Denise C. Park

Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

The pathophysiological process of Alzheimers disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimers Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease‐modifying therapies may be most efficacious.

The Adaptive Brain: Aging and Neurocognitive Scaffolding

There are declines with age in speed of processing, working memory, inhibitory function, and long-term memory, as well as decreases in brain structure size and white matter integrity. In the face of these decreases, functional imaging studies have demonstrated, somewhat surprisingly, reliable increases in prefrontal activation. To account for these joint phenomena, we propose the scaffolding theory of aging and cognition (STAC). STAC provides an integrative view of the aging mind, suggesting that pervasive increased frontal activation with age is a marker of an adaptive brain that engages in compensatory scaffolding in response to the challenges posed by declining neural structures and function. Scaffolding is a normal process present across the lifespan that involves use and development of complementary, alternative neural circuits to achieve a particular cognitive goal. Scaffolding is protective of cognitive function in the aging brain, and available evidence suggests that the ability to use this mechanism is strengthened by cognitive engagement, exercise, and low levels of default network engagement.

Models of visuospatial and verbal memory across the adult life span

The authors investigated the distinctiveness and interrelationships among visuospatial and verbal memory processes in short-term, working, and long-term memories in 345 adults. Beginning in the 20s, a continuous, regular decline occurs for processing-intensive tasks (e.g., speed of processing, working memory, and long-term memory), whereas verbal knowledge increases across the life span. There is little differentiation in the cognitive architecture of memory across the life span. Visuospatial and verbal working memory are distinct but highly interrelated systems with domain-specific short-term memory subsystems. In contrast to recent neuroimaging data, there is little evidence for dedifferentiation of function at the behavioral level in old compared with young adults. The authors conclude that efforts to connect behavioral and brain data yield a more complete understanding of the aging mind.

A lifespan database of adult facial stimuli.

Faces constitute a unique and widely used category of stimuli. In spite of their importance, there are few collections of faces for use in research, none of which adequately represent the different ages of faces across the lifespan. This lack of a range of ages has limited the majority of researchers to using predominantly young faces as stimuli even when their hypotheses concern both young and old participants. We describe a database of 575 individual faces ranging from ages 18 to 93. Our database was developed to be more representative of age groups across the lifespan, with a special emphasis on recruiting older adults. The resulting database has faces of 218 adults age 18–29, 76 adults age 30–49, 123 adults age 50–69, and 158 adults age 70 and older. These faces may be acquired for research purposes fromhttp://agingmind.cns.uiuc.edu/facedb/. This will allow researchers interested in using facial stimuli access to a wider age range of adult faces than has previously been available.

Mediators of Long-Term Memory Performance Across the Life Span

An individual-differences approach was used to examine the component processes that predict episodic long-term memory performance. A total of 301 participants ages 20-90 received a 7-hr cognitive battery across 3 days. Key constructs hypothesized to affect long-term memory function were assessed, including multiple measures of working memory and perceptual speed. Latent-construct, structural equation modeling was used to examine the relationship of these measures and age to different types of long-term memory tasks. Speed was a key construct for all 3 types of memory tasks, mediating substantial age-related variance; working memory was a fundamental construct for free and cued recall but not spatial memory. The data suggest that both speed and working memory are fundamental to explaining age-related changes in cognitive aging but that the relative contributions of these constructs vary as a function of the type of memory task.

Aging and the Neural Correlates of Successful Picture Encoding: Frontal Activations Compensate for Decreased Medial-Temporal Activity

We investigated the hypothesis that increased prefrontal activations in older adults are compensatory for decreases in medial-temporal activations that occur with age. Because scene encoding engages both hippocampal and prefrontal sites, we examined incidental encoding of scenes by 14 young and 13 older adults in a subsequent memory paradigm using functional magnetic resonance imaging (fMRI). Behavioral results indicated that there were equivalent numbers of remembered and forgotten items, which did not vary as a function of age. In an fMRI analysis subtracting forgotten items from remembered items, younger and older adults both activated inferior frontal and lateral occipital regions bilaterally; however, older adults showed less activation than young adults in the left and right parahippocampus and more activation than young adults in the middle frontal cortex. Moreover, correlations between inferior frontal and parahippocampal activity were significantly negative for old but not young, suggesting that those older adults who showed the least engagement of the parahippocampus activated inferior frontal areas the most. Because the analyses included only the unique activations associated with remembered items, these data suggest that prefrontal regions could serve a compensatory role for declines in medial-temporal activations with age.

Effect of Age on Event-Based and Time-Based Prospective Memory

The magnitude of age differences on event- and time-based prospective memory tasks was investigated in 2 experiments. Participants performed a working memory task and were also required to perform either an event- or time-based prospective action. Control participants performed either the working memory task only or the prospective memory task only. Results yielded age differences on both prospective tasks. The age effect was particularly marked on the time-based task. Performance of the event-based prospective task, however, had a higher cost to performance on the concurrent working memory task than the time-based task did, suggesting that event-based responding has a substantial attentional requirement. The older adults also made a significant number of time-monitoring errors when time monitoring was their sole task. This suggests that some time-based prospective memory deficits in older adults are due to a fundamental deficit in time monitoring rather than to prospective memory.

Human Neuroscience and the Aging Mind: A New Look at Old Problems

In this article, marking the 65th anniversary of the Journal of Gerontology, we offer a broad-brush overview of the new synthesis between neuroscientific and psychological approaches to cognitive aging. We provide a selective review of brain imaging studies and their relevance to mechanisms of cognitive aging first identified primarily from behavioral measurements. We also examine some new key discoveries, including evidence favoring plasticity and compensation that have emerged specifically from using cognitive neuroscience methods to study healthy aging. We then summarize several recent neurocognitive theories of aging, including our own model-the Scaffolding Theory of Aging and Cognition. We close by discussing some newly emerging trends and future research trajectories for investigating the aging mind and brain.

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

Implementation Intentions and Facilitation of Prospective Memory

Forming detailed implementation intentions for a future behavior can increase the probability that the behavior is actually completed. We investigated whether this intention effect could be used to improve prospective memory in older adults. As expected, participants who formed an implementation intention were more than twice as likely to self-initiate the intended behavior (writing down the day of the week on every sheet of paper received during the experiment) compared with participants who either were merely instructed to do so or actively rehearsed the instruction. Forming an implementation intention, however, did not improve performance on a task that required a response to salient cues. We conclude that detailed implementation intentions facilitate prospective memory on tasks that lack salient cues and require self-initiation.