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. Author manuscript; available in PMC: 2017 Jan 31.
Published in final edited form as: JAMA Neurol. 2016 Aug 1;73(8):994–1001. doi: 10.1001/jamaneurol.2016.0832

Total MRI small vessel disease burden in cerebral amyloid angiopathy: a concept validation imaging-pathological study

Andreas Charidimou 1, Sergi Martinez-Ramirez 1, Yael D Reijmer 1, Jamary Oliveira-Filho 1, Arne Lauer 1, Duangnapa Roongpiboonsopit 1, Matthew Frosch 2, Anastasia Vashkevich 1, Alison Ayres 1, Jonathan Rosand 1,3,4, Mahmut Edip Gurol 1, Steven M Greenberg 1, Anand Viswanathan 1
PMCID: PMC5283697  NIHMSID: NIHMS842141  PMID: 27366898

Abstract

Importance

Cerebral amyloid angiopathy (CAA) is characteristically associated with MRI biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiological aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA.

Objectives

To develop a composite score to capture the total brain MRI burden of small vessel disease in CAA, based on the most salient imaging signatures of the disease. Furthermore, to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage (ICH) during life or bleeding-related neuropathologic changes.

Design

MRI-pathological study.

Setting

Single centre neuropathological CAA cohort based on eligible patients from the Massachusetts General Hospital (MGH) (1997–2012).

Participants

Patients with both pathological evidence of CAA (i.e. any presence of CAA from routinely collected brain biopsy, biopsy at hematoma evacuation or autopsy) and available brain MRI sequences of adequate quality including T2-weighted, T2*-weighted gradient-recalled echo (T2*-GRE) and/or SWI and FLAIR sequences.

Main outcomes and measures

Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces and white matter hyperintensities. All four MRI lesions were incorporated into a pre-specified ordinal total small vessel disease score ranging from 0–6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, ICH number and other imaging markers not included in the score were explored using logistic and ordinal regression.

Results

In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (OR: 2.40; 95%CI: 1.06–5.45; p=0.035) and CAA presentation with symptomatic ICH (OR: 2.23; 95%CI: 1.07–4.64; p=0.033) were independently associated with the total MRI small vessel disease score. The score was associated with small acute diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses.

Conclusions and Relevance

Our study provides evidence for concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.

Keywords: Intracerebral hemorrhage, MRI, cerebral amyloid angiopathy, cerebral small vessel disease

Introduction

Sporadic cerebral amyloid angiopathy (CAA) is the most common cause of symptomatic lobar intracerebral haemorrhage (ICH) in the elderly and results from cerebrovascular amyloid-β deposition, preferentially involving cortical and leptomeningeal small vessels.1–4 CAA is frequently present in the brain of patients with Alzheimer’s disease, but can also have an independent contribution in age-related cognitive decline.5,6

CAA is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury including multiple strictly lobar cerebral microbleeds (CMBs),7 cortical superficial siderosis (cSS),8 centrum semiovale perivascular spaces (CSO-PVS)9,10 and white matter hyperintensities (WMH),1,11 Although these neuroimaging markers probably reflect distinct pathophysiological aspects or steps in CAA,4,12 they are often closely related. No studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. A comprehensive approach might have potential advantages over individual markers, providing a practical framework to better assess the impact of CAA-related damage on clinical outcomes.13

Recently, the approach of assessing total MRI small vessel disease burden has been developed and applied in patients at high risk for ischaemic small vessel damage, including lacunar or non-disabling cortical stroke.14–16 By summing different MRI features of ischaemic small vessel disease in one measure (with one point assigned for each: lacunar infarct, CMBs, basal ganglia perivascular spaces and WMH), the authors demonstrated that a higher score is independently related to lacunar stroke subtype and certain vascular risk factors (age, hypertension, smoking etc.).14 In patients with lacunar stroke, this score was associated with blood pressure15 and cognition.16 Furthermore, the score was associated with lower general cognitive ability in 680 older participants.17

In this study we pre-specified and developed a total MRI small vessel disease score specifically tailored for CAA patients, based on the four major imaging signatures of the disease as described in a consensus report on CAA neuroimaging biomarkers. In a cohort with pathological evidence of CAA, we investigated whether this is a valid construct by examining: (a) whether the total MRI CAA score is associated with symptomatic CAA-related intraparenchymal bleeding events during life and severe CAA on neuropathologic examination; and (b) the association between the total MRI CAA score and other characteristic imaging findings in CAA including small positive lesions on diffusion-weighted imaging (DWI)18 and occipital-predominant WMH.19,20

