Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. pe21
[DOI: 10.1126/sageke.2006.10.pe21]

PERSPECTIVES

From Bedside to Bench: Does Mental and Physical Activity Promote Cognitive Vitality in Late Life?

Stephanie Studenski, Michelle C. Carlson, Howard Fillit, William T. Greenough, Arthur Kramer, and George W. Rebok

The authors are in the School of Medicine and VA Pittsburgh GRECC, University of Pittsburgh, Pittsburgh, PA 15213, USA (S.S.); the Center on Aging and Health and the Department of Mental Health at The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA (M.C.C. and G.W.R.); the Institute for the Study of Aging and the Alzheimer's Drug Discovery Foundation, New York, NY 10153, USA and The Mount Sinai Medical Center, New York, NY , 10029 USA (H.F.); the Beckman Institute and the Departments of Psychology (W.T.G and A.K.), Psychiatry, and Cell and Developmental Biology (W.T.G.) at the University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. E-mail: sas33{at}pitt.edu (S.S.)

http://sageke.sciencemag.org/cgi/content/full/2006/10/pe21

Key Words: Alzheimer's disease • cognitive function • dementia • cognitive reserve • physical activity • exercise

Introduction

There is a great need for interventions to prevent or treat cognitive disability. Indeed, there is already a substantial market for existing products with purported benefits to cognitive functioning (1, 2). The purpose of the third annual Bedside to Bench conference held in Philadelphia on 1 to 3 March 2006 was to convene a broad multidisciplinary group of investigators with expertise in cognition, aging, physical exercise, brain structure and function, psychosocial factors, animal models of disease, human epidemiologic and intervention studies, and community-based intervention models, to examine existing and emerging evidence regarding exercise, activity, and cognition. The group considered both preclinical and clinical effects of exercise on cognition and the potential mechanisms of action, identified gaps in current knowledge, and recommended key opportunities and next steps for researchers in the field. For an overview of the first two conferences in the Bedside to Bench series, see Fried Perspective (which covered the conference on frailty) and Wieland Perspective (which covered the conference on comorbidity and aging).

Cognitive Function and Aging

Evidence for a benefit of physical and cognitive activity in preventing or treating cognitive problems is dependent on the type of cognitive outcome being measured. Cognitive function comprises numerous components, including memory, language, executive function (that is, the ability to plan and schedule activities, focus on task-relevant information, perform multiple tasks or skills concurrently, and so on), judgment, attention, and perception (see de Fockert Perspective). As with other body systems and functions, many elements of cognitive function peak in young adulthood and then gradually decline thereafter (see "All In Your Mind" and Tuszynski Perspective).

However, not all cognitive functions decline at the same time or at the same rate (see Thal Perspective). In studies of healthy, community-dwelling older adults, decline occurs at markedly different rates across various domains of cognitive ability (3-6). In a recent study, declines in cognitive function occurred first and most precipitously on a measure of executive function called the Trail Making Test, Part B (7). Such changes in executive function preceded declines in memory, whereas psychomotor speed declined modestly over a 6-year interval. Thus, age-related cognitive changes are multidimensional and progress across a continuum of severity, often over many decades. A decline in executive function has been associated with a concurrent decline in "independent activities of daily living" function, which is a prerequisite for a diagnosis of dementia (8, 9). Efforts to modestly elevate an individual's competence on various cognitive functions or to slightly reduce the rate of functional decline across cognitive abilities in midlife could produce greater benefits in the long term by, for example, delaying the onset of dementia (10).

Cognitive changes that accompany aging range from dementia to age-related subtle alterations in specific cognitive domains. By definition, a diagnosis of dementia is based on deficits in more than one cognitive domain of sufficient severity to limit daily function. Abnormal cognitive performance that does not yet affect daily function has been termed "mild cognitive impairment," or MCI, which may involve memory loss (amnestic type MCI) or other cognitive functions such as language, motor planning, or executive functions (single nonamnestic or multiple nonamnestic MCI) (11, 12). Age-associated memory impairment (or mild memory loss), which is not as severe as amnestic MCI, is present in almost 40% of individuals 60 years of age and older (12).

