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Doctor of Philosophy




Montero-Odasso, Manuel


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's 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 (< 75nmol/L) vitamin D serum levels) made significant improvements, and only in measures of physical performance.

Chapter 4's 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.

Summary for Lay Audience

Decline in cognition and physical function (i.e., memory and muscle strength) is a normal part of aging. The decline is faster in vulnerable older adults diagnosed with mild cognitive impairment and/or frailty. Mild cognitive impairment is considered a pre-dementia state, and frailty is a decline in overall health. Older adults diagnosed with cognitive impairment are more likely to be frail and vice versa. Brain connectivity (i.e., areas of the brain that activate or "turn on" together) may be compromised in both groups. It may also help explain important behavioural changes (i.e., memory improvement) following physical exercise (i.e., jogging).

Chapter 2 showed that brain connectivity improves following physical exercise, but changes have very little impact on cognitive or physical function. Chapter 3 showed that high-dose vitamin D supplementation improved physical but not cognitive function, and only in those that were the most vulnerable (i.e., frail and/or low vitamin D levels). Chapter 3 also provided support for the inclusion of vitamin D in Chapter 4, where I explored the impact of various lifestyle interventions on brain connectivity. Physical exercise improved brain connectivity and adding cognitive training and vitamin D supplementation created some additional changes. Similar to chapter 2, changes in brain connectivity showed no relationship with changes in cognitive or physical performance. Pre-intervention differences in health status may have affected the results of chapter 2 and 4. So, in Chapter 5, I explored and then showed that frailty status is associated with brain connectivity, and the relationship differs by sex.

My studies revealed that interventions improve brain connectivity, but how these changes impact cognitive or physical function remains unclear. Vitamin D has some benefits on brain connectivity and improves physical performance. Researchers should consider frailty status, sex and, vitamin D levels when measuring brain connectivity.

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This work is licensed under a Creative Commons Attribution 4.0 License.

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