Blood Glucose Levels and Genetic Factors as Predictors of Neurocognitive Outcomes

Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive cognitive decline, is becoming increasingly prevalent as the population ages. There is no effective treatment for AD, so manipulating modifiable risk factors before clinical symptoms of dementia develop may be the most effective course to prevent, delay, or modify the course of AD. Type II diabetes mellitus (DM), characterized by hyperglycemia and insulin resistance, affects over a quarter of older adults and has been linked with AD, cognitive decline, and brain atrophy. Because DM is preventable and treatable, it represents an intervention target for AD. This dissertation investigated the association between glucose levels and three outcomes – performance on a battery of cognitive tests over time, time to symptom onset of mild cognitive impairment (MCI) or dementia, and cortical thickness in AD-signature regions (i.e., entorhinal cortex, inferior temporal gyrus, parahippocampal gyrus pars triangularis, precuneus, superior frontal and parietal gyri, supramarginal gyrus, and temporal pole). Additionally, it investigated how two genes – apolipoprotein E (APOE) and translocase of the outer mitochondrial membrane (TOMM) 40 – may modify the relationship between glucose and these outcomes. Both the APOE ε4 allele and the TOMM40 very long/very long (VL/VL) genotype (versus the short/short (S/S) genotype) have been associated with increased risk of dementia, cognitive decline, and brain atrophy, and some evidence suggests that these genetic factors may further increase the risk in individuals with DM. This research was conducted using data from the BIOCARD Study (n=349), which enrolled primarily middle-aged individuals, three-quarters of whom had a first-degree relative with dementia. The goal of the study was to examine the early signs and symptoms of AD in a high-risk cohort. For this dissertation, baseline blood glucose level, which was ascertained from a blood draw in a clinical exam, was the primary predictor and was available for 333 participants. APOE and TOMM40 genotypes were also determined from blood samples. Age of MCI or dementia symptom onset was determined through consensus diagnosis. At annual visits, participants completed a neuropsychological test battery, and at baseline and bi-annually, participants completed magnetic resonance imaging (MRI) scans. The first paper in this study used linear mixed effects models (LMMs) and generalized estimating equation (GEE) models to investigate the association between glucose and cognitive performance over time. We used confirmatory factor analysis (CFA) to create one factor based on performance on tests of executive function (the executive function factor) and one factor based on performance on tests of memory (the memory factor). We found that higher baseline glucose was associated with greater decline on the executive function factor score in both LMMs (B=-0.005; 95% CI -0.008, -0.001) and GEE models (B=-0.004; 95% CI -0.007, -0.001) that controlled for age, sex, race, education, depression, and medical conditions (i.e., cardiovascular conditions, hypertension, hypercholesterolemia, traumatic brain injury (TBI)). Interaction analyses using LMMs found that higher glucose was associated with significant decline in executive function score in ε4 carriers (B=-0.013; 95% CI -0.020, -0.006), but not in non-carriers (B=-0.002, 95% CI -0.006, 0.002). In LMMs, higher glucose was also associated with poorer memory factor score over time in subjects with the S/S genotype (B=-0.013; 95% CI -0.024, -0.002), versus the VL/VL genotype (B=0.004; 95% CI -0.003, 0.010). The second paper in this study used Cox proportional hazard models to investigate the association between baseline blood glucose level and time to MCI or dementia symptom onset, as well as the association between the interaction of APOE and glucose and TOMM40 and glucose and time to symptom onset. We did not find an association between glucose level and time to symptom onset; additionally, we did not find that APOE or TOMM40 modified this relationship. In the final paper, linear regression analyses showed that glucose level was associated with reduced cortical thickness in the parahippocampal gyrus (B=-0.002; 95% CI -0.003, -0.0001) and temporal pole (B=-0.002; 95% CI -0.003, -0.0002) in a fully-adjusted model. Additionally, higher glucose levels were associated with thinner measures of the superior parietal gyri (B=-0.001; 95% CI -0.002, 0.0005 vs. B=0.0007; 95% CI 3.05e-6, 0.001) and temporal pole (B=-0.004; 95% CI -0.008, -0.0009 vs. B=-0.0003; 95% CI -0.002, 0.001) in ε4 allele carriers versus non-carriers. This evidence suggests that even in middle-aged, cognitively healthy samples, higher levels of glucose, even in those without DM, can negatively impact cognitive performance and cortical thickness. Maintaining normal blood glucose levels may be important in middle age for reducing risk of cognitive decline, AD, and brain atrophy

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

Vascular Risk, Functional Connectivity, and Episodic Memory in Older Adults

Resting-state functional magnetic resonance imaging and functional connectivity (FC) analyses are used to explore functional brain networks underlying a diverse array of abilities. Functional networks are composed of regions throughout the brain whose activity is closely linked to form a coherent network. One functional network, the default mode network (DMN), is thought to subserve self-referential thought and autobiographical memory. DMN regions include the ventromedial prefrontal cortex, inferior parietal lobe, hippocampus, and the primary hub of this network, the posterior cingulate cortex (PCC). For reasons yet unknown, DMN FC declines in aging, which is associated with memory impairment. Vascular risk may be an important contributor to age-related DMN disruption through its effects on gray and white matter integrity. The present study examined relationships among vascular risk, DMN FC, and episodic memory in older adults using FC analyses and structural equation modeling. Several regions found to be functionally related to the PCC were those identified in prior research on the DMN, but also included areas not typically implicated in the DMN, such as the cerebellum and basal ganglia. Stronger FC between the PCC and parahippocampal gyrus predicted better memory performance, confirming the importance of medial temporal lobe structures for memory. FC between the PCC and several other areas, such as the cerebellum, basal ganglia, and limbic regions, also predicted memory performance, suggesting the importance of executive functioning and emotion for memory in aging. Correlations between FC and vascular risk were found in the basal ganglia, cerebellum, and inferior temporal gyrus, suggesting vascular risk may modify associations between the DMN and cortical and subcortical regions. Finally, a mediational model was tested in which DMN FC mediated the relationship between vascular risk and memory. This was compared to an alternative model with depressive symptoms as a mediator. Vascular risk was unrelated to memory and DMN FC in all models, while stronger DMN FC predicted poorer memory performance. Neither DMN FC nor depressive symptoms acted as mediators. The impact of vascular risk on the DMN in aging should be further explored using a comprehensive multimethod approach, along with other potential causes of age-related DMN disruption