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

Abstract

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...

Plasma Glial Fibrillary Acidic Protein Detects Alzheimer Pathology and Predicts Future Conversion to Alzheimer Dementia in Patients With Mild Cognitive Impairment

“…Glial brillary acidic protein (GFAP) is expressed in the cytoskeleton of astrocytes and has been found signi cantly increased in CSF in AD and other neurodegenerative diseases compared to healthy controls (12)(13)(14)(15). GFAP has also been recently measured in plasma and serum, where it was found increased in different neurological conditions, including AD (16)(17)(18)(19)(20)(21)(22)(23)(24). Increase of plasma GFAP in AD patients was associated to amyloid-PET positivity and worse outcomes in global cognition (22,24,25).…”

Overlapping Protein Accumulation Profiles of CADASIL and CAA

“…76 In CAA without underlying AD pathology, 58 proteins from eight studies were found to be enhanced or decreased. A comparison between proteins differentially regulated in CADASIL and CAA studies highlighted 19 shared proteins changed in the same direction, which made up roughly 33% of the enhanced or decreased CAA proteins (Figure 1B and Table 2 15,17,18,26,42,69,70,74,86,89,104 ). Functional STRING version 11 (https://string-db.org/) analysis demonstrated that 18 of the 19 shared proteins are known or predicted to interact with each other, with an average per protein 5.6 predicted and known interactions with other shared proteins listed in Table 2 (Figure 1C).…”