# Intracerebral Hemorrhage in Patients With CADASIL: Additive Impact of the NOTCH3 R544C Variant and Hypertension?

Chih-Hao Chen, Yu-Wen Cheng, Ruiting Zhang, Sophie Tezenas Du Montcel, Stéphanie Guey, Dominique Hervé, Sung-Chun Tang, Hugues Chabriat

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## To cite this version:

Chih-Hao Chen, Yu-Wen Cheng, Ruiting Zhang, Sophie Tezenas Du Montcel, Stéphanie Guey, et al. Intracerebral Hemorrhage in Patients With CADASIL: Additive Impact of the NOTCH3 R544C Variant and Hypertension?. Stroke, 2025, 56 (8), pp.2159-2166. 10.1161/STROKEAHA.124.050484. hal-05285765

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# Intracerebral Hemorrhage in CADASIL Patients: Additive Impact of NOTCH3 R544C Variant and Hypertension?

Chih-Hao Chen, MD, PhD¹; Yu-Wen Cheng, MD, PhD¹; Ruiting Zhang, MD, PhD²;
Sophie Tezenas Du Montcel, MD, PhD³; Stéphanie Guey, MD, PhD⁴; Dominique
Hervé, MD⁴; Sung-Chun Tang, MD, PhD¹; Hugues Chabriat, MD, PhD⁴

¹ National Taiwan University Hospital, Neurology, Taipei, Taiwan

² The Second Affiliated Hospital of Zhejiang University, School of Medicine,
Hangzhou, China

³ Sorbonne Université, Paris Brain Institute, Inria, AP-HP, Paris, France

⁴ Lariboisière Hospital AP-HP, Université Paris Cité and INSERM U1161, FHU NeuroVasc, Paris, France

**Corresponding author:** Sung-Chun Tang, MD, PhD

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

E-mail: [sctang@ntuh.gov.tw](mailto:sctang@ntuh.gov.tw)

Manuscript word count: 3728

Number of table: 4; number of figure: 2

Number of supplementary table: 4
# ABSTRACT

## Background

Intracerebral hemorrhage (ICH) is increasingly recognized in CADASIL, especially in Asian patients with the *NOTCH3* R544C variant. The associations between ICH, *NOTCH3* variants and hypertension remain unclear.

## Methods

We enrolled patients from two independent CADASIL cohorts in France (recruited since 2003) and Taiwan (recruited since 2019) and performed a cross-sectional retrospective analysis. Clinical history and evaluation were collected using standardized questionnaires and scales, while neuroimaging features were assessed with the CADA-MRIT inventory tool. Patients with and without history of ICH were compared. Logistic regression and mediation analyses were conducted to identify factors associated with ICH.

## Results

Of 552 patients with CADASIL (440 from France and 112 from Taiwan), 34 (6.2%) had history of ICH. Patients with ICH were older (62.9±11.4 vs 53.4±12.3 years), had higher proportion of *NOTCH3* R544C variant (79.4% vs 15.3%) and hypertension (85.3% vs 24.9%). Analysis of MRI data showed that they had more cerebral microbleeds, worse cerebral atrophy, and higher number of dilated perivascular spaces in basal ganglia. Hypertension (OR 7.90, 95% CI 2.83 – 22.08) and *NOTCH3* R544C variant (OR 9.91, 95% CI 3.84 – 25.57) were each independently associated with ICH, while no multiplicative interaction was detected between these two factors ($P_{interaction}=0.81$). Having both *NOTCH3* R544C variant and hypertension carried an additive effect on the risk of ICH (36.9% if both present, 8.8% if having *NOTCH3* R544C variant without hypertension, 5.4% if having hypertension without *NOTCH3*
R544C variant, and 0.6% if both absent; *P*<sub>trend</sub> < 0.001). Finally, in the mediation
analysis, 49.9% of the effects of *NOTCH3* R544C variant on the occurrence of ICH
would be explained by the effects of hypertension.

**Conclusion**

Both the *NOTCH3* R544C variant and hypertension appear to be independent risk factors for ICH in CADASIL, with a potential additive effect. However, due to the study's cross-sectional design and population-specific factors, causality cannot be established. Prospective studies are thus needed to validate these findings and clarify underlying mechanisms.

**Non-standard Abbreviations and Acronyms**

CADASIL, Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and

Leukoencephalopathy

CMB, cerebral microbleed

dPVS, dilated perivascular space

ICH, intracerebral hemorrhage

WMH, white matter hyperintensities
# 1 BACKGROUND

Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and

Leukoencephalopathy (CADASIL) caused by characteristic cysteine *NOTCH3*

mutations is the most common hereditary cause of stroke worldwide.¹ However, the

phenotype of CADASIL seems to vary widely among patients with different mutations

and across different ethnicities. While intracerebral hemorrhage (ICH) is rarely

observed in Caucasian patients, it is reported as a common feature of the disease in

East Asian patients.² According to a recent meta-analysis, the overall prevalence of

ICH in CADASIL would be around 10%.³ However, it would reach approximately 18%

in Asian patients contrasting with only 2% in their European counterparts.³

Furthermore, in Asian patients with a specific *NOTCH3* R544C variant, the

prevalence of ICH might be even up to 30%.⁴,⁵ On the other hand, a history of

hypertension is present in more than 70% of CADASIL patients with ICH.²

Hypertension is also an independent risk factor of ICH in East Asian CADASIL

patients with predominant *NOTCH3* R544C variant.⁵,⁶ The inter-relationship between

a specific genetic variant and hypertension and their potential effects on the risk of

ICH in CADASIL patients are yet to be explored.

In the present study, we hypothesized that both the *NOTCH3* R544C variant and

a past history of hypertension were independently associated with the occurrence of

ICH. For this purpose, we aimed to investigate whether the R544C variant and

hypertension had synergistic effects on ICH, and whether the effects of hypertension

on ICH were modified by the presence of the R544C variant.

