Cortical superficial siderosis, APOE genotype, and hemorrhage risk in cerebral amyloid angiopathy

Prachi Mehndiratta, MD The deposition of Ab amyloid in the walls of cortical Tadeusz A. Mendel, MD, and leptomeningeal blood vessels characterizes cerePhD bral amyloid angiopathy (CAA).1 Clinical presentation of CAA ranges from transient neurologic events to cognitive decline to symptomatic intracerebral Correspondence to hemorrhage (ICH). Radiologically, CAA can present Dr. Mehndiratta: with structural brain lesions (e.g., microbleeds, white [email protected] matter hyperintensities, or microinfarcts). Imaging evaluation can demonstrate alterations of vascular Neurology® 2015;84:1190–1191 physiology or direct visualization of the deposits with amyloid radioligands.2 More recently, cortical superficial siderosis (CSS) has emerged as an imaging marker of CAA pathophysiology, with a characteristic predilection for the cerebral convexities, seen as a linear residue of blood products in the superficial layers of the cerebral cortex or in the subarachnoid spaces on T2* or gradientecho MRI.3 An analysis of 1,062 patients (mean age 69.6 years) from the population-based Rotterdam Scan Study found that 0.7% of individuals with cerebral microbleeds in lobar locations also had CSS.4 In another cohort, those with memory difficulties had higher prevalence of CSS as compared to those with no cognitive impairment or dementia.5 Due to the considerable overlap between CAA and cognitive impairment, several investigators have questioned the development of CAA in the setting of an ongoing neurodegenerative process. Many researchers now propose a common therapeutic approach for patients with Alzheimer dementia and CAA due to common mechanisms of Ab accumulation in both diseases.6 Alzheimer disease and CAA share putative genetic factors, such as the APOE genotype in both diseases.7,8 The e variants within the APOE gene are an important genetic risk factor for lobar spontaneous ICH (sICH).7,8 More recently, Shoamanesh et al.9 described a close relationship between the presence of CSS and the APOE e2 genotype. The presence of one or more copies of the e4 allele is a potent risk factor for the occurrence of Alzheimer dementia. The role of APOE genotype in the pathophysiology of CAA and cognitive impairment or CAA and ICH remain unclear.

In this issue of Neurology®, Charidimou et al.10 report the results from their study evaluating the relationship between CAA and the APOE genotype in patients with pathologically proven CAA with and without ICH. Their final cohort comprised 105 patients with pathologically proven CAA: 54 with spontaneous ICH and 51 without. The burden of small vessel disease, lobar microbleeds, and enlarged perivascular spaces in the 2 groups were similar. The patients with CAA with ICH more commonly had APOE e2 (48.7% vs 21.4%), although this did not reach significance, perhaps due to the small sample size (p 5 0.075). Those who developed ICH had a higher prevalence of CSS (51.9% vs 19.6%, p 5 0.0001). By contrast, patients with nonhemorrhagic CAA were likely to have a greater prevalence of the APOE e4 genotype. These intriguing results raise several possibilities. The greater prevalence of disseminated CSS in patients with hemorrhagic CAA is consistent with previous results and fits the theory that CSS occurs due to leaking of blood from involved cortical and leptomeningeal vessels.1 The association of distinct APOE signatures with the 2 groups lends credence to a genetic basis for different phenotypic presentations of CAA. Patients who develop hemorrhagic CAA may prove distinct from those with nonhemorrhagic CAA, with different APOE genotypes invoking disparate pathways for disease occurrence. The study has several important clinical implications for diagnosis and therapeutic treatment of CAA. It is plausible that early genetic testing of patients with CAA may help predict risk for cognitive impairment or ICH. Additionally, practitioners could tailor antiplatelet and anticoagulant therapy depending on the risk for ICH and consider novel immunomodulatory therapy for those with cognitive impairment or with an APOE e4 genotype. The strengths of the study are the relatively large sample size of patients with pathologically proven CAA and a systematic approach to characterization of imaging results. However, potential biases in study design must be considered when interpreting these

See page 1206 From the Department of Neurology (P.M.), University of Virginia, Charlottesville; and the Institute of Psychiatry and Neurology (T.A.M.), Second Department of Neurology, Warsaw, Poland. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1190

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results. The authors concede the possibility of selection bias due to lack of genetic information on all patients. A sampling bias could have been introduced due to pathologic evaluation of the more clinically advanced patients. The authors acknowledge that the differences in clinical presentation may arise from the longer duration of disease in patients with nonhemorrhagic CAA or the e4 genotype. Further investigations into mechanisms that drive these differences are warranted and need to account for these issues. Practitioners should direct their attention towards appropriately diagnosing CAA and identifying imaging markers that increase risk for hemorrhage. One potential avenue would be to consider formal neuropsychological testing in patients with nonhemorrhagic CAA as well as APOE genotype testing in those with signs of cognitive impairment. The community awaits validation of these results in even larger CAA cohorts.








STUDY FUNDING No targeted funding reported.

9. DISCLOSURE The authors report no disclosures. Go to Neurology.org for full disclosures.

REFERENCES 1. Linn J, Wollenweber FA, Lummel N, et al. Superficial siderosis is a warning sign for future intracranial hemorrhage. J Neurol 2013;260:176–181.


Greenberg SM, Salman R, Biessels GJ, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014;13:419–428. Charidimou A, Peeters AP, Jager R, et al. Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy. Neurology 2013;81: 1666–1673. Vernooij MW, Ikram MA, Hofman A, et al. Superficial siderosis in the general population. Neurology 2013;73: 202–205. Zonneveld HI, Goos JD, Wattjes MP, et al. Prevalence of cortical superficial siderosis in a memory clinic population. Neurology 2014;82:698–704. Werring DJ, Sperling R. Inflammatory cerebral amyloid angiopathy and amyloid modifying therapies: variations on the same ARIA? Ann Neurol 2013;73:439–441. Greenberg SM, Briggs ME, Hyman BT, et al. Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke 1996;27:1333–1337. Rannikmae K, Samarasekera N, Martinez-Gonzalez NA, et al. Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2013;84:901–908. Shoamanesh A, Martinez-Ramirez S, Oliveira-Filho J, et al. Interrelationship of superficial siderosis and microbleeds in cerebral amyloid angiopathy. Neurology 2014; 83:1838–1843. Charidimou A, Martinez-Ramirez S, Shoamanesh A, et al. Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes. Neurology 2015;84:1206–1212.

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March 24, 2015


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Cortical superficial siderosis, APOE genotype, and hemorrhage risk in cerebral amyloid angiopathy Prachi Mehndiratta and Tadeusz A. Mendel Neurology 2015;84;1190-1191 Published Online before print February 25, 2015 DOI 10.1212/WNL.0000000000001406 This information is current as of February 25, 2015 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/84/12/1190.full.html


This article cites 10 articles, 5 of which you can access for free at: http://www.neurology.org/content/84/12/1190.full.html##ref-list-1

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This article, along with others on similar topics, appears in the following collection(s): All Cerebrovascular disease/Stroke http://www.neurology.org//cgi/collection/all_cerebrovascular_disease_ stroke Intracerebral hemorrhage http://www.neurology.org//cgi/collection/intracerebral_hemorrhage MRI http://www.neurology.org//cgi/collection/mri

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Cortical superficial siderosis, APOE genotype, and hemorrhage risk in cerebral amyloid angiopathy.

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