Brain Imaging Correlates of Developmental Coordination Disorder and Associated Impairments

Developmental Coordination Disorder (DCD) is a common developmental disorder characterised by an inability to learn age appropriate complex motor skills. The first aim of this thesis was to characterise additional cognitive impairments and their relationship with motor difficulties in school aged children with DCD. The second aim was to investigate grey and white matter neuroimaging correlates of motor and cognitive deficits identified. Thirty six children aged 8-10 years who met DSM-5 criteria for DCD and an age-matched typically developing group (N=17) underwent standardised assessments of motor, intellectual, attention, speech and language skills as well as structural and diffusion-weighted MRI scans. Grey matter correlates of impairments were identified using subcortical volumetrics and surface-based analyses of cortical morphology. White matter correlates were examined using tractography and fixel-based fibre morphology of the pyramidal tracts, corpus callosum and cerebellar peduncles. Alongside impaired motor skills, children with DCD performed poorer than controls on several domains of executive function (attention and processing speed) and speech motor control. Motor skills did not correlate with impairments in other domains. Cortical thickness was significantly reduced in the left central sulcus in children with DCD compared to controls. Poor motor skills correlated with measures in left sensorimotor circuitry, posterior cingulate cortex and anterior insula. Poor speech motor control was associated with measures in the thalamus and corticobulbar tract. Poor sustained attention was linked to measures in the right superior cerebellar peduncle. Lower processing speed was associated with reduced mean cortical surface area. Children with DCD show co-occurring impairments in attention and speech motor control. DCD is associated with sensorimotor circuits as well as regions that form part of the default mode and salience networks. Disruption of subcortical circuits may underlie additional impairments. This study provides novel evidence of the neural correlates of DCD

Lifestyle, cognitive aging, and brain correlates

Inter-individual differences in level and rate of cognitive decline typically seen in aging have been linked to inter-individual differences in lifestyle factors such as leisure activities, including physical activity. The general aim of this thesis was to further our understanding of how and why leisure activity engagement is related to aging-related changes in cognitive performance. Specifically, we sought to (a) identify lifestyle components that are associated with late-life cognitive performance, (b) identify brain correlates of these lifestyle components that are also relevant for cognitive performance, and (c) explore the relative importance of lifestyle- and health-related factors for predicting cognitive change, as well as interactive effects among these factors. In Study I and II, we investigated associations between 3-year changes in leisure activities and concurrent changes in cognitive performance and white matter microstructure in 563 (Study I) and 442 (Study II) participants aged 81 years and older. Study I documented changes in white matter microstructure in the corticospinal (CS) tract to be associated with changes in perceptual speed. In Study II, we observed that concurrent change in frequency of engagement in social activities (e.g. going out to eat in a restaurant, going to the movies, concerts, or the theater) was related to change in both white matter microstructure in the CS tract and in perceptual speed. Change in white matter microstructure in the CS tract statistically accounted for the association between changes in frequency of social leisure activities and perceptual speed. In Study III, we turned to D2/3 dopamine receptor (D2/3DR) availability as a potential brain correlate of lifestyle and cognition in aging. We investigated D2/3DR availability, cognitive performance, and physical activity in 178 healthy adults aged 64-67 years. Participants completed tests of working memory, episodic memory, and processing speed, and a leisure activity questionnaire. Subjective intensity, but not frequency, across the activities each individual performed was associated with D2/3DR availability in caudate nucleus as well as with episodic and working memory. Episodic memory was also related to D2/3DR availability in the caudate, forming a correlative triad with physical activity intensity and caudate D2/3DR availability. In Study IV, we applied a new data-mining technique called structural equation modelling trees and forests to investigate the relative importance of leisure activity engagement, physical activity, and other age- and health-related factors in predicting subsequent 6-year change in perceptual speed in 1046 participants aged 60 years and older. With regard to variable importance, a measure that subsumes main effects and interactions among predictors, frequency of leisure activities was not unimportant, although less important than age, retirement status, walking speed, and multimorbidity. Conceivably, the association between leisure activity engagement and subsequent cognitive decline is conditional upon age- and health-related factors included in the current analyses. Regarding aim (a), identifying lifestyle components related to cognitive aging, we identified change in social activities to be related to change in perceptual speed (Study II). We also found that subjective intensity, but not frequency, of physical activity was related to episodic and working memory (Study III). Regarding the relative importance of frequency of leisure activity engagement as a predictor of change in cognition, we observed some importance of all types of activities, except for physical activity, in predicting change in perceptual speed (Study IV). Concerning aim (b), identifying brain correlates of lifestyle components and cognitive performance, we observed white matter microstructural changes to be related to changes in both leisure activity and perceptual speed (Study II), and D2/3DR availability (Study III) to be related to both subjective physical activity intensity and episodic memory. Regarding aim (c), exploring the relative importance of lifestyle components as predictors of subsequent cognitive decline (Study IV), we found rather small effects of the lifestyle components investigated in Studies II and III, but still found leisure activities to be informative as predictors when using a data-mining approach that takes interactive effects with other predictors into account. The studies in this thesis contribute with new data on associations between lifestyle and cognitive aging, and on brain measures correlated with these two factors. Specifically, we are the first to show parallel changes in leisure activity, white matter microstructure, and perceptual speed. We are also the first to observe an association between physical activity intensity and D2/3DR availability. In sum, the present results indicate that engaging in social activities in very late life and physical activity intensity around retirement age are related to cognitive performance and associated brain parameters. Although the issue of causal directionality remains unresolved, leisure activities are correlates and informative predictors of cognitive decline

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

The Mediating Role of Processing Speed in Reading-Related White Matter Tracts and Word Reading Skills of Adult Survivors of Childhood Brain Tumor

The purpose of this study was to investigate the relationship between word reading and white matter (WM) integrity in the reading system and test a theory-based moderated mediation model such that relationship of WM integrity with word reading is mediated by processing speed and indirect effect is moderated by group. Thirty-seven adult survivors of childhood brain tumor and typically developing adults participated (mean age=24.19(4.51) years, 62% female). Tractography identified the WM tract for three reading system connections. Fractional anisotropy of the IFOF and PT-OT tracts were significantly correlated with word reading in survivors (r=.55, .46, respectively;

Understanding preclinical dementia : early detection of dementia through cognitive and biological markers

Dementia is becoming a growing healthcare crisis, therefore identifying individuals at risk or in the earliest stages of dementia is essential if prevention or disease modification is to be achieved. The objective of this thesis was to examine cognitive performance and decline during the preclinical phase and explore the ability of cognitive and biological markers to identify those at risk of future dementia. Data from a population-based longitudinal study, SNAC-K, were used to investigate this aim. Study I examined the ability of neuropsychological tests, genetics, and structural MRI volumes to predict dementia six years later. Models were systematically created to identify the best combinations for prediction. A model containing all three modalities: hippocampal volume, a task of category fluency, presence of an APOE ɛ4 allele, white-matter hyperintensities volume, and a task of general knowledge, displayed the most predictive value (AUC=.924; C.I=.883–.965). However, this model did not significantly improve predictive value over one containing only cognitive and genetic markers, suggesting that minor increases in predictivity should be weighed against the costs of additional tests. Study II investigated the benefit of DTI, alongside neuropsychological tests, genetics, and brain volume markers in predicting future dementia. MD values for tracts CHC, CS, FMAJ, and IFOF (AUC=.837– .862) and the FA IFOF latent factor (AUC=.839) were significantly associated with dementia at six years. A final model consisting of a measure of perceptual speed, hippocampal volume, and MD of the FMAJ tract was created with the highest predictive value (AUC=.911). Assessment of microstructural white matter integrity via DTI was associated with future dementia but the additional benefit when combined with other markers was relatively small. Study III narrowed its focus to the ability of cognitive markers alone and the effect of modifying factors (age, sex, education, the presence of an ɛ4 allele, AD–only dementia, and time to diagnosis) on identifying those at risk of dementia. The most predictive model, consisting of category fluency, word recall, and pattern comparison, achieved good prediction values (AUC=.913) for dementia six years later. Tests in the domains of category fluency, episodic memory, and perceptual speed were, in general, good predictors across all subgroups and up to 6 years before a dementia diagnosis. However, cognitive tests became increasingly unreliable at predicting dementia beyond that time. Study IV explored the trajectories of cognitive decline over a 12-year period during the preclinical stage of dementia, before examining the ability of early cognitive decline in identifying those with increased likelihood of future dementia. Persons in the preclinical phase showed increased rate of decline in all cognitive domains compared to those who did not develop dementia (β:-.07 to -.11), this difference was particularly noticeable closer to diagnosis. Those classified as fast decliners for 3 or more cognitive tests demonstrated the highest risk of dementia (HR: 3.38, CI: 1.91-6.01). Although, changes in early rates of decline were small and rates of decline may be more predictive closer to diagnosis. Collectively, these studies confirm a long preclinical period in dementia development, which allows for the use of a wide range of markers (cognitive, genetic, MRI, and DTI) capable of identifying those at high risk of dementia. The ability of these markers to predict future dementia is increased through combining within and between modalities

Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments

Background Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. Methods DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. Results 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study

The influence of body fat distribution on white matter integrity

Objective: Obesity has become a great health problem and increases the risk for cardiovascular and metabolic diseases as well as for cognitive impairments including brain alterations in gray and white matter structure and function. The differentiation of adipose tissue in visceral adipose tissue and subcutaneous adipose tissue was found to be greatly relevant due to its different composition and consequent potential for metabolic complications. Hence, the objective of this study was to investigate the relationship between body fat distribution, especially visceral and subcutaneous adipose tissue, and white matter integrity. Methods: Diffusion tensor imaging (DTI) of the brain and whole body magnetic resonance imaging were performed of 48 healthy young to middle-aged lean, overweight and obese participants. The collected data included participant’s sex, age, body mass index, total body volume, volume of total, subcutaneous and visceral adipose tissue, total intracranial volume and DTI data of the brain. By using a region-of-interest-based approach, the DTI parameters fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were analyzed and correlated with the body mass index, total adipose tissue, subcutaneous and visceral adipose tissue, controlling for age, sex, total intracranial volume and BMI. Results: We found significant positive correlations between visceral adipose tissue and mean diffusivity and radial diffusivity values in the hippocampal part of the left cingulum (p < 0.005, corrected for number of tested regions) and marginally significant positive correlations in the forceps major and hippocampal part of the right cingulum (p < 0.05). Subcutaneous and total adipose tissue did not show significant correlations with DTI parameters. Conclusion: Our DTI study contributed to the current knowledge of the relationship between visceral adipose tissue and white matter integrity. We conclude that increased visceral adipose tissue is associated with reduced white matter integrity in regions which are known to be important for emotional and cognitive functioning. Therefore we suggest that increased visceral adipose tissue may increase the risk for emotional and cognitive impairment. Still further longitudinal studies may determine causal impact of visceral adipose tissue and its clinical relevance

The Examination of White Matter Microstructure, Autism Traits, and Social Cognitive Abilities in Neurotypical Adults

The purpose of this study was to examine the relationships among mentalizing abilities, self-reported autism traits, and two white matter tracts, uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF), in neurotypical adults. UF and ILF were hypothesized to connect brain regions implicated in a neuroanatomical model of mentalizing. Data were available for 24 neurotypical adults (mean age = 21.92 (4.72) years; 15 women). Tract-based spatial statistics (TBSS) was used to conduct voxelwise cross-participant comparisons of fractional anisotropy (FA) values in UF and ILF as predicted by mentalizing abilities and self-reported autism traits. Self-reported autism traits were positively related to FA values in left ILF. Results suggest that microstructural differences in left ILF are specifically involved in the expression of subclinical autism traits in neurotypical individuals

The relation among aging, dopamine-regulating genes, and neurocognition

When people are getting old, they often feel increasingly harder to concentrate, and become slower and more inflexible during tasks that involve focused attention, information maintenance in the face of distractions, and when fast switching according to changing goals is required. These cognitive functions are collectively referred to as working memory (WM). Both cross-sectional and longitudinal studies have reported WM impairment in aging. Moreover, aging is accompanied by alterations in brain structure, brain function, and dopaminergic neurotransmission. This thesis sought to link WM to brain structure, brain function, and dopamine (DA)-related genes in large samples of younger and older adults. The chief aims were to provide neural and genetic evidence to increase our understanding of the mechanisms of age-related deficits in WM. The DRD2/ANKK1-Taq1A polymorphism has been associated with DA D2 receptor densities in caudate. In study I, we investigated the effects of this polymorphism on grey-matter (GM) volume in striatum in older adults, and examined whether the genetic effect interacts with age. Results showed that the A allele of the DRD2/ANKK1-Taq1A polymorphism was associated with smaller GM volume in caudate and this effect was only observed in older adults (>72 years). The DRD2-C957T polymorphism has been linked to DA D2 receptor densities in both striatum and extrastriatal areas, such as in prefrontal cortex (PFC). In study II, we investigated the genetic effects of two DRD2 polymorphisms on WM functioning and examined how these effects may interact with adult age. In comparing younger and older adults, we found that the old had lower caudate activity in a highly demanding WM task. In addition, there were single and joint genetic effects of the two DRD2 polymorphisms on WM performance and frontostriatal brain activity. The genetic effects on brain function were observed in older, but not in younger adults, suggesting magnified genetic effects in aging. In study III, we related white-matter integrity with WM performance in a large sample across a wide age range. Results demonstrated that WM was associated with white-matter integrity in multiple tracts, indicating that WM functioning relies on global structural connections among multiple brain regions. Moreover, white-matter integrity could partially account for the age-related difference in WM. The COMT-Val158Met polymorphism has been associated with PFC DA levels. In this study, we found genetic effects of COMT on white-matter microstructure, suggesting a relation between dopaminergic function and white-matter integrity. In study IV, we investigated changes of white-matter integrity and WM performance using longitudinal data. We found that white-matter integrity declined across 10 years in the whole sample (25-80 years) and the decline was greater for older than for younger adults, reflecting a non-linear relation between age and white matter. More importantly, we found change – change associations of white-matter integrity and WM performance in several tracts including genu and body of corpus callosum and superior longitudinal fasciculus, suggesting that impaired WM performance in aging might reflect age-related decrease of white-matter integrity in these tracts. Collectively, these studies demonstrate age-related differences and changes in brain structure and brain function associated with impaired WM performance in aging. The findings support and extend previous work on the roles of DA in WM functioning and brain integrity in aging, and contribute to our understanding of neural and genetic correlates of WM, and how these are affected in aging