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Late Life Cognitive Disorders☆
Late Life Cognitive Disorders☆ LD Ravdin, Weill Medical College of Cornell University, New York, NY, USA ã 2014 Elsevier Inc. All rights reserved.
Introduction Patterns of Age-Related Cognitive Decline and Cognitive Disorders Significant Loss of Mental Faculties Is Not a Normal Part of the Aging Process Mild Cognitive Impairment Is a Risk Factor for Dementia AD Is the Most Common Form of Dementia Mixed Dementia (Primary Dementia Plus Vascular Disease) Is Likely Underdiagnosed Cognitive Disorders Can Present Initially as Behavior or Personality Change Dementia Can Occur in Conjunction with Movement Disorders Not All Cognitive Disorders Are Progressive or Irreversible Differentiating Normal Cognitive Changes from Disease-Associated Impairment Neuropsychology: The Study of Brain Behavior Relationships Cognitive Disorders Can Be Differentiated Based on Neuropsychological Profiles Preservation of Cognitive Function with Aging References
1 1 2 2 2 3 4 4 4 5 5 5 5 6
Introduction As we age, changes in the physical aspects of our bodies have corresponding changes in function. Transformation in physical stature as a result of aging may be accompanied by reduced flexibility or decreased motor speed, and although it is not a welcome change, it is one with an observable correlate that is often understood or expected. In contrast, changes in cognition are not associated with any directly observable physical alteration, and as a result, they can be unexpected or a source of distress. However, there are in fact structural changes that occur in the brain as we age. These changes over time result from loss of neurons that occurs throughout the life span, resulting in decreased brain weight and volume. This is influenced in part by genetics, but is also affected by the environment and lifestyle factors, such as nutritional status, alcohol consumption, tobacco usage, level of education, and history of trauma. These lifestyle factors may be associated with one’s vulnerability to developing cognitive disorders with aging. For example, high levels of education have been associated with cognitive reserve, a concept that supposes that an individual’s education and other life experiences create a supply of skills or a knowledge base that can be called upon in situations when cognitive functioning is challenged (i.e., following neuronal loss from injury or disease). In theory, individuals with greater cognitive reserve (e.g., better educated) may be able to sustain greater cerebral insult before cognition becomes noticeably compromised. On the contrary, factors such as cerebral insult sustained in one’s lifetime (traumatic head injury) may increase risk for development of cognitive disorders in late life. Perhaps one of the most striking examples of this comes from the literature on professional boxers who, as a result of their occupation, sustain repeated blows to the head. Boxers with greater exposure to the sport have been found to be at increased risk for late life cognitive decline. More common everyday examples include increased vulnerability associated with the deleterious effects of a lifetime of chronic alcohol consumption, tobacco use, or prolonged nutritional deficiencies.
Patterns of Age-Related Cognitive Decline and Cognitive Disorders It is difficult to gauge whether the changes one experiences in thinking abilities can be attributable to normal aging, or if there is an issue of greater concern. Normal age-related changes in cognition are not disabling, and generally present as more of a nuisance than a real problem. They do not interfere with an individual’s ability to carry on conversations, manage finances, and coordinate other basic everyday activities. Differentiating normal age-related changes in cognition from disease-associated impairment can be a challenge, even for health-care practitioners. Not all aspects of thinking abilities decline with age. Studies show that over-learned verbal information, such as vocabulary, general fund of knowledge, and reasoning, tend to stay relatively intact until advanced old age. The degree to which these abilities do decline is relatively small and typically imperceptible by others. In comparison, performance-based skills, such as novel problem solving or tests that involve speed of information processing, tend to show more significant age-related declines. Perhaps the most frequent cognitive complaint of older adults is decreased memory, especially with advanced aging. Common complaints include entering a room and forgetting what you went in there for, forgetting names, and misplacing basic everyday ☆
