Brief Report

Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease

Frank Arne Wollenweber, Ebru Baykara, Marialuisa Zedde, Benno Gesierich, Melanie Achmüller, Eric Jouvent, Anand Viswanathan, Stefan Ropele, Hugues Chabriat, Reinhold Schmidt, Christian Opherk, Martin Dichgans, Jennifer Linn, Marco Duering
https://doi.org/10.1161/STROKEAHA.117.016833
Stroke. 2017;48:1404-1407
Originally published March 31, 2017

Abstract

Background and Purpose—Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features.

Methods—Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2*-weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space.

Results—cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients.

Conclusions—cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA.

Introduction

Cortical superficial siderosis (cSS) has recently been recognized as an imaging marker with high prognostic relevance in patients with cerebral amyloid angiopathy (CAA).1 The presence of cSS is associated with intracranial hemorrhage,2,3 transient focal neurological episodes, and cognitive decline.4 However, little is known about the specificity of this marker. In particular, it remains unknown whether nonamyloid associated small vessel disease (SVD) may also present with cSS.

Patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) develop SVD at young age. Hence, this hereditary disease serves as a model for pure and severe nonamyloid-associated SVD.

The objectives of the current study are (1) to determine whether cSS is also present in SVD types other than CAA and (2) to compare the patterns of SVD tissue lesions in CAA with cSS with those observed in other types of SVD. Therefore, we first determine the prevalence of cSS in patients with CADASIL and a population-based sample. Second, we systematically compare SVD imaging features, that is, cerebral microbleeds (CMB) and white matter hyperintensities (WMH) between CAA with cSS, CADASIL, and population-based controls.

Methods

Detailed Methods are provided in the online-only Data Supplement.

Subjects

Subjects were drawn from 3 prospective studies: 364 patients with CADASIL from the Paris-Munich study,5 372 population-based, healthy subjects from the ASPFS (Austrian Stroke Prevention Family Study),6 and 100 subjects with cSS and possible/probable CAA from the SuSPect-CAA study (NCT01856699).

Magnetic Resonance Imaging

CMB7 and cSS were identified on T2*-weighted gradient echo images by 2 trained raters (F.A.W. and E.B.). WMH of presumed vascular origin7 were segmented on fluid-attenauted inversion recovery images. Segmented lesion masks were registered to a common standard space.

Statistical Analysis

Analyses were performed in R (version 3.2.2). Differences in characteristics and SVD lesion load between samples were analyzed using the Kruskal–Wallis test with Dunn post hoc tests (for continuous variables, R package PMCMR) or χ2 tests with post hoc tests (for categorical variables, R package fifer). To account for multiple comparisons, all P values were Bonferroni corrected. The similarity of the WMH distribution between samples was evaluated by a colocalization analysis using linear correlation on voxel-wise lesion frequencies.

Results

Demographic, clinical, and magnetic resonance imaging characteristics of the study samples, and the results of group comparisons are presented in the Table.

View this table:
Table.

Characteristics of the Study Samples

Although patients with CADASIL showed severe SVD imaging features (Table; Figure 1A), cSS was absent in the entire sample. Only 2 subjects from the population-based sample had cSS. One of them also had a high number of lobar CMB (n=28), suggesting the presence of CAA.

Figure 1.
Figure 1.

Frequency of cerebral microbleeds (CMB) and white matter hyperintensities (WMH). A, Box plots for CMB counts and normalized WMH volumes in each sample. B, Regional CMB counts (lobar, deep, and infratentorial) for patients with at least 1 CMB. Note the log scale for global and regional CMB count.

We next compared the spatial distribution of CMB and WMH between samples (Figures 1B and 2). CMB in CADASIL were predominantly deep and infratentorial. However, among CADASIL patients with CMB, lobar areas were affected in nearly every second patient and even strictly lobar involvement occurred in 1 of 10 (Table). For WMH, the colocalization analysis showed that lesion distribution was most similar between CAA with cSS and CADASIL (R2=0.68; P<10–15), whereas colocalization was less strong between CAA with cSS and population-based controls (R2=0.52; P<10–15) as well as CADASIL and population-based controls (R2=0.31; P<10–15).

Figure 2.
Figure 2.

Spatial distribution of cerebral microbleeds (CMB; A) and white matter hyperintensities (WMH; B). A, Each sphere represents 1 CMB in the sample. Maps are superimposed onto the T1 standard space template. B, Aside from frequent WMH in the temporal pole in patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), the overall pattern was comparable between the three samples. CAA indicates cerebral amyloid angiopathy; cSS, cortical superficial siderosis; and PC, population-based controls

Discussion

cSS is a frequent finding in patients with histologically proven CAA.8 The current study demonstrates that cSS is absent in a large cohort of patients with a severe nonamyloid-associated SVD because of CADASIL and exceedingly rare in a population-based sample. Hence, our results indicate that cSS is not a general marker for SVD, but strongly indicative of the presence of CAA. This is in line with a recent study, which found positive amyloid PET in 12 cSS cases.9

Our findings on the frequency and distribution of both CMB and WMH show a substantial overlap between samples and therefore suggest a limited value of these imaging markers in discriminating different forms of SVD. Of note, this also applies to lobar CMB, which are considered typical for CAA.

It is commonly hypothesized that cSS reflects the result of recurrent focal convexity hemorrhages triggered by vascular amyloid.1 Recent data from Abeta antibody trials in Alzheimer disease support this hypothesis: Treatment groups developed cSS in a time, dose, and APOE-dependent manner.10,11 Our results suggest that these convexity hemorrhages are typically absent in nonamyloid-associated SVD.

Strengths of this study include the prospectively collected data and the large sample sizes in all groups. A potential limitation is the use of different magnetic resonance field strengths (1.5T and 3T), which might have led to an underestimation of CMB on 1.5T scans. Furthermore, study patients were mostly in early- and middle-stage disease, precluding definite conclusions for late stages. Still, the samples were well representative for an outpatient clinic setting, in which cSS can be of high utility.

Conclusions

These findings provide further evidence that cSS is an imaging marker for CAA. Longitudinal data are needed to investigate the value of cSS in therapeutic decision making.

Sources of Funding

This study was supported by the Ludwig-Maximilians-University Förderung für Forschung und Lehre (FöFoLe) program (808), the Else Kröner-Fresenius-Stiftung (2014_A200), and the Vascular Dementia Research Foundation.

Disclosures

None.

Footnotes

  • Received October 19, 2016.
  • Revision received January 24, 2017.
  • Accepted February 1, 2017.

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  • Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease
    Frank Arne Wollenweber, Ebru Baykara, Marialuisa Zedde, Benno Gesierich, Melanie Achmüller, Eric Jouvent, Anand Viswanathan, Stefan Ropele, Hugues Chabriat, Reinhold Schmidt, Christian Opherk, Martin Dichgans, Jennifer Linn and Marco Duering
    Stroke. 2017;48:1404-1407, originally published March 31, 2017
    https://doi.org/10.1161/STROKEAHA.117.016833
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