Achieving and Maintaining Cognitive Vitality With Aging

Mayo Clin Proc, July 2002, Vol 77 Cognitive Vitality With Aging 681 Review Achieving and Maintaining Cognitive Vitality With Aging HOWARD M. FILLIT, MD; ROBERT N. BUTLER, MD; ALAN W. O’CONNELL, PHD; MARILYN S. ALBERT, PHD; JAMES E. BIRREN, PHD; CARL W. COTMAN, PHD; WILLIAM T. GREENOUGH, PHD; PAUL E. GOLD, PHD; ARTHUR F. KRAMER, PHD; LEWIS H. KULLER, MD; THOMAS T. PERLS, MD; BARBARA G. SAHAGAN, PHD; AND TIM TULLY, PHD enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging. Mayo Clin Proc. 2002;77:681-696 Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive AAMI = age-associated memory impairment; AD = Alzheimer disease; apoE4 = apolipoprotein E4; BDNF = brain-derived neurotrophic factor; CREB = cyclic adenosine monophosphate response element binding protein; FDA = Food and Drug Administration; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; NGF = nerve growth factor; NSAID = nonsteroidal anti-inflammatory drug; PET = positron emission tomography; SPECT = single-photon emission computed tomography longer, more active lives.1 However, most older individuals still face late life with changes in cognitive function that affect quality of life2 and increase mortality.3 Cognitive vitality in old age is impaired by both “normal cognitive aging” and diseases that cause dementia, primarily Alzheimer disease (AD) and vascular dementia. Although the cognitive impairments associated with normal aging have been defined and may impair quality of life,4-7 cognitive decline with aging is not inevitable, and many older adults, including some centenarians, appear to avoid cognitive decline even into the 11th decade of life.8,9 Recent research has resulted in new information identifying clinical risk factors for cognitive aging that are potentially modifiable. These new data support an emerging basis for primary and secondary prevention efforts to achieve and maintain cognitive vitality in late life. In this review, we discuss research that associates various risk factors with normal cognitive aging. Because most of these risk factors are potentially modifiable or manageable, such research should be of interest to physicians who provide preventive care counseling to older persons hoping to maintain cognitive vitality with aging. T he “longevity revolution” has increased the focus on many aspects of health in aging. The older population is growing rapidly, and individuals are typically living Fro m the Ins titute fo r the Study o f Aging, Inc , Ne w Yo rk, NY (H.M.F., A.W.O.); De partme nt o f Ge riatric s , Me dic ine , and Ne uro bio lo gy, Mo unt Sinai Me dic al Ce nte r, Ne w Yo rk, NY (H.M.F.); Inte rnatio nal Lo nge vity Ce nte r, Ne w Yo rk, NY (R.N.B.); De partme nt o f Ps yc hiatry and Ne uro lo gy, Mas s ac hus e tts Ge ne ral Ho s pital, Bo s to n, Mas s (M.S.A.); Unive rs ity o f Califo rnia Ce nte r o n Aging, Lo s Ange le s (J.E.B.); De partme nt o f Ne uro lo gy, Bio lo gy and Be havio r, Unive rs ity o f Califo rnia, Irvine (C.W.C.); Be c kman Ins titute (W.T.G., A.F.K.) and De partme nt o f Ps yc ho lo gy and Ne uro s c ie nc e Pro gram (P.E.G.), Unive rs ity o f Illino is at Urbana-Champaign, Urbana; De partme nt o f Epide mio lo gy, Unive rs ity o f Pitts burgh Graduate Sc ho o l o f Public He alth, Pitts burgh, Pa (L.H.K.); Ge riatric s , Bo s to n Me dic al Ce nte r, Bo s to n, Mas s (T.T.P.); Pfize r, Inc , Gro to n, Co nn (B.G.S.); and Co ld Spring Harbo r Labo rato ry, Co ld Spring Harbo r, NY (T.T.). This wo rk was c o s po ns o re d by the Ins titute fo r the Study o f Aging, Inc , the Inte rnatio nal Lo nge vity Ce nte r, the Natio nal Ins titute o n Aging, and Canyo n Ranc h He alth Re s o rts . The wo rk was als o s uppo rte d by Pfize r, Inc , Eis ai, Inc , Jans s e n Pharmac e utic als , Ne uro c he m, Inc , Elan Pharmac e utic als (fo rme rly Athe na Ne uro s c ie nc e s , Inc ), and the Fide lity Fo undatio n. Addre s s re print re que s ts and c o rre s po nde nc e to Ho ward M. Fillit, MD, Ins titute fo r the Study o f Aging, Inc , 7 6 7 Fifth Ave , Suite 4 6 0 0 , Ne w Yo rk, NY 1 0 1 5 3 (e -mail: hfillit@ rs lmgmt.c o m). Mayo Clin Proc. 2002;77:681-696 681 © 2002 Mayo Foundation for Medical Education and Research For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. 682 Cognitive Vitality With Aging COGNITIVE AGING Neuropsychology Cognitive decline, although a relatively common occurrence, cannot be considered an inevitable part of aging. Nature provides clear examples of elderly people who maintain cognitive vitality, even in extreme old age. Many older adults who live into their ninth decade retain high cognitive function,10 and centenarians who maintain their intellect negate the myth of the inevitability of cognitive decline.11,12 The aging brain remains capable of adapting to stimuli, and although declines in specific cognitive functions occur, some cognitive functions increase with age and can compensate for those functions that may decline. In addition, normal older persons and even those with mild cognitive deficits can benefit from cognitive training.13-15 People who reach old age with greater stores of knowledge may show increased adaptivity.2 Some cognitive functions, such as vocabulary, improve with age.16 Older people who are socially interactive and use additional information resources in solving everyday problems also show adaptivity.2 Taken together, these findings suggest that individuals have varying degrees of “functional reserve” in their brains. Persons with high functional reserve may have increased capacity to keep learning and adapting despite age-related changes.17 Increasing this functional reserve should promote cognitive vitality with aging. Neurobiology The underpinning of this functional reserve is likely to be brain plasticity, the ability of the brain to change structurally in response to stimuli. Recent neuroscience research shows that plasticity occurs via several mechanisms. In young animals, complex experience results in an angiogenic effect to increase vascular supply to the brain.18,19 Long-term enhancement of hippocampal synaptic connections occurs with acquisition of knowledge, although this process occurs more slowly in older animals than in young animals.20 Synaptogenesis and angiogenesis also occur in the cerebellar cortex of the adult rat in response to stimuli.21 The number of synapses per neuron may increase in rats exposed to more stimulatory vs less stimulatory environments.22 In old rats, a stimulating environment helps reverse age-related gliosis in the hippocampus, which is associated with damage.23 Finally, the widely held belief that the adult brain cannot make new neurons (neurogenesis) has been challenged recently by a growing body of new data. Animal studies have demonstrated that neuronal precursors in the dentate gyrus of the hippocampus, an area of the brain associated with learning and memory, continue to produce new neurons in adulthood.24,25 Studies in rats and mice show that a stimulatory environment,26,27 estrogen,28 Mayo Clin Proc, July 2002, Vol 77 and aerobic exercise (running) also stimulate such new neuron production.29 Neurogenesis has also been