23

# 24 METHODS

## 25 Patients Enrollment and Assessment

The data that support the findings of this study are available from the
corresponding author upon reasonable request. This was a cross-sectional
retrospective analysis of patients from two independent CADASIL registries in France
and Taiwan. The details of the cohorts have been published previously.⁷,⁸ Briefly, the
French cohort corresponded to a long-term prospective study recruiting CADASIL
patients aged 18 or more at the National Referral Center for Rare Cerebrovascular
disorders in France from June 2003 up to February 2021. Patients were referred for
evaluation of suspected CADASIL, and were followed longitudinally through
scheduled outpatient visits, with standardized clinical assessments and brain MRIs
performed at baseline and during follow-up. As a specialized tertiary center, this
cohort captures a broad clinical spectrum but may underrepresent the most severely
disabled individuals living far from the center and having difficulty traveling to the
center during follow-up. The Taiwan registry included CADASIL patients enrolled at
the National Taiwan University Hospital from February 2019 to July 2022. Inclusion
required the presence of clinical symptoms (e.g., stroke, cognitive impairment, or gait
disturbance) and MRI features consistent with cerebral small vessel disease (e.g.,
multiple lacunes, microbleeds, or moderate-to-severe white matter hyperintensities).
Genetic testing for NOTCH3 mutations followed a two-step protocol, starting with
hotspot analysis (R544C) and followed by a complete NOTCH3 exon sequencing if
needed. Patients were evaluated and followed prospectively in the outpatient setting,
with standardized clinical documentation and imaging protocols. Written informed
consent was obtained from all participants. The study was approved by the research
ethics committee of participating sites (France: updated agreement CEEI-IRB-17/388;
Taiwan: National Taiwan University Hospital 201810003RIND). The study adhered to
the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology)
guideline for the observational cohort study.

All patients had undergone genetic testing and were confirmed to have an
unequivocal cysteine-altering variant(s) of the *NOTCH3* gene. The demographic data and clinical status were obtained upon enrollment by standardized questionnaires and scales designed by each study site. History of hypertension was defined by either (1) patients reporting hypertension diagnosis by physicians or (2) patients taking blood-pressure lowering medications. Stroke was defined as an acute episode of focal neurological dysfunction lasting longer than 24 h with neuroimaging revealing focal infarction or hemorrhage in the brain relevant to the symptoms. ICH was defined as the sudden onset of focal neurological deficit with non-traumatic intraparenchymal hemorrhage observed on head CT or MRI scans. A history of ICH was documented at the time of enrollment. Cognitive function was assessed by the mini-mental status examination and functional status by the modified Rankin Scale.

## MRI Assessment

All patients underwent at least one brain MRI scan upon enrolment. The MRI protocol was not harmonized between the two study sites, but each sites included core sequences such as T1, T2, FLAIR-T2, and iron-sensitive sequence (T2\*, GRE, or SWI). We recently developed and validated the CADA-MRIT inventory tool to assess neuroimaging features of CADASIL across different MRI scanners, protocols, and even countries.⁹ Briefly, this tool allows to grade semi-quantitatively and very quickly the extent of white matter hyperintensities (WMH), dilated perivascular space (dPVS), and atrophy, as well as the numbers of lacunes, cerebral microbleeds (CMBs), large infarcts or macro-hemorrhages.

## Statistical Analyses

Firstly, demographic data and imaging features were compared between patients with and without *NOTCH3* R544C variant. According to data characteristics and distribution, Student's t-tests, Mann-Whitney U tests or chi-square tests were used to identify any difference in demographic factors, comorbidities or imaging features
79 between the two groups. For lacune and CMB grade, Cochrane-Armitage trend test 80 was used. Thereafter, patients with and without ICH were compared following the 81 same procedure. Moreover, within the subset of ICH patients, the patients with and 82 those without the *NOTCH3* R544C variant were additionally compared to help 83 evaluate the specific impact of this genetic variant on the occurrence and severity of 84 ICH.

85 Logistic regression analysis was used to test the independent and/or combined 86 effects of the R544C variant, hypertension, and their potential multiplicative 87 interaction (R544C × hypertension) on the likelihood of experiencing ICH. Potential 88 confounders such as age, sex, diabetes mellitus, and MRI markers were adjusted for 89 in the model. Since the R544C variant was almost exclusively found in the Taiwanese 90 cohort, the recruiting site was not adjusted for in the main model but was considered 91 in the sensitivity analysis.

92 We also conducted a sensitivity analysis using CMB as an alternative outcome 93 measure, given their established role as a surrogate marker for ICH. Logistic 94 regression models were applied to examine the associations between hypertension, 95 the R544C variant, and two CMB outcomes: any CMB (presence vs. absence) and 96 moderate-severe CMB (CMB grade 2–3 in CADA-MRIT), using the same covariates 97 as in the primary analysis.

98 In addition, patients were categorized into four groups: individuals without 99 hypertension and without the R544C variant, those with hypertension but without the 100 R544C variant, those without hypertension but with the R544C variant, and those with 101 both hypertension and the R544C variant. The prevalence of ICH in these four groups 102 was compared by the Cochrane-Armitage trend test. The odds of experiencing ICH 103 were calculated using the group without hypertension and without the R544C variant 104 as the reference group. To investigate a potential additive effect between
hypertension and the R544C variant,¹⁰ we further estimated the relative risk of
interaction between these two factors by calculating the risk ratio (Relative Excess
Risk due to Interaction, RERI<sub>RR</sub>) and attributable proportion. RERI<sub>RR</sub> measures the
additional risk from the combined effect of hypertension and the R544C variant,
beyond their individual effects; a positive RERI suggests an additive effect. The
attributable proportion indicates the proportion of disease risk in those exposed to
both factors that can be attributed to their additive interaction.

Lastly, mediation analysis was conducted to investigate whether the effect of the
R544C variant on ICH occurrence was mediated by hypertension. This advanced
statistical technique allowed to search for any potential causal pathway and quantify
indirect effects of the genetic variant through hypertension. The *proc causalmed*
package in the SAS software was applied, using age and sex as covariates.
Specifically, the total effect of R544C variant on ICH risk was estimated, followed by
the controlled direct effect—which quantifies the effect of R544C on ICH while holding
hypertension constant. The natural indirect effect was also computed, representing
the portion of the effect mediated through hypertension. The percentage of mediation
was then calculated to determine the proportion of the R544C effect on ICH that could
be attributed to hypertension.

