Topical Review
Section Editors: Jean-Marc Olivot, MD, PhD, and Chelsea Kidwell, MD
Diagnosis of Cerebral Amyloid Angiopathy
Evolution of the Boston Criteria
Steven M. Greenberg, MD, PhD; Andreas Charidimou, MD, PhD
T he history of how to diagnosis cerebral amyloid angiopa-
thy (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 crite-
ria 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 poten-
tial for disease-modifying therapy.
The history of CAA diagnostic criteria also illustrates
broader issues for other major central nervous system dis-
eases. If the brain were as accessible to direct tissue exam-
ination during life as the blood or even the liver, diagnosis
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and staging of brain disorders such as cerebral small-vessel
or neurodegenerative disease would be relatively straight-
forward and the state of clinical trials would presumably be
more advanced. Given the relative inaccessibility of brain tis-
sue, 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 cri-
teria have contributed to the search 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 discus-
sions between one of the authors (Dr Greenberg), Drs Carlos
Kase, Daniel Kanter, and the late Michael Pessin. The crite-
ria 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
Received October 16, 2017; final revision received November 30, 2017; accepted December 7, 2017.
From the Department of Neurology, Massachusetts General Hospital Stroke Research Center, Boston.
Correspondence to Steven M. Greenberg, MD, PhD, Department of Neurology, MGH Stroke Research Center, 175 Cambridge St, Suite 300, Boston,
MA 02114. E-mail sgreenberg@partners.org
(Stroke. 2018;49:491-497. DOI: 10.1161/STROKEAHA.117.016990.)
© 2018 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
491
imaging plus clinical exclusions, and an additional category
of probable CAA with supporting pathology based on clini-
cal 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 histopatho-
logic 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
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) junc-
tion, 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 prob-
able 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 convex-
ity subarachnoid bleeds or cSS13—count toward the multiple
DOI: 10.1161/STROKEAHA.117.016990
 492  Stroke  February 2018

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 lesion
Probable 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 lesion
Probable 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
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or disseminated)
  Age ≥55 y
  Absence of other cause of hemorrhage*
CAA indicates cerebral amyloid angiopathy; CMB, cerebral microbleed; cSS,
cortical superficial siderosis; CT, computed tomography; ICH, intracerebral
hemorrhage; and MRI, magnetic resonance imaging.
*Other causes of hemorrhage (differential diagnosis of lobar hemorrhages):
antecedent head trauma, hemorrhagic transformation of an ischemic stroke,
arteriovenous malformation, hemorrhagic tumor, warfarin therapy with
international normalization ratio >3, and vasculitis.
lobar hemorrhages required for probable CAA, or alterna-
tively preclude probable CAA if in deep territories. The ratio-
nale 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 event of
vessel leakage and therefore provides independent evidence
for the underlying small-vessel condition. The increasingly
widespread use of blood-sensitive T2*-weighted MRI meth-
ods 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 con-
nected to ICHs that have ruptured into the subarachnoid space,
are considered as part of a single bleeding event and thus not
counted as separate hemorrhages (Figures 1C and 2C). A sec-
ond 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
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 hemor-
rhage (*), 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.
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.
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.
 Greenberg and Charidimou   Boston Criteria for Diagnosis of CAA   493

Figure 2. Patterns of cortical superficial

siderosis (cSS) in patients with cerebral
amyloid angiopathy (CAA). A, Suscepti-
bility-weighted imaging (SWI) magnetic
resonance imaging (MRI) showing a single
sulcus with cSS (arrow), classified as
focal cSS. B, SWI showing cSS affect-
ing 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 cor-
responding 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.
