This application is being submitted in response to PA-18-591 in accordance with NOT-OD-18-194. Down syndrome (DS) individuals develop Alzheimer's disease (AD) neuropathology by 40 years of age, with clinical dementia typically observed at ages over 50 years. Due to the genetic underpinning of AD in DS, there has been an assumption in the field that DS individuals represent pure cases of AD, and this assumption has been made in the absence of evidence to that fact. Neuropathological studies in DS have focused on AD pathologies; plaques and tangles, as well as neurodegeneration. Based on data we generated several years ago, exploring neuroinflammatory states in the DS brain using autopsy tissue, we have generated a hypothesis that DS brain also exhibits early cerebrovascular damage, leading to vascular contributions to cognitive impairment and dementia (VCID) in DS. At the University of Kentucky, we have outstanding resources to study DS. We have both autopsy brain tissue for DS at different ages, and we have a longitudinal clinical cohort where we have been following DS individuals over the age of 25 for eight years. These individuals undergo cognitive testing and MRI imaging, as well as giving blood samples for fluid biomarker studies. Novel findings already published from the longitudinal study include early white matter disruptions, unique neuroinflammatory responses, and altered brain metabolism. Recent findings from the study highlight early cerebrovascular changes in the DS brain. As a result of these recent, exciting findings, we propose to explore neurovascular astrocyte changes in the DS brain, and explore some recently identified, novel fluid biomarkers that we find associate significantly with small vessel ischemic disease and vascular cognitive impairment. These data will further add to the parent RO1 grant. Our overarching hypothesis is that DS brains show similar VCID changes to the neurovascular astrocytes, leading to astrocytic degeneration early in the disease process and this is accompanied by changes in endothelial and microglial cell activation. To test our hypotheses, we will leverage our autopsy brain tissue and plasma from our longitudinal clinical cohort. We propose two specific aims for this supplement:
Specific Aim 1 : Test the hypothesis that neurovascular astrocyte degeneration is present early in the DS brain and is associated with cerebrovascular pathology.
Specific Aim 2 : Test the hypothesis that endothelial activation and a neuroinflammatory response accompanies cerebrovascular pathologies in a longitudinally followed DS cohort.
| Price, Brittani R; Norris, Christopher M; Sompol, Pradoldej et al. (2018) An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia. J Neurochem 144:644-650 |
| Sudduth, Tiffany L; Weekman, Erica M; Price, Brittani R et al. (2017) Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience 341:42-51 |
