REACH-EpiVCID

Caused by advanced cerebral small vessel disease (CSVD), intracerebral hemorrhage (ICH) leaves survivors
with a very high risk of incident vascular cognitive impairment and dementia (VCID). While aggressive blood
pressure (BP) reduction can reduce the risk of VCID and recurrent stroke, more than 50% of ICH survivors have
BP above target, particularly individuals with adverse social determinants of health (SDOH). The parent study,
REACH-ICH (R01NS093870), will fill gaps in our knowledge about the role of SDOH after ICH by identifying
SDOH-induced environmental risk factors that impact a) VCID after ICH, b) BP treatment resistance, and c)
engagement with a program designed to improve treatment of BP. 700 ICH survivors are currently being enrolled
through REACH-ICH at multiple centers, divided among White, Black, Hispanic, and Asian participants.
Participants are screened with an extensive battery for SDOH exposures, and are followed longitudinally for BP
treatment response, cognitive decline, and recurrent stroke. 607 of the participants will receive genome-wide
genotyping under the award.
Additional analyses building on the REACH-ICH infrastructure could yield biological mechanisms induced by
adverse SDOH environments that could be amenable to therapeutic development, at a fraction of the cost of a
standalone study. This proposed project, REACH-EpiVCID, will examine epigenetic mediators between SDOH
exposures and adverse cognitive outcomes after ICH, as well as BP treatment resistance. Epigenetic changes
have already been identified in association with environmental exposures such as air pollution, and have
established associations in cardiovascular disease. We will extend these observations to a cohort heavily
enriched for CSVD and with an historically high burden of adverse SDOH exposures. REACH-EpiVCID will a)
identify epigenetic changes associated with environmental differences induced by SDOH, b) identify epigenetic
changes associated with incident VCID and BP treatment resistance after ICH, and c) combine epigenetic
associations with DNA genotypes to perform formal mediation analyses and causal inference testing via
Mendelian randomization. Epigenetic changes and the mechanistic pathways they highlight are potentially
modifiable by small molecules or by behavioral change, and so putative causal associations mediating the effect
of SDOH on VCID will represent highly relevant candidates for development of novel treatments to prevent VCID
and improve BP treatment resistance after ICH. Further, because epigenetic mediators between SDOH and
VCID are likely to be initiated by adverse environmental exposures, treatment targets arising from this approach
stand to have the greatest benefits in marginalized populations at greatest risk for these exposures, promoting
health equity through biologically informed treatments as strategies to ameliorate the structural contributors to
SDOH continue to evolve with time.

Grant Number: 1RF1NS139183-01
NIH Institute/Center: NIH
Principal Investigator: Christopher Anderson