The history of how to diagnosis cerebral amyloid angiopathy (CAA) tells the story of the disease itself. CAA is defined by histopathology—deposition of β-amyloid in the cerebrovasculature—and through the 1980s the disorder was only diagnosed in patients with available brain tissue from hematoma evacuation, biopsy, or most commonly postmortem examination.1 Introduction of the imaging-based Boston criteria for diagnosis of CAA in the 1990s2,3 allowed a diagnosis of probable CAA in living patients with no available brain tissue and substantially moved the field from the pathologist’s realm to the clinicians. The Boston criteria for CAA have become the basis for clinical decision-making as well as a rapidly growing body of literature4 investigating the disease’s clinical manifestations, phenotypic spectrum, progression, and potential for disease-modifying therapy.
The history of CAA diagnostic criteria also illustrates broader issues for other major central nervous system diseases. If the brain were as accessible to direct tissue examination during life as the blood or even the liver, diagnosis and staging of brain disorders such as cerebral small-vessel or neurodegenerative disease would be relatively straightforward and the state of clinical trials would presumably be more advanced. Given the relative inaccessibility of brain tissue, however, diagnostic approaches have needed to rely on indirect but nonetheless powerful methods such as magnetic resonance imaging (MRI). The current article will review the evolution and application of the Boston criteria, how the criteria have contributed to the tìm kiếm for CAA biomarkers, and future directions in this still evolving field.
Development and Validation of the Boston Criteria for CAA
The Boston criteria for diagnosing CAA arose from discussions between one of the authors (Dr Greenberg), Drs Carlos Kase, Daniel Kanter, and the late Michael Pessin. The criteria were first published in 1995 in the Methods section of an analysis of CAA and the apolipoprotein E ε4 allele2 and in 1996 as a table in a clinical-pathological case report.3 Using the category terminology applied to other brain disorders such as Alzheimer disease,5,6 they defined definite CAA based on full autopsy, probable or possible CAA based on brain imaging plus clinical exclusions, and an additional category of probable CAA with supporting pathology based on clinical scenarios of having limited brain tissue from biopsy or hematoma evacuation (Table 1). Definite CAA requires high neuropathological severity (including features of advanced vasculopathy such as amyloid replacement and splitting of the blood vessel wall)7,8 to avoid diagnosing the condition when the pathology is only mild and incidental. Lesser histopathologic severity is required for probable CAA with supporting pathology to reflect the smaller amount of sampled tissue and consequent lower likelihood of identifying the most advanced foci of disease.9
Table 1. Modified Boston Criteria for CAA
Definite CAA Full postmortem examination demonstrating: Lobar, cortical, or cortical–subcortical hemorrhage Severe CAA with vasculopathy Absence of other diagnostic lesionProbable CAA with supporting pathology Clinical data and pathological tissue (evacuated hematoma or cortical biopsy) demonstrating: Lobar, cortical, or cortical–subcortical hemorrhage (including ICH, CMB, or cSS) Some degree of CAA in specimen Absence of other diagnostic lesionProbable CAA Clinical data and MRI or CT demonstrating: Multiple hemorrhages (ICH, CMB) restricted to lobar, cortical, or cortical–subcortical regions (cerebellar hemorrhage allowed), or single lobar, cortical, or cortical–subcortical hemorrhage and cSS (focal or disseminated) Age ≥55 y Absence of other cause of hemorrhage*Possible CAA Clinical data and MRI or CT demonstrating: Single lobar, cortical, or cortical–subcortical ICH, CMB, or cSS (focal or disseminated) Age ≥55 y Absence of other cause of hemorrhage*
The key diagnostic category for clinical practice and research is probable CAA, the highest level of diagnostic certainty currently achievable without obtaining brain tissue. As first formulated (original Boston criteria), probable CAA entailed neuroimaging demonstration of multiple (ie, 2 or more) hemorrhages restricted to lobar brain regions,2,3 defined as cerebral cortex, the corticosubcortical (grey-white) junction, and subcortical white matter. A modification to count blood products in cortical sulci (cortical superficial siderosis, cSS) as one additional hemorrhagic lesion (modified Boston criteria), was proposed and validated in 2010.10 The most recent version of the criteria are thus known as the modified Boston criteria (Table 1). The requirement for multiple strictly lobar hemorrhages is based on the lobar predilection of CAA pathology and recurrent intracerebral hemorrhages (ICHs),1 an anatomic distribution that is in near-perfect contrast to the deep hemispheric and brain stem locations favored by ICHs caused by hypertensive arteriopathy.11 Because CAA typically spares these deep territories, the presence of any hemorrhagic lesions in basal ganglia, thalamus, or pons preclude the probable CAA diagnosis. Cerebellar hemorrhages can result from either CAA or hypertensive arteriopathy and are therefore not counted by the Boston criteria, either in favor or against a probable CAA diagnosis.