observed in the neocortex of adult primates.25,30 The decline in cognitive function seen with apparently normal aging is associated with structural changes in the brain. Even early in the aging process, changes such as cerebral atrophy, ventricular enlargement, and hippocampal atrophy may be evident in some, but not all, individuals.31,32 Ultimately, the underlying pathologic basis of cognitive decline must be loss of synapses, neurons, neurochemical inputs and neuronal networks.33,34 However, neuronal loss is no longer thought to be a characteristic and inevitable feature of normal brain aging.35 In normal aging, some disruptions in neural networks occur, but cell death is not as common as it is in dementia.36 Indeed, as noted previously, neurogenesis, the production of new neurons, appears to continue throughout life, including old age.25,26 The cause of changes in brain structure and function with aging is unknown. Some processes required for maintaining normal neural function may become dysregulated with aging, causing neural damage.2 Dysregulated inflammation (activation of microglia, cytokine release, and acute-phase response) may contribute to neuronal damage.37,38 Oxidative stress, an imbalance between oxidative and antioxidant processes, may also cause neuronal damage in the aging brain.39,40 The pathologic changes associated with AD differ substantially from normal brain aging. Although some minor deposition of β-amyloid peptide and neurofibrillary tangles may occur in the aging brain, the amount and distribution of these deposits are greatly increased in AD. Deposition of β-amyloid is thought to be a primary factor in causing AD,38 resulting in neuronal cell death and disruption of neural networks in AD. Tangles are believed to either contribute to and/or to be a sign of neuronal cell dysfunction and death and are associated with an abnormally phosphorylated form of a brain protein called tau. In tangles, tau twists into paired helical filaments that form intracellular occlusions associated with disruption of microtubules. The precise mechanism underlying the aberrant assembly of tau into tangles is unknown, but the available evidence suggests that hyperphosphorylation of tau is involved.41,42 Clinical and Investigational Paradigms Many investigators have studied the characteristics of normal cognitive aging. Cognition is a combination of skills, including attention, learning, memory, language, and praxis, and executive functions, such as decision making, goal setting, planning, and judgment. A hallmark of normal cognitive aging is slowed speed of processing.43,44 This slowed speed of processing may be the “bottleneck” that causes other deficits in cognitive function. Researchers For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. Mayo Clin Proc, July 2002, Vol 77 hypothesize that slow speed of processing impairs cognition because simultaneous cognitive operations cannot be successfully executed and the products of early processing are not available when later processing is completed (“simultaneity”).44 Slowed speed of processing may contribute to declines in visual and verbal memory, abstraction, naming, verbal fluency, and recall.45-50 As a result, older individuals may have difficulty performing tasks that require holding and integrating multiple items in memory (eg, remembering a telephone number that one just looked up after being distracted by a question). From a clinical and an investigational perspective, 3 types of cognitive decline with aging have been recognized: age-associated memory impairment (AAMI),5 mild cognitive impairment (MCI),4 and dementia. Age-associated memory impairment is a clinical paradigm that attempts to describe changes in cognition that occur with normal aging.51 Although age-associated memory impairment is a commonly used term for older persons with complaints of memory loss, other concepts and terms, such as age-related cognitive decline52 and cognitive impairment–no dementia,53 have also been used to describe persons with mild memory loss. People experiencing AAMI complain of memory loss but generally have normal scores on psychometric testing for their age group.5 This syndrome has been variously termed benign senescent forgetfulness and aging-related cognitive decline. For persons older than 50 years who complain of subjective memory loss, AAMI is defined as cognitive function that is 1 SD below the mean for young individuals on at least 1 psychometric memory test.5,54 Most data indicate that patients with AAMI do not progress to dementias such as AD. In addition, most data indicate that AAMI is not a prodromal state for MCI because less than 1% of people with AAMI will develop dementia. However, certainly some individuals with very early dementia may complain of mild memory loss akin to AAMI as their first symptom.55 Nevertheless, more studies of rates of progression of AAMI to MCI or dementia are needed. Mild cognitive impairment describes older persons with subjective complaints of memory loss and objective psychometric measures of memory impairment compared with individuals of the same age.4 However, these individuals do not have pronounced impairments in daily function and generally do not have impairment of other cognitive functions such as language or abstract thinking. Therefore, by definition, they do not have dementia. In a study of MCI, subjects performed 1.5 SDs below the mean for agematched adults on memory tests, whereas other cognitive functions appeared relatively unaffected.4 At least in some patients, MCI may be a prodromal syndrome of dementia. Up to 15% of individuals with MCI develop dementia Cognitive Vitality With Aging 683 each year, and 50% with MCI will develop dementia within 3 years of diagnosis. However, whether MCI is a separate entity or an early prodromal stage of dementia remains a matter of debate56 because all individuals with MCI do not inevitably have progression to AD.57 A recent study found that older patients with memory complaints who convert to AD differ by at least 1.5 SDs from normal older patients on 3 of 17 cognitive tests. Based on these studies, selected clinical interview questions may be useful to identify such converters, particularly questions related to delayed recall.58 Dementia can be broadly defined as a syndrome of progressive global cognitive impairment severe enough to affect daily function.59 The term dementia is reserved for chronic, progressive, irreversible, global cognitive impairment. Dementia is common in old age, with up to 25% of people older than 75 years and 40% of people older than 80 years having the illness.60 The most common causes are clearly AD and vascular dementia. Other causes of dementia include Parkinson disease, Lewy body disease, and other more rare neurodegenerative conditions.61,62 As discussed previously, at present there is no known neuropathogenic relationship between cognitive aging and AD. Alzheimer disease is not considered an accelerated form of cognitive aging, but rather a disease primarily of old persons. STRATEGIES TO PROM OTE COGNITIVE VITALITY WITH AGING Emerging research has resulted in a growing understanding of the potentially modifiable risk factors associated with cognitive decline in late life, and several interventions are being evaluated in research studies to prevent cognitive decline and dementia in older persons (Table 1).63 Early Detection Early detection is essential to implementation of strategies to prevent cognitive decline. General approaches to early detection of cognitive impairment are neuropsychological testing, imaging, and use of biomarkers and genetic markers. At present, most of these strategies, particularly brain imaging, are being evaluated primarily for use in the early detection of MCI or dementia. Neuropsychological Testing.—Neuropsychological testing is clearly the most practical method of evaluation of cognitive decline with normal aging. Because there is considerable interindividual variation in cognitive decline with normal aging, neuropsychometric examination could potentially evaluate an individual’s cognitive strengths and weaknesses and potentially lead to an intervention plan of cognitive training that is tailored to that individual’s needs. Indeed, clinical programs along these lines are evolving in For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. 684 Cognitive Vitality With Aging Table 1. Possible Strategies to Promote Cognitive Vitality With Aging Early detection of individuals at risk Neuropsychological testing Neuroimaging Biomarkers Genetic markers Lifestyle management Build “cognitive reserve” by remaining intellectually and socially active Continue lifelong learning Engage in regular mental exercise Maintain active social networks Remain involved in the community by occupational or voluntary activity Engage in regular physical exercise Reduce or minimize the effects of stress Ensure appropriate nutrition and avoid nutritional deficiencies Manage medical comorbidities Hypertension Diabetes Hyperlipidemia Depression Sleep disorders Polypharmacy Sensory impairments Avoid alcohol, smoking, and illicit drug abuse Pharmaceutical approaches Cognitive enhancers Neurotrophins Anti-inflammatory agents Antioxidants Hormones clinical practice, often using computer-based technology to expedite the process of both evaluation and training. Although neuropsychological approaches have the advantage of measuring the actual function of interest (ie, cognitive function), neuropsychometrics are time-consuming, and considerable effort is required to detect subtle neuropsychological impairments that can be compared with agematched norms. Several studies64-66 have investigated neuropsychological testing paradigms for early detection of cognitive impairment in individuals with early AD, MCI, or AAMI. However, routine neuropsychological testing for the evaluation of normal cognitive aging cannot be recommended at this time. Many brief and practical mental status tests are available in clinical practice to screen and assess cognitive function in older persons, but these are primarily geared toward the detection of more severe cognitive impairment due to dementia. The Mini-Mental State Examination (MMSE)67 is probably the most widely used and has been validated for screening for cognitive impairment in older persons in a community setting. Because the MMSE and Mayo Clin Proc, July 2002, Vol 77 instruments like it were primarily developed to detect dementia, they are not sensitive enough to detect the mild cognitive changes associated with normal aging. In clinical practice, patients who complain of memory impairment and who may have AAMI or MCI will generally score normally on screening instruments such as the MMSE. When indicated or desired, these individuals may be given more extensive psychometric testing by an expert neuropsychologist to distinguish patients with AAMI or MCI from those with dementia. Specifically with regard to screening for cognitive impairment due to dementia, the US Preventive Services Task Force found in 1996 that evidence was insufficient to recommend for or against cognitive screening for dementia in asymptomatic older people in routine clinical practice because not enough data had been accumulated to gauge the benefit of such screening for preventing the medical, psychological, and social consequences of dementia.68 However, with Food and Drug Administration (FDA) approval of modestly effective and safe cholinesterase inhibitors and advances in the understanding of AD care management, the impetus for screening and early detection may have changed considerably.69,70 Early detection means that people can receive new treatments and effective care management, which are crucial to promoting cognitive, emotional, and functional health during a time of cognitive frailty and in preserving the health of the caregiver. As the prevalence of cognitive impairment increases to approach 25% of individuals older than 75 years, it may be effective to screen these individuals on some regular basis (eg, every 2 years) for cognitive impairment. With ongoing clinical trials of the cholinesterase inhibitors and other drugs for the treatment of AAMI and MCI, the paradigm for screening for cognitive impairment may change even more in the future. One could envision a future in which treatments for normally aging individuals with slowed speed of processing and mild short-term memory impairment may be available and would justify routine neuropsychological assessment as part of an annual “health in aging” examination. Clearly, however, that day has not yet arrived. Brain Imaging Techniques.—As with neuropsychological evaluations, brain imaging techniques, such as computed tomography, magnetic resonance imaging (MRI), functional MRI, positron emission tomography (PET) scanning, and single-photon emission computed tomography (SPECT), have been primarily investigated as methods for the early, preclinical detection of dementia. These imaging techniques show considerable promise as methods to detect the early brain changes that occur before the clear clinical expression of MCI and AD.71-75 In particular, MRI measurements of hippocampal atrophy appear to be sensitive enough to detect individuals with MCI at risk For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. Mayo Clin Proc, July 2002, Vol 77 for subsequent progression to AD.76,77 Ongoing longitudinal studies are evaluating this technology. In the future, this technology may be able to detect early hippocampal atrophy before the onset of clinically apparent dementia. PET scanning also shows promise for the early detection of metabolic changes in the temporal-parietal cortex that are associated with subsequent progression to AD.78 In addition, PET scanning may be useful for the early detection of plaques and tangles associated with AD.72 Recent work in mice suggests that radioligands and use of SPECT and PET may allow the detection of brain deposits of β-amyloid in living patients with AD. These radioligands may be useful to identify individuals at risk of developing AD and for monitoring disease progression and to show the effect of a therapeutic intervention.79 However, other than identifying individuals at risk for AD, imaging currently has no application in those experiencing normal cognitive aging, other than as investigational tools. In the future, imaging (particularly PET and functional MRI) might be useful for identifying cognitive strengths and weaknesses of the aging brain. Biomarkers.