Clinically Silent Alzheimer\u27s and Vascular Pathologies Influence Brain Networks Supporting Executive Function in Healthy Older Adults

Aging is associated with declines in executive function. We examined how executive functional brain systems are influenced by clinically silent Alzheimer’s disease (AD) pathology and cerebral white matter hyperintensities (WMHs). Twenty-nine younger adults and thirty-four cognitively normal older adults completed a working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Older adults further underwent lumbar cerebrospinal fluid (CSF) draw for assessment of AD pathology and FLAIR imaging for assessment of WMHs. Accurate working memory performance in both age groups was associated with high fronto-visual functional connectivity (fC). However, in older adults, higher expression of fronto-visual fC was linked with lower levels of clinically silent AD pathology. In addition, AD pathology and WMHs were each independently related to increased fMRI response in the left dorsolateral prefrontal cortex, a pattern associated with slower task performance. Our results suggest that clinically silent AD pathology is related to lower expression of a fronto-visual fC pattern supporting executive task performance. Further, our findings suggest that AD pathology and WMHs appear to be linked with ineffective increases in frontal response in CN older adults

The Moderating Effect of Physical Activity on the Association between White Matter Hyperintensities and Gait Characteristics

The objectives of this thesis were; 1) to assess the effect of white matter hyperintensities (WMH) burden on motor outcomes among older individuals in presence and absence of overt neurological conditions and 2) to evaluate whether physical activity (PA) moderated the association between WMH and gait velocity and stride time variability (STV), under single and dual-task conditions, in a geriatric clinic sample. Study 1 systematically reviewed the literature demonstrating that greater WMH burden was associated with predefined motor outcomes. Notably, gait velocity emerged as a well-studied characteristic. Study 2 confirmed that WMH negatively affected gait velocity. STV and dual-task gait conditions did not reveal significance. Additionally, PA did not moderate the association between WMH and gait velocity, although conditional effects showed significance for low and moderate levels of PA. This finding extends support for the efficacy of physical activity in attenuating the effects of WMH on mobility

Multimodal neuroimaging of vestibular and postural networks: Investigating the pathophysiology of idiopathic dizziness in older adults

Successful ageing - the preservation of good performance into old age, is an aspiration for many and a challenge for society. Modifiable factors which account for ageing-related functional decline should thus be identified and reduced. As life expectancy increases, brain ageing and its functional consequences become an increasingly important target for research and intervention. Cerebral small vessel disease, largely driven by vascular risk factors, has emerged as a strong contributor to cognitive and balance decline in late life. Though the early effects of cerebral small vessel disease on cognition are increasingly better understood, its symptomatic effects on other functional systems are not well characterised. In this thesis, I investigated the long recognised, but pathophysiologically enigmatic syndrome of dizziness in older adults, not accounted for by neurological disease or vestibular dysfunction. I considered the hypothesis that this ‘idiopathic dizziness’ is secondary to cerebral small vessel disease through its deleterious effects on white matter networks which subserve vestibular perceptual processes and/or the control of balance. I first defined the functional anatomy of the core human vestibular cortex by its functional connectivity (Chapter 3). I related the resulting anatomical subregions to behavioural and task neuroimaging data to define a vestibular network involved in self-motion perception. I proceeded to characterise the syndrome of idiopathic dizziness using clinical, cognitive and behavioural (vestibular function, balance and gait) data from patients and controls (Chapter 4). I combined this data with structural and diffusion magnetic resonance imaging data to investigate the pathophysiology of idiopathic dizziness. I found that frontal white matter tracts relevant to the control of balance had lower integrity in patients with idiopathic dizziness than controls. These findings occurred in the context of excess vascular risk, and markers of cerebral small vessel disease. Additionally, I found vestibular function and perception were normal in patients with idiopathic dizziness. The results suggest disrupted balance control may underpin idiopathic dizziness in cerebral small vessel disease. I proceeded to investigate whether neural correlates of balance control were altered in idiopathic dizziness as a model for mild balance impairment in cerebral small vessel disease (Chapter 5). To do this, I applied electroencephalography during quiet standing and related brain activity to spontaneous sway. I showed idiopathic dizziness was linked to altered cortical activity in relation to balance control, and this cortical activity was influenced by the burden of cerebral small vessel disease. Additionally, patients with idiopathic dizziness uniquely engaged a low frequency postural connectivity network, consistent with a different mode of postural control. Overall, the results within this thesis show a relationship between idiopathic dizziness and vascular injury to frontal tracts involved in the control of balance in cerebral small vessel disease. Small vessel disease may disrupt the cortical control of balance as a basis for symptoms in this syndrome.Open Acces

Rumination and executive dysfunction: Risk factors for vascular depression

Introduction: The widely-supported vascular depression hypothesis is underspecified with respect to cognitive mechanisms by which high cerebrovascular burden (CVB) and neuropathology relate to depressive symptoms. Integration of the vascular depression hypothesis with the CaR-FA-X model, a framework of affect regulation mechanisms, suggest that Rumination (R) and executive dysfunction (X) may increase due to altered recruitment of the dorsolateral prefrontal cortex resulting from high CVB and underlying neuropathology. This process would contribute to depressive symptomatology among older adults with high CVB. The progression of examined hypotheses included mediation models examining mechanistic relationships between predictors (CVB, DLPFC activation), cognitive correlates (rumination, executive functioning), and affective outcomes (depressive symptoms). Method: A sample of 52 community-dwelling, stroke-free, individuals over the age of 70, without history of severe mental illness, dementia, or severe cognitive impairment, completed the Ruminative Responses Scale, provided self-reported cerebrovascular burden data (cardiac disease, hypertension, diabetes, high cholesterol), and completed executive function tasks (Stroop, Flanker) while their hemodynamic response was measured using fNIRS. The Geriatric Depression Scale was used to assess depressive symptomatology. Prefrontal cortical recruitment was assessed using functional near-infrared spectroscopy (fNIRS). Results: A progression of conventional and bootstrapped regression-based models broadly supported relationships between CVB and depressive symptoms, but not between DLPFC activation and depressive symptoms. No mechanistic relationships were found, with respect to analyses testing prospective cognitive mediators. Conclusions: Primary findings from this study indicate that cerebrovascular burden predicts depressive symptomatology among older adults and is related to a reduction in inhibitory control ability. Further, these findings inform CVB measurement and mental health implications of contrasting approaches to CVB measurement. A primary contribution of this thesis is that results appear to support utilization of fNIRS, a low-cost and accessible neuroimaging paradigm, for the study of lateralized cognition among older adults

Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

White matter integrity in physically fit older adults

Background: White matter (WM) integrity declines with normal aging. Physical activity may attenuate age-related WM integrity changes and improve cognitive function. This study examined brain WM integrity in Masters athletes who have engaged in life-long aerobic exercise training. We tested the hypothesis that life-long aerobic training is associated with improved brain WM integrity in older adults. Methods: Ten Masters athletes (3 females, age = 72.2 ± 5.3 years, endurance training \u3e15 years) and 10 sedentary older adults similar in age and educational level (2 females, age = 74.5 ± 4.3 years) participated. MRI fluid-attenuated-inversion-recovery (FLAIR) images were acquired to assess white matter hyperintensities (WMH) volume. Diffusion tensor imaging (DTI) was performed to evaluate the WM microstructural integrity with a DTI-derived metric, fractional anisotropy (FA) and mean diffusivity (MD). Results: After normalization to whole-brain volume, Masters athletes showed an 83% reduction in deep WMH volume relative to their sedentary counterparts (0.05 ± 0.05% vs. 0.29 ± 0.29%, p b 0.05). In addition, we found an inverse relationship between aerobic fitness (VO2max) and deep WMH volume (r = −0.78, p \u3c 0.001). Using TBSS, Masters athletes showed higher FA values in the right superior corona radiata (SCR), both sides of superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFO), and left inferior longitudinal fasciculus (ILF). In addition, Masters athletes also showed lower MD values in the left posterior thalamic radiation (PTR) and left cingulum hippocampus. Conclusions: These findings suggest that life-long exercise is associated with reducedWMH and may preserveWM fiber microstructural integrity related to motor control and coordination in older adults

The orbitofrontal cortex functionally links obesity and white matter hyperintensities

© 2020, The Author(s).Many studies have linked dysfunction in cognitive control-related brain regions with obesity and the burden of white matter hyperintensities (WMHs). This study aimed to explore how functional connectivity differences in the brain are associated with WMH burden and degree of obesity using resting-state functional magnetic resonance imaging (fMRI) in 182 participants. Functional connectivity measures were compared among four different groups: (1) low WMH burden, non-obese; (2) low WMH burden, obese; (3) high WMH burden, non-obese; and (4) high WMH burden, obese. At a large-scale network-level, no networks showed significant interaction effects, but the frontoparietal network showed a main effect of degree of obesity. At a finer node level, the orbitofrontal cortex showed interaction effects between periventricular WMH burden and degree of obesity. Higher functional connectivity was observed when the periventricular WMH burden and degree of obesity were both high. These results indicate that the functional connectivity of the orbitofrontal cortex is affected by the mutual interaction between the periventricular WMHs and degree of obesity. Our results suggest that this region links obesity with WMHs in terms of functional connectivity11sciescopu

Distinct Patterns of Default Mode and Executive Control Network Circuitry Contribute to Present and Future Executive Function in Older Adults

Executive function (EF) performance in older adults has been linked with functional and structural profiles within the executive control network (ECN) and default mode network (DMN), white matter hyperintensities (WMH) burden and levels of Alzheimer\u27s disease (AD) pathology. Here, we simultaneously explored the unique contributions of these factors to baseline and longitudinal EF performance in older adults. Thirty-two cognitively normal (CN) older adults underwent neuropsychological testing at baseline and annually for three years. Neuroimaging and AD pathology measures were collected at baseline. Separate linear regression models were used to determine which of these variables predicted composite EF scores at baseline and/or average annual change in composite ΔEF scores over the three-year follow-up period. Results demonstrated that low DMN deactivation, high ECN activation and WMH burden were the main predictors of EF scores at baseline. In contrast, poor DMN and ECN WM microstructure and higher AD pathology predicted greater annual decline in EF scores. Subsequent mediation analysis demonstrated that DMN WM microstructure uniquely mediated the relationship between AD pathology and ΔEF. These results suggest that functional activation patterns within the DMN and ECN and WMHs contribute to baseline EF while structural connectivity within these networks impact longitudinal EF performance in older adults

Slowing Down: Age-Related Neurobiological Predictors of Processing Speed

Processing speed, or the rate at which tasks can be performed, is a robust predictor of age-related cognitive decline and an indicator of independence among older adults. This review examines evidence for neurobiological predictors of age-related changes in processing speed, which is guided in part by our source based morphometry findings that unique patterns of frontal and cerebellar gray matter predict age-related variation in processing speed. These results, together with the extant literature on morphological predictors of age-related changes in processing speed, suggest that specific neural systems undergo declines and as a result slow processing speed. Future studies of processing speed – dependent neural systems will be important for identifying the etiologies for processing speed change and the development of interventions that mitigate gradual age-related declines in cognitive functioning and enhance healthy cognitive aging