Several methodologic issues arise in applying the Boston criteria in practice. One is that all types of hemorrhagic lesions—ICHs, cerebral microbleeds (CMBs),12 and (since publication of the modified Boston criteria)10 acute convexity subarachnoid bleeds or cSS13—count toward the multiple lobar hemorrhages required for probable CAA, or alternatively preclude probable CAA if in deep territories. The rationale for counting all types of hemorrhagic lesions is that while different hemorrhage sizes may arise by distinct pathogenic mechanisms,14 each presumably represents a distinct sự kiện of vessel leakage and therefore provides independent evidence for the underlying small-vessel condition. The increasingly widespread use of blood-sensitive T2*-weighted MRI methods has greatly influenced detection of CMBs (Figure 1) and cSS (Figure 2) and thus the diagnosis of CAA as discussed below. Conversely hemorrhagic lesions that may be part of a larger hemorrhage, such as smaller extensions in proximity to a larger hemorrhage or foci of cSS near or directly connected to ICHs that have ruptured into the subarachnoid space, are considered as part of a single bleeding sự kiện and thus not counted as separate hemorrhages (Figures 1C and 2C). A second practical issue is that a hemorrhagic lesion in the centrum semiovale can seem a long distance from the outer surface of the brain and still be quite close to the corticosubcortical junction (Figure 1D) because of the undulating curves of the cortical gyri. Hemorrhages are considered deep hemispheric only when clearly involving the basal ganglia, thalamus, or internal capsule.
Figure 1. Patterns of cerebral microbleeds (CMB). A, Multiple strictly lobar CMB on T2*-weighted magnetic resonance imaging (MRI) of a 69-year-old woman who presented with a spontaneous lobar intracerebral hemorrhage. Brain autopsy showed advanced cerebral amyloid angiopathy (CAA). B, Mixed CMB (arrowheads) affecting the right thalamus, a deep hemispheric territory, as well as lobar brain regions and therefore not fulfilling Boston criteria for probable CAA. C, Subacute left frontoparietal lobar hemorrhage (*), numerous strictly lobar CMB (white arrowheads), and a left frontal focus of cortical superficial siderosis (white arrow) on susceptibility-weighted imaging (SWI) MRI of a 78-year-old woman. The image additionally shows foci of CMB (orange arrowheads) and cortical superficial siderosis (red arrows, also seen in magnified image) that are immediately adjacent to the lobar hemorrhage and therefore not counted as separate lesions in determining the number of lobar hemorrhagic foci. D, SWI from a 71-year-old man with memory loss and CAA on brain biopsy. The yellow arrows point to CMB in the right temporal and right occipital lobes that might seem distant from the brain surface, but would be counted as lobar microbleeds. The aligned T1-weighted slice shows that their positions (* on the right) are within or very close to the cortical ribbon.
Figure 2. Patterns of cortical superficial siderosis (cSS) in patients with cerebral amyloid angiopathy (CAA). A, Susceptibility-weighted imaging (SWI) magnetic resonance imaging (MRI) showing a single sulcus with cSS (arrow), classified as focal cSS. B, SWI showing cSS affecting multiple cortical sulci, classified as disseminated (>3 affected sulci). C, SWI images from a 68-y-old man with a right parasagittal CAA-related spontaneous lobar intracerebral hemorrhage (*). The arrow points to an area of cSS close to the hematoma on the axial slice. The corresponding sagittal slice (right) shows that this cSS focus connects to the lobar hemorrhage and thus would not be counted as an independent hemorrhagic lesion. There are multiple lobar cerebral microbleeds in the left hemisphere.
