Review

International Journal of Stroke

2021, Vol. 16(4) 356–369
A practical approach to the management ! 2020 World Stroke Organization
Article reuse guidelines:
of cerebral amyloid angiopathy sagepub.com/journals-permissions
DOI: 10.1177/1747493020974464
journals.sagepub.com/home/wso

Mariel G Kozberg1,2,3 , Valentina Perosa1,2,3,4, M Edip Gurol2,3

and Susanne J van Veluw1,2,3

Abstract
Cerebral amyloid angiopathy is a common small vessel disease in the elderly involving vascular amyloid-b deposition.
Cerebral amyloid angiopathy is one of the leading causes of intracerebral hemorrhage and a significant contributor to
age-related cognitive decline. The awareness of a diagnosis of cerebral amyloid angiopathy is important in clinical practice
as it impacts decisions to use lifelong anticoagulation or nonpharmacological alternatives to anticoagulation such as left
atrial appendage closure in patients who have concurrent atrial fibrillation, another common condition in older adults.
This review summarizes the latest literature regarding the management of patients with sporadic cerebral amyloid
angiopathy, including diagnostic criteria, imaging biomarkers for cerebral amyloid angiopathy severity, and management
strategies to decrease intracerebral hemorrhage risk. In a minority of patients, the presence of cerebral amyloid
angiopathy triggers an autoimmune inflammatory reaction, referred to as cerebral amyloid angiopathy-related inflamma-
tion, which is often responsive to immunosuppressive treatment in the acute phase. Diagnosis and management of
cerebral amyloid angiopathy-related inflammation will be presented separately. While there are currently no effective
therapeutics available to cure or halt the progression of cerebral amyloid angiopathy, we discuss emerging avenues for
potential future interventions.

Keywords
Cerebral amyloid angiopathy, intracerebral hemorrhage, microbleeds, cortical superficial siderosis, microinfarcts, small
vessel disease

Received: 21 July 2020; accepted: 16 September 2020

Introduction There are currently no effective treatments available

Cerebral amyloid angiopathy (CAA) is characterized to cure or halt the progression of CAA. Management of
by amyloid-b deposits in the walls of leptomeningeal patients mostly centers around reducing the risk of
and cortical blood vessels.1,2 CAA can lead to symp- first-time or recurrent lobar ICH. This review provides
tomatic lobar intracerebral hemorrhages (ICHs) as well an up to date and comprehensive discussion of mag-
as smaller regions of bleeding including cerebral micro- netic resonance imaging (MRI) markers of CAA, par-
bleeds (CMBs) and cortical superficial siderosis (cSS). ticularly delving into the utilization of these markers to
There are a few genetic mutations that result in a pure determine a patient’s individual risk of future ICH.
form of CAA, characterized by early occurrence of ICH Strategies for ICH risk reduction in CAA will be
and in some cases cognitive dysfunction.1 However, in
the great majority of patients, CAA is a sporadic dis-
1
ease that shows some overlap with Alzheimer’s disease MassGeneral Institute for Neurodegenerative Disease, Massachusetts
General Hospital, Harvard Medical School, Charlestown, MA, USA
(AD) pathology. 2
Department of Neurology, Massachusetts General Hospital, Harvard
In addition to being a cause of lobar ICH, sporadic Medical School, Boston, MA, USA
CAA is an important etiology of cognitive impairment 3
Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research
and gait instability in the elderly.3 While CAA is clas- Center, Department of Neurology, Massachusetts General Hospital,
sically thought of as a disease leading to cerebral bleed- Harvard Medical School, Boston, MA,USA
4
Department of Neurology, Otto-von-Guericke University, Magdeburg,
ing, recent work has demonstrated that CAA also Germany
induces widespread ischemic changes including cortical
Corresponding author:
microinfarcts and white matter hyperintensities Mariel G Kozberg, Department of Neurology, Massachusetts General
(WMH), pathologies which are associated with cogni- Hospital, 55 Fruit Street, Boston, MA 02115, USA.
tive decline.4,5 Email: [email protected]