Functional Reserves

The point where cognitive declines become clinically apparent usually depends on a threshold where deficits start to impede usual functioning. A core concept of aging states that an individual's vulnerability for crossing clinical thresholds is lessened when he or she possesses more physiological and functional reserve--in other words, the greater the amount of reserve, the greater the amount of loss that has to occur before such loss interferes with functioning. Cognitive functions, as other body functions, show great heterogeneity among individuals in terms of peak capacity, rates of loss, and development of clinically abnormal cognition or dementia. The prevention of cognitive disability might depend, at least in part, on increasing an individual's cognitive reserves, independent of any treatment of underlying disease pathology. Reserves could be increased by increasing peak capacity early in life, by reducing rates of age- or disease-related decline, or by providing "boosts" throughout an individual's lifetime.

There is as yet no agreement on how to measure cognitive reserve or whether it should be conceptualized as a unitary construct or a set of more discrete processes. Cognitive reserve might be defined as capacity beyond what is needed for daily functioning or, alternatively, as the ability to tolerate (to be more resilient or adaptive to) brain pathology (13). The types and the magnitude of demands that various cognitive tasks make on cognitive reserve, and the related neuroimaging manifestations, are not yet understood. Reserve may involve both passive and active processes of the brain: neural or brain reserve capacity, such as brain size or synapse count, and compensatory responses across functional brain networks (14).

Optimal cognitive health is not just the absence of dementia or cognitive deficits but rather the "development and preservation of a multidimensional cognitive structure that allows elderly people to maintain social connectedness, an ongoing sense of purpose, and the ability to function independently and to permit functional recovery" (15). Thus, there may be a relationship between optimal cognitive health and optimal cognitive reserve. Given the range of cognitive performances, reserves, and rates of decline among individuals, interventions involving physical and cognitive activity should target a wide range of cognitive objectives. Interventions could be designed to optimize overall cognitive functioning, increase cognitive reserve, slow rates of decline, delay clinical thresholds, remediate mild cognitive impairments, or improve function among patients with dementia.

Animal Models for Studying the Effects of Activity on Cognition

Animal models provide exceptional insights into the molecular, genetic, and cellular mechanisms that underlie the effects of physical and cognitive activity on cognition. In addition, they can be used to assess the outcome of activity-related interventions. Experimental interventions include treadmill training, wheel running, and enriched environments. Treadmill training is a form of controlled, forced exercise, whereas wheel running is typically a voluntary form of exercise, but neither one involves intellectual activity (16). Enriched or complex environments are intended to stimulate social, perceptual, and motor activities by housing animals in groups in large cages with structures for exploration, physical activity, and sensorimotor learning (17, 18).

Exercise and environment appear to enhance learning through neural and vascular cell proliferation, enhanced synaptic number and function, and glial proliferation and hypertrophy; all these processes are regulated by complex cascades of cell signals. Brain plasticity (which involves the development of new neurons and cellular reorganization) was previously thought not to occur in the adult brain but has now been repeatedly shown to occur primarily in the hippocampal dentate gyrus and olfactory bulb (19, 20). Stem cells in these regions of the adult brain can differentiate into neurons and in most other regions into new glia. Such cytogenesis may be regulated by hormones, growth factors, neurotransmitters, and genetics (21, 22).

New nerve cells are generated by stimuli from a range of activities. In a series of experiments, groups of adult mice were assigned to running, learning, swimming, or an enriched environment that promoted activity, socialization, and problem solving (23). Running promoted the most stem cell proliferation and differentiation, as well as prolonged survival of new cells, compared with the other activities. In this study, however, the enriched environment did not include a running wheel, which is a typical component. In addition, running improved learning (24). Exercise has been proposed to enhance long-term potentiation of the dentate gyrus, a process involved in learning (25, 26). Similar effects of running on neurogenesis and learning have also been found in mice who began running late in life (26).

Rats raised in complex environments, which promote both physical and mental exercise, have more synapses per nerve cell in various brain regions than rats raised in standard laboratory cages (27). This effect occurs in rats of a wide range of ages, suggesting that there is no "critical period" for the response (28). Exercise also enhances the formation and survival of glial support cells in the brain, including astrocytes, increases myelinization of neurons, and promotes new capillary formation (29-31).

