Medicine, Faculty of
Occupational Science and Occupational Therapy, Department of
Physical Therapy, Department of
DSpace
UBCV
Cirone, Victoria
Master of Science - MSc
University of British Columbia
Sixty-one percent of Canadians with dementia are female. Neuroendocrine changes during perimenopause may contribute to females’ higher prevalence of dementia. Perimenopause is a critical window to promote female brain health. Exercise is a promising strategy targeting a key modifiable risk factor for dementia — physical inactivity — and promotes cognitive function. High-intensity interval training (HIIT) involves anaerobic exercise intervals interspersed with aerobic rest periods and improves cardiorespiratory fitness. High-intensity interval training addresses the lack-of-time barrier to exercise experienced by many perimenopausal females. High-intensity interval training’s effects on cognitive function and brain health in perimenopausal females has not been examined. Thus, I conducted a feasibility study to assess the feasibility, safety, and explore the effects of 12 weeks of HIIT on cardiorespiratory fitness, verbal episodic memory, and structural neuroimaging outcomes. Feasibility outcomes include: 1) recruitment rate (primary feasibility outcome); 2) adherence; and 3) withdrawal rate. Safety was assessed by the number of most-likely or definitely-related adverse events. Cardiorespiratory fitness was assessed by maximal oxygen consumption (VO2max). Verbal episodic memory was assessed by Rey Auditory Verbal Learning Test immediate and 30-minute delayed recall. Total, left, and right hippocampal volume were measured by T1-weighted magnetic resonance imaging. Myelin content was measured by myelin water fraction. The traffic light system for feasibility criteria categorized feasibility outcomes as: 1) go; 2) amend; or 3) stop. Point estimates for the secondary objective outcomes included mean change, standard deviation, percent change, and Cohen’s d. Sixteen perimenopausal females (mean age = 48.94 years) were recruited in 21 months. Eleven participants were included in the point estimate analysis. Recruitment rate (0.76 participants per month) and withdrawal rate (18.75%) were in the “amend” category. Adherence (87.95%) was in the “go” category. There were five adverse events related to the intervention or study procedures. The HIIT intervention had a positive and large effect on immediate and 30-minute delayed recall, and a positive and small effect on cardiorespiratory fitness and structural neuroimaging outcomes. Based on the results of this feasibility study, future studies should consider: 1) offering a hybrid exercise intervention; and 2) re-evaluating exogenous hormones and depression symptomology exclusion criteria.
FEASIBILITY OF HIGH-INTENSITY INTERVAL TRAINING IN PERIMENOPAUSE TO PROMOTE COGNITIVE FUNCTION AND BRAIN HEALTH by Victoria Cirone B.Sc., McMaster University, 2022 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Rehabilitation Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) November 2024 © Victoria Cirone, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Feasibility of High-Intensity Interval Training in Perimenopause to Promote Cognitive Function and Brain Health submitted by Victoria Cirone in partial fulfilment of the requirements for the degree of Master of Science in Rehabilitation Sciences Examining Committee: Teresa Liu-Ambrose, Professor, Department of Physical Therapy, University of British Columbia Supervisor Cindy Barha, Assistant Professor, Faculty of Kinesiology, University of Calgary Supervisory Committee Member Nárlon Cássio Boa Sorte Silva, Assistant Professor, Department of Health, Kinesiology & Applied Physiology, Concordia University Supervisory Committee Member Todd Handy, Professor, Department of Psychology, University of British Columbia Supervisory Committee Member Linda Li, Professor, Department of Physical Therapy, University of British Columbia Additional Examiner iii Abstract Sixty-one percent of Canadians with dementia are female. Neuroendocrine changes during perimenopause may contribute to females’ higher prevalence of dementia. Perimenopause is a critical window to promote female brain health. Exercise is a promising strategy targeting a key modifiable risk factor for dementia — physical inactivity — and promotes cognitive function. High-intensity interval training (HIIT) involves anaerobic exercise intervals interspersed with aerobic rest periods and improves cardiorespiratory fitness. High-intensity interval training addresses the lack-of-time barrier to exercise experienced by many perimenopausal females. High-intensity interval training’s effects on cognitive function and brain health in perimenopausal females has not been examined. Thus, I conducted a feasibility study to assess the feasibility, safety, and explore the effects of 12 weeks of HIIT on cardiorespiratory fitness, verbal episodic memory, and structural neuroimaging outcomes. Feasibility outcomes include: 1) recruitment rate (primary feasibility outcome); 2) adherence; and 3) withdrawal rate. Safety was assessed by the number of most-likely or definitely-related adverse events. Cardiorespiratory fitness was assessed by maximal oxygen consumption (VO2max). Verbal episodic memory was assessed by Rey Auditory Verbal Learning Test immediate and 30-minute delayed recall. Total, left, and right hippocampal volume were measured by T1-weighted magnetic resonance imaging. Myelin content was measured by myelin water fraction. The traffic light system for feasibility criteria categorized feasibility outcomes as: 1) go; 2) amend; or 3) stop. Point estimates for the secondary objective outcomes included mean change, standard deviation, percent change, and Cohen’s d. Sixteen perimenopausal females (mean age = 48.94 years) were recruited in 21 months. Eleven participants were included in the point estimate analysis. Recruitment rate (0.76 iv participants per month) and withdrawal rate (18.75%) were in the “amend” category. Adherence (87.95%) was in the “go” category. There were five adverse events related to the intervention or study procedures. The HIIT intervention had a positive and large effect on immediate and 30-minute delayed recall, and a positive and small effect on cardiorespiratory fitness and structural neuroimaging outcomes. Based on the results of this feasibility study, future studies should consider: 1) offering a hybrid exercise intervention; and 2) re-evaluating exogenous hormones and depression symptomology exclusion criteria. v Lay Summary More females have dementia than males. Research shows that perimenopause may be a critical time to reduce dementia risk as many females experience difficulties thinking as well as changes in the brain. However, perimenopause occurs during midlife when many people are very busy. High intensity interval training (HIIT) is a time-efficient way of exercising. Thus HIIT is a promising approach to promote brain health for perimenopausal females who may have limited time to exercise. I carried out a 12-week feasibility study to determine if HIIT was feasible and to explore its effects on fitness, memory, and the brain in perimenopausal females. Feasibility studies are critical in planning larger studies that aim to provide more definitive evidence. Sixteen perimenopausal females were recruited and 11 completed the study as part of my thesis. Recruitment targets were lower than expected, and the eligibility criteria should be revisied for future studies. vi Preface This thesis consists of materials written and compiled by Victoria Cirone. The content of this thesis was reviewed by Professors Teresa Liu-Ambrose, Todd Handy, Linda Li and Assistant Professors Cindy Barha and Nárlon Cássio Boa Sorte Silva. Their feedback was implemented in the final version of this thesis. All of the data presented in this thesis was conducted in the Aging, Mobility, and Cognitive Health Lab at the Centre for Aging SMART and Djavad Mowafaghian Centre for Brain Health at the University of British Columbia. Victoria Cirone was responsible for the concept formation, data interpretation, and manuscript composition. Victoria Cirone completed the data analysis for the primary objective outcomes, cardiorespiratory fitness, verbal episodic memory, and myelin content. Dr. Nárlon Cássio Boa Sorte Silva completed hippocampal volume data analysis. Victoria Cirone completed the quality checks and statistical analysis for the hippocampal volume analysis. Ethical approval for this study was approved by the University of British Columbia Research Ethics Board (H20-00925) and Vancouver Coastal Health Research Ethics Board (V20-00925). Co-investigators for the study included: Dr. Walid Alkeridy, Dr. Cindy Barha, Dr. Ryan Falck, Dr. Liisa Galea, Dr. Vesna Sossi, Dr. Roger Tam, Dr. Nárlon Cássio Boa Sorte Silva. The study team members were: Nathan Wei, Patrick Chan, Matthew Noseworthy, Sarah Heath, Victoria Cirone, Alexis Bullock, and Sofia Grant. Research staff and graduate students in the Aging, Mobility, and Cognitive Health Lab were responsible for recruitment, assessments, intervention delivery, and data cleaning. Dr. Teresa Liu-Ambrose, Dr. Ryan Falck, Sofia Grant, and Alexis Bullock developed the study intervention. vii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ....................................................................................................................... vii List of Tables .................................................................................................................................x List of Figures .............................................................................................................................. xi List of Abbreviations ................................................................................................................ xii Acknowledgements .................................................................................................................... xiii Dedication ................................................................................................................................... xiv Chapter 1: Introduction ................................................................................................................1 1.1 Overview ................................................................................................................................... 1 1.2 Importance of Cognitive Health During Aging ....................................................................... 1 1.2.1 Cognitive Function in Aging, and Sex Differences .................................................. 2 1.2.2 Structural Brain Changes in Aging, and Sex Differences ......................................... 4 1.3 Sex Differences Cognitive Impairment and Dementia ........................................................... 6 1.4 Menopausal Transition as a Critical Window to Promote Female Brain Health .................... 7 1.4.1 Role of Estrogens ..................................................................................................... 8 1.4.2 Menopause Transition and Cognitive Health .......................................................... 9 1.4.3 Menopause Transition and Brain Health ................................................................. 