The statistical significance level was *P* < 0.05. All analyses were performed using
the SAS software, version 9.4. Anonymized data not published within this article are
available by request from qualified investigators.

## 127 RESULTS

### 128 Characteristics of the enrolled patients

Initially, 450 French and 112 Taiwanese cases were identified. After excluding 10
patients without neuroimaging data available, 552 CADASIL patients were finally
considered for analysis. Of them, 106 harbored the *NOTCH3* R544C variant.

Compared to patients without R544C variants, those with R544C variants were older
at enrollment (median, 63 vs 53 years), less likely to have headache, mood
symptoms, or seizures as the first symptom, had higher prevalence of vascular risk
factors including hypertension, diabetes mellitus, and hyperlipidemia. Besides, 25.5%
of R544C variant carriers had a positive history of ICH, comparing to only 1.6% in the
non-R544C group (Table S1). Also, R544C variant carriers exhibited less severe
WMH (especially in the superficial region) but higher grades of CMB, dPVS in basal
ganglia and brain atrophy as well as a higher prevalence of macrohemorrhages
(Table S2).

## Comparisons between patients with and without ICH

Among CADASIL patients, 34 (6.2%) had suffered from ICH. The median age of
the first ICH was 61 years (IQR 53 – 69). The most common location of ICH was the
thalamus (n=17), followed by basal ganglia (n=7) and cortical-subcortical regions
(n=7). The other hemorrhagic lesions were distributed in the pons (n=2) and
cerebellum (n=1). The median size of hematoma was 2.6 ml (IQR 0.8 – 4.6). Patients
with ICH were older and more likely to have *NOTCH3* R544C variant (79.4% vs
15.3%, p<0.0001). They also had a higher prevalence of hypertension (85.3% vs
24.9%), diabetes mellitus (29.4% vs 7.7%), and hyperlipidemia (61.8% vs 41.0%).
They had a lower MMSE score and higher mRS score at baseline. Of note, patients
with ICH was less likely to receive antithrombotics (18.2% vs. 53.1%) but the statin
use was comparable (39.4% vs. 32.9%); however there were substantial missing data
for these items (n=225 and 224, respectively). On brain MRI, patients with ICH had
less severe WMH but higher grades of CMB, dPVS in basal ganglia and brain atrophy
(Table 1).

Within the ICH group, 7 patients did not have R544C variant (non-R544C ICH).
Their *NOTCH3* variants were located on EGFr 5 (n=1), 8 (n=1), 15 (n=2), 25 (n=1), 30 (n=1) and EGFr 31 (n=1). Patients with R544C ICH (n=27) were older at their first ICH (median, 62 vs 54 years) than the others. The prevalence of hypertension was high in both groups (n=24, 88.9% vs n=5, 71.4%). Of note, 19 of 29 patients (66%) were known to be hypertensive before the ICH events. The location and size of ICH were also comparable between the two groups. On MRI, the ICH group with the R544C variant had higher grades of CMB (median, 3 vs 1), dPVS in basal ganglia, and atrophy than the other group (Table 2).

## Effects of hypertension and of the R544C variant on ICH

Logistic regression analysis showed that both hypertension (odds ratio (OR) 7.90, 95% CI 2.81 – 22.08) and R544C variant (OR 9.91, 95% CI 3.84 – 25.57) were independently associated with ICH after adjustment for age and sex (Table 3). These results remained consistent even after additional adjustment for diabetes mellitus and other MRI markers (grades of CMB, lacunes, and basal ganglia dPVS). Additionally, the model did not show any significant multiplicative interaction between hypertension and R544C variant (*P*<sub>interaction</sub> = 0.81). When considering the recruiting site, hypertension remained significantly associated with ICH (OR 6.32, 95% CI 2.12 – 18.87), while the R544C variant became non-significant (OR 1.53, 95% CI 0.25 – 9.23). These findings were further supported by the sensitivity analysis, where similar associations were observed when using any CMB or moderate-severe CMB as the outcome (Table S3). The data confirmed the association between both hypertension and the R544C variant with the number (or presence) of CMB in line with the results obtained when analyzing ICH. However, as observed with ICH, the association between CMB and the R544C variant did not persist either to the adjustment for the study sites.

The prevalence of ICH was 0.6% in patients without the R544C variant and
183 without hypertension, 5.4% in those without the R544C variant but with hypertension,
184 7.3% in those with the R544C variant and without hypertension, and 36.9% in
185 patients with both the R544C variant and hypertension ($P_{trend} < 0.001$; Figure 1).

186 Compared to the group without the R544C variant and without hypertension, the age-
187 and sex-adjusted odds ratio were 9.23 (95% CI 1.74 – 48.94), 12.00 (95% CI 1.86 –
188 77.27), and 86.03 (95% CI 18.39 – 402.5), respectively for the same groups (Table 4).

189 The RERI<sub>RR</sub> was 43.77, indicating that there was an additive effect between
190 hypertension and the R544C variant on the occurrence of ICH. The attributable
191 proportion was 0.68, suggesting that 68% of the risk of ICH in patients having both
192 the R544C variant and hypertension was due to the presence of this additive effect.

193 Due to highly unequal distribution of the R544C variant in the French and
194 Taiwanese cohorts, we examined the above separately from the two recruiting sites.
195 In the French cohort (n=440), only 4 patients had the R544C variant. All 4 patients
196 had a history of hypertension, and one developed ICH. In the Taiwan cohort (n=112),
197 102 patients carried R544C variants. 41 of them did not have history of hypertension
198 and 3 developed ICH (7.3%), while 23 (38%) in the other 61 patients who had history
199 of hypertension developed ICH (Table S4). The RERI<sub>RR</sub> could not be calculated due
200 to the presence of zero in individual cells.

