Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds
Authors: Simon Fandler-Höfler, Sebastian Eppinger, Gareth Ambler, Philip Nash, Markus Kneihsl, Keon-Joo Lee, Jae-Sung Lim, Masayuki Shiozawa, Masatoshi Koga, Linxin Li, Caroline Lovelock, Hugues Chabriat, Michael Hennerici, Yuen Kwun Wong, Henry Ka Fung Mak, Luis Prats-Sanchez, Alejandro Martínez-Domeño, Shigeru Inamura, Kazuhisa Yoshifuji, Ethem Murat Arsava, Solveig Horstmann, Jan Purrucker, Bonnie Yin Ka Lam, Adrian Wong, Young Dae Kim, Tae-Jin Song, Robin Lemmens, Ender Uysal, Zeynep Tanriverdi, Natan M. Bornstein, Einor Ben Assayag, Hen Hallevi, Jeremy Molad, Masashi Nishihara, Jun Tanaka, Shelagh B. Coutts, Alexandros Polymeris, Benjamin Wagner, David J. Seiffge, Philippe Lyrer, L. Jaap Kappelle, Rustam Al-Shahi Salman, Maria Valdes Hernandez, Hans R. Jäger, Gregory Y. H. Lip, Urs Fischer, Marwan El-Koussy, Jean-Louis Mas, Laurence Legrand, Christopher Karayiannis, Thanh Phan, Sarah Gunkel, Nicolas Christ, Jill Abrigo, Winnie Chu, Thomas Leung, Francesca Chappell, Stephen Makin, Derek Hayden, David J. Williams, Werner H. Mess, M. Eline Kooi, Carmen Barbato, Simone Browning, Anil M. Tuladhar, Noortje 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 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 Necioglu Orken, Vincent Thijs, Ji Hoe Heo, Vincent Mok, Roland Veltkamp, Hakan Ay, Toshio Imaizumi, Kui Kai Lau, Eric Jouvent, Peter M. Rothwell, Kazunori Toyoda, Hee-Joon Bae, Joan Marti-Fabregas, Duncan Wilson, Jonathan Best, Franz Fazekas, Christian Enzinger, David J. Werring, Thomas Gattringer
Journal: JAMA Network Open (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;amp;lt; .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P &amp;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.