PROJECT SUMMARY
Spontaneous intracerebral hemorrhage (sICH) survivors are at high risk for developing vascular contributions
to cognitive impairment and dementia (VCID). However, there is limited data on the predictors and
mechanisms associated with VCID after sICH. Therefore, it is critically important to confirm novel biomarkers in
sICH survivors that may be associated with the development of and progression to VCID. Recent literature has
highlighted the discovery of new silent brain infarcts (SBIs) on MRI shortly after hospitalization in upwards of
50% of sICH patients. Though clinically undetectable, the mechanism through which SBIs in sICH lead to
worse functional outcomes in multiple cohort studies remains unclear. SBIs have been a well-described risk
factor for cognitive impairment and dementia in the general population. Given this epidemiologic data, cognitive
impairment may be driving the worse functional outcomes described in SBI positive sICH patients. This
proposal aims to determine whether SBIs are associated with worse cognitive outcomes and two key
mechanisms implicated in VCID development—white matter hyperintensities (WMH) progression and systemic
inflammation. In preliminary data, sICH patients with SBIs exhibit lower levels of global cognition, and lower
levels of episodic and working memory—two important cognitive domains affected in VCID. Furthermore, we
found that SBIs in sICH are linked to more rapid WMH progression and elevated chronic systemic inflammation
as measured by a three-finger toxin called soluble urokinase-type plasminogen activator receptor (suPAR). To
achieve our overall objective, we will test the hypothesis that SBIs in sICH are longitudinally associated over 1
year with: (Aim #1) a lower cognitive level and more rapid cognitive decline; (Aim #2) more rapid WMH
progression as measured by serial MRI; and (Aim #3) higher chronic systemic inflammation as measured by
serum suPAR. This research is highly significant since it will establish SBIs as an early, easily identifiable
neuroimaging biomarker for sICH patients at risk for VCID and mechanisms associated with VCID. This study
is innovative because it will: (1) generate comprehensive cognitive outcomes models in sICH; (2) employ a
novel WMH segmentation technique to measure volumetric WMH progression; (3) measure suPAR—a
treatable inflammatory protein—to assess systemic vascular inflammation. Ultimately, the knowledge gained
from this proposal will provide the necessary groundwork to support future treatment trials aimed at reducing
the cognitive morbidity associated with sICH through novel therapies that promote WMH regression and
reduce suPAR levels. Currently, minimal therapies exist to improve the outcomes for this disease.