201 **Mediation analysis**

202 Finally, we applied mediation analysis to test whether the effects of R544C
203 variant on ICH were mediated by HTN. The original effect of R544C variant on ICH
204 was 9.91 (3.84 – 25.57; *P* < 0.001). The controlled direct effect of the risk of R544C
205 variant on ICH, after hypertension was controlled, was 9.91 (0.51 – 19.3; *P* = 0.06).
206 The natural indirect effect of the risk of hypertension on ICH, given the assumption
207 that all patients had R544C variant, was 1.89 (1.34-2.45, *P* = 0.002). The R544C
208 variant was also associated with and increased risk of hypertension (OR 4.21, 95% CI
2.61 – 6.80, *P* < 0.001). The percentage explained by mediation is 49.9%, which
means that 49.9% of the effects of R544C on ICH may be explained (or changed) by
the effects of R544C on hypertension, which in turn influence the occurrence of ICH
*(Figure 2).*

213

214 DISCUSSION

The main findings of the present study can be summarized as follows: (1)
CADASIL patients with ICH were older, had more vascular risk factors, and exhibited
more cerebral small vessel disease lesions on MRI; (2) both the *NOTCH3* R544C
variant and hypertension are independent risk factors for ICH, and may have, when
combined, additive effects on the risk of ICH; (3) half of the effects of the R544C
variant on ICH would be mediated through hypertension, while the other half would
not.

Our study confirmed with previous findings that hypertension is a risk factor for
both microhemorrhage and macrohemorrhage in CADASIL.<sup>5, 6, 11</sup> The majority of ICH
in our cases was located in non-lobar regions, which is compatible with ICH
associated with hypertensive microangiopathy.<sup>12</sup> The combined effect of hypertension
and the R544C variant showed a positive additive interaction, indicating a heightened
risk in patients with both hypertension and the R544C variant. The prevalence of
hypertension in the Taiwanese CADASIL patients was around 50% and higher than
the prevalence of about 20% in European patients.<sup>11, 13-16</sup> Nonetheless, in CADASIL
patients with ICH the prevalence of hypertension is more than 70% in both R544C
and non-R544C variants, suggesting that the hypertension plays a critical role in the
occurrence of ICH regardless of the R544C variant status. Prior data showed that in
CADASIL patients whose blood pressure levels were actively controlled to
guideline-recommended targets, a higher 90-day mean diastolic BP (&gt;80 mmHg)
predicted incident stroke, increased number of lacunes and cerebral microbleeds, 235 suggesting a role of BP levels in disease progression.¹⁷ While our study demonstrates 236 that a history of hypertension is strongly associated with ICH, we acknowledge that 237 we did not directly assess BP levels, the adequacy of BP control, or detailed 238 treatment regimens. Future studies incorporating longitudinal BP monitoring and 239 treatment data will be essential to clarify this relationship. 240

In our study, ICH can occur in 7.3% of the R544C variant carriers without any 241 history of hypertension. The mediation analysis unveiled that only about half of the 242 effects of the R544C variant on the occurrence of ICH was mediated by hypertension. 243 These results suggest some direct pathophysiological effects of the R544C variant in 244 the development of ICH, unrelated to hypertension. Interestingly, previous data 245 obtained using the Taiwan Biobank showed that carriers of the *NOTCH3* R544C 246 mutation had lower systolic blood pressure than the general population.¹⁸ This 247 discrepancy with our results may have different sources. In the Taiwan Biobank 248 cohort, more younger and asymptomatic individuals were included than in our 249 CADASIL sample. Conversely, in our patients, the diagnosis of hypertension was 250 based on clinical judgment, with an increased likelihood of diagnosis due to a 251 mandatory medical consultation at entry which was not needed to set up the biobank. 252 From a different perspective, this seemingly conflicting result strengthens our 253 hypothesis that the effects of the R544C variant are independent on the occurrence of 254 ICH and not related to hypertension. 255

Whether other hemorrhagic-prone NOTCH3 variants exist is still under debate. 256 Traditionally, patients with *NOTCH3* EGFr 1-6 cysteine-altering variants are known to 257 have an earlier age of ischemic stroke onset and more severe WMH.¹⁹, ²⁰ Another 258 study using three-tier EGFr domain risk stratification classified EGFr 1-6 as a 259 high-risk group, whereas EGFr 13-14, where R544C is located, being classified as 260
261 medium-risk.²¹ In our study, 6 out of 7 non-R544C ICH cases had variants in 262 NOTCH3 EGFr 7-34, highlighting a potential association with hemorrhagic stroke with 263 variants located in these EGFr domains. We therefore cannot rule out the possibility 264 that not only patients with the R544C variant, but also other individuals having 265 different ‘medium-risk’ variants in NOTCH3 EGFr 7-34, may also have a greater 266 tendency to develop hemorrhagic brain lesions. This could be particularly possible 267 due to the longer disease duration, their older age, and the increased prevalence of 268 hypertension with aging. 269

270 Little is known about the specific risk of ICH associated with DM. A potential link 271 between blood glycemia and the development of cerebral microbleeds in sporadic 272 SVD²² or CADASIL¹¹ has been however already reported. Diabetes is known to 273 contribute to small vessel disease through endothelial dysfunction and blood-brain 274 barrier disruption, potentially increasing the global hemorrhagic risk.²³, ²⁴ In the 275 present study, the ICH group had a higher prevalence of DM, which may also reflect a 276 general clustering of vascular risk factors, particularly in older individuals. When DM 277 was incorporated into our multivariable model, the association of ICH with DM was no 278 longer significant, suggesting that DM itself may not be an independent risk factor in 279 our two cohorts. 280

281 Finally, the median age of first ICH in our cohort was 61 years, which is not far 282 from the mean age of the first ICH at 56.6 ± 15.7 years estimated from multiple 283 CADASIL case reports.² In contrast, the average age of first ischemic stroke has been 284 reported to be between 45 to 50 years in multiple large CADASIL cohorts worldwide.⁸, 285 ¹⁴, ²⁵, ²⁶ Even in our patients with the R544C variant, who are more prone to develop 286 ICH, the average age of ICH (61.6 ± 11.6 years) was still older than that of ischemic 287 stroke (57.9 ± 9.2 years). Our findings suggest that ICH may occur later in CADASIL 288 progression, but this interpretation should be approached with caution, as stroke 289
287 onset varies widely depending on genetic background and vascular risk factors.

