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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Cerebral Amyloid AngiopathyDiagnosis, Clinical Implications, and Management Strategiesin 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

Fro

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Ad

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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) isincreasing as the population ages (1).Because AF is the pathophysiologic substrate

for stroke in at least 30% of patients, the primarytreatment goal remains prevention of ischemicstroke. Many patients with AF have risk factors forboth ischemic and hemorrhagic stroke; therefore,the therapy decision must be individualized to bal-ance the competing risks of thromboembolism andhemorrhage.

Anticoagulation lowers the risk of ischemic stroke,but also increases bleeding risks, including intrace-rebral hemorrhage (ICH). Scoring systems have beendeveloped for both embolic and hemorrhagic strokerisk and are often used in combination whencontemplating initiation of oral anticoagulation (2,3).

Although these scoring systems take into accountsystemic risk factors, they do not take into account

m the aDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester,

chester, Minnesota; cDepartment of Internal Medicine, Mayo Clinic, Roch

olescent Medicine, Mayo Clinic, Rochester, Minnesota. The authors have

contents of this paper to disclose.

nuscript received May 26, 2017; revised manuscript received July 14, 201

other factors such as fragility, fall risk, adherence tomedication, or adequacy of medical care. The HAS-BLED score (4) is used to estimate bleeding risk withanticoagulation, but does not adequately account forcerebral amyloid angiopathy (CAA), a prevalent riskfactor for ICH in the elderly. Recent advances in theunderstanding of CAA and its implications for themanagement of patients with AF are the focus of thisreview.

WHAT IS CAA?

CAA is a cerebrovascular disease caused by thedeposition of b-amyloid in the walls of cerebralarteries, arterioles, and capillaries. The depositedmaterial is composed of the breakdown product ofamyloid precursor protein, which is cleaved by b- andg-secretases into amyloid-beta (Ab) fragments of

Minnesota; bDepartment of Neurology, Mayo Clinic,

ester, Minnesota; and the dDivision of Pediatric and

reported that they have no relationships relevant to

7, accepted July 14, 2017.

FIGURE 1 Mechanism of Produ

Mechanism of production, degra

shown. Amyloid precursor prote

beta-amyloid (Ab) peptides. The

Ab42). Ab42 is the main peptide

main peptide associated with ce

degraded by metalloproteinases

the blood–brain barrier via low-

drained via the lymphatic system

ABBR EV I A T I ON S

AND ACRONYMS

Ab = amyloid-beta

AD = Alzheimer dementia

AF = atrial fibrillation

CAA = cerebral amyloid

angiopathy

CMB = cerebral microbleed

cSAH = convexal subarachnoid

hemorrhage

cSS = cortical superficial

siderosis

ICH = intracerebral

hemorrhage

LAAO = left atrial appendage

occlusion

MRI = magnetic resonance

imaging

PET = position emission

tomography

DeSimone et al. J A C C V O L . 7 0 , N O . 9 , 2 0 1 7

CAA and AF Clinical Management A U G U S T 2 9 , 2 0 1 7 : 1 1 7 3 – 8 2

1174

different amino acid lengths (Ab40 and Ab42)(Figure 1) (5). CAA selectively involves thecerebral vasculature, primarily the lep-tomeningeal and cortical vessels. Unlikeparenchymal amyloid deposition in Alz-heimer dementia (AD), which is composedmainly of Ab42, the b-amyloid protein in CAAis primarily Ab40 (6,7). Deposition follows atypical pattern, with Ab initially deposited inthe tunica media and adventitia. Later, Abaccumulates in all layers of the vessel walland causes loss of smooth muscle cells (8).This is followed by disruption of the bloodvessel wall leading to microaneurysm for-mation and fibrinoid necrosis.