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Among 3 hospital-based studies of patients presenting pri-
marily with ICH who underwent T2*-weighted MRI,10,15,16
probable CAA by original Boston criteria showed sensitivi-
ties ranging from 57.9% to 76.9% and specificities of 87.5%
to 100%. One head-to-head comparison of original to modi-
fied 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 increas-
ing 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

CAA Pathology+Subjects CAA Pathology−Subjects
Setting (ICH+/ICH−) (ICH+/ICH−) Sensitivity Specificity
MRI-neuropathology studies
 Hospital-based15 11 (11/0) 4 (4/0) 72.7% 100%
 Hospital-based10 38 (27/11) 22 (22/0) 57.9% (71.1%*) 95.5% (95.5%*)
 Hospital-based16 14 (9/5) 10 (10/0) 76.9% 87.5%
 Hospital-based17
33 (0/33) 22 (0/22) 42.4% 90.9%
 Population-based17 22 (0/22) 25 (0/25) 4.5% 88.0%
MRI-genetic studies
CAA mutation+subjects
 Hospital-based, Dutch-type CAA
18
15 ICH+ NA 100% ICH+ NA
12 ICH− 16.7% ICH−
Data only from individuals with both T2*-weighted MRI and histopathologic or genetic diagnosis. CAA indicates cerebral amyloid
angiopathy; ICH, intracerebral hemorrhage; and MRI, magnetic resonance imaging.
*Using modified Boston criteria. All other values use original Boston criteria.
 494  Stroke  February 2018
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 defini-
tion, 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 muta-
tion-negative individuals were not scanned. Another report
identified 5 individuals carrying other CAA-associated APP
mutations (Iowa-, Italian-, and Flemish-types) whose hemor-
rhagic 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 (dis-
cussed below). These concerns notwithstanding, the studies
suggest that the modified probable CAA criteria have (1) rea-
sonably high specificity for pathological CAA in all settings,
and (2) high sensitivity among patients presenting with symp-
tomatic hemorrhages, possibly lower sensitivity for non-ICH
presentations, and quite low sensitivity in the general popula-
tion. 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
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higher CMB counts17 points to the additional possibility that
likelihood of CAA follows a graded relationship with hemor-
rhage 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 influ-
enced 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 indi-
cate 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 vox-
els). Additional lesions detected on even further reductions in
voxel size (to 75 µm isotropic) mostly represented CMB mim-
ics 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 pathol-
ogy, 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 hyper-
tensive 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 diagnos-
tic uncertainty, patients in this mixed category pose substantial
challenges to clinicians (see Future Directions below).
Role of the Boston Criteria in the Search
for Biomarkers
The ability to diagnose CAA during life with good specificity
is a prerequisite for identifying other biomarkers of the dis-
ease’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 identify-
ing a range of nonhemorrhagic biomarkers of CAA. Basing a
biomarker on probable CAA rather than requiring histopatho-
logic confirmation runs the risk that individuals wrongly diag-
nosed 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 bio-
markers made possible by the Boston criteria are (1) white
matter T2 hyperintensities,26 with tendency for posterior pre-
dominance27 or a multiple subcortical spot pattern28; (2) altered
diffusion tensor imaging parameters such as global mean diffu-
sion29 or diffusion tensor-derived global efficiency30; (3) vascular
reactivity to functional stimulation31,32; (4) cortical thickness33;
(5) punctate diffusion weighted imaging hyperintensities sug-
gestive of acute microinfarcts34,35; (6) enlarged perivascular
spaces in the centrum semiovale36,37; (7) positron-emission
tomography labeling with the amyloid ligands Pittsburgh com-
pound 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 muta-
tion suggest that reduced functional reactivity, microinfarcts,
 Greenberg and Charidimou   Boston Criteria for Diagnosis of CAA   495
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 auto-
immune syndrome of CAA-related inflammation (CAA-ri).49
Being able to diagnose CAA-ri by clinical and imaging fea-
tures alone is clinically important, as it allows patients to
begin immunosuppressive treatment without the morbid-
ity 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 sug-
gests 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 asso-
ciation with antiamyloid immunotherapy trials,51 suggesting
possible common mechanisms.
Future Directions in CAA Diagnosis
The history of the Boston criteria highlights some broader
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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 overrid-
ing consideration for determining eligibility for research tri-
als, 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 comprehen-
siveness. The probable CAA definition is reasonably straight-
forward to apply with a single cutoff set at 2 or more strictly
lobar hemorrhagic lesions, but more complex criteria incorpo-
rating other lesion categories and biomarkers might improve
accuracy and be more useful for research.