10 1.5 Exercise and Cognitive Health .............................................................................................. 11 1.6 Exercise and Brain Health ..................................................................................................... 12 1.7 The Relevance of High Intensity Interval Training in Perimenopause .................................. 13 1.8 What is Known/Not Known ................................................................................................... 14 viii 1.9 Objectives .............................................................................................................................. 15 1.9.1 Hypotheses .............................................................................................................. 15 Chapter 2: Methods ....................................................................................................................16 2.1 Ethics Approval ...................................................................................................................... 16 2.2 Study Design ........................................................................................................................... 16 2.3 Recruitment and Screening ..................................................................................................... 16 2.4 Participants and Sample Size ................................................................................................. 16 2.4.1 Inclusion Criteria .................................................................................................... 17 2.4.2 Exclusion Criteria ................................................................................................... 17 2.4.3 MRI Exclusion Criteria .......................................................................................... 18 2.5 Study Procedures .................................................................................................................. 18 2.5.1 Measurements ........................................................................................................ 18 2.5.2 Baseline Descriptive Characteristics ...................................................................... 18 2.5.3 Feasibility and Safety .............................................................................................. 19 2.5.4 VO2max Test ............................................................................................................. 20 2.5.5 Cognitive Assessment ............................................................................................ 21 2.5.6 MRI acquisition ...................................................................................................... 22 2.5.7 Myelin Water Fraction Analysis ............................................................................. 23 2.5.8 Hippocampal Volume Segmentation ..................................................................... 24 2.5.9 High Intensity Interval Training Protocol .............................................................. 24 2.6 Statistical Analysis ................................................................................................................ 26 2.6.1 Baseline Descriptive Characteristics ....................................................................... 26 2.6.2 Feasibility ................................................................................................................ 26 ix 2.6.3 Outcome Evaluation ................................................................................................ 28 Chapter 3: Results ...................................................................................................................... 29 3.1 Participants ............................................................................................................................. 28 3.2 Baseline Descriptive Characteristics ...................................................................................... 32 3.3 Feasibility Outcomes ............................................................................................................. 34 3.3.1 Recruitment Rate ................................................................................................ 34 3.3.2 Adherence ........................................................................................................... 34 3.3.3 Withdrawal Rate ................................................................................................. 34 3.4 Safety .................................................................................................................................... 35 3.5 Point Estimates ...................................................................................................................... 35 Chapter 4: Discussion ................................................................................................................ 38 4.1 Limitations ............................................................................................................................. 43 4.2 Future Directions and Conclusions ........................................................................................ 44 Bibliography ................................................................................................................................45 x List of Tables Table 1. Bruce Protocol Stages .................................................................................................... 21 Table 2. High Intensity Interval Training Protocol ...................................................................... 26 Table 3. Traffic Light System for Feasibility Criteria .................................................................. 27 Table 4. Baseline descriptive characteristics of all study participants ......................................... 33 Table 5. Feasibility Outcome Results and Traffic Light Feasibility Criteria Category ............... 32 Table 6. Point Estimate Results ................................................................................................... 36 Table 7. Point Estimate Results for Centre for Epidemiological Studies Depression Score ....... 42 xi List of Figures Figure 1. Varying levels of cognitive aging: normal aging, mild cognitive impairment, and dementia .......................................................................................................................................... 2 Figure 2. Neurocognitive domains defined in the Diagnostic and Statistical Manual of Mental Disorder Fifth Edition .................................................................................................................... 3 Figure 3. Stages of Reproductive Aging Workshop+10 Staging System ....................................... 8 Figure 4. Participant flow chart through study procedures ........................................................... 31 Figure 5. Magnetic Resonance Imaging Subset ............................................................................ 32 Figure 6. Immediate Recall on the Rey Auditory Verbal Learning Test ...................................... 37 Figure 7. 30-minute Delayed Recall on the Rey Auditory Verbal Learning Test ........................ 37 xii List of Abbreviations AD Alzheimer’s Disease ApoE ε4 Apolipoprotein E ε4 AT Aerobic Training CES-D Centre for Epidemiological Studies Depression Scale CRF Cardiorespiratory Fitness DECEAS Decomposition and Component Analysis of Exponential Signals DICOM Digital Imaging and Communications in Medicine DSM-5 Diagnostic and Statistical Manual of Mental Disorders Fifth Edition E2 17β-estradiol FCI Functional Comorbidity Index FSL FMRIB’s Software Library GRASE Gradient and Spin Echo HIIT High-Intensity Interval Training HR Heart Rate HRT Hormone Replacement Therapy MCI Mild Cognitive Impairment MoCA Montreal Cognitive Assessment MPRAGE Magnetization Prepared Rapid Gradient Echo MRI Magnetic Resonance Imaging MWF Myelin Water Fraction NifTI Neuroimaging Informatics Technology Initiative PA Physical Activity PAR-Q+ Physical Activity Readiness Questionnaire PET Positron Emission Tomography RAVLT Rey Auditory Verbal Learning Test ROI Region of Interest STRAW +10 Stages of Reproductive Aging Workshop +10 Staging System T1w T1-weighted VO2max Maximal Oxygen Consumption xiii Acknowledgements This thesis would not be possible without everyone who has supported me academically and personally. Firstly thank you to my supervisor Prof. Teresa Liu-Ambrose for your fantastic mentorship. I am grateful to have such a hard-working, passionate, and attentive supervisor. Thank you for building a collaborative research environment where everyone can work better together. Above all, thank you for being there for me. Thank you to my supervisory committee, Assistant Prof. Cindy Barha, Prof. Todd Handy, Assistant Prof. Nárlon Cássio Boa Sorte Silva, and Prof. Linda Li for pushing me to think critically about every aspect of my project. A special thank you to Assistant Prof. Nárlon Cássio Boa Sorte Silva who was so patient and supportive while teaching me the myelin water fraction analysis. Thank you to each and every participant for your enthusiasm and dedication to participating in this study. I cannot thank you enough for your contribution to women’s health research. To the students, postdoctoral fellows, and staff of the Aging, Mobility, and Cognitive Health Lab – thank you for helping me with this project. I am lucky to be surrounded by such a fantastic team. Thank you to Sarah Heath, Sarah Crummey, Sioban Tatara, and Nathan Wei for your hard work recruiting and coordinating this study. Thank you to the Canadian Institute of Health Research for awarding me the Canadian Graduate Scholarship-Master’s and supporting me financially. Thank you to my parents, family, and friends for supporting me through all the ups and downs of graduate school. Your enthusiasm for this research means a lot to me. Supporting my personal wellbeing allowed me to put everything I can into everything I do. xiv Dedication I dedicate this thesis to all the people in my life who have inspired this research, supported this research, and feel seen by this research. From my grandparents and parents fostering my sense of independence and paving the path to graduate school, to the enthusiastic participants who are passionate about advancing women’s health research: this is for you. 1 Chapter 1: Introduction 1.1 Overview Seventy-eight million people worldwide will be living with dementia by 2030. 1 Approximately 650,000 Canadians have dementia. 2 According to Statistics Canada, this number is expected to increase as the Canadian population ages. 3 Dementia is a clinical syndrome which significantly impacts global cognitive function, memory, executive functions, and functional independence beyond what is expected by age and ultimately lowers quality of life. 1,4 There are sex differences in the prevalence of dementia and Alzheimer’s Disease (AD, the most common form of dementia). Sixty-one percent of Canadians with dementia are female. 2 In 2020, 3.47 million females were projected to have AD compared with 2.34 million males in the United States. 5 It is projected that the prevalence will increase by 119.7% in females compared with a 95% increase in males by 2060. 5 Given that there is no cure for dementia, developing strategies to promote cognitive and brain health among females is of significant societal importance. 6 1.2 Importance of Cognitive Health During Aging Aging is defined as a steady decline in physiological processes that result in some degree of cognitive impairment. 7 Cognitive health is a concern for older adults as the risk of neurodegenerative diseases increases with age. 8 Promoting cognitive health throughout adulthood is necessary for keeping adults on the path of healthy cognitive aging (Figure 1) to maintain their functional independence and quality of life. 1,9 Increasing age negatively affects various cognitive functions. 10 Age-related changes in memory and executive function differ for males and females. 11 2 Figure 1. Varying levels of cognitive aging: normal aging, mild cognitive impairment, and dementia. Figure adapted from Zhou et al., 2023. 9 1.2.1 Cognitive Function in Aging, and Sex Differences Cognitive function is defined as the performance of mental processes. 12 Various cognitive functions (e.g. fluid reasoning, visuospatial abilities, and episodic memory) peak in early adulthood and decline thereafter. 13 These processes facilitate the learning and processing of novel information as well as attending to the environment. 14 The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) 15 defines six domains of cognitive function: 1) perception-motor function; 2) language; 3) learning and memory; 4) social cognition; 5) complex attention; and 6) executive functions (Figure 2). Aging impacts learning and memory, complex attention, and executive functions the most. 16,17 Learning and memory are divided into several subdomains as shown in Figure 2. There are two main categories of memory: explicit and implicit. Explicit memory includes semantic and episodic memory. Episodic memory recalls details of specific events and significantly declines after age 60. 18 Implicit memory is subconscious and plays a role in motor skills; it does not significantly change with age. 19 3 Figure 2. Neurocognitive domains defined in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Figure adapted from the DSM-5 framework for the diagnosis of neurocognitive disorders (© 2009 Springer Nature BV, by permission). 15 Complex attention includes many subdomains such as sustained attention, divided attention, selective attention, and processing speed. These subdomains describe the capacity to focus on specific stimuli. 14 Sustained attention is used when selectively attending to stimuli. Divided attention is involved in attending to multiple stimuli. 14 Age-related declines in sustained and divided attention begin at age 40 and continue past 60 years old. 20 There are three major components of executive function: inhibition, set shifting, and working memory. 21 Inhibition includes the ability to inhibit a response to a stimulus. 22 Set shifting is the ability to switch attention between different tasks. 23 Working memory is the ability to simultaneously monitor, process, and maintain information. 22 Inhibition, set shifting, and working memory decline with aging. 24-26 Cohort studies indicate that females have better episodic memory compared with males. There is mixed evidence if females’ episodic memory declines faster than males. The Longitudinal Aging Study Amsterdam (adults over 55 years old) and Doetinchem Cohort Study (adults over 45 years old) show that females have better episodic memory yet it declines 10% faster in females compared with males. 27 Data pooled from five American cohort studies 4 (median age of 58 years old) show that females have higher executive functions and memory scores at baseline compared with males. 28 Compared with males, females show a faster rate of decline in executive functions but not episodic memory after a 20-year follow-up. 28 1.2.2 Structural Brain Changes in Aging, and Sex Differences Aging is associated with changes in brain structure and function; for my thesis, I will focus on brain structure. 29 The brain is made of white and grey matter which work together to carry out cognitive functions. 30 Myelinated nerve fibres, one component of white matter, exchange information between areas of grey matter. 30 Grey matter forms the cerebral cortex and contain neuron somas, dendrites, axons, and neuroglia. Grey matter is responsible for processing and releasing information to the white matter. 31 Global, cortical, and subcortical volume decreases with age via white and grey matter degeneration. 32,33 Certain regions of the brain are more susceptible to age-related declines. These regions include the frontal, temporal, parietal, and hippocampal regions. 32,34 Age has the strongest effect on the frontal and temporal lobe volumes. 34 Age-related changes in white matter are more prominent than grey matter. 14 Specifically, myelin degeneration drives decreased white matter volume. 35,36 Myelin surrounds the axon and allows for rapid and efficient nerve conduction. Oligodendrocytes produce myelin sheaths and surround the axon with the myelin. 37 Myelin water imaging from magnetic resonance imaging (MRI) can structurally quantify myelin in vivo from the water content in white matter.35 The myelin sheath is composed of lipid bilayers with water molecules trapped within them. The water within the lipid bilayers can be indexed as myelin water fraction (MWF), a surrogate measure of myelin content. 38,39 Lower MWF indicates lower myelin content. 5 Myelin water fraction starts to decrease at age 50 and significantly decreases after age 60. 40 The prefrontal and lateral-posterior temporal cortices show the highest age-related decline in myelin compared with the occipital lobes in healthy adults ages 22 to 81 years old. 41 The prefrontal and temporal cortices are involved in executive functions and memory — cognitive functions that are susceptible to age-related changes. Increasing age is associated with lower grey matter volume in the frontal, temporal, and parietal cortices in healthy older adults. 42 The prefrontal cortex shows the most atrophy. 42 Within the temporal cortex, hippocampal grey matter volume decreases after a 5 year follow-up in healthy adults ages 26 to 82 years old. Adults older than 50 years old show a significantly higher rate of atrophy compared with adults younger than 50 years old. 43 Grey matter volume is preserved in the primary somatosensory, motor, and visual cortices with age. 42 The decline in grey matter volume may be due to cell senescence shown through decreasing neuronal size and synaptic density. 44,45 There are sex differences in the age-related changes in brain health. 46-48 White and grey matter volumes change differently between sexes with age. Middle-aged females (40 to 60 years old) 49 have lower white and grey matter volumes in the frontal and temporal regions compared with age-matched males. 50,51 Females have lower myelin content in the fornix and cingulum compared with males in older adulthood (over 60 years old). 52,53 Males have lower grey matter volumes cross-sectionally and greater rate of grey matter atrophy compared with females in older adulthood. 46,54,55 There is mixed evidence regarding sex differences in hippocampal volume. One cohort study report no significant differences in hippocampal volume between males and females in 554 adults ages 20 to 79 years old. 48 In a meta-analysis of 33 studies, hippocampal volume is significantly different between females and males. 56 There is an age and sex 6 interaction on hippocampal volume in 2383 adults ages 21 to 90 years old. Females above the median age of the sample (53 years old) have a larger grey matter volume in the posterior-superior region of the left hippocampus compared with males above 53 years old. 47 1.3 Sex Differences in Cognitive Impairment and Dementia One new case of dementia is detected every 3 seconds. 57 Cognitive impairment ranges from subjective cognitive decline, mild cognitive impairment (MCI), to dementia (Figure 1). 58,59 Subjective cognitive decline is a person’s perceived decline in cognitive function. 59 Subjective cognitive decline in older adulthood is associated with an increased risk of mild cognitive impairment and dementia. 60 Subjective cognitive decline is more strongly associated with dementia risk in females compared with males. 61 Mild cognitive impairment is defined as lower cognitive function expected for age and education level but does not affect activities of daily living. 62 Amnestic MCI (memory deficits) is more prevalent in males, whereas the prevalence of non-amnestic MCI (non-memory deficits in cognitive function. 63-65 Females are more likely to progress from MCI to AD. 66 Pooled estimates show that females have a higher incidence of dementia. Overall, the incidence of dementia is 16.14 per 1000 people in per year in females compared with 12.3 per 1000 people per year in males. 67 However the sex-specific incidence of dementia differs by geographic region. 2,5,67 Cohort studies from Europe, North America, and Latin America show that females and males have a similar incidence of dementia; the highest incidence is in females from low to middle income countries. 67 The higher prevalence and incidence of dementia in females cannot be completely attributed to females having a longer lifespan. Changing sex hormone levels in midlife (ages 40 to 60) 49 could play a role in negative changes in cognitive functions and brain structure. 68 Females with a shorter average 7 reproductive period (time from menarche to menopause) of less than 34.4 years have a higher risk of dementia. 69 The menopause transition – or perimenopause – is a time of marked hormonal changes for females and is a critical period to promote brain health. 1.4 Menopausal Transition as a Critical Window to Promote Female Brain Health Perimenopause negatively impacts the brain. 50,70 Evidence suggests that perimenopause is a key contributor to female’s greater lifetime risk for dementia. 71,72 The Stages of Reproductive Aging Workshop+10 Staging System (STRAW+10) 73 defines the menopause transition as two out of the last ten menstrual cycles differing more than seven days and more than one menstrual period in the last 12 months (Figure 3). Perimenopause occurs in midlife, with an average age range of 42 to 52 years, and lasts four to eight years. 74,75 By 2030 it is projected that there will be 1.2 billion perimenopausal and postmenopausal females worldwide. 76 8 Figure 3. Stages of Reproductive Aging Workshop+10 Staging System. Reproductive aging classification system for females encompassing menstrual cycle, endocrine, and symptomatic changes. 73 1.4.1 Role of Estrogens During perimenopause estrogen levels are dysregulated then significantly decrease. 77,78 Estrogens are steroid hormones responsible for reproductive, cardiovascular, and brain function. 79 There are three types of estrogens: estrone, 17β-estradiol (E2), and estriol. 17β-estradiol is the main circulating type in premenopausal females and the most potent form of the estrogens. 80 The fluctuations in E2 could be contributing to markers of worsening brain health in perimenopause. 79 17β-estradiol affects mitochondrial function in the brain. It regulates glucose uptake, metabolism, and adenosine triphosphate production. 