JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 70, NO.

9, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.07.724

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Cerebral Amyloid Angiopathy

Diagnosis, Clinical Implications, and Management Strategies
in Atrial Fibrillation

Christopher V. DeSimone, MD, PHD,a Jonathan Graff-Radford, MD,b Majd A. El-Harasis, MBBS,c
Alejandro A. Rabinstein, MD,b Samuel J. Asirvatham, MD,a,d David R. Holmes, JR, MDa

ABSTRACT

With an aging population, clinicians are more frequently encountering patients with atrial fibrillation who are also at
risk of intracerebral hemorrhage due to cerebral amyloid angiopathy, the result of b-amyloid deposition in cerebral
vessels. Cerebral amyloid angiopathy is common among elderly patients, and is associated with an increased risk of
intracerebral bleeding, especially with the use of anticoagulation. Despite this association, this entity is absent in current
risk–benefit analysis models, which may result in underestimation of the chance of bleeding in the subset of patients with
this disease. Determining the presence and burden of cerebral amyloid angiopathy is particularly important when
planning to start or restart anticoagulation after an intracerebral hemorrhage. Given the lack of randomized trial data to
guide management strategies, we discuss a heart–brain team approach that includes clinician–patient shared decision
making for the use of pharmacologic and nonpharmacologic approaches to diminish stroke risk. (J Am Coll Cardiol
2017;70:1173–82) © 2017 by the American College of Cardiology Foundation.

T he prevalence of atrial fibrillation (AF) is

increasing as the population
Because AF is the pathophysiologic substrate
for stroke in at least 30% of patients, the primary
ages (1).
other factors such as fragility, fall risk, adherence to
medication, or adequacy of medical care. The HAS-
BLED score (4) is used to estimate bleeding risk with
anticoagulation, but does not adequately account for
treatment goal remains prevention of ischemic cerebral amyloid angiopathy (CAA), a prevalent risk
stroke. Many patients with AF have risk factors for factor for ICH in the elderly. Recent advances in the
both ischemic and hemorrhagic stroke; therefore, understanding of CAA and its implications for the
the therapy decision must be individualized to bal- management of patients with AF are the focus of this
ance the competing risks of thromboembolism and review.
hemorrhage.
Anticoagulation lowers the risk of ischemic stroke, WHAT IS CAA?
but also increases bleeding risks, including intrace-
rebral hemorrhage (ICH). Scoring systems have been CAA is a cerebrovascular disease caused by the
developed for both embolic and hemorrhagic stroke deposition of b-amyloid in the walls of cerebral
risk and are often used in combination when arteries, arterioles, and capillaries. The deposited
contemplating initiation of oral anticoagulation (2,3). material is composed of the breakdown product of
Although these scoring systems take into account amyloid precursor protein, which is cleaved by b - and
systemic risk factors, they do not take into account g-secretases into amyloid-beta (Ab ) fragments of
Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; bDepartment of Neurology, Mayo Clinic,
Rochester, Minnesota; cDepartment of Internal Medicine, Mayo Clinic, Rochester, Minnesota; and the dDivision of Pediatric and
Adolescent Medicine, Mayo Clinic, Rochester, Minnesota. The authors have reported that they have no relationships relevant to
the contents of this paper to disclose.

Manuscript received May 26, 2017; revised manuscript received July 14, 2017, accepted July 14, 2017.
1174 DeSimone et al. JACC VOL. 70, NO. 9, 2017

CAA and AF Clinical Management AUGUST 29, 2017:1173–82

ABBREVIATIONS different amino acid lengths (A b40 and Ab 42) neurovasculature is the most likely cause (9).
AND ACRONYMS (Figure 1) (5). CAA selectively involves the Although deposition of Ab protein underlies sporadic
cerebral vasculature, primarily the lep- CAA and AD, several other genetic forms of
Ab = amyloid-beta
tomeningeal and cortical vessels. Unlike amyloidosis can involve the brain. These include
AD = Alzheimer dementia
parenchymal amyloid deposition in Alz- cystatin C, which is associated with hereditary cere-
AF = atrial fibrillation
heimer dementia (AD), which is composed bral hemorrhage with amyloidosis-Icelandic type;
CAA = cerebral amyloid mainly of A b 42, the b-amyloid protein in CAA transthyretin associated with familial transthyretin
angiopathy
is primarily A b40 (6,7). Deposition follows a amyloidosis; gelsolin, associated with familial
CMB = cerebral microbleed
typical pattern, with A b initially deposited in amyloidosis of the Finnish type; and familial British
cSAH = convexal subarachnoid
the tunica media and adventitia. Later, A b Dementia and familial Danish dementia, which are
hemorrhage
accumulates in all layers of the vessel wall both caused by mutations in the ITM2B gene (10–12).
cSS = cortical superficial
siderosis
and causes loss of smooth muscle cells (8).
This is followed by disruption of the blood CAA AND CLINICAL IMPLICATIONS
ICH = intracerebral
hemorrhage vessel wall leading to microaneurysm for-
LAAO = left atrial appendage mation and fibrinoid necrosis. CAA is prevalent in the elderly. In a community-based
occlusion Although the exact mechanism by which autopsy cohort, CAA was shown to be more common
MRI = magnetic resonance Ab accumulates in the vessel wall is un- in demented versus nondemented individuals with
imaging known, impaired perivascular clearance of an overall frequency of 84.9% (13); 57.8% had mild to
PET = position emission Ab and subsequent pathologic buildup in the moderate CAA, and 18.9% had moderate to severe
tomography
CAA. Moderate and severe CAA predisposes to ICH
and is also associated with cognitive impairment and
F I G U R E 1 Mechanism of Production, Degradation, and Deposition of Ab in Cortical Arteries
an increased risk of death.

