Liu-Ambrose, Teresa (University of British Columbia)
Eng, Janice (University of British Columbia); Boyd, Lara (University of British Columbia); Hsiung, Robin (University of British Columbia); Feldman, Howard (University of British Columbia); Jacova, Claudia (University of British Columbia); Lee, Philip (University of British Columbia); Brasher, Penny (Vancouver Coastal Health Research Institute).
The main goal of the proposed study is to determine whether a group-based aerobic exercise training program will retard the progression of Vascular Cognitive Impairment (VCI), by improving cognitive function, global executive function, and consequently daily life function.
We propose a six-month randomized controlled trial of aerobic-based exercise training with a six-month follow-up period. There will be three measurement periods within the 12-month duration of study: 1) baseline; 2) six months (i.e., completion of exercise intervention period); and 3) 12 months (i.e., completion of the follow-up period). This work is essential as VCI is the second most common cause of dementia 3-6 and may be the most under-diagnosed and undertreated form of cognitive dysfunction in older adults 7. VCI is defined as the loss of cognitive function resulting from ischemic, ischemic-hypoxic, or hemorrhagic brain lesions as a result of cerebro-vascular disease and cardiovascular pathologic changes. As VCI is predominantly a sub-cortical frontal form of dementia with prominent executive dysfunction 8, it directly impairs everyday function 9, such as managing finances, transportation, or the telephone. Taken together, VCI severely interferes with the ability to function autonomously within society 10.
Although there is growing recognition of a close relationship between AD and vascular dementia including several vascular risk factors 11, vascular pathology in the brain 12, 13, and common pathogenic mechanisms such as neurotransmitter abnormalities 14. VCI is specifically linked to large vessel disease, small vessel disease, sub-cortical ischemic vascular disease, and non-infarct ischemic changes and atrophy 15. Recent studies suggest that sub-cortical ischemic vascular disease sub-type is a more homogenous form of the disease with a more predictable outcome 16. Small vessel disease often presents as undetected "covert" strokes in the sub-cortical white matter, resulting in cognitive deficit of processing speed and executive functions. A number of epidemiological studies suggest that modification of vascular risk factors, such as hypertension, diabetes mellitus, and hypercholesterolemia may be helpful in retarding the progression of VCI 17-20. However, the optimal timing and type of intervention has not been resolved.
One extremely promising approach to slowing the progression of VCI is aerobic-based exercise training. Randomized trials of various exercise interventions have proven that exercise has many systemic benefits 21. Exercise can lead to health benefits through reduction of the vascular risk factors associated with metabolic syndrome 22-26. Critically, evidence is mounting that exercise has benefits for cognitive function among seniors. Specifically, a recent study published in the Journal of the American Medical Association 27 showed that a general exercise program can maintain cognitive performance among seniors at risk for AD. Aerobic-based exercise training as an intervention strategy for individuals with VCI is attractive as it could be delivered at a population-level and thus, is highly cost-effective.
We aim to extend previous work in this area by carrying out a proof-of-concept study aimed at investigating the effect of a six-month, thrice-weekly, aerobic-based exercise training program on cognitive function, global executive function, and the everyday function among seniors with mild Sub-cortical Ischemic Vascular Cognitive Impairment (SIVCI). Secondly, we aim to investigate the effect of this aerobic-based exercise training program on three key executive processes: set shifting, response inhibition, and working memory 28, in addition to quality of life, mood, physical function, and health resource utilization. Within a subset, we will also acquire both anatomical and functional MRI to gain insight to the impact of aerobic-based exercise training on white matter disease and the neural network associated with executive functioning among seniors with mild SIVCI. We will also acquire high-resolution Pittsburg compound B positron emission tomography (PiB-PET) scans to examine the co-existence of amyloid pathology in SIVCI. Furthermore, we will use this PiBPET data to investigate how amyloid pathology affects change in cognitive function, global executive function, and everyday function as a result of aerobic-based exercise training among seniors with mild SIVCI. Finally, we will investigate the effects of aerobic-based exercise training on levels of homocysteine (HCS), C-reactive protein (CRP), and interleukin-6 (IL-6). Standard biomarkers including fasting serum glucose, Hemoglobin (Hgb) A1c, and lipid profile will also be obtained for comparison. This will allow us to secondarily assess the effect of exercise on these markers, and their relationships in the diagnosis and management of mild SIVCI. We also aim to investigate the possible interaction between aerobic-based exercise training and APOE genotype on change in cognition and everyday function among our study participants. The target population will be seniors living in the community who present with mild SIVCI due to small vessel disease. We define mild SIVCI as those with Folstein’s Mini-Mental Examination State (MMSE) 29 scores of > 20/30.
The impact of our proposed work can be significant. Delay of onset and/or retardation of progression of dementia (both of AD and VCI type) by only one year would reduce the number of clinical cases of dementia by 9.2 million by 2050 in the US alone 30. Based on the success of past work investigating the impact of aerobic-based exercise training on cognition and brain function in both demented and non-demented populations 31, the likelihood of translating these benefits to individuals with SIVCI is high. As we are facing a looming global epidemic of dementia due to the world’s aging population, it is imperative that we promptly identify preventive strategies can either delay the onset or retard the progression of dementia. We predict that aerobic-based exercise training is one ideal method by which we can retard the progression of SIVCI through a beneficial effect on cognitive function, global executive function, and everyday function, and will test this assumption directly (Primary Objective and Hypothesis). In addition, we will explore the mechanisms underlying change in cognition and everyday function among seniors with mild SIVCI as a result of aerobic-based exercise training. Specifically, we will examine the role of coexisting amyloid pathology, blood and genetic biomarkers, white matter disease, and brain activation. Currently, the clinical diagnosis and management of SIVCI is not well established; knowledge gained from our study will lead to better diagnosis and screening, as well as improved selection of those who may best benefit from aerobic-based exercise training.