Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia

Structural and functional differences in medial prefrontal cortex underlie distractibility and suppression deficits in ageing.

Older adults experience deficits in working memory (WM) that are acutely exacerbated by the presence of distracting information. Human neurophysiological studies have revealed that these changes are accompanied by a diminished ability to suppress visual cortical activity associated with task-irrelevant information. Although this is often attributed to deficits in top-down control from a prefrontal cortical source, this has not yet been directly demonstrated. Here we evaluate the neural basis of distraction's negative impact on WM and the impairment in neural suppression in older adults by performing structural and functional MRIs while older participants engage in tasks that require remembering relevant visual stimuli in the context of overlapping irrelevant stimuli. Analysis supports both an age-related distraction effect and neural suppression deficit, and extends our understanding by revealing an alteration in functional connectivity between visual cortices and a region in the default network, the medial prefrontal cortex (mPFC). Moreover, within the older population, the magnitude of WM distractibility and neural suppression are both associated with individual differences in cortical volume and activity of the mPFC, as well as its associated white-matter tracts

Neural Substrates of Reserve Observed in a Non-Demented Aging Population

Cognitive decline in dementia does not correspond precisely to the amount of neurodegeneration in the brain. This discrepancy in brain damage and its clinical manifestation has been explicated by the concept of reserve. Brain reserve inferred from the brain size had moderate success in explaining the discrepancy, and numerous studies have reported the effects of education supporting cognitive reserve. Yet the neural substrates of reserve have been elusive. Utilizing optimized voxel-based morphometry, we have identified brain regions that were significantly smaller in individuals with low cognitive performance (LCP) compared to those with normal cognitive performance (NCP) in community-residing non-demented elderly people both with low educational attainment. It was assumed that the cognitive performance in this population reflected long-standing cognitive functioning of the individual, possibly the reserve, based on their stable follow-up performance and clinical interviews. Bilateral precuneus, right superior frontal gyrus and left middle frontal gyrus were smaller in individuals with LCP. Further, the LCP individuals had weaker correlation between the gray matter volume of those regions and the rest of the cortex. On the other hand, volume of these regions was more tightly correlated with the K-DRS Total score in these individuals. Finally, an outcome study of the community sample from which this study's participants were recruited from reported five times higher risk of dementia in the LCP group. Precuneus and prefrontal cortex are proposed as key sites comprising the neural substrates that underlie the reserve

Neural Substrates of Reserve Observed in a Non-Demented Aging Population

Cognitive decline in dementia does not correspond precisely to the amount of neurodegeneration in the brain. This discrepancy in brain damage and its clinical manifestation has been explicated by the concept of reserve. Brain reserve inferred from the brain size had moderate success in explaining the discrepancy, and numerous studies have reported the effects of education supporting cognitive reserve. Yet the neural substrates of reserve have been elusive. Utilizing optimized voxel-based morphometry, we have identified brain regions that were significantly smaller in individuals with low cognitive performance (LCP) compared to those with normal cognitive performance (NCP) in community-residing non-demented elderly people both with low educational attainment. It was assumed that the cognitive performance in this population reflected long-standing cognitive functioning of the individual, possibly the reserve, based on their stable follow-up performance and clinical interviews. Bilateral precuneus, right superior frontal gyrus and left middle frontal gyrus were smaller in individuals with LCP. Further, the LCP individuals had weaker correlation between the gray matter volume of those regions and the rest of the cortex. On the other hand, volume of these regions was more tightly correlated with the K-DRS Total score in these individuals. Finally, an outcome study of the community sample from which this study's participants were recruited from reported five times higher risk of dementia in the LCP group. Precuneus and prefrontal cortex are proposed as key sites comprising the neural substrates that underlie the reserve

Relationships between Age and White Matter Integrity in Children with Phenylketonuria

Objective: Phenylketonuria (PKU) is a hereditary metabolic disorder associated with cognitive compromise. Diffusion tensor imaging (DTI) has allowed detection of poorer microstructural white matter integrity in children with PKU, with decreased mean diffusivity (MD) in comparison with healthy children. However, very little research has been conducted to examine the trajectory of white matter development in this population. The present study investigated potential differences in the developmental trajectory of MD between children with early- and continuously-treated PKU and healthy children across a range of brain regions. Methods: Children with PKU (n = 31, mean age = 12.2 years) were recruited through metabolic clinics, and their MD findings across 10 brain regions of interest (ROIs) were compared with those of healthy control children (n = 51, mean age = 12.0 years). Hierarchical linear regressions, including age, group, and the age by group interaction, were performed on MD for each ROI. For ROIs with significant interactions, Pearson correlations between age and MD were obtained and compared across groups. Results: The age by group interaction was significant for the splenium and genu of the corpus callosum, the optic radiation, and the hippocampus (p \u3c 0.05 in all instances). The relationship between MD and age was significant for all 4 of these ROIs within the PKU group but none within the control group. In all instances, MD decreased as a function of increasing age. The relationship between age and MD was significantly different between the PKU and control groups for the optic radiation, hippocampus, and genu of the corpus callosum (z \u3c -1.96 in all instances). Conclusions: A stronger age-related decrease in MD was identified for children with PKU in comparison with healthy children in 4 ROIs, indicating that the trajectory of white matter development is abnormal in children with PKU. Further research using longitudinal methodology is needed to fully elucidate our understanding of white matter development in PKU