CAA AND BLEEDING RISK. Pathologic studies have

demonstrated that lobar ICH in the elderly is
commonly due to CAA (14). Patients with prior CAA-
related ICH had an almost 5-fold hazard, compared
with deep hypertensive-related ICH, of having
recurrent ICH (15). Furthermore, the risk of ICH is
higher in patients receiving anticoagulation (16).
ICH associated with warfarin has a poor outcome
even with reversal of anticoagulation, leaving >70%
of patients disabled or dead (17). Improved hyper-
tension control in younger individuals has reduced
the rates of ICH; however, lobar ICH among elderly
individuals on antithrombotics is increasing, likely
due to the increased frequency and severity of CAA
with aging (18–20).
Despite the clinical implications of CAA, risk
schema such as the HAS-BLED score do not take into
account biomarkers associated with the presence of
CAA, and thus may underestimate the risk of ICH,
especially in elderly patients.

CAA AND COGNITIVE IMPAIRMENT. In addition to

the implications and risk of hemorrhagic stroke, CAA
has been associated with cognitive impairment in the
Mechanism of production, degradation, and deposition of Ab in arteries of the cortex is elderly (21,22). Although CAA can occur in the
shown. Amyloid precursor protein (APP) is broken down by b- and g-secretases to form absence of significant AD pathology, there is often
beta-amyloid (Ab) peptides. These peptides are of different amino acid length (Ab40 and overlap (20–22). The majority of AD patients have
Ab42). Ab42 is the main peptide associated with Alzheimer dementia (AD). Ab40 is the
coexisting CAA; this has been reported in up to 80%
main peptide associated with cerebral amyloid angiopathy. These peptides can be
degraded by metalloproteinases, astrocytes, or macrophages, or are transported across
to 90% of AD patients (13–15). The Honolulu–Asian
the blood–brain barrier via low-density lipoprotein (LDL) receptor–related protein 1, and ageing study demonstrated that individuals with AD
drained via the lymphatic system. and CAA have a lower cognitive performance
compared with AD without CAA (23).
JACC VOL. 70, NO. 9, 2017 DeSimone et al. 1175
AUGUST 29, 2017:1173–82 CAA and AF Clinical Management

F I G U R E 2 Boston Criteria and Modified Boston Criteria for Diagnosis of CAA-Related Hemorrhage

Boston Criteria

Probable CAA with

Definite CAA supporting pathology Probable CAA† Possible CAA†

• Full post-mortem • Clinical data and • Clinical data and MRI/CT: • Clinical data and
pathologic evaluation pathology (biopsy or multiple hemorrhages MRI/CT: single lobar,
• Lobar, cortical, or evacuated hematoma) restricted to lobar, cortical,or cortico-
cortico-subcortical • Lobar, cortical, or cortical, or cortico- subcortical
hemorrhage cortico-subcortical subcortical regions hemorrhage
• Severe* CAA with hemorrhage • Age ≥ 55 • Age ≥ 55
vasculopathy • Some degree of CAA
in specimen

• Single lobar, cortical, • Focal‡ or

or cortico-subcortical disseminated#
hemorrhage AND superficial siderosis Modified
focal‡ or disseminated# • Absence of another Boston
superficial siderosis cause of superficial Criteria
• Absence of another siderosis
cause of superficial
siderosis

Standard Boston Criteria and Modified Boston criteria (data from Knudsen et al. [29] and Linn et al. [30]) for the diagnosis of intracerebral
bleeding associated with an underlying cause of cerebral amyloid angiopathy (CAA). These criteria are useful in making the diagnosis of the
likelihood of CAA (criteria are listed for definite, probable with supporting pathology, probable, and possible). The modified criteria are currently
used for the in vivo diagnosis of possible or probable CAA (without pathologic evidence). *Olichney et al. (31) described the criteria for
severity of CAA. †Absence of another cause for hemorrhage. ‡Siderosis restricted to #3 sulci. #Siderosis affecting $4 sulci. CT ¼ computed
tomography; MRI ¼ magnetic resonance imaging.

CAA and AD are both associated with the apolipo-

protein E (ApoE) ε4 allele (23,24). ApoE is a protein F I G U R E 3 Vascular Pathology That Can Be Found in the Aging Brain
that plays an essential role in lipid metabolism by
binding to cell wall receptors involved in the transfer
of various lipoproteins during lipolysis. Three major
polymorphisms (ε2, ε3, and ε4) exist, which are
differentiated based on the simple alteration of a sin-
gle amino acid (23). The ε4 allele is a risk factor for AD
and CAA (25) and this relationship between ε4 and CAA
is dose-dependent (26). The ε2 allele is associated with
a higher risk of CAA-related lobar ICH, but a lower risk
of AD. Carriers of either an ε2 or ε4 allele have been
found to have a higher risk of ICH recurrence (27).
CAA has also been shown to be associated with
decreased perceptual speed and episodic memory
even after controlling for AD pathology (13). AF is also
associated with cognitive impairment; this associa-
tion seems to be related to ischemic damage and is
independent of AD pathology (28). It is possible that
elderly patients with AF and CAA may be at particu-
larly high risk of cognitive decline, although this
requires further study. Various forms of vascular pathology associated with cerebral amyloid angiopathy
(CAA) can be present in the aging brain. These include leukoaraiosis, cortical superficial
DIAGNOSIS OF CAA siderosis, lobar intracerebral hemorrhage, microinfarcts, and lobar microbleeds.
Deep microbleeds can also be present and are most reflective of hypertensive
Definite diagnosis of CAA requires pathologic exami- arteriopathy.
nation of brain tissue. At autopsy, amyloid is found to
1176 DeSimone et al. JACC VOL. 70, NO. 9, 2017

