Sex-informed precision medicine in acute ischemic stroke

• Applicant: Dr. Anna Bonkhoff
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460362683

Our first research aim will be focused on increasing the clinical actionability of sex-specific lesion pattern effects by enhancing their spatial, temporal and functional outcome resolution. Our previous work suggests that acute stroke severity in female patients is explained by more widespread lesion pattern. In particular, stroke lesions in the left posterior circulation underlay a higher stroke severity only in women. We will here investigate whether such sex-specific lesion pattern effects persist and influence chronic functional outcome. We will furthermore aim to identify sex-specific brain-region-wise lesion effects on domain-specific stroke symptoms. We will address these aims by investigating lesion pattern in ~1,600 acute ischemic stroke patients originating from the MRI-GENIE study with available information on chronic modified Rankin Scale scores and developing multi-output Bayesian hierarchical models to simultaneously predict various stroke symptoms based on brain-region-wise lesion information of ~1,000 acute ischemic stroke patients recruited for the DISCOVERY study. The promise of this aim is to identify sex-specific effects of acute brain-region-specific lesions on subtle brain functions and to determine their impact on long-term outcomes. Our second research aim will be to augment the prediction of acute and chronic stroke outcomes and explore potential origins of sex differences in lesion pattern effects by leveraging lesion network maps. First, we will evaluate the capacities of structural lesion topography and functional lesion network maps (i.e., the functional connectivity of every brain voxel to the lesion) for subject-level predictions of acute stroke severity and chronic functional outcome. Secondly, we will explore potential origins of sex differences in lesion pattern by aiming to predict the male/female status based on sex-specific lesion network maps. Therefore, we will first estimate the overall, sex-agnostic functional disconnection load for ~1,600 MRI-GENIE patients, and also compute sex-specific lesion network maps based on male- and female-specific functional connectivity. The combination of structural lesion information and lesion network maps may then not only enhance prediction models across men and women, but also ascertain sex differences in the ”functional disconnection fingerprint”; conceivably uncovering more far-reaching disruptions of the connectome in women, representing underpinnings of their often observed greater stroke severity.Altogether, both aims will put an emphasis on enriching our understanding of the sex-specific brain organization as implicated in individual outcomes after ischemic stroke. Developed patient-level prediction models may help to plan personalized rehabilitative regimens and novel insights have the potential to unravel future targets for more tailored, sex-specific interventions in clinical stroke care, with an ultimate objective to improve overall stroke outcomes.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Natalia Rost