7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral amyloid angiopathy : Steven M Greenberg, MD, PhD : Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 08, 2023. INTRODUCTION Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta-peptide deposits within small- to medium-sized blood vessels of the brain and leptomeninges. CAA is an important cause of lobar intracerebral hemorrhage in older adults [1,2]. In addition to intracerebral hemorrhage, CAA may present with transient neurological symptoms, an inflammatory encephalopathy, as a contributor to cognitive impairment, or with incidental microbleeds or hemosiderosis on magnetic resonance imaging (MRI). The clinical features, diagnosis, and management of CAA is discussed here. Alzheimer disease, which is also characterized by abnormal amyloid beta-peptide deposits in the brain, is discussed separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease" and "Clinical features and diagnosis of Alzheimer disease".) Other causes of intracerebral hemorrhage are discussed in detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Superficial siderosis".) EPIDEMIOLOGY The incidence of CAA is strongly age dependent. By autopsy, CAA can be identified by the replacement of at least some cerebral blood vessel walls with amyloid beta-peptide. In one series of 784 autopsy cases, the prevalence of CAA ranged from 2.3 percent for patients between the ages of 65 and 74, 8.0 percent for those age 75 to 84, and 12.1 percent in patients over the https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 1/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate age of 85 [3]. In an autopsy study of 1079 patients whose mean age at death was 89.7 years, the prevalence of moderate-to-severe CAA was 36 percent [4]. CAA-related symptoms are uncommon at ages younger than 60 years but can occur in middle-aged or younger individuals either sporadically or due to rare genetic or iatrogenic causes [5-7]. The prevalence of CAA among older patients with dementia is higher than those without dementia. In a systematic review of population-based studies, nearly 60 percent of patients with dementia showed CAA pathology compared with less than 40 percent among those without dementia [8]. Among patients with Alzheimer disease, more than 80 percent had pathologic evidence of CAA [9]. PATHOPHYSIOLOGY Pathogenesis The pathology of CAA involves deposition of amyloid beta-peptide within the cerebral vasculature. Vascular amyloid deposits in CAA are biochemically similar to the material comprising senile plaques in Alzheimer disease [1]. The primary constituent of each is amyloid beta-peptide, a 39 to 43 amino acid fragment of the amyloid precursor protein (APP). Development of CAA The factors other than aging that initiate and promote amyloid beta-peptide deposition leading to CAA are not well understood. Genetic factors can cause CAA in an autosomal dominant manner and can increase the risk for sporadic CAA (see 'Genetic susceptibilities' below). Rarely, deposition of amyloid beta-peptide may occur with a neurosurgical procedure and/or exposure to cadaveric central nervous system tissue, and clinical manifestations of iatrogenic CAA may subsequently develop decades later [7,10-12]. Development of hemorrhage Vascular rupture and bleeding in CAA appear to be a multistep process involving the deposition of amyloid beta-peptide in the vascular wall and subsequent vascular changes such as concentric splitting of the vascular wall. The relationship between CAA and hypertension is debated. Although many patients with CAA- related hemorrhage are normotensive [13-15], elevated blood pressure nonetheless appears to contribute to the risk of hemorrhage recurrence [16]. Despite shared pathologic features, the pathophysiology of CAA and Alzheimer disease appear distinct [17]. There is no clinical overlap between amyloid beta CAA and the non-central nervous system systemic amyloidoses, such as primary (amyloid AL) and secondary (amyloid AA) amyloidosis. Genetic susceptibilities CAA is sporadic in most patients. A small minority of patients have an identified monogenic cause [18,19]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 2/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Amyloid precursor protein variant Variant forms of the gene that encodes the APP are responsible for some cases of early-onset CAA that are inherited in an autosomal dominant pattern. While most of these variants are also associated with at least some of the neuropathologic features of Alzheimer disease, at least two APP variants (Glu693Gln and Leu705Val) have been reported to cause autosomal-dominant CAA with minimal parenchymal amyloid plaques or neurofibrillary