—As with brain imaging, the primary purpose of current research regarding the development of biomarkers is targeted for early detection of individuals at high risk for AD who might benefit from intensive prevention programs. For example, low levels of β-amyloid and high levels of tau-related antigens in cerebrospinal fluid have been reported to correlate with AD.80-85 Blood levels of β-amyloid have also been correlated with AD in some studies.82 However, the potential role of biomarkers for the preclinical detection of sporadic AD remains undefined.86 At present, because the actual biological basis of normal cognitive aging remains unknown, there are no clinically valuable or relevant biomarkers that would be useful in the context of normal cognitive aging, and careful psychometric testing remains the most relevant and sensitive test for these purposes. Genetic Markers.—Although genetic factors are not currently potentially modifiable, they may play a role in risk for cognitive decline with aging. Although the apolipoprotein E4 (apoE4) genotype75,87 is associated with increased risk of dementia, there is no evidence that the apoE4 genotype is associated with an increased risk of cognitive decline with aging. Because not all persons with the apoE4 genotype develop dementia, apoE4 is probably a susceptibility factor that interacts with other factors (such as head trauma and cholesterol)88 to cause dementia.89-91 More recently, loci have been identified that are associated with extreme longevity in pedigrees of humans. Of note, individuals in these families appear to be protected from cognitive decline well into the 10th and 11th decades of life. A gene loci located on chromosome 4 associated Cognitive Vitality With Aging 685 with extreme longevity has been identified among centenarians with intact cognitive function.8 Ultimately, the identification of such protective genes could lead to new therapeutic targets to promote cognitive vitality in late life. Lifestyle Factors Promoting Brain Reserve: Lifelong Learning, Social Engagement, and Occupational Complexity.—Some studies92-95 have shown that low education and poor linguistic ability are correlated with cognitive decline in late life, although others have not found this association.96 Other studies93,97-99 have found a similar association of these factors with dementia in late life. Although education may be a marker of socioeconomic status, the association of education with cognitive decline and dementia appears to be independent of socioeconomic status. However, the association of low education with cognitive decline may also be related to selection bias in studies. Clearly, more research needs to be done, and prospective trials will likely be almost impossible to design and conduct. Social disengagement is an independent risk factor for cognitive decline among cognitively intact older persons.100 Berkman101 suggests that social engagement most likely challenges individuals to communicate and participate in exchanges that stimulate cognitive capacities. Other studies102-104 have suggested that individuals who have rich and satisfying social engagement patterns and who engage in continuing complex nonoccupational activities may be protected against dementia in late life. These data suggest that maintenance of social engagement and avoidance of social isolation may be important in maintaining cognitive vitality in old age. Considerable animal data indicate that environmental enrichment and stimulation increase capillary formation, synaptogenesis, and neurogenesis, even in older animals.18,19,23,25-27,29 Complex intellectual work increases the cognitive functioning of older workers.105 Work may also increase social interactions and a sense of self-efficacy, both of which may be important to maintenance of cognitive vitality.1 These findings may have important implications for the structure of retirement in old age and support the common wisdom that volunteerism and continued participation in the workforce may play a role in maintaining cognitive reserve and vitality in aging. These animal and human data suggest that lifelong learning and maintenance of occupational and social engagement may contribute to cognitive vitality in late life perhaps by promoting biological “cognitive reserve” through increased synaptic complexity and neurogenesis. However, definitive research studies, such as prospective randomized clinical trials, to support this possibility have not been performed. For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. 686 Cognitive Vitality With Aging Cognitive Training.—Studies13-15,106-111 have shown that training can improve various cognitive functions in older adults, including reasoning, memory storage and retrieval, visual perception, attention, and skill coordination. Indeed, a small but growing body of evidence suggests that skills learned during training can be transferred to similar tasks. However, training is often specific to the skills trained and learned (eg, training for memory enhancement does not transfer to tasks that rely on the rapid scanning of the environment). Therefore, training interventions need to be tailored to the cognitive problems exhibited by the individual, generally determined by neuropsychometrics testing. The effect of training on prevention of cognitive decline is an area of research interest.2 Although older adults with mild cognitive deficits can be trained to improve certain cognitive functions, there is a paucity of such resources and programs in clinical practice, and the effectiveness of existing “mental exercise” programs has not been shown. Physical Exercise.—Animal models clearly show a beneficial effect of physical exercise on cognitive function.29 This effect may be mediated, in part, through increased levels of brain-derived neurotrophic factor (BDNF),112,113 a neurotrophin involved with learning, longterm potentiation, cell health and survival, and protection from injury.114 Although several studies115-119 show improvement in cognitive function with physical exercise or better cognitive function in older persons who exercise, some do not.120,121 These discrepancies among studies may be related to differences in the types of exercise promoted (aerobic, anaerobic, strenuous) and in the general health of the participants at baseline.122 Determining direct beneficial cognitive effects of exercise from its effects on mood and other factors such as stress is difficult. In addition to these neurobiologic mechanisms, physical exercise also ameliorates vascular risk factors and medical comorbidities that contribute to cognitive decline.21 Although more human research is clearly needed in this area, these new data support the notion that engaging in physical exercise, including enjoyable leisure-time activities, can contribute to maintaining cognitive vitality and preventing cognitive decline in late life, either directly or through the avoidance of medical comorbidities such as vascular disease. Stress Reduction.