81 This key steroid hormone has several receptors in the cerebral cortex, amygdala, and midbrain. 79,82 The frontal lobe (and notably the 9 prefrontal cortex) and hippocampus have estradiol receptors illustrating its role in cognitive function. 83,84 There is evidence to support an association between estrogens and episodic memory. 17β-estradiol levels are positively associated with episodic memory irrespective of menopause stage in females in a cross-sectional study of adults ages 45 to 55. 85 The positive association extends into older adulthood for females. 86,87 Also lifetime exposure to estrogens may influence episodic memory in females. Older females with a high lifetime exposure to estrogens (more than 39.5 years between menarche and menopause) have significantly better episodic memory compared with older females with a low lifetime exposure to estrogen. 88 1.4.2 Menopause Transition and Cognitive Health Approximately 60% of females report memory problems during perimenopause. 89 There is objective evidence to support these subjective changes. 90 Perimenopausal females have lower episodic memory over a three-year follow-up compared with males ages 42 to 60 years old. 91 Verbal episodic memory involves the encoding, storing, and retrieval of verbal information. 92 Longitudinal studies from the Study of Women’s Health Across the Nation show that verbal episodic memory declines across a four to six year follow-up period in perimenopause. 93-95 Similarly, in a 14-year longitudinal cohort study, delayed recall significantly declines in perimenopause compared with pre- and postmenopause. 96 Verbal episodic memory is relevant because it is the strongest predictor of the conversion from MCI to dementia in late life and decreases during aging. 97,98 In addition to reductions in cognitive function brain structure declines in perimenopause. 51,91,99 10 1.4.3 Menopause Transition and Brain Health There is mixed evidence if hippocampal volume changes in perimenopause. Females ages 40 to 65 have lower hippocampal volume compared with males ages 40 to 65, but this comparison does not stratify by pre, peri, or post-menopause. 51 Perimenopausal females from the Human Connectome Project in Aging have lower hippocampal volume compared with age-matched males. 100 Menopausal status (premenopause, perimenopause, or postmenopause) weakly predicted hippocampal volume in an observational study of healthy adults ages 45 to 60 years old. 51 Postmenopausal females show a significant rate of hippocampal atrophy whereas perimenopausal females do not over a two to three year follow-up period. 91 Earlier age at menopause is associated with lower hippocampal volume in postmenopausal Apolipoprotein E ε4 (ApoE ε4) carriers compared with non-carriers. 101 Apolipoprotein E ε4 is relevant as it is a genetic risk factor for AD. 102 Myelin catabolism is observed in postmenopausal animal models. 103 Mitochondrial respiration rates decline and there is a shift to ketogenesis. This pathway may ultimately lead to myelin catabolism postmenopause. 103 Decreasing myelin content is a proposed mechanism of white matter degeneration. This is in addition to oligodendrocyte damage and axonal degeneration. 103,104 Myelin is of particular interest because it is responsible for the rapid conduction of neuronal signals. 38 In perimenopause the brain is trying to meet energy demands under changing mitochondrial respiration rates. In animal models of perimenopause enzymes that form ketone bodies for cerebral metabolism (ketogenesis) are upregulated. 105 However, potential myelin content changes in perimenopausal females have yet to be investigated. 11 Perimenopause is a critical period to promote brain health. 106 Interventions such as exercise target physical inactivity — a modifiable risk factor for dementia. 107 Being physically inactive in midlife doubles the risk of dementia in late life compared with being physically active. 108 Vigorous intensity physical activity is positively associated higher verbal episodic memory only in perimenopausal females but not age matched males. 109 Very few studies have investigated the potential effects of exercise on cognitive function and brain health in midlife (including perimenopause), thus this area warrants further investigation. 106,110,111 1.5 Exercise and Cognitive Health Exercise is a subset of physical activity (PA) that is planned, structured, and repetitive with the goal of improving or maintaining physical fitness. 112 It is classified by the frequency, intensity, type, and time in which it is done. 113 The various types of exercise include aerobic training (AT), resistance training, and interval training. Aerobic training is defined as any activity using large muscle groups that is rhythmic and can be maintained. 113 Resistance training is a type of anaerobic training that requires exerting a force against free-weights and machines. 113 Interval training is made up of vigorous to supramaximal intervals (20 to 240 seconds) interspersed with light to moderate-intensity periods of rest (60 to 360 seconds). 113 High intensity interval training is made up of anaerobic exercise intervals at 80-100% peak heart rate (20-240 seconds) interspersed with aerobic periods of rest (60 to 360 seconds). 113 Research on exercise to promote healthy cognitive aging has commonly focused on older adults. 114-118 Thus, little is known about exercise’s potential effects on cognitive function in middle adulthood. Evidence suggests that higher PA levels and cardiorespiratory fitness (CRF) are associated with better verbal episodic memory and processing speed in midlife. 119 Midlife PA is positively associated with a slower decline in cognitive function. 120 Aerobic and resistance 12 training have a small to medium effect sizes on cognitive function in a systematic review and meta-analysis in adults over age 50. 115 Resistance training has a significant effect on executive function, memory, and working memory. 115 In a systematic review and meta-analysis of 29 studies, only five studies compare the effects of HIIT and moderate intensity continuous training on cognitive function in older adults. 121 A 5-year HIIT or moderate-intensity continuous training intervention in older adults did not elicit significant effects on verbal memory compared with controls. The analysis compares HIIT with an active control group that met national PA guidelines. This might affect the between-group comparison. In contrast, sedentary older adults who completed a 12-week HIIT intervention have significantly higher high-interference memory compared with older adults in the moderate-intensity continuous training and stretching control groups. 122 1.6 Exercise and Brain Health A systematic review and meta-analysis of 22 studies shows that exercise has a positive effect on total hippocampal volume in healthy and cognitively impaired older adults. 123 The potential effects of AT on hippocampal volume are commonly studied due to exercise-induced adaptations in the brain. 124,125 For females with probable MCI six months of AT improves total, left, and right hippocampal volume. 126 A systematic review and meta-analysis by Firth and colleagues (including healthy and cognitively impaired adults) concludes that AT has a significant effect on left hippocampal volume. 127 A meta-analysis of nine studies in healthy older adults shows that AT does not show significant effects on total hippocampal volume. 109 The differing populations and methodology for quantifying hippocampal volume may mask AT’s effects on hippocampal volume in systematic reviews and meta-analyses. 13 There is evidence showing a positive association between CRF and myelin. Cardiorespiratory fitness, measured by maximal oxygen consumption (VO2max), is positively associated with whole brain myelin content in healthy older adults ages 22 to 94. 128 Furthermore, a cross-sectional association between PA and myelin content is observed in older adults with cerebral small vessel disease and mild cognitive impairment. 129 There is very limited experimental evidence investigating exercise’s effects on myelin in clinical (non-demyelinating) populations. 1.7 The Relevance of High Intensity Interval Training in Perimenopause There is limited evidence of exercise’s effects on cognitive function and brain health in middle age. High intensity interval training could be a promising intervention for perimenopausal females because it is 1) time-efficient at increasing CRF over weeks compared with moderate intensity AT; 130 and 2) improves cardiovascular disease risk factors such as low-density lipoprotein cholesterol, hypertension, and plasma insulin levels. 131 HIIT can increase CRF by ~10% and increases cardiac output, stroke volume, and arteriovenous oxygen difference resulting in higher CRF. 132,133 High cardiovascular fitness in midlife is associated with a reduced incidence of dementia after a 40 year follow-up in females ages 28 to 60. 134 Cardiorespiratory fitness is an important outcome as it declines in midlife. 135 Cardiorespiratory fitness in midlife is positively associated with processing speed, 119 although research is limited. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission states that physical inactivity, high low-density lipoprotein cholesterol, diabetes, a hypertension in midlife are modifiable risk factors for dementia in late life. Cardiovascular disease risk (i.e. blood pressure, cholesterol level, and diabetes) in midlife is negatively associated with episodic memory in 501 adults 40 to 65 years old. 136 14 Perimenopausal females face a lack-of-time and lack-of-energy barrier to exercising. 137,138 Ovariectomized rats who have lower estradiol levels ran shorter distances and spent less time running compared with sham-operated and ovariectomized with estrogen-supplemented rats. 139 This shows that decreasing estrogen levels lower the motivation to exercise. Furthermore, perimenopausal females are balancing their careers, hobbies, and any caregiving responsibilities while experiencing sleep disturbances, hot flashes, altered mood and sleep. 140 High-intensity interval training could be a suitable exercise intervention as it addresses the lack-of-time barrier in perimenopausal females. It is paramount to first investigate the feasibility of a HIIT intervention before examining its effects on cognitive function and brain health. 1.8 What is Known/Not Known What is known: 1. Perimenopausal females face lack-of-time and lack-of-energy barriers to exercising. 137,138 2. Being physically active in midlife and a higher CRF is associated with a reduced incidence of dementia. 134 3. Perimenopause is a critical time to address the negative changes such as lower verbal episodic memory, lower hippocampal volume in postmenopausal ApoE ε4 carriers with an earlier age of menopause, and a shift to ketogenesis in animal models of perimenopause. 94,95,101,103 What is not known: 1. The feasibility of conducting a HIIT intervention in perimenopausal females. 2. If HIIT will elicit a positive change in cardiorespiratory fitness, verbal episodic memory, hippocampal volume, and myelin content in perimenopausal females. 15 1.9 Objectives Primary Objective: To determine if a 12-week thrice-weekly HIIT intervention is feasible in perimenopausal females defined recruitment rate (primary feasibility outcome), adherence, withdrawal rate, and number of adverse events criteria defined by the traffic light system for feasibility criteria. 