Detrimental effects of intracerebral haemorrhage on patients with CADASIL harbouring NOTCH3 R544C mutation

et al. 2020

Preprint

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BackgroundStroke remains the most cumbersome disease burden in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to investigate whether plasma biomarkers can reflect disease severity and predict stroke recurrence in CADASIL patients. MethodsSixty-three CADASIL patients (mean age 58.9±9.3 years old, male 63%) from a multicenter registry and 17 controls were recruited. Plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), were measured using an ultra-sensitive single molecule array at baseline. Neuroimaging markers assessed included the Fazekas scale of white matter hyperintensity, numbers of lacunes and cerebral microbleeds (CMBs). Cox proportional hazards regression models were applied to calculate the hazard ratio (HR) of plasma biomarkers at baseline for predicting incident stroke during follow-up. ResultsPlasma NfL, GFAP, and UCHL1 levels were significantly elevated in the CADASIL patients than in the controls. Among the CADASIL patients, both plasma NfL and GFAP levels positively correlated with the numbers of CMBs (r = 0.32 and r = 0.37, respectively; both p < 0.05). Higher plasma levels of NfL and GFAP were associated with any stroke (odds ratio 2.02, 95% confidence interval CI 1.06-3.87) and ICH (odds ratio 2.06, 95% CI 1.26-3.35) at baseline, respectively. Within a mean follow-up period of 3.1 Common.EditSubmissionSteps.Transform.EquationText 2.1 years, 10 patients (16%) had incident stroke and 6 of them were ICH. Higher baseline NfL (HR 1.93, 95% CI 1.19-3.13) predicted any incident stroke, whereas higher GFAP (HR 2.80, 95% CI 1.21-6.53) predicted incident ICH. ConclusionsIn CADASIL patients, plasma NfL can be a promising biomarker for monitoring incident stroke, whereas GFAP may have a role in cerebral hemorrhage. Background 3Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene, leading to devastating disease burden with stroke and vascular dementia in the affected adults.(1) Neuroimaging features such as white matter hyperintensity (WMH), lacunes, and cerebral microbleeds (CMBs) may occur 10 to 15 years before the onset of stroke or cognitive decline.(1) In East Asian, p.R544C in exon 11 on NOTCH3 gene is the most prevalent hot spot mutation and accounted for more than 70% of the patients in their CADASIL cohorts.(2, 3) Regarding the vascular events, ischemic stroke (IS) or transient ischemic attack are considered the cardinal features in CADASIL. Despite that intracerebral hemorrhage (ICH) is considered a rare manifestation in Caucasian CADASIL patients, a significant proportion of East Asian patients harboring p.R544C NOTCH3 mutation also suffer from ICH, and those with ICH are more prone to have recurrent stroke.(4, 5) Although the natural course of the disease has been ex...

Section: Discussionmentioning

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Section: Discussionmentioning

confidence: 99%

Section: Participants and Clinical Informationmentioning

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Section: Introductionmentioning

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Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

et al. 2020

Preprint

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“…Regarding the vascular events, ischemic stroke (IS) or transient ischemic attack is considered the cardinal features in CADASIL. Despite that intracerebral hemorrhage (ICH) is considered a rare manifestation in Caucasian CADASIL patients, a significant proportion of East Asian patients harboring p.R544C NOTCH3 mutation also suffer from ICH, and those with ICH are more prone to have recurrent stroke [4,5]. Although the natural course of the disease has been extensively depicted, establishing reliable biomarkers to predict the occurrence of a vascular event including IS and ICH is crucial for developing an effective prevention strategy.…”

Section: Introductionmentioning

confidence: 99%

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

et al. 2020

J Neuroinflammation

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Background: Stroke remains the most cumbersome disease burden in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to investigate whether plasma biomarkers can reflect disease severity and predict stroke recurrence in CADASIL patients. Methods: Sixty-three CADASIL patients (mean age 58.9 ± 9.3 years old, male 63%) from a multicenter registry and 17 controls were recruited. Plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), were measured using an ultra-sensitive single molecule array at baseline. Neuroimaging markers assessed included the Fazekas scale of white matter hyperintensity, numbers of lacunes, and cerebral microbleeds (CMBs). Cox proportional hazards regression models were applied to calculate the hazard ratio (HR) of plasma biomarkers at baseline for predicting incident stroke during follow-up. Results: Plasma NfL, GFAP, and UCHL1 levels were significantly elevated in the CADASIL patients than in the controls. Among the CADASIL patients, both plasma NfL and GFAP levels positively correlated with the numbers of CMBs (r = 0.32 and r = 0.37, respectively; both p < 0.05). Higher plasma levels of NfL and GFAP were associated with any stroke (odds ratio 2.02, 95% confidence interval [CI] 1.06-3.87) and ICH (odds ratio 2.06, 95% CI 1.26-3.35) at baseline, respectively. Within a mean follow-up period of 3.1 ± 2.1 years, 10 patients (16%) had incident stroke and 6 of them were ICH. Higher baseline NfL (HR 1.93, 95% CI 1.19-3.13) predicted any incident stroke, whereas higher GFAP (HR 2.80, 95% CI 1.21-6.53) predicted incident ICH. Conclusions: In CADASIL patients, plasma NfL can be a promising biomarker for monitoring incident stroke, whereas GFAP may have a role in cerebral hemorrhage.

Imaging‐based pregenetic screening for NOTCH3 p.R544C mutation in ischemic stroke in Taiwan

et al. 2020

Ann Clin Transl Neurol

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Objective: To develop an easily applicable screening score to guide NOTCH3 p.R544C genetic testing for patients who presented with acute ischemic cerebrovascular events in Taiwan. Methods: 1734 patients who presented with ischemic cerebrovascular events were enrolled from the Formosa Stroke Genetic Consortium stroke registry and were screened for the NOTCH3 p.R544C mutation. Clinical and MRI characteristics of NOTCH3 p.R544C mutation carriers (n = 36) and a subset of noncarriers (n = 673) were tested in a logistic regression model to identify key features associated with the NOTCH3 p.R544C carrier status. Variables and their odds ratios in the regression model were used to develop the R544C screening score to predict positive NOTCH3 p.R544C test results. Results: We constructed the R544C screening score using five clinical and imaging characteristics, including stroke onset before 50 years of age, the small vessel occlusion subtype, a family history of stroke/TIA in siblings, external capsule involvement, and advanced deep white matter hyperintensity. The area under the ROC curve of the screening score was 0.867 (95% CI = 0.810-0.924). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 0.75, 0.88, 0.13, 0.99, and 0.88, respectively, for a cutoff score of 5 points. In addition, the R544C screening score was validated in another cohort composed of 235 stroke patients with comparable performance (area under the ROC curve = 0.957, 95% CI = 0.916-0.997). Interpretations: For Taiwanese patients presenting with acute ischemic cerebrovascular events, the R544C screening score is easily applicable and can efficiently select high-risk patients for NOTCH3 p.R544C mutation test. 1952 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association NOTCH3 p.R544C Pregenetic Screening in Ischemic Stroke Y. Cheng et al.