Change History: August 2014: LD Ravdin has updated abstract and the section on Mild Cognitive Impairment Is a Risk Factor for Dementia.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.03086-5
1
2
Late Life Cognitive Disorders
Table 1
Common factors associated with changes in cognition
Lifestyle changes (retirement, residential move) Death of spouse, relatives, friends Diminution of social network Sleep disturbance Depression Chronic pain Sensory changes (i.e., reduced vision or hearing) Medication side effects
objects such as glasses or keys. Many have referred to this in jest as ‘senior moments,’ given their increased frequency in older adults. These types of forgetting are similar to difficulties encountered in the early stage of a cognitive disorder, yet they differ in terms of frequency and severity. Although forgetting where you put your car key can be distressing, it is something that may be regarded as a normal memory failure or result of inattention. However, forgetting that you need the key to start the car, or confusion about how to use it, would be a better indicator of an issue that warrants medical attention. Cognitive complaints can often signify other issues of clinical concern. Table 1 shows common conditions that may initially present with complaints of cognitive difficulties. It has been said that if you think you have Alzheimer’s disease (AD), you probably don’t. The reasoning here is that those with disease-associated impairments in cognition are often not the ones who complain about it most; it is typically family members that are more concerned. Individuals with early dementia may be aware of a change in cognition but tend to minimize the impact on their everyday functioning. Lack of complaint should not be erroneously assumed to be indicative of a lack of impairment.
Significant Loss of Mental Faculties Is Not a Normal Part of the Aging Process Years ago, it was generally accepted that losing one’s mental faculties was a normal part of the aging process referred to as senility. Many of those individuals previously identified as senile probably had what is now recognized as AD or some other form of dementia. The term senility has fallen out of favor because its use implies an unknown etiology, and as a result, no specified treatment or defined prognosis. Instead, the term dementia is used as a way to describe impairment in cognition, usually in the domain of memory plus some other aspect of cognition, that interferes with an individual’s ability to function independently. There have been major advances in the field of cognitive disorders in the past decade. Most notably, now there are treatment options for dementia, and although they were originally thought to simply delay disease progression, more recent evidence suggests that these agents may in fact be disease modifiers. In recent years, increasing efforts have focused on diagnosing dementia in its earliest stages, since treatment at the first indication of cognitive compromise may prove to be the most beneficial.
Mild Cognitive Impairment Is a Risk Factor for Dementia The term mild cognitive impairment (MCI) has been used to describe cognitive decline greater than expected as compared to age-matched peers, yet not at a level consistent with a dementing disorder. In its original conception, the term implied mild memory changes (now referred to as amnestic MCI), but the concept has evolved to include difficulties in other cognitive domains (nonamnestic MCI) as well as mild changes in more than one cognitive domain (MCI-multidomain). MCI reflects cognitive difficulties in the context of otherwise normal functioning (no interruption in activities of daily living). Individuals with MCI can be viewed as being in a transitional state between normal age-related decline and dementia, yet they may not necessarily progress to a dementing condition. Estimates vary, but numbers are as high as suggesting up to 40% of patients with MCI develop dementing conditions within three years of diagnosis. Figure 1 shows the annual rates of conversion from MCI to dementia over a 48-month period. The literature suggests that those with amnestic MCI are most likely to go on and develop AD at a rate of 15–25% per year. Those with MCI multidomain and nonamnestic MCI may progress to Alzheimer’s or some other form of dementia (e.g., frontotemporal dementia, vascular dementia, Lewy body dementia) or other conditions associated with cognitive compromise. More recently, researchers have used the term early MCI to describe a group of individuals who function at 1 standard deviation below the mean for their age group. Presumably, this is a precursor to MCI, which as been defined as 1.5 standard deviations below the mean on formal cognitive testing.
