Lifestyle factors and neuroimaging metrics as predictors of cognitive performance in healthy aging

Despite all the advances made in health-related and psychological sciences, advancing age continues to be accompanied by cognitive decline. Aging is usually associated with major changes in the structure and functioning of the brain that lead to impairments in multiple cognitive functions. The trajectories of age-related effects on the brain and cognition exhibit considerable differences across cognitive domains and across individuals, and investigating approaches and factors that might prevent brain and cognitive decline during aging is considered a topic of great scientific and public health relevance. The overall goal of this thesis was to evaluate age-related differences in brain structure and functional connectivity to further our understanding of the neural mechanisms involved in age-related declines in cognition. This thesis also aimed to investigate the influence of lifestyle factors on age differences in cognition, and in that regard, I focused on the effects of sleep quality and physical activity on memory. In Study 1, I assessed the impact of aging on grey matter volume of the medial temporal lobe MTL and prefrontal cortex PFC and compared the relative contributions of MTL and PFC structures to age differences in associative memory. My findings emphasize the critical role of the frontal lobes, and the control processes they subserve, in determining the detrimental effects of age on memory. Additionally, I observed that the relationship between frontal grey matter volume and memory was not moderated by age or sex, suggesting that greater volume in PFC structures relates to better memory performance across the lifespan and in both sexes. In Study 2, I assessed the effects of age on functional brain networks. Given the essential role of the arousal system (ARAS) in cortical activation and previous findings of disrupted ARAS functioning with age, I investigated the hypothesis that age-related changes in ARAS-cortical functional connectivity may contribute to commonly observed age-related differences in cortical connectivity. The findings of this study showed that the arousal system is functionally connected to widespread cortical regions and suggest that age differences in functional connectivity within the cortex may be driven by age-related changes in the brainstem and these altered connectivity patterns have important implications for cognitive health. In Study 3, I investigated the relationship between sleep quality, physical activity, and memory in middle-age and older adults, in addition to assessing the impact of the COVID-19 pandemic on participants’ mood and sleep quality. Our results showed that people who were more active reported better sleep quality and showed better memory, and better sleep quality was associated with better memory. Moreover, our findings also showed that some of the beneficial effects of physical activity on cognition are partially mediated by improved sleep. Additionally, this study indicated that the COVID-19 pandemic had a deleterious effect on people’s sleep quality and overall well-being. Taken together, these studies suggest that aging is associated with disruptive effects on brain structure and function, and that these changes are associated with age-related cognitive decline. Additionally, our study supported the association between lifestyle factors, more specifically, sleep quality and physical activity, and cognitive performance during aging

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

Examination of Compensatory Network in Healthy Aging Adults with Graph Theory

Master'sMASTER OF ENGINEERIN

Distinct resting-state functional connections associated with episodic and visuospatial memory in older adults.

Episodic and spatial memory are commonly impaired in ageing and Alzheimer's disease. Volumetric and task-based functional magnetic resonance imaging (fMRI) studies suggest a preferential involvement of the medial temporal lobe (MTL), particularly the hippocampus, in episodic and spatial memory processing. The present study examined how these two memory types were related in terms of their associated resting-state functional architecture. 3T multiband resting state fMRI scans from 497 participants (60-82 years old) of the cross-sectional Whitehall II Imaging sub-study were analysed using an unbiased, data-driven network-modelling technique (FSLNets). Factor analysis was performed on the cognitive battery; the Hopkins Verbal Learning test and Rey-Osterreith Complex Figure test factors were used to assess verbal and visuospatial memory respectively. We present a map of the macroscopic functional connectome for the Whitehall II Imaging sub-study, comprising 58 functionally distinct nodes clustered into five major resting-state networks. Within this map we identified distinct functional connections associated with verbal and visuospatial memory. Functional anticorrelation between the hippocampal formation and the frontal pole was significantly associated with better verbal memory in an age-dependent manner. In contrast, hippocampus-motor and parietal-motor functional connections were associated with visuospatial memory independently of age. These relationships were not driven by grey matter volume and were unique to the respective memory domain. Our findings provide new insights into current models of brain-behaviour interactions, and suggest that while both episodic and visuospatial memory engage MTL nodes of the default mode network, the two memory domains differ in terms of the associated functional connections between the MTL and other resting-state brain networks