tangles [18-20]. The Dutch-type Glu693Gln APP pathologic variant is associated with cerebral amyloid deposition with a more aggressive course than patients with sporadic CAA [21]. The causative amino acid substitutions in these hereditary forms of CAA may increase the toxic effects of amyloid beta-peptide on the vessel wall [22,23], decrease the peptide's susceptibility to proteolysis [24], or impair its clearance from the central nervous system [25]. Apolipoprotein E Patients carrying the apolipoprotein E (APOE) epsilon 2 (e2) or epsilon 4 (e4) alleles appear to be at greater risk for CAA-related hemorrhage than those with only the common APOE epsilon 3 (e3) allele [26-30]. One systematic review found evidence for a dose-dependent association between APOE e4 and sporadic CAA [31]. APOE e4 also promotes deposition of amyloid beta-peptide in Alzheimer disease [32] and following severe head injury [33]. APOE e2 or e4 alleles are present in approximately two-thirds of patients with CAA compared with only about one-quarter of older adult controls without evidence of CAA. These alleles are associated with an increased likelihood of having a CAA-related hemorrhage [26,27], earlier age of disease onset (mean age of first hemorrhage 75 versus 82 years in patients who are not carriers of APOE e2 or e4), and a greater risk of hemorrhage recurrence (two-year cumulative recurrence rate of 28 percent in carriers of e2 or e4 versus 10 percent for the APOE e3/e3 genotype) [34]. The APOE e2 and e4 alleles act via separate mechanisms. APOE e4 increases amyloid beta- peptide deposition [32]. APOE e2 causes amyloid-laden vessels to undergo changes such as concentric wall splitting and necrosis that predispose to rupture [27,35,36]. Patients with CAA who have both APOE e2 and e4 alleles appear to have a particularly early onset of disease and a high risk of early recurrence [27,34]. Carriers of the APOE e2 allele also have larger intracerebral hemorrhage (ICH) volumes, increased mortality, and worse functional outcomes compared with noncarriers, while these associations are not seen for carriers of the APOE e4 allele [37]. Data from a population-based, case-control study suggest that the risk of lobar ICH associated with APOE alleles may be modified by variation elsewhere in the APOE gene [38]. Notably, overall APOE haplotype (combination of multiple alleles on one chromosome) was https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 3/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate also independently associated with lobar ICH, suggesting the presence of regulatory variants that could influence the effect of APOE e2 or e4 on the risk of lobar ICH [39]. CR1 gene variant A case-control genetic association study that included a prospective followup of 178 ICH survivors found that a variant within the CR1 gene (rs6656401) influences the risk and recurrence of CAA-related ICH [40]. In the same report, this genetic variant was also associated with the severity of vascular amyloid deposition on pathologic examination of 544 autopsy studies from two community-based clinical-pathological studies of aging. ACUTE INTRACEREBRAL HEMORRHAGE The most common clinical manifestation of CAA is acute lobar intracerebral hemorrhage (ICH) ( image 1) [41]. The term "lobar" refers to location in the cortex and subcortical white matter of a hemispheric lobe of the brain; this contrasts with the deep locations, such as putamen, thalamus, and pons, which are characteristic of hypertensive hemorrhage. The lobar location of the hemorrhages reflects the underlying distribution of the vascular amyloid deposits, which favor cortical vessels and largely spare white matter, deep gray matter, and the brainstem. Involvement of the blood vessels in the cerebellum and leptomeninges can also give rise to the less common clinical presentations of cerebellar or subarachnoid/subdural hemorrhage. Clinical features The clinical presentation of CAA-related hemorrhage varies with the lesion size and brain region impacted. Lobar hemorrhages can cause hemiparesis from involvement of pyramidal motor neurons and tracts. A large lobar hemorrhage may cause depressed consciousness from direct involvement or secondary mass effect on reticular activating system networks. In comparison, smaller lobar or cerebellar hemorrhages may cause more limited focal deficits related to the underlying brain structure impacted. The clinical presentation of intracerebral hemorrhage is described in more detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'.) In rare cases, small cortical hemorrhages may irritate meningeal nociceptors to cause isolated headache. They may also infrequently be asymptomatic, found on imaging pursued for other indications [42,43]. (See 'Microbleeds' below.) Imaging features Imaging findings in acute hemorrhage can vary in size and location, but specific imaging patterns and associated findings are common in CAA-related hemorrhage. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 4/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Lobar regions CAA-related lobar hemorrhages preferentially arise in posterior lobar brain regions. Analysis of the spatial distribution of 321 intracerebral hemorrhages in 59 patients with CAA revealed that hemorrhages were significantly more likely to occur in the temporal and occipital than the frontal and parietal lobes (ratio of actual to expected hemorrhages 1.37, 1.43, 0.58, and 1.0, respectively) [44]. The explanation for the posterior brain clustering of CAA hemorrhages is undetermined, but it may be related to as-yet unknown characteristics of posterior circulation vessels that influence amyloid beta- peptide elimination or to increased vulnerability of these brain regions to minor trauma [44,45]. CAA-related lobar hemorrhages often extend beyond the brain tissue into the subarachnoid and subdural spaces and, less frequently, may rupture into ventricles [46,47]. Extension of the hemorrhage into the subarachnoid space and the presence of elongated "finger-like" projections appear to be characteristic features of CAA-related lobar hemorrhages that may assist in diagnosis [48]. Cerebellum The cerebellum may contain variable amounts of vascular amyloid in individuals with CAA. The cerebellum is also a site of CAA-related hemorrhage, with predilection for the cerebellar cortex and vermis rather than the cerebellar nuclei and deep white matter [49-51]. Convexity subarachnoid hemorrhage Subarachnoid hemorrhage can also occur within the convexity of the cerebral hemispheres (cSAH) in patients with CAA due to amyloid deposition at the cortical surface. cSAH may occur along with acute ICH, located either adjacent to or remote from the ICH. In addition, patients may present with isolated cSAH and seizures or other focal symptoms due to dysfunction of underlying cortex. (See 'Transient focal neurologic episodes' below.) Associated chronic hemorrhagic findings T2*-weighted gradient-echo or susceptibility- weighted brain MRI sequences obtained in patients with an acute lobar hemorrhage may also show chronic cerebral microbleeds (CMBs) and/or cortical superficial siderosis (cSS). CMBs are typically asymptomatic lesions and are found in the juxtacortical and cortical lobar regions with a predilection for temporal and occipital lobes. cSS represents cSAH in the chronic phase. The presence of cSS likely reflects severe CAA in the leptomeningeal vessels [52]. (See 'Incidental chronic imaging features' below.) Differential diagnosis Differentiation of nontraumatic lobar ICH related to CAA from other causes depends upon the clinical and radiographic appearance. Other causes include: Lobar extension of a hypertensive hemorrhage (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis") https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 5/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Hemorrhagic transformation of an ischemic stroke (see "Neuroimaging of acute stroke") Hemorrhagic venous infarction from cerebral venous thrombosis (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis") Hemorrhage of arteriovenous malformation (AVM) (see "Vascular malformations of the central nervous system") Hemorrhagic tumor (see "Overview of the clinical features and diagnosis of brain tumors in adults") Clinical features that favor diagnoses other than CAA include younger age (many hemorrhages attributed to AVM occur before age 35 to 40 [53]), prodromal symptoms (progressive headache may suggest cerebral venous thrombosis), or patient-level risk factors (eg, active metastatic cancer may suggest hemorrhagic tumor, high thromboembolic risk in a patient with atrial fibrillation not treated with anticoagulation may suggest hemorrhagic transformation of ischemic infarct). Imaging features may also help identify diagnoses other than CAA in patients with lobar hemorrhage ( table 1). Brain MRI can help identify evidence of acute ischemia or enhancement associated with tumors. Corresponding computed tomographic (CT) angiography or MR angiographic studies can help identify the presence of an associated arterial or venous occlusion or AVM. This differential diagnosis and the evaluation to determine etiology is discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Diagnostic approach The presence of CAA should be suspected clinically in patients age 50 years or older with or without a clinical manifestation of CAA who have