A few aspects of probable CAA seem like promising oppor-
tunities 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 suggest-
ing 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 incorpora-
tion 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 account
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 diag-
nosis 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 individu-
als 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.
References
1. Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke.
1987;18:311–324.
2. Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT.
Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with
amyloid angiopathy. Ann Neurol. 1995;38:254–259. doi: 10.1002/
ana.410380219.
3. Greenberg SM, Edgar MA. Case records of the Massachusetts general
hospital, case 22–1996. N. Engl. J. Med. 1996;335:189–196.
4. Charidimou A, Fox Z, Werring DJ, Song M. Mapping the landscape of
cerebral amyloid angiopathy research: an informetric analysis perspec-
tive. J Neurol Neurosurg Psychiatry. 2016;87:252–259. doi: 10.1136/
jnnp-2015-310690.
5. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan
EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-
ADRDA Work Group under the auspices of Department of Health
and Human Services Task Force on Alzheimer’s disease. Neurology.
1984;34:939–944.
6. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr,
Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease:
recommendations from the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic guidelines for Alzheimer’s
disease. Alzheimers Dement. 2011;7:263–269. doi: 10.1016/j.
jalz.2011.03.005.
7. Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED,
Richardson EP. Cerebral amyloid angiopathy without and with cere-
bral hemorrhages: a comparative histological study. Ann Neurol.
1991;30:637–649.
8. Mandybur TI. Cerebral amyloid angiopathy: the vascular pathology and
complications. J Neuropathol Exp Neurol. 1986;45:79–90.
9. Greenberg SM, Vonsattel JP. Diagnosis of cerebral amyloid angiopathy.
Sensitivity and specificity of cortical biopsy. Stroke. 1997;28:1418–1422.
 496  Stroke  February 2018
10. Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M,
et al. Prevalence of superficial siderosis in patients with cerebral
amyloid angiopathy. Neurology. 2010;74:1346–1350. doi: 10.1212/
WNL.0b013e3181dad605.
11. Fisher CM. Pathological observations in hypertensive cerebral hemor-
rhage. J Neuropathol Exp Neurol. 1971;30:536–550.
12. Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi
Salman R, Warach S, et al; Microbleed Study Group. Cerebral micro-
bleeds: a guide to detection and interpretation. Lancet Neurol.
2009;8:165–174. doi: 10.1016/S1474-4422(09)70013-4.
13. Charidimou A, Linn J, Vernooij MW, Opherk C, Akoudad S, Baron JC,
et al. Cortical superficial siderosis: detection and clinical significance in
cerebral amyloid angiopathy and related conditions. Brain. 2015;138(pt
8):2126–2139. doi: 10.1093/brain/awv162.
14. Greenberg SM, Nandigam RN, Delgado P, Betensky RA, Rosand
J, Viswanathan A, et al. Microbleeds versus macrobleeds: evidence
for distinct entities. Stroke. 2009;40:2382–2386. doi: 10.1161/
STROKEAHA.109.548974.
15. Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagno-
sis of cerebral amyloid angiopathy: validation of the Boston criteria.
Neurology. 2001;56:537–539.
16. Charidimou A, Jaunmuktane Z, Baron JC, Burnell M, Varlet P, Peeters
A, et al. White matter perivascular spaces: an MRI marker in pathology-
proven cerebral amyloid angiopathy? Neurology. 2014;82:57–62. doi:
10.1212/01.wnl.0000438225.02729.04.
17. Martinez-Ramirez S, Romero JR, Shoamanesh A, McKee AC, Van
Etten E, Pontes-Neto O, et al. Diagnostic value of lobar microbleeds
in individuals without intracerebral hemorrhage. Alzheimers Dement.
2015;11:1480–1488. doi: 10.1016/j.jalz.2015.04.009.
18. van Rooden S, van der Grond J, van den Boom R, Haan J, Linn J,
Greenberg SM, et al. Descriptive analysis of the Boston criteria applied
to a Dutch-type cerebral amyloid angiopathy population. Stroke.
2009;40:3022–3027. doi: 10.1161/STROKEAHA.109.554378.