141 Secondary Objective: To describe the potential change, using point estimates, of a thrice-weekly 12-week HIIT intervention on 1) CRF measured by VO2max as a measure of intervention fidelity; 2) verbal episodic memory measured by immediate recall and 30-minute delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) 3) total, left, and right hippocampal volume from T1-weighted (T1w) MRI scans; and 4) myelin content measured by whole-brain MWF in perimenopausal females. 1.9.1 Hypotheses 1. I hypothesize that a 12-week HIIT intervention will be feasible to conduct defined by the traffic light system for feasibility criteria for recruitment rate, adherence, withdrawal rate. I hypothesize the HIIT intervention will be feasible to conduct. 2. After a 12-week HIIT intervention, I hypothesize that there will be positive change scores calculated as post-HIIT minus pre-HIIT values for VO2max, immediate and 30-minute delayed recall, total, left, and right hippocampal volume, and whole-brain MWF. 16 Chapter 2: Methods 2.1 Ethics Approval Ethics were approved by the University of British Columbia Research Ethics Board (H20-00925) and Vancouver Coastal Health Research Ethics Board (V20-00925). All participants provided written informed consent. Participants were reimbursed up to $60 for parking and transportation fees. 2.2 Study Design A feasibility study of a 12-week thrice-weekly HIIT intervention among 16 perimenopausal females ages 40 to 55 years old. 2.3 Recruitment and Screening Participants were recruited from the Metro Vancouver Area, British Columbia. Recruitment materials included print posters and online advertisements (e.g. X, Instagram, and Reach BC). A Research Assistant assessed study eligibility and discussed the study procedures. The Montreal Cognitive Assessment (MoCA), 142 STRAW +10, 73 Physical Activity Readiness Questionnaire (PAR-Q+), 143 and Positron Emission Tomography (PET)-MRI safety screening evaluated study eligibility. 2.4 Participants and Sample Size No formal sample size was calculated for this pilot study of feasibility and point estimates. The overall sample size was 16 perimenopausal females based on available resources, funding, and timelines. 17 2.4.1 Inclusion Criteria Individuals were included if they: 1) were female; 2) were 40 to 55 years old; 3) were perimenopausal (i.e. >7 day difference in consecutive menstrual cycle length, amenorrhea >60 day, and/or have had >1 menstrual period in the last 12 months) 73 based on the STRAW+10 Staging System (Figure 3); 4) had an intact uterus; 5) were in sufficient health to participate in HIIT according to the PAR-Q+ 143; 6) completed high school education; 7) could read, write, and speak English. 2.4.2 Exclusion Criteria Individuals were excluded if they: 1) had engaged in > 60 minutes of moderate to vigorous training per week in the three months prior to the study; 2) had engaged in HIIT in the last six months; 3) had a diagnosis of cognitive impairment or dementia; 4) had a diagnosis of a neurodegenerative disease; 5) were at high risk of cardiac complications during exercise; 6) had clinically important neuropathy or severe musculoskeletal or joint disease that impairs mobility; 7) had been on any hormone therapy (estrogen, androgen, or progesterone), hormonal birth control, or hormonal intrauterine device in the last 12 months; 8) were planning to participate, or already enrolled in, a concurrent clinical drug or exercise trial; 9) had surgical menopause; 10) had an endometrial ablation; 11) had been diagnosed with polycystic ovarian syndrome; 12) had a body mass index <15 or diagnosed with anorexia nervosa; 13) were undergoing chemotherapy, or had received chemotherapy in the last year; 14) had premature ovarian failure. Those with a CES-D score of >16/60 were initially excluded. However this criterion was changed to an outcome as it posed significant barriers to recruitment. 18 2.4.3 MRI Exclusion Criteria MRI safety screening was completed during the initial screening call. The presence of the following were contraindications for MRI scans: 1) cardiac pacemaker, wires, or defibrillator; 2) metal in eye or orbit; 3) steel brain aneurysm clip; 4) pregnancy or breastfeeding; 5) stainless steel intrauterine device; 6) any surgery or tattoos (including makeup tattoos) within the past 6 weeks; 7) history of radiation therapy or exposure to other high amounts of radiation; 8) recurring metastasis; 9) claustrophobia; 10) artificial heart valve; 11) ear or eye implant; 12) titanium brain aneurysm clip; 13) implanted drug infusion pump; 14) electrical stimulator for nerves or bones; 15) coil, catheter or filter in any blood vessel; or 16) orthopedic hardware (artificial joint, plate, screws, rods) or other metallic fragments. 2.5 Study Procedures 2.5.1 Measurements All assessments were completed at baseline and after the 12-week HIIT intervention. The assessments were conducted within a two-week period of each other. Measurements included a VO2max test, cognitive assessment, and MRI. 2.5.2 Baseline Descriptive Characteristics Baseline descriptive characteristics included age, education level, height, weight, Functional Comorbidity Index (FCI) score, Centre for Epidemiological Studies Depression Scale (CES-D) score, MoCA score, and STRAW+10 stage. 73,142,144,145 The FCI is a 21-item questionnaire developed to measure comorbidities associated with physical function. Participants are asked if they are currently or previously diagnosed with a 19 condition. Each comorbidity was assigned one point and scores ranged from zero to 21. A higher number indicated a greater presence of comorbidities. The CES-D is a 20-item questionnaire that measured depression symptomology. 144 Participants were asked to what extent in the last week they might have felt of behaved in the past week. The possible range of scores was zero to 60 with a higher score indicated greater symptomology. 144 A score of 16 or higher indicated individuals at-risk of depression. The MoCA is a 10-minute screening tool of cognitive function. 142 It assessed working memory, visuospatial abilities, executive functions, attention, language, and orientation. It is scored out of 30, where 26 or more was considered cognitively normal. 142 A score of 25 was an indicator of some cognitive impairment. The STRAW+10 classified stages of reproductive aging. 73 Stages -5 to -3a included reproductive (premenopause). -2 and -1 included the menopause transition. +1a to +2 included postmenopause. -2 (early menopause transition) was classified when 2 out of the last 10 menstrual cycles varied more than 7 days. -1 (late menopause transition) was classified by amenorrhea of more than 60 days. 2.5.3 Feasibility and Safety Feasibility metrics included: 1) recruitment rate; 2) adherence; and 3) withdrawal rate. Contact information from everyone who contacted the study, screened, eligible, and enrolled were recorded. Recruitment rate was calculated as the number of participants enrolled divided by the number of months spent recruiting. High-intensity interval training class attendance was recorded for adherence calculations. Adherence was determined as the average proportion of HIIT classes attended divided by the 20 HIIT classes offered. The intervention was extended as needed if a participant missed more than two exercise classes in one week. Withdrawal requests were noted for calculating the withdrawal rate. Withdrawals were calculated by dividing withdrawal requests by the number of enrolled participants. Adverse events were defined as unexpected or unwanted medical occurrence that a participant experiences during a study that may or may not be caused from the study procedures or intervention. All adverse events were reported to the Data and Safety Monitoring Committee and relevant university and health authority ethics boards by the study coordinator. The Data and Safety Monitoring Committee reviewed all adverse events on a monthly basis. They determined whether they were or were not related to the study and would stop the study if they are of sufficient concern. Number of most-likely related or definitely-related adverse events from the study procedures or intervention were recorded. 2.5.4 VO2max Test Cardiorespiratory fitness was assessed by VO2max on the Bruce protocol pre- and post-intervention using the VMAXTM Encore Metabolic Cart (https://www.vyaire.com/). 146 First, physical descriptors such as age, height, and weight were collected. Then, a 12-lead electrocardiogram collected heart rate and cardiac electrical activity data on CardioCard (https://nasiff.com/). Next, resting heart rate and blood pressure were measured with the Primacare (https://www.primacaremedical.com/) sphygmomanometer and stethoscope. If there were no contraindications, the participant completed the Bruce protocol until a relative or absolute contraindication was met, or the participant requested to stop. 21 The Bruce protocol is a maximal treadmill exercise test in which the speed and grade of the treadmill increased every three minutes (Table 1). 146 It included a two-minute warm up and cool-down. Heart rate was monitored every minute, blood pressure every three minutes, and perceived rate of exertion from the Borg Scale every three minutes. Table 1. Bruce Protocol Stages. Treadmill grade and speed for the Bruce Protocol used for assessing VO2max. Stage Minute Speed (km/hour) Grade (%) 1 0:00 - 2:59 2.7 10 2 3:00 – 5:59 4.0 12 3 6:00 – 8:59 5.4 14 4 9:00 – 11:59 6.8 16 5 12:00 – 14:59 8.0 18 6 15:00 – 17:59 8.9 20 7 18:00 – 20:59 9.7 22 8 21:00 – 23:59 10.5 24 2.5.5 Cognitive Assessment The RAVLT assessed verbal episodic memory. 25 To administer the RAVLT, 15 unrelated words were read at one word per second. Then the participant recalled as many words as possible. This was repeated five times for the same list of words. Next, a second and different list of 15 words was read and the participant had recall words from that list. Afterwards the participant was asked to recall as many words as they could from the first list. After 30 minutes the participant had to recall the words from the first list. Then the participant was shown a list of 30 words and asked which words they recognize from the first list (the list they were read five 22 times). The number of words recalled and intrusions were recorded after each trial. The total number of words recalled after learning trials (Immediate recall) and 30-minute delayed recall were selected as outcomes. These outcomes were selected because: 1) total number of trials reflected immediate recall as one part of verbal episodic memory; and 2) 30-minute delayed recall was the best individual predictor of the conversion from MCI to dementia. 