288 Aging and increasing vascular comorbidities may contribute to ICH risk, but further

289 prospective studies are needed to confirm whether ICH consistently occurs later than

290 ischemic events in CADASIL across different populations.

291 The strengths of our study include the large sample size for such a rare disease,

292 the incorporation of genetic analysis, the application of advanced statistical models to

293 account for confounding factors, and the inclusion of comprehensive MRI markers.

294 Our study has several limitations. First, most of the R544C cases are from Taiwan.

295 Unknown biological differences and environmental exposures between patients in

296 France and Taiwan could represent important confounding factors and biases. Thus,

297 such differences may explain that the R544C variant was no longer significant on the

298 risk of ICH after adjusting for the recruiting site. This is, however, not valid if we

299 consider, as we did, the Taiwanese recruiting site as a proxy for the R544C and want

300 to emphasize the independent effects of the R544C variant itself. Second, its

301 cross-sectional, retrospective design limits causal inferences, and recruitment bias as

302 well as potential confounding factors cannot be fully excluded. Future prospective

303 studies with longitudinal follow-up are thus needed to confirm our findings. Third, the

304 definition of hypertension in our study was purely based on the clinical history. We did

305 not have access to detailed blood pressure data, so it is unclear how hypertension

306 was controlled and the duration of exposure to hypertension in our patients.

307 Nevertheless, our results further emphasize the crucial importance of controlling

308 vascular risk factors in CADASIL patients. Fourth, differences in diagnostic processes,

309 clinical assessments, and medical care between France and Taiwan may introduce

310 additional heterogeneity. Because the French cohort study was initiated before the

311 Taiwanese cohort study, the hypothesis of a selection bias due to the age of diagnosis

312 and related to the progression of our knowledge about the disease cannot be ruled
out either. Nonetheless, we think that our pragmatic approach still provides valuable
insights and extends the generalizability of the findings beyond a single-country
context. Finally, we did not have external validation in another cohort to test the result.
Future partnerships with international cohorts will be invaluable for validating our
findings and enhancing their generalizability.

In conclusion, our results suggest that both *NOTCH3* R544C variant and
hypertension are independent risk factors for ICH in CADASIL patients. Our findings
suggest a potential additive effect between these two factors, emphasizing the need
for individualized vascular risk management. However, given the study's
cross-sectional design, the absence of longitudinal BP data, and the
population-specific distribution of the R544C variant, causal relationships cannot be
definitively established. Future studies incorporating prospective follow-up and
broader genetic analyses are needed to validate these findings and further clarify the
mechanisms underlying ICH risk in CADASIL.

327

328 **Disclosure**: All authors declare no conflict of interests.

329 **Funding**: This study was supported by grants from National Science and Technology
Council (NSTC 113-2314-B-002-278-MY3 & 113-2314-B-002-102-MY3) and
Academia Sinica (AS-GC-111-L04), Taiwan.

332 **Acknowledgement**: We thank Dr. Sheng-Hsuan Lin, MD, ScD, ScM (Institute of
Statistics, National Yang Ming Chiao Tung University, Taipei, Taiwan) for providing
statistical consultation for this work.

335 **Supplemental Material**: Table S1-S4
**Figure 1.** Proportion of patients with intracerebral hemorrhage (ICH) stratified by presence of hypertension and NOTCH3 R544C variant.

**Figure 2.** Mediation analysis of the effects of NOTCH3 R544C variant and hypertension on the occurrence of intracerebral hemorrhage (ICH). The upper section illustrates the direct association between the NOTCH3 R544C variant and ICH, while the lower section represents the mediation model, where hypertension acts as a partial mediator between the R544C variant and ICH. Overall, 49.9% of the total effect of the R544C variant on ICH is mediated through hypertension.