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Kozberg et al. 357

discussed in depth, including the management of fre- A number of nonhemorrhagic imaging findings are
quently comorbid cardiovascular risk factors, with a also suggestive of a diagnosis of CAA and scale with
particular focus on the avoidance of systemic anticoa- CAA severity including WMH, MRI-visible perivascu-
gulation and potential alternatives to anticoagulation. lar spaces (PVS), lobar lacunes, and cortical microin-
Additionally, this review includes a discussion of farcts (Figure 1).4 An updated version of the Boston
emerging potential future therapies for CAA, ranging Criteria (version 2.0), which takes into account these
from decreasing production of amyloid-b to enhancing nonhemorrhagic findings, is expected to be released
amyloid-b clearance. soon.11 WMH are lesions visible on T2-weighted
fluid-attenuated inversion recovery (FLAIR) MRI
(Figure 1), strongly associated with small vessel disease
Diagnosis of CAA and thought to be in part ischemic in etiology. When
While direct visualization of vascular amyloid-b in severe, WMH can also be seen on CT as hypoattenuat-
CAA requires brain biopsy or autopsy, a set of clinical ing lesions. These lesions are observed either around the
and MRI-based diagnostic criteria termed the (modi- ventricles or more widespread across the white matter
fied) Boston Criteria have been validated to enable the centrum semiovale. WMH in the centrum semiovale
diagnosis of CAA without the need to obtain brain and posterior regions of the brain are particularly asso-
tissue.6,7 These criteria indicate that the presence of ciated with CAA.12,13 The severity of WMH correlates
cortical hemorrhagic lesions including lobar ICH, with vascular amyloid-b burden,14 number of CMBs,12
strictly cortical CMBs, and/or cSS without the presence lobar ICH risk,15,16 plasma amyloid-b 40 levels,17 and
of deeper hemorrhages in patients >55 years of age is cognitive impairment (as discussed further below). The
highly sensitive and specific for CAA. CMBs and cSS extent of these lesions is classically assessed using the
can be observed with gradient echo and susceptibility- Fazekas grading scale,18 though computer-assisted seg-
weighted MRI sequences (Figure 1). CMBs are found mentation techniques are also utilized for research stu-
more frequently in posterior brain regions, but they can dies.17,19 The presence of more than 10 subcortical
be seen anywhere in the cortex in the presence of CAA.8 WMH spots in one hemisphere (not affected by ICH)
Recent work has also demonstrated that the presence of was also found to be significantly more common in
strictly superficial cerebellar microbleeds is associated patients with CAA when compared to hypertensive
with CAA.9,10

Figure 1. Hemorrhagic and nonhemorrhagic lesions associated with CAA. Representative scans from multiple patients with
probable CAA are shown. Top row (left to right): noncontrast CT scan, susceptibility-weighted MRI, susceptibility-weighted MRI,
and susceptibility-weighted MRI. Bottom row (left to right): T2-weighted FLAIR MRI, T2-weighted MRI, diffusion-weighted MRI,
and T2-weighted FLAIR MRI. Arrows point to representative examples of each lesion in each panel.
CMBs: cerebral microbleeds; cSS: cortical superficial siderosis; ICH: intracerebral hemorrhage; WMH: white matter hyperin-
tensities; EPVS: enlarged perivascular spaces; CMI: cerebral microinfarct.

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arteriopathy, a feature that can suggest CAA diagnosis amyloid-b42 isoforms are decreased in the CSF of
in the appropriate setting.8 patients with CAA or AD, whereas tau levels are
MRI-visible PVS are interstitial fluid-filled spaces increased.31 CAA is associated with predominantly vas-
surrounding blood vessels which appear as small cular deposition of amyloid-b40 isoforms, while AD is
elongated structures on T1- or T2-weighted MRI associated with parenchymal deposition of predomin-
sequences20 (Figure 1). These spaces can be differen- antly amyloid-b42. Although CSF analysis alone does
tiated from prior areas of infarction by the absence of not sufficiently differentiate between CAA and AD, stu-
a surrounding hyperintense ring on T2-weighted dies do suggest significantly lower levels of CSF amy-
FLAIR MRI.20 A recent study comparing patients loid-b40 in patients with CAA as compared to those
with CAA-related ICH to those with hypertensive with AD.31,32 Importantly, CSF analysis in individuals
arteriopathy-related ICH found that MRI-visible PVS with a hereditary form of CAA (i.e. Dutch-type CAA)
located in the centrum semiovale were significantly reveals that decreased amyloid-b40 levels in CSF is an
more prevalent in patients with CAA-related ICH, early feature in the disease pathogenesis.33 Amyloid-
while MRI-visible PVS at the level of the basal ganglia PET tracers including florbetapir and 11C-Pittsburgh
were indicative of hypertensive arteriopathy. The compound (B) (PiB) label both parenchymal and vas-
degree of centrum semiovale MRI-visible PVS was cular amyloid-b. Amyloid PET may be useful as an
associated with known hemorrhagic imaging markers adjunct test for CAA diagnosis in cognitively healthy
of CAA including cSS and CMBs.21 people and to differentiate CAA from hypertensive
Along the same lines, it was recently observed that arteriopathy particularly in patients with only micro-
lacunar infarcts in the centrum semiovale (and not the bleeds (no ICH) (Figure 2), a pattern of nonhemorrha-
basal ganglia), so-called ‘‘lobar lacunes,’’ are more gic MRI markers strongly suggestive of CAA, or mixed
commonly found in patients with CAA compared to location ICH/microbleeds.34–37 In fact, a recent study
hypertensive arteriopathy22,23 (Figure 1). The presence demonstrated that, in cognitively normal patients, flor-
of lobar lacunes correlates with increased risk of recur- betapir-PET can be used to diagnose probable CAA
rent ICH in CAA patients.24 Although the patho- with high sensitivity (100%) and specificity (90%).34
physiological mechanisms remain to be elucidated, However, like CSF markers of amyloid-b, differenti-
this imaging marker may be a useful marker in the ation between vascular and parenchymal amyloid-b
management of CAA. deposition and thus between CAA and parenchymal
Microinfarcts are small ischemic lesions, a subset of AD pathologies is challenging.
which can be observed with 7T or even conventional
(i.e. 1.5-3T) MRI in the cortical gray matter
(Figure 1).25 Neuropathological studies have shown,
however, that MRI drastically underestimates the Figure 2. Florbetapir-PET scans from representative
number of cortical microinfarcts.26–28 In CAA, micro- patients with CAA and hypertensive arteriopathy. Left: scan
infarcts are associated with regional CAA severity and from a patient with CAA demonstrating decreased gray-
may indicate more severe vascular amyloid-b depos- white contrast, indicating increased gray matter florbetapir
ition.26 Cortical microinfarcts are thought to be import- uptake (positive scan). Right: scan from a patient with
ant contributors to cognitive dysfunction in CAA and hypertensive arteriopathy demonstrating clear gray-white
other cerebral microangiopathies. contrast throughout (negative scan). Adapted from Gurol
Finally, diagnostic tools to assess for amyloid-b can et al34.
also be supportive of a CAA diagnosis, particularly in HTN: hypertension; PET: positron emission tomography;
cases with diagnostic uncertainty between CAA and/or CAA: cerebral amyloid angiopathy.
hypertensive arteriopathy as the etiology of hemor-
rhage.29 Differentiating between CAA and hypertensive
arteriopathy is crucial as recurrent ICH risk differs sig-
nificantly.30 Hypertensive arteriopathy typically leads
to hemorrhage in deeper locations as opposed to
CAA. Some patients present with mixed location ICH
and CMBs (deep and lobar). Recent studies have sug-
gested that hypertensive arteriopathy is the predomin-
ant pathology in these mixed ICH/CMB cases.29
The two most commonly used techniques to assess
amyloid-b levels in the brain are cerebrospinal fluid
(CSF) samples and amyloid-positron emission tomog-
raphy (PET) scans. The levels of both amyloid-b40 and