characteristic acute or chronic hemorrhagic findings and/or white matter features on brain MRI in the absence of an alternative cause. Definite CAA is only diagnosed postmortem. A full pathologic examination of the brain showing amyloid deposition with vasculopathy, evidence of brain hemorrhage, and absence of other diagnostic lesions confirms CAA [54]. During life, the diagnosis of probable CAA can be made with clinical evaluation and MRI of the brain. Examination of a sample of brain tissue obtained by brain biopsy further supports the diagnosis but is infrequently performed. For all patients, we use hemorrhagic imaging features on T2*-weighted MRI sequences and additional white matter markers to support the diagnosis of probable CAA. (See 'Imaging-based diagnosis' below.) For select patients in whom imaging features are equivocal or the cause of a clinical manifestation is uncertain, we use additional adjunctive testing. (See 'Adjunctive diagnostic https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 6/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate testing for some patients' below.) Imaging-based diagnosis All patients with suspected CAA should undergo brain MRI, including T2*-weighted sequences, which accentuate the signal dropout caused by iron- containing deposits left by old hemorrhages ( image 2) [55]. Chronic lobar hemorrhages, cSS, and CMBs appear dark on such sequences. Inclusion of white matter features, including enlarged perivascular spaces in the centrum semiovale and multispot pattern subcortical hyperintensities on T2-weighted sequences in the MRI criteria for probable CAA, increased the diagnostic sensitivity in version 2.0 of the Boston criteria [56]. (See 'The Boston criteria for CAA' below.) To support the diagnosis of probable CAA with MRI, we look for the presence of either of the following findings not attributable to another cause [56] (see 'Differential diagnosis' above): Two or more hemorrhagic lesions (ICH, CMB, cSAH, or cSS foci in any combination) in the lobar brain regions, entirely sparing regions typical of hypertensive hemorrhage (basal ganglia, thalamus, or pons) ( image 3 and image 4 and image 5 and image 6) [57-59] One lobar hemorrhagic lesion and one white matter lesion, defined as either severe (ie, >20 per hemisphere) dilated perivascular spaces in the centrum semiovale or multiple (ie, >10) ovoid-shaped white matter hyperintensities on T2-weighted imaging in bilateral subcortical regions A single hemorrhagic lesion (eg, lobar hemorrhage, cSAH, cSS focus, or lobar CMB) or isolated white matter features create less diagnostic certainty but can be suggestive of the diagnosis (classified as "possible CAA"). The Boston criteria for CAA The Boston criteria provide a framework for various levels of diagnostic certainty in patients with intracerebral hemorrhage with or without pathologic tissue analysis ( table 2). Initial versions of the criteria included clinical, radiologic, and pathologic data to support the diagnosis of CAA [54,58]. The Boston criteria version 2.0 for sporadic CAA update the modified Boston criteria to include expanded imaging findings (hemorrhagic and white matter features) with validation data across multiple time epochs, medical centers, and both hemorrhagic and nonhemorrhagic clinical presentations ( table 2). (See 'Transient focal neurologic episodes' below and 'Cerebral amyloid angiopathy-related inflammation' below and 'Cognitive impairment' below and 'Incidental chronic imaging features' below.) https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 7/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate In a retrospective, multicenter review of 341 patients who presented with clinical features consistent with CAA and had both MRI and brain tissue available for analysis, the inclusion of additional imaging findings to the Boston criteria version 2.0 produced a higher diagnostic accuracy for probable CAA than the previous modified Boston criteria (84.8 versus 79.8 percent) [56]. The specificity was 95 percent for both sets of criteria. Adjunctive diagnostic testing for some patients While not commonly performed for evaluation and diagnosis of most patients with typical symptoms and imaging findings, additional testing to support the diagnosis of probable CAA may be performed in circumstances when the above criteria are not met. Follow up brain MRI Follow-up imaging, typically three to six months after the acute event, may show resolution of the acute hemorrhage and help exclude underlying alternative causes. Interval development of subclinical neuroimaging findings, namely strictly lobar CMB or cSS, may provide further support for the diagnosis of CAA. (See 'Microbleeds' below and 'Cortical superficial siderosis' below.) Brain biopsy Brain biopsies are done rarely for the diagnosis of CAA. However, brain tissue may be obtained during surgical evacuation of select acute lobar hemorrhages. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Evacuated hematoma specimens and accompanying leptomeningeal or parenchymal tissue from older adult patients should routinely be examined with Congo red stain or beta-amyloid immunostain for CAA. Based upon data from a postmortem model, nearly all blocks of tissue from brains with CAA-related hemorrhage demonstrate some degree of CAA [3], often with evidence of advanced disease such as complete amyloid replacement of the smooth muscle layer or the appearance of vessel breakdown [60-62]. Signs of advanced disease are rare in single-tissue specimens from asymptomatic older adult brains; thus, their presence points toward a degree of CAA severe enough to cause hemorrhage. Cerebrospinal fluid analysis Up to a 50 percent reduction in levels of cerebrospinal fluid (CSF) amyloid beta 42 and beta 40 protein have been found in patients with CAA [63]. In combination with the finding of mildly increased total tau levels, CSF analysis distinguished patients with CAA from normal controls with a high degree of accuracy. Similar results were obtained in an independent study [64]. We obtain CSF when the imaging diagnosis is uncertain and when confirming the diagnosis may affect clinical decisions, such as whether to give or withhold antithrombotic treatment. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 8/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Positron emission tomography Positron emission tomography (PET) using 11C- Pittsburgh compound B (PIB), a ligand that binds to beta-amyloid, demonstrates increased uptake in patients with CAA-related hemorrhage compared with normal controls [65,66]. Another PET study of the amyloid ligand florbetapir showed elevated retention in patients with CAA but not hypertension-related intracerebral hemorrhages [67]. Compared with patients with Alzheimer disease, median binding of PIB is lower in CAA and may differ in its distribution. Current and future hemorrhagic lesions in patients with CAA appear to occur preferentially in local regions of concentrated amyloid detected by PIB [68,69]. PET imaging is typically used in research settings. Genetic testing There is no clearly defined clinical role for genetic testing in sporadic CAA. In particular, apolipoprotein E (APOE) genotype is neither sensitive nor specific for the diagnosis of CAA, as the epsilon 2 (e2) and epsilon 4 (e4) alleles are present in only a subset of patients [26,27]. Acute management Acute CAA-related hemorrhage is treated like other acute nontraumatic intracerebral hemorrhages. Of note, surgical biopsy or hematoma resection appears to carry little or no additional risk in CAA compared with other types of ICH and can be performed when indicated [70]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Evaluation and management of elevated intracranial pressure in adults".) Prevention of recurrent hemorrhage Survivors of lobar hemorrhage and patients with other clinical manifestations of CAA are at risk for future hemorrhagic complications (see 'Prognosis' below). This risk should be factored into decision-making when assessing the risks and benefits of other medications for patients with CAA. Managing anticoagulant and antiplatelet medications Because of the risk of spontaneous lobar hemorrhage in patients with CAA, we weigh the risks and benefits of using of anticoagulant and antiplatelet agents at an individual-level, in agreement with guidelines from the American Heart Association [71]. The major determinants of ICH risk in CAA patients are: History of prior ICH Presence of particular CAA-associated imaging features such as disseminated cSS (see 'Incidental chronic imaging features' below) Class of agent used (highest ICH risk with warfarin, then the direct oral anticoagulants [DOACs; also called non-vitamin K antagonist oral anticoagulants, or NOACs], then antiplatelet agents, and lowest with no agent) https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 9/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Duration of treatment Warfarin in particular increases both the frequency (approximately 7- to 10-fold) and severity (approximately 60 percent mortality) of cerebral hemorrhage [72-74]. The benefit of anticoagulants or antiplatelets is determined by the strength of the clinical indication and the availability of alternative treatments. In select patients with compelling indications for anticoagulation due to high risk of thromboembolism and absence of alternatives, anticoagulation