In nonhuman primates, physical exercise on a treadmill increased capillary formation in the motor cortex of mature, but not young, animals (32). There was a substantial increase in neurogenesis in the hippocampal dentate gyrus of older animals, and neurons persisted for months after the training ended. Although there was little or no neurogenesis in the cerebral cortex, treadmill training increased the number of glial cells in that region of the brain (33).

Brain-derived neurotrophic factor (BDNF) is necessary for learning and memory. It mediates the consolidation phase (storage of long-term potentiation), stimulates the differentiation phase of neurogenesis, and protects neurons from injury. Concentrations of BDNF are lower in brains of Alzheimer's disease patients (34). In rodents, BDNF mRNA concentrations increase after 1 week of exercising, and exercise enhances wayfinding in a water maze test (35). Experimental blockade of BDNF eliminates the effects of exercise on learning (36). After training and a period of inactivity, BDNF can be induced more quickly with reexposure to exercise (37). Thus, exercise may prime the brain to respond to repeat experiences by inducing a "state of readiness" through molecular memory mechanisms.

Voluntary exercise reduces oxidative stress, promotes BDNF-induced synaptic plasticity, and also affects downstream signaling pathways by modulating energy metabolism (38). BDNF itself increases mitochondrial activity (39) and glucose metabolism (40), and oxidative stress reduces BDNF concentrations (41). A model of brain plasticity posits that exercise, diet, and neural injury affect energy metabolism, which in turn influences BDNF levels, subsequent synaptic activity, and ultimately cognition (38).

Exercise may have a protective role on cognition in the TGCRND8 mouse model of Alzheimer's disease. Treadmill running increased neurogenesis and improved water maze performance in the TGCRND8 mouse, while reducing beta amyloid burden (42). Environmental enrichment in these mice decreased amyloid precursor protein processing and promoted amyloid clearance (43); it has also been shown to promote cognition in the presence of stable amyloid levels (44).

Next Steps in the Study of Animal Models

Conference attendees noted several important gaps in current knowledge of the role of activity on cognition. For example, the "dose" of activity is difficult to measure and, thus, optimal dose cannot be determined. Furthermore, there are limited measures of cognition in animals, and longer term studies of activity and cognition have yet to be performed. Thus, future studies should expand the repertoire of cognitive testing and improve measurements of activity.

There is a need for studies that will determine the effects of frequency, intensity, and duration of exercise on cognition. Few studies have examined the effects of repeated periods of experience, and virtually none have determined whether intermittent periods of exercise or cognitive activity interact in a synergistic or occlusive manner. Existing data often confound exercise and enrichment or use forced exercise, which may introduce a stress confounder. Animal studies that attempt to model human lifestyle choices or that vary the level and frequency of exercise are exceedingly rare. Genetically modified mice should be developed to further elucidate the signaling pathways that mediate the effects of exercise on cognition. Finally, researchers need to perform long-term studies to assess the mechanisms responsible for the chronic effects of exercise on cognition.

Human Studies on the Effects of Physical Activity on Cognition

Leisure-time physical activity throughout life has been shown to protect against late-life cognitive decline and dementia in several studies (45-51). In a study using objective measures of aerobic capacity, peak oxygen consumption predicted multiple cognitive functions 6 years after the measurement was taken (52). Although the majority of observational studies found a relationship between physical activity and cognition, some have not (53, 54), and yet others have found that different factors can mask such a relationship, such as the presence of genetic risk factors for dementia (47). Observational studies are vulnerable to multiple forms of bias, including censoring, reverse causation, and multiple confounders. Furthermore, such studies are sometimes difficult to compare because they involve diverse participating populations, use different measures of activity and cognition, and preclinical cognitive impairment among participants may affect outcomes (55-57).