CAA and AF Clinical Management AUGUST 29, 2017:1173–82

F I G U R E 4 Evolution of CAA in a Single Patient

(A) A T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI demonstrating right hemisphere convexal subarachnoid hemorrhage due to CAA (5 years before
lobar hemorrhage). (B) A T2-weighted FLAIR MRI demonstrating recurrent right hemisphere convexal subarachnoid hemorrhage 1 year later. (C) Susceptibility-
weighted imaging demonstrating superficial siderosis in the right hemisphere (chronic hemosiderin). (D) Amyloid positron emission tomography (using Pittsburgh
compound B) demonstrates increased asymmetric amyloid deposition (red circle) compared to the contralateral side (blue circle), predicting the location of lobar
hemorrhage 3 years later on noncontrast head CT (E) and at autopsy (F). Abbreviations as in Figure 2.

be deposited most commonly in the small and
medium-sized arteries and arterioles of the lep-
tomeningeal and cortical areas (5). Yet, brain biopsy
carries with it significant risk in all individuals,
especially in those at increased risk of bleeding such
as the elderly and/or on anticoagulation therapy.
Thus, clinical diagnostic criteria that facilitate the
diagnosis without the need for sampling of tissue are
extremely important.
A set of clinical and radiological criteria (known as
the Boston criteria) have been developed and vali-
dated for the diagnosis of probable and possible CAA
(Figure 2) (29–31). The following are the radiological
manifestations of CAA: lobar ICH, convexal sub-
arachnoid hemorrhage (cSAH), cerebral microbleeds
(CMBs), cortical superficial siderosis (cSS), and white
matter hyperintensity in posterior brain regions.
LOBAR ICH. The most common clinical presentation
of CAA is a lobar ICH (Figures 3 and 4E and 4F). CAA
accounts for 37% to 74% of nontraumatic lobar hem-
orrhages in the elderly (29,32,33). CAA has a temporal
and occipital affinity likely reflecting the larger A b
burden in blood vessels located in these regions
(34,35).
CONVEXAL SUBARACHNOID HEMORRHAGE. CAA is
the most common cause of cSAH in the elderly (36)
(Figures 3 and 4A). Often, cSAH due to CAA presents
with recurrent transient ischemic attack–like events
manifested by stereotyped paresthesia and motor
JACC VOL. 70, NO. 9, 2017 DeSimone et al. 1177
AUGUST 29, 2017:1173–82 CAA and AF Clinical Management

F I G U R E 5 Brain MRI Demonstration of Lobar Microbleeds in a Patient With CAA

(A-F) Multiple slices of the cortex using T2* gradient recalled echo sequencing, which allows the identification of areas of chronic blood deposition such as cerebral
microbleeds. When these have a lobar distribution, they tend to be more consistent with CAA, whereas deep bleeds are more commonly associated with hypertensive
arteriopathy. These sections demonstrate multiple lobar cerebral microbleeds consistent with CAA (black arrows). Abbreviations as in Figure 2.

dysfunction. The presence of cSAH is associated with associated with a higher risk of future ICH among
higher risk of future lobar ICH (Figure 4B) (37). patients on antithrombotic medications (18).

CEREBRAL MICROBLEEDS. The introduction of CORTICAL SUPERFICIAL SIDEROSIS. The presence

hemosiderin-sensitive magnetic resonance imaging
(MRI) sequences (such as T2*-gradient recalled echo
or susceptibility-weighted imaging techniques) has
allowed increased recognition of CMBs, which are
small areas of chronic blood deposition (Figure 5) (38).
Deep CMBs are associated with hypertensive small
vessel disease, whereas lobar CMBs are more likely to
be associated with CAA (39). CMBs are a risk factor for
both ICH and ischemic stroke (40–43) and are asso-
ciated with shorter survival and cognitive impairment
(44). The risk of ICH increases with the number of
CMBs (40) and the presence of CMBs was found to be
of cSS refers to hemosiderin deposition in the sub-pial
layers of the brain and often occurs after cSAH (45)
(Figures 3 and 4C). On MRI, cSS is identified by
hemosiderin-sensitive sequences (30). The frequency
of cSS is markedly increased in histology-proven CAA
(60%) (30,38). The presence of cSS in patients with
suspected CAA is associated with early recurrence of
ICH (46).
WHITE MATTER HYPERINTENSITY. CAA is also asso-
ciated with white matter hyperintensity on MRI.
The white matter hyperintensity pattern in CAA
patients has a posterior predilection consistent with
1178 DeSimone et al. JACC VOL. 70, NO. 9, 2017

CAA and AF Clinical Management AUGUST 29, 2017:1173–82

C E NT R A L IL LU ST R A T I O N CAA and AF Management: Factors Associated with Increased Risk of Thromboembolism

and Intracerebral Hemorrhage

DeSimone, C.V. et al. J Am Coll Cardiol. 2017;70(9):1173–82.

