Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.

Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer's disease (AD), Parkinson's disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain's immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state.

Functional Connectivity Within and Between n-Back Modulated Regions: An Adult Lifespan Psychophysiological Interaction Investigation.

Introduction: Working memory (WM) and its blood-oxygen-level-dependent-related parametric modulation under load decrease with age. Functional connectivity (FC) generally increases with WM load; however, how aging impacts connectivity and whether this is load-dependent, region-dependent, or associated with cognitive performance is unclear. Methods: This study examines these questions in 170 healthy adults (meanage = 52.99 ± 19.18) who completed functional magnetic resonance imaging scanning during an n-back task (0-, 2-, 3-, and 4-back). The FC was estimated by utilizing a modified generalized psychophysiological interaction approach with seeds from fronto-parietal (FP) and default mode (DM) regions that modulated to n-back difficulty. The FC analyses focused on both connectivity during WM engagement (task vs. control) and connectivity in response to increased WM load (linear slope across conditions). Each analysis utilized within- and between-region FC, predicted by age (linear or quadratic), and its associations with in- and out-of-scanner task performance. Results: Engaging in WM either generally (task vs. control) or as a function of difficulty strengthened integration within- and between-FP and DM regions. Notably, these task-sensitive functional connections were robust to the effects of age. Stronger negative FC between FP and DM regions was also associated with better WM performance in an age-dependent manner, occurring selectively in middle-aged and older adults. Discussion: These results suggest that FC is critical for engaging in cognitively demanding tasks, and its lack of sensitivity to healthy aging may provide a means to maintain cognition across the adult lifespan. Thus, this study highlights the contribution of maintenance in brain function to support working memory processing with aging.

Greater BOLD Variability is Associated With Poorer Cognitive Function in an Adult Lifespan Sample.

Moment-to-moment fluctuations in brain signal assessed by functional magnetic resonance imaging blood oxygenation level dependent (BOLD) variability is increasingly thought to represent important "signal" rather than measurement-related "noise." Efforts to characterize BOLD variability in healthy aging have yielded mixed outcomes, demonstrating both age-related increases and decreases in BOLD variability and both detrimental and beneficial associations. Utilizing BOLD mean-squared-successive-differences (MSSD) during a digit n-back working memory (WM) task in a sample of healthy adults (aged 20-94 years; n = 171), we examined effects of aging on whole-brain 1) BOLD variability during task (mean condition MSSD across 0-2-3-4 back conditions), 2) BOLD variability modulation to incrementally increasing WM difficulty (linear slope from 0-2-3-4 back), and 3) the association of age-related differences in variability with in- and out-of-scanner WM performance. Widespread cortical and subcortical regions evidenced increased mean variability with increasing age, with no regions evidencing age-related decrease in variability. Additionally, posterior cingulate/precuneus exhibited increased variability to WM difficulty. Notably, both age-related increases in BOLD variability were associated with significantly poorer WM performance in all but the oldest adults. These findings lend support to the growing corpus suggesting that brain-signal variability is altered in healthy aging; specifically, in this adult lifespan sample, BOLD-variability increased with age and was detrimental to cognitive performance.

Dynamic range in BOLD modulation: lifespan aging trajectories and association with performance.

Alteration of dynamic range of modulation to cognitive difficulty has been proposed as a salient predictor of cognitive aging. Here, we examine in 171 adults (aged 20-94 years) the effects of age on dynamic modulation of blood oxygenation-level dependent activation to difficulty in parametrically increasing working memory (WM) load (0-, 2-, 3-, and 4-back conditions). First, we examined parametric increases and decreases in activation to increasing WM load (positive modulation effect and negative modulation effect). Second, we examined the effect of age on modulation to difficulty (WM load) to identify regions that differed with age as difficulty increased (age-related positive and negative modulation effects). Weakened modulation to difficulty with age was found in both the positive modulation (middle frontal, superior/inferior parietal) and negative modulation effect (deactivated) regions (insula, cingulate, medial superior frontal, fusiform, and parahippocampal gyri, hippocampus, and lateral occipital cortex). Age-related alterations to positive modulation emerged later in the lifespan than negative modulation. Furthermore, these effects were significantly coupled in that greater upmodulation was associated with lesser downmodulation. Importantly, greater fronto-parietal upmodulation to difficulty and greater downmodulation of deactivated regions were associated with better task accuracy and upmodulation with better WM span measured outside the scanner. These findings suggest that greater dynamic range of modulation of activation to cognitive challenge is in service of current task performance, as well as generalizing to cognitive ability beyond the scanner task, lending support to its utility as a marker of successful cognitive aging.