Functional Resting State Connectivity in Individuals At-Risk for Alzheimer\u27s Disease

Resting state functional magnetic resonance imaging studies have examined the connectivity between the hippocampus (HIPP) and the posterior cingulate (PC) in individuals with Alzheimer\u27s disease (AD), mild cognitive impairment (MCI), and younger individuals at risk for AD. The present study aimed to examine the functional connectivity between these two memory structures and targets of AD neurodegeneration in cognitively intact elders at risk for AD (positive for ApolipoE protein (ε4) and family history of dementia), MCI, and healthy controls. Seeds and regions of interest were defined in the bilateral hippocampus and posterior cingulate, and the time courses were cross-correlated to generate a value of functional connectivity between two structures for comparisons across groups. Results indicate the presence of greater functional connectivity between the left HIPP and PC in healthy elders at risk compared to patients with MCI and healthy controls and a general reduction in functional connectivity between bilateral HIPP and PC in patients with MCI. This marker of increased functional connectivity, during the resting state of the brain, found in cognitively intact elders at risk compared to cognitively intact controls and symptomatic patients with MCI might be an important diagnostic tool to identify those most vulnerable for the development of AD

Relationship between white matter alteration and encoding related brain activation in connected brain regions

Background: Aging is associated with alterations of white matter and brain activation. Functional MRI studies in elderly subjects showed changes in encoding related brain activation such as hyperactivation in frontal areas and hypoactivation in occipital gyrus in comparison to a younger control group. A contributing factor could be alterations of white matter integrity, resulting from age-related small vessel disease (SVD), a pathology that effects the small vessels of the brain or Wallerian Degeneration (WD) that explains axonal degeneration distal of an injury. These processes lead to changes such as white matter hyperintensities (WMH) detected by MRI or microstructural change assessed by the diffusion tensor imaging (DTI), marker mean diffusivity (MD) or peak width (PW). It was hypothesized that the directionality of the structure-function relationship of the brain is dependent on the investigated brain region. We aim to verify this assumption. Other studies focused on frontal brain regions. Instead we implemented a whole-brain analysis of the structure-function relationship. Therefore, the goal of this study was to investigate changes in white matter as a predictor of changed encoding-related brain activation in anatomically connected brain regions in cognitively normal performing older subjects. Furthermore, there are different theories that try to explain the changed brain activation in association with white matter change, such as compensatory mechanisms, dedifferentiation theory or inefficient neuronal processes. To gain a better understanding we examined the association between decreased brain activation respectively increased white matter changes in relation to cognitive performance of the subjects. Methods: Cognitively healthy elderly subjects (N = 35) performed a face-name matching paradigm within the fMRI scanner with the encoding phase being relevant in the present study. The integrity of white matter was determined with measurement of WMH volume and DTI based markers such as MD and PW. We performed ANOVAs with DTI-markers as dependent and activation as the independent variable. Furthermore, we performed ANOVAs with white matter change or brain activation as dependent variable and cognitive performance as independent variable. Since we assumed that there are local differences of white matter change we created boxplots for the chosen MD, PW and WMH-ratio within the chosen fiber tracts and global MD, PW and WMH-ratio. Additionally, we computed a correlation matrix between tract-specific MD or PW for a comparison of these two markers. Results: We could demonstrate a significant positive association between PW in the inferior fronto-occipital fasciculus left (IFOF L) and the activation in the left frontal gyrus as well as PW in the inferior longitudinal fasciculus right (ILF R) and activation in the occipital gyrus. Furthermore, the data revealed no significant result for the relationship between white matter change and cognition or brain activation and cognition. The boxplot showed a significant difference between the white matter tracts when using MD and PW as marker. Because of its low burden we had to exclude WMH-ratio as a marker for white matter change. The correlation-matrix revealed that PW within the tracts correlated less with each other than MD. Conclusion: These results suggest that microstructural changes lead to increased brain activation due to decreased white matter connectivity and reduced fidelity of data transmission. Additionally, the subjects' cognitive performance appears not to benefit from the increased brain activation. Thus, the negative structure-function relationship seems not to be based on a compensatory mechanism or dedifferentiation theory but most likely on an inefficient neuronal response. White matter change can be considered as regionally variable as revealed by the boxplots and the correlation matrix. However, the structure-function relation seems not be dependent on brain region, because the whole brain analysis showed a consistent directionality of the structure-function relationship