The elderly population poses a particular management challenge as they often have risk factors that portend a higher risk of both thromboembolism and hemorrhage
simultaneously. Although certain factors like age and hypertension increase both the risk of ischemic and hemorrhagic stroke, other factors more specific to
thrombosis and hemorrhage are described in the figure. AF ¼ atrial fibrillation; CAA ¼ cerebral amyloid angiopathy; ICH ¼ intracerebral hemorrhage; LVAD ¼ left
ventricular assist device.

pathologic data demonstrating the occipital lobe as
having the greatest CAA burden (47).
AMYLOID PET. Recently, the development of amyloid
PET has allowed measurement of amyloid burden
in vivo (48) (Figure 4D). Amyloid PET detects both
parenchymal and cerebrovascular deposition of am-
yloid. The role of amyloid PET in the diagnosis and
management of CAA requires further research, but
preliminary studies are promising (49–51).
CEREBROSPINAL FLUID Ab MEASUREMENTS.
Measuring the concentration of A b proteins in the
cerebrospinal fluid has been proposed as a potential
biomarker for CAA. This is based on neuropatholog-
ical evidence that amyloid b40 and b42 proteins are
deposited in the cerebral vasculature (52). Reduced
levels of A b 40 and Ab42 in the cerebrospinal fluid of
CAA patients compared with controls have been
demonstrated. Similarly, reduced levels of amyloid
b 40 and b 42 were also found in patients with cSAH
and superficial siderosis compared with healthy con-
trols (53,54).
CAA AND CLINICAL MANAGEMENT OF AF. Stroke
risk in AF increases with age, from 1.5% for patients
in their 50s to 23.5% for patients in their 80s (55).
This risk clearly supports the need for ischemic
stroke prophylaxis among elderly patients with AF.
However, elderly patients with AF are also at high
risk of ICH, particularly if they have underlying
CAA. This risk is particularly high in patients with a
previous lobar ICH or other radiological features
associated with a higher risk of ICH (Central
Illustration).
JACC VOL. 70, NO. 9, 2017 DeSimone et al. 1179
AUGUST 29, 2017:1173–82 CAA and AF Clinical Management