MRI-histopathologic studies to date10,15–17 have provided validating evidence for the Boston criteria probable CAA diagnosis (Table 2), with sensitivities that seem to depend in part on the clinical presentation of the patients examined. Among 3 hospital-based studies of patients presenting primarily with ICH who underwent T2*-weighted MRI,10,15,16 probable CAA by original Boston criteria showed sensitivities ranging from 57.9% to 76.9% and specificities of 87.5% to 100%. One head-to-head comparison of original to modified criteria10 suggested that incorporation of cSS presence improved sensitivity without lowering specificity (Table 2). A fourth study17 analyzed a hospital-based cohort of non-ICH individuals with other clinical presentations such as cognitive impairment or transient focal neurological episodes, and found lower sensitivity of 42.4% and similar specificity of 90.9%. A regression model of these data showed that increasing lobar CMB counts predicted greater likelihood of CAA pathology. The same study17 also analyzed a community-based cohort of individuals with T2*-weighted MRI and subsequent autopsy, finding the probable CAA diagnosis to have low sensitivity of only 4.5% for pathological CAA with specificity of 88.0%.
Table 2. Summary of Validation Studies of Boston Criteria Probable CAA
SettingCAA Pathology+Subjects (ICH+/ICH−)CAA Pathology−Subjects (ICH+/ICH−)SensitivitySpecificityMRI-neuropathology studies Hospital-based1511 (11/0)4 (4/0)72.7phần trăm100% Hospital-based1038 (27/11)22 (22/0)57.9% (71.1%*)95.5% (95.5%*) Hospital-based1614 (9/5)10 (10/0)76.9phần trăm87.5% Hospital-based1733 (0/33)22 (0/22)42.4phần trăm90.9% Population-based1722 (0/22)25 (0/25)4.5phần trăm88.0phần trămMRI-genetic studiesCAA mutation+subjects Hospital-based, Dutch-type CAA1815 ICH+ 12 ICH−NA100% ICH+ 16.7% ICH−NA
The Boston criteria have also been validated by MRI-genetic correlation in individuals carrying CAA-specific, fully penetrant APP (amyloid precursor protein) mutations (Table 2). Among carriers of the Dutch-type APP mutation, 15 of 15 with symptomatic hemorrhagic stroke had multiple strictly lobar hemorrhagic lesions meeting original probable CAA criteria (outside of the age ≥55 requirement).18 Only 2 of 12 mutation carriers without symptomatic ICH met this definition, suggesting high sensitivity for symptomatic Dutch-type hereditary disease but low sensitivity for the presymptomatic phase. Specificity could not be estimated in this study, as mutation-negative individuals were not scanned. Another report identified 5 individuals carrying other CAA-associated APP mutations (Iowa-, Italian-, and Flemish-types) whose hemorrhagic lesions also met modified probable CAA criteria.19
The above validation studies have notable limitations: small sample sizes, restriction primarily to a single site and to white participants, and varying T2*-weighted MRI methods (discussed below). These concerns notwithstanding, the studies suggest that the modified probable CAA criteria have (1) reasonably high specificity for pathological CAA in all settings, and (2) high sensitivity among patients presenting with symptomatic hemorrhages, possibly lower sensitivity for non-ICH presentations, and quite low sensitivity in the general population. The trend for sensitivity to increase with greater severity or later stage of CAA presumably reflects the long-recognized observation that CAA pathology needs to be substantially advanced before it is severe enough to trigger hemorrhages.7,8 The regression analysis showing increasing specificity with higher CMB counts17 points to the additional possibility that likelihood of CAA follows a graded relationship with hemorrhage number rather than a sharp threshold at ≥2 hemorrhages.
Variation in MRI hemorrhage detection adds a further layer of complexity. CMB detection in particular12 is strongly influenced by a range of factors in MRI acquisition and processing, including magnetic field strength, echo time, scan resolution, incorporation of phase information (used in susceptibility-weighted imaging20), or weighted averaging across multiple echo times (used in susceptibility-weighted angiography21). Systematic comparisons of concurrently obtained MRIs indicate that these parameters substantially affect the number of CMBs counted by raters,22,23 which means any study of CAA-associated CMB will be influenced by the precise MRI method used. Recent ex vivo MRI analysis of postmortem brains24 suggests that the theoretical goal of close to 100% CMB detection might ultimately be achievable, but only with very high resolution (on the order of 200 µm isotropic voxels). Additional lesions detected on even further reductions in voxel size (to 75 µm isotropic) mostly represented CMB mimics such as small-vessel occlusions or microaneurysms rather than bona fide microbleeds.
The possible CAA Boston criteria category refers to individuals with exactly 1 hemorrhagic lesion,15 or (per modified Criteria) cSS only without ICH or CMB.10 Little MRI-pathological correlation has been performed in possible CAA. Of the 8 individuals in the initial validation study15 with only an isolated lobar ICH on T2*-weighted MRI, 3 had CAA pathology, supporting the interpretation that possible CAA carries less diagnostic certainty than probable CAA. The impact of MRI parameters on which individuals are diagnosed with probable versus possible CAA has not been systematically analyzed, but based on the above is likely considerable. Another commonly encountered pattern is mixed hemorrhagic lesions located in both lobar and deep territories (Figure 1B). A recent analysis of 75 patients with mixed-ICH25 found 66 (88%) to be hypertensive and have other markers of hypertensive small-vessel disease such as higher serum creatinine and abundant enlarged perivascular spaces in the basal ganglia relative to patients with probable CAA. These findings suggest contribution from hypertensive arteriopathy, but do not preclude overlapping CAA in at least a subset. Because of the high level of diagnostic uncertainty, patients in this mixed category pose substantial challenges to clinicians (see Future Directions below).
Role of the Boston Criteria in the Tìm kiếm for Biomarkers
The ability to diagnose CAA during life with good specificity is a prerequisite for identifying other biomarkers of the disease’s presence, severity, and future behavior. The probable CAA diagnosis—derived from the number and distribution of hemorrhagic lesions—has indeed been the basis for identifying a range of nonhemorrhagic biomarkers of CAA. Basing a biomarker on probable CAA rather than requiring histopathologic confirmation runs the risk that individuals wrongly diagnosed will yield spurious findings, either false-positives or more likely false-negatives because of misclassification of the exposure variable of CAA. The experience in CAA research, however, suggests this approach is preferable to the alternative of restricting studies solely to pathologically verified CAA. This latter approach carries its own major limitations in both sample size and generalizability, as brain tissue (whether from hematoma evacuation, biopsy, or autopsy) becomes available not at random but rather in select subgroups with particularly severe or atypical clinical courses.
Among the long (and likely still growing) list of CAA biomarkers made possible by the Boston criteria are (1) white matter T2 hyperintensities,26 with tendency for posterior predominance27 or a multiple subcortical spot pattern28; (2) altered diffusion tensor imaging parameters such as global mean diffusion29 or diffusion tensor-derived global efficiency30; (3) vascular reactivity to functional stimulation31,32; (4) cortical thickness33; (5) punctate diffusion weighted imaging hyperintensities suggestive of acute microinfarcts34,35; (6) enlarged perivascular spaces in the centrum semiovale36,37; (7) positron-emission tomography labeling with the amyloid ligands Pittsburgh compound B and florbetapir38–42; and (8) reduced cerebrospinal fluid concentrations of β-amyloid.43–45 These multimodal biomarkers serve as both important windows into the pathogenesis of CAA and candidate outcome markers for clinical trials.46
The dependence of the Boston criteria CAA diagnosis on hemorrhagic lesions limits analysis of any biomarkers that appear before or entirely without CAA-related bleeding. The major approach to circumventing this limitation has been to study prehemorrhage carriers of penetrant CAA-related APP mutations. Analysis of such carriers of the Dutch-type mutation suggest that reduced functional reactivity, microinfarcts, and white matter T2 hyperintensities may precede CAA-related CMBs or ICH.47,48
One further application of the Boston criteria has been as a starting point for formulating diagnostic criteria for the autoimmune syndrome of CAA-related inflammation (CAA-ri).49 Being able to diagnose CAA-ri by clinical and imaging features alone is clinically important, as it allows patients to begin immunosuppressive treatment without the morbidity of brain biopsy. Proposed criteria for probable CAA-ri50 require hemorrhagic lesions consistent with probable CAA as well as additional clinical and imaging features: presentation with headache, decreased consciousness, behavioral changes, focal signs or seizure, and MRI evidence of white matter T2 hyperintensities that are asymmetrical and extend to the immediately subcortical white matter. In a validation study,50 probable CAA-ri criteria were met by 14 of 17 individuals with pathologically confirmed CAA-ri versus 1 of 37 with pathologically confirmed noninflammatory CAA, yielding a sensitivity of 82% and specificity of 97%. The high specificity is particularly relevant from a clinical standpoint, as it suggests brain biopsy can be safely avoided in patients meeting probable CAA-ri criteria. The subcortical white matter T2 hyperintensities in CAA-ri have similar appearance to edema-type amyloid-related imaging abnormalities observed in association with antiamyloid immunotherapy trials,51 suggesting possible common mechanisms.
