Abstract
Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3–4 years later (NC = 8; MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: p = 0.001; Aβ1-42: p = 0.0004) and T2 (Aβ1-40: p = 0.001; Aβ1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
Highlights
Sporadic Cerebral Amyloid Angiopathy (CAA) is a leading cause of intracerebral haemorrhage (ICH) and vascular dementia in older adults and is associated with the accumulation of amyloid-β (Aβ) in the cerebral vasculature [1]
The current study is the first to report on plasma Aβ1-40 and Aβ1-42 alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) MCs and NCs from the same pedigree, using the ultrasensitive Single Molecule Array (Simoa) technology, wherein lower plasma Aβ1-40 and Aβ1-42 levels were observed in MCs compared to the NCs in line with our hypothesis
Findings from these cross-sectional analyses using the ultrasensitive Simoa technology platform suggest that plasma Aβ1-40 and Aβ1-42 may serve as potential candidates for a CAA diagnostic biomarker panel, further validation studies are necessary in sporadic CAA
Summary
Sporadic Cerebral Amyloid Angiopathy (CAA) is a leading cause of intracerebral haemorrhage (ICH) and vascular dementia in older adults and is associated with the accumulation of amyloid-β (Aβ) in the cerebral vasculature [1]. CAA pathology is widely seen in patients with Alzheimer’s disease (AD), of whom around 80% exhibit CAA co-morbidity [3]. The co-presence of CAA in AD, even in the absence of overt ICH, may negatively influence the progression of AD-related neurodegeneration [4,5]. Diagnosis using pre-symptomatic CAA markers will provide clinicians with an opportunity to inform patients on the potential risks of thrombolysis or anticoagulation therapy and, treating or lowering other modifiable risk-factors for ICH and vascular dementia such as hypertension, diabetes, hypercholesterolaemia and smoking
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