Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update

Abstract

Sporadic cerebral amyloid angiopathy (CAA) is a very common small vessel disease of the brain, showing preferential and progressive amyloid-βdeposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. CAA now encompasses not only a specific cerebrovascular pathological trait, but also different clinical syndromes - including spontaneous lobar intracerebral haemorrhage (ICH), dementia and 'amyloid spells' - an expanding spectrum of brain parenchymal MRI lesions and a set of diagnostic criteria - the Boston criteria, which have resulted in increasingly detecting CAA during life. Although currently available validated diagnostic criteria perform well in multiple lobar ICH, a formal diagnosis is currently lacking unless a brain biopsy is performed. This is partly because in practice CAA MRI biomarkers provide only indirect evidence for the disease. An accurate diagnosis of CAA in different clinical settings would have substantial impact for ICH risk stratification and antithrombotic drug use in elderly people, but also for sample homogeneity in drug trials. It has recently been demonstrated that vascular (in addition to parenchymal) amyloid-βdeposition can be detected and quantified in vivo by positron emission tomography (PET) amyloid tracers. This non-invasive approach has the potential to provide a molecular signature of CAA, and could in turn have major clinical impact. However, several issues around amyloid-PET in CAA remain unsettled and hence its diagnostic utility is limited. In this article we systematically review and critically appraise the published literature on amyloid-PET (PiB and other tracers) in sporadic CAA. We focus on two key areas: (a) the diagnostic utility of amyloid-PET in CAA and (b) the use of amyloid-PET as a window to understand pathophysiological mechanism of the disease. Key issues around amyloid-PET imaging in CAA, including relevant technical aspects are also covered in depth. A total of six small-scale studies have addressed (or reported data useful to address) the diagnostic utility of late-phase amyloid PET imaging in CAA, and one additional study dealt with early PiB images as a proxy of brain perfusion. Across these studies, amyloid PET imaging has definite diagnostic utility (currently tested only in probable CAA): it helps rule out CAA if negative, whether compared to healthy controls or to hypertensive deep ICH controls. If positive, however, differentiation from underlying incipient Alzheimer's disease (AD) can be challenging and so far, no approach (regional values, ratios, visual assessment) seems sufficient and specific enough, although early PiB data seem to hold promise. Based on the available evidence reviewed, we suggest a tentative diagnostic flow algorithm for amyloid-PET use in the clinical setting of suspected CAA, combining early- and late-phase PiB-PET images. We also identified ten mechanistic amyloid-PET studies providing early but promising proof-of-concept data on CAA pathophysiology and its various manifestations including key MRI lesions, cognitive impairment and large scale brain alterations. Key open questions that should be addressed in future studies of amyloid-PET imaging in CAA are identified and highlighted.

Keywords: CAA; Florbetapir; Microbleeds; PET; PiB; Small vessel disease.

Fig. 1

Flow chart of study identification and selection.

Fig. 2

Typical PiB uptake images (one axial brain cut) in aged healthy controls (HC), probable CAA and AD. From left to right are shown examples of i) normal scan (i.e., PiB −) in an aged HC; ii) positive PiB scan (i.e., PiB +) in another aged HC, adopting the typical ‘Alzheimer disease (AD)-like pattern’, namely uptake highest in frontal cortex; iii) PiB-probable cerebral amyloid angiopathy (pCAA) subject; iv) PiB + pCAA subject, AD-like pattern; v) PiB + pCAA subject, with ‘CAA-like pattern’, namely equal uptake in occipital and frontal cortex; and vi) PiB + AD subject, AD-like pattern. Note that these images are shown only for illustrative purposes as significant overlap exists between these typical patterns across clinical entities (see Discussion).

Fig. 3

Early-phase PiB Occipital/Posterior cingulate cortex uptake ratio in probable CAA and AD. The difference in ratio between the two groups is highly significant (p = 0.002; Mann-Whiney test). This graph shows the presence of a substantial though limited overlap between the two populations, with a ratio around one discriminating all AD subjects vs 9/11 CAA subjects. See Methods and (Farid et al., 2015) for details.

Fig. 4

Diagnostic flow chart algorithm of possible amyloid-PET use in the clinical setting of suspected CAA, based on currently available evidence presented in this review article. This stepwise algorithm is based on three successive steps: i) late-phase amyloid PiB-PET is compared to young controls; ii) if PiB +, then the regional pattern is compared to AD; iii) if still unclear, then the pattern of early PiB images are compared to AD. Note this is a tentative work-flow that is not to be used as evidence-based for routine clinical practice but meant to serve as starting point for future studies.