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.

Functional magnetic resonance imaging data of incremental increases in visuo-spatial difficulty in an adult lifespan sample.

These data provide coordinates generated from a large healthy adult lifespan sample undergoing functional Magnetic Resonance Imaging (fMRI) while completing a spatial judgment task with varying levels of difficulty, as well as a control categorical condition. The data presented here include the average blood-oxygen-dependent (BOLD) response to the spatial judgment vs. the control task, as well as the BOLD response to incremental increasing difficulty; see also "Age-related Reduction of BOLD Modulation to Cognitive Difficulty Predicts Poorer Task Accuracy and Poorer Fluid Reasoning Ability" (Rieck et al., 2017) [1].

Frontoparietal activation during visual conjunction search: Effects of bottom-up guidance and adult age.

We conducted functional magnetic resonance imaging (fMRI) with a visual search paradigm to test the hypothesis that aging is associated with increased frontoparietal involvement in both target detection and bottom-up attentional guidance (featural salience). Participants were 68 healthy adults, distributed continuously across 19 to 78 years of age. Frontoparietal regions of interest (ROIs) were defined from resting-state scans obtained prior to task-related fMRI. The search target was defined by a conjunction of color and orientation. Each display contained one item that was larger than the others (i.e., a size singleton) but was not informative regarding target identity. Analyses of search reaction time (RT) indicated that bottom-up attentional guidance from the size singleton (when coincident with the target) was relatively constant as a function of age. Frontoparietal fMRI activation related to target detection was constant as a function of age, as was the reduction in activation associated with salient targets. However, for individuals 35 years of age and older, engagement of the left frontal eye field (FEF) in bottom-up guidance was more prominent than for younger individuals. Further, the age-related differences in left FEF activation were a consequence of decreasing resting-state functional connectivity in visual sensory regions. These findings indicate that age-related compensatory effects may be expressed in the relation between activation and behavior, rather than in the magnitude of activation, and that relevant changes in the activation-RT relation may begin at a relatively early point in adulthood. Hum Brain Mapp 38:2128-2149, 2017. © 2017 Wiley Periodicals, Inc.

Age-related reduction of BOLD modulation to cognitive difficulty predicts poorer task accuracy and poorer fluid reasoning ability.

Aging is associated with reduced resources needed to perform difficult cognitive tasks, but the neural underpinnings are not well understood, especially as there is scant evidence linking functional brain differences to aging cognition. Therefore, the current study examined modulation of fMRI activation from easier to harder spatial distance judgments across a large lifespan sample (N=161; ages 20-94) to identify when in the lifespan modulation to difficulty begins to show deficits and if age-related modulation predicts cognition. Analyses revealed two sets of regions in which modulation increased with difficulty due to either more activation (positive modulation) or more deactivation (negative modulation) to difficulty. These two networks evidenced differential aging trajectories: a right-lateralized fronto-parietal network that decreased in modulation to difficulty between middle- and older-age, and a network of regions in ventromedial prefrontal cortex, posterior cingulate, left angular and middle frontal gyri that showed decreased modulation at the transition from younger to middle-age. Critically, older adults who maintained negative modulation to difficulty showed higher task accuracy. Further, individuals who showed greater coupling between positive and negative modulation performed better on a fluid reasoning task. Age-related preservation of coupled modulation in both cognitive control regions and regions typically associated with default network may be a salient marker of how the brain adapts to maintain cognitive function as we age.