Mapping the Impact and Plasticity of Cortical-Cardiovascular Interactions in Vascular Disease Using Structural and Functional MRI

There is growing interest in the role of vascular disease in accelerating age-related decline in cerebrovascular structural and functional integrity. Since an increased number of older adults are surviving chronic diseases, of which cardiovascular disease (CVD) is prevalent, there is an urgent need to understand relationships between cardiovascular dysfunction and brain health. It is unclear if CVD puts the brains of older adults, already experiencing natural brain aging, at greater risk for degeneration. In this thesis, the role of CVD in accelerating brain aging is explored. Because physical activity is known to provide neuroprotective benefits to brains of older adults, the role of physical activity in mediating disease effects were also explored. Using novel neuroimaging techniques, measures of gray matter volume and cerebrovascular hemodynamics were compared between groups of coronary artery disease patients and age-matched controls, to describe regional effects of CVD on the brain. In a sub-set of patients, imaging measures were repeated after completion of a 6-month exercise training, part of a cardiac rehabilitation program, to examine exercise effects. Differences in cerebrovascular hemodynamics were measured as changes in resting cerebral blood flow (CBF) and changes in cerebrovascular reactivity (CVR) to hypercapnia (6% CO2) using a non-invasive perfusion magnetic resonance imaging technique, arterial spin labelling (ASL). We found decreased brain volume, CBF and CVR in several regions of the brains of coronary artery disease patients compared to age-matched healthy controls. The reductions in CBF and CVR were independent of underlying brain atrophy, suggesting that changes in cerebrovascular function could precede changes in brain structure. In addition, increase in brain volume and CBF were observed in some regions of the brain after exercise training, indicating that cardiac rehabilitation programs may have neurorehabiliation effects as well. Since, CBF measured with ASL is not the [gold] standard measure of functional brain activity, we examined the regional correlation of ASL-CBF to glucose consumption rates (CMRglc) measured with positron emission tomography (PET), a widely acceptable marker of brain functional activity. Simultaneous measurements of ASL-CBF and PET-CMRglc were performed in a separate study in a group of older adults with no neurological impairment. Across brain regions, ASL-CBF correlated well with PET-CMRglc, but variations in regional coupling were found and demonstrate the role of certain brain regions in maintaining higher level of functional organization compared to other regions. In general, the results of the thesis demonstrate the impact of CVD on brain health, and the neurorehabiliation capacity of cardiac rehabilitation. The work presented also highlights the ability of novel non-invasive neuroimaging techniques in detecting and monitoring subtle but robust changes in the aging human brain

Sub-Clinical Cognitive Decline and Resting Cerebral Blood Flow in Middle Aged Men

Although dementia is associated with both global and regional cerebral blood flow (CBF) changes, little is known about cerebral perfusion in the early pre-clinical stages of cognitive decline preceding overt cognitive dysfunction. The aim of this study was to investigate the association of early sub-clinical cognitive decline with CBF. The study participants were recruited from a cohort of Danish men born in 1953. Based on a regression model we selected men who performed better (Group A, n=94) and poorer (Group B, n=95) on cognitive testing at age 57 than expected from testing at age 20. Participants underwent supplementary cognitive testing, blood sampling and MRI including measurements of regional and global CBF. Regional CBF was lower in group B than in group A in the posterior cingulate gyrus and the precuneus. The associations were attenuated when corrected for global atrophy, but remained significant in regions of interest based analysis adjusting for regional gray matter volume and vascular risk factors. No influence of group on global CBF was observed. We conclude that early sub-clinical cognitive decline is associated with reduced perfusion in the precuneus and posterior cingulate gyrus independently of regional atrophy and vascular risk factors, but cannot be statistically separated from an association with global atrophy

Gray-Matter Degeneration in Presenile Alzheimer's Disease

Previous comparisons between presenile Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT) did not control for disease severity and duration. In the current study, 18 patients with each diagnosis were matched for disease duration, cognitive dysfunction, and behavioral symptoms (using the modified Mini-Mental Status [mMMS] examination and the Blessed Dementia Rating Scale [BDRS]). Regional cerebral blood flow (rCBF) was quantified by the 133xenon inhalation technique, and several indices of tissue perfusion were examined. The two variables of primary interest were relative gray-matter weight and a gray-matter perfusion index, the initial slope index. Presenile onset was associated with loss of gray-matter relative weight (35% in presenile patients versus 39% in senile patients and healthy control subjects, p = 0.006), with neither perfusion nor disease severity differences between the two dementia samples. This loss of gray matter was significantly related to both severity and duration of disease in the patients with presenile AD, but not in patients with SDAT. These findings lend support to previous suggestions of greater degenerative process in presenile AD and confirm the need to examine and control age of onset in future investigations of AD. Further, correlation analysis suggests greater proportion of common variance among clinical and physiological indices in presenile AD

Impaired cerebrovascular function in coronary artery disease patients and recovery following cardiac rehabilitation