Future Directions in CAA Diagnosis
The history of the Boston criteria highlights some broader issues in devising criteria for diseases where definitive tissue diagnosis is often not feasible. One is the inherent tradeoff between sensitivity and specificity, whereby highly sensitive criteria run the risk of false-positive diagnoses and highly specific criteria yield more false-negatives. There is no single correct balance, and indeed different applications may require different priorities. Diagnostic specificity may be the overriding consideration for determining eligibility for research trials, for example, whereas sensitivity may be key to assessing clinical risk for antithrombotic treatment. A second tension is how to balance ease of use versus complexity and comprehensiveness. The probable CAA definition is reasonably straightforward to apply with a single cutoff set at 2 or more strictly lobar hemorrhagic lesions, but more complex criteria incorporating other lesion categories and biomarkers might improve accuracy and be more useful for research.
A few aspects of probable CAA seem like promising opportunities for improvement. One is incorporating cSS severity as well as presence. Disseminated cSS, defined as involving >3 sulci (Figure 2B), is associated with clinical markers of disease severity such as recurrent ICH52,53 and post-ICH dementia54 as well as other imaging biomarkers such as abundant enlarged perivascular spaces in the centrum semiovale,55 suggesting that extent of cSS carries useful diagnostic information. Another area for potential improvement is diagnosing CAA in individuals with hemorrhagic lesions in mixed lobar and deep territories (Figure 1B), particularly when the lobar CMB greatly outnumber the deep. A recent analysis, for example, defined a CMB ratio of lobar to deep CMB for individuals in this mixed category and found higher ratios to correlate with increasing Pittsburgh compound B-positron-emission tomography signal,56 suggesting likely CAA. Finally, one can imagine improvements to the Boston criteria via incorporation of nonhemorrhagic imaging biomarkers. Counting severe enlarged perivascular spaces in the centrum semiovale as an additional lesion, for example, enhanced the Boston criteria’s sensitivity without worsening specificity in a small series.16 Any incorporation of additional markers will need to tài khoản for the possibility noted above that their sensitivity/specificity may vary with CAA presentation (ICH, non-ICH symptoms, or asymptomatic).
As a next step toward updating and improving the diagnosis of CAA, a multicenter effort to update and externally validate the Boston criteria has recently been undertaken by the International CAA Association. This project will analyze all available clinical and neuroimaging data from individuals age ≥50 with any of the potential CAA-related clinical presentations, MRI imaging, and histopathologic diagnoses. The goal is to produce and validate a data-driven version 2.0 of the Boston criteria that will meet the needs of clinicians and investigators and help maintain the rapid pace of progress toward better treatment of CAA.
Sources of Funding
Dr Greenberg is supported by grants from the National Institutes of Health (R01 AG26484, R01 NS070834, R01 NS096730, U24 NS100591). Dr Charidimou is supported from the Bodossaki Foundation (postdoctoral fellowship).
Disclosures
None.
Footnotes
Correspondence to Steven M. Greenberg, MD, PhD, Department of Neurology, MGH Stroke Research Center, 175 Cambridge St, Suite 300, Boston, MA 02114. E-mail
[email protected]
