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. 2024 Oct 1;7(10):e2439571.
doi: 10.1001/jamanetworkopen.2024.39571.

Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds

Simon Fandler-Höfler  1   2 , Sebastian Eppinger  1   3 , Gareth Ambler  4 , Philip Nash  2 , Markus Kneihsl  1   3 , Keon-Joo Lee  5 , Jae-Sung Lim  6 , Masayuki Shiozawa  7 , Masatoshi Koga  7 , Linxin Li  8 , Caroline Lovelock  8 , Hugues Chabriat  9   10   11 , Michael Hennerici  12 , Yuen Kwun Wong  13 , Henry Ka Fung Mak  14 , Luis Prats-Sanchez  15 , Alejandro Martínez-Domeño  15 , Shigeru Inamura  16 , Kazuhisa Yoshifuji  16 , Ethem Murat Arsava  17 , Solveig Horstmann  18 , Jan Purrucker  18 , Bonnie Yin Ka Lam  19 , Adrian Wong  19 , Young Dae Kim  20 , Tae-Jin Song  21 , Robin Lemmens  22   23 , Ender Uysal  24 , Zeynep Tanriverdi  25 , Natan M Bornstein  26   27 , Einor Ben Assayag  27   28 , Hen Hallevi  27   28 , Jeremy Molad  27   28 , Masashi Nishihara  29 , Jun Tanaka  30 , Shelagh B Coutts  31 , Alexandros Polymeris  32 , Benjamin Wagner  32 , David J Seiffge  2   32   33 , Philippe Lyrer  32 , L Jaap Kappelle  34 , Rustam Al-Shahi Salman  35 , Maria Valdes Hernandez  35 , Hans R Jäger  36 , Gregory Y H Lip  37   38 , Urs Fischer  33 , Marwan El-Koussy  39 , Jean-Louis Mas  40   41 , Laurence Legrand  42   43 , Christopher Karayiannis  44 , Thanh Phan  45 , Sarah Gunkel  46 , Nicolas Christ  46 , Jill Abrigo  47 , Winnie Chu  47 , Thomas Leung  48 , Francesca Chappell  49   50 , Stephen Makin  51 , Derek Hayden  52   53 , David J Williams  54   55 , Werner H Mess  56 , M Eline Kooi  57   58 , Carmen Barbato  2   59 , Simone Browning  2   59 , Anil M Tuladhar  60 , Noortje Maaijwee  61 , Anne Cristine Guevarra  62 , Anne-Marie Mendyk  63 , Christine Delmaire  63   64 , Sebastian Köhler  65 , Robert van Oostenbrugge  66 , Ying Zhou  67 , Chao Xu  67 , Saima Hilal  68 , Caroline Robert  69 , Christopher Chen  69 , Min Lou  67 , Julie Staals  66 , Régis Bordet  63 , Nagaendran Kandiah  62 , Frank-Erik de Leeuw  70 , Robert Simister  2   59 , Daniel Bos  71 , Peter J Kelly  53 , Joanna Wardlaw  49   50 , Yannie Soo  48 , Felix Fluri  46 , Velandai Srikanth  44 , David Calvet  40 , Simon Jung  33 , Vincent I H Kwa  72 , Stefan T Engelter  32   73 , Nils Peters  32   73 , Eric E Smith  31 , Hideo Hara  29 , Yusuke Yakushiji  30   74 , Dilek Necioglu Orken  75 , Vincent Thijs  76   77 , Ji Hoe Heo  20 , Vincent Mok  19 , Roland Veltkamp  18   78 , Hakan Ay  17   79 , Toshio Imaizumi  16 , Kui Kai Lau  13 , Eric Jouvent  9 , Peter M Rothwell  8 , Kazunori Toyoda  7 , Hee-Joon Bae  5 , Joan Marti-Fabregas  15 , Duncan Wilson  2   80 , Jonathan Best  2 , Franz Fazekas  1 , Christian Enzinger  1 , David J Werring  2 , Thomas Gattringer  1   3 ; Microbleeds International Collaborative Network
Affiliations

Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds

Simon Fandler-Höfler et al. JAMA Netw Open. .