97,147 2.5.6 MRI acquisition All MRI scans were completed with the GE SIGNA 3T Scanner. Scans for six participants were completed before a scanner upgrade in January 2024. The remainder of MRIs were completed post-upgrade. No one received a baseline MRI scan pre-upgrade and their final MRI scan post-upgrade. Three-dimensional T1w images used the Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence with the following parameters pre-upgrade: TE = 3.2ms TR = 2783ms TI = 900ms, flip angle θ = 8° FOV = 256 x 256mm, slice thickness = 1.0 mm, number of slices = 206, and voxel size = 1mm. Multi-echo gradient and spin echo (GRASE) T2 relaxation sequences with 32 echoes collected MWF data. GRASE parameters were: TE = 10ms, TR = 1000ms, FA = 90, FOV = 224 x 186, slice thickness = 5.0mm, and number of slices = 20. The MPRAGE sequence parameters post-upgrade were: TE = 3.1ms TR = 2700ms TI = 1000ms, flip angle θ = 8°, FOV = 256 x 256mm, slice thickness = 1.0 mm, number of slices = 206, and voxel size = 1mm. MWF data was unable to be collected post-upgrade as there were technical difficulties with the GRASE sequence. 23 2.5.7 Myelin Water Fraction Analysis Whole-brain MWF was assessed by myelin water imaging from baseline and final MRI. T1-weighted images were converted from Digital Imaging and Communications in Medicine (DICOM) format to Neuroimaging Informatics Technology Initiative (NifTI) format. GRASE DICOM to NifTI on MATLAB R2022b (Version 9.13). Quality checks on the MPRAGE and GRASE images noted the presence of any flow artifacts, lesions, and head motion. Then, all 32 GRASE volumes were combined using fslmerge to make one 4D GRASE volume. Next, a 4D image was used to create a MWF map using Decomposition and Component Analysis of Exponential Signals (DECEAS). 148 Advanced Normalization Tools was used for linear and non-linear registration, and within-subject template creation. 149 FMRIB’s Software Library (FSL) was used to extract and compute the MWF values. The pipeline includes the following steps: 1) baseline and final GRASE images were cross-sectionally registered to their respective T1w anatomical images; 2) MWF maps were cross-sectionally registered to the participant’s T1w image using transformation matrices generated from GRASE to T1w linear registration; 3) then the cross-sectionally registered images were co-registered to the within-subject T1w anatomical template to allow for longitudinal comparisons. This template was created by co-registering baseline and final T1w images for each participant; 4) for each participant non-linear transformations registered 15 white matter tracts from the Johns Hopkins University atlas to the participant’s within-subject T1w anatomical space. The tracts derived from an MRI standard template that was created at the UBC MRI Research Centre by Dvorak and colleagues; 150 5) FSL’s command fslstats extracted and computed MWF values for a whole-brain region of interest (ROI) merging all 15 ROIs together. These ROIs include: cingulum, corona radiata (anterior, posterior, and 24 superior), corpus callosum (body, genu, and splenium), external capsule, fornix, internal capsule (anterior, posterior, retrolenticular), posterior thalamic radiation, sagittal stratum, and superior longitudinal fasciculus. MWF values were derived from a tract-based mask which combined the 15 regions of interest from the Dvorak atlas. A higher MWF value indicates a higher level of myelin content. 151 2.5.8 Hippocampal Volume Segmentation FreeSurfer version 7.3.2 analyzed hippocampal volume data from T1w images. 152 FreeSurfer was developed by the Martinos Centre for Biomedical Imaging by the Laboratory for Computational Neuroimaging (https://surfer.nmr.mgh.harvard.edu/fswiki). First, the NifTI files were inspected in the same manner as for the MWF analysis. The FreeSurfer recon-all longitudinal pipeline was used for processing the longitudinal data. The recon-all pipeline included skull stripping, motion correction, Talairach registration, and atlas registration to form a within-subject template used for segmentation and surface reconstruction. 153 There is an association between hippocampal volume and verbal episodic memory; 154,155 left hippocampal volume is correlated with and predicted verbal episodic memory in older adults. 156,157 Given the negative changes in verbal episodic memory in perimenopause, it is worth investigating left, right, and total hippocampal volume. The Hippocampal Subfields and Nuclei of Amygdala longitudinal script automatically segmented the left and right hippocampus. 153 Total hippocampal volume was calculated by adding the left and right hippocampal volume. 2.5.9 High Intensity Interval Training Protocol High-intensity interval training sessions were completed three times per week at the Centre for Aging SMART at Vancouver General Hospital on non-consecutive days (i.e., Monday, Wednesday, and Friday). All training sessions lasted approximately one hour, including 50 25 minutes of exercise on a treadmill. Participants trained at a treadmill speed and grade necessary to reach target heart rate (HR) during each interval, as measured by a Polar H9 HR Sensor. Sessions included dynamic and static stretches, a five-minute treadmill warm-up, and a three-minute treadmill cool-down. Target HR for the work intervals was set at 90% of their maximum HR. Rest interval target HR was 65% of their maximum HR. Target HR was adjusted on an individual basis if any adverse events occurred. The HIIT protocol is based on reverse periodization where the program starts with high intensity, low volume training. 158 To maintain the relative intensity of each training session, the duration of each interval was increased, then the work to rest ratio decreased in weeks 7 to 12. As shown in Table 2, the HIIT protocol progressed in the following manner: Week 1: 16 x 1 minute of work and 1 minute of rest; Week 2: 8 x 2 minutes of work and 2 minutes of rest; Week 3: 1 x 4 minutes of work with 4 minutes of rest and 4 x 3 minutes of work with 3 minutes of rest; Week 4 to 6: 4 x 4 minute of work with 4 minutes of rest; week 7 to 9: 4 x 4 minute of work with 3 minutes of rest; Week 10 to 12: 4 x 4 minutes of work with 2 minutes of rest. Perceived exercise intensity was assessed using the Borg Rating of Perceived Exertion. 159 26 Table 2. High Intensity Interval Training Protocol. Work intervals were at 90% of maximum heart rate and rest intervals were at 65% of maximum heart rate. 2.6 Statistical Analysis 2.6.1 Baseline Descriptive Characteristics All data analyses were completed with R version 4.3.2 as implemented in RStudio version 2023.12.0 Build 369. Baseline descriptive characteristics included age, education level, height, weight, body mass index, MoCA score, CES-D score, FCI score, and STRAW+10. Means and standard deviations, or count (%) were reported from baseline descriptive characteristics. 2.6.2 Feasibility We reported feasibility metrics as defined in section 2.5.3. The traffic light system for feasibility criteria (Table 3) categorized the feasibility outcomes. 141 Green (go) indicated the criterion was met, yellow (amend) indicated that changes should be made before a larger trial, and red (stop) indicated that there irreparable issues and larger trial should not move forward. 141 Work Interval (minutes) Rest Interval (minutes) Number of Intervals Week 1 1 1 16 Week 2 2 2 8 Week 3 4 4 1 3 3 3 Weeks 4-6 4 4 4 Weeks 7-9 4 3 4 Weeks 10-12 4 2 4 27 The criteria for this feasibility study were set by researchers so the study was completed within an appropriate timeline and budget. This study was deemed feasible to conduct if one participant was recruited per month. Additional feasibility criteria were met if there was: (1) an adherence > 60% for the exercise classes; and (2) a withdrawal rate < 15%. A physical activity promotion study for middle aged adults with rheumatoid arthritis recruited five to six participants per month. 160 Furthermore, a 12-week HIIT intervention in pre- and post-menopausal females recruited 3.45 participants per month. 131 However due to the strict eligibility criteria, and the large time commitment from study assessments (i.e. VO2max test, cognitive assessment, and PET-MRI) a “go” category of one participant per month was set. The “amend” category ranged from one participant every one to two months based on available resources and timelines. In a study investigating the feasibility of strength training for 18 weeks in middle-aged adults has a 24% withdrawal rate (55 out of 226 initial sample). 161 A PA promotion intervention for females over 50 years old accounted for a 15% withdrawal rate. 162 Thus a withdrawal rate ranging from 15 to 25% was set for the “amend” category. Table 3. Traffic Light System for Feasibility Criteria. Criteria Outcome Green (Go) Yellow (Amend) Red (Stop) Recruitment Rate > 1 participant per month 1 participant per 1 to 2 months < 1 participant per 2 months Adherence > 60% < 60% to 33% < 33% Withdrawal Rate < 15% 15% to 25% > 25% 28 2.6.3 Outcome Evaluation We reported mean change scores (calculated as the mean of the post-intervention score to pre-intervention difference), their standard deviations, percent change, and effect sizes (Cohen’s d) for: VO2max, immediate recall, 30-minute delayed recall, total, left, and right hippocampal volume, and whole-brain MWF. 163 29 Chapter 3: Results 3.1 Participants After 211 people were screened, 192 were excluded because they were ineligible (n = 150), not interested (n = 7), or they contacted the study after recruitment closed (n = 35) (Figure 4). The three main reasons for ineligibility were the inability to commit to an in-person study (Cannot Commit in Figure 4) (60/150, 40%), hormone replacement therapy, hormonal birth control, or intrauterine device (Exogenous Hormones in Figure 4) (37/150, 24.7%), or were not perimenopausal (14/150, 9.3%). In Figure 4 Activity level or HIIT included the exclusion criteria of engaging in > 60 minutes of moderate to vigorous training per week in the three months prior to the study or HIIT in the last six months (10/150, 6.7%); Medical Procedures included the exclusion criteria of an endometrial ablation, hysterectomy, or surgical menopause (n = 9/150, 6.0%); Other included various reasons such as allergies to the PET-MRI contrast; Medical Reasons polycystic ovarian syndrome or contraindications to the assessments or HIIT intervention (5/150, 3.33%). 19 perimenopausal females were eligible. Three of the eligible participants were excluded from the study (baseline assessments not scheduled) because of data collection timelines. 16 participants were enrolled. One participant withdrew after the VO2max test thus only height, weight, MoCA, and STRAW+10 data was collected. 15 participants completed baseline assessments. Two participants withdrew during the intervention due to personal reasons. Two participants were completing the intervention when the point estimate data was analyzed. Therefore, there was data from 11 participants for baseline and final timepoints. Eight MRI scans at baseline and final timepoints were collected (Figure 5). Two participants did not complete the baseline MRI due to claustrophobia and concern from the PET 30 tracer radiation. One participant did not complete the final MRI due to concern from the PET tracer radiation. Due to technical difficulties MWF data was collected for five out eight participants. 