Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses, cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline.
Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity.
Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging, fluid attenuated inversion recovery and arterial spin labeling.
Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age, AD neuropathology and declines in cognition.
Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity, CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1), WM structural integrity (Aim 1), and CVF improvements (Aim 2), and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signs of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.
The proposed study will identify early changes in brain inflammation, cerebrovascular dysfunction and white matter integrity losses that signal changes in cognition, behavior, and functioning reflecting Alzheimer disease (AD) in adults with Down syndrome (DS). Identifying the earliest signs of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration. .
|Head, Elizabeth; Helman, Alex M; Powell, David et al. (2018) Down syndrome, beta-amyloid and neuroimaging. Free Radic Biol Med 114:102-109|
|Miranda, Andre M; Herman, Mathieu; Cheng, Rong et al. (2018) Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease. Cell Rep 23:2967-2975|
|Di Domenico, Fabio; Tramutola, Antonella; Foppoli, Cesira et al. (2018) mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia. Free Radic Biol Med 114:94-101|
|Barone, Eugenio; Arena, Andrea; Head, Elizabeth et al. (2018) Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism. Free Radic Biol Med 114:84-93|
|Head, Elizabeth; Powell, David K; Schmitt, Frederick A (2018) Metabolic and Vascular Imaging Biomarkers in Down Syndrome Provide Unique Insights Into Brain Aging and Alzheimer Disease Pathogenesis. Front Aging Neurosci 10:191|
|Babulal, Ganesh M; Quiroz, Yakeel T; Albensi, Benedict C et al. (2018) Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need. Alzheimers Dement :|
|Lanzillotta, Chiara; Tramutola, Antonella; Meier, Shelby et al. (2018) Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. J Alzheimers Dis 62:347-359|
|Head, Elizabeth; Phelan, Michael J; Doran, Eric et al. (2017) Cerebrovascular pathology in Down syndrome and Alzheimer disease. Acta Neuropathol Commun 5:93|
|Barone, Eugenio; Head, Elizabeth; Butterfield, D Allan et al. (2017) HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology. Free Radic Biol Med 111:262-269|
|Tramutola, Antonella; Di Domenico, Fabio; Barone, Eugenio et al. (2017) Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology. Antioxid Redox Signal 26:280-298|
Showing the most recent 10 out of 42 publications