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.

Public Health Relevance

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. .

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD064993-09
Application #
9417955
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Parisi, Melissa
Project Start
2009-09-30
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
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
Carmona-Iragui, MarĂ­a; Balasa, Mircea; Benejam, Bessy et al. (2017) Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease. Alzheimers Dement 13:1251-1260
LeVine 3rd, Harry; Spielmann, H Peter; Matveev, Sergey et al. (2017) Down syndrome: age-dependence of PiB binding in postmortem frontal cortex across the lifespan. Neurobiol Aging 54:163-169
Doran, Eric; Keator, David; Head, Elizabeth et al. (2017) Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP. J Alzheimers Dis 56:459-470
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
Day, Ryan J; McCarty, Katie L; Ockerse, Kayla E et al. (2016) Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain. Aging Dis 7:267-77
Head, Elizabeth; Lott, Ira T; Wilcock, Donna M et al. (2016) Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology. Curr Alzheimer Res 13:18-29
Wilcock, Donna M; Schmitt, Frederick A; Head, Elizabeth (2016) Cerebrovascular contributions to aging and Alzheimer's disease in Down syndrome. Biochim Biophys Acta 1862:909-14
Anderson-Mooney, Amelia J; Schmitt, Frederick A; Head, Elizabeth et al. (2016) Gait dyspraxia as a clinical marker of cognitive decline in Down syndrome: A review of theory and proposed mechanisms. Brain Cogn 104:48-57

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