (MDS) or suspected of MDS: A retrospective analysis of nationwide samples in Japan.

Bone marrow (BM) examination is a key element in the diagnosis and prognostic grading of myelodysplastic syndromes (MDSs), and obtaining adequate BM cell samples is critical for accurate test results. Massive haemodilution of aspirated BM samples is a well-known problem; however, its incidence in patients with MDS has not been well studied. We report the first study to examine the incidence of massive haemodilution in nationwide BM samples aspirated from patients diagnosed with or suspected of MDS in Japan. Among 283 cases available for analysis, BM smears from 92 cases (32.5%) were hypospicular (massively haemodiluted) and, particularly, no BM particles were observed in 52 cases (18.4%). Regarding hypospicular cases, we examined how the doctors in charge interpreted the BM smears of their patients. In only 19 of 92 cases (20.7%), doctors realised that the BM smears were haemodiluted. Furthermore, the BM biopsy, which can help diagnose hypospicular cases, was oftentimes not performed when the haemodilution was overlooked by doctors (not performed in 50 of 73 such cases). These real-world data highlight that not only researchers who are working to improve diagnostic tests but also clinicians who perform and use diagnostic tests must realise this common and potentially critical problem.

Predominant determinants for evaluation of right parasternal approach in transthoracic echocardiography in aortic stenosis: a study based on three-dimensional cardiac computed tomography analysis.

The maximum blood flow velocity through the aortic valve (AVmax) using Doppler transthoracic echocardiography (TTE) is important in assessing the severity of aortic stenosis (AS). The right parasternal (RP) approach has been reported to be more useful than the apical approach, but the anatomical rationale has not been studied. We aimed to clarify the influence of the angle formed by the ascending aorta and left ventricle on Doppler analysis by TTE (Sep-Ao angle) and three-dimensional multidetector computed tomography (3D-MDCT) in patients with AS. A total of 151 patients evaluated using the RP approach and 3D-MDCT were included in this study. The Sep-Ao angle determined using TTE was compared with that determined using 3D-MDCT analysis. In MDCT analysis, the left ventricular (LV) axis was measured in two ways and the calcification score was calculated simultaneously. The Sep-Ao angle on TTE was consistent with that measured using 3D-MDCT. In patients with an acute Sep-Ao angle, the Doppler angle in the apical approach was larger, potentially underestimating AVmax. Multivariate analysis revealed that an acute Sep-Ao angle, large Doppler angle in the apical approach, smaller Doppler angle in the RP approach, and low aortic valve calcification were independently associated with a higher AVmax in the RP approach than in the apical approach. The Sep-Ao angle measured using TTE reflected the 3D anatomical angle. In addition to measurements using the RP approach, technical adjustments to minimize the Doppler angle to avoid bulky calcification should always be noted for accurate assessment.