may be used after discussion with the patient regarding risks and benefits. We reserve anticoagulation in CAA patients for those at high-risk for thromboembolic complications related to specific indications. These may include: Cancer-related thrombophilia with high risk of or prior venous thromboembolism (see "Risk and prevention of venous thromboembolism in adults with cancer") Hypercoagulable (acquired and inherited) conditions (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors") Mechanical prosthetic heart valve replacement (see "Antithrombotic therapy for mechanical heart valves") Other temporary high-risk indications for anticoagulation (see "Atrial fibrillation: Left atrial appendage occlusion", section on 'Postprocedure management' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement") Because ICH risk is a function of antithrombotic treatment duration as well as type, we recommend in these situations the shortest and least intense treatment course that is still compatible with effective thrombosis prevention. In other patients, we pursue alternatives to anticoagulation, based on indication. Atherosclerotic disease We reserve aspirin for selected patients with CAA who have clear indications for antiplatelet therapy. Aspirin appears to increase the risk of hemorrhage but to a lesser extent than anticoagulants [75]. However, some data in patients with established atherosclerotic risk factors suggest antiplatelet use may not increase the risk of ICH recurrence. In an open-label trial of 537 patients with a history of occlusive vascular disease who developed ICH, patients were assigned to restart or avoid antiplatelet therapy at a median of 76 days following ICH [76]. At a median two-year follow- https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 10/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate up, there was a trend toward less ICH recurrence in those assigned to restart antiplatelet therapy (4 versus 9 percent; hazard ratio 0.51, 95% CI 0.25-1.03). Atrial fibrillation The management of atrial fibrillation in patients with CAA-related ICH is uncertain. Left atrial appendage closure is a reasonable treatment option for individuals with CAA who are at high risk for atrial fibrillation-related cardioembolic stroke [77]. (See "Atrial fibrillation: Left atrial appendage occlusion" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Of note, some retrospective studies have reported good outcomes for patients with atrial fibrillation who were restarted on anticoagulation with warfarin after recovery from an anticoagulant-related intracerebral hemorrhage [78]. Conclusions from these retrospective analyses are limited by the likelihood of indication bias regarding which patients were or were not re-anticoagulated, but they offer a rationale for randomized trials to address this question [79]. The DOACs appear at least as effective as warfarin for prevention of ischemic strokes in patients with atrial fibrillation and confer lower risks for ICH. While they have not been studied for this indication, some experts use these agents (dabigatran, apixaban, edoxaban, rivaroxaban) for patients with atrial fibrillation and CAA who are at high risk for both ischemic and hemorrhagic stroke. Other potential alternatives to anticoagulation in high-risk patients with atrial fibrillation are discussed separately. Some nonsteroidal anti-inflammatory medications have weak antithrombotic properties. We prefer the nonacetylated salicylates (eg, magnesium salicylate) drugs over other nonsteroidal anti-inflammatory drugs as they do not appear to affect platelet function. Thrombolytic therapy We do not routinely offer thrombolytic therapy for indications such as acute ischemic stroke, myocardial infarction, or pulmonary embolism in patients with a history of CAA-related ICH. Intravenous thrombolysis for ischemic stroke is contraindicated in patients with a history of ICH [80]. Endovascular mechanical thrombectomy may be an option for patients with a history of lobar ICH. Because patients with CAA are at risk of hemorrhagic complications from thrombolytic therapy, the risks and benefits of acute therapies should be discussed with patients or their proxies whenever possible. A large trial evaluating the use of tissue-type plasminogen activator for acute myocardial infarction identified severe CAA at postmortem examination in two of five patients with intracerebral hemorrhagic complications [81]. Additionally, in one analysis of acute ischemic https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 11/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate stroke, patients reported an association between number of cortical microbleeds