Abbreviations: aOR, adjusted odds ratio; ICH, intracerebral hemorrhage.
<table><caption>Table 1. Clinical and imaging features between patients with and without ICH</caption><thead><tr><th></th><th>With ICH</th><th>Without ICH</th><th>P value</th></tr></thead><tbody><tr><td>Case number</td><td>34</td><td>518</td><td></td></tr><tr><td>Age at enrolment, median (IQR)</td><td>63 (55 – 70)</td><td>54 (45 – 62)</td><td>0.0002</td></tr><tr><td>Age of first ICH, median (IQR)</td><td>61 (53 – 69)</td><td>-</td><td>-</td></tr><tr><td>Female sex, n (%)</td><td>18 (52.9%)</td><td>279 (53.9%)</td><td>0.92</td></tr><tr><td>Education years, median (IQR)</td><td>12 (9 – 15)</td><td>12 (9 – 15)</td><td>0.88</td></tr><tr><td>Enrolled from Taiwan, n (%)</td><td>28 (82%)</td><td>84 (16%)</td><td>&lt;0.0001</td></tr><tr><td>R544C variant carriers</td><td>27 (79.4%)</td><td>79 (15.3%)</td><td>&lt;0.0001</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>29 (85.3%)</td><td>129 (24.9%)</td><td>&lt;0.0001</td></tr><tr><td>Diabetes mellitus</td><td>10 (29.4%)</td><td>40 (7.7%)</td><td>&lt;0.0001</td></tr><tr><td>Hyperlipidemia</td><td>21 (61.8%)</td><td>212 (41.0%)</td><td>0.02</td></tr><tr><td>Ever smoking</td><td>9 (26.5%)</td><td>228 (44.0%)</td><td>0.045</td></tr><tr><td>No any vascular risk factors</td><td>0 (0%)</td><td>131 (25.3%)</td><td>&lt;0.0001</td></tr><tr><td>Antithrombotic use *</td><td>7 (18.2%)</td><td>156 (53.1%)</td><td>&lt;0.0001</td></tr><tr><td>Statin use #</td><td>13 (39.4%)</td><td>97 (32.9%)</td><td>0.45</td></tr><tr><td>MMSE, median (IQR)</td><td>27 (22 – 28)</td><td>28 (25 – 30)</td><td>0.03</td></tr><tr><td>mRS, median (IQR)</td><td>1 (1 – 3)</td><td>1 (0 – 2)</td><td>0.02</td></tr><tr><td>CADA-MRIT</td><td></td><td></td><td></td></tr><tr><td>Periventricular WMH, median (IQR)</td><td>3 (2 – 3)</td><td>3 (2 – 3)</td><td>0.88</td></tr><tr><td>Deep WMH, median (IQR)</td><td>3 (2 – 3)</td><td>3 (2 – 3)</td><td>0.93</td></tr><tr><td>Superficial WMH, median (IQR)</td><td>0 (0 – 0)</td><td>1 (1 – 3)</td><td>&lt;0.0001</td></tr><tr><td>Total WMH, median (IQR)</td><td>6 (5 – 6)</td><td>7 (6 – 9)</td><td>&lt;0.0001</td></tr><tr><td>Lacune grade</td><td></td><td></td><td></td></tr><tr><td>Grade 0: 0, n (%)</td><td>4 (11.8%)</td><td>143 (27.6%)</td><td rowspan="4">0.42</td></tr><tr><td>Grade 1: 1 – 5, n (%)</td><td>19 (55.9%)</td><td>155 (29.9%)</td></tr><tr><td>Grade 2: 6 – 10, n (%)</td><td>10 (29.4%)</td><td>93 (18.0%)</td></tr><tr><td>Grade 3: &gt;10, n (%)</td><td>1 (2.9%)</td><td>127 (24.5%)</td></tr><tr><td>CMB grade</td><td></td><td></td><td></td></tr><tr><td>Grade 0: 0, n (%)</td><td>1 (2.9%)</td><td>299 (57.7%)</td><td rowspan="4">&lt;0.0001</td></tr><tr><td>Grade 1: 1 – 5 / 1 – 10, n (%)</td><td>8 (23.5%)</td><td>124 (23.9%)</td></tr><tr><td>Grade 2: 6 – 10 / 11 – 20, n (%)</td><td>8 (23.5%)</td><td>34 (6.6%)</td></tr><tr><td>Grade 3: &gt;10 / &gt;20, n (%)</td><td>17 (50.0%)</td><td>61 (11.8%)</td></tr><tr><td>Basal ganglia dPVS, median (IQR)</td><td>1.5 (1 – 2)</td><td>1 (0 – 1)</td><td>&lt;0.0001</td></tr><tr><td>Centrum semiovale dPVS, median (IQR)</td><td>0 (0 – 1)</td><td>0 (0 – 1)</td><td>0.68</td></tr></tbody></table>
<table><tr><td>Superficial atrophy, median (IQR)</td><td>1.5 (1 – 2)</td><td>0 (0 – 1)</td><td>&lt;0.0001</td></tr><tr><td>Deep atrophy, median (IQR)</td><td>1 (0 – 2)</td><td>0 (0 – 1)</td><td>&lt;0.0001</td></tr><tr><td>Any large infarct (≥1), n (%)</td><td>0 (0%)</td><td>14 (2.7%)</td><td>0.99</td></tr><tr><td>Any macrobleed (≥1), n (%)</td><td>29 (85.3%)</td><td>12 (2.3%)</td><td>&lt;0.0001</td></tr></table>

* missing = 225; # missing = 224

Abbreviations: ICH, intracerebral hemorrhage; MMSE, mini-mental state exam; mRS, modified Rankin Scale; CADA-MRIT, CADASIL MRI Inventory Tool; WMH, white matter hyperintensity; CMB, cerebral microbleed; dPVS, dilated perivascular space.
<table><caption>Table 2. Imaging features between patients with R544C ICH and non-R544C ICH</caption><thead><tr><th></th><th>R544C ICH</th><th>Non-R544C ICH</th><th>P value</th></tr></thead><tbody><tr><td>Case number</td><td>27</td><td>7</td><td></td></tr><tr><td>Age of first ICH, median (IQR)*</td><td>62 (53 – 69)</td><td>54 (52 – 58)</td><td>0.02</td></tr><tr><td>Female sex, n (%)</td><td>13 (48.2%)</td><td>2 (28.6%)</td><td>0.41</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>24 (88.9%)</td><td>5 (71.4%)</td><td>0.27</td></tr><tr><td>Diabetes mellitus</td><td>8 (29.6%)</td><td>2 (28.6%)</td><td>0.99</td></tr><tr><td>Hyperlipidemia</td><td>17 (63.0%)</td><td>4 (57.1%)</td><td>0.99</td></tr><tr><td>Ever smoking</td><td>8 (29.6%)</td><td>1 (14.3%)</td><td>0.64</td></tr><tr><td>Antithrombotic use</td><td>6 (22.2%)</td><td>0 (0.0%)</td><td>0.56</td></tr><tr><td>Statin use</td><td>12 (44.4%)</td><td>1 (16.7%)</td><td>0.36</td></tr><tr><td>MMSE, median (IQR)</td><td>27 (21 – 28)</td><td>28 (25 – 29)</td><td>0.50</td></tr><tr><td>mRS, median (IQR)</td><td>1 (1 – 3)</td><td>1 (1 – 3)</td><td>0.65</td></tr><tr><td>ICH location</td><td></td><td></td><td>0.46</td></tr><tr><td>Lobar</td><td>5 (18.5%)</td><td>2 (28.6%)</td><td></td></tr><tr><td>Basal ganglia</td><td>7 (25.9%)</td><td>0 (0.0%)</td><td></td></tr><tr><td>Thalamus</td><td>13 (48.1%)</td><td>4 (57.1%)</td><td></td></tr><tr><td>Infratentorium</td><td>2 (7.4%)</td><td>1 (14.3%)</td><td></td></tr><tr><td>ICH size (ml), median (IQR)</td><td>2.9 (0.8 – 6.3)</td><td>1.0 (0.8 – 2.0)</td><td>0.15</td></tr><tr><td>CADA-MRIT</td><td></td><td></td><td></td></tr><tr><td>Periventricular WMH, median (IQR)</td><td>3 (2 – 3)</td><td>2 (2 – 3)</td><td>0.26</td></tr><tr><td>Deep WMH, median (IQR)</td><td>3 (2 – 3)</td><td>3 (3 – 3)</td><td>0.38</td></tr><tr><td>Superficial WMH, median (IQR)</td><td>0 (0 – 0)</td><td>1 (0 – 1)</td><td>0.002</td></tr><tr><td>Total WMH, median (IQR)</td><td>6 (5 – 6)</td><td>6 (5 – 7)</td><td>0.41</td></tr><tr><td>Lacune grade</td><td></td><td></td><td></td></tr><tr><td>Grade 0: 0, n (%)</td><td>3 (11.1%)</td><td>1 (14.3%)</td><td rowspan="4">0.52</td></tr><tr><td>Grade 1: 1 – 5, n (%)</td><td>15 (55.6%)</td><td>4 (57.1%)</td></tr><tr><td>Grade 2: 6 – 10, n (%)</td><td>8 (29.6%)</td><td>2 (28.6%)</td></tr><tr><td>Grade 3: &gt;10, n (%)</td><td>1 (3.7%)</td><td>0 (0%)</td></tr><tr><td>CMB grade</td><td></td><td></td><td></td></tr><tr><td>Grade 0: 0, n (%)</td><td>0 (0%)</td><td>1 (14.3%)</td><td rowspan="4">&lt;0.0001</td></tr><tr><td>Grade 1: 1 – 5 / 1 – 10, n (%)</td><td>5 (18.5%)</td><td>3 (42.9%)</td></tr><tr><td>Grade 2: 6 – 10 / 11 – 20, n (%)</td><td>7 (25.9%)</td><td>1 (14.3%)</td></tr><tr><td>Grade 3: &gt;10 / &gt;20, n (%)</td><td>15 (55.6%)</td><td>2 (28.6%)</td></tr><tr><td>Basal ganglia dPVS, median (IQR)</td><td>2 (1 – 2)</td><td>1 (0 – 1)</td><td>0.001</td></tr><tr><td>Centrum semiovale dPVS, median</td><td>0 (0 – 1)</td><td>0 (0 – 0)</td><td>0.10</td></tr></tbody></table>
<table><thead><tr><th>(IQR)</th><th></th><th></th><th></th></tr></thead><tbody><tr><td>Superficial atrophy, median (IQR)</td><td>2 (1 – 2)</td><td>0 (0 – 1)</td><td>0.02</td></tr><tr><td>Deep atrophy, median (IQR)</td><td>1 (1 – 2)</td><td>1 (0 – 1)</td><td>0.10</td></tr><tr><td>Any large infarct (≥1), n (%)</td><td>0 (0%)</td><td>0 (0%)</td><td>NA</td></tr><tr><td>Any macrobleed (≥1), n (%)</td><td>23 (85.2%)</td><td>6 (85.7%)</td><td>0.73</td></tr></tbody></table>

