3. Project Summary/Abstract Intracerebral hemorrhage (ICH) is the most severe subtype across the spectrum collectively known as cerebral small vessel disease (CSVD). Our researchers have previously identified a genome-wide significant association at the locus Chr1q22 for ICH which replicated in an independent population. This finding was then replicated in other CSVD phenotypes of white matter hyperintensity, microbleeds and total stroke with a particular risk for small vessel ischemic stroke. The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study then performed deep sequencing of the locus which found that rare and common variants associated with ICH clustered in the promotor and enhancer regions of a gene labeled polyamine modulating factor-1 (PMF1). PMF1 is a key transcription factor in the polyamine metabolism pathway. Polyamines are ubiquitous and our major sources are dietary and from gut microbiota and are posited to have both beneficial and toxic forms. Thus, our own data and literature support strongly implicates polyamine metabolism may be a critical and novel risk factor for CSVD. We further obtained funding to measure polyamine and acrolein levels and found significant differences between cases and controls as proof of technique and proof of concept data. We further identified a strong trend of specific ratios of polyamines associated with neuoroimaging correlates of global tractography utilizing advanced diffusion tensor imaging. Thus, the genomic convergence of common variant, rare variant, RNA gene expression, protein and metabolomic data identifies polyamine metabolism as a potential novel risk factor for CSVD and thereby vascular dementia, the second leading cause of Alzheimer’s Disease and Related Dementias. Our investigators have developed a novel Micellar Electrokinetic Chromatography (MEKC) with Colinear Laser Induced Fluorescence Detection (LIFD) method to accurately measure both acetylated and unacetylated forms of each of the major polyamines. The current proposal seeks to recruit 400 controls from the NIA funded DECADE grant which will have baseline MRI including DTI along with blood sampling and decades of cardiovascular risk factors in a biracial cohort. The current proposal will measure polyamines and it’s toxic byproduct, acrolein in the baseline DECADE sample as well as perform a 36 month-plus repeat MRI with DTI (GERFHS V) and obtain multiple blood samples, extensive dietary history and cognitive evaluations to evaluate polyamine and acrolein levels and their correlation with the development of future CSVD. If successful, we will be able to define high risk populations for future intervention studies as well as target polyamine levels utilizing dietary and/or pharmacologic techniques in future studies. The proposal extends a 20 year history to identify a novel genetic and environmental risk factor for hemorrhagic stroke and it’s principal cause, CSVD. PHS 398/2590 (Rev. 06/09) Page Conti...