Erratum in

  • Error in Author Name.
    [No authors listed] [No authors listed] JAMA Netw Open. 2025 Feb 3;8(2):e251456. doi: 10.1001/jamanetworkopen.2025.1456. JAMA Netw Open. 2025. PMID: 39976974 Free PMC article. No abstract available.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Koga reported receiving personal fees from KOWA Company, AstraZeneca, Bayer Yakuhin, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Bristol Myers Squibb (BMS), Pfizer, Janssen Pharmaceuticals, Otsuka Pharmaceutical and grants from Daiichi Sankyo and Nippon Boehringer Ingelheim outside the submitted work. Dr Purrucker reported receiving personal fees from Abbott, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Akcea, BMS, and Pfizer outside the submitted work. Dr Bornstein reported receiving personal fees from Ever Neuro Pharma and Boehringer Ingelheim Israel outside the submitted work. Dr Seiffge reported receiving personal fees (paid to institution) from AstraZeneca and Bayer outside the submitted work. Dr Fischer reported receiving grants from Swiss National Science Foundation, Swiss Heart Foundation, Medtronic, Stryker, Rapid Medical, Penumbra, Phenox, Boehringer Ingelheim; and personal fees (paid to institution) from Medtronic, Stryker, and CSL Behring outside the submitted work; participating in advisory boards (with fees paid to institution) for AstraZeneca (formerly Alexion/Portola), Boehringer Ingelheim, Biogen, AbbVie, and Acthera; serving as a member of a clinical event committee of the Coating to Optimize Aneurysm Treatment in the New Flow Diverter Generation study (Phenox) and of the data and safety monitoring committee of the TITAN, Large Artery Occlusion Treated in Extended Time With Mechanical Thrombectomy, and IN EXTREMIS trials; and serving as president of the Swiss Neurological Society and president-elect of the European Stroke Organisation outside the submitted work. Dr Phan reported receiving personal fees from Pfizer, BMS, and Bayer outside the submitted work. Dr Makin reported receiving grants from Dunhill Medical Trust, Scottish Chief Scientists Office, and National Health Service Research Scotland outside the submitted work. Dr Mess reported receiving grants from the Dutch Heart Foundation during the conduct of the study. Dr Kooi reported receiving grants (paid to institution) from the Center of Translational Molecular Medicine during the conduct of the study. Dr Köhler reported receiving grants from Adriana Rinsum-Ponsen Stichting Private Charity during the conduct of the study. Dr Staals reported receiving grants from Stichting Adriana van Rinsum-Ponsen Private Charity during the conduct of the study. Dr Wardlaw reported receiving grants from Wellcome Trust, Research Councils UK, and Row Fogo Charitable Trust during the conduct of the study. Dr Kwa reported receiving grants from ZonMw outside the submitted work. Dr Thijs reported receiving personal fees from Boehringer Ingelheim, Bayer, and Medtronic outside the submitted work. Dr Veltkamp reported receiving grants from Bayer, Boehringer Ingelheim, BMS, Pfizer, Daiichi Sankyo and personal fees from Bayer and AstraZeneca outside the submitted work. Dr Toyoda reported receiving personal fees from Otsuka, Daiichi Sankyo, Bayer, Janssen, and BMS outside the submitted work. Dr Werring reported receiving personal fees from Bayer, Novo Nordisk, AstraZeneca, and Alnylam outside the submitted work. Dr Gattringer reported receiving grants from the Austrian Science Fund and personal fees from Boehringer Ingelheim, Novartis, and AstraZeneca outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart of Patient Selection
MICON indicates Microbleeds International Collaborative Network; TIA, transient ischemic attack.
Figure 2.
Figure 2.. Linear Comparison of Rates of Cerebral Microbleeds, Lacunes, and Moderate-to-Severe White Matter Hyperintensities by Age and Sex
Figure 3.
Figure 3.. Kaplan-Meier Curves for Recurrent Ischemic Stroke, Intracranial Hemorrhage, and Mortality for Female and Male Patients Without and With Cerebral Microbleeds (CMB), Adjusted for Age
See this image and copyright information in PMC

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