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Kozberg et al. 359

subarachnoid space and/or the chronic manifestation

ICH risk stratification and risk reduction of prior sulcal subarachnoid hemorrhage. cSS often
Lobar ICH is a significant cause of morbidity and mor- presents clinically as transient focal neurological epi-
tality in patients with CAA,38 and much of the man- sodes (TFNEs), which are discussed in detail below.
agement of CAA centers around reducing a patient’s A patient’s risk of ICH scales with the multifocality
risk of future ICH. Understanding a patient’s individ- and extent of cSS; a recent prospective study of 313
ual ICH risk is essential for both the counseling of patients with CAA-related ICH found that annual
patients and families and determining the risk-benefit risk of ICH increases with the extent of cSS, with
balance for anticoagulation agents. annual ICH recurrence rates of 26.9% in patients
with bilateral disseminated cSS.43
The mechanisms connecting cSS and ICH remain
Risk stratification
unclear. Pathological studies observed that cSS is asso-
Cortical microbleeds and ICH risk. A large portion of ciated with increased local leptomeningeal amyloid-b
patients with CAA present for neurological care with but with decreased global cortical amyloid-b.45,46 In
mild cognitive impairment, gait instability, or transient contrast, CMBs are associated with increased global
neurological symptoms and are subsequently diagnosed cortical vascular amyloid-b.26 These findings, in add-
with CAA through an MRI of the brain demonstrating ition to associations between cSS and apolipoprotein
cortical CMBs but no larger hemorrhages. Making a E allele 22 (as discussed further below), have led to
diagnosis of CAA with these isolated imaging findings the hypothesis that there may be different phenotypes
is crucial—these patients are at significantly higher risk of CAA including (1) patients with more prominent
for ICH than the general population.30,39 Additionally, leptomeningeal disease and cSS (and potentially
establishing a diagnosis at this stage may prevent the higher ICH risk) and (2) patients with more prominent
need for further extensive work-up and may enable cortical CAA and CMBs.26,47 Of note, the Piedmont
patients to participate in future trials at an early time- mutation form of hereditary form of CAA resulting
point in their disease course. from a mutation in amyloid precursor protein (APP;
In a recent observational study, patients diagnosed Leu705Val) is associated with prominent leptomenin-
with CAA with CMBs (with no history of ICH) were geal CAA with relative sparing of the cortical vessels
found to have a 5% annual risk of ICH.39 This risk is and typically presents with a severe lobar ICH pheno-
significantly higher than the incidence of ICH in the gen- type.48,49 These findings support the notion that severe
eral population which is 0.025%40 (and higher than the leptomeningeal CAA puts patients at risk for both cSS
annual risk of recurrent ICH in patients with hyperten- and ICH.
sive arteriopathy-associated ICH which is  2%).30
Additionally, a study of 4759 participants with cortical Apolipoprotein E allele status and ICH risk. Apolipoprotein
and/or deep CMBs followed over an 8-year period E alleles 22 (APOE2) and 24 (APOE4) have both been
found that the risk of hemorrhagic and ischemic stroke associated with CAA and risk of lobar ICH.50–54
increased with number of CMBs.41 Patients in this study APOE4 is associated with increased parenchymal and
with cortical CMBs without deep CMBs (consistent with vascular amyloid-b and is the strongest genetic risk
a diagnosis of CAA) were at a higher risk of ICH than factor for late onset AD, while APOE2 may track
those with solely deep CMBs. more closely with the severity of vascular pathology
For patients with CMBs and a prior lobar ICH, and ICH risk.47,55 A recent meta-analysis demonstrated
annual risk of recurrent lobar ICH increases to an association between cSS severity and APOE2,56 and
approximately 10%.30 As discussed above, nonhemor- prior neuropathological work also identified a relation-
rhagic imaging features such as the extent of WMH, ship between cSS and APOE2.45 However, these rela-
MRI-visible PVS in the centrum semiovale, lobar tionships have yet to be fully elucidated.
lacunes, and cortical microinfarcts are suggestive of
more severe CAA and are associated with increased
ICH risk.15,16,42
Risk reduction
Reducing the risk of ICH in CAA predominantly cen-
cSS and ICH risk. cSS has recently emerged as one of the ters around managing comorbidities including cardio-
strongest predictors of future ICH.44,45 cSS refers to the vascular risk factors and decision-making surrounding
presence of blood products in the subarachnoid space anticoagulation (Figure 3).
and superficial cortical layers, represented on MRI by
curvilinear susceptibility artifact lining the sulci. These Long-term blood pressure management. Blood pressure
findings are thought to represent leakage of blood management is critical for reducing the risk of CAA-
products from leptomeningeal blood vessels into the related ICH as well as hypertensive angiopathy-related

