Ilana J. Bennett

Cerebral White Matter Integrity and Cognitive Aging: Contributions from Diffusion Tensor Imaging

The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior–posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.

Age-Related Differences in Multiple Measures of White Matter Integrity: A Diffusion Tensor Imaging Study of Healthy Aging

Diffusion tensor imaging (DTI) measures diffusion of molecular water, which can be used to calculate indices of white matter integrity. Early DTI studies of aging primarily focused on two global measures of integrity; the average rate (mean diffusivity, MD) and orientation coherence (fractional anisotropy, FA) of diffusion. More recent studies have added measures of water movement parallel (axial diffusivity, AD) and perpendicular (radial diffusivity, RD) to the primary diffusion direction, which are thought to reflect the neural bases of age differences in diffusion (i.e., axonal shrinkage and demyelination, respectively). In this study, patterns of age differences in white matter integrity were assessed by comparing younger and healthy older adults on multiple measures of integrity (FA, AD, and RD). Results revealed two commonly reported patterns (Radial Increase Only and Radial/Axial Increase), and one relatively novel pattern (Radial Increase/Axial Decrease) that varied by brain region and may reflect differential aging of microstructural (e.g., degree of myelination) and macrostructural (e.g., coherence of fiber orientation) properties of white matter. In addition, larger age differences in FA in frontal white matter were consistent with the anterior–posterior gradient of age differences in white matter integrity. Together, these findings complement other recent studies in providing information about patterns of diffusivity that are characteristic of healthy aging. Hum Brain Mapp, 2010.

Diffusion tensor imaging of cerebral white matter integrity in cognitive aging

In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing a new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

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 correlates of implicit sequence learning in healthy aging

Previous research has identified subcortical (caudate, putamen, hippocampus) and cortical (dorsolateral prefrontal cortex, DLPFC; frontal motor areas) regions involved in implicit sequence learning, with mixed findings for whether these neural substrates differ with aging. The present study used diffusion tensor imaging (DTI) tractography to reconstruct white matter connections between the known gray matter substrates, and integrity of these tracts was related to learning in the alternating serial reaction time task (ASRT) in younger and healthy older adults. Both age groups showed significant sequence learning (better performance to predictable, frequently occurring vs. less frequent events), with an age-related difference in the late learning stage. Caudate-DLPFC and hippocampus-DLPFC tract integrity were related to ASRT sequence learning, and these brain-behavior relationships did not differ significantly between age groups. Additionally, age-related decreases in caudate-DLPFC tract integrity mediated age-related differences in late stage sequence learning. Together, these findings complement studies of gray matter substrates underlying implicit sequence learning, and provide evidence for similar white matter integrity-sequence learning relationships in younger and healthy older adults.

Memory Evaluation in Mild Cognitive Impairment using Recall and Recognition Tests

Amnestic mild cognitive impairment (MCI) is a selective episodic memory deficit that often indicates early Alzheimers disease. Episodic memory function in MCI is typically defined by deficits in free recall, but can also be tested using recognition procedures. To assess both recall and recognition in MCI, MCI (n = 21) and older comparison (n = 30) groups completed the USC-Repeatable Episodic Memory Test. Subjects memorized two verbally presented 15-item lists. One list was used for three free recall trials, immediately followed by yes/no recognition. The second list was used for three-alternative forced-choice recognition. Relative to the comparison group, MCI had significantly fewer hits and more false alarms in yes/no recognition, and were less accurate in forced-choice recognition. Signal detection analysis showed that group differences were not due to response bias. Discriminant function analysis showed that yes/no recognition was a better predictor of group membership than free recall or forced-choice measures. MCI subjects recalled fewer items than comparison subjects, with no group differences in repetitions, intrusions, serial position effects, or measures of recall strategy (subjective organization, recall consistency). Performance deficits on free recall and recognition in MCI suggest a combination of both tests may be useful for defining episodic memory impairment associated with MCI and early Alzheimers disease.

Two Forms of Implicit Learning in Young Adults with Dyslexia

Implicit learning is thought to underlie the acquisition of many skills including reading. Previous research has shown that some forms of implicit learning are reduced in individuals with dyslexia (e.g., sequence learning), whereas other forms are spared (e.g., spatial context learning). However, it has been proposed that dyslexia‐related motor dysfunction may have contributed to the implicit sequence learning deficits reported earlier. To assess implicit sequence learning in the absence of a motor sequence, 16 young adults diagnosed with dyslexia (20.6 ± 1.5 years) and 18 healthy controls (20.8 ± 2.0 years) completed a triplet frequency learning task (TRIP) that involved learning a sequential regularity in which the location of certain events followed a repeating pattern, but motor responses did not. Participants also completed the spatial contextual cueing task (SCCT), which involved learning a spatial regularity in which the location of distractors in some visual arrays predicted the target location. In addition, neuropsychological tests of real‐word and pseudo‐word reading were administered. TRIP task analyses revealed no between‐group differences in pattern learning, but a positive correlation between individual learning scores and reading ability indicated that poor readers learned less well than did good readers. Thus, earlier reports of reduced implicit sequence learning in dyslexics cannot be entirely accounted for by motor sequencing deficits. No significant correlations or group differences in learning were found for SCCT. These findings offer additional evidence for a link between poor reading and impaired implicit sequence learning.

White matter tract integrity predicts visual search performance in young and older adults.

Functional imaging research has identified frontoparietal attention networks involved in visual search, with mixed evidence regarding whether different networks are engaged when the search target differs from distracters by a single (elementary) versus multiple (conjunction) features. Neural correlates of visual search, and their potential dissociation, were examined here using integrity of white matter connecting the frontoparietal networks. The effect of aging on these brain-behavior relationships was also of interest. Younger and older adults performed a visual search task and underwent diffusion tensor imaging (DTI) to reconstruct 2 frontoparietal (superior and inferior longitudinal fasciculus; SLF and ILF) and 2 midline (genu, splenium) white matter tracts. As expected, results revealed age-related declines in conjunction, but not elementary, search performance; and in ILF and genu tract integrity. Importantly, integrity of the superior longitudinal fasciculus, ILF, and genu tracts predicted search performance (conjunction and elementary), with no significant age group differences in these relationships. Thus, integrity of white matter tracts connecting frontoparietal attention networks contributes to search performance in younger and older adults.

Advances in functional neuroanatomy: A review of combined DTI and fMRI studies in healthy younger and older adults

Structural connections between brain regions are thought to influence neural processing within those regions. It follows that alterations to the quality of structural connections should influence the magnitude of neural activity. The quality of structural connections may also be expected to differentially influence activity in directly versus indirectly connected brain regions. To test these predictions, we reviewed studies that combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) in younger and older adults. By surveying studies that examined relationships between DTI measures of white matter integrity and fMRI measures of neural activity, we identified variables that accounted for variability in these relationships. Results revealed that relationships between white matter integrity and neural activity varied with (1) aging (i.e., positive and negative DTI-fMRI relationships in younger and older adults, respectively) and (2) spatial proximity of the neural measures (i.e., positive and negative DTI-fMRI relationships when neural measures were extracted from adjacent and non-adjacent brain regions, respectively). Together, the studies reviewed here provided support for both of our predictions.

Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan

Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20-89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus.