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The Increasing Impact of Cerebral Amyloid Angiopathy: Essential New JNNP Online First, published on August 26, 2017 as 10.1136/jnnp-2016-314697 Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-314697 on 26 August 2017. Downloaded from REVIEW The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice Gargi Banerjee,1 Roxana Carare,2 Charlotte Cordonnier,3 Steven M Greenberg,4 Julie A Schneider,5 Eric E Smith,6 Mark van Buchem,7 Jeroen van der Grond,7 Marcel M Verbeek,8,9 David J Werring1 For numbered affiliations see ABSTRact Furthermore, CAA gained new relevance with the end of article. Cerebral amyloid angiopathy (CAA) has never been advent of anti-Aβ immunotherapies for the treat- more relevant. The last 5 years have seen a rapid ment of Alzheimer’s disease (AD), as a sizeable Correspondence to increase in publications and research in the field, with proportion of those treated went on to develop Dr David J Werring, The National Hospital for Neurology and the development of new biomarkers for the disease, imaging features of CAA-related inflammation as 5 Neurosurgery, UCL Institute thanks to advances in MRI, amyloid positron emission an unintended consequence. This, together with of Neurology, Queen Square, tomography and cerebrospinal fluid biomarker analysis. advances in our understanding of the impact of London WC1N 3BG, UK; d. The inadvertent development of CAA-like pathology CAA on cognition, in the context of ICH, ageing werring@ ucl. ac. uk in patients treated with amyloid-beta immunotherapy and AD, has broadened the clinical spectrum Received 1 March 2017 for Alzheimer’s disease has highlighted the importance of disease to which the contribution of CAA is Revised 26 April 2017 of establishing how and why CAA develops; without recognised. The 5th International CAA Conference, Accepted 18 May 2017 this information, the use of these treatments may held in Boston, Massachusetts in September 2016 be unnecessarily restricted. Our understanding of (https:// caaforum. org/ event/ 5th- international- caa- the clinical and radiological spectrum of CAA has conference- 2016- boston- ma/), highlighted many of continued to evolve, and there are new insights into these developments, as well as a need to update the the independent impact that CAA has on cognition in current diagnostic Boston criteria to better reflect the context of ageing and intracerebral haemorrhage, these new wide-ranging clinical and radiological as well as in Alzheimer’s and other dementias. While findings. copyright. the association between CAA and lobar intracerebral This review aims to provide a clinically oriented haemorrhage (with its high recurrence risk) is now well update on these recent advances, focusing on those recognised, a number of management dilemmas remain, in the last 5 years, since our last comprehensive particularly when considering the use of antithrombotics, review.3 Specifically, we will focus on newly identi- anticoagulants and statins. The Boston criteria for CAA, fied biomarkers for CAA and their potential mecha- in use in one form or another for the last 20 years, are nistic implications, as well as the latest insights into now being reviewed to reflect these new wide-ranging the pathophysiology and causes of CAA. We will clinical and radiological findings. This review aims to also report on the expanding spectrum of clinical provide a 5-year update on these recent advances, as presentations associated with CAA, before finally well as a look towards future directions for CAA research considering the ongoing management dilemmas and clinical practice. that face physicians working in neurology, elderly http://jnnp.bmj.com/ care and stroke medicine, among others, when faced with this disease. INTRODUCTION Cerebral amyloid angiopathy (CAA), a cerebral BIOMARKERS ADVANCES AND MECHANISTIC small vessel disease (SVD) characterised by the pres- INSIGHTS ence of amyloid-beta (Aβ) protein within cortical Insights from hereditary cerebral haemorrhage on September 23, 2021 by guest. Protected and leptomeningeal blood vessel walls,1 is a condi- with amyloidosis-Dutch type (HCHWA-D) tion of increasing clinical and mechanistic impor- Establishing the natural history of sporadic CAA tance. Although recognised pathologically since the is difficult, in part due to the limited sensitivity of early 20th century, CAA had been sidelined until our current diagnostic criteria,6 7 and also due to it was more firmly associated with lobar intracere- the high prevalence of comorbid changes caused bral haemorrhage (ICH) many years later.2 3 This, by ageing and other neurodegenerative disorders. together with the use of blood-sensitive magnetic Moreover, most of these clinical and radiological resonance