A number of clinical trials have examined the effect of physical exercise on cognition. A recent meta-analysis found that physical exercise produced a significant positive effect on cognition, and particularly on executive functions (58). Exercise had a larger effect on cognition when aerobic training was combined with strength training and when training lasted longer than 30 minutes. Furthermore the effect was greater among older than midlife adults and among women than men. This meta-analysis noted numerous methodological challenges, including differences in ages of participants, in measures of cognition, in types and intensity of exercise, and in types of control interventions.

Recently, Colcombe and colleagues reported the results of several studies that examined the influence of differences in fitness among participants and of different exercise training programs on brain structure and function using magnetic resonance imaging (MRI) (see Gazzaley Perspective). They examined the influence of a 6-month fitness training program on the brain's response to a focused task that required an individual to selectively process specific information while ignoring other, task-irrelevant information (59). They found that individuals assigned to a "walking group" showed improved performance on the focused-attention task and more efficient patterns of brain activation by MRI analysis. The same effects were not observed in a toning and stretching control group. In a separate study, the same authors found fitness-related differences in the volume of specific brain regions using MRI techniques that precisely quantify brain region volume. Compared with the less fit group, the group that was more fit had larger brain region areas in the frontal and temporal gray matter, as well as the anterior white matter (60). The increase in fitness interacted with hormone replacement therapy to increase the volume of gray matter in the prefrontal cortex in a study of postmenopausal women (61).

Cognitive Activity and Cognition

Evidence from epidemiological studies suggests that mid- and late-life exposure to enriched or complex environments has measurable, beneficial effects on cognition and on the risk for dementia (53, 54, 62-66). These benefits appear to extend beyond activities traditionally viewed as being cognitively stimulating, such as reading newspapers and books and doing crossword puzzles, to those offering moderate levels of cognitive stimulation, such as volunteering, playing cards, civic activity, and assisting family members. In one study of healthy older women, participation in moderately stimulating activities was as beneficial as that in highly stimulating activities for ameliorating declines in memory and psychomotor speed (67). In contrast, participation in less stimulating cognitive activity, such as watching television, did not alter rates of cognitive decline, on average. When television viewing preferences were examined, it was found that individuals who watched talk shows or soap operas rather than news programs (as in the reference group) were 7 to 13 times as likely to show impairment on measures of attention and memory (68).

Observational studies have shown value in informing the design of targeted and sustainable interventions. They help to characterize the types and patterns of cognitive activity that older adults elect to do and enjoy, to explore behaviors associated with cognitive functions, and to identify potential mediators and confounders. Nevertheless, as noted above, observational research is restricted with respect to identifying underlying causes. This is because cognitive capacity may influence the selection of cognitive activities, retrospective recall of midlife cognitive activity is not always accurate, and the makeup of particular cohorts may skew the results of a study (69). However, a study that attempted to address some of the biases mentioned above by following a cohort of twins prospectively to monitor the development of dementia, found that midlife cognitive activity was protective against disease risk (70).

Initial clinical trials of cognitive activity focused on the "early aging" of individuals in the sixth and seventh decade of life and targeted cognitive functions thought to be the first to decline with age, such as abstract reasoning, perceptual speed, and working memory. Cognitive training improved cognitive performance modestly, and some gains were still detectable several years later (71-73). These studies, however, did not assess how cognitive training affected cognitively based daily functions, had limited follow up, lacked "intention-to-treat analysis" (in which all participants are included in the analysis regardless of whether they completed the intervention), and used local samples, rather than nationally representative groups. In addition, their findings were not replicated in other studies.

The next generation of clinical trials was designed to overcome some of these limitations. A national multisite study called ACTIVE (for Advanced Cognitive Training for Independent and Vital Elderly) used three cognitively demanding interventions (memory, reasoning, and speed training) and examined direct effects both on target cognitive domains and on activities of daily living. ACTIVE also used participants more representative of the population at large and used an intention-to-treat analysis. Each of the three cognitive interventions affected the target cognitive domain, but the benefit did not transfer to other cognitive domains or to daily activity (74). Subsequent "booster" training sessions helped sustain the beneficial effects on the target domain (75). Interestingly, persons with mild memory impairment at baseline benefited just as much as those without memory impairment on reasoning and speed training but not as much on memory training (76).