—Animal models and some human studies123 show that chronic stress results in hippocampal atrophy through a glucocorticoid-mediated mechanism. Studies124-126 in humans suggest that it is how stress is perceived that is critical and that it is the sense of being overwhelmed by stress that influences brain structures and may result in associated memory defects. Acute stress is also associated with impaired cognitive functioning,127 especially in older adults. Posttraumatic stress disorder is a Mayo Clin Proc, July 2002, Vol 77 good example of the short- and long-term effects of acute stress on the human brain.128 The long-term effects of chronic stress on cognitive function may result in decreased cognitive reserve, resulting from neurotoxicity, neuroendocrine changes, or other factors. These data indicate that stress contributes to cognitive decline. Cognitively frail, elderly individuals with decreased brain reserve may be particularly at risk. Clinical strategies for stress reduction may include activities that have other health benefits (eg, exercise). Training in stress reduction, including adaptive (as opposed to maladaptive) methods for responding to stress, may be useful as a means to promote cognitive vitality for selected individuals. Clinical studies are needed to show that stress reduction improves cognitive function in elderly individuals. Sleep.—Cognitive vitality may be compromised substantially by sleep disorders, and older persons are especially susceptible to this effect. Biological alterations in sleep patterns occur with age.129 As a result, older persons often experience sleep fractionation and other changes. Sleep fractionation may adversely affect cognitive function and is associated with poor memory and learning.130 In addition, older individuals are at increased risk for sleep apnea and hypopnea and for the adverse cognitive effects of sedatives and hypnotics, which are frequently prescribed to treat sleep disorders in older persons. Older patients complaining of cognitive impairment should be questioned about their sleep patterns. Strategies to promote sleep hygiene and avoidance of daytime napping are often effective in improving sleep, whereas some older patients may require evaluation and treatment for sleep disorders. Nutrition.—Some studies131,132 suggest that caloric restriction early in life has a beneficial effect on cognition with aging, but other studies133 do not show such an association. Caloric restriction in older persons is not recommended because of the risk of malnutrition. Malnutrition can cause long-term cognitive impairment.134 Isolated vitamin deficiencies, particularly B12 deficiency, are associated with cognitive disorders (including dementia) in elderly individuals that may be attributed to “normal cognitive aging” but, in fact, represent a potentially reversible disorder.135 Antioxidants, such as vitamin E and vitamin C, may be important in protecting the brain from oxidant injury. Some studies136,137 suggest a protective effect of these antioxidants against cognitive decline. Other studies138-140 suggest an association of antioxidant intake with protection against the risk of dementia. However, there are no prospective randomized, controlled studies showing that antioxidants promote cognitive vitality or protect against dementia. Although several of these studies are ongoing, more research is needed to determine the benefits of dietary antioxidant For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. Mayo Clin Proc, July 2002, Vol 77 interventions in both short- and long-term clinical trials.139 In older individuals taking antioxidants, clinicians should caution against excess vitamin intake as a means of promoting cognitive vitality. The use of a daily multivitamin is probably prudent, provided the recommendations of the Institute of Medicine’s Food and Nutrition Board regarding the levels of vitamins C and E for older persons are adhered to. M anaging M edical Comorbidities Accumulating data also show that many medical conditions, particularly those identified as risk factors for cardiovascular disease, are also risk factors for cognitive decline with aging and dementia in older individuals. Potentially reversible medical illnesses may also cause cognitive impairment in older individuals. These include adverse drug reactions; depression; metabolic, nutritional, and endocrine disturbances; tumors; normal-pressure hydrocephalus; trauma, including subarachnoid hemorrhage; alcoholism and other forms of substance abuse; sensory loss (vision and hearing problems); and infection.61 During the early stages of these disorders, memory disturbances and other cognitive dysfunction may be attributed to “cognitive aging”; eventually they may cause delirium or dementia. Clearly, many older individuals may have more than one of these medical comorbidities, which may increase their risk of cognitive impairment. Hypertension.—Data indicating a relationship between blood pressure and late-life cognitive function in the absence of dementia suggest that hypertension is a risk factor for impaired cognitive function in late life.141 Several studies142-144 have also identified hypertension as a risk for vascular dementia, presumably through the occurrence of both large and small strokes. Launer et al145 have shown that elevated levels of blood pressure in middle age increase the risk for late-life dementia in men never treated with antihypertensive medication. Small (lacunar) strokes causing cognitive impairment are often “strategic” strokes that are not clinically apparent and may not be associated with motor or sensory deficits. In counseling middle-aged and older persons regarding the importance of compliance with hypertension treatment, clinicians can inform them that control of hypertension is a means of reducing stroke and, therefore, the cognitive decline associated with cerebrovascular disease. In addition, effective management of hypertension may also prevent clinically nonapparent lacunar strokes and “strategic” strokes in localized regions that affect cognition alone without affecting motor function. Diabetes.—Diabetes at midlife is a risk for cognitive decline,146 and older women with diabetes have lower levels of cognitive function than do women without diabetes.147 Poor metabolic control (sustained hyperglycemia) in Cognitive Vitality With Aging 687 people with diabetes has been linked to reduced cognitive functioning.148 The relationship between diabetes and cognitive impairment is complicated. Glucose is needed for all types of cognition.149 However, the relationship between glucose and cognitive function follows an inverted U-shaped curve,150 with impaired cognitive function occurring as a result of both acute hyperglycemia and hypoglycemia.151,152 Therefore, the long-term health risks and benefits of tight glucose control on cognition must be carefully considered in older individuals. In addition, diabetes is associated with other comorbid conditions, such as hypertension, atherosclerosis, and altered insulin concentrations,153,154 that may also affect cognitive function through various mechanisms. These data indicate that diabetes is a risk factor for cognitive decline.147 The failure to control diabetes adequately may contribute to cognitive decline through several mechanisms. More research is needed to determine the risks of tight glucose control on cognitive function. More studies of treatments for diabetes need to include their impact on cognitive outcomes in older persons. Hyperlipidemia and Atherosclerosis.