As the population ages, encountering a patient

F I G U R E 6 Risk Factors Associated With ICH and Potential Management Strategies
with AF and CAA is becoming an increasingly com-
mon clinical scenario. In patients with AF, the use of
anticoagulation increases the risk of lobar ICH (56,57).
Because most cases of warfarin-associated ICH occur
when the International Normalized Ratio is within the
therapeutic range (58), tight control of International
Normalized Ratio is not sufficient to prevent ICH.
Several lines of evidence support that an underlying
vasculopathy contributes to the risk of anticoagulant-
associated ICH. ICH on warfarin is associated with the
presence of an APOE ε2 allele (59). In addition, the
APOE ε2 allele (59) is associated with worse clinical
outcomes among patients with lobar ICH (60), sug-
gesting that prognosis can be negatively impacted by
underlying CAA.
In patients with CAA and a history of lobar ICH, the
risk of recurrent bleeding is increased (27,61,62). This
risk is even greater with anticoagulation or the pres-
ence of cSS or CMBs on MRI (16,63). Therefore, pa-
tients with cSS, lobar CMBs, or prior lobar ICH on
anticoagulation represent those with the greatest risk
of future hemorrhage (Figure 6) (18,42,64). When
available, brain MRIs should be reviewed in detail
Cerebral amyloid angiopathy (CAA) increases the risk of having an intracerebral hemor-
before prescribing anticoagulation to elderly patients.
rhage (ICH). It is important to recognize that certain imaging findings that can suggest
The cost versus benefit of obtaining a brain MRI to the diagnosis of CAA in patients. These include the presence of cerebral microbleeds,
assess future ICH risk before deciding on anti- cortical superficial siderosis, or a prior lobar ICH. Adding an anticoagulant in this setting
coagulation has never been studied formally and, increases the risk of hemorrhage. Disseminated cortical superficial siderosis (cSS) and
therefore, cannot be recommended routinely; how- prior lobar ICH may have the highest risk of future hemorrhage (bold). CMB ¼ cerebral
microbleed; DOAC ¼ direct oral anticoagulant.
ever, it is the focus of ongoing research efforts
because of the major clinical and economic implica-
tions of ICH. However, brain MRI scanning may be
indicated clinically in elderly patients with cognitive because those who resumed anticoagulation after ICH
decline or previous ICH and in such cases it would be may represent individuals whose clinicians deemed
prudent to review for the presence of cSS and CMBs them to be at a lower risk of recurrent ICH, and
before prescribing anticoagulation for AF. therefore these results must be interpreted
The available evidence is insufficient to assess the cautiously.
risk-benefit of anticoagulation in patients with pre- The direct oral anticoagulants dabigatran, rivar-
vious ICH because these patients have typically been oxaban, apixaban, and edoxaban have been shown to
excluded from randomized, controlled studies eval- have a lower risk of ICH compared with warfarin in
uating oral anticoagulants for AF (65). The 2016 large-scale clinical trials (68–70). In a substudy of the
guidelines for the management of AF from the Euro- AVERROES trial (Apixaban Versus Acetylsalicylic Acid
pean Society of Cardiology suggested that oral anti- [ASA] to Prevent Stroke in Atrial Fibrillation Patients
coagulation for stroke prevention in AF should Who Have Failed or Are Unsuitable for Vitamin K
probably be avoided in patients with symptomatic Antagonist Treatment), apixaban was found to have
lobar ICH and probable or confirmed CAA (66), the same amount of new microbleeds in comparison
although this recommendation remains a matter of with aspirin (71). However, to date, these agents have
debate given the growing evidence from observa- not been specifically tested in patients with a history
tional studies of persistent benefit from anti- of ICH (especially CAA-associated ICH), to examine
coagulation after an ICH (67). Yet, these observational the risk of ICH recurrence. Furthermore, only dabi-
studies have lacked sufficient detail to characterize gatran has an approved reversal agent (idarucizumab)
the likelihood of CAA among ICH patients. Further- that can be used to rapidly and effectively reverse the
more, observational studies that have examined anticoagulant effect in case of an ICH. In a multi-
outcomes in patients with ICH may be confounded center study, andexanet alfa (a recombinant modified
1180 DeSimone et al.
CAA and AF Clinical Management
F I G U R E 7 Heart–Brain Team Schema for Consideration of Pharmacologic and
Nonpharmacologic Therapies in a Patient With Atrial Fibrillation and CAA
Schema from our multidisciplinary clinic that involves input from cardiologists, neurol-
ogists, and radiologists. The risks and benefits of anticoagulation are reviewed by these
experts based on existing data. Additional review of brain imaging to identify features
suggestive of CAA can be performed if clinical suspicion is high. After an informed
discussion with the patient, those deemed to be at low risk of hemorrhage can be
considered for warfarin or DOACs. Those at a higher risk of bleeding can considered for
left atrial appendage occlusion or close observation with no therapy. *The use of DOACs
in those at higher risk of bleeding requires further data, but they are associated with a
lower risk of intracranial hemorrhage than warfarin. CHA2DS2-VASc ¼ congestive heart
failure, hypertension, age $75 years, diabetes mellitus, prior stroke, transient ischemic
attack, or thromboembolism, vascular disease, age 65–74 years, sex category (female);
HAS-BLED ¼ hypertension, abnormal renal or liver function, stroke, bleeding, labile
international normalized ratio, elderly, drugs or alcohol; LAA ¼ left atrial appendage;
