Modeling Cerebral Microbleeds and Striatal Brain Iron in Adult Congenital Heart Disease in Relationship to Differential Genetic Risk for Alzheimer Disease

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Emerging data suggests that the soaring population of adult survivors of congenital heart disease (CHD), are at increased risk of developing cognitive decline and early-onset dementia. The role of other important risk factors for dementia, including the presence of cerebral microbleed, elevated brain iron levels, and apolipoprotein E (APOE) genotype in adult CHD is unknown. With an allele frequency of 14%, APOE-ε4 is present in approximately 25% of the US population and associated with increased risk of Alzheimer’s Disease. Our overall hypothesis the presence of cerebral microbleeds and elevated brain iron levels predict poor neurocognitive outcomes and accelerating presenile (early onset) dementia risk in adult CHD and that this relationship is moderated by APOE genotype. In the current ancillary Ro1 to the NHLBI-funded Pediatric Heart Network (PHN) MINDS study, we are measuring acquired brain injury and multi-modal neuroimaging biomarkers leveraging the neurocognitive testing of the patient cohort between 18-30 years of age and utilizing the well- established infrastructure already in place for the parent PHN MINDS study. There is limited research about the long-term impact of CHD on these relevant neuroimaging biomarkers [cerebral microbleeds measures with susceptibility weighted imaging (SWI) and striatal brain iron measured with resting functional imaging (BOLD)] that have been developed in detail utilizing large-scale dementia risk populations (Alzheimer’s Disease Neuroimaging Initiatives- ADNI). Our preliminary data in adult CHD MINDS patients demonstrate findings that overlap with Alzheimer’s disease which includes a high prevalence (>50%) of young adult CHD patients with cortical and subcortical microbleeds as identified with SWI imaging. The goal of this administrative supplement is to expand the delineation of neuroimaging biomarkers to deeply characterized features of these cerebral microbleeds (using quantitative SWI) and rigorously quantitate striatal brain iron (using resting BOLD imaging). The MINDS parent study also includes an extensive NIH-Tool Box neurocognitive/neurobehavioral testing battery. We will eventually be able to leverage the extensive parent MINDS study biological specimen collection/analysis which includes not only DNA, but also ApoE genotyping data and other vascular stress and resilience genotypes. Our specific aims for this administrative supplement are: Specific Aim #1: Cerebral Microbleeds: Quantitate multi-dimensional features of cerebral microbleeds using SWI imaging. Advanced neuroinformatic techniques will be employed including spatial morphometry and machine learning techniques. We will correlate features of cerebral microbleeds with neurocognitive outcomes (primary), cardiovascular related patient/medical factors data (secondary), future ApoE genotyping (exploratory). Specific Aim #2: Striatal Brain Iron Measurement: Leverage the current MINDS neuroimaging protocol to quantitate striatal brain iron using resting state BOLD imaging. Correlation with features of cerebral microbleeds, neurocognitive outcomes and future ApoE genotype in the MINDS cohort will also be performed. The results from our proposed administrative supplement to our current Ro1 grant will help to elucidate the way interactions between cerebral microbleeds, striatal brain iron and APOE genotyping abnormalities give rise to cognitive-behavioral phenotypes by leveraging the NHLBI-funded PHN MINDS study. By delineating and identifying which adult CHD patients are mostly likely at risk for cognitive decline/dementia at the earlier time point possible will allow us to employ prevention of modifiable risk factors. Reciprocally, the results from our proposed administrative supplement will help inform the relationship between APOE ε4 genotype expression and cerebral microbleeds and striatal brain iron which may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these brain alterations holds inherent value for not only prognostication, but also the development and evaluation of preventive treatment therapies for not only CHD- related dementia, but also Alzheimer disease, possibly employed during the young adult period.