Neuroimaging biomarkers of small vessel disease in cerebral amyloid angiopathy‐related intracerebral hemorrhage

Abstract Aims The significance of the correlation of computed tomography (CT)–based cerebral small vessel disease (SVD) markers with the clinical outcomes in patients with cerebral amyloid angiopathy (CAA)‐related intracerebral hemorrhage (ICH) remains uncertain. Thus, this study aimed to explore the relationship between SVD markers and short‐term outcomes of CAA‐ICH. Methods A total of 183 patients with CAA‐ICH admitted to the Xuanwu Hospital, and Beijing Fengtai You'anmen Hospital, from 2014 to 2021 were included. The multivariate logistic regression analysis was performed to identify the correlation between SVD markers based on CT and clinical outcomes at 7‐day and 90‐day. Results Of the 183 included patients, 66 (36%) were identified with severe SVD burden. The multivariate analysis showed that the total SVD burden, white matter lesion (WML) grade, and brain atrophy indicator were independent risk factors for unfavorable outcomes at 90‐day. The brain atrophy indicator was independently associated with mortality at 90‐day. Severe cortical atrophy was significantly associated with early neurological deterioration. Conclusions The neuroimaging profiles of SVD based on CT in patients with CAA‐ICH might predict the short‐term outcome more effectively. Further studies are required to validate these findings and identify modifiable factors for preventing CAA‐ICH development.


| INTRODUC TI ON
Cerebral amyloid angiopathy (CAA) is a cerebral small-vessel disease caused by the deposition of β-amyloid in the walls of arteries, arterioles, and capillaries in the cerebral cortex and overlying leptomeninges. 1 CAA is well recognized as a common cause of spontaneous lobar intracerebral hemorrhage (ICH), which is the most devastating form of stroke, with a considerable death rate approaching 50%. 2 Although patients with CAA-ICH have mild symptoms, a higher risk of recurrent and/or multiple hemorrhages may result in higher morbidity and mortality. 3 Unfortunately, no effective treatment and prevention methods are available. The surgical treatment during the acute phase is controversial. 4 Therefore, understanding the outcomes of the disease and the prognostic factors may help make clinical decisions.
Previous studies demonstrated a stronger correlation between ICH and underlying SVD. The neuroimaging abnormalities assessed using magnetic resonance imaging (MRI)/CT scan can lead to an unfavorable functional outcome and ICH recurrence. [5][6][7][8][9][10][11] The characteristic neuroimaging biomarkers of SVD are also observed in CAA, such as cerebral microbleeds, cortical superficial siderosis, white matter lesion (WML), enlarged perivascular space, lacunes, and cerebral atrophy. 12 Whether the underlying SVD burden is a significant predictor of unfavorable short-term outcome in patients with CAA-ICH is not certain to date. Compared with emergency MRI, CT brain scans are still the main approach for patients with ICH in the acute phase in most hospitals, especially in primary hospitals. Furthermore, the results of MRI in the subacute phase may be influenced due to the enlarged edema and hematoma. Hence, exploring the significance of CT markers for CAA-ICH in the hyperacute and acute phases is essential.
Hence, this study was performed to investigate whether the preexisting SVD features on baseline CT had a prognostic significance in patients with CAA-ICH to improve their applicability in clinical practice.

| Clinical data collection
The medical records of patients were collected, including age, sex, comorbid conditions (history of hypertension, atrial fibrillation, diabetes mellitus, hyperlipidemia, coronary artery disease, prior ischemic stroke or transient ischemic attack, or ICH), toxic habits (smoking or alcohol), use of medications (antiplatelets, anticoagulants, and antihypertensives), systolic and diastolic blood pressure, Glasgow Coma Scale (GCS) score, and National Institutes of Health Stroke Scale (NIHSS) score on admission.