Methods

Case selection and clinical data collection

We used data from a neuropathological defined CAA cohort based on eligible patients from the Massachusetts General Hospital (MGH) (1997–2012), who were systematically identified using overlapping methods as described.12,21 Patients with both pathological evidence of CAA (i.e. any presence of CAA from routinely collected brain biopsy, biopsy at hematoma evacuation or autopsy) and available in vivo brain MRI sequences of adequate quality including T2-weighted, T2*-weighted gradient-recalled echo (T2*-GRE) and/or SWI and FLAIR sequences, were considered for the study, as previously described.12,21

The clinical presentation of included patients was ascertained based on all available data, and was classified as: (a) symptomatic lobar ICH (confirmed on neuroimaging); or (b) presentation without ICH (including cognitive impairment, transient focal neurological episodes, or other neurological symptoms) at the time of the MRI.12

Standard Protocol Approvals, Registrations, and Patient Consents

The study received ethical approval by the Institutional Review Board of MGH.

Pathological data collection

Morphological assessment was performed in routine haematoxylin-eosin staining and the presence or absence and severity of vascular amyloid-β deposition was confirmed by immunohistochemical detection (anti–Ab 6E10 (1:200; Signet Laboratories, Dedham, MA) and congo red staining. Cases were considered positive for CAA when they had at least one leptomeningeal or cortical vessel with amyloid-β reported by an experienced neuropathologist, providing enough information to reliably classify CAA severity according to modified Vonsattel grading system.22,23 We systematically extracted information on the presence of CAA-related vasculopathic changes, defined as vessel-within-vessel appearance (sometimes called “double-barrelling”) and fibrinoid necrosis, corresponding to modified Vonsattel grade 3 and grade 4 respectively and hence severe CAA.23

Neuroimaging data and analysis

Imaging for all patients included T2-weighted, FLAIR, T2*-GRE (field strength: 1.5T, slice thickness: 5mm, slice gap: 1mm, echo time: 24 msec) and/or susceptibility-weighted imaging (field strength: 3T, slice thickness: 1.2mm, slice gap: 0mm, echo time: 21 msec).21 MR images were reviewed blinded to all clinical and histopathological by trained observers, according to STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).24 For patients with multiple MRIs available, the MRI closest to the neuropathological assessment was examined.

CMBs presence and number were evaluated according to current consensus criteria.11 The presence and number of “macro” ICHs (>5 mm in diameter)25 was also noted. cSS was defined as linear residues of chronic blood products in the superficial layers of the cerebral cortex showing a characteristic “gyriform” pattern of low signal on blood-sensitive sequences as previously described.26 The distribution and severity of cSS was classified as focal (restricted to ≤3 sulci) or disseminated (≥4 sulci).8 cSS contiguous or potentially anatomically connected with any lobar ICH were not included in the aforementioned categories.

PVS were assessed in line with STRIVE definitions24 and rated on axial T2-weighted MR images, using a previously described validated 4-point visual rating scale (0=no PVS, 1=<10 PVS, 2=11–20 PVS, 3=21–40 PVS and 4=>40 PVS) in the basal ganglia and CSO.9,27 Deep and periventricular WMH were assessed according to the four-point Fazekas rating scale.28 WMH in the frontal and occipital lobe were further evaluated separately on axial FLAIR as described by Zhu et al.19 The frontal-occipital gradient (the WMH score in the frontal lobe minus that in the occipital lobe) was calculated (ranging −6 to 6; >0 implies frontal dominance and <0 implies occipital dominance).19

All available diffusion-weighted images were reviewed for the presence of small (generally <4mm) hyperintensities by trained raters.29

Total MRI burden of small vessel disease in CAA

We pre-specified an ordinal scale representing the total burden of small vessel disease in CAA by incorporating the four most characteristic MRI markers of the disease (lobar CMBs, cSS, CSO-PVS and WMH). For lobar CMBs a point was awarded if 2–4 CMBs were present and two points for ≥5 CMBs. Presence of cSS was awarded with one point if focal and two points if disseminated. Presence of CSO-PVS was counted if there were moderate-to-severe (grade 3–4, i.e. >20) PVS (one point if present). Presence of WMH was defined as either (early) confluent deep (i.e. the region between juxtacortical and ventricular areas) WMH (Fazekas score ≥2) or irregular periventricular WMH extending into the deep white matter (Fazekas score 3) (one point if either present), as recently described.14 Hence, the score ranged from a minimum of 0 to a maximum of 6 points, creating an ordinal scale.