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Figure 3. Managing comorbidities in patients with CAA to reduce intracerebral hemorrhage risk. Recommendations for
management of cardiovascular risk factors in patients with CAA (a); possible alternatives to lifelong anticoagulation in patients
with CAA, based on the clinical indication (b). Individualized decisions regarding anticoagulation should be made through multi
disciplinary discussions, involving patients and families.
BP: blood pressure; ACC/AHA: American College of Cardiology/American Heart Association; DVT: deep vein thrombosis; PE:
pulmonary embolism; IVC: inferior vena cava; LAAC: left atrial appendage closure; APLAS: antiphospholipid antibody syndrome;
ICH: intracerebral hemorrhage.

(a)

(b)

ICH.57 An observational study of patients with lobar significantly higher risk of ICH (both lobar and deep
and deep ICH found an association between elevated ICH).66 A recent analysis of patients from the longitu-
blood pressures and recurrent ICH risk in both dinal, prospective Framingham study demonstrated an
groups.58 While the severity of hypertension correlated association between statin use and deep ICH, but not
with ICH recurrence risk, the study also demonstrated with lobar ICH.53 Interestingly, a recent observational
an association between blood pressures in the prehyper- study of 345,531 patients followed for 9.5 years demon-
tensive range (systolic 120–139 mmHg/diastolic 80–89 strated a decrease in ICH risk with statin use while still
mmHg) and ICH risk. These findings and work from finding an association between lower LDL levels and
others suggest patients with a diagnosis of CAA should increased ICH risk.67
ideally have blood pressures maintained at <120/80 Given the potential benefits of statins in cerebral
mmHg.59 small vessel disease, current recommendations are to
In addition to prehypertension being a risk factor for pursue statin therapy in patients with CAA who have
ICH, a long-term trajectory of increasingly elevated a clear indication per ACC/AHA guidelines. However,
blood pressures may contribute to ischemic stroke benefits and risks of statin use should be discussed with
and ICH risk.59 Visit-to-visit variability in blood pres- all patients at a higher ICH risk.65,68 The SATURN
sures has also been shown to be associated with CMB study, an NIH-funded randomized controlled trial
and WMH progression60 as well as all-cause mortality, (RCT), will assess the potential benefit/harm of con-
cardiovascular disease, and stroke.61 tinuation versus discontinuation of statins in patients
who survived a lobar ICH. This study will hopefully
Lipid management. Aggressive lipid management is an provide a much-needed answer to the dilemma of
effective form of secondary ischemic stroke preven- statin use in CAA.69
tion.62 However, reduced low-density lipoprotein
(LDL) levels (less than 70–80 mg/dL) have been asso- Glucose management. A recent prospective study of
ciated with an increased risk of ICH.63–65 ICH patients 96,110 participants demonstrated that both low (<4
randomized to high-dose statin had a significantly ele- mmol/L) and high (>7 mmol/L) fasting blood glucose
vated risk of recurrent ICH in the sroke prevention by levels are associated with increased ICH risk; however,
aggressive reduction in cholesterol level (SPARCL) the association between high fasting blood glucose and
study.62 A recent prospective study followed 96,043 ICH risk was only found for patients with deep ICH.70
participants with no prior history of stroke or myocar- The number of lobar ICHs in this study was limited.
dial infarction over 9 years of follow-up and found that Additionally, a subgroup analysis of the INTERACT2
participants with LDL levels <70 mg/dL had a study demonstrated a strong association between