| Imaging analysis
All patients underwent noncontrast head CT scans on admission using standardized techniques (recommended slice thickness, 5 mm). All imaging data were assessed by two experienced radiologists blinded to the clinical outcome and other clinical information of patients. They were supposed to achieve a consensus in the case of any disagreement.
On account of irregular hematoma, the focal areas for each layer were multiplied by slice thickness to yield ICH volumes. The WML grade was rated using the Van Swieten Scale (range 0-4). Lacunes were defined as subcortical rounded or ovoid, fluid-filled (with cerebrospinal fluid signal intensity) lesions of 3-15 mm in diameter, consistent with a previous cerebral infarct or hemorrhage. Severe WMLs were considered if the Van Swieten Scale score was ≥2 in either anterior or posterior periventricular white matter. The cerebral atrophy was recorded on the contralateral side of the hematoma by four parameters. Two linear measurements comprised frontal ratio and third ventricle Sylvian fissure distance, which were measured as described earlier. 7 A higher frontal ratio and a shorter third ventricle Sylvian fissure distance, separately, proved more advanced cerebral atrophy.
We evaluated central and cortical brain atrophy using a 3-point scale as previously described (none, modest, and severe). 7 The SVD burden score (0-3) was assessed as previously described: 1 point was assigned for (1) severe WML, (2) severe (≥2) lacunes, and (3) presence of severe deep or cortical brain atrophy. 11 Severe SVD burden was considered if the score was ≥2, and severe brain atrophy was considered if the scale of visual rating was ≥2 in deep or cortical regions.

| Outcome assessment
Four clinical prognostic end points were assessed: early neurological deterioration (END), hematoma expansion (HE) within 7 days, unfavorable functional outcome, and mortality within 3 months.
END was defined as an increase of four or more points in NIHSS score or a decrease of two or more points in GCS score within 7 days of enrollment. HE was defined as an absolute increase in hematoma volume of >12.5 ml or a relative increase of >33% within 3 days. 15 Unfavorable functional outcome was measured at 90-day with an mRS score of 4-6.

| Statistical analysis
All data were analyzed using SPSS, version 25.0. Continuous variables were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR) based on their distribution and results of the Kolmogorov-Smirnov test. They were compared using the t test or Mann-Whitney U test depending on whether the variables were normally distributed. The categorical variables were presented as percentages and compared using Pearson's chi-square test or continuous-correction chi-square test as appropriate.
We explored the role of each SVD marker individually and the total SVD burden based on brain CT. The univariate logistic regression analysis was performed to assess the relationship between SVD neuroimaging markers and clinical outcomes. To address any concealed confounder, we included confounding variables with a p value

| RE SULTS
A total of 196 patients with CAA-ICH who initially met our criteria were admitted to Xuanwu Hospital, Capital Medical University, and Beijing Fengtai You'anmen Hospital between 2014 and 2021. Of these, 183 patients with complete data (including 2 with CAA with supportive pathology, 66 with probable, and 115 with possible CAA) were finally included. The flowchart of this study is presented in Figure 1.
Patients with severe SVD burden were older (77 vs 68, p < 0.001), and had lower median admission diastolic blood pressure (80 vs 87, p = 0.018) and higher NIHSS score (8 vs 3, p = 0.022). The demographic and clinical characteristics in each group are shown in Table 1.

| Regression analysis for total SVD burden
The univariate logistic regression analysis showed that more patients with severe SVD had unfavorable outcomes at 90-day (59% vs 31%, p < 0.001) compared with the patients without severe SVD ( Table 2).
The multivariate logistic regression analysis was used to adjust for confounding factors. The results showed that SVD burden (adjusted p < 0.001; OR, 2.74; 95% CI, 1.61-4.67) was still an independent factor for unfavorable outcomes. No significant difference was found in HE and neurological deterioration in 7 days and mortality at 90-day between the two groups (p > 0.05 each) ( Table 3).

| Regression analysis for individual neuroimaging markers
We also analyzed different neuroimaging markers to determine their role in the prognosis of CAA-ICH.