AD Is the Most Common Form of Dementia One hundred years ago, there was not as much concern about late life dementing disorders, mainly because people were not living long enough to get them. AD is an age-related disorder, and as a result the incidence has dramatically increased over the years as the
Late Life Cognitive Disorders
MCI
3
Alzheimer disease
100
MCI, %
80 60 40 20 0 Initial examination
12
24 mo
36
48
Figure 1 Annual rates of conversion from mild cognitive impairment (MCI) to dementia over 48 months. Reproduced from Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, and Kokmen E (1999) Mild cognitive impairment: Clinical characteristics and outcome. Archives of Neurology 56(3): 303–308. Copyright © (1999) American Medical Association. All rights reserved. Table 2
Common forms of dementia
Alzheimer’s disease Vascular dementia (also referred to as multi-infarct dementia, Binswanger’s disease) Primary progressive aphasia Dementia with Lewy bodies Corticobasal degeneration Posterior cortical atrophy Infectious diseases (HIV dementia, syphilis, Creutzfeldt-Jakob disease) Structural abnormalities (hydrocephalus, tumors) Toxic substances (alcohol, exposure to heavy metals)
population throughout the world is living longer. Numbers of affected individuals will differ across countries as a function of life expectancy. World-wide estimates suggest over 25 million people have dementia, and this estimate is expected to double every 20 years. These staggering projections are likely the result of numerous factors, including increased life expectancies, greater awareness, as well as the availability of treatments that are delaying the disease process and possibly extending the lives of affected individuals. AD is the most common form of dementia. The neuropathology of senile plaques and neurofibrillary tangles that are characteristic of the disease are also found to a much lesser degree in the brains of healthy older adults. Aside from age, other hypothesized risk factors for development of AD include female gender, history of head trauma, and low levels of education. There are rare forms of AD that are associated with genetic risk factors, but the most common form of the disease is likely a result of a combination of genes and the environment. Genetic risk associated with the most common form of the disorder has been associated with the presence of a particular type of gene that makes a form of a protein present in all individuals. Presence of a specific form of this gene (Apolipoprotein-e4 allele; APOE-e4) has been associated with increased chance of developing late-onset sporadic AD. APOE is a susceptibility factor for development of AD; its presence does not determine who will get the disease. Given its low sensitivity and specificity as well as equivocal predictive value for an individual patient, testing for APOE (APOE genotyping) is not recommended for clinical purposes. In AD, the primary symptoms of memory decline tend to come on slowly. It often takes a year or longer before these symptoms come to medical attention. Symptoms of forgetfulness and confusion are often observed by family members, since the affected individual typically has diminished insight, and even if they admit to memory problems, they tend to minimize the impact on their everyday life. In its most common manifestation, AD is slowly progressive, and cognitive decline may occur over a period of 8 to 10 years or longer before death. AD is just one type of dementia. Table 2 lists common forms of dementia. In the advanced stages, all progressive dementias present with very similar clinical manifestations, and it is difficult to distinguish among them.
Mixed Dementia (Primary Dementia Plus Vascular Disease) Is Likely Underdiagnosed Perhaps the second most common form of dementia is that attributable to vascular disease. Aging of the cerebrovasculature (blood vessels in the brain) can result in cognitive difficulties ranging from mild deficits to a full-blown dementia (vascular dementia, also referred to as multi-infarct dementia or Binswanger’s disease). These changes frequently occur in conjunction with Alzheimer’s-like plaques and tangles, resulting in a mixed dementia (i.e., neuropathology of both AD and vascular dementia). Given the prevalence of age-related changes in the cerbrovasculature, and the fact that vascular disease risk factors have also been found to be associated
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Late Life Cognitive Disorders
with increased risk for AD, mixed dementias likely occur more frequently than they are recognized. In fact, some investigators have reasonably argued that mixed dementias may be the most common cause of late-life cognitive disorders. Although initially used to describe AD symptoms in the presence of cognitive impairment attributable to vascular disease, the term mixed dementia is also used to represent the combination of other primary dementing disorders and evidence of cerebrovascular compromise.