Rx ¼ prescription; other abbreviations as in Figures 2 and 6.
human factor Xa decoy protein) effectively achieved
hemostasis in patients who presented with acute
major bleeding (predominantly gastrointestinal or
intracranial) after the administration of a factor Xa
inhibitor (apixaban, rivaroxaban, edoxaban,
enoxaparin). However, 18% of patients developed
thrombotic events during the 30-day follow-up (72).
JACC VOL. 70, NO. 9, 2017
AUGUST 29, 2017:1173–82
NONPHARMACOLOGIC APPROACHES FOR
STROKE PREVENTION
Left atrial appendage occlusion (LAAO) is an alter-
native for patients with AF who have a high risk of
bleeding with long-term anticoagulation (73). LAAO
has been shown to be beneficial for stroke prevention
in AF (74–76) and does not require the use of long-
term anticoagulation (77). Patients with CAA, espe-
cially those with prior lobar ICH or markers of
particularly high risk of ICH (multiple CMBs, cSS),
may be reasonable candidates for this intervention.
Currently, an individualized risk–benefit analysis
of LAAO should only occur on a case-by-case basis as
part of shared decision making collaboration between
the clinician and patient. Further research is required
to define the practice of LAAO technologies without
the need for anticoagulation, especially in high-risk
patients, such as those with probable CAA and pre-
vious lobar ICH. Until then, the current LAAO regis-
tries are necessary to provide this valuable
information.
One potential approach to optimizing care in pa-
tients at risk may be the development of specialized
heart–brain clinics. Our model includes close collab-
oration among cardiology (general, interventional,
and electrophysiology), neurology (stroke special-
ists), and neuroradiology to address complex situa-
tions such as the decision of what stroke prevention
strategy to recommend and implement in patients
with AF and probable CAA. This multidisciplinary,
patient-centered approach is suited to provide the
highly individualized care required in these cases
(Figure 7).
CONCLUSIONS
CAA is a widely prevalent but often overlooked entity
in the overall management of patients with AF. CAA is
associated with cognitive impairment and a pro-
pensity for ICH. In patients with AF, the current
clinical risk scores do not sufficiently take CAA into
account. Increased awareness of CAA among clini-
cians may decrease the risk and/or incidence of ICH.
Thus, risk factors for thromboembolism and ICH—
including the likelihood of CAA—should be weighed
carefully when considering anticoagulation. Data on
alternative treatments to warfarin for the manage-
ment of patients with AF who also have CAA are
emerging. Research quantifying risk of CAA to modify
risk schema such as the HAS-BLED score will be
or necessary to provide clinically relevant numerical
criteria. Therapies such as LAAO and direct oral an-
ticoagulants seem to be promising; however, more
JACC VOL. 70, NO. 9, 2017
AUGUST 29, 2017:1173–82
research is necessary to define best practices for
prevention of stroke, ICH, and cognitive decline in
patients with AF and CAA. Randomized trials are
being developed to determine the value of oral anti-
coagulation in patients with a previous history of ICH
and will hopefully include sufficient patients with
lobar ICH to define the best strategy for this subset of
patients.
REFERENCES
1. Morin DP, Bernard ML, Madias C, Rogers PA,
Thihalolipavan S, Estes NA III. The state of the art:
atrial fibrillation epidemiology, prevention, and
treatment. Mayo Clinic Proceedings 2016;91:
1778–810.
2. Roldán V, Marín F, Manzano-Fernández S, et al.
The HAS-BLED score has better prediction accu-
racy for major bleeding than CHADS2 or CHA2DS2-
VASc scores in anticoagulated patients with atrial
fibrillation. J Am Coll Cardiol 2013;62:2199–204.
3. Dzeshka MS, Lane DA, Lip GYH. Stroke and
bleeding risk in atrial fibrillation: navigating the
alphabet soup of risk-score acronyms (CHADS2,
CHA2DS2-VASc, R2CHADS2, HAS-BLED, ATRIA,
and More). Clin Cardiol 2014;37:634–44.
4. Lip GYH, Frison L, Halperin JL, Lane DA.
Comparative validation of a novel risk score for
predicting bleeding risk in anticoagulated patients
with atrial fibrillation. J Am Coll Cardiol 2011;57:
173–80.
5. Revesz T, Holton JL, Lashley T, et al. Genetics
and molecular pathogenesis of sporadic and he-
reditary cerebral amyloid angiopathies. Acta Neu-
ropathol 2009;118:115–30.
6. Roher AE, Lowenson JD, Clarke S, et al. beta-
Amyloid-(1-42) is a major component of cerebro-
vascular amyloid deposits: implications for the
pathology of Alzheimer disease. Proc Natl Acad Sci
U S A 1993;90:10836–40.
7. Attems J, Lintner F, Jellinger KA. Amyloid b
peptide 1–42 highly correlates with capillary ce-
rebral amyloid angiopathy and Alzheimer disease
pathology. Acta Neuropathol 2004;107:283–91.
8. Keable A, Fenna K, Yuen HM, et al. Deposition
of amyloid b in the walls of human leptomeningeal
arteries in relation to perivascular drainage path-
ways in cerebral amyloid angiopathy. Biochim
Biophys Acta 2016;1862:1037–46.
9. Weller RO, Djuanda E, Yow H-Y, Carare RO.
Lymphatic drainage of the brain and the patho-
physiology of neurological disease. Acta Neuro-
pathol 2008;117:1.
10. Akiyama H, Kondo H, Arai T, et al. Expression
of BRI, the normal precursor of the amyloid pro-
tein of familial British dementia, in human brain.
Acta Neuropathol 2004;107:53–8.
11. Vidal R, Barbeito AG, Miravalle L, Ghetti B.
Cerebral amyloid angiopathy and parenchymal
amyloid deposition in transgenic mice expressing
the Danish mutant form of human BRI2. Brain
Pathol 2009;19:58–68.
ACKNOWLEDGMENT The authors thank Dr. Paul W.
Armstrong for his review and comments.
ADDRESS FOR CORRESPONDENCE: Dr. David R.
Holmes, Jr., Department of Cardiovascular Diseases,
Mayo Clinic College of Medicine, 200 First Street
SouthWest, Rochester, Minnesota 55905. E-mail:
holmes.david@mayo.edu.