Although the exact mechanism by whichAb accumulates in the vessel wall is un-known, impaired perivascular clearance ofAb and subsequent pathologic buildup in the

ction, Degradation, and Deposition of Ab in Cortical Arteries

dation, and deposition of Ab in arteries of the cortex is

in (APP) is broken down by b- and g-secretases to form

se peptides are of different amino acid length (Ab40 and

associated with Alzheimer dementia (AD). Ab40 is the

rebral amyloid angiopathy. These peptides can be

, astrocytes, or macrophages, or are transported across

density lipoprotein (LDL) receptor–related protein 1, and

.

neurovasculature is the most likely cause (9).Although deposition of Ab protein underlies sporadicCAA and AD, several other genetic forms ofamyloidosis can involve the brain. These includecystatin C, which is associated with hereditary cere-bral hemorrhage with amyloidosis-Icelandic type;transthyretin associated with familial transthyretinamyloidosis; gelsolin, associated with familialamyloidosis of the Finnish type; and familial BritishDementia and familial Danish dementia, which areboth caused by mutations in the ITM2B gene (10–12).

CAA AND CLINICAL IMPLICATIONS

CAA is prevalent in the elderly. In a community-basedautopsy cohort, CAA was shown to be more commonin demented versus nondemented individuals withan overall frequency of 84.9% (13); 57.8% had mild tomoderate CAA, and 18.9% had moderate to severeCAA. Moderate and severe CAA predisposes to ICHand is also associated with cognitive impairment andan increased risk of death.

CAA AND BLEEDING RISK. Pathologic studies havedemonstrated that lobar ICH in the elderly iscommonly due to CAA (14). Patients with prior CAA-related ICH had an almost 5-fold hazard, comparedwith deep hypertensive-related ICH, of havingrecurrent ICH (15). Furthermore, the risk of ICH ishigher in patients receiving anticoagulation (16).

ICH associated with warfarin has a poor outcomeeven with reversal of anticoagulation, leaving >70%of patients disabled or dead (17). Improved hyper-tension control in younger individuals has reducedthe rates of ICH; however, lobar ICH among elderlyindividuals on antithrombotics is increasing, likelydue to the increased frequency and severity of CAAwith aging (18–20).

Despite the clinical implications of CAA, riskschema such as the HAS-BLED score do not take intoaccount biomarkers associated with the presence ofCAA, and thus may underestimate the risk of ICH,especially in elderly patients.

CAA AND COGNITIVE IMPAIRMENT. In addition tothe implications and risk of hemorrhagic stroke, CAAhas been associated with cognitive impairment in theelderly (21,22). Although CAA can occur in theabsence of significant AD pathology, there is oftenoverlap (20–22). The majority of AD patients havecoexisting CAA; this has been reported in up to 80%to 90% of AD patients (13–15). The Honolulu–Asianageing study demonstrated that individuals with ADand CAA have a lower cognitive performancecompared with AD without CAA (23).

FIGURE 3 Vascular Pathology That Can Be Found in the Aging Brain

Various forms of vascular pathology associated with cerebral amyloid angiopathy

(CAA) can be present in the aging brain. These include leukoaraiosis, cortical superficial

siderosis, lobar intracerebral hemorrhage, microinfarcts, and lobar microbleeds.

Deep microbleeds can also be present and are most reflective of hypertensive

arteriopathy.

FIGURE 2 Boston Criteria and Modified Boston Criteria for Diagnosis of CAA-Related Hemorrhage

Boston Criteria

Definite CAAProbable CAA with

supporting pathology Probable CAA† Possible CAA†

Full post-mortempathologic evaluationLobar, cortical, orcortico-subcorticalhemorrhageSevere* CAA withvasculopathy

•

•

•

Clinical data andpathology (biopsy orevacuated hematoma)Lobar, cortical, orcortico-subcorticalhemorrhageSome degree of CAAin specimen

•

•

•

Clinical data and MRI/CT: multiple hemorrhagesrestricted to lobar,cortical, or cortico-subcortical regionsAge ≥ 55

•

•

Single lobar, cortical,or cortico-subcorticalhemorrhage ANDfocal‡ or disseminated#

superficial siderosisAbsence of anothercause of superficialsiderosis

•

•

Focal‡ ordisseminated#

superficial siderosisAbsence of anothercause of superficialsiderosis

•

•ModifiedBostonCriteria

Clinical data and MRI/CT: single lobar, cortical,or cortico-subcorticalhemorrhageAge ≥ 55

•

•

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.

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CAA and AD are both associated with the apolipo-protein E (ApoE) ε4 allele (23,24). ApoE is a proteinthat plays an essential role in lipid metabolism bybinding to cell wall receptors involved in the transferof various lipoproteins during lipolysis. Three majorpolymorphisms (ε2, ε3, and ε4) exist, which aredifferentiated based on the simple alteration of a sin-gle amino acid (23). The ε4 allele is a risk factor for ADand CAA (25) and this relationship between ε4 and CAAis dose-dependent (26). The ε2 allele is associated witha higher risk of CAA-related lobar ICH, but a lower riskof AD. Carriers of either an ε2 or ε4 allele have beenfound to have a higher risk of ICH recurrence (27).

CAA has also been shown to be associated withdecreased perceptual speed and episodic memoryeven after controlling for AD pathology (13). AF is alsoassociated with cognitive impairment; this associa-tion seems to be related to ischemic damage and isindependent of AD pathology (28). It is possible thatelderly patients with AF and CAA may be at particu-larly high risk of cognitive decline, although thisrequires further study.

DIAGNOSIS OF CAA

Definite diagnosis of CAA requires pathologic exami-nation of brain tissue. At autopsy, amyloid is found to

FIGURE 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.

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be deposited most commonly in the small andmedium-sized arteries and arterioles of the lep-tomeningeal and cortical areas (5). Yet, brain biopsycarries with it significant risk in all individuals,especially in those at increased risk of bleeding suchas the elderly and/or on anticoagulation therapy.Thus, clinical diagnostic criteria that facilitate thediagnosis without the need for sampling of tissue areextremely important.

A set of clinical and radiological criteria (known asthe Boston criteria) have been developed and vali-dated for the diagnosis of probable and possible CAA(Figure 2) (29–31). The following are the radiologicalmanifestations of CAA: lobar ICH, convexal sub-arachnoid hemorrhage (cSAH), cerebral microbleeds

(CMBs), cortical superficial siderosis (cSS), and whitematter hyperintensity in posterior brain regions.

LOBAR ICH. The most common clinical presentationof CAA is a lobar ICH (Figures 3 and 4E and 4F). CAAaccounts for 37% to 74% of nontraumatic lobar hem-orrhages in the elderly (29,32,33). CAA has a temporaland occipital affinity likely reflecting the larger Abburden in blood vessels located in these regions(34,35).

CONVEXAL SUBARACHNOID HEMORRHAGE. CAA isthe most common cause of cSAH in the elderly (36)(Figures 3 and 4A). Often, cSAH due to CAA presentswith recurrent transient ischemic attack–like eventsmanifested by stereotyped paresthesia and motor

FIGURE 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.

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dysfunction. The presence of cSAH is associated withhigher risk of future lobar ICH (Figure 4B) (37).

CEREBRAL MICROBLEEDS. The introduction ofhemosiderin-sensitive magnetic resonance imaging(MRI) sequences (such as T2*-gradient recalled echoor susceptibility-weighted imaging techniques) hasallowed increased recognition of CMBs, which aresmall areas of chronic blood deposition (Figure 5) (38).Deep CMBs are associated with hypertensive smallvessel disease, whereas lobar CMBs are more likely tobe associated with CAA (39). CMBs are a risk factor forboth 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 ofCMBs (40) and the presence of CMBs was found to be

associated with a higher risk of future ICH amongpatients on antithrombotic medications (18).

CORTICAL SUPERFICIAL SIDEROSIS. The presenceof cSS refers to hemosiderin deposition in the sub-piallayers of the brain and often occurs after cSAH (45)(Figures 3 and 4C). On MRI, cSS is identified byhemosiderin-sensitive sequences (30). The frequencyof cSS is markedly increased in histology-proven CAA(60%) (30,38). The presence of cSS in patients withsuspected CAA is associated with early recurrence ofICH (46).

WHITE MATTER HYPERINTENSITY. CAA is also asso-ciated with white matter hyperintensity on MRI.The white matter hyperintensity pattern in CAApatients has a posterior predilection consistent with

CENTRAL ILLUSTRATION CAA and AF Management: Factors Associated with Increased Risk of Thromboembolismand 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.

