Andrew C. Hebrank

β-Amyloid burden in healthy aging Regional distribution and cognitive consequences

Objective: Several lines of evidence suggest that pathologic changes underlying Alzheimer disease (AD) begin years prior to the clinical expression of the disease, underscoring the need for studies of cognitively healthy adults to capture these early changes. The overall goal of the current study was to map the cortical distribution of &bgr;-amyloid (A&bgr;) in a healthy adult lifespan sample (aged 30–89), and to assess the relationship between elevated amyloid and cognitive performance across multiple domains. Methods: A total of 137 well-screened and cognitively normal adults underwent A&bgr; PET imaging with radiotracer 18F-florbetapir. A&bgr; load was estimated from 8 cortical regions. Participants were genotyped for APOE and tested for processing speed, working memory, fluid reasoning, episodic memory, and verbal ability. Results: A&bgr; deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions. A subset of cognitively normal adults aged 60 and over show markedly elevated deposition, and also had a higher rate of APOE ε4 (38%) than nonelevated adults (19%). A&bgr; burden was linked to poorer cognitive performance on measures of processing speed, working memory, and reasoning. Conclusions: Even in a highly selected lifespan sample of adults, A&bgr; deposition is apparent in some adults and is influenced by APOE status. Greater amyloid burden was related to deleterious effects on cognition, suggesting that subtle cognitive changes accrue as amyloid progresses. GLOSSARY: A&bgr;: &bgr;-amyloid AD: Alzheimer disease DLBS: Dallas Lifespan Brain Study DLPFC: dorsolateral prefrontal cortex ETS: Educational Testing Service FWHM: full width at half maximum GLM: general linear model MCI: mild cognitive impairment OFC: orbital-frontal cortex ROI: region of interest SUVR: standardized uptake value ratio WAIS: Wechsler Adult Intelligence Scale

Age and culture modulate object processing and object-scene binding in the ventral visual area.

Behavioral differences in the visual processing of objects and backgrounds as a function of cultural group are well documented. Recent neuroimaging evidence also points to cultural differences in neural activation patterns. Compared with East Asians, Westerners’ visual processing is more object focused, and they activate neural structures that reflect this bias for objects. In a recent adaptation study, East Asian older adults showed an absence of an object-processing area but normal adaptation for background areas. In the present study, 75 young and old adults (half East Asian and half Western) were tested in an fMR-adaptation study to examine differences in object and background processing as well as object—background binding. We found equivalent background processing in the parahippocampal gyrus in all four groups, diminished binding processes in the hippocampus in elderly East Asians and Westerners, and diminished object processing in elderly versus young adults in the lateral occipital complex. Moreover, elderly East Asians showed significantly less adaptation response in the object areas than did elderly Westerners. These findings demonstrate the malleability of perceptual processes as a result of differences in cohort-specific experiences or in cultural exposure over time.

The Impact of Sustained Engagement on Cognitive Function in Older Adults The Synapse Project

In the research reported here, we tested the hypothesis that sustained engagement in learning new skills that activated working memory, episodic memory, and reasoning over a period of 3 months would enhance cognitive function in older adults. In three conditions with high cognitive demands, participants learned to quilt, learned digital photography, or engaged in both activities for an average of 16.51 hr a week for 3 months. Results at posttest indicated that episodic memory was enhanced in these productive-engagement conditions relative to receptive-engagement conditions, in which participants either engaged in nonintellectual activities with a social group or performed low-demand cognitive tasks with no social contact. The findings suggest that sustained engagement in cognitively demanding, novel activities enhances memory function in older adulthood, but, somewhat surprisingly, we found limited cognitive benefits of sustained engagement in social activities.

Age differences in default mode activity on easy and difficult spatial judgment tasks

The default network is a system of brain areas that are engaged when the mind is not involved in goal-directed activity. Most previous studies of age-related changes in default mode processing have used verbal tasks. We studied non-verbal spatial tasks that vary in difficulty. We presented old and young participants with two spatial judgment tasks: an easy categorical judgment and a more demanding coordinate judgment. We report that (a) Older adults show markedly less default network modulation than young on the demanding spatial task, but there is age equivalence on the easy task; (b) This Age × Task interaction is restricted to the default network: Brain areas that are deactivated by the tasks, but that are outside the default network, show no interaction; (c) Young adults exhibit significantly stronger functional connectivity among posterior regions of the default network compared with older adults, whereas older adults exhibit stronger connectivity between medial prefrontal cortex and other sites; and (d) The relationship of default activity to reaction time performance on the spatial tasks is mediated by age: in old adults, those who deactivate the default network most also perform best, whereas the opposite is true in younger adults. These results extend the findings of age-related changes in default mode processing and connectivity to visuo-spatial tasks and demonstrate that the results are specific to the default network.

Effects of beta-amyloid accumulation on neural function during encoding across the adult lifespan

Limited functional imaging evidence suggests that increased beta-amyloid deposition is associated with alterations in brain function, even in healthy older adults. However, the majority of these findings report on resting-state activity or functional connectivity in adults over age 60. Much less is known about the impact of beta-amyloid on neural activations during cognitive task performance, or the impact of amyloid in young and middle-aged adults. The current study measured beta-amyloid burden from PET imaging using (18)Florbetapir, in a large continuous age sample of highly-screened, healthy adults (N=137; aged 30-89 years). The same participants also underwent fMRI scanning, performing a memory encoding task. Using both beta-amyloid burden and age as continuous predictors of encoding activity, we report a dose-response relationship of beta-amyloid load to neural function, beyond the effects of age. Specifically, individuals with greater amyloid burden evidence less neural activation in bilateral dorsolateral prefrontal cortex, a region important for memory encoding, as well as reduced neural modulation in areas associated with default network activity: bilateral superior/medial frontal and lateral temporal cortex. Importantly, this reduction of both activation and suppression as a function of amyloid load was found across the lifespan, even in young- and middle-aged individuals. Moreover, this frontal and temporal amyloid-reduced activation/suppression was associated with poorer processing speed, verbal fluency, and fluid reasoning in a subgroup of individuals with elevated amyloid, suggesting that it is detrimental, rather than compensatory in nature.