TA B L E 2 CT-based total SVD burden and clinical outcomes within 90 days
The univariate analysis showed that cortical atrophy (p = 0.026) was the factor affecting hematoma enlargement and it (p = 0.003) was also the risk factor for neurological deterioration within 7 days of onset. At 90-day follow-up, the factors contributing to unfavorable outcome included WML (p < 0.001) and four parameters of cerebral atrophy (all p for trend <0.05). Finally, cortical atrophy and the third ventricle Sylvian fissure distance were associated with mortality within 3 months (all p for trend <0.05) ( Table S1).
The multiple logistic regression analysis of different clinical outcomes was performed to adjust the influence of potential con- Note: All analyses were adjusted for age, sex, diastolic blood pressure, NIHSS score, GCS score, hematoma volume, and intraventricular hemorrhage. Data are n (%) or median (IQR).
Abbreviation: WML, White matter lesion. a A total of 157 patients were included in the analysis of hematoma expansion.
This study was novel in exploring the relationship between SVD and the short-term prognosis of CAA-related hemorrhage. In line with previously published findings on spontaneous ICH, 5,7-11 SVD based on CT might indicate the early prognosis of patients with CAArelated hemorrhage. Also, higher SVD scores were independently correlated with a higher likelihood of achieving an unfavorable outcome at 3-month in CAA-related ICH. Several possible explanations account for this. In CAA, a kind of SVD, the deposition of Aβ may impair the architecture and influence the vasomotor function of vessels, potentially leading to stroke or ICH. The total burden of SVD causes diffuse changes in brain microstructure, which impairs cognition, especially in mid-to-late life. 16 The SVD burden in individuals with CAA is often noticeable, as the CAA progresses, the key brain networks vital for rehabilitation, learning, and cognitive reserve are likely to disrupt. Hence, the severity of neuroimaging abnormalities assessed by CT and MRI scans, such as WML, cortical cerebral microinfarcts 17 and brain atrophy, indicate the frailty of the underlying brain, which influences susceptibility to, and recovery from, ICH.
In this study, we also found that severe WML was related to unfavorable functional outcomes at 90-day, which was similar to the results of a meta-analysis. 18 WML manifests the loss of vascular supply and blood-brain barrier integrity, demyelination, arteriosclerosis, myelin loss, gliosis, venous collagen tissue hyperplasia, and spongiosis. 19,20 In patients with CAA, WML is related to vascular Aβ load, damaging the integrity of vascular supply and blood-brain barriers and leading to microaneurysms or fibrinoid necrosis. Long-term ischemia and hypoxia in brain tissue leads to demyelination of white matter, which impacts connectivity and plasticity of the brain. [21][22][23] Hence, on the one hand, reduced neuroplasticity may have an adverse impact on the neurological function recovery after ICH. On the other hand, WML is linked to the degeneration of deep medullary veins, which might alter hemodynamics, cause interstitial fluid reflux, 24 and may affect the clearance of hematoma and perihematomal edema. In a nutshell, these pathological manifestations of preexisting leukoencephalopathy may affect hematoma absorption and neurological rehabilitation, thus affecting the prognosis of patients.
After adjusting for known predictors of spontaneous ICH, significant associations of severe cerebral atrophy with END, unfavorable functional outcome, and mortality were still observed, which was in line with most previous data. 25 In our study, we also found that age had an effect on mortality at 3 months, even after adjusting for imaging markers and other indicators. Firstly, cortical thinning appeared to be an MRI feature of CAA, which also provided evidence of neurodegeneration. Brain atrophy in CAA-ICH might, in part, represent neurodegeneration processes, which were characterized by the death of neurons and supporting cells in the neurovascular unit, accompanied by progressive deterioration of cognitive and motor function attributable to functional outcome detrimentally. 26 Secondly, in previous studies, the decrease of deep medullary veins has been linked to cerebral atrophy, which may be related to the neurodegenerative changes occurring in venules over time. 27 In patients with CAA, vascular dysfunction has also been found to lead to gray matter disease, contributing to cortical atrophy. 28

| CON CLUS IONS
Higher total SVD burden based on CT was independently associated with 90-day functional outcome in patients with CAA-ICH. Taking cerebral SVD on baseline CT into account when determining prognosis in patients with acute CAA-ICH is promising. Further large-scale prospective studies are warranted to confirm our findings and also to elucidate the pathophysiological mechanism between SVD and CAA-ICH.

ACK N OWLED G M ENTS
We would like to thank all patients who participated in this study for their cooperation.