In defining these cut-offs we took into account current evidence from cross-sectional and longitudinal studies in CAA. We aimed to distinguish the weights of haemorrhagic imaging markers of CAA (lobar CMBs, cSS), from other non-haemorrhagic markers (CSO-PVS, WMH) which might also occur with high frequency in other diseases. For example, multiple (≥2) strictly lobar CMBs are the most common and characteristic imaging feature of CAA and are part of the Boston criteria;8,30 the presence of ≥5 CMBs is associated with recurrent lobar ICH.31 cSS, particularly disseminated, is a common haemorrhagic marker of CAA,26 associated with future lobar ICH risk.32 The prespecified definition of CSO-PVS (i.e. >20, grade 3) was found to be more strongly related to CAA.9,10,33 The WMH cutoffs chosen are also in line with the scores used in the suggested total MRI scale for ischaemic small vessel disease14–17 based on those Fazekas scores related to small vessel disease in a histopathological study.34

As an exploratory analysis, we tested the effect of using two alternative scores: (a) an expanded score additionally including the presence of occipital predominant WMH19 as another element (1 extra point–hence a total score ranging 0–7); and (b) a simplified version of the CAA score in line with the original MRI score suggested for ischaemic small vessel disease.14–16 For this simplified score, we rated the presence (yes vs. no) of each of the four MRI features above and assigned one point for each (i.e. presence of any lobar CMBs, any cSS, moderate-to-severe CSO-PVS and extensive WMH), resulting in an ordinal scale of 0–4.

Statistical analysis

To investigate the construct validity of this score, our statistical approach was to use the total MRI score as the dependent variable against clinical and neuropathologic markers of CAA severity. We performed univariable ordinal logistic regression to investigate the association between the MRI small vessel disease score with clinical characteristics, presence of CAA-associated vasculopathic changes and CAA clinical presentation with ICH. We performed multivariable ordinal logistic regression exploring the independent association between the presence of vasculopathic changes and CAA clinical presentation with the small vessel disease score (as dependent variable), controlling for age, sex and hypertension. To further account for potential biases of the size of pathology specimen (biopsy vs. autopsy), with full autopsy being more likely to demonstrate both some CAA as well as severe CAA pathology than biopsy, we adjusted for this in a sensitivity analysis.

Separate univariable and multivariable ordinal regression analyses were used to assess the association between the small vessel disease score and diffusion-weighted imaging lesions, occipital predominant WMH presence and symptomatic ICH number, adjusting for age and sex, and additionally for CAA-related vasculopathic changes and clinical presentation.

We tested the effect of the occipital predominant WMH as an additional score element and the alternative simplified total MRI small vessel disease score using a similar approach.

Significance level was set at 0.05. We used Stata software (Version 11.2, StataCorp.). In the ordinal regression models the proportional odds assumption was checked using relevant tests (‘omodel’ command). Collinearity was tested using the variance inflation factor (vif <10 for all variables). The manuscript was prepared with reference to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.35

Results

In total, 104 patients with pathologically-defined CAA were included: 52 with autopsies, 22 with brain biopsies and 30 with pathological samples from hematoma evacuations. Fifty-three patients presented with symptomatic, spontaneous lobar ICH, while 51 patients presented without any symptomatic ICH at baseline. Patients without ICH presented either with cognitive impairment (n=42, median Clinical Dementia Rating score 1; interquartile range [IQR] 0.5–2), transient focal neurological episodes (n=3), or a combination of other symptoms (n=6; including altered mental status, or seizures consistent with inflammatory CAA). Clinical and imaging characteristics are shown in Table 1. As we have previously reported mild (Vonsattel grade 1) or moderate to severe (Vonsattel grades 2–4) CAA were equally represented in the groups (p>0.2).12 Among the 52 patients with autopsy data, 39 (75%) had evidence of arteriolosclerosis (i.e. concentric hyaline thickening of small arteries) in deep (basal ganglia or deep white matter) perforating arterioles, which was moderate-to-severe in 31 cases.

Table 1.

Clinical and imaging and genetic characteristics of the CAA study cohort.

Whole CAA
cohort*¥
(N=105)		 CAA with
ICH
(N=54)		 CAA
without ICH
(N=51)		 p-value
Age, mean (95% CI), years 72.7 (71.1–74.2) 71.6 (69.4–73.7) 73.9 (71.5–76.2) 0.148
Sex, female n (%) 55 (52.4) 33 (63.1) 22 (43.1) 0.065
Hypertension, n (%) 66 (64.7) 30 (57.8) 36 (72) 0.131
Antithrombotic drug use, n (%) 40 (44.4) 15 (36.6) 25 (51) 0.170
Time from MRI-pathology, months,
median (IQR) 		5.3 (0.3–31.4) 1.3 (0.2–11) 23.3 (1.4–50.7) 0.0002
High grade CSO-EPVS (>20), n (%) 57 (54.8) 29 (54.7) 28 (54.9) 0.985
High grade BG-EPVS (>20), n (%) 25 (24) 11 (20.8) 14 (27.5) 0.424
Lobar CMBs presence, n (%) 63 (60) 36 (66.7) 27 (52.9) 0.151
Lobar CMBs count, median (IQR) 2 (0–27) 3 (0–23) 2 (0–31) 0.411
Presence of cSS, n (%) 38 (39.2) 28 (51.9) 10 (19.6) 0.001
  Focal cSS, n (%) 17 (16.2) 10 (18.5) 7 (13.7) 0.505
  Disseminated cSS, n (%) 21 (20) 18 (33.3) 3 (5.9) <0.0001
Small acute DWI lesions, n (%) 15 (17.4) 9 (20.9) 6 (14) 0.394
Frontal-Occipital gradient, n (%) 50 (49) 26 (51) 24 (47.1) 0.689
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-

We used Pearson’s χ2 or Fisher exact test and 2-sample t test (for normal distributions) or Wilcoxon rank sum (for non-normal distributions) to compare characteristics between CAA patients presenting with versus without ICH.

*

CAA pathological samples: 52 from autopsies, 22 from brain biopsies and 30 with pathological samples from hematoma evacuations.

¥

Two different MRI scanners were used during the study period: a Siemens Trio at 3T (used in 25% of the patients) and a GE Signa at 1.5T. CMBs were detected on T2*-GRE (field strength: 1.5T, slice thickness: 5mm, slice gap: 1mm, echo time: 24 msec) and/or susceptibility-weighted imaging (field strength: 3T, slice thickness: 1.2mm, slice gap: 0mm, echo time: 21 msec), respectively.

Eighteen (17.3%) patients had none of the MRI markers of small vessel disease included in the score. The majority of these patients (15/18) had only mild CAA pathology. The distribution of total small vessel disease score severity is shown in Figure 2. CAA patients with ICH had higher ratings of small vessel disease burden compared to those presenting without ICH (median score, IQR: 3 (1–5) vs. 2 (1–4) respectively; p=0.015). In univariable analysis, total small vessel disease score was associated with the presence of CAA-related vasculopathic changes on pathology (OR: 2.21; 95%CI: 1.02–4.78; p=0.045) and CAA presentation with ICH (OR: 2.37; 95%CI: 1.19–4.72; p=0.015), but not with age, hypertension, sex, or antithrombotic drug use. None of the different MRI markers comprising the score were individually associated with vasculopathic changes in univariable or multivariable logistic regression analyses including all four markers (all p>0.1).

Figure 2.

Figure 2

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Total MRI small vessel disease score distribution for all CAA patients and separately for patients presenting with and without ICH. Mann–Whitney test CAA with ICH vs CAA without ICH: p=0.015.

In multivariable ordinal regression, the total score was associated both with the presence of vasculopathic changes and CAA presentation with ICH (Table 2). The results remained consistent and of similar effect size when hypertension was not included in the model, when the size of the pathology specimen (biopsy vs. autopsy), time from MRI to pathology and if different blood-sensitive MRI sequences were included in sensitivity analyses (data not shown). There was an increasing MRI score with increasing macrobleed count on MRI (median no: 1; range: 1–6) in the patient group with symptomatic ICH (Coef. 1.77; 95%CI: 0.08–3.45; p=0.04).

