Age-related differences in resting-state, task-related, and structural brain connectivity: graph theoretical analyses and visual search performance.

Previous magnetic resonance imaging (MRI) research suggests that aging is associated with a decrease in the functional interconnections within and between groups of locally organized brain regions (modules). Further, this age-related decrease in the segregation of modules appears to be more pronounced for a task, relative to a resting state, reflecting the integration of functional modules and attentional allocation necessary to support task performance. Here, using graph-theoretical analyses, we investigated age-related differences in a whole-brain measure of module connectivity, system segregation, for 68 healthy, community-dwelling individuals 18-78 years of age. We obtained resting-state, task-related (visual search), and structural (diffusion-weighted) MRI data. Using a parcellation of modules derived from the participants' resting-state functional MRI data, we demonstrated that the decrease in system segregation from rest to task (i.e., reconfiguration) increased with age, suggesting an age-related increase in the integration of modules required by the attentional demands of visual search. Structural system segregation increased with age, reflecting weaker connectivity both within and between modules. Functional and structural system segregation had qualitatively different influences on age-related decline in visual search performance. Functional system segregation (and reconfiguration) influenced age-related decline in the rate of visual evidence accumulation (drift rate), whereas structural system segregation contributed to age-related slowing of encoding and response processes (nondecision time). The age-related differences in the functional system segregation measures, however, were relatively independent of those associated with structural connectivity.

Accelerated Brain Atrophy, Microstructural Decline and Connectopathy in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) has recently been linked to cognitive impairment. We hypothesized that AMD modifies the brain aging trajectory, and we conducted a longitudinal diffusion MRI study on 40 participants (20 with AMD and 20 controls) to reveal the location, extent, and dynamics of AMD-related brain changes. Voxel-based analyses at the first visit identified reduced volume in AMD participants in the cuneate gyrus, associated with vision, and the temporal and bilateral cingulate gyrus, linked to higher cognition and memory. The second visit occurred 2 years after the first and revealed that AMD participants had reduced cingulate and superior frontal gyrus volumes, as well as lower fractional anisotropy (FA) for the bilateral occipital lobe, including the visual and the superior frontal cortex. We detected faster rates of volume and FA reduction in AMD participants in the left temporal cortex. We identified inter-lingual and lingual-cerebellar connections as important differentiators in AMD participants. Bundle analyses revealed that the lingual gyrus had a lower streamline length in the AMD participants at the first visit, indicating a connection between retinal and brain health. FA differences in select inter-lingual and lingual cerebellar bundles at the second visit showed downstream effects of vision loss. Our analyses revealed widespread changes in AMD participants, beyond brain networks directly involved in vision processing.

Depth- and curvature-based quantitative susceptibility mapping analyses of cortical iron in Alzheimer's disease.

In addition to amyloid beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been associated with elevated iron in deep gray matter nuclei using quantitative susceptibility mapping (QSM). However, only a few studies have examined cortical iron, using more macroscopic approaches that cannot assess layer-specific differences. Here, we conducted column-based QSM analyses to assess whether AD-related increases in cortical iron vary in relation to layer-specific differences in the type and density of neurons. We obtained global and regional measures of positive (iron) and negative (myelin, protein aggregation) susceptibility from 22 adults with AD and 22 demographically matched healthy controls. Depth-wise analyses indicated that global susceptibility increased from the pial surface to the gray/white matter boundary, with a larger slope for positive susceptibility in the left hemisphere for adults with AD than controls. Curvature-based analyses indicated larger global susceptibility for adults with AD versus controls; the right hemisphere versus left; and gyri versus sulci. Region-of-interest analyses identified similar depth- and curvature-specific group differences, especially for temporo-parietal regions. Finding that iron accumulates in a topographically heterogenous manner across the cortical mantle may help explain the profound cognitive deterioration that differentiates AD from the slowing of general motor processes in healthy aging.

Quantitative susceptibility mapping of brain iron in healthy aging and cognition.

Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging (MRI) technique that can assess the magnetic properties of cerebral iron in vivo. Although brain iron is necessary for basic neurobiological functions, excess iron content disrupts homeostasis, leads to oxidative stress, and ultimately contributes to neurodegenerative disease. However, some degree of elevated brain iron is present even among healthy older adults. To better understand the topographical pattern of iron accumulation and its relation to cognitive aging, we conducted an integrative review of 47 QSM studies of healthy aging, with a focus on five distinct themes. The first two themes focused on age-related increases in iron accumulation in deep gray matter nuclei versus the cortex. The overall level of iron is higher in deep gray matter nuclei than in cortical regions. Deep gray matter nuclei vary with regard to age-related effects, which are most prominent in the putamen, and age-related deposition of iron is also observed in frontal, temporal, and parietal cortical regions during healthy aging. The third theme focused on the behavioral relevance of iron content and indicated that higher iron in both deep gray matter and cortical regions was related to decline in fluid (speed-dependent) cognition. A handful of multimodal studies, reviewed in the fourth theme, suggest that iron interacts with imaging measures of brain function, white matter degradation, and the accumulation of neuropathologies. The final theme concerning modifiers of brain iron pointed to potential roles of cardiovascular, dietary, and genetic factors. Although QSM is a relatively recent tool for assessing cerebral iron accumulation, it has significant promise for contributing new insights into healthy neurocognitive aging.

High-resolution multi-shot diffusion imaging of structural networks in healthy neurocognitive aging.

Healthy neurocognitive aging has been associated with the microstructural degradation of white matter pathways that connect distributed gray matter regions, assessed by diffusion-weighted imaging (DWI). However, the relatively low spatial resolution of standard DWI has limited the examination of age-related differences in the properties of smaller, tightly curved white matter fibers, as well as the relatively more complex microstructure of gray matter. Here, we capitalize on high-resolution multi-shot DWI, which allows spatial resolutions < 1 mm3 to be achieved on clinical 3T MRI scanners. We assessed whether traditional diffusion tensor-based measures of gray matter microstructure and graph theoretical measures of white matter structural connectivity assessed by standard (1.5 mm3 voxels, 3.375 µl volume) and high-resolution (1 mm3 voxels, 1µl volume) DWI were differentially related to age and cognitive performance in 61 healthy adults 18-78 years of age. Cognitive performance was assessed using an extensive battery comprising 12 separate tests of fluid (speed-dependent) cognition. Results indicated that the high-resolution data had larger correlations between age and gray matter mean diffusivity, but smaller correlations between age and structural connectivity. Moreover, parallel mediation models including both standard and high-resolution measures revealed that only the high-resolution measures mediated age-related differences in fluid cognition. These results lay the groundwork for future studies planning to apply high-resolution DWI methodology to further assess the mechanisms of both healthy aging and cognitive impairment.

Age-related differences in frontoparietal activation for target and distractor singletons during visual search.

Age-related decline in visual search performance has been associated with different patterns of activation in frontoparietal regions using functional magnetic resonance imaging (fMRI), but whether these age-related effects represent specific influences of target and distractor processing is unclear. Therefore, we acquired event-related fMRI data from 68 healthy, community-dwelling adults ages 18-78 years, during both conjunction (T/F target among rotated Ts and Fs) and feature (T/F target among Os) search. Some displays contained a color singleton that could correspond to either the target or a distractor. A diffusion decision analysis indicated age-related increases in sensorimotor response time across all task conditions, but an age-related decrease in the rate of evidence accumulation (drift rate) was specific to conjunction search. Moreover, the color singleton facilitated search performance when occurring as a target and disrupted performance when occurring as a distractor, but only during conjunction search, and these effects were independent of age. The fMRI data indicated that decreased search efficiency for conjunction relative to feature search was evident as widespread frontoparietal activation. Activation within the left insula mediated the age-related decrease in drift rate for conjunction search, whereas this relation in the FEF and parietal cortex was significant only for individuals younger than 30 or 44 years, respectively. Finally, distractor singletons were associated with significant parietal activation, whereas target singletons were associated with significant frontoparietal deactivation, and this latter effect increased with adult age. Age-related differences in frontoparietal activation therefore reflect both the overall efficiency of search and the enhancement from salient targets.