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Kozberg et al. 361

hyperglycemia and poor outcomes post-ICH, although Decision-making regarding initiation or continu-
most patients in this study had a deep location of ation of anticoagulation in patients who are at both
ICH.71 More work is needed to further delineate the high ischemic and hemorrhagic risk depends on both
relationship between blood glucose levels and ICH an individual patient’s risk of ICH, the indication for
risk in CAA. anticoagulation, potential alternatives to anticoagula-
tion, and the required duration of anticoagulation as
Antiplatelet use. Current guidance is that antiplatelet outlined below.77 A recent study analyzed data from
agents for primary prevention of cardiovascular two longitudinal cohort studies of patients with antic-
events should be avoided in patients with CAA unless oagulation-associated ICH utilized MRI markers (cSS
the patient has a clear, evidence-based indication for and CMBs) and APOE genotype to create a risk strati-
antiplatelet use.72 Prior studies have demonstrated fication tool for recurrent ICH,54 which may aid in
increased CMBs73,74 and ICH rates16,75 with antiplate- clinical decision-making.
let use.
However, antiplatelet agents do offer significant Nonvalvular atrial fibrillation. One of the most
benefits for cardiovascular disease and should be used common indications for anticoagulation is for ischemic
in patients with CAA in situations in which there is a stroke prevention in patients with atrial fibrillation.85
clear indication such as secondary prevention or other Clinically, the CHA2DS2-VASC score is typically used
FDA-approved situations such as after coronary or to assess the annual risk of ischemic stroke in a patient
cardiac procedures. The REstart or STop antithrombo- with atrial fibrillation and to determine whether antic-
tics randomised trial (RESTART) study was a pro- oagulation is indicated.86 Some providers use the HAS-
spective randomized trial of 537 patients who BLED score to assess the risk of major bleeding events
presented with an ICH while on antiplatelet therapy secondary to anticoagulation; however, this score has
for secondary prevention.76 Patients were randomized poor predictive value overall, and it was not designed to
to either restart or avoid antiplatelet therapy. be used in patients with significant ICH risk. A recent
Investigators did not find a significant difference in multicenter observational study showed that HAS-
ICH recurrence between the two groups, leading them BLED score’s predictive value for ICH was less than
to conclude that the benefits of antiplatelet therapy for 50%, (i.e. worse than the flip of a coin), so it is not used
secondary prevention likely exceed the ICH-related in the field of neurology.87 In general, anticoagulation,
risks. especially long-term anticoagulant use, should be
avoided in all patients with CAA, if possible. As men-
Anticoagulation. Anticoagulation significantly increases tioned above, patients and families should be engaged
the risk of ICH and ICH-related mortality, even in in shared decision-making discussions regarding poten-
patients with low baseline ICH risk. The risk of ICH tial initiation of anticoagulation in patients at risk for
increases by 2–5 with anticoagulation with warfarin both ischemic and hemorrhagic events.
and non-vitamin K oral anticoagulants (NOACs).77,78 Left atrial appendage closure (LAAC) has recently
While hemorrhagic complications may occur less fre- emerged as a viable alternative to anticoagulation and
quently with NOACs than with warfarin,79–82 this find- should be considered in patients with elevated ICH
ing may not apply to patients at high risk for ICH as risk.77 In patients with atrial fibrillation, over 90% of
these patients were excluded from all trials comparing thrombi form in the left atrial appendage and therefore
NOACs to warfarin. The three-month mortality of LAAC may help prevent thrombus formation and sub-
patients with anticoagulation-associated ICH is sequent ischemic stroke.88 Multiple devices have been
approximately 50% for patients taking warfarin83,84 developed for LAAC, and the currently only FDA-
or NOACs.79,80 approved device with the largest amount of data sup-
Because of the risk of ICH, ideally lifelong anticoa- porting its use is the WATCHMAN device (Boston
gulation should be avoided in all patients with CAA; Scientific, Marlborough, MA). LAAC via the
however, there are cases in which the potential benefits WATCHMAN has been shown to be noninferior to
of anticoagulation may outweigh the risks, especially warfarin and apixaban at ischemic stroke preven-
for short-duration anticoagulant use. We note that tion.89–91 Other devices include (1) the AMPLATZER
there have been no RCTs to date of anticoagulation AMULET (St Jude Medical/Abbot, Minneapolis, MN)
use in patients with known CAA. Therefore, for all device, for which the IDE RCT comparing it to
patients at risk for both ischemic and hemorrhagic WATCHMAN was completed and results are currently
events, patients and families should be engaged in pending, (2) the AtriClip which can be used for LAAC
shared decision-making discussions regarding potential during open heart surgery (Atricure Inc., West Chester,
initiation of anticoagulation for all indications dis- OH),93 and (3) the LARIAT suture delivery system
cussed below. (SentreHeart, Redwood City, CA). CHAMPION AF