31 Figure 4. Participant flow chart from screening to completing the intervention. Count of participants as of August 29 2024. Abbreviations: HIIT = High-Intensity Interval Training Enrolled (n = 16) Baseline Assessments Completed (n = 15) Participant Characteristics, Maximal Oxygen Consumption Test, Cognitive Assessment Eligible (n = 19) Final Assessments Completed (n = 11) Maximal Oxygen Test, Cognitive Assessment Withdrew during intervention (n = 2) • Personal reasons Withdrew after maximal oxygen consumption test (n = 1) • Work commitments Screened (n = 211) Excluded (n = 192) • Ineligible (n = 150) • Cannot commit (n = 60) • Exogenous hormones (n = 37) • Not perimenopausal (n = 20) • Activity level or HIIT (n = 10) • Medical procedures (n = 9) • Medical reasons (n = 7) • Other (n = 5) • Age (n = 2) • Not interested (n = 7) • Recruitment closed (n = 35) Excluded from study (n = 3) • Study timeline Data not included point estimate analysis (n = 2) • In the intervention 32 Figure 5. Magnetic Resonance Imaging Subset. Count of participants as of August 29 2024. 3.2 Baseline Descriptive Characteristics Baseline descriptive characteristics for all 16 participants, regardless of completing the intervention are presented in Table 4. Education level, FCI score, and CES-D score (height, weight, MoCA, and STRAW+10 not included) was available for 15 participants as one participant withdrew before the baseline cognitive assessment. Participants had a mean age of 48.94 (SD = 3.97). Four participants (25.0%) had some university education or a diploma, 12 participants (75.0%) had a university degree. Mean CES-D score was 18.13 (SD = 12.72). Thirteen participants (81.2%) were in the early menopause transition and three (18.8%) were in the late menopause transition. Final Assessments Completed (n = 11) Maximal Oxygen Test, Cognitive Assessment Magnetic Resonance Imaging Subset (n = 8) Hippocampal Volume (n = 8), Myelin Water Fraction (n = 5) Did not complete baseline magnetic resonance imaging (n = 2) • Claustrophobia (n = 1) • Concern from positron emission tomography tracer radiation (n = 1) Did not complete final magnetic resonance imaging • Concern from positron emission tomography tracer radiation (n = 1) 33 Table 4. Baseline descriptive characteristics of all study participants. (n = 16) unless otherwise indicated. Variablesa Mean (SD) (n = 16) Age (years) 48.94 (3.47) Education (n, %)b,c Some University Certificate or Diploma University Degree 4 (25.0) 12 (75.0) Height (centimetres) 166.22 (7.16) Weight (kilograms) 72.99 (15.99) Body Mass Index (kilograms/metres2) 26.23 (4.54) Functional Comorbidity Index (/21)c,d 1.47 (1.19) Centre for Epidemiological Studies Depression Scale (/60)c,e 18.13 (12.72) Montreal Cognitive Assessment (/30) 28.25 (2.11) STRAW+10 Stage (n, %)b Early Menopause Transition Late Menopause Transition 13 (81.2) 3 (18.8) Abbreviations: FCI = Functional Comorbidity Index, CES-D = Centre for epidemiological studies depression scale, MoCA = Montreal Cognitive Assessment, STRAW+10 = Stages of Reproductive Aging Workshop +10 aMean (standard deviation) reported for age, height, weight, FCI, CES-D, and MoCA bCount (n) and percent (%) were reported for education and STRAW+10 Stage cData from 15 participants dHigher score indicates a higher number of comorbidities eHigher score indicates higher depression symptomology 34 3.3 Feasibility Outcomes 3.3.1 Recruitment Rate Results from the feasibility outcomes are presented in Table 5. Sixteen participants were enrolled in 21 months (October 2022 to July 2024). The primary feasibility outcome of recruitment rate was 0.76 participants per month and in the “amend” category of the traffic light system for feasibility criteria. Table 5. Feasibility Outcome Results and Traffic Light System for Feasibility Criteria Category. (n = 16) Variables Observed Value Traffic Light Feasibility Category Recruitment Ratea (participants/month) 0.76 Amend Adherence (%)b 87.95 Go Withdrawal Rate (%) 18.75 Amend aRecruitment period: October 2022 to July 2024 (21 months) bIncludes data from 15 participants 3.3.2 Adherence Based on 15 participants, overall adherence to the HIIT intervention was 87.95%. This feasibility outcome was in the “go” category. This calculation included participants who were completing the intervention and participants who withdrew from the intervention. 3.3.3 Withdrawal Rate The withdrawal rate was 18.75%, three out of 16 participants withdrew from the study. Two participants withdrew due to personal matters and one participant withdrew because of competing work demands. Withdrawal rate was in the “amend” category. 35 3.4 Safety There were five adverse events that were most-likely related or definitely related to the study. One adverse event occurred from dizziness and fatigue. Two adverse events occurred due to a rapid heartbeat, experienced during HIIT, from a pre-existing condition in the same participant. One adverse event was from muscle soreness. One adverse event was a reaction at the injection site of the radioactive tracer used for the PET-MRI. None of the adverse events resulted in participants missing the intervention or withdrawing. 3.5 Point Estimates Mean change (pre- to post-intervention), standard deviation, percent change, and effect size for CRF, immediate recall, 30-minute delayed recall, total, left, and right hippocampal volume, and whole-brain MWF are presented in Table 6. For CRF there was a mean change of 1.8 ml/kg/min on VO2max (SD = 7.49), a 5.77% increase, and small effect (Cohen’s d = 0.24). Immediate recall had a mean change of 7.55 words (SD = 6.09) and a 14.52% increase. 30-minute delayed recall had a mean change of 2.09 words (SD = 2.23) and a 19.48% increase. The HIIT intervention had a large effect size (Cohen’s d = 1.24 and 0.94 respectively) on immediate recall and 30-minute delayed recall. Total hippocampal volume had a mean change of 45.37 mm3, 0.64% increase, and a very small effect size (Cohen’s d = 0.05). Left hippocampal volume had a mean change of 17.26 mm3, 0.50% increase, and a very small effect size (Cohen’s d = 0.04). Right hippocampal volume had a mean change of 28.12 mm3, 0.79% increase, and a very small effect size (Cohen’s d = 0.08). Whole-brain MWF showed a mean change of 0.0037 (SD = 0.01), 2.7% increase, and a small effect (Cohen’s d = 0.23) pre- to post-intervention. 36 Table 6. Point Estimate Results. Mean change, percent change, standard deviation, and effect size for cardiorespiratory fitness, immediate recall, 30-minute delayed recall, total left, and right hippocampal volume, and whole-brain MWF. Variables a Baseline Mean (SD) Final Mean (SD) Mean Change Percent Change Standard Deviation Effect Size Effect Size Interpretation CRF (ml/kg/min) 31.2 (7.22) 33.0 (7.76) 1.80 5.77% 7.49 0.24 Small Immediate Recall (words) 52 (6.84) 59.55 (5.24) 7.55 14.52% 6.09 1.24 Large 30-Minute Delayed Recall (words) 10.73 (2.9) 12.82 (1.25) 2.09 19.48% 2.23 0.94 Large Total Hippocampal Volume (mm3) 7020.61 (841.77) 7065.98 (862.92) 45.37 0.64% 852.41 0.05 Very Small Left Hippocampal Volume (mm3) 3481.39 (483.06) 3498.39 (486.71) 17.26 0.50% 484.89 0.04 Very Small Right Hippocampal Volume (mm3) 3539.22 (362.21) 3567.34 (385.25) 28.12 0.79% 373.90 0.08 Very Small Whole-Brain MWF (/1) 0.1308 (0.012) 0.1344 (0.019) 0.0036 2.7% 0.01 0.23 Small Abbreviations: CRF = Cardiorespiratory Fitness, MWF = Myelin Water Fraction b11 participants completed baseline and final VO2max tests, 8 participants completed MRIs with MWF data available for 5 participants 37 Figure 6. Immediate Recall on the Rey Auditory Verbal Learning Test. The thick solid line represents the median. The boxes represent the interquartile range from quartile 1 to quartile 3 (25% to 75% of values). The thin solid lines are located at +1.5x the interquartile range. The dashed thin line connects quartile 1 and 3 respectively with the value for +1.5x the interquartile range. Figure 7. 30-minute Delayed Recall on the Rey Auditory Verbal Learning Test. The thick solid line represents the median. The boxes represent the interquartile range from quartile 1 to quartile 3 (25% to 75% of values). The thin solid lines are located at +1.5x the interquartile range. The dashed thin line connects quartile 1 and 3 respectively with the value for +1.5x the interquartile range. 38 Chapter 4: Discussion This feasibility study investigated the feasibility of a 12-week HIIT intervention and described its effects on CRF, verbal episodic memory, hippocampal volume, and myelin content in perimenopausal females. Adherence was the only feasibility outcome to meet the “go” criteria. Recruitment rate and withdrawal rate were in the “amend” stage of feasibility criteria. The factors affecting recruitment rate and withdrawal rate should change before a larger trial. The intervention elicited a positive mean change with a small effect on cardiorespiratory fitness, hippocampal volume, and whole-brain MWF. There was a large effect from the intervention on immediate recall and 30-minute delayed recall. Data from the recruitment process illustrated key reasons that individuals were unable to participate and provided insight for timely recruitment in future trials. Out of the 211 people being screened, 19 participants were eligible, and 16 participants were enrolled in 21 months. Seven participants were not interested in participating, thus not included in the exclusion criteria calculations (i.e. percent of people excluded from the study). The key reasons people were unable to participate in the study were: 1) inability to commit to attending in-person sessions (60/150, 40%); 2) the use of hormone replacement therapy (HRT), hormonal birth control, or hormonal intrauterine device (37/150, 24.7%); or 3) were not perimenopausal (14/150, 9.3%). It was not recorded who was based on which type of hormones i.e. HRT, hormonal birth control, or a hormonal intrauterine device. Perimenopausal females experience a lack-of-time barrier to exercising. 137 While the routine of regular exercise is valuable, the initial energy to build that routine with competing life demands is a barrier. 137,138 Furthermore, concerns of Covid-19 virus transmission during assessments and exercise classes could have decreased the ability to commit to in-person sessions, and thus the recruitment rate. 164 Perimenopausal females responded to 39 both print and online advertisements. Future studies should include both forms of advertisements, use social media to maximize study advertisement reach in the Greater Vancouver Area, British Columbia. In the Canadian Longitudinal Study on Aging 9.5% of adults 45 to 85 years old use HRT. 165 Hormone replacement therapy is becoming increasingly accepted to address vasomotor symptoms in perimenopause as stated by clinical practice guidelines and position statements from the Society of Obstetricians and Gynaecologists of Canada and North American Menopause Society. 166-168 In future studies recruitment rates will likely be affected if perimenopausal females on HRT are excluded. The initial eligibility criteria excluded approximately 20 perimenopausal females with a CES-D score of 16 or more indicating a risk of depressive symptoms. 169 This eligibility criterion posed significant barriers to recruitment as there is a higher risk of depression symptoms in perimenopause. 170 Perimenopausal females have a higher risk of depressive symptoms 171 and are two to four times more likely to have a depressive episode independent of a history of depression and vasomotor symptoms. 