Dementia, brain structure, and vascular risk factors in very old blacks and whites

Dementia is a disease of old age, and a major cause of disability and mortality in the elderly. African American or blacks have higher dementia prevalence and incidence than Caucasians or whites, and such racial disparities tend to be largest in the oldest old (≥ 85 years of age). Moreover, the oldest old is the fastest growing segment of the elderly population in US. Therefore, reducing racial disparities in dementia in the oldest old is of high public health relevance. Racial differences in dementia should have neurological correlates on racial differences in brain structure. However, among previous studies examining racial differences in brain structure, most applied neuroimaging methods with low resolution, and detected only brain macro-structural characteristics in cohorts of young old adults. Moreover, the sample sizes of oldest old blacks in previous works were too small to draw final conclusions. In this dissertation, a review of dementia, brain structure, and vascular risk factors is conducted first (Section 2), followed by an overview of their racial differences between elderly blacks and whites (Section 3). Gaps in knowledge and a proposal to address these gaps are presented in Section 4 and Section 5. The proposal involves leveraging an existing cohort of community-dwelling black and white adults (≥ 79 years of age) into an evaluation of brain structure and dementia. In this cohort, cutting-edge and high resolution neuroimaging modalities have been applied to obtain measures of brain structure at baseline and three years after, and data on vascular risk factors have been recorded at regular intervals in the previous decade. This dissertation work will not only provide estimates of dementia prevalence rates in very old blacks and whites in the context of other important determinants of dementia, but also offer new evidence for the pathophysiology of the association between race and dementia. The primary hypothesis is that racial differences in dementia or cognition is related to racial differences in vascular risk factors, and this is explained by racial differences in brain structural abnormalities

Falling Head Over Heels: Investigating the higher-level cognitive and electrophysiological processes underlying gait control and falls in older adults and stroke survivors

Falls are a common problem for Ireland’s older adults and stroke survivors, which have severe consequences for the individual and high care costs for the state. Current clinical interventions that focus solely on musculoskeletal function are not evidenced to be consistently effective in the long term, or in those older adults without muscle and bone impairments (Cadore, Rodríguez-Mañas, Sinclair, & Izquierdo, 2013; Teasell, McRae, Foley, & Bhardwaj, 2002). The role of cognition in gait control and falls has become increasingly apparent, with higher-level executive functions exhibiting a clear relationship with falls and cognitive decline with ageing (Morris, Lord, Bunce, Burn, & Rochester, 2016). This research aims to address a gap in the literature by identifying the specific higher-level executive processes that play a role in gait control, and examining if these processes are impaired in older adults and stroke survivors with a high risk of falling. Behavioural and electrophysiological measures were used to examine walking gait in both single- and dual-task conditions, as well as cognitive performances and the associated event-related potentials in healthy young and older adult “fallers” and “non-fallers”, and also in a sample of stroke survivors. The results suggest that executive top-down processes (working memory in particular), play a role in gait control during dual-task walking generally, and that executive processes are relied upon more in older age. This work suggests that there may also be neural markers of “successful” ageing that differentiate fallers from non-fallers, and that there can be substantial recovery of both cognition and gait post-stroke. These findings support the resource capacity and compensatory theories of neurocognitive ageing, and suggest that executive neuropsychological tasks could be developed to offer alternative cognitive/neural fall screening assessments and rehabilitation programmes for stroke patients and the wider older adult population

Falling Head Over Heels: Investigating the higher-level cognitive and electrophysiological processes underlying gait control and falls in older adults and stroke survivors

Falls are a common problem for Ireland’s older adults and stroke survivors, which have severe consequences for the individual and high care costs for the state. Current clinical interventions that focus solely on musculoskeletal function are not evidenced to be consistently effective in the long term, or in those older adults without muscle and bone impairments (Cadore, Rodríguez-Mañas, Sinclair, & Izquierdo, 2013; Teasell, McRae, Foley, & Bhardwaj, 2002). The role of cognition in gait control and falls has become increasingly apparent, with higher-level executive functions exhibiting a clear relationship with falls and cognitive decline with ageing (Morris, Lord, Bunce, Burn, & Rochester, 2016). This research aims to address a gap in the literature by identifying the specific higher-level executive processes that play a role in gait control, and examining if these processes are impaired in older adults and stroke survivors with a high risk of falling. Behavioural and electrophysiological measures were used to examine walking gait in both single- and dual-task conditions, as well as cognitive performances and the associated event-related potentials in healthy young and older adult “fallers” and “non-fallers”, and also in a sample of stroke survivors. The results suggest that executive top-down processes (working memory in particular), play a role in gait control during dual-task walking generally, and that executive processes are relied upon more in older age. This work suggests that there may also be neural markers of “successful” ageing that differentiate fallers from non-fallers, and that there can be substantial recovery of both cognition and gait post-stroke. These findings support the resource capacity and compensatory theories of neurocognitive ageing, and suggest that executive neuropsychological tasks could be developed to offer alternative cognitive/neural fall screening assessments and rehabilitation programmes for stroke patients and the wider older adult population