—Hyperlipidemia has been associated with cerebral atrophy.31 Atherosclerosis at middle age increases the prevalence of cerebral white matter lesions in late life.155 In addition, a moderate association exists between carotid atherosclerosis and poor cognitive function in men aged 59 to 71 years.156 Hyperlipidemia has also been identified as a risk factor for dementia.157 Recent data in animal models indicate that hyperlipidemia increases β-amyloid deposition in the brain and that cholesterol-lowering treatment reduces amyloid accumulation,158,159 one of the hallmarks of AD.160 In a population-based study,161 all markers of atherosclerosis were associated with both AD and vascular dementia. These recent data suggest that cholesterol and atherosclerosis are risk factors for cognitive decline due to dementia and indicate that lowering cholesterol may prevent cognitive decline. Several studies currently under way are investigating the effects of lipid-lowering agents (3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors) in AD (www.aging-institute.org/gs18.htm). However, at present, there are no data that prospectively show that lowering cholesterol prevents cognitive decline in normally aging individuals. Depression.—Persons who have a high sense of selfefficacy are more likely to maintain cognitive function over time.1,116 Depression, which is common in older persons, clearly has important deleterious effects on cognitive function162 and is the most common cause of reversible cognitive impairment and dementia in older individuals. Clinicians need to have a high index of suspicion for depression in older persons and must be particularly aware of the For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. 688 Cognitive Vitality With Aging effects of depression on cognitive function. In individuals complaining of cognitive dysfunction, depression should be considered as a possible reversible and treatable cause. Polypharmacy.—Many older people take medications that may impair cognitive function. Multiple medications have adverse central nervous system effects for which older persons with decreased cognitive reserve are especially at risk.163 Adverse drug reactions are a common cause of reversible cognitive decline in elderly patients. A careful medication review can eliminate medications that may adversely affect cognitive function. Several classes of medications cause cognitive adverse effects more commonly than others, such as anxiolytics, hypnotic-sedative agents, antipsychotics, antihistamines, and anticholinergics. Sensory Impairments.—Visual and auditory deficits are common in older persons. Sensory impairments can be a cause of isolation, loss of mental stimulation, and even depression. Common treatable causes of sensory impairments, such as glaucoma, cataracts, and impacted cerumen, should be treated with a view to their importance for maintaining cognitive function, particularly in frail, older persons. By encouraging the use of technological aids, cognitive function in older persons can be optimized through improved ability to sense environmental information and more effectively interact with the environment.164 Head Trauma.—Head trauma is an important source of brain damage that often goes unrecognized.165 Repeated low-level head trauma may also contribute to cognitive decline in apparently normal aging. Chronic head trauma in professional soccer players has been associated with impaired performance in memory, planning, and visuoperceptual tasks compared with a control group of noncontact sport athletes.166 Cognitive performance of professional soccer players was inversely related to the number of concussions incurred and the frequency of “heading” the ball while playing soccer. Dementia pugilistica from boxing is another example of the impact of chronic head trauma on cognitive function. An early case-control study167 found head injury to be a significant risk factor for AD, although a recent study168 did not corroborate these findings. Individuals with the apoE4 genotype may be at greater risk for cognitive decline after head trauma.88 Older persons who fall are at risk for subarachnoid hemorrhage that may cause reversible cognitive decline. Substance Use and Abuse: Smoking, Alcohol, and Illicit Drugs.—Nicotine may have a beneficial effect on cognition by enhancing attention.169 Nicotinic agonists remain an active area of research in drug discovery and drug development as cognitive enhancers.170,171 We are aware of no studies on the relationship between smoking and cognitive decline associated with normal aging or of studies of the effect of smoking on cognition in normally aging indi- Mayo Clin Proc, July 2002, Vol 77 viduals. One case-control study172 found an inverse relationship between smoking and AD, but later studies103,168,173 found that smoking does not positively affect the onset or severity of AD. Smoking is associated with increased vascular disease, particularly stroke, which may cause vascular dementia.174 Clearly, smoking should not be recommended because of potential nicotine effect on cognition in elderly individuals. Given the relationship of smoking with pulmonary and vascular comorbidities, particularly stroke, smoking may contribute to cognitive decline in older persons, but prospective data to demonstrate this are lacking. The Baltimore Epidemiologic Catchment Area survey of the National Institute of Mental Health showed that alcoholism is highly prevalent among people older than 65 years.175 In mice, alcohol abuse has been shown to cause brain deficits and reduced cognitive performance.176 However, investigators have shown an inverted U- or J-shaped relationship between alcohol consumption and cognitive performance that suggests that very moderate alcohol consumption might positively affect cognitive function, perhaps mediated by a favorable effect on vascular comorbidities.177 However, the effect may vary from person to person. In non–apoE4 carriers, moderate drinking was found to protect against cognitive decline, but apoE4 carriers who drank moderately experienced an increased risk.178 Excessive, long-term alcohol consumption is associated with dementia.179 Despite some health benefit claims for very moderate alcohol consumption, we believe the cognitive tolerance of older individuals to alcohol is low, and the danger of alcohol abuse is high. In older individuals with decreased cognitive reserve, even very moderate long-term alcohol consumption may impair cognition. Older individuals complaining of memory loss and cognitive decline should be queried about their alcohol consumption and a trial of abstinence recommended if appropriate in an attempt to regain optimal cognitive function. Contrary to popular belief, substance abuse with illicit drugs occurs in elderly individuals and can contribute to cognitive decline. Long-term marijuana abuse has been associated with subtle impairment of