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(the new generation WATCHMAN FLEX) and assess for DVT resolution can also aid the decision-
CATALYST (AMPLATZER AMULET) are ongoing making process.
RCTs comparing the outcomes of LAAC to NOACs in
the general nonvalvular atrial fibrillation populations. Antiphospholipid antibody syndrome. Patients with
LAAC and ICH risk stratification strategies were also antiphospholipid antibody syndrome (APLAS) have a
recently reviewed in detail.77 significant risk of arterial and venous thrombosis and
Initial studies of the WATCHMAN device require lifelong anticoagulation with warfarin.97
excluded patients with past history of ICH as these Unfortunately, there is no alternative to anticoagula-
studies had a long-term warfarin arm and a short tion for this patient population. Despite the ICH risk,
course of warfarin was used for LAAC (typically anticoagulation should be continued as long as the
45 days for the WATCHMAN) to allow for device diagnosis of APLAS is appropriately established.
endothelialization to prevent thrombi formation on
the device surface.93 However, studies have demon-
Management of TFNEs
strated noninferiority with NOACs for short-term
anticoagulation post LAAC,93,94 and dual antiplatelet Patients with CAA frequently experience TFNEs,
therapy can be used as an alternative to short-term intermittent episodes of transient neurological symp-
anticoagulation postprocedurally.95,96 It is important toms (<24 h), including sensory symptoms (paresthe-
to note the difference between short term (six weeks sias and numbness), focal weakness, and language
post LAAC) anticoagulation versus lifelong anticoa- disturbances.98 TFNEs can be stereotyped and are
gulation as the risk of ICH increases over years. sometimes described as having a spreading progres-
Decisions regarding the use of short-term anticoagu- sion. While the pathophysiology remains largely
lation or dual antiplatelet therapy should be made in unknown, these are thought to represent cortical
conjunction with a cardiology team based on a risk spreading depolarizations,99 potentially triggered by
versus benefit analysis accounting for a patient’s indi- regions of cSS and also associated with acute convex-
vidual ICH risk (as discussed above). ity subarachnoid hemorrhage.98,100 There is limited
data available for treatment of TFNEs in CAA.
Mechanical valves. Patients with mechanical valves Providers often trial antiepileptic medications which
require lifelong anticoagulation, and warfarin con- have been shown to be effective at CSD reduction in
tinues to be the only approved anticoagulation agent migraineurs101,102 such as valproic acid, lamotrigine,
for this indication. Given the significant risk of throm- and topiramate in patients with recurrent TFNEs
bus formation on mechanical valves, the benefits of with anecdotal benefit.
anticoagulation in this scenario outweigh the risks of Of note, TFNEs can be misdiagnosed as transient
ICH even in patients with CAA. However, in patients ischemic attacks, and one should consider obtaining
with particularly high risk as discussed above (e.g. gradient echo or susceptibility-weighted MRI to
multifocal cSS with history of prior ICH), depending assess for CMBs and cSS in patients with focal neuro-
on the clinical scenario, one may need to consider logical deficits. Antithrombotics should not be started
replacement with a bioprosthetic valve. or escalated if the correct diagnosis is TFNEs.

Intracardiac thrombus, pulmonary embolism, deep vein

thrombosis. The presence of a new/fresh intracardiac
Management of cognitive impairment
thrombus is an absolute indication for anticoagulation Many patients with CAA present with mild cognitive
given the associated risk of ischemic stroke. However, impairment. Cortical microinfarcts have been asso-
in patients with CAA, one can consider short-term ciated with cognitive impairment independent of AD
repeat imaging to assess for thrombus resolution in pathology both in CAA and other disease pro-
order to minimize time spent on anticoagulation. cesses.5,25,28,103 Neuropathological studies have demon-
In cases of pulmonary embolism (PE), treatment strated that microinfarcts occur in brain regions with
depends on the clinical severity of the PE balanced increased amyloid-b burden and are associated with ves-
with a patient’s individualized risk of ICH. Short- sels with significant amyloid-b deposition.104 In addition
term anticoagulation is allowed in most situations, to microinfarcts, WMHs and atrophy and structural net-
but decision-making should be multidisciplinary. work alterations have been shown to contribute to cog-
Lastly, in patients diagnosed with a deep vein throm- nitive impairment in patients with CAA.105–107
bosis (DVT), inferior vena cava filters can be con- There are currently no effective treatments for these
sidered as a short-term alternative to anticoagulation cognitive symptoms in CAA patients. Given these
in patients at high risk for ICH. A short-term course symptoms may represent a relatively early manifest-
of anticoagulation with interval repeat imaging to ation of CAA (preceding lobar ICH), prompt