Neuroprotective Effects of Cardiorespiratory Fitness on White Matter Integrity and Cognition Across the Adult Lifespan

Objective: Cardiorespiratory fitness (CRF) is associated with decreased risk for cognitive decline. Accumulating evidence has linked CRF to more conserved white matter (WM) integrity and better cognitive performance in older adults. Additional research is needed to determine: (1) which WM tracts are most strongly related to CRF, (2) whether CRF-related benefits on WM translate to enhanced executive functioning (EF), and (3) if the neuroprotective effects of CRF are age-dependent. This study aimed to evaluate CRF as an intervention for modulating decreased WM integrity and EF in aging. Method: Participants were community-dwelling adults (N = 499; ages 20-85) from the open-access Nathan Kline Institute – Rockland Sample (NKIRS) with CRF (bike test), self-report of physical activity, diffusion tensor imaging (DTI), and EF data. Mixed-effect modeling tested the interaction between CRF and age on WM integrity (global and local microstructure). Significant WM tracts were retained for structural equation modeling to determine whether enhanced microstructure mediated a positive relationship between CRF and EF. Results: Among older participants (age 60), CRF was significantly related to stronger whole-brain (z-score slope = 0.11) and local WM integrity within five tracts (z-score slope range = 0.14 – 0.20). In support of the age-dependent hypothesis, the CRF–WM relationship was comparably weaker (z-score slopes 0.11) and more limited (one WM tract) in younger adults. CRF was more consistently related to WM than self-report of physical activity. Although CRF was linked to enhanced WM integrity, its potential benefits on EF were not directly observed. Conclusion: The findings highlight the importance of positive lifestyle factors, such as physical activity, in maintaining brain health in senescence. CRF may selectively preserve a collection of anterior and posterior WM connections related to visuomotor function

Body-brain Dynamics - An Observational Epidemiological Perspective

Given the significant public health burden caused by brain abnormalities and dementia, there is a great need for identifying intervention strategies to delay the progression of brain abnormalities. Among the interventions tested, non-pharmacological approaches and lifestyle modifications have received great attention. Indeed, the beneficial effects of physical activity on brain and mental health have been well documented. However, it remains unanswered how little and which component of physical activity could boost a change in brain structure and function, especially in adults aged 80 years and older who are at high risk of developing brain abnormalities and dementia. Answering these questions is important because structured aerobic exercise from current physical activity recommendations may not be feasible for older persons living with physical functional limitations and chronic diseases. It needs to be understood whether the positive effects of physical activity on brain health remain independent of health-related conditions. Another important question is which aspect of brain structure would benefit most from physical activity. For instance, brain areas in the frontal lobe are critical for executive function, a capstone for maintaining independence in late life, and the hippocampus is important for memory formation. To answer these questions, I first critically reviewed the literature on the relationship between physical activity, fitness, and brain structure in older adults. Second, I collected objectively measured physical activity data in a group of older adults with existing data on brain structure. I also analyzed existing data on physical activity, fitness, and brain structure obtained by advanced neuroimaging techniques. The public health significance of my dissertation is to provide scientific recommendations of physical activity on preserving brain structural integrity in community-dwelling older adults. In conclusion, being exercise active and higher fitness are associated with greater microstructural integrity localized in the medial temporal lobe, independent of each other and health-related conditions. In a small subset of very old adults, more steps taken and longer duration of physical activity are associated with greater microstructural integrity in the superior longitudinal fasciculus connecting the frontal lobe and the lateral portion of the temporal lobe, independent of physical function and health-related conditions

Investigating the Relationship Between Vascular Health, Gait, and Cognition in Community-Dwelling Older Adults Without Dementia