memory, attention, and information processing,180-183 although the degree of cognitive impairment is less than that seen with long-term alcohol abuse.180,181 The psychoactive drug 3,4-methylenedioxymethamphetamine (ecstasy) has also been associated with memory impairment.184 Impairment of cognitive function has not been as clearly shown with other hallucinogens such as lysergic acid diethylamide.184,185 Persons who consume stimulants such as cocaine or crack-cocaine experience pronounced brain pathologic conditions and cognitive impairment.186,187 Additional research is needed to investi- For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. Mayo Clin Proc, July 2002, Vol 77 gate the long-term effects of drug use on cognitive vitality in later life, particularly because many baby boomers who may have experimented with drugs in the 1960s remain intermittent or continuous users of marijuana and other drugs and are now entering their later years. PHARM ACEUTICAL APPROACHES Although most pharmaceutical research to date has focused on the development of drugs to prevent or treat dementia, interest is growing in the development of pharmacologic agents for cognitive enhancement in older persons experiencing normal cognitive aging.188 Some agents are being evaluated for AAMI and MCI.54 Drugs That Enhance Cognition The basal forebrain cholinergic system plays a key role in normal memory and learning.38 Currently, there are 4 FDA-approved cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galanthamine) for treatment of cognitive impairment in AD.189,190 These drugs have been shown to significantly improve or maintain cognitive function and daily function in about 60% of patients with mild to moderate AD.191-193 These cholinesterase inhibitors are currently being investigated for the treatment of cognitive impairment in patients with MCI and AAMI. Some preliminary data indicate that cholinesterase inhibitors may have value in the treatment of cognitive disorders associated with normal aging.194 There is no evidence that these medications play a role in the prevention of cognitive decline or AD. Muscarinic agonists195 target postsynaptic muscarinic M1 receptors and have been shown to improve cognitive function in animal models and humans.196 Although these agents have shown some improvement in cognitive function in patients with AD, agents in this class have been severely limited because of their adverse effects. Continued research on these agents may yet result in an approved drug.197 Another approach to address impaired cholinergic transmission is to target nicotinic cholinergic receptor ligands to allosterically potentiate submaximal neurotransmission.198 Glutamate modulators are also being evaluated as cognitive enhancers. Glutamate neurotransmission plays a role in cognition and is affected in AD.189 Memantine is a noncompetitive N-methyl-D-aspartate modulator that interacts with N-methyl-D-aspartate receptors. This agent is currently in phase 3 clinical trials for vascular dementia and severe AD. In a recent study,199 memantine improved function and reduced care dependency in AD patients with severe dementia. Ampakines, a novel class of agents, augment glutaminergic pathways and increase the production of BDNF and nerve growth factor (NGF) in brain areas Cognitive Vitality With Aging 689 involving memory, which also makes them potential disease-modifying agents. The ampakine CX516 enhances short-term memory in rats through a synaptic mechanism200,201 and is currently undergoing clinical evaluation for early AD and MCI. Cyclic adenosine monophosphate response element binding protein (CREB) has been linked with longterm memory formation in animals.202 Indeed, blocking CREB expression blocks long-term memory formation,203 whereas enhancing CREB expression potentiates longterm memory.204 These results suggest that agents that promote CREB expression may be promising for promoting long-term memory formation, even in normally aging individuals. Other products that are available as alternative medicines purport to enhance cognition in normally aging individuals. Huperzine A is a cholinergic agent available as a neutraceutical.205 One recent clinical trial suggested that gingko biloba may be of benefit in patients with AD.206 Phosphatidylserine has also been investigated as a treatment for AAMI with some benefit in clinical trials.207 Several other strategies for improving cognition in patients with AAMI have also been investigated.52 Cholinesterase inhibitors, muscarinic agonists, nicotinic agonists, glutamate modulators, CREB activators, and alternative medicines are an exciting new group of therapeutics that may be useful in the future for the treatment of cognitive decline in individuals experiencing normal cognitive aging. However, these agents require further study for their use in normal aging and are either not available or not indicated for healthy individuals at this time. Protective Agents Neurotrophins.—Because various neuronal insults occur with normal aging, promoting the survival of neurons could be useful in preventing or treating normal cognitive aging. Neurotrophins such as BDNF and NGF are protein growth factors that control the survival, growth, or differentiation of neurons and other cells derived from neuroectoderm. Modulation of neutrophin activity may be approached by targeting local neurotrophin synthesis, neurotrophin receptors, or signal transduction pathways associated with neurotrophin activity.208 The purine derivative AIT-082 promotes NGF-induced neurite extension in cell culture by activating transcription of neurotrophic factors in regions of the brain associated with learning and memory.209 AIT-082 has also been shown to improve working memory in mice.210 This agent is currently in phase 2 clinical trials for AD. A second agent, CEP-1347, is a small molecule that rescues neurons from apoptosis. CEP-1347 has been shown to promote motor neuron survival.211 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. 690 Cognitive Vitality With Aging Anti-inflammatory Agents.—There is no evidence that inflammation plays a role in normal cognitive aging. However, inflammation is recognized as an important component of the neuropathology of AD. Several epidemiologic studies212 have shown that patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) have a lower incidence of AD. Indeed, patients taking NSAIDs have only about a third of the activated microglia seen in other patients with senile plaques.37 In animal models using transgenic mice, amyloid deposition is suppressed by NSAIDs.213 A pharmacologic rationale exists for the use of aspirin to prevent cognitive impairment because aspirin may play a role in preventing strokes and, therefore, vascular dementia.214 However, only limited data are available on the use of aspirin to prevent cognitive decline.214,215 Studies testing the value of NSAIDs in the prevention of AD are currently in progress. A recent trial of the corticosteroid prednisone failed to show any effect in slowing the rate of progression of existing AD.216 At this time, anti-inflammatories should not be taken as a means to prevent cognitive aging or dementia. Antioxidants.