* Compared by log-rank test.

Abbreviations: ICH, intracerebral hemorrhage; MMSE, mini-mental state exam; mRS, modified Rankin Scale; WMH, white matter hyperintensity; CMB, cerebral microbleed; dPVS, dilated perivascular space.
<table><caption>Table 3. Effects of hypertension and R544C variant on ICH</caption><thead><tr><th rowspan="2"></th><th colspan="2">Hypertension</th><th colspan="2">R544C variant</th></tr><tr><th>aOR (95% CI)</th><th>P value</th><th>aOR (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Model 1</td><td>8.32 (3.00 – 23.10)</td><td>&lt;0.001</td><td>11.09 (4.48 – 27.49)</td><td>&lt;0.001</td></tr><tr><td>Model 2</td><td>7.90 (2.83 – 22.08)</td><td>&lt;0.001</td><td>9.91 (3.84 – 25.57)</td><td>&lt;0.001</td></tr><tr><td>Model 3</td><td>6.12 (2.05 – 18.29)</td><td>0.001</td><td>4.64 (1.54 – 13.94)</td><td>0.006</td></tr><tr><td>Model 4</td><td>6.32 (2.12 – 18.87)</td><td>0.001</td><td>1.53 (0.25 – 9.23)</td><td>0.64</td></tr></tbody></table>

Model 1 includes only hypertension and the R544C variant. Model 2 is adjusted for age and sex. Model 3 is further adjusted for diabetes mellitus, and grades of cerebral microbleeds (CMB), lacunes, and basal ganglia dilated perivascular space (dPVS). Model 4 was finally adjusted for the study site.

<table><caption>Table 4. Additive effect of hypertension and R544C variant on ICH</caption><thead><tr><th>Group</th><th>Total<br>n</th><th>ICH cases</th><th>OR (95% CI)</th><th>Age- &amp; sex-adjusted<br>OR (95% CI)</th></tr></thead><tbody><tr><td>Hypertension (-), R544C (-)</td><td>353</td><td>2 (0.6%)</td><td>Ref</td><td>Ref</td></tr><tr><td>Hypertension (+), R544C (-)</td><td>93</td><td>5 (5.4%)</td><td>9.97 (1.90-52.24)</td><td>9.23 (1.74 – 48.94)</td></tr><tr><td>Hypertension (-), R544C (+)</td><td>41</td><td>3 (7.3%)</td><td>13.9 (2.24-85.51)</td><td>12.00 (1.86 – 77.27)</td></tr><tr><td>Hypertension (+), R544C (+)</td><td>65</td><td>24 (36.9%)</td><td>102.7 (23.4-450.4)</td><td>86.03 (18.39 – 402.5)</td></tr></tbody></table>
## REFERENCES

1. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. *The Lancet. Neurology*. 2009;8:643-653

2. Sukhonpanich N, Markus HS. Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in cadasil: A case series and systematic review. *J Neurol. 2024;271:2423-2433*

3. Lai QL, Zhang YX, Wang JJ, Mo YJ, Zhuang LY, Cheng L, Weng ST, Qiao S, Liu L. Occurrence of intracranial hemorrhage and associated risk factors in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: A systematic review and meta-analysis. *J Clin Neurol. 2022;18:499-506*

4. Chen CH, Tang SC, Cheng YW, Tsai HH, Chi NF, Sung PS, Yeh HL, Lien LM, Lin HJ, Lee MJ, et al. Detrimental effects of intracerebral haemorrhage on patients with cadasil harbouring notch3 r544c mutation. *J Neurol Neurosurg Psychiatry*. 2019;90:841-843