Multimodal imaging : functional, structural, and molecular brain correlates of cognitive aging

Aging is associated with a decline in many (but not all) cognitive abilities. Although it remains largely unknown how changes in brain integrity relate to cognitive deficits, these changes are likely expressed across interrelated functional, structural, and molecular layers. This complexity calls for a multimodal imaging approach in age-related mind-brain research. Hence, in this thesis, different imaging modalities were combined in order to study the neural basis of cognitive aging. Study I investigated functional connectivity patterns among three large-scale functional brain networks (i.e., default mode [DMN], frontoparietal control [FPN], and dorsal attention [DAN] networks) during rest and task in younger and older adults. The FPN was flexible in its affiliation to other networks, given that it was more functionally connected to the DMN during rest and to the DAN during task performance. Age-related differences were stable across states for the FPN, but were only present for connectivity between the DMN and DAN during the task. Taken together, these results suggest that resting-state is not sufficient to uncover the entire functional connectome of the human brain. Study II identified brain iron as a potential source of age-related differences in connectivity. Greater striatal iron content was associated with lower intrinsic functional connectivity of the caudate and putamen. Additionally, more iron was associated with less connectivity between the putamen and the rest of the brain. Functional connectivity within the putamen was also linked to motor ability, indicating that iron-related connectivity features are behaviorally meaningful. Study III explored the relationship between functional and structural connectivity, and showed that increased homotopic functional connectivity in the prefrontal cortex was associated with worse microstructural degeneration of the corpus callosum, and exacerbated working memory decline. However, given that the association between function and structure was weak, results also suggest that homotopic functional connectivity can be resilient to change in the integrity of its structural paths. Study IV found that dopamine and iron in the putamen were positively associated, but only up until middle age. Together with the fact that dopamine requires iron for its synthesis, these results indicate that, for individuals without excessive iron accumulation, more iron is associated with higher dopaminergic activity. Higher iron load in the putamen was also linked to better processing speed for those in middle age. Collectively, the studies show that functional connectivity is influenced by mental state, white-matter changes, and molecular properties, with the latter also being interrelated among themselves. These different features are associated with performance and interact with each other, suggesting that cognitive decline is linked to a multitude of changes in brain integrity, and that age-related alterations in the human brain are complex and multifaceted

A longitudinal resting-state functional connectivity analysis on trauma exposure and post-traumatic stress symptoms in older individuals

BACKGROUND: Given the present demographic shift towards an aging society, there is an increased need to investigate the brain's functional connectivity in the context of aging. Trauma exposure and post-traumatic stress disorder (PTSD) symptoms are factors known to impact healthy aging and have been reported to be associated with functional connectivity differences. In the present study, we examined and compared differences in within-default mode network (DMN), within-salience network (SN) and between-DMN-SN functional connectivity, between trauma-exposed individuals with and without PTSD symptoms as well as non-traumatized individuals in a non-clininical older adult sample. METHODS: Resting state functional MRI and behavioral data is taken from the Longitudinal Healthy Aging Brain Database Project (LHAB). For the present analysis, participants who completed the questionnaires on trauma exposure and PTSD symptoms (N = 110 individuals of which n = 50 individuals reported previous trauma exposure and n = 25 individuals reported PTSD symptoms; mean age = 70.55 years, SD = 4.82) were included. RESULTS: The reporting of PTSD symptoms relative to no symptoms was associated with lower within-DMN connectivity, while on a trend level trauma-exposed individuals showed higher within-SN connectivity compared to non-trauma exposed individuals. Consistent with existing models of healthy aging, between-DMN-SN functional connectivity showed an increase across time in older age. CONCLUSION: Present results suggest that alterations in within-DMN and within-SN functional connectivity also occur in non-treatment seeking older adult populations with trauma exposure and in association with PTSD symptoms. These changes manifest, alongside altered between-DMN-SN functional connectivity, in older age supposedly independent of aging-related functional desegregation