—Oxidative stress is a rational target for slowing cognitive aging. However, to our knowledge, no studies of antioxidants in normal cognitive aging have been performed. One study showed that vitamin E in high doses (presumably required to achieve therapeutic levels within the brain) and selegiline, a monoamine oxidase inhibitor, both delayed time to institutionalization in patients with moderate AD.217 Newer, more potent central nervous system–specific antioxidants are currently being investigated.218,219 Hormones.—Decreased estrogen levels after menopause have been associated with the cognitive decline that occurs in older women. Estrogen has both neurotrophic and neuroprotective effects.220 Animal studies221 show a clear benefit of estrogen or selective estrogen receptor modulators on cognitive function. Estrogen stimulates formation of neurons in the dentate gyrus of the rat.28 Some cross-sectional and longitudinal studies222-225 have shown that use of oral estrogen replacement therapy may protect against age-related decline in cognitive function and dementia in older women. The Women’s Health Initiative Memory Study59 is investigating the effects of estrogen on the prevention of dementia. Estrogen is also being considered for treatment of MCI54 because it has other health benefits for the younger cohort of the aged population. Estrogen may improve subclinical cognitive changes in recently postmenopausal women.226 A recent trial failed to show efficacy of estrogen therapy for older women with existing AD.227 Use of estrogen replacement therapy should be considered by the clinician in the context of overall patient risks and benefits. No recommendation can be Mayo Clin Proc, July 2002, Vol 77 made at this time on using estrogen to prevent or treat cognitive decline. Testosterone has been suggested to have some benefit in improving cognitive function in men. Men who are hypogonadal may have cognitive and emotional changes that respond to testosterone replacement.228,229 Ongoing trials are evaluating the possible risks and benefits of testosterone therapy for older men with cognitive decline and dementia. Several agents that have been historically marketed for general health benefits are now being touted for cognitive vitality. Dehydroepiandrosterone is a natural precursor of estrogen and testosterone that has been advertised as a supplement to boost memory and to cure many ills of aging. Melatonin, another over-the-counter substance, may have a mild hypnotic effect.230 Melatonin levels may decrease with age, which may be associated with insomnia in some older people. Because lack of sleep is implicated in memory dysfunction, marketers are promoting melatonin to increase cognitive vitality. Human growth hormone levels also decline with age,231 and cognitive benefits of treatment with human growth hormone have been proposed. More research is needed to evaluate these hormonal agents1,232 because they are unproven therapies for preventing and treating cognitive decline. Until more clinical trial data are obtained, clinicians should not recommend these hormonal agents for the treatment of cognitive decline, particularly because these hormones may have serious adverse effects. CONCLUSION Cognitive vitality is essential to quality of life and survival in older persons. Research on cognitive aging indicates that cognitive decline is not an inevitable part of aging. Studies in animals have clearly shown considerable plasticity in the aging brain. Recent studies have identified several risk factors for cognitive decline that are modifiable, including lifestyle factors and medical comorbidities. These emerging scientific data have important implications for preventing and managing cognitive decline with aging. In addition, therapeutic strategies in development may contribute substantially to the practice of prevention and treatment of cognitive decline in older persons. Nevertheless, more research is clearly needed to advance our knowledge of the prevention and treatment of cognitive aging.2 Additional studies are needed to define the specific changes that occur with normal cognitive aging at the molecular, cellular, organ system, and individual levels. Research on biomarkers associated with cognitive impairment and advanced brain imaging techniques is also needed. Better animal models of cognitive aging must be For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. Mayo Clin Proc, July 2002, Vol 77 developed for descriptive studies and the design of proofof-concept prevention studies. Primary and secondary prevention trials for delaying cognitive aging in older persons, such as the ongoing cognitive aging studies within the Women’s Health Initiative funded by the National Institute on Aging, are clearly needed. Further research is also needed with regard to behavioral interventions (such as cognitive training and physical exercise) that may promote cognitive vitality in older individuals. Health in aging is a key issue in the longevity revolution. However, most efforts to date with regard to healthy aging have focused on medical and physical functional aspects of health. Unfortunately, the maintenance of cognitive health has not been a primary public policy issue. Perhaps, given the emerging data described herein, policy initiatives can now begin to advance the goal of achieving and maintaining cognitive vitality. Recent research on the effect of lifestyle factors and medical comorbidities on cognitive vitality could become the basis for populationbased programs to increase awareness among the general population and among clinicians about the real potential to achieve cognitive vitality in old age. In the future, with continuing research and better clinical care, we may expect that, for an increasing percentage of aging individuals, it is possible to set the goal that cognitive function might change little, if at all, from its level in middle age. Cognitive vitality is crucial to optimal aging. This has been known for thousands of years. In the words of Marcus Tullius Cicero (106-43 BCE), “To live is to think.” Although we still have much to learn, data are now beginning to form the scientific basis for achieving and maintaining cognitive vitality in late life through primary and secondary prevention in clinical practice. We thank Dennis Evans, MD, Neil Buckholz, PhD, and Marcelle Morrison-Bogorad, PhD, for their participation and contributions to this work. We are also grateful to Tonya Lee, Nora O’Brien, MA, and Sue Reynolds-Foley, MHA, for their invaluable help. REFERENCES 1. Rowe JW, Kahn RL. Successful Aging. New York, NY: Pantheon Books; 1998. 2. Committee on Future Directions for Cognitive Research on Aging; Stern PC, Carstensen LL, eds. The Aging Mind: Opportunities in Cognitive Research. Washington, DC: National Academy Press; 2000. 3. Bosworth HB, Schaie KW. Survival effects in cognitive function, cognitive style, and sociodemographic variables in the Seattle Longitudinal Study. Exp Aging Res. 1999;25:121-139. 4. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome [published correction appears in Arch Neurol. 1999;56:760]. Arch Neurol. 1999;56:303-308. 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