5. Liao YC, Hu YC, Chung CP, Wang YF, Guo YC, Tsai YS, Lee YC. Intracerebral hemorrhage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Prevalence, clinical and neuroimaging features and risk factors. *Stroke*. 2021;52:985-993

6. Lee JS, Ko K, Oh JH, Park JH, Lee HK, Floriolli D, Paganini-Hill A, Fisher M. Cerebral microbleeds, hypertension, and intracerebral hemorrhage in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. *Frontiers in neurology*. 2017;8:203

7. Chen CH, Chu YT, Chen YF, Ko TY, Cheng YW, Lee MJ, Chen PL, Tang SC, Jeng JS. Comparison of clinical and neuroimaging features between notch3 mutations and nongenetic spontaneous intracerebral haemorrhage. *European journal of neurology*. 2022;29:3243-3254

8. Dupé C, Guey S, Biard L, Dieng S, Lebenberg J, Grosset L, Alili N, Hervé D, Tournier-Lasserve E, Jouvent E, et al. Phenotypic variability in 446 cadasil patients: Impact of notch3 gene mutation location in addition to the effects of age, sex and vascular risk factors. *Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism*. 2023;43:153-166

9. Zhang R, Chen CH, Tezenas Du Montcel S, Lebenberg J, Cheng YW, Dichgans M, Tang SC, Chabriat H. The cada-mrit: An mri inventory tool for evaluating cerebral lesions in cadasil across cohorts. *Neurology*. 2023;101:e1665-e1677

10. VanderWeele TJ, Knol MJ. A tutorial on interaction. *Epidemiologic Methods*. 2014;3

11. Viswanathan A, Guichard JP, Gschwendtner A, Buffon F, Cumurcuic R, Boutron C, Vicaut E, Holtmannspotter M, Pachai C, Bousser MG, et al. Blood pressure and haemoglobin a1c are associated with microhaemorrhage in cadasil: A two-centre
cohort study. *Brain*. 2006;129:2375-2383

12. Sheth KN. Spontaneous intracerebral hemorrhage. *N Engl J Med*. 2022;387:1589-1596

13. Liao YC, Hsiao CT, Fuh JL, Chern CM, Lee WJ, Guo YC, Wang SJ, Lee IH, Liu YT, Wang YF, et al. Characterization of cadasil among the han chinese in taiwan: Distinct genotypic and phenotypic profiles. *PloS one*. 2015;10:e0136501

14. Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of cadasil and the effect of cardiovascular risk factors on phenotype: Study in 200 consecutively recruited individuals. *Stroke*. 2010;41:630-634

15. Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the cadasil phenotype. *Brain*. 2004;127:2031-2038

16. Chen CH, Cheng YW, Chen YF, Tang SC, Jeng JS. Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in cadasil. *J Neuroinflammation*. 2020;17:124

17. Chen CH, Liao YC, Cheng YW, Chung CP, Lee YC, Tang SC. High daily diastolic blood pressure predicts incident stroke, lacune, and cerebral microbleeds in cadasil. *J Stroke*. 2024;26:112-115

18. Lin E, Kuo PH, Liu YL, Wang TJ, Yang AC, Tsai SJ. The cysteine-altering p.R544c variant in the notch3 gene is a probable candidate for blood pressure and relevant traits in the taiwan biobank. *J Neurol*. 2023;270:5536-5544

19. Cho BPH, Jolly AA, Nannoni S, Tozer D, Bell S, Markus HS. Association of notch3 variant position with stroke onset and other clinical features among patients with cadasil. *Neurology*. 2022;99:e430

20. Rutten JW, Dauwerse HG, Gravesteijn G, van Belzen MJ, van der Grond J, Polke JM, Bernal-Quiros M, Lesnik Oberstein SA. Archetypal notch3 mutations frequent in public exome: Implications for cadasil. *Annals of clinical and translational neurology*. 2016;3:844-853

21. Hack RJ, Gravesteijn G, Cerfontaine MN, Santroos MA, Gatti L, Kopczak A, Bersano A, Duering M, Rutten JW, Lesnik Oberstein SAJ. Three-tiered egfr domain risk stratification for individualized notch3-small vessel disease prediction. *Brain*. 2023;146:2913-2927

22. Yu M, Jia Y, Yang D, Zhang R, Jiang Y, Zhang G, Qiao H, Han H, Shen R, Ning Z, et al. Association between haemoglobin a1c and cerebral microbleeds in community-based stroke-free individuals: A cross-sectional study. *Diabetes Metab Res Rev*. 2022;38:e3557

23. Boulanger M, Poon MT, Wild SH, Al-Shahi Salman R. Association between diabetes mellitus and the occurrence and outcome of intracerebral hemorrhage. *Neurology*. 2016;87:870-878
24. Bahadar GA, Shah ZA. Intracerebral hemorrhage and diabetes mellitus: Blood-brain barrier disruption, pathophysiology and cognitive impairments. *CNS Neurol Disord Drug Targets*. 2021;20:312-326

25. Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of cadasil: Clinical findings in 102 cases. *Annals of neurology*. 1998;44:731-739

26. Primo V, Graham M, Bigger-Allen AA, Chick JM, Ospina C, Quiroz YT, Manent J, Gygi SP, Lopera F, D'Amore PA, et al. Blood biomarkers in a mouse model of cadasil. *Brain research*. 2016;1644:118-126
<figure><img src="image_3.png" /></figure>

Hypertension (-),
NOTCH3 R544C (-)

Hypertension (+),
NOTCH3 R544C (-)

Hypertension (-),
NOTCH3 R544C (+)

Hypertension (+),
NOTCH3 R544C (+)
R544C variant

aOR 9.91 (3.84 – 25.57), P<0.001

ICH

aOR 4.21 (2.61 – 6.80),
P<0.001

Hypertension

Percentage mediated = 49.9%

aOR 1.89 (1.34 – 2.45),
P=0.002

R544C variant

aOR 9.91 (0.51 – 19.30), P=0.06

ICH