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pathologic data demonstrating the occipital lobe ashaving the greatest CAA burden (47).

AMYLOID PET. Recently, the development of amyloidPET has allowed measurement of amyloid burdenin vivo (48) (Figure 4D). Amyloid PET detects bothparenchymal and cerebrovascular deposition of am-yloid. The role of amyloid PET in the diagnosis andmanagement of CAA requires further research, butpreliminary studies are promising (49–51).

CEREBROSPINAL FLUID Ab MEASUREMENTS.

Measuring the concentration of Ab proteins in thecerebrospinal fluid has been proposed as a potentialbiomarker for CAA. This is based on neuropatholog-ical evidence that amyloid b40 and b42 proteins aredeposited in the cerebral vasculature (52). Reducedlevels of Ab40 and Ab42 in the cerebrospinal fluid of

CAA patients compared with controls have beendemonstrated. Similarly, reduced levels of amyloidb40 and b42 were also found in patients with cSAHand superficial siderosis compared with healthy con-trols (53,54).

CAA AND CLINICAL MANAGEMENT OF AF. Strokerisk in AF increases with age, from 1.5% for patientsin their 50s to 23.5% for patients in their 80s (55).This risk clearly supports the need for ischemicstroke prophylaxis among elderly patients with AF.However, elderly patients with AF are also at highrisk of ICH, particularly if they have underlyingCAA. This risk is particularly high in patients with aprevious lobar ICH or other radiological featuresassociated with a higher risk of ICH (CentralIllustration).

FIGURE 6 Risk Factors Associated With ICH and Potential Management Strategies

Cerebral amyloid angiopathy (CAA) increases the risk of having an intracerebral hemor-

rhage (ICH). It is important to recognize that certain imaging findings that can suggest

the diagnosis of CAA in patients. These include the presence of cerebral microbleeds,

cortical superficial siderosis, or a prior lobar ICH. Adding an anticoagulant in this setting

increases the risk of hemorrhage. Disseminated cortical superficial siderosis (cSS) and

prior lobar ICH may have the highest risk of future hemorrhage (bold). CMB ¼ cerebral

microbleed; DOAC ¼ direct oral anticoagulant.

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As the population ages, encountering a patientwith AF and CAA is becoming an increasingly com-mon clinical scenario. In patients with AF, the use ofanticoagulation increases the risk of lobar ICH (56,57).Because most cases of warfarin-associated ICH occurwhen the International Normalized Ratio is within thetherapeutic range (58), tight control of InternationalNormalized Ratio is not sufficient to prevent ICH.Several lines of evidence support that an underlyingvasculopathy contributes to the risk of anticoagulant-associated ICH. ICH on warfarin is associated with thepresence of an APOE ε2 allele (59). In addition, theAPOE ε2 allele (59) is associated with worse clinicaloutcomes among patients with lobar ICH (60), sug-gesting that prognosis can be negatively impacted byunderlying CAA.

In patients with CAA and a history of lobar ICH, therisk of recurrent bleeding is increased (27,61,62). Thisrisk 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 onanticoagulation represent those with the greatest riskof future hemorrhage (Figure 6) (18,42,64). Whenavailable, brain MRIs should be reviewed in detailbefore prescribing anticoagulation to elderly patients.The cost versus benefit of obtaining a brain MRI toassess future ICH risk before deciding on anti-coagulation has never been studied formally and,therefore, cannot be recommended routinely; how-ever, it is the focus of ongoing research effortsbecause of the major clinical and economic implica-tions of ICH. However, brain MRI scanning may beindicated clinically in elderly patients with cognitivedecline or previous ICH and in such cases it would beprudent to review for the presence of cSS and CMBsbefore prescribing anticoagulation for AF.

