Cerebral amyloid angiopathy (CAA) results from deposition of β‐amyloid in the media and adventitia of small arteries and capillaries of the leptomeninges and cerebral cortex and is a major cause of ...lobar intracerebral hemorrhage and cognitive impairment in the elderly. CAA is associated with a high prevalence of magnetic resonance imaging markers of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Although advanced CAA is present in approximately ¼ of brains with Alzheimer disease (AD), fewer than half of CAA cases meet pathologic criteria for AD. This review will discuss the pathophysiology of CAA and focus on new imaging modalities and laboratory biomarkers that may aid in the clinical diagnosis of individuals with the disease. Ann Neurol 2011;70:871–880
Paravascular drainage of solutes, including β-amyloid (Aβ), appears to be an important process in brain health and diseases such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). ...However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aβ accumulation in the brain.
•Spontaneous low-frequency oscillations can be observed in arterioles in awake mice•Vasomotion drives paravascular clearance of solutes from the brain•Paravascular clearance is impaired in the context of cerebral amyloid angiopathy
van Veluw et al. demonstrate that vasomotion is a major driving force for paravascular clearance of solutes from the brain. Loss of vascular smooth muscle cells and reduced vasomotion in the context of amyloid deposition is associated with impaired clearance.
The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and ...cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.
As life expectancy grows, brain health is increasingly seen as central to what we mean by successful aging-and vascular brain health as central to overall brain health. Cerebrovascular pathologies ...are highly prevalent independent contributors to age-related cognitive impairment and at least partly modifiable with available treatments. The current Focused Update addresses vascular brain health from multiple angles, ranging from pathophysiologic mechanisms and neuroimaging features to epidemiologic risk factors, social determinants, and candidate treatments. Here we highlight some of the shared themes that cut across these distinct perspectives: (1) the lifetime course of vascular brain injury pathogenesis and progression; (2) the scientific and ethical imperative to extend vascular brain health research in non-White and non-affluent populations; (3) the need for improved tools to study the cerebral small vessels themselves; (4) the potential role for brain recovery mechanisms in determining vascular brain health and resilience; and (5) the cross-pathway mechanisms by which vascular and neurodegenerative processes may interact. The diverse perspectives featured in this Focused Update offer a sense of the multidisciplinary approaches and collaborations that will be required to launch our populations towards improved brain health and successful aging.
Sporadic cerebral amyloid angiopathy is a common, well-defined small vessel disease and a largely untreatable cause of intracerebral haemorrhage and contributor to age-related cognitive decline. The ...term 'cerebral amyloid angiopathy' now encompasses not only a specific cerebrovascular pathological finding, but also different clinical syndromes (both acute and progressive), brain parenchymal lesions seen on neuroimaging and a set of diagnostic criteria-the Boston criteria, which have resulted in increasingly detected disease during life. Over the past few years, it has become clear that, at the pathophysiological level, cerebral amyloid angiopathy appears to be in part a protein elimination failure angiopathy and that this dysfunction is a feed-forward process, which potentially leads to worsening vascular amyloid-β accumulation, activation of vascular injury pathways and impaired vascular physiology. From a clinical standpoint, cerebral amyloid angiopathy is characterized by individual focal lesions (microbleeds, cortical superficial siderosis, microinfarcts) and large-scale alterations (white matter hyperintensities, structural connectivity, cortical thickness), both cortical and subcortical. This review provides an interdisciplinary critical outlook on various emerging and changing concepts in the field, illustrating mechanisms associated with amyloid cerebrovascular pathology and neurological dysfunction.
Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used ...worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations.
In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994–2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012–18, n=59) and a geographical validation cohort (non-Boston cases 2004–18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy.