19. Sellal F, Wallon D, Martinez-Almoyna L, Marelli C, Dhar A, Oesterlé
H, et al. APP mutations in cerebral amyloid angiopathy with or without
cortical calcifications: report of three families and a literature review.
J Alzheimers Dis. 2017;56:37–46. doi: 10.3233/JAD-160709.
Downloaded from http://ahajournals.org by on February 10, 2022
20. Haacke EM, Xu Y, Cheng YC, Reichenbach JR. Susceptibility weighted
imaging (SWI). Magn Reson Med. 2004;52:612–618. doi: 10.1002/
mrm.20198.
21. Boeckh-Behrens T, Lutz J, Lummel N, Burke M, Wesemann T, Schöpf
V, et al. Susceptibility-weighted angiography (SWAN) of cerebral veins
and arteries compared to TOF-MRA. Eur J Radiol. 2012;81:1238–1245.
doi: 10.1016/j.ejrad.2011.02.057.
22. Vernooij MW, Ikram MA, Wielopolski PA, Krestin GP, Breteler MM,
van der Lugt A. Cerebral microbleeds: accelerated 3D T2*-weighted
GRE MR imaging versus conventional 2D T2*-weighted GRE MR
imaging for detection. Radiology. 2008;248:272–277. doi: 10.1148/
radiol.2481071158.
23. Nandigam RN, Viswanathan A, Delgado P, Skehan ME, Smith EE,
Rosand J, et al. MR imaging detection of cerebral microbleeds: effect
of susceptibility-weighted imaging, section thickness, and field strength.
AJNR Am J Neuroradiol. 2009;30:338–343. doi: 10.3174/ajnr.A1355.
24. van Veluw SJ, Charidimou A, van der Kouwe AJ, Lauer A, Reijmer
YD, Costantino I, et al. Microbleed and microinfarct detection in amy-
loid angiopathy: a high-resolution MRI-histopathology study. Brain.
2016;139(pt 12):3151–3162. doi: 10.1093/brain/aww229.
25. Pasi M, Charidimou A, Boulouis G, Auriel E, Ayres A, Schwab KM, et
al. Mixed location (deep and lobar) intracererbral hemorrhage and micro-
bleeds: underlying microangiopathy and risk of recurrence. Neurology.
2017. In press.
26. Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri
T, et al. Plasma beta-amyloid and white matter lesions in AD, MCI,
and cerebral amyloid angiopathy. Neurology. 2006;66:23–29. doi:
10.1212/01.wnl.0000191403.95453.6a.
27. Thanprasertsuk S, Martinez-Ramirez S, Pontes-Neto OM, Ni J, Ayres
A, Reed A, et al. Posterior white matter disease distribution as a predic-
tor of amyloid angiopathy. Neurology. 2014;83:794–800. doi: 10.1212/
WNL.0000000000000732.
28. Charidimou A, Boulouis G, Haley K, Auriel E, van Etten ES, Fotiadis
P, et al. White matter hyperintensity patterns in cerebral amyloid angi-
opathy and hypertensive arteriopathy. Neurology. 2016;86:505–511. doi:
10.1212/WNL.0000000000002362.
29. Viswanathan A, Patel P, Rahman R, Nandigam RN, Kinnecom C,
Bracoud L, et al. Tissue microstructural changes are independently
associated with cognitive impairment in cerebral amyloid angiopathy.
Stroke. 2008;39:1988–1992. doi: 10.1161/STROKEAHA.107.509091.
30. Reijmer YD, Fotiadis P, Martinez-Ramirez S, Salat DH, Schultz A,
Shoamanesh A, et al. Structural network alterations and neurological
dysfunction in cerebral amyloid angiopathy. Brain. 2015;138(pt 1):179–
188. doi: 10.1093/brain/awu316.
31. Dumas A, Dierksen GA, Gurol ME, Halpin A, Martinez-Ramirez S,
Schwab K, et al. Functional magnetic resonance imaging detection
of vascular reactivity in cerebral amyloid angiopathy. Ann Neurol.
2012;72:76–81. doi: 10.1002/ana.23566.