Aging and risk taking: toward an integration of cognitive, emotional, and neurobiological perspectives

In this article, we characterize the relationship between natural aging and risky decision making through an integration of cognitive, emotional, and neurobiological theories on the effects of natural aging. Based on the existing evidence, we propose that the positivity emotional bias in elderly adults steers them away from taking high risks and toward more conservative approaches during decision making as part of their positive emotional regulatory strategies. However, aging is also associated with marked declines in cognitive functioning, such as attention and working memory, as well as impaired reinforcement-based associative learning, which arises from anatomical and functional declines in the dopaminergic transmission systems and in distinct brain regions such as the dorsolateral prefrontal cortex and hippocampus. In consequence, elderly adults may deviate from their usual conservative stance and toward more risk-taking tendencies, as observed in a subset of studies, if the demands of the risk-taking task exceed their cognitive and learning capacities. More empirical investigations are needed to determine the key factors that influence elderly individuals' decision making and behavior in risky situations. Research in this field is likely to have important practical implications for the financial and medical decision making of elderly adults, as well as promoting designated help targeting the elderly population in making important life decisions.published_or_final_versio

Investigating White Matter Lesion Load, Intrinsic Functional Connectivity, and Cognitive Abilities in Older Adults

Changes to the while matter of the brain disrupt neural communication between spatially distributed brain regions and are associated with cognitive changes in later life. While approximately 95% of older adults experience these brain changes, not everyone who has significant white matter damage displays cognitive impairment. Few studies have investigated the association between white matter changes and cognition in the context of functional brain network integrity. This study used a data-driven, multivariate analytical model to investigate intrinsic functional connectivity patterns associated with individual variability in white matter lesion load as related to fluid and crystallized intelligence in a sample of healthy older adults (n = 84). Several primary findings were noted. First, a reliable pattern emerged associating whole-brain resting-state functional connectivity with individual variability in measures of white matter lesion load, as indexed by total white matter lesion volume and number of lesions. Secondly, white matter lesion load was associated with increased network disintegration and dedifferentiation. Specifically, lower white matter lesion load was associated with greater within- versus between-network connectivity. Higher white matter lesion load was associated with greater between-network connectivity compared to within. These associations between intrinsic functional connectivity and white matter lesion load were not reliably associated with crystallized and fluid intelligence performance. These results suggest that changes to the white matter of the brain in typically aging older adults are characterized by increased functional brain network dedifferentiation. The findings highlight the role of white matter lesion load in altering the functional network architecture of the brain

Cognitive-Motor Integration In Normal Aging And Preclinical Alzheimer's Disease: Neural Correlates And Early Detection

The objectives of the studies included in this dissertation were to characterize how the ability to integrate cognition into action is disrupted by both normal and pathological aging, to evaluate the effectiveness of kinematic measures in discriminating between individuals who are and are not at increased Alzheimer’s disease (AD) risk, and to examine the structural and functional neural correlates of cognitive-motor impairment in individuals at increased AD risk. The underlying hypothesis, based on previous research, is that measuring visuomotor integration under conditions that place demands on visual-spatial and cognitive-motor processing may provide an effective behavioural means for the early detection of brain alterations associated with AD risk. To this end, the first study involved testing participants both with and without AD risk factors on visuomotor tasks using a dual-touchscreen tablet. Comparisons between high AD risk participants and both young and old healthy control groups revealed significant performance disruptions in at-risk participants in the most cognitively demanding task. Furthermore, a stepwise discriminant analysis was able to distinguish between high and low AD risk participants with a classification accuracy of 86.4%. Based on the prediction that the impairments observed in high AD risk participants reflect disruption to the intricate reciprocal communication between hippocampal, parietal, and frontal brain regions required to successfully prepare and update complex reaching movements, the second and third studies were designed to examine the underlying structural and functional connectivity associated with cognitive-motor performance. Young adult and both low AD risk and high AD risk older adult participants underwent anatomical, diffusion-weighted, and resting-state functional connectivity scans. These data revealed significant age-related declines in white matter integrity that were more pronounced in the high AD risk group. Decreased functional connectivity in the default mode network (DMN) was also found in high AD risk participants. Furthermore, measures of white matter integrity and resting-state functional connectivity with DMN seed-regions were significantly correlated with task performance. These data support our hypothesis that disease-related disruptions in visuomotor control are associated with identifiable brain alterations, and thus behavioural assessments incorporating both cognition and action together may be useful in identifying individuals at increased AD risk