Advanced MR imaging at 7T of neurovascular abnormalities across the life span of individuals with schizophrenia

About This Grant

Schizophrenia (scz) affects 0.5-1% of the American population with devastating consequence. The fate of older individuals with scz is of particular concern: this population is rapidly increasing, estimated to reach 1.1 million in the US by 2025, complicated by advanced medical age and early mortality (> 20 years shorter life span). Further, there is accumulating evidence that, in at least a subset of older patients, scz is a progressive disorder, resulting in remarkably high rates of dementia (greater than 10x that of the general population), reduced response to pharmacological and nonpharmacological treatments, and severe impairments in social function and community integration. We hypothesize that dysfunction of the cerebral microvasculature and the CSF circulation and clearance system are critical pathophysiological factors contributing to this deterioration. We propose to use advanced multimodal MR imaging at high magnetic field (7T) to test the hypothesis that microvasculature and CSF circulation and clearance deteriorate with aging in scz, resulting in impaired cognition, functional capacity, brain aging, and treatment response. 90 individuals with scz (to include schizoaffective disorder), ranging in age from 18 to >70, and 60 matched controls, will be recruited from our ongoing Schizophrenia Phenotype Study (SPS). Each individual will receive a comprehensive diagnostic, clinical and neuropsychological assessment and then an MRI scan. In Aim 1, Quantitative MRI of microvasculature, we will use a novel imaging method developed by our group, iVASO, for mapping arteriolar cerebral blood volume (CBVa), a key measure of the microvasculature. We hypothesize, based on our preliminary work, that CBVa decreases in scz with age and disease duration relative to matched controls. In Aim 2, Quantitative MRI of CSF circulation and clearance, we will use a novel imaging method, “Dynamic Susceptibility Contrast in the CSF” (cDSC), also developed by our group, to assess CSF volume in the choroid plexus, lateral ventricle, and perivascular space, and CSF flow in the meningeal lymphatic vessels. We hypothesize that CSF circulation/clearance will also decline with age in scz, and that measures of the components of the system will be correlated. In Aim 3, Exploratory Measures, we will determine the relationship of microvascular and CSF flow measures to each other, develop a composite index that integrates all useful measurements, and model the extent to which microvascular and CSF flow in scz mediates the relationship between age and cognition, treatment response, function, and brain age, a biomarker based on structural MRI. Overall, establishing the relationship among aging, microvasculature, CSF flow, clinical outcomes, and biomarkers of age in scz has the potential to provide important insights into scz pathogenic mechanisms associated with aging, biomarkers of disease state, latent subtypes of scz, and new therapeutic targets.