12. Yamada M. Cerebral amyloid angiopathy: an
overview. Neuropathology 2000;20:8–22.
13. Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS,
Bennett DA, Schneider JA. Cerebral amyloid
angiopathy pathology and cognitive domains in
older persons. Ann Neurol 2011;69:320–7.
14. Gilbert JJ, Vinters HV. Cerebral amyloid angi-
opathy: incidence and complications in the aging
brain. I. Cerebral hemorrhage. Stroke 1983;14:
915–23.
15. Biffi A, Halpin A, Towfighi A, et al. Aspirin and
recurrent intracerebral hemorrhage in cerebral
amyloid angiopathy. Neurology 2010;75:693–8.
16. Haley KE, Greenberg SM, Gurol ME. Cerebral
microbleeds and macrobleeds: should they influ-
ence our recommendations for antithrombotic
therapies? Curr Cardiol Rep 2013;15:425.
17. Dowlatshahi D, Butcher KS, Asdaghi N, et al.
Poor prognosis in warfarin-associated intracranial
hemorrhage despite anticoagulation reversal.
Stroke 2012;43:1812–7.
18. Lovelock CE, Cordonnier C, Naka H, et al.
Antithrombotic drug use, cerebral microbleeds,
and intracerebral hemorrhage a systematic review
of published and unpublished studies. Stroke
2010;41:1222–8.
19. Flaherty ML, Kissela B, Woo D, et al. The
increasing incidence of anticoagulant-associated
intracerebral hemorrhage. Neurology 2007;68:
116–21.
20. Lovelock CE, Molyneux AJ, Rothwell PM.
Change in incidence and aetiology of intracerebral
haemorrhage in Oxfordshire, UK, between 1981
and 2006: a population-based study. Lancet
Neurol 2007;6:487–93.
21. Greenberg SM, Gurol ME, Rosand J, Smith EE.
Amyloid angiopathy–related vascular cognitive
impairment. Stroke 2004;35:2616–9.
22. Gorelick PB, Scuteri A, Black SE, et al. Vascular
contributions to cognitive impairment and de-
mentia a statement for healthcare professionals
from the American Heart Association/American
Stroke Association. Stroke 2011;42:2672–713.
23. Zannis VI, Breslow JL, Utermann G, et al.
Proposed nomenclature of apoE isoproteins, apoE
genotypes, and phenotypes. J lipid Res 1982;23:
911–4.
24. Verghese PB, Castellano JM, Holtzman DM.
Apolipoprotein E in Alzheimer’s disease and other
neurological disorders. Lancet Neurol 2011;10:
241–52.
DeSimone et al. 1181
CAA and AF Clinical Management
25. Greenberg SM, William Rebeck G,
Vonsattel JPG, Gomez-Isla T, Hyman BT. Apoli-
poprotein E ε4 and cerebral hemorrhage associ-
ated with amyloid angiopathy. Ann Neurol 1995;
38:254–9.
26. Rannikmäe K, Samarasekera N, Martînez-
Gonzâlez NA, Salman RA-S, Sudlow CL. Genetics
of cerebral amyloid angiopathy: systematic review
and meta-analysis. J Neurol Neurosurg Psychiatry
2013;84:901–8.
27. O’Donnell HC, Rosand J, Knudsen KA, et al.
Apolipoprotein E genotype and the risk of recur-
rent lobar intracerebral hemorrhage. N Engl J Med
2000;342:240–5.
28. Graff-Radford J, Madhavan M, Vemuri P, et al.
Atrial fibrillation, cognitive impairment, and neu-
roimaging. Alzheimers Dement 2016;12:391–8.
29. Knudsen KA, Rosand J, Karluk D,
Greenberg SM. Clinical diagnosis of cerebral am-
yloid angiopathy: validation of the Boston Criteria.
Neurology 2001;56:537–9.
30. Linn J, Halpin A, Demaerel P, et al. Prevalence
of superficial siderosis in patients with cerebral
amyloid angiopathy. Neurology 2010;74:1346–50.
31. Olichney JM, Hansen LA, Hofstetter CR,
Grundman M, Katzman R, Thal LJ. Cerebral
infarction in Alzheimer’s disease is associated with
severe amyloid angiopathy and hypertension. Arch
Neurol 1995;52:702–8.
32. Rosand J, Muzikansky A, Kumar A, et al. Spatial
clustering of hemorrhages in probable cerebral
amyloid angiopathy. Ann Neurol 2005;58:459–62.
33. Itoh Y, Yamada M, Hayakawa M, Otomo E,
Miyatake T. Cerebral amyloid angiopathy: a sig-
nificant cause of cerebellar as well as lobar cere-
bral hemorrhage in the elderly. J Neurol Sci 1993;
116(2):135–41.
34. Tian J, Shi J, Smallman R, Iwatsubo T, Mann D.
Relationships in Alzheimer’s disease between the
extent of Ab deposition in cerebral blood vessel
walls, as cerebral amyloid angiopathy, and the
amount of cerebrovascular smooth muscle cells
and collagen. Neuropathol Appl Neurobiol 2006;
32:332–40.
35. Attems J, Jellinger K, Thal D, Van Nostrand W.
Review: sporadic cerebral amyloid angiopathy.
Neuropathol Appl Neurobiol 2011;37:75–93.
36. Kumar S, Goddeau RP, Selim MH, et al.
Atraumatic convexal subarachnoid hemorrhage:
clinical presentation, imaging patterns, and etiol-
ogies. Neurology 2010;74:893–9.
1182 DeSimone et al.
CAA and AF Clinical Management
37. Wilson D, Hostettler IC, Ambler G, Banerjee G,
Jäger HR, Werring DJ. Convexity subarachnoid
haemorrhage has a high risk of intracerebral hae-
morrhage in suspected cerebral amyloid angiop-
athy. J Neurol 2017;264:664–73.
38. Vernooij M, van der Lugt A, Ikram M, et al.
Prevalence and risk factors of cerebral micro-
bleeds The Rotterdam Scan Study. Neurology
2008;70:1208–14.
39. Greenberg SM, Vernooij MW, Cordonnier C,
et al. Cerebral microbleeds: a guide to detection
and interpretation. Lancet Neurol 2009;8:165–74.
40. Greenberg SM, Eng JA, Ning M, Smith EE,
Rosand J. Hemorrhage burden predicts recurrent
intracerebral hemorrhage after lobar hemorrhage.
Stroke 2004;35:1415–20.
41. Jeon S-B, Kang D-W, Cho A-H, et al. Initial
microbleeds at MR imaging can predict recurrent
intracerebral hemorrhage. J Neurol 2007;254:
508–12.
42. van Etten ES, Auriel E, Haley KE, et al. Inci-
dence of symptomatic hemorrhage in patients
with lobar microbleeds. Stroke 2014;45:2280–5.
43. Akoudad S, Portegies MLP, Koudstaal PJ, et al.
Cerebral microbleeds are associated with an
increased risk of stroke. The Rotterdam Study.
Circulation 2015;132(6):509–16.
44. Benedictus MR, Prins ND, Goos JC,
Scheltens P, Barkhof F, van der Flier WM. Micro-
bleeds, mortality, and stroke in Alzheimer disease:
the MISTRAL study. JAMA Neurol 2015;72:539–45.
45. Linn J, Herms J, Dichgans M, et al. Subarach-
noid hemosiderosis and superficial cortical hemo-