The available evidence is insufficient to assess therisk-benefit of anticoagulation in patients with pre-vious ICH because these patients have typically beenexcluded from randomized, controlled studies eval-uating oral anticoagulants for AF (65). The 2016guidelines for the management of AF from the Euro-pean Society of Cardiology suggested that oral anti-coagulation for stroke prevention in AF shouldprobably be avoided in patients with symptomaticlobar ICH and probable or confirmed CAA (66),although this recommendation remains a matter ofdebate given the growing evidence from observa-tional studies of persistent benefit from anti-coagulation after an ICH (67). Yet, these observationalstudies have lacked sufficient detail to characterizethe likelihood of CAA among ICH patients. Further-more, observational studies that have examinedoutcomes in patients with ICH may be confounded

because those who resumed anticoagulation after ICHmay represent individuals whose clinicians deemedthem to be at a lower risk of recurrent ICH, andtherefore these results must be interpretedcautiously.

The direct oral anticoagulants dabigatran, rivar-oxaban, apixaban, and edoxaban have been shown tohave a lower risk of ICH compared with warfarin inlarge-scale clinical trials (68–70). In a substudy of theAVERROES trial (Apixaban Versus Acetylsalicylic Acid[ASA] to Prevent Stroke in Atrial Fibrillation PatientsWho Have Failed or Are Unsuitable for Vitamin KAntagonist Treatment), apixaban was found to havethe same amount of new microbleeds in comparisonwith aspirin (71). However, to date, these agents havenot been specifically tested in patients with a historyof ICH (especially CAA-associated ICH), to examinethe risk of ICH recurrence. Furthermore, only dabi-gatran has an approved reversal agent (idarucizumab)that can be used to rapidly and effectively reverse theanticoagulant effect in case of an ICH. In a multi-center study, andexanet alfa (a recombinant modified

FIGURE 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.

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human factor Xa decoy protein) effectively achievedhemostasis in patients who presented with acutemajor bleeding (predominantly gastrointestinal orintracranial) after the administration of a factor Xainhibitor (apixaban, rivaroxaban, edoxaban, orenoxaparin). However, 18% of patients developedthrombotic events during the 30-day follow-up (72).

NONPHARMACOLOGIC APPROACHES FOR

STROKE PREVENTION

Left atrial appendage occlusion (LAAO) is an alter-native for patients with AF who have a high risk ofbleeding with long-term anticoagulation (73). LAAOhas been shown to be beneficial for stroke preventionin 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 ofparticularly high risk of ICH (multiple CMBs, cSS),may be reasonable candidates for this intervention.

Currently, an individualized risk–benefit analysisof LAAO should only occur on a case-by-case basis aspart of shared decision making collaboration betweenthe clinician and patient. Further research is requiredto define the practice of LAAO technologies withoutthe need for anticoagulation, especially in high-riskpatients, such as those with probable CAA and pre-vious lobar ICH. Until then, the current LAAO regis-tries are necessary to provide this valuableinformation.

One potential approach to optimizing care in pa-tients at risk may be the development of specializedheart–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 preventionstrategy to recommend and implement in patientswith AF and probable CAA. This multidisciplinary,patient-centered approach is suited to provide thehighly individualized care required in these cases(Figure 7).

CONCLUSIONS

CAA is a widely prevalent but often overlooked entityin the overall management of patients with AF. CAA isassociated with cognitive impairment and a pro-pensity for ICH. In patients with AF, the currentclinical risk scores do not sufficiently take CAA intoaccount. 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 weighedcarefully when considering anticoagulation. Data onalternative treatments to warfarin for the manage-ment of patients with AF who also have CAA areemerging. Research quantifying risk of CAA to modifyrisk schema such as the HAS-BLED score will benecessary to provide clinically relevant numericalcriteria. Therapies such as LAAO and direct oral an-ticoagulants seem to be promising; however, more

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research is necessary to define best practices forprevention of stroke, ICH, and cognitive decline inpatients with AF and CAA. Randomized trials arebeing developed to determine the value of oral anti-coagulation in patients with a previous history of ICHand will hopefully include sufficient patients withlobar ICH to define the best strategy for this subset ofpatients.

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 StreetSouthWest, Rochester, Minnesota 55905. E-mail:holmes.david@mayo.edu.

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KEY WORDS Alzheimer’s dementia, atrialfibrillation, cerebral amyloid angiopathy,direct oral anticoagulant, management