© 2016 Anazodo, Shoemaker, Suskin, Ssali, Wang and St. Lawrence. Coronary artery disease (CAD) poses a risk to the cerebrovascular function of older adults and has been linked to impaired cognitive abilities. Using magnetic resonance perfusion imaging, we investigated changes in resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to hypercapnia in 34 CAD patients and 21 age-matched controls. Gray matter volume (GMV)s were acquired and used as a confounding variable to separate changes in structure from function. Compared to healthy controls, CAD patients demonstrated reduced CBF in the superior frontal, anterior cingulate (AC), insular, pre- and post-central gyri, middle temporal, and superior temporal regions. Subsequent analysis of these regions demonstrated decreased CVR in the AC, insula, post-central and superior frontal regions. Except in the superior frontal and precentral regions, regional reductions in CBF and CVR were identified in brain areas where no detectable reductions in GMV were observed, demonstrating that these vascular changes were independent of brain atrophy. Because aerobic fitness training can improve brain function, potential changes in regional CBF were investigated in the CAD patients after completion of a 6-months exercise-based cardiac rehabilitation program. Increased CBF was observed in the bilateral AC, as well as recovery of CBF in the dorsal aspect of the right AC, where the magnitude of increased CBF was roughly equal to the reduction in CBF at baseline compared to controls. These exercise-related improvements in CBF in the AC is intriguing given the role of this area in cognitive processing and regulation of cardiovascular autonomic control

The Relationship between Cortical Blood Flow and Sub-Cortical White-Matter Health across the Adult Age Span

Degeneration of cerebral white matter is commonly observed in aging, and the associated degradation in neural connectivity contributes to cognitive decline in older adults. Vascular dysfunction has been implicated as a potential mechanism for general age-related neural tissue deterioration; however, no prior study has examined the direct relationship between cortical vascular health and subcortical white-matter integrity. In this work, we aimed to determine whether blood supply to the brain is associated with microstructural integrity of connective tissue, and whether such associations are regionally specific and mainly accounted for by aging. We examined the association between cerebral blood flow (CBF) in the cortical mantle, measured using arterial spin labeling (ASL), and subcortical white-matter integrity, measured using diffusion tensor imaging (DTI), in a group of healthy adults spanning early to late adulthood. We found cortical CBF to be significantly associated with white-matter integrity throughout the brain. In addition, these associations were only partially tied to aging, as they remained even when statistically controlling for age, and when restricting the analyses to a young subset of the sample. Furthermore, vascular risk was not a prominent determinant of these effects. These findings suggest that the overall blood supply to the brain is an important indicator of white-matter health in the normal range of variations amongst adults, and that the decline in CBF with advancing age may potentially exacerbate deterioration of the connective anatomy of the brain

The effects of structural and functional damage to limbic structures on cognitive abilities

Functional and degenerative damage to regions of the limbic system are often associated with cognitive impairments in different aspects of memory. Neuroimaging studies in post-traumatic stress disorder (PTSD) and Alzheimer’s disease (AD) have reported selective hippocampal atrophy. Neuroimaging studies in panic disorder have also suggested reduced functional activity in the right parahippocampal gyrus. It is unclear whether this hippocampal damage is responsible for the emergence of selective neuropsychological deficits. Abnormal activity in limbic structures has also been reported in PTSD patients exposed to trauma-related stimuli. This thesis was concerned with examining the effects of structural and functional damage to the limbic system on selective cognitive abilities. The limbic structures under investigation included the hippocampus, parahippocampal gyrus, anterior cingulate cortex and amygdala. In order to investigate this issue, a series of neuropsychological and neuroimaging experiments were carried out using groups of patient populations, such as panic disorder, PTSD and AD, known to exhibit abnormalities to the limbic structures. An fMRI study, using the Color Stroop and Emotional Stroop task was also administered to PTSD patients and healthy controls.Results from the neuropsychological studies showed greater impairments in topographical/spatial memory compared to verbal memory in all groups of patients. In addition, voxel-based correlation analyses found that both PTSD and AD are associated with neuropsychological deficits in the area of visuo-spatial and topographical memory that may be explained by the regional brain atrophy in limbic structures. Abnormalities of the parahippocampal gyri and cingulate cortex and possibly the amygdalae in the fMRI study also suggested a dysregulation in limbic-cortical networks in PTSD. This thesis has demonstrated that damage to limbic structures might contribute to the cognitive abnormalities of panic disorder, PTSD and AD

Mechanisms linking obesity and its metabolic comorbidities with cerebral grey and white matter changes

Obesity is a preventable risk factor for cerebrovascular disorders and it is associated with cerebral grey and white matter changes. Specifically, individuals with obesity show diminished grey matter volume and thickness, which seems to be more prominent among fronto-temporal regions in the brain. At the same time, obesity is associated with lower microstructural white matter integrity, and it has been found to precede increases in white matter hyperintensity load. To date, however, it is unclear whether these findings can be attributed solely to obesity or whether they are a consequence of cardiometabolic complications that often co-exist with obesity, such as low-grade systemic inflammation, hypertension, insulin resistance, or dyslipidemia. In this narrative review we aim to provide a comprehensive overview of the potential impact of obesity and a number of its cardiometabolic consequences on brain integrity, both separately and in synergy with each other. We also identify current gaps in knowledge and outline recommendations for future research

Altered hippocampal function in major depression despite intact structure and resting perfusion

Background: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation. Method: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed. Results: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow. Conclusions: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression