Estimating individual trajectories of structural and cognitive decline in mild cognitive impairment for early prediction of progression to dementia of the Alzheimer's type.

Only a third of individuals with mild cognitive impairment (MCI) progress to dementia of the Alzheimer's type (DAT). Identifying biomarkers that distinguish individuals with MCI who will progress to DAT (MCI-Converters) from those who will not (MCI-Non-Converters) remains a key challenge in the field. In our study, we evaluate whether the individual rates of loss of volumes of the Hippocampus and entorhinal cortex (EC) with age in the MCI stage can predict progression to DAT. Using data from 758 MCI patients in the Alzheimer's Disease Neuroimaging Database, we employ Linear Mixed Effects (LME) models to estimate individual trajectories of regional brain volume loss over 12 years on average. Our approach involves three key analyses: (1) mapping age-related volume loss trajectories in MCI-Converters and Non-Converters, (2) using logistic regression to predict progression to DAT based on individual rates of hippocampal and EC volume loss, and (3) examining the relationship between individual estimates of these volumetric changes and cognitive decline across different cognitive functions-episodic memory, visuospatial processing, and executive function. We find that the loss of Hippocampal volume is significantly more rapid in MCI-Converters than Non-Converters, but find no such difference in EC volumes. We also find that the rate of hippocampal volume loss in the MCI stage is a significant predictor of conversion to DAT, while the rate of volume loss in the EC and other additional regions is not. Finally, individual estimates of rates of regional volume loss in both the Hippocampus and EC, and other additional regions, correlate strongly with individual rates of cognitive decline. Across all analyses, we find significant individual variation in the initial volumes and the rates of changes in volume with age in individuals with MCI. This study highlights the importance of personalized approaches in predicting AD progression, offering insights for future research and intervention strategies.

The behavioral and neural effects of parietal theta burst stimulation on the grasp network are stronger during a grasping task than at rest.

Repetitive transcranial magnetic stimulation (TMS) is widely used in neuroscience and clinical settings to modulate human cortical activity. The effects of TMS on neural activity depend on the excitability of specific neural populations at the time of stimulation. Accordingly, the brain state at the time of stimulation may influence the persistent effects of repetitive TMS on distal brain activity and associated behaviors. We applied intermittent theta burst stimulation (iTBS) to a region in the posterior parietal cortex (PPC) associated with grasp control to evaluate the interaction between stimulation and brain state. Across two experiments, we demonstrate the immediate responses of motor cortex activity and motor performance to state-dependent parietal stimulation. We randomly assigned 72 healthy adult participants to one of three TMS intervention groups, followed by electrophysiological measures with TMS and behavioral measures. Participants in the first group received iTBS to PPC while performing a grasping task concurrently. Participants in the second group received iTBS to PPC while in a task-free, resting state. A third group of participants received iTBS to a parietal region outside the cortical grasping network while performing a grasping task concurrently. We compared changes in motor cortical excitability and motor performance in the three stimulation groups within an hour of each intervention. We found that parietal stimulation during a behavioral manipulation that activates the cortical grasping network increased downstream motor cortical excitability and improved motor performance relative to stimulation during rest. We conclude that constraining the brain state with a behavioral task during brain stimulation has the potential to optimize plasticity induction in cortical circuit mechanisms that mediate movement processes.

Person-specific and precision neuroimaging: Current methods and future directions.

Most neuroimaging studies of brain function analyze data in normalized space to identify regions of common activation across participants. These studies treat interindividual differences in brain organization as noise, but this approach can obscure important information about the brain's functional architecture. Recently, a number of studies have adopted a person-specific approach that aims to characterize these individual differences and explore their reliability and implications for behavior. A subset of these studies has taken a precision imaging approach that collects multiple hours of data from each participant to map brain function on a finer scale. In this review, we provide a broad overview of how person-specific and precision imaging techniques have used resting-state measures to examine individual differences in the brain's organization and their impact on behavior, followed by how task-based activity continues to add detail to these discoveries. We argue that person-specific and precision approaches demonstrate substantial promise in uncovering new details of the brain's functional organization and its relationship to behavior in many areas of cognitive neuroscience. We also discuss some current limitations in this new field and some new directions it may take.

Dynamic Recovery: GABA Agonism Restores Neural Variability in Older, Poorer Performing Adults.

Aging is associated with cognitive impairment, but there are large individual differences in these declines. One neural measure that is lower in older adults and predicts these individual differences is moment-to-moment brain signal variability. Testing the assumption that GABA should heighten neural variability, we examined whether reduced brain signal variability in older, poorer performing adults could be boosted by increasing GABA pharmacologically. Brain signal variability was estimated using fMRI in 20 young and 24 older healthy human adults during placebo and GABA agonist sessions. As expected, older adults exhibited lower signal variability at placebo, and, crucially, GABA agonism boosted older adults' variability to the levels of young adults. Furthermore, poorer performing older adults experienced a greater increase in variability on drug, suggesting that those with more to gain benefit the most from GABA system potentiation. GABA may thus serve as a core neurochemical target in future work on aging- and cognition-related human brain dynamics.SIGNIFICANCE STATEMENT Prior research indicates that moment-to-moment brain signal variability is lower in older, poorer performing adults. We found that this reduced brain signal variability could be boosted through GABA agonism in older adults to the levels of young adults and that this boost was largest in the poorer performing older adults. These results provide the first evidence that brain signal variability can be restored by increasing GABAergic activity and suggest the promise of developing interventions targeting inhibitory systems to help slow cognitive declines in healthy aging.

Age-Related Differences in White Matter: Understanding Tensor-Based Results Using Fixel-Based Analysis.

Aging is associated with widespread alterations in cerebral white matter (WM). Most prior studies of age differences in WM have used diffusion tensor imaging (DTI), but typical DTI metrics (e.g., fractional anisotropy; FA) can reflect multiple neurobiological features, making interpretation challenging. Here, we used fixel-based analysis (FBA) to investigate age-related WM differences observed using DTI in a sample of 45 older and 25 younger healthy adults. Age-related FA differences were widespread but were strongly associated with differences in multi-fiber complexity (CX), suggesting that they reflected differences in crossing fibers in addition to structural differences in individual fiber segments. FBA also revealed a frontolimbic locus of age-related effects and provided insights into distinct microstructural changes underlying them. Specifically, age differences in fiber density were prominent in fornix, bilateral anterior internal capsule, forceps minor, body of the corpus callosum, and corticospinal tract, while age differences in fiber cross section were largest in cingulum bundle and forceps minor. These results provide novel insights into specific structural differences underlying major WM differences associated with aging.

GABA levels in ventral visual cortex decline with age and are associated with neural distinctiveness.

Age-related neural dedifferentiation-a decline in the distinctiveness of neural representations in the aging brain-has been associated with age-related declines in cognitive abilities. But why does neural distinctiveness decline with age? Based on prior work in nonhuman primates and more recent work in humans, we hypothesized that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) declines with age and is associated with neural dedifferentiation in older adults. To test this hypothesis, we used magnetic resonance spectroscopy (MRS) to measure GABA and functional MRI (fMRI) to measure neural distinctiveness in the ventral visual cortex in a set of older and younger participants. Relative to younger adults, older adults exhibited lower GABA levels and less distinct activation patterns for faces and houses in the ventral visual cortex. Furthermore, individual differences in GABA within older adults positively predicted individual differences in neural distinctiveness. These results provide novel support for the view that age-related reductions of GABA contribute to age-related reductions in neural distinctiveness (i.e., neural dedifferentiation) in the human ventral visual cortex.

Age differences in functional network reconfiguration with working memory training.

Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task-related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default-mode network for younger adults, it enhanced efficiency within a task-specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default-mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between-network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age-related trajectories in functional network reorganization with WM training.