The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4–82·7) and 84·6% (71·9–93·1) in the derivation cohort, 92·5% (79·6–98·4) and 89·5% (66·9–98·7) in the temporal validation cohort, 80·2% (70·8–87·6) and 81·5% (61·9–93·7) in the geographical validation cohort, and 74·5% (65·4–82·4) and 95·0% (83·1–99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732–0·861) in the derivation cohort, 0·910 (0·828–0·992) in the temporal validation cohort, 0·808 (0·724–0·893) in the geographical validation cohort, and 0·848 (0·794–0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% 54·9–73·4; specificity 95·0% 83·1–99·4; AUC 0·798 0·741–0854; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard.
The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations.
US National Institutes of Health (R01 AG26484).
The risk of ischaemic stroke in patients with underlying conditions, such as nonvalvular atrial fibrillation, has been extensively studied, yielding widely used scales with at least moderate ...predictive value, such as the CHA2DS2-VASc and ATRIA scores.1 Conversely, scales developed for risk of major bleeding, such as HAS-BLED, appear to have low ability to predict intracranial haemorrhage or discriminate between risk of ischaemic stroke and intracranial haemorrhage.2 For the purpose of clinical decision-making regarding antithrombotic therapy after ischaemic stroke or transient ischaemic attack, it is reasonable to focus on risk of intracranial haemorrhage, rather than extracranial bleeding, because of the disproportionate burden of mortality and long-term disability attributable specifically to intracranial haemorrhage.3 The study by Jonathan Best and colleagues4 published in The Lancet Neurology, incorporates detection of cerebral microbleeds into risk prediction models for intracranial haemorrhage, representing a substantial step towards a successful metaphorical two-handed clap. The authors did a patient-level analysis of data from 15 784 individuals with ischaemic stroke or transient ischemic attack, treated with an antithrombotic drug, enrolled at 38 hospitals in 18 countries, as part of the Microbleeds International Collaborative Network (MICON). The challenging decision of whether to use anticoagulants in individuals with both indications for anticoagulation, such as non-valvular atrial fibrillation, and risks, such as previous intracranial haemorrhage, has triggered multiple ongoing randomised clinical trials.7 Because the direct oral anticoagulants consistently show lower intracranial haemorrhage risk than vitamin K antagonists,8 warfarin is not a rational option in this situation and all ongoing trials are testing direct oral anticoagulants.
Intracerebral hemorrhage (ICH), the most devastating form of stroke, has no specific therapy proven to improve outcome by randomized controlled trial. Location and baseline hematoma volume are strong ...predictors of mortality, but are nonmodifiable by the time of diagnosis. Expansion of the initial hematoma is a further marker of poor prognosis that may be at least partly preventable. Several risk factors for hematoma expansion have been identified, including baseline ICH volume, early presentation after symptom onset, anticoagulation, and the CT angiography spot sign. Although the biological mechanisms of hematoma expansion remain unclear, accumulating evidence supports a model of ongoing secondary bleeding from ruptured adjacent vessels surrounding the initial bleeding site. Several large clinical trials testing therapies aimed at preventing hematoma expansion are in progress, including aggressive blood pressure reduction, treatment with recombinant factor VIIa guided by CT angiography findings, and surgical intervention for superficial hematomas without intraventricular extension. Hematoma expansion is so far the only marker of outcome that is amenable to treatment and thus a potentially important therapeutic target.
Summary Cerebral microbleeds (CMBs) are increasingly recognised neuroimaging findings in individuals with cerebrovascular disease and dementia, and in normal ageing. There has been substantial ...progress in the understanding of CMBs in recent years, particularly in the development of newer MRI methods for the detection of CMBs and the application of these techniques to population-based samples of elderly people. In this Review, we focus on these recent developments and their effects on two main questions: how CMBs are detected, and how CMBs should be interpreted. The number of CMBs detected depends on MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength, and image post-processing, emphasising the importance of taking into account MRI technique in the interpretation of study results. Recent investigations with sensitive MRI techniques have indicated a high prevalence of CMBs in community-dwelling elderly people. We propose a procedural guide for identification of CMBs and suggest possible future approaches for elucidating the role of these common lesions as markers for, and contributors to, small-vessel brain disease.
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