ABSTRACT NUMBER: ESOC2026A2218 A MULTISYSTEM BRAIN–BODY AXIS LINKING ORGAN HEALTH, CORTICAL MICROSTRUCTURE AND SMALL VESSEL DISEASE

Abstract Background and aims Systemic failure of vascular, metabolic and immunological homeostasis is a relevant driver of cerebrovascular diseases, in which dysfunction across multiple peripheral organ systems converges on the brain and promotes tissue injury. However, the shared contribution of multisystem organ health to brain structure and cognition remains insufficiently characterized. Methods We leveraged clinical, laboratory, and imaging data from the Hamburg City Health Study (n=2487) to map the brain-body interface. Using partial least squares (PLS) correlation, we analyzed the multivariate association between systemic biological markers – reflecting cardiovascular, metabolic, immune, renal, and dental health – and gray matter microstructure (free-water imaging) (Figure 1). Furthermore, we examined the resulting pattern of cortical microstructural differences with respect to (1) its association with MRI markers of cerebral small vessel disease (CSVD) and accelerated brain aging, and (2) its mediating role in the relationship between systemic organ markers and cognitive function. Results We identified a multivariate association between impaired multisystem organ health and reduced cortical structural integrity explaining 77.1% of shared variance. The association was primarily driven by markers of metabolic, immune, renal, and dental health (Figure 2). Higher adherence to this adverse brain-body profile was associated with greater CSVD burden and accelerated brain aging. Mediation analyses demonstrated that cortical microstructural integrity partially mediated the association between systemic organ health and cognitive performance (Figure 3). Conclusions Our findings support brain-body interactions linking multisystem organ health to cortical microstructural integrity, brain aging, CSVD, and cognition, driven specifically by metabolic, immune, renal, and dental health. Conflict of interest JG has received speaker fees from Lundbeck, Janssen-Cilag, Lilly, Otsuka and Boehringer outside the submitted work. JF reported receiving personal fees from Acandis, Cerenovus, Microvention, Medtronic, Phenox, and Penumbra; receiving grants from Stryker and Route 92; being managing director of eppdata; and owning shares in Tegus and Vastrax; all outside the submitted work. GT has received fees as consultant or lecturer from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daichi Sankyo, Portola, and Stryker outside the submitted work. MJ has received fees as consultant from Bristol-Myers Squibb. RT has received consulting honoraria from Abbott, Amgen, Astra Zeneca, Psyros, and Roche and speaker honoraria from Abbott, Amgen, Astra Zeneca, Roche and Siemens. Furthermore he is co-founder and shareholder of the ART-EMIS Hamburg GmbH. The remaining authors declare no conflicts of interest. Figure 1 - belongs to Methods Figure 2 - belongs to Results Figure 3 - belongs to Results