Assessment Of The Interplay Between Regional β-Amyloid Burden And White Matter Hyperintensities On Cognition And Default Mode Network In Clinically Normal Older Participants

Objective: Alzheimer’s disease (AD) and subcortical vascular dementia are considered the most common pathologic contributors to dementia in the aging population. Both frequently coexist in over 80% of community dwelling adults with dementia. The neuropathological development of AD arguably begins with β-amyloid (Aβ) deposition in the brain. This series of studies aims to test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in preclinical AD (pAD) (study1). Since mixed dementia is widely recognized as the norm rather than the exception, the second study aimed to explore the relation between regional and global Aβ and WMH with core cognitive function (executive function (EF) and memory) scores in cognitively normal (CN) older adults (study2). Finally, the relationship between WMH and Aβ is strongly determined by the spatial distribution of the two pathologies, so the third study aimed to quantify Aβ in Default mode network (DMN) regions to examine whether cerebral small vessels disease (SVD) disruption of connectivity affects Aβ deposition in disconnected DMN regions (study3). Method: Global and regional Standard Uptake Value ratios (SUVr) from Aβ-PET, WMH volumes from MRI FLAIR images, and cognitive test scores were analyzed across a sample of CN participants. Linear regression models adjusted for age, sex and education used to assess the relationships between regional SUVr and cognitive test scores across 99 CN from Sanders Brown Center on Aging (study1). Moderation, and mediation modeling were used to define the interplay between global, regional Aβ and WMHs measures in relation to EF and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 CN from the Alzheimer’s Disease Neuroimaging Initiative ADNI (study2). The association of WMH volume in anatomically defined white matter tracts of atlas-based fiber tract with Aβ SUVr specifically in connected cortical regions within DMN was tested across sample of 74 CN from ADNI3. Results: EF performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p \u3c 0.05). The moderation regression analysis showed additive effects of Aβ and WMH over baseline memory and EF scores (p =0.401 and 0.061 respectively) and synergistic effects over follow-up EF (p \u3c 0.05). Through mediation analysis, the data from study 2 showed that WMH affects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. Finally, the regression analysis from study 3 demonstrated that increased WMH volumes in superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in inferior parietal lobule (IPL) (p \u3c 0.05). Conclusion: While the prevailing view in the field suggests that memory performance is the earliest clinical hallmark of AD, the present data demonstrate that changes in EF, mediated by Aβ deposition in the precuneus and posterior cingulate may precede memory decline in pAD. After adding the second key driver of cognitive decline in CN, the finding suggested that WMH dependent changes in baseline cognitive performance are related to direct effect of WMH and an indirect effect through both global and regional Aβ burden. Further studies are needed to show the longitudinal influences of WMH on Aβ distributions in participants with mixed dementia

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction

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

Effects of methamphetamine on prenatally exposed children in Cape Town: cognition and intrinsic functional brain connectivity

Methamphetamine use among pregnant women is an increasing problem in South Africa. The aim of this cross-sectional exploratory study was to examine the possible neurotoxic effects of prenatal methamphetamine exposure (PME) on cognition and the developing brain in a sample of affected children in Cape Town, South Africa. Thus, this is a two-part study: the first part examines the effects of PME on neuropsychological outcomes, and the second part examines the effects of PME on intrinsic functional brain connectivity. Children with PME (n = 23) and unexposed controls (n = 22) completed a battery of neurocognitive assessments, and a smaller sub-sample (n = 36; 19 children with PME, 17 unexposed controls) also underwent resting-state functional magnetic resonance imaging (RS-fMRI). Independent samples t-tests revealed that children with PME scored significantly more poorly on measures of IQ, learning and memory, confrontation naming, visual-motor integration, and fine motor co-ordination, when compared to controls. Hierarchical regression analyses confirmed that PME has a significant effect on cognitive performance, and that this effect largely withstands the effects of potentially confounding sociodemographic and anthropometric variables. Independent component analyses revealed significant betweengroup differences in functional brain networks detected in task-free RS-fMRI in children with PME. Specifically, there is evidence for compromised connectivity within and between the basal ganglia network and default mode network in children with PME. Overall, the findings contribute to the small but growing literature on the cognitive effects of PME. The current study is the first to document preliminary evidence indicating aberrant intrinsic functional brain connectivity in children with PME, and suggests that further investigation of potential associations between particular neurocognitive deficits and such aberrant connectivity might be warranted