Cerebral Amyloid Angiopathy: Clinical Presentation, Sequelae and Neuroimaging Features-An Update

Abstract

The prevalence of cerebral amyloid angiopathy (CAA) has been shown to increase with age, with rates reported to be around 50-60% in individuals over 80 years old who have cognitive impairment. The disease often presents as spontaneous lobar intracerebral hemorrhage (ICH), which carries a high risk of recurrence, along with transient focal neurologic episodes (TFNE) and progressive cognitive decline, potentially leading to Alzheimer's disease (AD). In addition to ICH, neuroradiologic findings of CAA include cortical and subcortical microbleeds (MB), cortical subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS). Non-hemorrhagic pathologies include dilated perivascular spaces in the centrum semiovale and multiple hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). A definitive diagnosis of CAA still requires histological confirmation. The Boston criteria allow for the diagnosis of a probable or possible CAA by considering specific neurological and MRI findings. The recent version, 2.0, which includes additional non-hemorrhagic MRI findings, increases sensitivity while maintaining the same specificity. The characteristic MRI findings of autoantibody-related CAA-related inflammation (CAA-ri) are similar to the so-called "amyloid related imaging abnormalities" (ARIA) observed with amyloid antibody therapies, presenting in two variants: (a) vasogenic edema and leptomeningeal effusions (ARIA-E) and (b) hemorrhagic lesions (ARIA-H). Clinical and MRI findings enable the diagnosis of a probable or possible CAA-ri, with biopsy remaining the gold standard for confirmation. In contrast to spontaneous CAA-ri, only about 20% of patients treated with monoclonal antibodies who show proven ARIA on MRI also experience clinical symptoms, including headache, confusion, other psychopathological abnormalities, visual disturbances, nausea and vomiting. Recent findings indicate that treatment should be continued in cases of mild ARIA, with ongoing MRI and clinical monitoring. This review offers a concise update on CAA and its associated consequences.

Keywords: Boston criteria; amyloid-related imaging abnormalities; antibody treatment; cerebral amyloid angiopathy; inflammation; intracerebral hemorrhage; magnetic resonance imaging; sequelae.

Figure 5

Non-hemorrhagic and hemorrhagic MRI features in cerebral amyloid angiopathy (CAA). Severe enlarged perivascular spaces (PVS) supratentorial ((a–c): T2-weighted images (WI), arrow); (e–g): Fluid attenuated inversion recovery (FLAIR) images (arrow) sparing the basal ganglia ((a,e): white arrowhead), characteristic for a centrum semiovale (CSO) PVS pattern. (f,g): Multiple partially conflating white matter hyperintensities in a multispot pattern (black arrowhead, WMH-MS). (d,h): Susceptibility-weighted images (SWI) exhibit additional hemorrhagic lesions, i.e., multiple cortical/subcortical microbleeds (MB, white arrowhead) and multifocal cortical superficial siderosis (cSS; (h), arrow); MRI 1.5 T Intera, Philips Healthcare.

Figure 1

Pathological sequelae due to cerebral amyloid angiopathy (CAA). 1: cortical subarachnoid hemorrhage (cSAH); 2: enlarged/severe centrum semiovale perivascular spaces (CSO PVS); 3: focal cortical thinning; 4: white matter hyperintensities in a multispot pattern (WMH MS); 5: cortical microbleeds (MB); 6: cortical superficial siderosis (cSS); 7: lobar intracerebral hemorrhage (ICH); 8: cortical/subcortical lacunar infarct.

Figure 2

Recurrent intracerebral hemorrhages (ICH) within 2 years in a 74-year-old man with a history of progressive cognitive impairment. The patient was on antihypertensive medication and a statin but had neither antithrombotic drugs nor anticoagulant therapy. The final diagnosis was new lobar ICB due to probable CAA in accordance with the 2.0 version of the Boston criteria [38]. Axial FLAIR (fluid attenuated inversion recovery) images (a–c) showing three ICHs at different time points parieto-occipital right ((a,d): arrow), temporal right ((b–e): arrow) and temporal left ((c,f): arrow); (d–f): susceptibility-weighted imaging (SWI; arrow) disclosing additional multiple microbleeds (MB) with temporal accentuation (d–f: arrowhead); MRI 1.5 T Siemens AREA.

Figure 3

Cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) in an 82-year-old woman with progressive cognitive decline and short-term memory disturbance. Axial T2-weighted images (WI) (a,b) showing distinct temporal mesial atrophy ((a), arrowhead), enlarged temporal horns ((a), arrow), vascular leukoencephalopathy ((b), arrowhead) and enlarged perivascular spaces (PVS; (b), arrow). Susceptibility-weighted imaging (SWI) ax. (c,d) disclosing multiple cortical and subcortical microbleeds (MB) (arrow), especially temporal and parietal; MRI 1.5 T Siemens AREA.