sequences to visualise asymptomatic features are thought to occur relatively late in the haemorrhagic events that far exceed those causing disease process; given that any potential window clinical symptoms, has expanded our understanding for treatment is likely to be at earlier stages of the To cite: Banerjee G, of what CAA is and its clinical significance.2–4 The disease, this is likely to significantly limit their use Carare R, Cordonnier C, et al. last 5 years have seen ongoing progress in this area, as feasible biomarkers. J Neurol Neurosurg Psychiatry Published Online First: [please thanks in part to the development of new tech- HCHWA-D is an autosomal dominant disease include Day Month Year]. nologies within the fields of magnetic resonance, that predominantly occurs in a limited number doi:10.1136/jnnp-2016- amyloid positron emission tomography ligands of families in the villages of Katwijk and Scheve- 314697 and cerebrospinal fluid (CSF) biomarker analysis.4 ningen in the Netherlands.8 A point mutation Banerjee G, et al. J Neurol Neurosurg Psychiatry 2017;0:1–13. doi:10.1136/jnnp-2016-314697 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd under licence. Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-314697 on 26 August 2017. Downloaded from (E693Q) of the amyloid precursor protein (APP) gene9 leads Related developments in sporadic CAA to extensive Aβ deposition in the cortical and leptomeningeal Imaging arterioles and arteries. The underlying pathology of these Aβ Neuroimaging remains a central component to the diagnosis of deposits is similar to that in sporadic CAA with minimal or CAA, with a focus on the presence of the haemorrhagic mani- no neurofibrillary pathology.8 9 Most importantly, mutation festations of the disease: lobar macrohaemorrhage, strictly lobar carriers develop symptoms (recurrent ICH and dementia10) microbleeds and cSS.6 7 The last 5 years have seen increased relatively early in life, usually between the ages of 50 and 60 understanding of these markers, as well as the emergence of new years. Therefore, using HCHWA-D as a model allows CAA-re- potential structural and functional imaging markers for CAA, all lated changes to be studied with minimal confounding by of which may be of both diagnostic and mechanistic relevance. comorbidities associated with ageing. This genetic condition Some notable recent advances are summarised here (table 1).19–30 also opens the possibility to find new disease markers, even in While multiple lobar ICH remains the strongest indicator for the presymptomatic phase. CAA, they are a late feature of the disease and may not be a prac- Previous studies have shown that the characteristic radio- tical outcome marker for clinical trials.31 The association between logical signs of sporadic CAA are mimicked in symptomatic cSS and CAA is now well recognised, reflected by its inclusion 7 HCHWA-D, namely numerous lobar microbleeds with or in the modified Boston criteria. Clinically, cSS is associated with 32 without cortical superficial siderosis (cSS).3 11 12 In presymp- transient focal neurological episodes (TFNE) and an increased 33–35 36 tomatic HCHWA-D, haemorrhagic changes are present, but risk of ICH, including early recurrent ICH. There is also more subtle; in recent studies, none or only one of the ‘clas- increasing evidence that cSS is associated with cognitive impair- sical’ signs (lobar microbleeds, macrohaemorrhage, cSS or ment, although it is not clear whether this is because cSS is a convexity subarachnoid haemorrhage, cSAH) were present.13 marker of severe CAA or because it has direct and independent 37–45 However, other disease markers such as white matter hyperin- effects on cognition. The other haemorrhagic marker of tensities (WMH) and cortical microinfarcts, which are ischaemic CAA, the presence of strictly lobar microbleeds, remains central manifestations of CAA,3 were already prevalent among presymp- to diagnosis. However, recent work reviewing diagnostic accu- tomatic HCHWA-D subjects.13 This indicates that these disease racy of using strictly lobar microbleeds alone found that while manifestations are among the earliest markers of the hereditary they were strongly predictive of CAA in a hospital cohort, this 46 form of CAA and precede ICH. In addition to explicit white was not the case in a healthy community population. This has matter changes, the grey matter is also specifically but subtly highlighted the importance of identifying new imaging markers for CAA that can further improve the specificity and sensitivity affected; recent data clearly showed that both patients with CAA 31 47 and HCHWA-D demonstrate similar patterns of cortical thin- of diagnosis, particularly outside ICH cohorts.
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