Age Differences in Vestibular Brain Connectivity Are Associated With Balance Performance.

Visual and auditory brain network connectivity decline with age, but less is known about age effects on vestibular functional connectivity and its association with behavior. We assessed age differences in the connectivity of the vestibular cortex with other sensory brain regions, both during rest and during vestibular stimulation. We then assessed the relationship between vestibular connectivity and postural stability. A sample of seventeen young and fifteen older adults participated in our study. We assessed the amount of body sway in performing the Romberg balance task, with degraded somatosensory and visual inputs. The results showed no significant difference in balance performance between age groups. However, functional connectivity analyses revealed a main effect of age and condition, suggesting that vestibular connectivity was higher in young adults than older adults, and vestibular connectivity increased from resting state to stimulation trials. Surprisingly, young adults who exhibited higher connectivity during stimulation also had greater body sway. This suggests that young adults who exhibit better balance are those who respond more selectively to vestibular inputs. This correlation is non-significant in older adults, suggesting that the relationship between vestibular functional connectivity and postural stability differs with age.

Neural correlates of working memory training: Evidence for plasticity in older adults.

Brain activity typically increases with increasing working memory (WM) load, regardless of age, before reaching an apparent ceiling. However, older adults exhibit greater brain activity and reach ceiling at lower loads than younger adults, possibly reflecting compensation at lower loads and dysfunction at higher loads. We hypothesized that WM training would bolster neural efficiency, such that the activation peak would shift towards higher memory loads after training. Pre-training, older adults showed greater recruitment of the WM network than younger adults across all loads, with decline at the highest load. Ten days of adaptive training on a verbal WM task improved performance and led to greater brain responsiveness at higher loads for both groups. For older adults the activation peak shifted rightward towards higher loads. Finally, training increased task-related functional connectivity in older adults, both within the WM network and between this task-positive network and the task-negative/default-mode network. These results provide new evidence for functional plasticity with training in older adults and identify a potential signature of improvement at the neural level.

Higher performers upregulate brain signal variability in response to more feature-rich visual input.

The extent to which brain responses differ across varying cognitive demands is referred to as "neural differentiation," and greater neural differentiation has been associated with better cognitive performance in older adults. An emerging approach has examined within-person neural differentiation using moment-to-moment brain signal variability. A number of studies have found that brain signal variability differs by cognitive state; however, the factors that cause signal variability to rise or fall on a given task remain understudied. We hypothesized that top performers would modulate signal variability according to the complexity of sensory input, upregulating variability when processing more feature-rich stimuli. In the current study, 46 older adults passively viewed face and house stimuli during fMRI. Low-level analyses showed that house images were more feature-rich than faces, and subsequent computational modelling of ventral visual stream responses (HMAX) revealed that houses were more feature-rich especially in V1/V2-like model layers. Notably, we then found that participants exhibiting greater face-to-house upregulation of brain signal variability in V1/V2 (higher for house relative to face stimuli) also exhibited more accurate, faster, and more consistent behavioral performance on a battery of offline visuo-cognitive tasks. Further, control models revealed that face-house modulation of mean brain signal was relatively insensitive to offline cognition, providing further evidence for the importance of brain signal variability for understanding human behavior. We conclude that the ability to align brain signal variability to the richness of perceptual input may mark heightened trait-level behavioral performance in older adults.

Network segregation varies with neural distinctiveness in sensorimotor cortex.

