Clinical considerations in early-onset cerebral amyloid angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is an important cerebral small vessel disease associated with brain haemorrhage and cognitive change. The commonest form, sporadic amyloid-β CAA, usually affects people in mid- to later life. However, early-onset forms, though uncommon, are increasingly recognized and may result from genetic or iatrogenic causes that warrant specific and focused investigation and management. In this review, we firstly describe the causes of early-onset CAA, including monogenic causes of amyloid-β CAA (APP missense mutations and copy number variants; mutations of PSEN1 and PSEN2) and non-amyloid-β CAA (associated with ITM2B, CST3, GSN, PRNP and TTR mutations), and other unusual sporadic and acquired causes including the newly-recognized iatrogenic subtype. We then provide a structured approach for investigating early-onset CAA, and highlight important management considerations. Improving awareness of these unusual forms of CAA amongst healthcare professionals is essential for facilitating their prompt diagnosis, and an understanding of their underlying pathophysiology may have implications for more common, late-onset, forms of the disease.

Keywords: Alzheimer’s disease; cerebral amyloid angiopathy; dementia; early-onset; stroke.

Figure 1

Imaging features of amyloid-β CAA. (A–D) Examples of brain imaging from individuals with sporadic amyloid-β CAA. CT images demonstrating (A) acute ICH and (B) acute convexity subarachnoid haemorrhage. Susceptibility-weighted MRI images demonstrating (C) disseminated cortical superficial siderosis of the right cerebral hemisphere and (D) lobar (cortical) cerebral microbleeds. B and C reprinted and adapted from Banerjee et al. (open access article distributed under the terms of the Creative Commons CC BY 4.0 license). (E–H) MRI from individuals with features of CAA accompanying familial Alzheimer’s disease. An old amygdala haemorrhage (arrow) and extensive white matter hyperintensities on T₂ FLAIR (E), with multiple microbleeds on T₂* imaging (F) in an APP duplication carrier. White matter hyperintensities on T₂ FLAIR (G) and widespread lobar microbleeds on susceptibility-weighted imaging (H) in an individual with the PSEN1 R269H mutation. E and F reprinted and adapted from McNaughton et al.G and H reprinted and adapted from Ryan et al. by permission of Oxford University Press.

Figure 2

Potential causes of early-onset CAA. AD = Alzheimer’s disease; ARIA = amyloid-related imaging abnormalities; CAA = cerebral amyloid angiopathy.

Figure 3

Schematics of the amyloid precursor protein (APP) and amyloid-β peptide. (A) Schematic of the amyloid precursor protein (APP). APP is a transmembrane glycoprotein that can exist in multiple isoforms of differing lengths, the most common in the brain being 695 amino acids in length (APP695). This schematic of APP demonstrates its larger extracellular N-terminal end and smaller intracellular C-terminal end (both green). The amyloid-β peptide (orange) starts in the extracellular domain and enters the transmembrane domain. (B) Schematic of the amyloid-β peptide and its amino acid sequence. The α-secretase cleavage site, in addition to those for β-secretase (two potential sites) and γ-secretase (multiple sites, resulting in amyloid-β fragments between 37 and 49 amino acids in length) are shown. Amino acids coloured yellow fall within the transmembrane section of APP. Mutations affecting the amino acids outlined in red have confirmed pathogenicity and are particularly associated with CAA.

Figure 4

Immunohistochemical staining of early-onset cerebral amyloidosis. Amyloid-β (Aβ) immunohistochemistry in an APP duplication and PSEN1 post-codon mutation case showing severe cerebral amyloid angiopathy (CAA) in both leptomeningeal and parenchymal blood vessels; there is also evidence of amyloid-β deposition in the capillaries. In familial British dementia (FBD) the amyloidogenic protein ABri is deposited in leptomeningeal and parenchymal blood vessels, as well as capillaries. In familial Danish dementia (FDD), both ADan and amyloid-β are found deposited as amyloid. ADan and amyloid-β are found within the same blood vessels shown in the leptomeningeal vessels on sequential sections. ADan and amyloid-β are also found in parenchymal vessels and capillaries. Scale bars = 50 µm.

Figure 5

An outline approach to investigating early-onset CAA. The order of investigations will necessarily depend on the clinical context for an individual patient and the investigations available at a particular centre. In cases where gene panel testing is requested, it is important to ensure that the method allows duplications (and other copy number variants) to be identified, as this is not universally the case. CAA = cerebral amyloid angiopathy.