Cardiovascular disease (CVD) risk factors contribute to neuropathological changes within regions of the brain that are involved with both cognitive and motor control processes, and have been identified as potentially modifiable dementia and gait dysfunction risk factors. Exercise training is a corner-stone treatment for vascular risk factor control, and evidence suggests that physical and cognitive training can benefit cognition and gait; however, the exercise training modality that can provide the greatest cognitive benefit remains elusive. Therefore, the purpose of this thesis was three-fold: (i) to determine whether CVD risk factors and gait were associated with cognitive functioning, (ii) to determine whether blood pressure dipping status was associated with cognitive and gait impairments in community-dwelling older adults, and iii) to examine the impact of a dual-task gait training and aerobic exercise (DAE) on cognition, gait, and vascular health. Cumulative CVD risk was an independent predictor of executive functioning. Cross-sectional differences in cognition and usual and dual-task gait were observed between older adults with preserved blood pressure dipping and non-dippers. Last, 26-weeks of DAE training improved cognition and usual and dual-task gait, and the improvements in cognition were maintained for at least 6 months after the exercise program. The management of traditional and novel CVD risk factors should be a primary aim of prevention strategies aimed at mitigating cognitive decline. Although DAE training can benefit cognition and gait, further work is required to unequivocally determine the efficacy of DAE training as a method to improve brain health in older adults without dementia

Physical and Mental Coordination in the Elderly: A Causal Role for the Cerebellum?

The mechanisms underlying the progressive changes in tissues and organs that characterise normal ageing remain unclear. The cerebellum is known to play a major role in motor function, but recent research suggests it plays an equivalent role in cognition. Working with the hypothesis that cortico-cerebellar loops ensure smooth and coordinated activity in both domains, this thesis investigates the possible role of the cerebellum in normal ageing and in interventions to improve function, seeking to contribute to both theoretical and applied approaches to ageing. Study one investigated relationships between motor and cognitive function using raw data from a national normative sample of adults aged 16 to 75, employing a test battery assessing motor and cognitive skills. Differences between age groups were demonstrated in some tests of complex processing speed, working memory and executive function, with suggestive evidence that senescence in tests is reflected in tests sensitive to cerebellar function. Study two refined the battery, while including further measures of motor and memory performance to investigate linkages between cognitive and cerebellar function. Using a sample of 256 older adults, results were variable but provided evidence that pegboard performance could act as a predictor of some cognitive functions. Study three investigated a proactive intervention for healthy older adults designed to improve cerebellar function, and therefore balance and executive function. This involved an 8-10 week self-administered, internet-based coordinative exercise intervention using a ‘cerebellar challenge’ suite of graded activities. Performance on a basket of tests was assessed before and after, and also compared with performance changes in a no-intervention control group. Significantly greater benefits for the intervention group than the controls were found for balance physical coordination and controlled information processing. Overall, these studies support current research indicating cerebellar contribution to both cognitive and motor problems arising in old age, and present evidence that non-verbal memory and controlled speeded information problems may be alleviated through targeted activities affecting cerebellar function improving postural stability and physical coordination

Brain Volume Differences and Proactive Interference: A VBM Investigation of Healthy Cognitive Aging.

Research on aging and memory has consistently demonstrated decreased memory performance in older adults, specifically on tasks measuring verbal and spatial memory. Memory decline in aging is partially related to interference from competing information. In older adults, the learning of new information is more adversely affected by already-formed memories (i.e. proactive interference) than in younger adults. However, interference of new information on already- formed memories (retroactive interference) is less affected by age. The present investigation examined the association between proactive and retroactive interference, and brain volume in young and older adults. Proactive and retroactive interference were assessed with a Modified modified free recall (MMFR) test. Participants (n=39) first studied AB and DE word pairs three times before undergoing a cued recall test. Following AB-DE testing, participants had only one study-test cycle of AC and FG word pairs. Finally, participants completed the MMFR test to evaluate their memory for all previously studied and tested words. Results revealed that older adults experienced significantly more proactive interference than younger adults (performance on MMFR-AC minus MMFR-FG), but both age groups performed similarly on the retroactive interference measures. It was hypothesized that brain volume, and specifically Hippocampal and prefrontal volume, would be significantly correlated to memory performance; however no significant correlations were found with any specific brain regions