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 incl...

Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance

“…As recently discussed in a critical review,12 it provided a window to understand the pathophysiological mechanisms of the disease, including the relationship of amyloid burden with important haemorrhagic and non-haemorrhagic MRI manifestations and large-scale brain alterations of CAA. The increased amyloid-PET uptake in patients with symptomatic CAA-ICH demonstrated here is consistent with previous reports, and most likely reflects ligand binding to cerebrovascular amyloid, in line with neuropathological data.…”

“…Therefore, developing a molecular imaging tracer specific for cerebrovascular amyloid would be a game-changer for the field, allowing for directly detecting and following CAA pathology in vivo. Of note, there is absence of natural history data on rate of vascular amyloid progression, captured in amyloid-PET studies in CAA 12. Accordingly, active research has recently focused on PET tracers able to selectively detect CAA versus parenchymal amyloid-Aβ plaques, and effectively 18 F-labelled or 68 Ga-labelled ligands targeting amyloid-β aggregates on cerebral vessels have been developed 53.…”

“…This study was conducted in line with the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy14 15 and with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, according to a prespecified protocol developed in-house and following a recentl systematic review on the topic 12…”

“…We searched PubMed (without language restriction) from 1 January 2007 (when the first study on amyloid PET in CAA was published) until 12 June 2017 (updating a recent systematic search12) using a combination of keyword search and medical subject heading (MeSH) terms: (PET OR PiB OR pittsburgh OR ‘positron emission tomography’ OR florbetapir) AND (‘amyloid angiopathy’). Reference lists from all included articles, review papers on the topic and the authors’ own files were also searched for relevant studies in English.…”

“…We therefore performed a systematic review and meta-analysis to synthesise evidence on the overall strength of amyloid-PET in patients with symptomatic sporadic CAA versus control groups, in terms of both global cortical amyloid load and occipital-to-global regional distribution, the two main metrics that characterise amyloid PET in CAA suggested in the literature 12. Regarding comparison groups, we considered the recently proposed two-pronged diagnostic approach involving comparison to both healthy aged or deep non-CAA-related ICH controls, and subjects with probable Alzheimer’s disease (AD) 12 13…”