Cerebral White Matter Mediation of Age-Related Differences in Picture Naming Across Adulthood.

As people age, one of the most common complaints is difficulty with word retrieval. A wealth of behavioral research confirms such age-related language production deficits, yet the structural neural differences that relate to age-related language production deficits remains an open area of exploration. Therefore, the present study used a large sample of healthy adults across adulthood to investigate how age-related white matter differences in three key left-hemisphere language tracts may contribute to age-related differences in language ability. Specifically, we used diffusion tensor imaging to measure fractional anisotropy (FA) and radial diffusivity (RD) which are indicators of white matter structure. We then used a series of path models to test whether white matter from the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus, and the frontal aslant tract (FAT) mediated age-related differences in one form of language production, picture naming. We found that FA, as well as RD from the SLF and FAT mediated the relation between age and picture naming performance, whereas a control tract (corticospinal) was not a mediator. Moreover, differences between mediation of picture naming and a control naming condition suggest that left SLF has a greater role in higher-order aspects of naming, such as semantic and lexical selection whereas left FAT is more sensitive to sensorimotor aspects of fluency or speech motor planning. These results suggest that dorsal white matter contributes to age-related differences in generating speech and may be particularly important in supporting word retrieval across adulthood.

Cortical iron mediates age-related decline in fluid cognition.

Brain iron dyshomeostasis disrupts various critical cellular functions, and age-related iron accumulation may contribute to deficient neurotransmission and cell death. While recent studies have linked excessive brain iron to cognitive function in the context of neurodegenerative disease, little is known regarding the role of brain iron accumulation in cognitive aging in healthy adults. Further, previous studies have focused primarily on deep gray matter regions, where the level of iron deposition is highest. However, recent evidence suggests that cortical iron may also contribute to cognitive deficit and neurodegenerative disease. Here, we used quantitative susceptibility mapping (QSM) to measure brain iron in 67 healthy participants 18-78 years of age. Speed-dependent (fluid) cognition was assessed from a battery of 12 psychometric and computer-based tests. From voxelwise QSM analyses, we found that QSM susceptibility values were negatively associated with fluid cognition in the right inferior temporal gyrus, bilateral putamen, posterior cingulate gyrus, motor, and premotor cortices. Mediation analysis indicated that susceptibility in the right inferior temporal gyrus was a significant mediator of the relation between age and fluid cognition, and similar effects were evident for the left inferior temporal gyrus at a lower statistical threshold. Additionally, age and right inferior temporal gyrus susceptibility interacted to predict fluid cognition, such that brain iron was negatively associated with a cognitive decline for adults over 45 years of age. These findings suggest that iron may have a mediating role in cognitive decline and may be an early biomarker of neurodegenerative disease.

Cerebral white matter connectivity, cognition, and age-related macular degeneration.

Age-related macular degeneration (AMD) is a common retina disease associated with cognitive impairment in older adults. The mechanism(s) that account for the link between AMD and cognitive decline remain unclear. Here we aim to shed light on this issue by investigating whether relationships between cognition and white matter in the brain differ by AMD status. In a direct group comparison of brain connectometry maps from diffusion weighted images, AMD patients showed significantly weaker quantitative anisotropy (QA) than healthy controls, predominantly in the splenium and left optic radiation. The QA of these tracts, however, did not correlate with the visual acuity measure, indicating that this group effect is not directly driven by visual loss. The AMD and control groups did not differ significantly in cognitive performance.Across all participants, better cognitive performance (e.g. verbal fluency) is associated with stronger connectivity strength in white matter tracts including the splenium and the left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. However, there were significant interactions between group and cognitive performance (verbal fluency, memory), suggesting that the relation between QA and cognitive performance was weaker in AMD patients than in controls.This may be explained by unmeasured determinants of performance that are more common or impactful in AMD or by a recruitment bias whereby the AMD group had higher cognitive reserve. In general, our findings suggest that neural degeneration in the brain might occur in parallel to AMD in the eyes, although the participants studied here do not (yet) exhibit overt cognitive declines per standard assessments.

