Fluid biomarkers in cerebral amyloid angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid β, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Keywords: amyloid beta; cerebral amyloid angiopathy; differential diagnosis; familial cerebral amyloid angiopathy; fluid biomarkers; surrogate endpoints.

Figure 1

A summary of the fluid biomarkers of cerebral amyloid angiopathy (CAA). The vascular deposition of Aβ leads to CAA (Greenberg et al., 2020). Iron can promote the production of Aβ, whereas MMPs can break down Aβ into soluble fragments (Hernandez-Guillamon et al., 2015; Uranga and Salvador, 2018). The MMPs could also play a harmful role in disrupting the blood–brain barrier (Gireud-Goss et al., 2021). Aβ may also contribute to neurodegeneration with the aid of tau protein (Rapoport et al., 2002). The oxidative stress induced by iron, pro-inflammatory cytokines, and tau results in neuronal damage (Teleanu et al., 2022). In response to this damage, production of GFAP can be induced in activated astrocytes (Abdelhak et al., 2022). NfL is another neuronal damage marker that could be utilised in CAA (Banerjee et al., 2020; Cheng et al., 2020; Plotzker et al., 2021). TGFβ-1, another protein produced by astrocytes, has a dual function and is involved in vascular deposition and clearance of Aβ and, at the same time, has neuroprotective effects (Diniz et al., 2019; Kapoor and Chinnathambi, 2023). C3, produced by the microglia, may play a role in the vascular deposition of Aβ and neurodegeneration (Saito et al., 2022). NLK and PDGFRβ, released by pericytes, are proposed to increase in response to Aβ and damage to pericytes, respectively (De Kort et al., 2021, 2022). Yet, neither NLK nor PDGFRβ has shown significant changes in CAA. Lactadherin and UA have anti-inflammatory and anti-oxidative features, respectively (Cheyuo et al., 2019; Mijailovic et al., 2022). However, their levels are decreased in CAA (Hu et al., 2014; Marazuela et al., 2021), preventing them from mitigating the neuroinflammation and oxidative stress present in CAA. Aβ, amyloid β; C3, complement 3; GFAP, glial fibrillary acidic protein; MMP, matrix metalloproteinase; NFL, neurofilament light chain; NLK, neuroleukin; PDGFRβ, platelet-derived growth factor receptor-β; TGFβ, transforming growth factor; UA, uric acid.