Table 2.

Multivariable ordinal logistic regression model of the total MRI small vessel disease score associations in the whole CAA cohort.

Variable OR (95% CI) p-value
Age (per year) 1.01 (0.97–1.05) 0.672
Sex, female 1.78 (0.87–3.66) 0.115
Hypertension, Yes vs. No 0.89 (0.42–1.88) 0.763
CAA-associated vasculopathic changes* 2.40 (1.06–5.45) 0.035
CAA with symptomatic ICH, Yes vs. No 2.23 (1.07–4.64) 0.033
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*

CAA-associated vasculopathic changes were defined as23 (a) fibrinoid necrosis in CAA-laden vessels, recognized as homogeneous discrete foci or segments of the vascular wall that contain smudgy eosinophilic material obscuring the cytoarchitecture; and (b) Concentric splitting of the wall of amyloid-laden vessels (‘double-barrelling’).

Small acute diffusion-weighted imaging lesions and occipital predominant WMH were associated with small vessel disease score in unadjusted ordinal regression, and remained so in fully adjusted models (Table 3).

Table 3.

Univariable and multivariable ordinal regression analyses of the association between total MRI small vessel disease score and DWI lesions as well as symptomatic ICH number. The association with ICH number was also explored using linear regression analyses.

Unadjusted OR (95%CI); p-value Age/sex adjusted OR (95%CI); p-value Fully adjusted† OR (95%CI); p-value
Acute small DWI lesions*
(yes vs. no) 		4.15 (1.58–10.92); p=0.004 3.94 (1.48–10.48); p=0.006 2.96 (1.10–7.95); p=0.032
Occipital predominant WMH
(yes vs. no) 		1.94 (0.85–4.39); p=0.114 2.02 (0.88–4.64); p=0.096 2.30 (1–5.27); p=0.050
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*

n=86 for the DWI analysis, because of missing data

†

Adjusted for: age, sex, vasculopathic changes and CAA clinical presentation

Alternative scores: Inclusion of occipital predominant WMH as a score element and simplified total MRI small vessel disease score

In the same multivariable regression model as above, the alternative score including occipital predominant WMH was associated with CAA-related vasculopathic changes (OR: 2.64; 95%CI: 1.13–6.14; p=0.025) and symptomatic ICH presentation (OR: 2.28; 95%CI: 1.09–4.79; p=0.029). However, while the simplified total MRI small vessel disease score was associated with CAA presentation with ICH (OR: 2.51; 95% CI: 1.19–5.30; p=0.016), there was only a trend for an association with vasculopathic changes presence (OR: 1.99; 95% CI: 0.88–4.48; p=0.099).

Discussion

In this study we developed an MRI small vessel disease score based on the four most characteristic neuroimaging signatures of sporadic CAA, to compile the overall brain burden of the disease. Using a neuropathologically-defined CAA cohort of patients presenting with and without ICH, we provide evidence of construct validity of our approach. The total small vessel disease score was found to be independently associated with CAA-related vasculopathic changes on pathology (a marker of CAA-related microangiopathy severity) and clinical presentation with symptomatic lobar ICH.

Studies have suggested pathology-based staging schemes for the extent of cerebral small vessel disease in ageing brains.36,37 In the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort, small vessel disease severity assessed using one of these pathology schemes, was correlated with cognitive impairment.37 Approaches to integrate a range of imaging manifestations of small vessel disease into one score have been recently advocated by an international working group (STRIVE).24 Some studies have presented a first attempt to capture the total MRI burden in ischaemic small vessel disease, validating this mainly in lacunar stroke populations.14–17 An assessment of total small vessel disease load on MRI has several potential advantages, as it avoids over-reliance on any one individual marker of small vessel disease. Hence, a more complete evaluation of the total burden may be important to understand the impact of small vessel disease on clinical outcomes such as disability and cognition.

In CAA, studies have shown that the combination of two different MRI markers of the disease (lobar CMBs and cSS; lobar CMBs and high grade CSO-PVS) increase diagnostic sensitivity.8,9 Our score provides a practical and easily applied structural MRI visual tool to comprehensively evaluate small vessel disease in CAA, using validated rating systems for each feature.24 We acknowledge that the assessment of the total MRI small vessel disease burden is complex, and different imaging features probably reflect distinct pathophysiological mechanisms in CAA.4,12 For example, cSS likely represents blood leaking episodes into the subarachnoid space from CAA-affected leptomeningeal vessels38 (as opposed to lobar CMBs which may arise from CAA-laden parenchymal vessels), whereas CSO-PVS might be related to cerebrovascular amyloid burden and drainage impairment10,39,40 and WMH to chronic ischaemia.41 The pathological substrates of small vessel disease imaging markers are however heterogenenous42,43 and direct histopathological-imaging correlations studies are notably underutilised in the field.44 Despite different mechanisms, these features are often related and co-occur in CAA patients.6 We also note that the chosen cut-offs and weightings in our CAA score might not be optimal and to a certain extent are arbitrary, although we did take into account the totality of current clinical, neuroimaging and neuropathological evidence from cross-sectional and longitudinal studies in defining different weights for these markers. Supporting our approach, none of the individual MRI lesions included in the score seem to be significantly driving the associations with CAA severity in isolation.

Clinically silent small areas of restricted diffusion on DWI MRI, thought to represent acute microinfarcts, are sometimes considered an additional marker of CAA.18 Their transient nature combined with the lack of neuropathological confirmation and their occurrence in hypertensive arteriopathy as well as in normal subjects45 may render it difficult to reliably use them as a specific biomarker of the disease. Based on these considerations, we did not include DWI lesions in the MRI small vessel disease score. We did however find an association between DWI lesions and total MRI score, indicating that they may be an additional marker of disease severity. Similarly, a more posterior distribution of WMH may be an additional promising marker for CAA,19,20 potentially associated with more severe disease.46

Our study has limitations. The fact that our score was tested on a clinical-pathology series of CAA, including patients with the most salient clinical manifestations of the disease, makes the current analysis powerful and informative for construct validity. However, this could also represent a constraint because of selection bias, as only symptomatic patients with both pathologic evaluation and brain MRI were included, likely representing patients at the more severe end of the disease spectrum. The differences in pathology sampling between autopsied brains and biopsies may have contributed to bias in that some CAA patients with negative brain biopsies may have been excluded. Another limitation of the current study is the retrospective (which means not all MRI sequence parameters were standardised) and cross-sectional design, which precludes any analysis on the prognostic significance of the small vessel disease scores. T1-sequences were not systematically obtained as part of the MRI protocol, precluding any assessment of lacunes and atrophy. Finally, the tacit implication of the current and previous scores is that there are only two major types of cerebral microvascular disease in the brain - CAA and 'everything else' (so called ‘hypertensive arteriopathy’, ranging from arteriolosclerosis, lipohyalinosis, fibrinoid necrosis, microaneurysm etc.) which is an oversimplification.44

Despite limitations, the suggested scale for CAA performed reasonably well in the current study and raises several questions as well as opportunities for further testing and development in large scale studies. Longitudinal cohorts should investigate whether this system, with or without modifications, can be used to assess the impact of CAA on clinical outcomes in different settings, including cognitive impairment, ICH risk and disability.13,47

Figure 1.

Figure 1

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CAA total small vessel disease score: MRI signatures, categories and points.

Acknowledgments

"Dr Andreas Charidimou and Dr Anand Viswanathan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis"

Funding

Funding organizations or sponsor did not have any role in: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnotes

Authors and their individual contributions to the manuscript

Statistical analysis was conducted by Dr A. Charidimou

A. Charidimou: study concept and design, data collection, imaging analysis, data analysis, write up

S. Martinez-Ramirez: data collection, imaging analysis, critical revisions

Y. D. Reijmer: critical revisions

J. Oliveira-Filho: data collection, imaging analysis, critical revisions

M. Frosch: data collection, pathological analysis, critical revisions

A. Vashkevich: data collection and management

A. Ayres: data collection and management

J. Rosand: data collection, critical revisions, supervision

M. E. Gurol: data collection, critical revisions, supervision

S. M. Greenberg: funding, study concept and design, data collection, critical revisions

A. Viswanathan: funding, study concept and design, data collection, write up, critical revisions

Disclosures

The authors report no disclosures relevant to this work.

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