Community-Based Physical and Cognitive Exercise Programs

There are now numerous nonprofit and commercial programs that promote physical and cognitive activity among older adults. Such programs take many forms, from development of franchises and onsite-based activities, to literature and computer-based instruction. Some develop formal staff-training protocols, whereas others interact directly with the consumers. However, at the moment there is little empirical support for the efficacy of these programs to positively influence cognitive vitality beyond improving the specific task that they target.

Enrichment and Multimodal Interventions

Promoting sustained physical and cognitively enriching activities requires incentives to adopt and maintain the new behavior. Thus, interventions that offer "real life" environments and tasks that can be generalized to different environments might promote better adoption and maintenance, but have not yet been fully tested for efficacy. One example of a multimodal intervention study is the Experience Corps (EC) project. EC represents a partnership between older adults and public schools in Baltimore, Maryland (77). Adults aged 60 and older are trained and then placed in teams in elementary school classrooms where they work directly with children and teachers to help develop literacy and math skills, assist in school libraries, teach methods of conflict resolution, and aid in monitoring school attendance. In addition to benefiting students, teachers, and schools (78, 79), the program benefits participating older adults. By doing personally meaningful activity in service to others (referred to as generative activity), older adults increase physical, cognitive, and social stimulation. A pilot, randomized trial of 148 older adults conducted over 4 to 8 months showed that generative activity led to specific improvements in physical activity and strength, increased social contacts, and reduced time spent in low cognitive demand activities, such as television viewing (80). Furthermore, individuals at greatest risk for cognitive impairment showed substantial clinically meaningful improvements in executive functions and memory as a result of participating in this short-term, multimodal activity intervention (79). These initial findings suggest that multimodal interventions may amplify effects of unimodal ones by simultaneously harnessing the effects of cognitive and physical activity in a social engagement model. Finally, pilot functional neuroimaging data in a subset of EC volunteers versus matched controls over a 6-month period demonstrated program-specific benefits in executive functions similar to those observed for physical activity (68).

Next Steps in Human Studies

Members of the conference identified several important gaps in the current knowledge regarding the effects of physical and mental activity on cognition. In particular, researchers need to determine the importance of the interaction between physical and cognitive activity and the role played by social integration. The types and intensity of reported physical and cognitive activities have only been partially characterized. Furthermore, the constructs of cognitive reserve are not thoroughly defined. The effects of the timing and course of activity during a lifetime are not clear. The effects of comorbid conditions, literacy, and ethnicity are understudied. Intervention studies so far have been limited to studying short- and intermediate-term effects and continue to use different populations, interventions, and outcome measures, making it difficult to compare results from one study to another.

Future studies using human subjects should clearly and consistently characterize the types of physical and cognitive activities used and should consider multimodal interventions that include a social dimension. In addition, these studies should examine the influence of health status, initial cognitive status, mood, gender, ethnicity, and literacy on the effects of activity on cognition. They should also continue to refine cognitive outcome measures that can be generalized across different studies. Some physical intervention studies involving older adults should assess cognitive outcomes. There is also a growing need for efforts to study how research findings are translated to community settings.

Conclusions

The potential of physical and cognitive exercise, and a multimodal enriched experience, in promoting cognitive health later in life is supported by a growing body of data from animal and human studies. As a result, the molecular mechanisms involved and the effects of such activities on intermediate outcomes, such as cognitive performance, are becoming clearer. Physical and cognitive exercise might increase an individual's cognitive reserve and promote a healthy brain, as well as delaying or reducing cognitive impairment and dementia. However, there is still no conclusive evidence that any type of exercise benefits cognitive function in daily life or that it prevents or delays dementia. Such evidence is likely to require large multicenter clinical trials that use clinically relevant endpoints such as diagnosis of new dementia.


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Citation: S. Studenski, M. C. Carlson, H. Fillit, W. T. Greenough, A. Kramer, G. W. Rebok, From Bedside to Bench: Does Mental and Physical Activity Promote Cognitive Vitality in Late Life? Sci. Aging Knowl. Environ. 2006 (10), pe21 (2006).








Science of Aging Knowledge Environment. ISSN 1539-6150