Influence of structural and functional brain connectivity on age-related differences in fluid cognition.

We used graph theoretical measures to investigate the hypothesis that structural brain connectivity constrains the influence of functional connectivity on the relation between age and fluid cognition. Across 143 healthy, community-dwelling adults 19-79 years of age, we estimated structural network properties from diffusion-weighted imaging and functional network properties from resting-state functional magnetic resonance imaging. We confirmed previous reports of age-related decline in the strength and efficiency of structural networks, as well as in the connectivity strength within and between structural network modules. Functional networks, in contrast, exhibited age-related decline only in system segregation, a measure of the distinctiveness among network modules. Aging was associated with decline in a composite measure of fluid cognition, particularly tests of executive function. Functional system segregation was a significant mediator of age-related decline in executive function. Structural network properties did not directly influence the age-related decline in functional system segregation. The raw correlational data underlying the graph theoretical measures indicated that structural connectivity exerts a limited constraint on age-related decline in functional connectivity.

Relationship between neural functional connectivity and memory performance in age-related macular degeneration.

Age-related macular degeneration (AMD) has been linked to memory deficits, with no established neural mechanisms. We collected resting-state brain functional magnetic resonance imaging and standardized verbal recall tests from 42 older adults with AMD and 41 age-matched controls. We used seed-based whole brain analysis to quantify the strength of functional connectivity between hubs of the default mode network and a network of medial temporal regions relevant for memory. Our results indicated neither memory performance nor network connectivity differed by AMD status. However, the AMD participants exhibited stronger relationships than the controls between memory performance and connectivity from the memory network hub (left parahippocampal) to 2 other regions: the left temporal pole and the right superior/middle frontal gyri. Also, the connectivity between the medial prefrontal cortex and posterior cingulate cortex of default mode network correlated more strongly with memory performance in AMD compared to control. We concluded that stronger brain-behavior correlation in AMD may suggest a role for region-specific connectivity in supporting memory in the context of AMD.

Response-level processing during visual feature search: Effects of frontoparietal activation and adult age.

Previous research suggests that feature search performance is relatively resistant to age-related decline. However, little is known regarding the neural mechanisms underlying the age-related constancy of feature search. In this experiment, we used a diffusion decision model of reaction time (RT), and event-related functional magnetic resonance imaging (fMRI) to investigate age-related differences in response-level processing during visual feature search. Participants were 80 healthy, right-handed, community-dwelling individuals, 19-79 years of age. Analyses of search performance indicated that targets accompanied by response-incompatible distractors were associated with a significant increase in the nondecision-time (t0) model parameter, possibly reflecting the additional time required for response execution. Nondecision time increased significantly with increasing age, but no age-related effects were evident in drift rate, cautiousness (boundary separation, a), or in the specific effects of response compatibility. Nondecision time was also associated with a pattern of activation and deactivation in frontoparietal regions. The relation of age to nondecision time was indirect, mediated by this pattern of frontoparietal activation and deactivation. Response-compatible and -incompatible trials were associated with specific patterns of activation in the medial and superior parietal cortex, and frontal eye field, but these activation effects did not mediate the relation between age and search performance. These findings suggest that, in the context of a highly efficient feature search task, the age-related influence of frontoparietal activation is operative at a relatively general level, which is common to the task conditions, rather than at the response level specifically.

Neural activation for actual and imagined movement following unilateral hand transplantation: a case study.

Transplantation of a donor hand has been successful as a surgical treatment following amputation, but little is known regarding the brain mechanisms contributing to the recovery of motor function. We report functional magnetic resonance imaging (fMRI) findings for neural activation related to actual and imagined movement, for a 54-year-old male patient, who had received a donor hand transplant 50 years following amputation. Two assessments, conducted 3 months and 6 months post-operatively, demonstrate engagement of motor-control related brain regions for the transplanted hand, during both actual and imagined movement of the fingers. The intact hand exhibited a more intense and focused pattern of activation for actual movement relative to imagined movement, whereas activation for the transplanted hand was more widely distributed and did not clearly differentiate actual and imagined movement. However, the spatial overlap of actual-movement and imagined-movement voxels, for the transplanted hand, did increase over time to a level comparable to that of the intact hand. At these relatively early post-operative assessments, brain regions outside of the canonical motor-control networks appear to be supporting movement of the transplanted hand.