32. Peca S, McCreary CR, Donaldson E, Kumarpillai G, Shobha N, Sanchez
K, et al. Neurovascular decoupling is associated with severity of cerebral
amyloid angiopathy. Neurology. 2013;81:1659–1665. doi: 10.1212/01.
wnl.0000435291.49598.54.
33. Fotiadis P, van Rooden S, van der Grond J, Schultz A, Martinez-
Ramirez S, Auriel E, et al; Alzheimer’s Disease Neuroimaging Initiative.
Cortical atrophy in patients with cerebral amyloid angiopathy: a
case-control study. Lancet Neurol. 2016;15:811–819. doi: 10.1016/
S1474-4422(16)30030-8.
34. Kimberly WT, Gilson A, Rost NS, Rosand J, Viswanathan A, Smith EE,
et al. Silent ischemic infarcts are associated with hemorrhage burden
in cerebral amyloid angiopathy. Neurology. 2009;72:1230–1235. doi:
10.1212/01.wnl.0000345666.83318.03.
35. Gregoire SM, Charidimou A, Gadapa N, Dolan E, Antoun N, Peeters
A, et al. Acute ischaemic brain lesions in intracerebral haemorrhage:
multicentre cross-sectional magnetic resonance imaging study. Brain.
2011;134(pt 8):2376–2386. doi: 10.1093/brain/awr172.
36. Charidimou A, Meegahage R, Fox Z, Peeters A, Vandermeeren Y,
Laloux P, et al. Enlarged perivascular spaces as a marker of underly-
ing arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort
study. J Neurol Neurosurg Psychiatry. 2013;84:624–629. doi: 10.1136/
jnnp-2012-304434.
37. Martinez-Ramirez S, Pontes-Neto OM, Dumas AP, Auriel E, Halpin
A, Quimby M, et al. Topography of dilated perivascular spaces in sub-
jects from a memory clinic cohort. Neurology. 2013;80:1551–1556. doi:
10.1212/WNL.0b013e31828f1876.
38. Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK,
et al. Imaging of amyloid burden and distribution in cerebral amyloid
angiopathy. Ann Neurol. 2007;62:229–234. doi: 10.1002/ana.21164.
39. Ly JV, Donnan GA, Villemagne VL, Zavala JA, Ma H, O’Keefe G,
et al. 11C-PIB binding is increased in patients with cerebral amyloid
angiopathy-related hemorrhage. Neurology. 2010;74:487–493. doi:
10.1212/WNL.0b013e3181cef7e3.
40. Baron JC, Farid K, Dolan E, Turc G, Marrapu ST, O’Brien E, et al.
Diagnostic utility of amyloid PET in cerebral amyloid angiopathy-
related symptomatic intracerebral hemorrhage. J Cereb Blood Flow
Metab. 2014;34:753–758. doi: 10.1038/jcbfm.2014.43.
41. Gurol ME, Becker JA, Fotiadis P, Riley G, Schwab K, Johnson KA,
et al. Florbetapir-PET to diagnose cerebral amyloid angiopathy: a
prospective study. Neurology. 2016;87:2043–2049. doi: 10.1212/
WNL.0000000000003197.
42. Charidimou A, Farid K, Baron JC. Amyloid-PET in sporadic cerebral
amyloid angiopathy: a diagnostic accuracy meta-analysis. Neurology.
2017;89:1490–1498. doi: 10.1212/WNL.0000000000004539.
43. Verbeek MM, Kremer BP, Rikkert MO, Van Domburg PH, Skehan
ME, Greenberg SM. Cerebrospinal fluid amyloid beta(40) is decreased
in cerebral amyloid angiopathy. Ann Neurol. 2009;66:245–249. doi:
10.1002/ana.21694.
44. Renard D, Wacongne A, Ayrignac X, Charif M, Fourcade G, Azakri S,
et al. Cerebrospinal fluid Alzheimer’s disease biomarkers in cerebral
amyloid angiopathy-related inflammation. J Alzheimers Dis. 2016;50:759–
764. doi: 10.3233/JAD-150621.
45. Martínez-Lizana E, Carmona-Iragui M, Alcolea D, Gómez-Choco M,
Vilaplana E, Sánchez-Saudinós MB, et al. Cerebral amyloid angiopa-
thy-related atraumatic convexal subarachnoid hemorrhage: an ARIA
before the tsunami. J Cereb Blood Flow Metab. 2015;35:710–717. doi:
10.1038/jcbfm.2015.25.
46. Greenberg SM, Al-Shahi Salman R, Biessels GJ, van Buchem M,
Cordonnier C, Lee JM, et al. Outcome markers for clinical trials in
cerebral amyloid angiopathy. Lancet Neurol. 2014;13:419–428. doi:
10.1016/S1474-4422(14)70003-1.
47. van Rooden S, Goos JD, van Opstal AM, Versluis MJ, Webb AG,
Blauw GJ, et al. Increased number of microinfarcts in Alzheimer dis-
ease at 7-T MR imaging. Radiology. 2014;270:205–211. doi: 10.1148/
radiol.13130743.
 Greenberg and Charidimou   Boston Criteria for Diagnosis of CAA   497
48. van Opstal AM, van Rooden S, van Harten T, Ghariq E, Labadie G,
Fotiadis P, et al. Cerebrovascular function in presymptomatic and
symptomatic individuals with hereditary cerebral amyloid angiopathy:
a case-control study. Lancet Neurol. 2017;16:115–122. doi: 10.1016/
S1474-4422(16)30346-5.
49. Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM. Clinical mani-
festations of cerebral amyloid angiopathy-related inflammation. Ann
Neurol. 2004;55:250–256. doi: 10.1002/ana.10810.
50. Auriel E, Charidimou A, Gurol ME, Ni J, Van Etten ES, Martinez-
Ramirez S, et al. Validation of clinicoradiological criteria for the diagno-
sis of cerebral amyloid angiopathy-related inflammation. JAMA Neurol.
2016;73:197–202. doi: 10.1001/jamaneurol.2015.4078.
51. Sperling RA, Jack CR Jr, Black SE, Frosch MP, Greenberg SM, Hyman
BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying
therapeutic trials: recommendations from the Alzheimer’s Association
Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367–385.
doi: 10.1016/j.jalz.2011.05.2351.
52. Boulouis G, Charidimou A, Pasi M, Roongpiboonsopit D, Xiong L,
Auriel E, et al. Hemorrhage recurrence risk factors in cerebral amyloid
angiopathy: comparative analysis of the overall small vessel disease
Downloaded from http://ahajournals.org by on February 10, 2022
severity score versus individual neuroimaging markers. J Neurol Sci.
2017;380:64–67. doi: 10.1016/j.jns.2017.07.015.
53. Charidimou A, Peeters AP, Jäger R, Fox Z, Vandermeeren Y, Laloux P,
et al. Cortical superficial siderosis and intracerebral hemorrhage risk
in cerebral amyloid angiopathy. Neurology. 2013;81:1666–1673. doi:
10.1212/01.wnl.0000435298.80023.7a.
54. Moulin S, Labreuche J, Bombois S, Rossi C, Boulouis G, Hénon H, et
al. Dementia risk after spontaneous intracerebral haemorrhage: a pro-
spective cohort study. Lancet Neurol. 2016;15:820–829. doi: 10.1016/
S1474-4422(16)00130-7.
55. Charidimou A, Jäger RH, Peeters A, Vandermeeren Y, Laloux P, Baron
JC, et al. White matter perivascular spaces are related to cortical super-
ficial siderosis in cerebral amyloid angiopathy. Stroke. 2014;45:2930–
2935. doi: 10.1161/STROKEAHA.114.005568.
56. Tsai HH, Tsai LK, Chen YF, Tang SC, Lee BC, Yen RF, et al. Correlation of
cerebral microbleed distribution to amyloid burden in patients with primary
intracerebral hemorrhage. Sci Rep. 2017;7:44715. doi: 10.1038/srep44715.
KEY WORDS: antemortem diagnosis ◼ cerebral amyloid angiopathy ◼ cerebral
hemorrhage ◼ siderosis