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Kozberg et al. 363

diagnosis, potentially through early detection of micro- of 26% in patients treated with immunosuppressive
infarcts, may provide a window for early intervention. agents as compared to 71% in patients not treated
with immunosuppression.118 Relapses can occur at the
Management of CAA-related initial site of inflammation and/or in additional sites.121
In the setting of relapse (or in patients having difficulty
inflammation
tolerating long-term steroids), steroid-sparing agents
A subset of patients with CAA develop episodes of such as mycophenolate and azathioprine can be
spontaneous inflammation. The most common present- considered.
ing symptoms of CAA-related inflammation (CAA-RI)
are headache, seizures, focal neurological deficits, and
subacute to acute cognitive decline.108–110 MRI features
Potential emerging treatments for CAA
typically include (1) asymmetric WMH which extend There is a great unmet need for the development of
subcortically, (2) hemorrhagic lesions including CMB novel therapeutic strategies aimed at halting or slowing
and cSS, and/or (3) postcontrast leptomeningeal down the progression of disease in CAA patients. In the
enhancement.108,109,111 CSF profiles are generally final section of this review, we briefly discuss recent
inflammatory, with a lymphocytic pleocytosis and ele- advancements in the development of novel candidates
vated protein, but these findings are not always pre- targeting the pathogenic cascade of events initiated by
sent.108,112 Interestingly, during acute episodes of amyloid-b. These approaches mainly revolve around
CAA-RI, anti-amyloid-b autoantibodies are found in amyloid-lowering strategies at different stages of dis-
the CSF, suggesting a spontaneous immune-mediated ease pathogenesis, including (antibody-mediated)
response to vascular amyloid-b in the brain.113 These removal of aggregated or soluble forms of amyloid-b,
imaging and clinical findings resemble amyloid-related reducing amyloid-b production, and nonpharmacologi-
imaging abnormalities (ARIA) in the context of anti- cal strategies to enhance amyloid-b clearance through
amyloid immunotherapy trials.114 perivascular drainage pathways (see Figure 4).
CAA-RI involves predominantly perivascular Antibody-mediated removal of amyloid-b from the
inflammation, whereas a related condition amyloid-b brain has long been the focus of attention in the AD
related angiitis (ABRA) involves both perivascu- field. Given the overlap in disease pathophysiology, a
lar and transmural inflammation and has many similar approach has been considered for patients with
similarities to CNS vasculitis.115–117 ABRA is an angio- CAA.122 Lessons learned from immunotherapy trials in
destructive process and, in addition to the above ima- AD patients, however, have important implications for
ging features, will commonly present with acute the translation to patients with CAA particularly with
microinfarcts. respect to safety considerations. Initial studies to
Patients with CAA-RI typically present with lower remove amyloid-b from the brains of patients with
rates of lobar ICH than patients with ‘‘noninflam- AD focused on active immunization.123 While this
matory’’ CAA at initial diagnosis.111 However, long- early attempt did demonstrate effective removal of
term strategies to reduce risk of future ICH (as amyloid-b plaques, 18/298 (6%) of treated patients
discussed above) should be utilized in these patients developed meningoencephalitis, which prompted trial
as well. discontinuation.124,125 These findings were consistent
The treatment of CAA-RI relies on intensive with ARIA126 and have been linked with the presence
immunosuppression, predominantly with steroids.118 of CAA on neuropathological examination.127 Since
A typical treatment course involves a high-dose intra- then, the focus has shifted to passive immunotherapy
venous steroid pulse followed by a prolonged steroid with anti-amyloid antibodies, yielding disappointing
taper (at least six months). Some providers use cyclo- results. A notable exception are recent reports from
phosphamide in addition to steroids, particularly in the phase 3 aducanumab trial suggesting slowing of
cases of ABRA given its similarities to CNS vascu- cognitive decline in AD patients treated with aducanu-
litis.115,118,119 Both CAA-RI and ABRA respond well mab compared to placebo controls.128–130 Yet, as in
to initial treatment in over 75% of patients.110,118–120 In previous passive immunotherapy trials, ARIA were
fact, if there is no clinical and radiographic improve- commonly observed, in as many as 47% of patients
ment to an initial steroid pulse, an alternate diagnosis receiving the highest dose.128–130 Indeed, ARIA occur
should be considered. more frequently in patients with APOE4 and cortical
Relapse rates remain largely unknown given the rela- CMBs on MRI, suggesting that coexisting CAA
tive rarity of the disease and inconsistent treatment increases the risk of ARIA in AD patients.126 Insights
protocols. A recent retrospective cohort study of 48 from neuropathological investigations suggest that
individuals with CAA-RI observed a recurrence rate removal of amyloid-b from severely affected vessels in

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364 International Journal of Stroke 16(4)

Figure 4. CAA pathogenesis and potential targets for intervention. Amyloid- (A) deposits and precursors are shown in blue;
potential interventions at each stage are shown in orange. A tangential cross-section of a diving arteriole is depicted; pial surface
to the right of the figure.
CAA: cerebral amyloid angiopathy; APP: amyloid precursor protein.

the context of advanced CAA may predispose these amyloid-b is another potential therapeutic option,
vessels to bleeding, which is in line with observations with the enzyme neprilysin demonstrating potential effi-
in patients with CAA-RI26. Therefore, immunotherapy cacy in mouse models.134
may not be the safest candidate approach for patients An alternative approach is targeting amyloid-b pro-
with CAA. To date, one anti-amyloid immunotherapy duction to halt the cascade of events leading up to vas-
trial has been performed in patients with CAA, which cular amyloid-b accumulation. Such a prevention
yielded negative results.131 Interestingly, although strategy may be particularly effective in presympto-
patients did not develop ARIA, vascular reactivity matic mutation carriers of hereditary forms of CAA.
(the primary outcome marker) was found to be reduced Inhibitors of the b-site amyloid cleaving enzyme have
in patients who received the antibody compared to pla- long been the leading option, but unfortunately recent
cebo controls, suggesting worsening of vascular func- trials in AD patients were halted due to cognitive wor-
tion in the short term. Since patients were only followed sening. Work is currently underway to develop anti-
for 90 days, it remains currently unknown what the sense oligonucleotides against the APP, awaiting
potential long-term effects are of immunotherapy in future results.135
patients with advanced CAA and whether immunother- Lastly, diminished clearance of amyloid-b through
apy directed at early disease stages might prove to be perivascular drainage pathways is thought to play an
more beneficial (and safer). important role in the pathophysiology of CAA.122
Therapies can also be targeted at soluble amyloid-b Low-frequency spontaneous oscillations of the arterial
removal. Tramiprosate is a low-molecular-weight agent vasculature, also known as vasomotion, are a potential
shown to bind to soluble amyloid-b and effectively driving force for clearance of waste products from the
decrease vascular amyloid-b in mouse models.132 This brain, including amyloid-b.136 These low-frequency
compound was tested in the first reported clinical trial arteriolar oscillations are particularly apparent during
of a candidate treatment in CAA patients and demon- slow-wave sleep and have been shown to be coupled to
strated safety and target engagement.133 It remains CSF flow dynamics in humans.137 Interestingly, enhan-
unclear whether this approach can effectively halt dis- cing vasomotion through sensory-evoked vascular
ease progression and prevent future ICH in patients reactivity was recently shown to increase clearance of
with CAA. Increasing proteolytic degradation of fluorescent tracers from the mouse brain.136 Further

