Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds
Simon Fandler‐Höfler, Sebastian Eppinger, Gareth Ambler, Philip S. Nash, Markus Kneihsl, Keon-Joo Lee, Jae‐Sung Lim, Masayuki Shiozawa, Masatoshi Koga, Linxin Li, Caroline Lovelock, Hugues Chabriat, Michael G. Hennerici, Yuen Kwun Wong, Henry Ma, Luís Prats‐Sánchez, Alejandro Martínez‐Domeño, Shigeru Inamura, Kazuhisa Yoshifuji, Ethem Murat Arsava, Solveig Horstmann, Jan Purrucker, Bonnie Lam, Adrian Wong, Young Dae Kim, Tae‐Jin Song, Robin Lemmens, Ender Uysal, Zeynep Tanrıverdi, Natan M. Bornstein, Einor Ben Assayag, Hen Hallevi, Jeremy Molad, Masashi Nishihara, Jun Tanaka, Shelagh B. Coutts, Alexandros A. Polymeris, Benjamin Wagner, David Seiffge, Philippe Lyrer, L. Jaap Kappelle, Rustam Al‐Shahi Salman, María Valdés Hernández, Hans Rolf Jäger, G. Y. H. Lip, Urs Fischer, Marwan El‐Koussy, Jean‐Louis Mas, Laurence Legrand, Christopher Karayiannis, Thanh G. Phan, Sarah Gunkel, Nicolas Christ, Jill Abrigo, Chiu‐Wing Winnie Chu, Thomas W. T. Leung, Francesca M. Chappell, Stephen Makin, Derek Hayden, David Williams, Werner H. Mess, M. Eline Kooi, Carmen Barbato, Simone Browning, Anil M. Tuladhar, Noortje A.M. Maaijwee, Anne Cristine Guevarra, Anne-Marie Mendyk, Christine Delmaire, Sebastian Köhler, Robert van Oostenbrugge, Ying Zhou, Chao Xu, Saima Hilal, Caroline Robert, Christopher Chen, Min Lou, Julie Staals, Régis Bordet, Nagaendran Kandiah, Frank-Erik de Leeuw, Robert Simister, Daniel Bos, Peter J. Kelly, Joanna M. Wardlaw, Yannie Soo, Felix Fluri, Velandai Srikanth, David Calvet, Simon Jung, Vincent I.H. Kwa, Stefan T. Engelter, Nils Peters, Eric E. Smith, Hideo Hara, Yusuke Yakushiji, Dilek Neci̇oğlu Örken, Vincent Thijs, Ji Hoe Heo, Vincent Mok
Abstract
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 < .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P < .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.