Figure 4

A 74-year-old man with progressive cognitive impairment suffering from temporary sensory–motoric deficits right. Cortical subarachnoid hemorrhage (cSAH) in the central sulcus ((a), CT: arrow; Siemens Somatom Emotion). MRI with sulcal hyperintense signal changes on fluid attenuated inversion recovery (FLAIR) images ((b), arrow), sulcal signal loss on susceptibility-weighted imaging (SWI, (c): arrow), additional multifocal cortical superficial siderosis (cSS) bilateral ((c–e), arrowhead); note the characteristic bilinear track-line appearance of cSS in the chronic stage ((c), arrowhead); (d,e): multiple cortical/subcortical microbleeds (MB, arrow); (f): SWI-phase image demonstrating paramagnetic effects in the central sulcus due to blood degeneration products (arrow); MRI 1.5 T Siemens AREA.

Figure 6

Cerebral amyloid angiopathy-related inflammation (CAA- ri) in a 72-year-old man suffering from subacute deterioration of consciousness and dizziness. (a–e): Initial MRI (upper row; MRI 3.0 T Siemens Magnetom) showing several hyperintense lesions preferentially in the subcortical occipital region ((a,b): arrow) without contrast enhancement on post-contrast T1-weighted images (T1 WI pc; (c), arrow), focal-accentuated microbleeds (MB) on T2* WI ((d), arrow) and susceptibility-weighted imaging (SWI; (e), arrow); note the higher sensitivity for MB on SWI (e) compared to T2* WI (d). (f–i): MRI (1.5 T Intera, Philips Healthcare) at readmission due to subacute severe psychosyndrome after tapered corticosteroid therapy. Multiple occasionally space-occupying hyperintense white matter lesions ((f,g): arrow) without contrast enhancement ((h), arrow) and progressive bilateral MBs ((i), arrow). Note the additional subacute small left frontal intracerebral hemorrhage (ICH; arrowhead). (j–m): Follow-up MRI (1.5 T Intera, Philips Healthcare) after several bouts of intravenous high-dosage methylprednisolone showing distinct regression of white matter lesions ((j,k): arrow) without contrast enhancement ((l), arrow), no significant new hemorrhagic lesions (m).

Figure 7

A 68-year-old woman suffering from progressive dizziness and visual blurring for several weeks (upper row) and acute deterioration (lower row) due to cerebral amyloid angiopathy-related inflammation (CAA-ri) with associated vasculitis (amyloid-beta-related angiitis, ABRA). (a–e): Multifocal hyperintense sulcal effusions ((a), arrow; fluid-attenuated inversion recovery (FLAIR)), focal small lesions with restricted diffusion temporo-parietal left ((b), arrowhead; diffusion-weighted imaging (DWI, b = 1000 s/mm²)), distinct multifocal leptomeningeal enhancement ((d), arrow; (c,d): T1 WI before (c) and after (d) contrast agent application); (e): multiple microbleeds (arrow, susceptibility-weighted imaging (SWI)). (f–i): Subacute lobar intracerebral hemorrhage (ICH; (f), arrow); (g,h): new cortical / subcortical infarcts ((g,h): arrowhead; DWI, b = 1000 s/mm², apparent diffusion coefficient (ADC) map); (g): T2* WI demonstrating inhomogeneous signal loss (arrow); MRI 1.5 T Intera, Philips Healthcare.

Figure 8

Histological specimen in cerebral amyloid angiopathy-related inflammation (CAA-ri) and associated vasculitis (amyloid-beta-related vasculitis, ABRA; biopsy of the pat. showed in Figure 7). (a): Beta A4 amyloid staining (10×) showing distinct immune histochemical evidence of beta amyloid (brown colored, arrow) in the vessel wall; (b): typical “apple green” color due to birefringence in polarized light (arrow; Congo-red staining, 10×); (c): leukocyte common antigen (LCA) staining (10×) disclosing lymphocytic infiltration in the arterial walls (arrow) and the leptomeninx (arrowhead); (d): hematoxylin-eosin staining (20×), also showing multinucleated giant cell (arrow) adjacent to the vessel wall (arrowhead). Courtesy L. Schweizer, Edinger–Institute, Neuropathology, Goethe University, Frankfurt.

Figure 9

Amyloid-related imaging abnormalities (ARIA). (a–d): Fluid-attenuated inversion recovery (FLAIR) images showing ARIA-E (edema, effusion) in a patient treated with aducanumab, week 14 (a), 30 (b), 34 (c) and 40 (d) after treatment initiation; sulcal effusions ((b), arrow) and edema in the occipital lobe ((c), arrowhead), completely decreased at week 40 (d). (e–h): T2*-weighted images (WI) demonstrating ARIA-H (hemorrhagic) in a 68-year-old woman treated with aducanumab, baseline (e,f) and week 18. (g,h): Cortical superficial siderosis (cSS; arrow) and microbleeds (MB; arrowhead); MRI 1.5T.