Accelerated Age-related Cognitive Decline: Impact of Exercise on Executive Function and Neuroplasticity (EXEC-study)

Abstract: Older adults with chronic kidney disease (CKD) present on the spectrum of Alzheimer's Disease and Related Dementias (ADRD) approximately 10 years earlier than age and sex matched controls. The prevalence of accelerated age-related cognitive decline and dementia is remarkably high in older adults with CKD, affecting as many as 20-50%. Cognitive impairment in this population leads to poor health outcomes, decreased medication and medical care adherence, functional decline and an accelerated loss of independence, and premature institutionalization. The accelerated age-related cognitive decline in patients with CKD is due, in part, to the CKD disease process itself, which leads to a reduction in white matter integrity that is superimposed on accelerated neurodegeneration of brain regions including atrophy of the hippocampus. Moreover, reduced kidney function is independently associated with lower cerebral blood flow leading to cerebral hypoperfusion, which further exacerbates cognitive decline. Current treatment regimens for CKD do not include strategies to prevent accelerated cognitive decline and related dementia. The available pharmaceutical therapies to enhance cognition have only modest short-term effects on slowing cognitive impairment, have intolerable side effects, and require dose-reduction in CKD patients. Thus, there is a pressing need to develop non-pharmacological therapies to prevent or forestall cognitive decline in older adults with CKD at risk for ADRD. The objective of this study is to test the hypothesis that a 6-month home-based walking exercise program in 116 older adults with mild cognitive impairment and CKD will improve executive function, cognitive subdomains, brain white matter integrity, structure, and functional connectivity compared to attention control. We will achieve this objective by addressing the following specific aims. 1: Does exercise work? Quantify change in executive cognitive function (primary outcome), and cognitive subdomains. 2. For whom does exercise work? Examine if factors (e.g. age, sex, cognitive impairment, and, comorbid conditions) moderate exercise-induced improvement in cognitive function domains at 6-months. 3. How does exercise work? Using MRI we will quantify change from baseline to 6-months in white matter integrity, functional connectivity, cerebral blood flow and perfusion, and hippocampal volume. We will also evaluate the mediation effects of total exercise volume on cognitive function domains and MRI measures at 6-months. Our long-term goal is to develop community-based, behavioral interventions to prevent age-related cognitive decline and ADRD in at risk populations across the lifespan. This study will address a critical gap in our understanding of the use of exercise in the prevention and treatment of accelerated age-related cognitive decline in older adults with CKD and mild cognitive impairment. By combining cognitive function assessment with MRI, we will be able to evaluate the brain-behavior response to exercise and discern the relationships at a level previously not conducted in this population. The potential clinical impact is high and readily translatable.