Gérard N. Bischof

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.

Neural Broadening or Neural Attenuation? Investigating Age-Related Dedifferentiation in the Face Network in a Large Lifespan Sample

Previous studies have found that cortical responses to different stimuli become less distinctive as people get older. This age-related dedifferentiation may reflect the broadening of the tuning curves of category-selective neurons (broadening hypothesis) or it may be due to decreased activation of category-selective neurons (attenuation hypothesis). In this study, we evaluated these hypotheses in the context of the face-selective neural network. Over 300 participants, ranging in age from 20 to 89 years, viewed images of faces, houses, and control stimuli in a functional magnetic resonance imaging session. Regions within the core face network and extended face network were identified in individual subjects. Activation in many of these regions became significantly less face-selective with age, confirming previous reports of age-related dedifferentiation. Consistent with the broadening hypothesis, this dedifferentiation in the fusiform face area (FFA) was driven by increased activation to houses. In contrast, dedifferentiation in the extended face network was driven by decreased activation to faces, consistent with the attenuation hypothesis. These results suggest that age-related dedifferentiation reflects distinct processes in different brain areas. More specifically, dedifferentiation in FFA activity may be due to broadening of the tuning curves for face-selective neurons, while dedifferentiation in the extended face network reflects reduced face- or emotion-selective activity.

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.

Obesity and Aging: Consequences for Cognition, Brain Structure, and Brain Function

Objectives This review focuses on the relationship between obesity and aging and how these interact to affect cognitive function. The topics covered are guided by the Scaffolding Theory of Aging and Cognition (STAC [Park and Reuter-Lorenz. Annu Rev Psychol 2009;60:173–96]—a conceptual model designed to relate brain structure and function to ones level of cognitive ability. Methods The initial literature search was focused on normal aging and was guided by the key words, “aging, cognition, and obesity” in PubMed. In a second search, we added key words related to neuropathology including words “Alzheimers disease,” “vascular dementia,” and “mild cognitive impairment.” Results The data suggest that being overweight or obese in midlife may be more detrimental to subsequent age-related cognitive decline than being overweight or obese at later stages of the life span. These effects are likely mediated by the accelerated effects obesity has on the integrity of neural structures, including both gray and white matter. Further epidemiological studies have provided evidence that obesity in midlife is linked to an increased risk for Alzheimers disease and vascular dementia, most likely via an increased accumulation of Alzheimers disease pathology. Conclusions Although it is clear that obesity negatively affects cognition, more work is needed to better understand how aging plays a role and how brain structure and brain function might mediate the relationship of obesity and age on cognition. Guided by the STAC and the STAC-R models, we provide a roadmap for future investigations of the role of obesity on cognition across the life span.

Neuroplasticity, Aging, and Cognitive Function

Publisher Summary This chapter addresses the evidence that indicates that cognitive interventions change neural function or structure of the brain. It also highlights that other excellent and recent comprehensive reviews of training effects in older adults are available. It also provides a brief overview of neural changes that occur in the brain with age, a theoretical model for understanding the relationship between neural changes with age and the role that interventions might play in heightening plasticity. Following this, it reviews extant evidence that addresses the relationship between neurocognitive function and cognitive interventions. The fitness research provides convincing evidence that there are modest gains to be realized in cognitive function by maintaining a moderate to high level of fitness at older ages. The evidence with respect to training and engagement studies is less clear, and the absolute number of studies available is very limited. Training studies that yield evidence for task-specific changes as a result of sustained experience with the training task provide a great deal of important evidence about the neural processes that underlie behavioral change, but do not necessarily demonstrate brain plasticity. The chapter concludes with unresolved questions and recommendations for future research in this important domain that has clearly captivated the interest of scientists and the public, as well as marketing executives and software companies.

Association of Longitudinal Cognitive Decline With Amyloid Burden in Middle-aged and Older Adults: Evidence for a Dose-Response Relationship

Importance Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults. Objective To examine whether a continuous, dose-response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults. Design, Setting, and Participants This cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([18F]-florbetapir) at baseline and cognitive assessments at baseline and a 4-year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline. Main Outcomes and Measures Linear mixed models assessed the effect of increasing baseline amyloid over time (SUVR × time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein &egr;4, and the random effect of intercepts were included as covariates. Results The mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR × time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle-aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein &egr;4 homozygotes. Conclusions and Relevance These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization.

The Synapse Project: Engagement in mentally challenging activities enhances neural efficiency

Purpose: Correlational and limited experimental evidence suggests that an engaged lifestyle is associated with the maintenance of cognitive vitality in old age. However, the mechanisms underlying these engagement effects are poorly understood. We hypothesized that mental effort underlies engagement effects and used fMRI to examine the impact of high-challenge activities (digital photography and quilting) compared with low-challenge activities (socializing or performing low-challenge cognitive tasks) on neural function at pretest, posttest, and one year after the engagement program. Methods: In the scanner, participants performed a semantic-classification task with two levels of difficulty to assess the modulation of brain activity in response to task demands. Results: The High-Challenge group, but not the Low-Challenge group, showed increased modulation of brain activity in medial frontal, lateral temporal, and parietal cortex—regions associated with attention and semantic processing—some of which were maintained a year later. This increased modulation stemmed from decreases in brain activity during the easy condition for the High-Challenge group and was associated with time committed to the program, age, and cognition. Conclusions: Sustained engagement in cognitively demanding activities facilitated cognition by increasing neural efficiency. Mentally-challenging activities may be neuroprotective and an important element to maintaining a healthy brain into late adulthood.

Networks of tau distribution in Alzheimer’s disease

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimers disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimers disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimers disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimers disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimers disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimers disease.

Amyloid deposition in younger adults is linked to episodic memory performance

Objective: To examine the relationship of β-amyloid (Aβ) deposition to episodic memory in younger (30–49 years), middle-older (50–69 years), and older adults (70–89 years). We hypothesized that subclinical levels of amyloid would be linked to memory in adults across the lifespan in a dose-dependent fashion. Of great interest was whether, within the younger group, a relationship between amyloid level and memory performance could be established. Methods: A total of 147 participants from the Dallas Lifespan Brain Study, aged 30–89, underwent PET imaging with 18F-florbetapir and cognitive assessment. We assessed the relationship between age group and amyloid and tested whether Aβ differentially affected memory performance across the 3 age groups. Results: We report a significant association of age to amyloid burden for younger and middle-older adults (r = 0.57 and 0.28, respectively), but not for the oldest group, although absolute level of amyloid increased across the age groups. Importantly, the youngest group showed a significant decrease in recall (r = −0.47, p = 0.004) and recognition memory (r = −0.48, p = 0.003) as a function of increases in Aβ burden, whereas this relationship was absent in the middle-older and oldest group (all p > 0.23). Conclusions: These results indicate that variance in subclinical levels of Aβ in younger adults is meaningful, and suggest that higher SUVRs relative to ones peers at a younger age is not entirely benign.

Is Tau Imaging More Than Just Upside-Down 18 F-FDG Imaging?

Several neurodegenerative disorders exhibit pathologic aggregation of the tau protein in the brain and are therefore summarized under the term tauopathies (1). Alzheimer disease (AD) is considered a tauopathy because, in addition to extraneuronal b-amyloid plaques, it is characterized by pathologic tau aggregation in the form of intraneuronal neurofibrillary tangles (2). In other tauopathies—including progressive supranuclear palsy, corticobasal degeneration, and some other disorders of the spectrum of frontotemporal lobar degenerative disorders—tau pathology may occur as the leading form of protein aggregation abnormality (3). The disappointing results of antiamyloid therapy approaches in AD (4,5) and the onset of novel anti-tau therapeutic concepts (6,7) have increased interest in the in vivo detection of tau pathology, which has been limited to postmortem examinations so far. Several PET tracers for cerebral tau deposits have been developed, and some have already been applied in vivo to patients with neurodegenerative disorders. The most widely used tracers are 18F-AV-1451, 18F-THK5351, and 11C-PBB3 (8,9). More recently, tracers such as 18F-MK-6240, 18F-RO6958948, 18F-PI-2620, and 18F-JNJ64349311 have been introduced, and further compounds are under evaluation (10–12). Although some of these compounds are already being tested in clinical trials (up to phase 3), all of the available tracers can currently still be considered in an exploratory stage and the available literature is still limited. In several studies, a strong similarity between the distribution of tau tracer retention in the brain and the extent of hypometabolic abnormalities (as measured with 18F-FDG PET) has been observed (Fig. 1) (13–16). Furthermore, these studies statistically demonstrated an inverse quantitative relationship between tau deposition and metabolism. While underscoring the hypothesis that tau pathology may be causally involved in the development of neuronal dysfunction, this upside-down similarity between the two methods raises the question of whether tau PET has additional clinical value over established 18F-FDG PET.