Age-related differences in the neural bases of phonological and semantic processes in the context of task-irrelevant information.

As we age we have increasing difficulty with phonological aspects of language production. Yet semantic processes are largely stable across the life span. This suggests a fundamental difference in the cognitive and potentially neural architecture supporting these systems. Moreover, language processes such as these interact with other cognitive processes that also show age-related decline, such as executive function and inhibition. The present study examined phonological and semantic processes in the presence of task-irrelevant information to examine the influence of such material on language production. Older and younger adults made phonological and semantic decisions about pictures in the presence of either phonologically or semantically related words, which were unrelated to the task. FMRI activation during the semantic condition showed that all adults engaged typical left-hemisphere language regions, and that this activation was positively correlated with efficiency across all adults. In contrast, the phonological condition elicited activation in bilateral precuneus and cingulate, with no clear brain-behavior relationship. Similarly, older adults exhibited greater activation than younger adults in several regions that were unrelated to behavioral performance. Our results suggest that as we age, brain-behavior relations decline, and there is an increased reliance on both language-specific and domain-general brain regions that are seen most prominently during phonological processing. In contrast, the core semantic system continues to be engaged throughout the life span, even in the presence of task-irrelevant information.

Language processing in age-related macular degeneration associated with unique functional connectivity signatures in the right hemisphere.

Age-related macular degeneration (AMD) is a retinal disease associated with significant vision loss among older adults. Previous large-scale behavioral studies indicate that people with AMD are at increased risk of cognitive deficits in language processing, particularly in verbal fluency tasks. The neural underpinnings of any relationship between AMD and higher cognitive functions, such as language processing, remain unclear. This study aims to address this issue using independent component analysis of spontaneous brain activity at rest. In 2 components associated with visual processing, we observed weaker functional connectivity in the primary visual cortex and lateral occipital cortex in AMD patients compared with healthy controls, indicating that AMD might lead to differences in the neural representation of vision. In a component related to language processing, we found that increasing connectivity within the right inferior frontal gyrus was associated with better verbal fluency performance across all older adults, and the verbal fluency effect was greater in AMD patients than controls in both right inferior frontal gyrus and right posterior temporal regions. As the behavioral performance of our patients is as good as that of controls, these findings suggest that preservation of verbal fluency performance in AMD patients might be achieved through higher contribution from right hemisphere regions in bilateral language networks. If that is the case, there may be an opportunity to promote cognitive resilience among seniors with AMD or other forms of late-life vision loss.

Functional modular architecture underlying attentional control in aging.

Previous research suggests that age-related differences in attention reflect the interaction of top-down and bottom-up processes, but the cognitive and neural mechanisms underlying this interaction remain an active area of research. Here, within a sample of community-dwelling adults 19-78 years of age, we used diffusion reaction time (RT) modeling and multivariate functional connectivity to investigate the behavioral components and whole-brain functional networks, respectively, underlying bottom-up and top-down attentional processes during conjunction visual search. During functional MRI scanning, participants completed a conjunction visual search task in which each display contained one item that was larger than the other items (i.e., a size singleton) but was not informative regarding target identity. This design allowed us to examine in the RT components and functional network measures the influence of (a) additional bottom-up guidance when the target served as the size singleton, relative to when the distractor served as the size singleton (i.e., size singleton effect) and (b) top-down processes during target detection (i.e., target detection effect; target present vs. absent trials). We found that the size singleton effect (i.e., increased bottom-up guidance) was associated with RT components related to decision and nondecision processes, but these effects did not vary with age. Also, a modularity analysis revealed that frontoparietal module connectivity was important for both the size singleton and target detection effects, but this module became central to the networks through different mechanisms for each effect. Lastly, participants 42 years of age and older, in service of the target detection effect, relied more on between-frontoparietal module connections. Our results further elucidate mechanisms through which frontoparietal regions support attentional control and how these mechanisms vary in relation to adult age.

