Clinical Management of Cerebral Amyloid Angiopathy

Abstract

Background: Cerebral amyloid angiopathy (CAA) represents a progressive cerebrovascular disorder, characterized by aberrant accumulation of beta-amyloid isoforms in cortical and leptomeningeal vessel walls of cerebrum and cerebellum. Methods: We sought to investigate the clinical manifestations, current different diagnostic tools, various therapeutic strategies and most uncommon subtypes of the disease. Results: The vast majority of CAA remains sporadic, with increasing prevalence with age and very frequent coexistence with Alzheimer's disease. Clinically, CAA can present with spontaneous lobar intracerebral hemorrhage, transient focal neurologic episodes attributed to convexity subarachnoid hemorrhage or cortical superficial siderosis, and progressive cognitive decline leading to dementia. Inflammatory CAA subtype should be recognized early and treated promptly so that better functional outcomes may be achieved. Moreover, genetic and iatrogenic CAA forms are rare, yet increasingly recognized during the last years. Therapeutic management remains challenging for clinicians, especially when markers indicative of higher bleeding risk are present. A targeted therapy does not currently exist. However, various clinical trials are in progress, focusing on offering new promising insights into the disease treatment. Conclusions: This review aims to deepen our understanding of CAA diagnosis and therapeutic approach but also summarizes current evidence on the most uncommon subtypes of this cerebral small-vessel disease.

Keywords: CAA-ri; amyloid PET; amyloid-β; brain MRI; cerebral amyloid angiopathy; cerebral microbleeds; cerebrospinal fluid biomarkers; cortical superficial siderosis; treatment.

Figure 1

Useful tools in the diagnosis of Cerebral Amyloid Angiopathy.

Figure 2

Neuroimaging findings in a patient with Cerebral Amyloid Angiopathy. Enlarged perivascular spaces in centrum semiovale (Panel (A)) and characteristic multispot white-matter hyperintensities pattern (Panel (B)) are detected in T2-weighted image and 3D fluid-attenuated inversion recovery sequence (FLAIR), respectively. Diffusion-weighted imaging (DWI) sequence (Panel (C)) showing a right parietal cortical microinfarct. Susceptibility-weighted imaging (SWI) sequences demonstrating multiple cerebral lobar microbleeds (Panel (D)) and disseminated cortical superficial siderosis (Panel (E)) in parietal lobes bilaterally. Fourteen months following CAA diagnosis, the patient presented focal neurological deficits attributed to a lobar hemorrhage of the right temporal lobe with characteristic finger-like projections (Panel (F)).

Figure 3

Radiological mimics of Cerebral Amyloid Angiopathy. A 68-year-old female patient with convexity subarachnoid hemorrhage, detected on brain Computed tomography (Panel (A)) and fluid-attenuated inversion recovery sequence (FLAIR) (Panel (B)), attributed to reversible cerebral vasoconstriction syndrome (RCVS) with characteristic vasoconstriction in the left pericallosal artery (Panel (C)). Another 58-year-old male patient with extensive infratentorial superficial siderosis (Panel (D), which was attributed to dural defect with extra-dural CSF, detected on T2-weighted fat saturated sequences. (Panels (E,F)). A 77-year-old female patient with multiple cortical and subcortical cerebral hemorrhagic lesions attributed to multiple cerebral cavernous malformations (Panels (G–J)).

Figure 4

Radiological mimics of Cerebral Amyloid Angiopathy. A 55-year-old male patient with multiple cerebral microinfarcts (Panel (A)), left parietal cortical superficial siderosis and lobar microbleeds (Panel (B)) attributed to primary angiitis of the Central Nervous System. Digital subtraction angiography revealed multiple intracranial stenoses in both proximal and distal arteries (Panel (C)). A 57-year-old female patient with multiple lobar and deep hemorrhagic lesions (Panels (D,E)) associated with confluent, bilateral, symmetric white matter hyperintensities on FLAIR sequences, with relative sparing of subcortical U-fibers (Panel (F)). Genome wide sequencing revealed the pathogenic mutation NM_001845.6:c.2245G>A, p.(Gly749Ser), leading to the diagnosis of COL4A1-related disorder.

Figure 5

Neuroimaging findings in a patient with Cerebral Amyloid Angiopathy-related inflammation. Three-dimensional fluid-attenuated inversion recovery sequence (FLAIR) revealing multiple bilateral asymmetric white matter hyperintensities (Panel (A)). Axial T2* images showing multiple lobar cerebral microbleeds (Panel (B)) and disseminated cortical superficial siderosis (Panel (C)). Diffusion-weighted imaging (DWI) sequence (Panel (D)) demonstrating multiple cortical and subcortical ischemic lesions (Panel (D)). T1-weighted imaging showing extensive leptomeningeal gadolinium enhancement (Panel (E)) with complete resolution following intravenous treatment with methylprednisolone (Panel (F)).