170 After assessing how prevalent mood changes are in perimenopause, this exclusion criterion was removed and changed to an outcome in the current study. Despite the challenges I faced in recruiting, once participants were enrolled, they adhered to the intervention. A systematic review and meta-analysis by Santos and colleagues 172 states that HIIT studies in adults have an adherence of 63%. Fifty-three females ages 40 to 62 state that an exercise routine, positive feelings after exercising, and accountability from others are enabling factors to exercise. 137 In a 24-week resistance training intervention, postmenopausal females ages 50 to 75 years old state that social support from exercising in a small group is a motivating factor to adhere to the exercise intervention. 173 The social interaction and accountability between fellow participants and from research staff could have affected adherence. 40 We observed a 18.75% withdrawal rate where 3/16 individuals withdrew. Key reasons for study withdrawal were personal reasons or work commitments. The mean CES-D score of 18.13 at baseline gave insight into depressive symptoms during perimenopause. A CES-D score greater than 16 indicates depressive symptoms (CES-D score > 16). 169 Future trials should include depressive symptoms or the prevalence of mood disorders as an outcome of interest. Middle-age women exercise approximately 13% of the time that they intend to. 174 Perimenopausal females have competing obligations to themselves (e.g. medical appointments or self-care) or others (e.g. careers or caregiving) affecting the amount of time they have to exercise. 137 Together, mental health and competing life demands in perimenopause affected study participation. Despite efforts of knowing participants’ pre-existing conditions and physician clearance to participate in the exercise intervention, there were adverse events. After additional screening from the echocardiogram during the VO2max test, two participants were sent for additional stress testing. Cardiovascular disease risk and prevalence of risk factors increases in perimenopause. 175,176 Future studies should include cardiovascular screening knowing that cardiovascular risk factors become more prevalent in perimenopause to ensure a safe exercise intervention. This was a small feasibility study and thus, I recognize the point estimates observed in this study may not be precise. Nevertheless, no other study has assessed the effect of exercise, of any type, on cognitive and brain outcomes in perimenopausal females. I felt it was important to report observed point estimates, including effect sizes. The intervention had a small effect on CRF with a high amount of variability. The CRF results are promising based on an increase of 1.8 ml/kg/min, 5.77% increase, with a mean VO2max of 33.0 ml/kg/min after 12 weeks of HIIT. Even though the study did not meet a minimal 41 clinically important difference of a 3.5 ml/kg/min increase pre- to post-intervention, the interventions supporting this value range from four weeks to two years. 177 An eight week 4 x 4 minute HIIT protocol showed a 9.48% and 10.17% increase in CRF in adults ages 40 to 49 years old and 50 to 59 years old, respectively. 178 The direction of change is in line with previous evidence. There is a moderating effect of baseline CRF on improvements in VO2max. Potentially, those with a higher baseline VO2max CRF have a lower mean change in VO2max compared with those who had a lower baseline CRF. 179 Future studies should examine how CRF could respond to a longer exercise intervention. The large effect on verbal episodic memory of immediate recall and 30-minute delayed recall from the HIIT intervention aligned with previous research. In a systematic review and meta-analysis there is a significant interaction between high-intensity exercise and memory in healthy adults. 180 Findings from this study align with previous evidence as episodic memory improves after a HIIT intervention in young female adults and older adults. 181,182 Currently the only evidence of a minimal clinically important difference is an increase of 1.4 words pre- to post-intervention, however this is from a 10-word recall list whereas the RAVLT uses 15 words. 25,183 Despite this, a mean change of 2.09 words and a large effect size are promising evidence for future exercise trials in perimenopausal females. The intervention had a very small and positive effect on total, left, and right hippocampal volumes. Right hippocampal volume had a larger mean change than the left hippocampal volume. The magnitude of these findings are unexpected and should be taken with caution given the intervention length. They are unexpected given the positive association between episodic memory and hippocampal volume in older adults, and that HIIT promotes the release of lactate and neurotrophic factors which are beneficial for brain health. 156,157,184,185 One explanation for 42 the results could be the intervention length. Wilckens and colleagues 123 state that there is a significant effect of exercise on hippocampal volume for interventions greater than 24 weeks. However it is promising there are positive change scores of 0.64%, 0.50%, 0.79% 128 for total, left, and right hippocampal volume respectively; as hippocampal volume declines 1.18% per year in adults over 50 years old. 43 Future studies with a longer intervention length are needed to examine the effects of exercise on hippocampal volume in perimenopausal females. The HIIT intervention had a small and positive effect on whole-brain MWF. There are few studies that examined the effects of physical activity or exercise using a specific measure of myelin content. Faulkner and colleagues show a positive association between CRF and VO2max in healthy adults ages 22 to 94 years old. There are stronger associations between CRF and VO2max in middle age and older adulthood. This study’s findings add to Faulkner and colleagues’ findings. HIIT elicits positive change on whole-brain MWF in addition to the association between CRF and VO2max they report. 128 The current mechanistic evidence is from animal models. In an animal model of demyelination, 40 minutes of daily aerobic exercise for three weeks improved expression of myelin basic protein and brain derived neurotrophic factor compared with controls. 186 A systematic review and meta-analysis by Feter and colleagues 187 reports positive effects of exercise on myelin sheath thickness in animal models. Notably, intervention lengths ranged from two to 17.5 weeks (mean = 10 weeks). Tarumi and colleagues found that trained middle aged adults (aged 46 to 61) with high CRF (42.5 + 5.2 ml/kg/min) have better white matter integrity (measured by diffusion-tensor imaging) compared with sedentary middle-aged adults. 188 These findings should be taken with caution as measures of white matter integrity from diffusion tensor imaging may not detect the subtle changes in myelin. 189 Further 43 randomized control trials should use specific methods of measuring myelin such as MWF for populations at-risk of declines in myelin. 4.1 Limitations The limitations of this feasibility study were the: 1) lack of formal qualitative analysis; and 2) hormone use and CES-D score in the exclusion criteria; 3) sociodemographic characteristics of the sample and; 4) lack of control group. A qualitative analysis of focus group could have shown common enablers, barriers, and preferences to participation. In turn, this would better inform future trials. REDCap surveys (https://redcap.ubc.ca/), focus group, and Qualtrics surveys (https://ubc.qualtrics.com) feedback data were recorded in a secure server. This feedback will inform future studies. Secondly, excluding people who were taking any exogenous hormones (i.e. HRT, hormonal birth control or hormonal intrauterine device) posed a significant challenge for recruitment. 26.1% of females ages 15 to 49 in the United States take exogenous hormones (e.g. hormonal birth control or hormonal intrauterine device.) 190 Since we excluded anyone taking exogenous hormones for this feasibility study, the study sample may not be representative of the target population given HRT’s increasing acceptability. 166-168 Future studies should reassess the exclusion criterion regarding exogenous hormones so it is more representative of perimenopausal females. Initially a CES-D score of less than 16 was an inclusion criterion. Excluding participants who would be otherwise eligible aside from the CES-D criterion decreased the recruitment rate. Additionally, the study sample was highly educated as all participants had at least some university education. Lower education level is associated with higher risk of cognitive impairment. 191 Thus future studies should aim for a sample with a diverse range of education levels to increase the generalizability of future study findings. Finally, a control group would allow us to assess the acceptability treatment groups. Given the lack-of- 44 energy and lack-of-time barriers perimenopausal females face, and the barriers to participating in an in-person study this feasibility study had one group so every participant enrolled would receive the exercise intervention. This was done in hopes of increasing feasibility. 4.2 Future Directions and Conclusions Future studies should consider a hybrid (mix of in-person vs online) exercise. In doing so perimenopausal females can have a more flexible exercise schedule while maintaining intervention delivery with in-person workouts. Exercise classes should be offered at multiple times in the day (if resources allow) so participants can exercise at a time that works best for them. The hybrid intervention will allow for some flexibility and relieve the mental load of balancing the in-person study commitment with other life responsibilities. Furthermore, the inclusion and exclusion criteria should be reassessed to ensure recruitment rate targets are met. With HRT’s increasing acceptability for vasomotor and genitourinary symptoms in perimenopause, serum E2 should be a covariate in future analyses. 166 This study investigated the feasibility of HIIT in perimenopausal females to promote cognitive function and brain health. To ensure a larger trial is feasible to conduct the 1) intervention delivery (include a hybrid intervention with flexible times); and 2) inclusion and exclusion criteria should be re-assessed so the recruitment and withdrawal rate meet feasibility targets. High-intensity interval training showed promising changes for verbal episodic memory. The effects of HIIT on cardiorespiratory fitness and neuroimaging require further investigation with a study including a larger sample size, longer intervention, and a control group. This study showed preliminary evidence that HIIT can be feasible with some amendments, and it has positive effects on cognitive function during perimenopause. 45 Bibliography 1. International, A. s. D. (2020). Dementia Statistics. https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/ 2. Canada, A. s. S. (2024). The Many Faces of Dementia in Canada 2, 132. 3. Canada, S. (2022). Canada's population estimates: Age and sex, July 1, 2022. 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Thesis/Dissertation
eng
Rehabilitation Sciences
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Liu-Ambrose, Teresa
Feasibility of high-intensity interval training in perimenopause to promote cognitive function and brain health
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