Task difficulty modulates brain activation in the emotional oddball task.

Previous functional magnetic resonance imaging (fMRI) studies have reported that task-irrelevant, emotionally salient events can disrupt target discrimination, particularly when attentional demands are low, while others demonstrate alterations in the distracting effects of emotion in behavior and neural activation in the context of attention-demanding tasks. We used fMRI, in conjunction with an emotional oddball task, at different levels of target discrimination difficulty, to investigate the effects of emotional distractors on the detection of subsequent targets. In addition, we distinguished different behavioral components of target detection representing decisional, nondecisional, and response criterion processes. Results indicated that increasing target discrimination difficulty led to increased time required for both the decisional and nondecisional components of the detection response, as well as to increased target-related neural activation in frontoparietal regions. The emotional distractors were associated with activation in ventral occipital and frontal regions and dorsal frontal regions, but this activation was attenuated with increased difficulty. Emotional distraction did not alter the behavioral measures of target detection, but did lead to increased target-related frontoparietal activation for targets following emotional images as compared to those following neutral images. This latter effect varied with target discrimination difficulty, with an increased influence of the emotional distractors on subsequent target-related frontoparietal activation in the more difficult discrimination condition. This influence of emotional distraction was in addition associated specifically with the decisional component of target detection. These findings indicate that emotion-cognition interactions, in the emotional oddball task, vary depending on the difficulty of the target discrimination and the associated limitations on processing resources.

Sources of disconnection in neurocognitive aging: cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume.

Age-related decline in fluid cognition can be characterized as a disconnection among specific brain structures, leading to a decline in functional efficiency. The potential sources of disconnection, however, are unclear. We investigated imaging measures of cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume as mediators of the relation between age and fluid cognition, in 145 healthy, community-dwelling adults 19-79 years of age. At a general level of analysis, with a single composite measure of fluid cognition and single measures of each of the 3 imaging modalities, age exhibited an independent influence on the cognitive and imaging measures, and the imaging variables did not mediate the age-cognition relation. At a more specific level of analysis, resting-state functional connectivity of sensorimotor networks was a significant mediator of the age-related decline in executive function. These findings suggest that different levels of analysis lead to different models of neurocognitive disconnection, and that resting-state functional connectivity, in particular, may contribute to age-related decline in executive function.

Cocaine dependence does not contribute substantially to white matter abnormalities in HIV infection.

This study investigated the association of HIV infection and cocaine dependence with cerebral white matter integrity using diffusion tensor imaging (DTI). One hundred thirty-five participants stratified by HIV and cocaine status (26 HIV+/COC+, 37 HIV+/COC-, 37 HIV-/COC+, and 35 HIV-/COC-) completed a comprehensive substance abuse assessment, neuropsychological testing, and MRI with DTI. Among HIV+ participants, all were receiving HIV care and 46% had an AIDS diagnosis. All COC+ participants were current users and met criteria for cocaine use disorder. We used tract-based spatial statistics (TBSS) to assess the relation of HIV and cocaine to fractional anisotropy (FA) and mean diffusivity (MD). In whole-brain analyses, HIV+ participants had significantly reduced FA and increased MD compared to HIV- participants. The relation of HIV and FA was widespread throughout the brain, whereas the HIV-related MD effects were restricted to the corpus callosum and thalamus. There were no significant cocaine or HIV-by-cocaine effects. These DTI metrics correlated significantly with duration of HIV disease, nadir CD4+ cell count, and AIDS diagnosis, as well as some measures of neuropsychological functioning. These results suggest that HIV is related to white matter integrity throughout the brain, and that HIV-related effects are more pronounced with increasing duration of infection and greater immune compromise. We found no evidence for independent effects of cocaine dependence on white matter integrity, and cocaine dependence did not appear to exacerbate the effects of HIV.