siderosis in cerebral amyloid angiopathy. Am J
Neuroradiolo 2008;29:184–6.
46. Roongpiboonsopit D, Charidimou A,
William CM, et al. Cortical superficial siderosis
predicts early recurrent lobar hemorrhage.
Neurology 2016;87:1863–70.
47. Charidimou A, Boulouis G, Haley K, et al. White
matter hyperintensity patterns in cerebral amyloid
angiopathy and hypertensive arteriopathy.
Neurology 2016;86:505–11.
48. Klunk WE, Engler H, Nordberg A, et al. Imaging
brain amyloid in Alzheimer’s disease with Pitts-
burgh compound-B. Ann Neurol 2004;55:306–19.
49. Gurol ME, Dierksen G, Betensky R, et al. Pre-
dicting sites of new hemorrhage with amyloid
imaging in cerebral amyloid angiopathy.
Neurology 2012;79:320–6.
50. Dierksen GA, Skehan ME, Khan MA, et al.
Spatial relation between microbleeds and amyloid
deposits in amyloid angiopathy. Ann Neurol 2010;
68:545–8.
51. Gurol ME, Becker JA, Fotiadis P, et al. Florbe-
tapir-PET to diagnose cerebral amyloid
JACC VOL. 70, NO. 9, 2017
AUGUST 29, 2017:1173–82
angiopathy: a prospective study. Neurology 2016; fibrillation and cerebral amyloid angiopathy.
87:2043–9. Stroke 2016;47:e190–2.
52. Verbeek MM, Kremer BP, Rikkert MO, Van 66. Kirchhof P, Benussi S, Kotecha D, et al. 2016
Domburg PH, Skehan ME, Greenberg SM. Cere- ESC Guidelines for the management of atrial
brospinal fluid amyloid b40 is decreased in cere- fibrillation developed in collaboration with EACTS.
bral amyloid angiopathy. Ann Neurol 2009;66: Eur Heart J 2016;37:2893–962.
245–9.
67. Murthy SB, Gupta A, Merkler AE, et al.
53. Martínez-Lizana E, Carmona-Iragui M, Restarting anticoagulant therapy after intracranial
Alcolea D, et al. Cerebral amyloid angiopathy- hemorrhage. A systematic review and meta-
related atraumatic convexal subarachnoid hemor- analysis. Stroke 2017;48:1594–600.
rhage: an ARIA before the tsunami. J Cereb Blood
68. Granger CB, Alexander JH, McMurray JJ, et al.
Flow Metab 2015;35:710–7.
Apixaban versus warfarin in patients with atrial
54. Renard D, Gabelle A, Hirtz C, Demattei C, fibrillation. N Engl J Med 2011;365:981–92.
Thouvenot E, Lehmann S. Cerebrospinal fluid
69. Connolly SJ, Ezekowitz MD, Yusuf S, et al.
Alzheimer’s disease biomarkers in isolated supra-
Dabigatran versus warfarin in patients with atrial
tentorial cortical superficial siderosis. J Alzheimers
fibrillation. N Engl J Med 2009;361:1139–51.
Dis 2016;54:1291–5.
70. Patel MR, Mahaffey KW, Garg J, et al. Rivar-
55. Wolf PA, Abbott RD, Kannel WB. Atrial fibril-
oxaban versus warfarin in nonvalvular atrial
lation as an independent risk factor for stroke: the
fibrillation. N Engl J Med 2011;365:883–91.
Framingham Study. Stroke 1991;22:983–8.
71. O’Donnell MJ, Eikelboom JW, Yusuf S, et al.
56. Maas MB, Rosenberg NF, Kosteva AR,
Effect of apixaban on brain infarction and micro-
Prabhakaran S, Naidech AM. Coagulopathy
bleeds: AVERROES-MRI assessment study. Am
disproportionately predisposes to lobar intracere-
Heart J 2016;178:145–50.
bral hemorrhage. Neurocrit Care 2013;18:166–9.
72. Connolly SJ, Milling TJ Jr., Eikelboom JW,
57. Pezzini A, Grassi M, Paciaroni M, et al.
et al. Andexanet alfa for acute major bleeding
Antithrombotic medications and the etiology of
associated with factor Xa inhibitors. N Engl J Med
intracerebral hemorrhage MUCH-Italy. Neurology
2016;375:1131–41.
2014;82:529–35.
73. Holmes DR Jr., Doshi SK, Kar S, et al. Left atrial
58. Rosand J, Hylek EM, O’donnell HC,
appendage closure as an alternative to warfarin
Greenberg SM. Warfarin-associated hemorrhage
for stroke prevention in atrial fibrillation: a
and cerebral amyloid angiopathy: a genetic and
patient-level meta-analysis. J Am Coll Cardiol
pathologic study. Neurology 2000;55:947–51.
2015;65:2614–23.
59. Rosand J, Hylek EM, O’Donnell HC,
74. Holmes DR Jr., Kar S, Price MJ, et al. Prospective
Greenberg SM. Warfarin-associated hemorrhage
randomized evaluation of the watchman left atrial
and cerebral amyloid angiopathy: a genetic and
appendage closure device in patients with atrial
pathologic study. Neurology 2000;55:947–51.
fibrillation versus long-term warfarin therapy: the
60. Biffi A, Anderson CD, Jagiella JM, et al. APOE PREVAIL trial. J Am Coll Cardiol 2014;64:1–12.
genotype and extent of bleeding and outcome in
75. Holmes DR Jr., Lakkireddy DR, Whitlock RP,
lobar intracerebral haemorrhage: a genetic asso-
Waksman R, Mack MJ. Left atrial appendage oc-
ciation study. Lancet Neurol 2011;10:702–9.
clusion: opportunities and challenges. J Am Coll
61. Van Etten ES, Gurol ME, van der Grond J, et al. Cardiol 2014;63:291–8.
Recurrent hemorrhage risk and mortality in he-
76. Wiebe J, Franke J, Lehn K, et al. Percutaneous
reditary and sporadic cerebral amyloid angiopathy.
left atrial appendage closure with the watchman
Neurology 2016;87:1482–7.
device: long-term results up to 5 years. J Am Coll
62. Eckman MH, Rosand J, Knudsen KA, Singer DE, Cardiol Intv 2015;8:1915–21.
Greenberg SM. Can patients be anticoagulated
77. Reddy VY, Möbius-Winkler S, Miller MA, et al.
after intracerebral hemorrhage? A decision anal-
Left atrial appendage closure with the watchman
ysis. Stroke 2003;34:1710–6.
device in patients with a contraindication for oral
63. Linn J, Wollenweber FA, Lummel N, et al. Su- anticoagulation: the ASAP Study (ASA Plavix
perficial siderosis is a warning sign for future intra- Feasibility Study With Watchman Left Atrial
cranial hemorrhage. J Neurol 2013;260:176–81. Appendage Closure Technology). J Am Coll Cardiol
2013;61:2551–6.
64. Charidimou A, Linn J, Vernooij MW, et al.
Cortical superficial siderosis: detection and clinical
significance in cerebral amyloid angiopathy and
related conditions. Brain 2015;138:2126–39.
KEY WORDS Alzheimer’s dementia, atrial
65. Stoker TB, Evans NR. Managing risk after fibrillation, cerebral amyloid angiopathy,
intracerebral hemorrhage in concomitant atrial direct oral anticoagulant, management