Normal aging is associated with declines in sensorimotor function. Previous studies have linked age-related behavioral declines to decreases in neural differentiation (i.e., dedifferentiation), including decreases in the distinctiveness of neural activation patterns and in the segregation of large-scale neural networks at rest. However, no studies to date have explored the relationship between these two neural measures and whether they explain the same aspects of behavior. To investigate these issues, we collected a battery of sensorimotor behavioral measures in older and younger adults and estimated (a) the distinctiveness of neural representations in sensorimotor cortex and (b) sensorimotor network segregation in the same participants. Consistent with prior findings, sensorimotor representations were less distinct and sensorimotor resting state networks were less segregated in older compared to younger adults. We also found that participants with the most distinct sensorimotor representations exhibited the most segregated sensorimotor networks. However, only sensorimotor network segregation was associated with individual differences in sensorimotor performance, particularly in older adults. These novel findings link network segregation to neural distinctiveness, but also suggest that network segregation may play a larger role in maintaining sensorimotor performance with age.

Effects of aging on encoding of walking direction in the human brain.

Human aging is characterized by impaired spatial cognition and reductions in the distinctiveness of category-specific fMRI activation patterns. Yet, little is known about age-related decline in neural distinctiveness of information that humans use when navigating spatial environments. Here, we asked whether neural tuning functions of walking direction are broadened in older versus younger adults. To test this idea, we developed a novel method that allowed us to investigate changes in fMRI-measured pattern similarity while participants navigated in different directions in a virtual spatial navigation task. We expected that directional tuning functions would be broader in older adults, and thus activation patterns that reflect neighboring directions would be less distinct as compared to non-adjacent directions. Because loss of distinctiveness leads to more confusions when information is read out by downstream areas, we analyzed predictions of a decoder trained on directional fMRI patterns and asked (1) whether decoder confusions between two directions increase proportionally to their angular similarity, (2) and how this effect may differ between age groups. Evidence for tuning-function-like signals was found in the retrosplenial complex and early visual cortex, reflecting the primarily visual nature of directional information in our task. Significant age differences in tuning width, however, were only found in early visual cortex, suggesting that less precise visual information could lead to worse directional signals in older adults. At the same time, only directional information encoded in RSC, but not visual cortex, correlated with memory on task. These results shed new light on neural mechanisms underlying age-related spatial navigation impairments and introduce a novel approach to measure tuning specificity using fMRI.

Temporal Dynamics of Corticocortical Inhibition in Human Visual Cortex: A TMS Study.

Paired-pulse transcranial magnetic stimulation (ppTMS) has been used extensively to probe local facilitatory and inhibitory function in motor cortex. We previously developed a reliable ppTMS method to investigate these functions in visual cortex and found reduced thresholds for net intracortical inhibition compared to motor cortex. The current study used this method to investigate the temporal dynamics of local facilitatory and inhibitory networks in visual cortex in 28 healthy subjects. We measured the size of the visual disturbance (phosphene) evoked by stimulating visual cortex with a fixed intensity, supra-threshold test stimulus (TS) when that TS was preceded by a sub-threshold conditioning stimulus (CS). We manipulated the inter-stimulus interval (ISI) and assessed how the size of the phosphene elicited by the fixed-intensity TS changed as a function of interval for two different CS intensities (45% and 75% of phosphene threshold). At 45% of threshold, the CS produced uniform suppression of the phosphene elicited by the TS across ISIs ranging from 2 to 200 ms. At 75% of threshold, the CS did not have a significant effect on phosphene size across the 2-15 ms intervals. Intervals of 50-200 ms exhibited statistically significant suppression of phosphenes, however, suppression was not uniform with some subjects demonstrating no change or facilitation. This study demonstrates that the temporal dynamics of local inhibitory and facilitatory networks are different across motor and visual cortex and that optimal parameters to index local inhibitory and facilitatory influences in motor cortex are not necessarily optimal for visual cortex. We refer to the observed inhibition as visual cortex inhibition (VCI) to distinguish it from the phenomenon reported in motor cortex.

Deactivation of somatosensory and visual cortices during vestibular stimulation is associated with older age and poorer balance.