The Impact of Increased Relational Encoding Demands on Frontal and Hippocampal Function in Older Adults

In the present study, we manipulated the cognitive effort in an associative encoding task using functional magnetic resonance imaging (fMRI). Older and younger adults were presented with two objects that were either semantically related or unrelated, and were required to form a relationship between the items. Both groups self-reported greater difficulty in completing the unrelated associative encoding task providing independent evidence of the associative difficulty manipulation. On both the low and high difficulty tasks, older adults showed a typical pattern of increased right inferior frontal recruitment relative to younger adults. Of particular interest was the finding that both groups showed increased activation as task difficulty increased in the left inferior frontal gyrus and left hippocampus. Overall, the results suggest that the aging brain is characterized by greater prefrontal processing, but that as cognitive demand increases, the networks used by older and younger adults are the largely the same.

Neural Specificity Predicts Fluid Processing Ability in Older Adults

We investigated whether individual differences in neural specificity—the distinctiveness of different neural representations—could explain individual differences in cognitive performance in older adults. Neural specificity was estimated based on how accurately multivariate pattern analysis identified neural activation patterns associated with specific experimental conditions. Neural specificity calculated from a same/different task on two categories of visual stimuli (faces and houses) significantly predicted performance on a range of fluid processing behavioral tasks (dot-comparison, digit-symbol, Trails-A, Trails-B, verbal-fluency) in older adults, whereas it did not correlate with a measure of crystallized knowledge (Shipley-vocabulary). In addition, the neural specificity measure accounted for 30% of the variance in a composite measure of fluid processing ability. These results are consistent with the hypothesis that loss of neural specificity, or dedifferentiation, contributes to reduced fluid processing ability in old age.

Neural dissociation of number from letter recognition and its relationship to parietal numerical processing

The visual recognition of letters dissociates from the recognition of numbers at both the behavioral and neural level. In this article, using fMRI, we investigate whether the visual recognition of numbers dissociates from letters, thereby establishing a double dissociation. In Experiment 1, participants viewed strings of consonants and Arabic numerals. We found that letters activated the left midfusiform and inferior temporal gyri more than numbers, replicating previous studies, whereas numbers activated a right lateral occipital area more than letters at the group level. Because the distinction between letters and numbers is culturally defined and relatively arbitrary, this double dissociation provides some of the strongest evidence to date that a neural dissociation can emerge as a result of experience. We then investigated a potential source of the observed neural dissociation. Specifically, we tested the hypothesis that lateralization of visual number recognition depends on lateralization of higher-order numerical processing. In Experiment 2, the same participants performed addition, subtraction, and counting on arrays of nonsymbolic stimuli varying in numerosity, which produced neural activity in and around the intraparietal sulcus, a region associated with higher-order numerical processing. We found that individual differences in the lateralization of number activity in visual cortex could be explained by individual differences in the lateralization of numerical processing in parietal cortex, suggesting a functional relationship between the two regions. Together, these results demonstrate a neural double dissociation between letter and number recognition and suggest that higher-level numerical processing in parietal cortex may influence the neural organization of number processing in visual cortex.

Culture differences in neural processing of faces and houses in the ventral visual cortex

Behavioral and eye-tracking studies on cultural differences have found that while Westerners have a bias for analytic processing and attend more to face features, East Asians are more holistic and attend more to contextual scenes. In this neuroimaging study, we hypothesized that these culturally different visual processing styles would be associated with cultural differences in the selective activity of the fusiform regions for faces, and the parahippocampal and lingual regions for contextual stimuli. East Asians and Westerners passively viewed face and house stimuli during an functional magnetic resonance imaging experiment. As expected, we observed more selectivity for faces in Westerners in the left fusiform face area (FFA) reflecting a more analytic processing style. Additionally, Westerners showed bilateral activity to faces in the FFA whereas East Asians showed more right lateralization. In contrast, no cultural differences were detected in the parahippocampal place area (PPA), although there was a trend for East Asians to show greater house selectivity than Westerners in the lingual landmark area, consistent with more holistic processing in East Asians. These findings demonstrate group biases in Westerners and East Asians that operate on perceptual processing in the brain and are consistent with previous eye-tracking data that show cultural biases to faces.

An fMRI study of episodic encoding across the lifespan: changes in subsequent memory effects are evident by middle-age.

Although it is well-documented that there are age differences between young and older adults in neural activity associated with successful memory formation (positive subsequent memory effects), little is known about how this activation differs across the lifespan, as few studies have included middle-aged adults. The present study investigated the effect of age on neural activity during episodic encoding using a cross-sectional lifespan sample (20-79 years old, N=192) from the Dallas Lifespan Brain Study. We report four major findings. First, in a contrast of remembered vs. forgotten items, a decrease in neural activity occurred with age in bilateral occipito-temporo-parietal regions. Second, when we contrasted forgotten with remembered items (negative subsequent memory), the primary difference was found between middle and older ages. Third, there was evidence for age equivalence in hippocampal regions, congruent with previous studies. Finally, low-memory-performers showed negative subsequent memory differences by middle age, whereas high memory performers did not demonstrate these differences until older age. Taken together, these findings delineate the importance of a lifespan approach to understanding neurocognitive aging and, in particular, the importance of a middle-age sample in revealing different trajectories.