and an elevated risk of hemorrhagic complications after systemic thrombolysis [82]. However, the specific treatment benefits of thrombolytic therapy in such patients were not assessed. Blood pressure control Although the vascular pathology in CAA does not appear primarily driven by hypertension, control of blood pressure within normal limits is nonetheless advisable. We use intensive blood pressure goals, as tolerated ( table 3). (See "Antihypertensive therapy for secondary stroke prevention", section on 'Patients with intracerebral hemorrhage'.) Support for lowering of blood pressure in patients diagnosed with CAA came from a secondary analysis of data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial [15]. At a median follow up of 3.9 years, those assigned to active treatment (perindopril plus indapamide) had a 77 percent reduction (3 versus 13 events) of probable CAA-related ICH. These results are consistent with observational data showing reduced risk of ICH recurrence among ICH survivors with lower ambulatory blood pressures [16]. Managing statin use We do not withhold statin agents for most CAA patients when otherwise indicated. While a number of studies have found an inverse relationship between total and low-density lipoprotein cholesterol and the risk of ICH [83,84], treatment with statins does not appear to increase the risk of primary ICH or to negatively impact prognosis according to a number of studies and meta-analyses [85-88]. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of statins'.) Prognosis Lobar hemorrhage in general is associated with features that are both favorable (their superficial location and tendency to spare the ventricles) and unfavorable to outcome (older age and somewhat larger hematoma size) [89-91]. Mortality Overall mortality in acute lobar hemorrhage due to CAA is in the range of 10 to 30 percent [90,91], with the best prognosis for patients with smaller hematomas (<50 mL) and higher level of consciousness on admission (Glasgow coma scale 8). Recurrence CAA carries a substantially higher risk of hemorrhage recurrence than for hypertensive hemorrhage. In two case series of ICH survivors, recurrence rates were 21 percent at 2 years and 24 percent at a median 2.6 years, respectively [34,92]. Another report of 104 survivors of primary lobar ICH found that patients with history of ICH prior to the index event were at approximately six times the risk as those without a previous history. The risk for recurrent ICH was even higher in those who had more than one prior ICH [75]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 12/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Recurrent hemorrhages have a tendency to arise in areas of prior hemorrhage [44]. Areas of high amyloid deposition on amyloid imaging appear to predict sites for future hemorrhage [68]. Recurrent ICH is more likely with increasing number of CMBs and disseminated cSS (see 'Incidental chronic imaging features' below). In a study of 94 consecutive survivors of primary lobar hemorrhage, the three-year cumulative risk of recurrent hemorrhage for patients with one, two, three to five, and six or greater CMBs on the baseline gradient-echo MRI was 14, 17, 38, and 51 percent, respectively (hazard ratio 1.7, 95% CI 1.2-2.4 for each increase in category) [93]. In a study of 118 patients diagnosed with CAA (104 with a symptomatic lobar ICH), the cumulative risk of new ICH at four years was 74 percent for the 27 individuals with disseminated cSS (defined as involving more than three cortical sulci) versus only 25 percent for the 77 without siderosis at baseline [94]. Similarly, the presence of cSAH in patients with CAA is associated with an increased risk of recurrent ICH [95]. Carriers of the e2 or e4 APOE alleles are also at increased risk compared with the more common APOE e3/e3 genotype [34]. (See 'Genetic susceptibilities' above.) Incident dementia The association of subsequent dementia in patients with lobar ICH may reflect an elevated rate of ICH recurrence and/or the relationship of CAA with cognitive impairment. In a study of 255 patients with lobar and nonlobar ICH followed for five years, patients with lobar ICH had higher rates of dementia (36 versus 21 percent) and higher rates of disability (60 versus 31 percent) compared with those with nonlobar ICH [96]. This finding is consistent with a prior study of 218 ICH survivors with one-year incidence of new- onset dementia of 23.4 percent for lobar ICH versus 9.2 percent for nonlobar ICH [97]. In another cohort of 97 patients with lobar ICH, the rate of dementia after median 2.5-year follow-up was 26 percent [98]. (See 'Cognitive impairment' below.) INCIDENTAL CHRONIC IMAGING FEATURES