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Kozberg et al. 365

research is needed to assess whether vasomotion can be 6. Knudsen KA, Rosand J, Karluk D and Greenberg SM.
enhanced in patients with CAA, either through nonin- Clinical diagnosis of cerebral amyloid angiopathy:
vasive sensory stimulation or promoting healthy sleep, validation of the Boston Criteria. Neurology 2001; 56:
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ficial siderosis in patients with cerebral amyloid angiopa-
Conclusions thy. Neurology 2010; 75: 1571.
8. Rosand J, Muzikansky A, Kumar A, et al. Spatial clus-
CAA is a small vessel disease which leads to lobar ICH, tering of hemorrhages in probable cerebral amyloid
cognitive impairment, and TFNEs in older adults. angiopathy. Ann Neurol 2005; 58: 459–462.
Increasing numbers of studies have provided bio- 9. Tsai H-H, Pasi M, Tsai L-K, et al. Superficial cerebellar
markers to diagnose CAA and predict the risk of microbleeds and cerebral amyloid angiopathy: a magnetic
first-time and recurrent lobar ICH. The availability of resonance imaging/positron emission tomography study.
non-anticoagulant stroke prevention strategies has Stroke 2020; 51: 202–208.
empowered physicians to circumvent the need for life- 10. Pasi M, Pongpitakmetha T, Charidimou A, et al.
long anticoagulant use even in patients with nonvalvu- Cerebellar microbleed distribution patterns and cerebral
lar atrial fibrillation. Despite these promising advances amyloid angiopathy: a magnetic resonance imaging and
in ischemic stroke and ICH prevention, there are cur- pathology-based study. Stroke 2019; 50: 1727–1733.
rently no effective disease-modifying treatments to slow 11. Charidimou A, Frosch MP, Al-Shahi Salman R, et al.
down or halt the progression of CAA. More work is Advancing diagnostic criteria for sporadic cerebral amyl-
oid angiopathy: study protocol for a multicenter MRI-
urgently needed to develop novel therapeutic strategies
pathology validation of Boston criteria v2.0. Int J Stroke
for CAA.
2019; 14: 956–971.
12. Charidimou A, Boulouis G, Haley K, et al. White matter
Declaration of conflicting interests hyperintensity patterns in cerebral amyloid angiopathy
The author(s) declared the following potential conflicts of and hypertensive arteriopathy. Neurology 2016; 86:
interest with respect to the research, authorship, and/or pub- 505–511.
lication of this article: Dr Gurol reports research grant sup- 13. Thanprasertsuk S, Martinez-Ramirez S, Pontes-Neto
port from AVID (a wholly owned subsidiary of Eli Lilly), OM, et al. Posterior white matter disease distribution as
Boston Scientific Corporation, and Pfizer. a predictor of amyloid angiopathy. Neurology 2014; 83:
794–800.
14. Gurol ME, Viswanathan A, Gidicsin C, et al. Cerebral
Funding amyloid angiopathy burden associated with leukoaraio-
The author(s) disclosed receipt of the following financial sup- sis: a positron emission tomography/magnetic resonance
port for the research, authorship and/or publication of this imaging study. Ann Neurol 2013; 73: 529–536.
article: Dr Gurol is funded by NIH (1R01NS114526-01A1, 15. Martı́-Fàbregas J, Medrano-Martorell S, Merino E, et al.
NS083711). Dr Van Veluw receives funding from the NIH MRI predicts intracranial hemorrhage in patients who
(R00 AG059893) and the Alzheimer’s Association (2019- receive long-term oral anticoagulation. Neurology 2019;
AARG-641299). 92: e2432–e2443.
16. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recur-
ORCID iD rent intracerebral hemorrhage in cerebral amyloid angio-
pathy. Neurology 2010; 75: 693–698.
Mariel G Kozberg https://orcid.org/0000-0002-9358-3262
17. Gurol ME, Irizarry MC, Smith EE, et al. Plasma beta-
amyloid and white matter lesions in AD, MCI, and cere-
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