Describing functional brain connectivity\u27s role in the relationship of multimodal interventions to improve cognitive and physical function in vulnerable (frailty & mild cognitive impairment) older adults.

Aging is associated with declining cognitive and physical function. The decline accelerates in older adults diagnosed with mild cognitive impairment (MCI), a pre-dementia state, and frailty, a state of decreased physiological reserve. Previous work shows that frailty modifies the relationship between dementia pathology and clinical symptoms. Functional brain network connectivity (FBNC) refers to brain areas that are anatomically separate but temporally related in their neural signaling; it is believed to enable the completion of complex cognitive and physical functions. FBNC is considered a sensitive biomarker for monitoring the progression of dementia syndromes and investigating the efficacy of interventional strategies. Therefore, this dissertation investigated if FBNC represents an underlying neurophysiological change responsible for alterations in the cognitive and physical function of vulnerable older adults after partaking in a lifestyle intervention. Furthermore, how improvements or lack thereof may reflect a relationship between frailty, sex, and dementia. First, I conducted a systematic review on the effect of physical exercise with and without other interventional strategies on FBNC in older adults with and without cognitive impairment (Chapter 2). Included studies (10/12) demonstrated increased within-network FBNC. Conversely, control groups showed no or alternative changes in FBNC. Only one of the included studies showed a correlation between FBNC and cognitive outcomes, and they did not control for multiple comparisons. Next, and given its inclusion in Chapter 4\u27s multimodal RCT, I conducted an open-label feasibility study in older adults to test the feasibility and efficacy of high-dose vitamin D independently. The study sample experienced no adverse events but only participants with the greatest deficits (i.e., frail and insufficient (\u3c 75nmol/L) vitamin D serum levels) made significant improvements, and only in measures of physical performance. Chapter 4\u27s RCT examined the impact of aerobic and resistance training separately and synergistically with cognitive training and/or high-dose vitamin D supplementation (multimodal intervention) on FBNC. I found that physical exercise increased connectivity between the Hippocampus and Angular Gyrus, representing regions within the Default Mode-Network. Adding cognitive training with or without high-dose vitamin D supplementation made some additional changes to exercise-induced FBNC alterations. Similar to our systematic review, FBNC showed no correlations with behavioral outcomes after controlling for multiple comparisons. Chapter 5 was motivated by a desire to determine if frailty alters FBNC. I found increasing (worse) frailty is associated with what is believed to be increasing between-network connectivity. Furthermore, the relationship between frailty and FBNC differed by sex. This dissertation provided support for FBNC as a potential biomarker to monitoring neural substrates vulnerable populations and their response to interventions. Specifically, lifestyle interventions, inclusive of exercise, are efficacious in increasing within-network FBNC, which is thought to reflect better brain function. Frailty status, sex, and baseline vitamin D levels appear to confound or interact with the effect of exercise interventions on FBNC. As such, researchers should explore these in future studies