Patients with CAA are frequently asymptomatic unless they develop a specific clinical episode. Evidence suggestive of CAA may be identified in asymptomatic patients who undergo brain MRI for unrelated symptoms (eg, chronic headaches). Microbleeds Chronic evidence of tiny asymptomatic bleeding within the brain can be detected on brain MRI and may reflect CAA. These microbleeds (or microhemorrhages) appear as 2 to 10 mm focal areas of hemosiderin deposition on gradient echo or other T2*-weighted https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 13/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate sequences ( image 7). In population-based studies, cerebral microbleeds are detected in 5 to 23 percent of older individuals [99-102]. Microbleeds can arise from small-vessel disease (CAA or hypertensive vasculopathy) and may represent a milder and somewhat distinct manifestation from overt (macro-)hemorrhage. Analysis of CAA patients in a neuroimaging study who underwent autopsy showed those with a large number of microbleeds had thicker-walled vessels due to beta-amyloid deposition compared with patients with a lower proportion or absence of microbleeds [103]. Microbleeds are also more prevalent among those using antiplatelet agents than nonusers [104,105]. Evaluation and differential diagnosis Focal areas of hemosiderin deposition on MRI should be reviewed with some care since lesions and structures other than hemorrhage can produce signal dropout. These include mineralization (particularly of the basal ganglia), flow-void from a cortical vessel, or adjacent air in the nasal sinuses. When establishing the presence of at least two hemorrhages, lesions that do not clearly represent independent hemorrhagic foci (for example, small blood deposits close to a larger hematoma) should not be counted. Cerebral microbleeds are not specific for CAA as they can be seen in multiple conditions. Such conditions may include: Hypertension [106,107] Cerebral cavernous malformations [108] Coagulopathy [109,110] Thrombocytopenia [111,112] Anticoagulant medications [113] Central nervous system vasculitis [114] Infective endocarditis [115] End-stage kidney failure [116] Traumatic brain injury [117] Prior cardiac surgery [118] While microbleeds in general are not specific to CAA, cortical microbleeds (CMBs; (ie, those restricted to the cerebral cortex or superficial cerebellar regions [cerebellar cortex and vermis]), suggest CAA [106,107]. In contrast, microbleeds that involve the basal ganglia, thalamus, or pons are believed to result from hypertensive microangiopathy. The association between lobar microbleeds and APOE e4 in the Rotterdam and other studies support the hypothesis that these more superficial lesions often originate from CAA [30,101,102,119,120]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 14/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Management and prognosis For patients with acute ischemic stroke and a known history of CAA with CMBs only (ie, without a history of lobar hemorrhage or cortical superficial siderosis), we do not withhold systemic intravenous thrombolytic therapy if they otherwise meet eligibility criteria ( table 4), in agreement with guideline statements from the American Heart Association [80]. Over the long-term, the risk of incident hemorrhage in patients with multiple CMBs is nonetheless substantial [121]. Thus, other measures for primary prevention are similar as for patients with an ICH presentation. (See 'Prevention of recurrent hemorrhage' above.) CMBs are associated with an elevated risk of death. One study found that an incidental finding of multiple CMBs in an older adult was associated with a sevenfold risk of stroke- related death compared to individuals without CMBs [122]. Cortical superficial siderosis Evidence of chronic bleeding at the surface of the brain seen on imaging as foci of cSS may be seen in patients with CAA. They likely reflect the chronic form of acute convexity subarachnoid hemorrhage ( image 6) [54,123,124]. cSS is typical at the convexities of the cerebral hemispheres in patients with CAA but may also be found along the cerebellar folia [51]. cSS is frequently found in CAA patients with microbleeds and appears to signal higher risk for future ICH, particularly disseminated cSS. (See 'Microbleeds' above and 'Prognosis' above.) cSS typically is an asymptomatic imaging finding but is also detected in many CAA patients who present with transient neurologic symptoms [124,125]. (See 'Transient focal neurologic episodes' below.) Evaluation and differential diagnosis cSS is common in patients with CAA (40 to 60 percent) but is unusual in patients with ICH of other cause (0 to 4 percent) [54,125].