Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds
Authors: Fandler-Höfler Simon , Eppinger Sebastian , Ambler Gareth , Nash Philip , Kneihsl Markus , Lee Keon-Joo , Lim Jae-Sung , Shiozawa Masayuki , Koga Masatoshi , Li Linxin , Lovelock Caroline , Chabriat Hugues , Hennerici Michael , Wong Yuen Kwun , Mak Henry Ka Fung , Prats-Sanchez Luis , Martínez-Domeño Alejandro , Inamura Shigeru , Yoshifuji Kazuhisa , Arsava Ethem Murat , Horstmann Solveig , Purrucker Jan , Lam Bonnie Yin Ka , Wong Adrian , Kim Young Dae , Song Tae-Jin , Lemmens Robin , Uysal Ender , Tanriverdi Zeynep , Bornstein Natan M. , Ben Assayag Einor , Hallevi Hen , Molad Jeremy , Nishihara Masashi , Tanaka Jun , Coutts Shelagh B. , Polymeris Alexandros , Wagner Benjamin , Seiffge David J. , Lyrer Philippe , Kappelle L. Jaap , Al-Shahi Salman Rustam , Hernandez Maria Valdes , Jäger Hans R. , Lip Gregory Y. H. , Fischer Urs , El-Koussy Marwan , Mas Jean-Louis , Legrand Laurence , Karayiannis Christopher , Phan Thanh , Gunkel Sarah , Christ Nicolas , Abrigo Jill , Chu Winnie , Leung Thomas , Chappell Francesca , Makin Stephen , Hayden Derek , Williams David J. , Mess Werner H. , Kooi M. Eline , Barbato Carmen , Browning Simone , Tuladhar Anil M. , Maaijwee Noortje , Guevarra Anne Cristine , Mendyk Anne-Marie , Delmaire Christine , Köhler Sebastian , van Oostenbrugge Robert , Zhou Ying , Xu Chao , Hilal Saima , Robert Caroline , Chen Christopher , Lou Min , Staals Julie , Bordet Régis , Kandiah Nagaendran , de Leeuw Frank-Erik , Simister Robert , Bos Daniel , Kelly Peter J. , Wardlaw Joanna , Soo Yannie , Fluri Felix , Srikanth Velandai , Calvet David , Jung Simon , Kwa Vincent I. H. , Engelter Stefan T. , Peters Nils , Smith Eric E. , Hara Hideo , Yakushiji Yusuke , Orken Dilek Necioglu , Thijs Vincent , Heo Ji Hoe , Mok Vincent , Veltkamp Roland , Ay Hakan , Imaizumi Toshio , Lau Kui Kai , Jouvent Eric , Rothwell Peter M. , Toyoda Kazunori , Bae Hee-Joon , Marti-Fabregas Joan , Wilson Duncan , Best Jonathan , Fazekas Franz , Enzinger Christian , Werring David J. , Gattringer Thomas ,   Microbleeds International Collaborative Network
Published: October 2024

Importance

Cerebral small vessel disease (SVD) is associated with various cerebrovascular outcomes, but data on sex differences in SVD are scarce.

Objective

To investigate whether the frequency, severity, and distribution of cerebral microbleeds (CMB), other SVD markers on magnetic resonance imaging (MRI), and outcomes differ by sex.

Design, Setting, and Participants

This cohort study used pooled individual patient data from the Microbleeds International Collaborative Network, including patients from 38 prospective cohort studies in 18 countries between 2000 and 2018, with clinical follow-up of at least 3 months (up to 5 years). Participants included patients with acute ischemic stroke or transient ischemic attack with available brain MRI. Data were analyzed from April to December 2023.

Main Outcomes and Measures

Outcomes of interest were presence of CMB, lacunes, and severe white matter hyperintensities determined on MRI. Additionally, mortality, recurrent ischemic stroke, and intracranial hemorrhage during follow-up were assessed. Multivariable random-effects logistic regression models, Cox regression, and competing risk regression models were used to investigate sex differences in individual SVD markers, risk of recurrent cerebrovascular events, and death.

Results

A total of 20 314 patients (mean [SD] age, 70.1 [12.7] years; 11 721 [57.7%] male) were included, of whom 5649 (27.8%) had CMB. CMB were more frequent in male patients, and this was consistent throughout different age groups, locations, and in multivariable models (female vs male adjusted odds ratio [aOR], 0.86; 95% CI, 0.80-0.92; P &amp;lt; .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P &amp;lt; .001) but a higher prevalence of severe white matter hyperintensities (aOR, 1.10; 95% CI, 1.01-1.20; P = .04) compared with male patients. A total of 2419 patients (11.9%) died during a median (IQR) follow-up of 1.4 (0.7-2.5) years. CMB presence was associated with a higher risk of mortality in female patients (hazard ratio, 1.15; 95% CI, 1.02-1.31), but not male patients (hazard ratio, 0.95; 95% CI, 0.84-1.07) (P for interaction = .01). A total of 1113 patients (5.5%) had recurrent ischemic stroke, and 189 patients (0.9%) had recurrent intracranial hemorrhage, with no sex differences.

Conclusions and Relevance

This cohort study using pooled individual patient data found varying frequencies of individual SVD markers between female and male patients, indicating potential pathophysiological differences in manifestation and severity of SVD. Further research addressing differences in pathomechanisms and outcomes of SVD between female and male patients is required.