Aging is associated with peripheral and central declines in vestibular processing and postural control. Here we used functional MRI to investigate age differences in neural vestibular representations in response to pneumatic tap stimulation. We also measured the amount of body sway in multiple balance tasks outside of the MRI scanner to assess the relationship between individuals' balance ability and their vestibular neural response. We found a general pattern of activation in canonical vestibular cortex and deactivation in cross modal sensory regions in response to vestibular stimulation. We found that activation amplitude of the vestibular cortex was correlated with age, with younger individuals exhibiting higher activation. Deactivation of visual and somatosensory regions increased with age and was associated with poorer balance. The results demonstrate that brain activations and deactivations in response to vestibular stimuli are correlated with balance, and the pattern of these correlations varies with age. The findings also suggest that older adults exhibit less sensitivity to vestibular stimuli, and may compensate by differentially reweighting visual and somatosensory processes.

Neural distinctiveness declines with age in auditory cortex and is associated with auditory GABA levels.

Neural activation patterns in the ventral visual cortex in response to different categories of visual stimuli (e.g., faces vs. houses) are less selective, or distinctive, in older adults than in younger adults, a phenomenon known as age-related neural dedifferentiation. In this study, we investigated whether neural dedifferentiation extends to the auditory cortex. Inspired by previous animal work, we also investigated whether individual differences in GABA are associated with individual differences in neural distinctiveness in humans. 20 healthy young adults (ages 18-29) and 23 healthy older adults (over 65) completed a functional magnetic resonance imaging (fMRI) scan, during which neural activity was estimated while they listened to music and foreign speech. GABA levels in the auditory, ventrovisual and sensorimotor cortex were estimated in the same individuals in a separate magnetic resonance spectroscopy (MRS) scan. Relative to the younger adults, the older adults exhibited both (1) less distinct activation patterns for music vs. speech stimuli and (2) lower GABA levels in the auditory cortex. Also, individual differences in auditory GABA levels (but not ventrovisual or sensorimotor GABA levels) were associated with individual differences in neural distinctiveness in the auditory cortex in the older adults. These results demonstrate that age-related neural dedifferentiation extends to the auditory cortex and suggest that declining GABA levels may play a role in neural dedifferentiation in older adults.

Michigan Neural Distinctiveness (MiND) study protocol: investigating the scope, causes, and consequences of age-related neural dedifferentiation.

BACKGROUND: Aging is often associated with behavioral impairments, but some people age more gracefully than others. Why? One factor that may play a role is individual differences in the distinctiveness of neural representations. Previous research has found that neural activation patterns in visual cortex in response to different visual stimuli are often more similar (i.e., less distinctive) in older vs. young participants, a phenomenon referred to as age-related neural dedifferentiation. Furthermore, older people whose neural representations are less distinctive tend to perform worse on a wide range of behavioral tasks. The Michigan Neural Distinctiveness (MiND) project aims to investigate the scope of neural dedifferentiation (e.g., does it also occur in auditory, motor, and somatosensory cortex?), one potential cause (age-related reductions in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)), and the behavioral consequences of neural dedifferentiation. This protocol paper describes the study rationale and methods being used in complete detail, but not the results (data collection is currently underway). METHODS: The MiND project consists of two studies: the main study and a drug study. In the main study, we are recruiting 60 young and 100 older adults to perform behavioral tasks that measure sensory and cognitive function. They also participate in functional MRI (fMRI), MR spectroscopy, and diffusion weighted imaging sessions, providing data on neural distinctiveness and GABA concentrations. In the drug study, we are recruiting 25 young and 25 older adults to compare neural distinctiveness, measured with fMRI, after participants take a placebo or a benzodiazepine (lorazepam) that should increase GABA activity. DISCUSSION: By collecting multimodal imaging measures along with extensive behavioral measures from the same subjects, we are linking individual differences in neurochemistry, neural representation, and behavioral performance, rather than focusing solely on group differences between young and old participants. Our findings have the potential to inform new interventions for age-related declines. TRIAL REGISTRATION: This study was retrospectively registered with the ISRCTN registry on March 4, 2019. The registration number is ISRCTN17266136 .

Independent Components of Neural Activation Associated with 100 Days of Cognitive Training.

Some cognitive training studies have reported working memory benefits that generalize beyond the trained tasks, whereas others have only found task-specific training effects. What brain networks are associated with general training effects, rather than task-specific effects? We investigated this question in the context of working memory training using the COGITO data set, a longitudinal project including behavioral assessments before and after 100 days of cognitive training in 101 younger (20-31 years) and 103 older (65-80 years) adults. Pre- and postassessments included verbal, numerical, and spatial measures of working memory. It was therefore possible to assess training effects on working memory at a general latent ability level. Previous analyses of these data found training-related improvements on this latent working memory factor in both young and old participants. fMRI data were collected from a subsample of participants (24 young and 15 old) during pre- and post-training sessions. We used independent component analysis to identify networks involved in a perceptual decision-making task performed in the scanner. We identified five task-positive components that were task-related: two frontal networks, a ventral visual network, a motor network, and a cerebellar network. Pre-training activity of the motor network predicted latent working memory performance before training. Additionally, activity in the motor network predicted training-related changes in working memory ability. These findings suggest activity in the motor network plays a role in task-independent working memory improvements and have implications for our understanding of working memory training and for the design and implementation of future training interventions.

Probing short-latency cortical inhibition in the visual cortex with transcranial magnetic stimulation: A reliability study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a non-invasive method to stimulate localized brain regions. Despite widespread use in motor cortex, TMS is seldom performed in sensory areas due to variable, qualitative metrics. OBJECTIVE: Assess the reliability and validity of tracing phosphenes, and to investigate the stimulation parameters necessary to elicit decreased visual cortex excitability with paired-pulse TMS at short inter-stimulus intervals. METHODS: Across two sessions, single and paired-pulse recruitment curves were derived by having participants outline elicited phosphenes and calculating resulting average phosphene sizes. RESULTS: Phosphene size scaled with stimulus intensity, similar to motor cortex. Paired-pulse recruitment curves demonstrated inhibition at lower conditioning stimulus intensities than observed in motor cortex. Reliability was high across sessions. CONCLUSIONS: TMS-induced phosphenes are a valid and reliable tool for measuring cortical excitability and inhibition in early visual areas. Our results also provide appropriate stimulation parameters for measuring short-latency intracortical inhibition in visual cortex.

Sensorimotor network segregation declines with age and is linked to GABA and to sensorimotor performance.

Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks.

Age-Related Declines in Occipital GABA are Associated with Reduced Fluid Processing Ability.

RATIONALE AND OBJECTIVES: Healthy aging is associated with pervasive declines in cognitive, motor, and sensory functioning. There are, however, substantial individual differences in behavioral performance among older adults. Several lines of animal research link age-related reductions of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, to age-related cognitive, motor, and sensory decline. Our study used proton magnetic resonance spectroscopy (MRS) at 3T to explore whether occipital GABA declines with age in humans and whether individual differences in occipital GABA are linked to individual differences in fluid processing ability. MATERIALS AND METHODS: We used a MEGA-PRESS sequence that combines frequency spectral editing with a point-resolved spectroscopy sequence to quantify GABA. Spectra were obtained from a 30 × 30 × 25 mm voxel placed in the occipital cortex of 20 young adults (mean age 20.7 years) and 18 older adults (mean age 76.5 years). Participants also performed 11 fluid processing tasks outside the scanner, the results of which were z-scored and averaged to calculate a summary measure of fluid processing ability. Regression analysis was employed to determine the relationship between GABA concentrations in the occipital cortex and a summary measure of fluid processing ability. RESULTS: Occipital GABA was significantly lower in older participants compared to the younger participants. We also observed a significant positive relationship between occipital GABA and fluid processing ability. In fact, higher GABA was associated with better task performance in 10 of the 11 tasks. CONCLUSION: These findings suggest that GABA levels decline with age in humans and are associated with declines in fluid processing ability.