Cognitive Disorders Can Present Initially as Behavior or Personality Change Not all cognitive disorders will present with complaints about memory or thinking as the primary symptom. Frontal systems dementias, such as Pick’s disease or frontotemporal dementia, may initially present as changes in behavior or personality. In some cases, there may be an exacerbation of premorbid personality characteristics, or behavior may be uncharacteristic of the individual. Cognition may be affected, but deficits may be secondary to behavioral disturbances such as impulsivity, poor judgment, reduced initiative and planning, and impaired ability to organize. The individual is unable to engage and interact effectively with the environment, resulting in difficulties learning and conducting everyday activities independently. For example, someone with a frontal systems dementia may be able to conduct each element of food preparation in isolation, but because they are unable to plan, organize, and sequence the events appropriately, they cannot prepare a meal. Presence of these types of symptoms can help in determining the etiology of the cognitive disturbance. Visual hallucinations and misidentification syndromes (e.g., Capgras syndrome, the belief that loved ones have been replaced by imposters) in the early stages of a dementia may be of diagnostic significance. For example, these behaviors are more likely to be seen in the early stages of dementia with Lewy bodies (DLB) than some of the other forms of dementia. Patients with DLB also present with confusion and cognitive difficulties not unlike that observed in AD, although their symptoms may fluctuate throughout the day between periods of lucidness and confusion. In addition, patients with DLB can be differentiated from AD by the presence of motor symptoms similar to those observed in Parkinson’s disease.
Dementia Can Occur in Conjunction with Movement Disorders Cognitive disturbances associated with movement disorders can progress to a global dementia. In movement disorders such as Parkinson’s disease, Huntington’s disease, corticobasal degeneration, and progressive supranuclear palsy, cognitive difficulties can occur in conjunction with or following initial symptoms of a disturbance in motor systems. In keeping with slowing of motor functions (bradykinesia) often found in these disorders, the cognitive disturbance typically reflects slowing of thought processes referred to as bradyphrenia. Performance on timed tasks is often particularly affected, as are skills generally referred to executive functions, which require organization and planning, rapid generation of responses, and task persistence. Cognitive deficits can be relatively mild but can advance to a full-blown dementia as the disease progresses, such that the cognitive disturbance may be indistinguishable from an Alzheimer’s-type dementia in the advanced stages.
Not All Cognitive Disorders Are Progressive or Irreversible The dementing disorders described thus far have generally referred to progressive and irreversible disturbances in cognition, the majority of which have a slow, insidious onset. Those characteristics do not appropriately describe all late-life cognitive disorders. Perhaps the best example of an acute alteration in mental status that is also reversible is delirium, which can closely follow medical illness and present as a sudden change in thinking abilities, reduced alertness, and confusion. This transient deficit has a fluctuating course throughout the day, but eventually resolves shortly after the disturbance that provoked it is alleviated. Delirium can be differentiated from dementia by several factors relating to the onset, course, and presentation (see Table 3). Delirium does not Table 3
Differential diagnosis of delirium versus dementia based on presenting features
Feature
Delirium
Dementia
Onset Arousal
Acute onset Reduced consciousness (drowsy, semicomatose) Clouded attention Fluctuating symptoms throughout the day
Insidious onset Alert
Attention Symptom fluctuation Behavioral changes a
Agitation and aggression
Dementia with Lewy bodies can present with fluctuating cognitive symptoms.
Intact attention Insignificant daily fluctuationsa Agitation and aggression usually not present until moderate to advanced stages
Late Life Cognitive Disorders
5
necessarily negate a subsequent diagnosis of dementia, and all else being equal, those with even mild symptoms of dementia are at greater risk for developing delirium relative to cognitively intact individuals. There are several types of dementias generally referred to as reversible dementias (e.g., normal pressure hydrocephalus, depression, metabolic/endocrine disturbances), but it is important to note that cognitive decline associated with these conditions is not always completely reversible. For example, if unrecognized, untreated, or subject to significant delays in treatment, the cognitive disturbance in patients with normal pressure hydrocephalus can evolve into a dementing disorder indistinguishable from other dementias (e.g., AD). The dementia syndrome of depression is typically regarded as a reversible condition; however, late life depression may be a warning signaling the earliest stages of a dementing disorder. There is a substantial literature describing a relationship between depression and cerebrovascular disease, and depression has been regarded as a prodrome to dementia and a risk factor for development of cognitive disorders such as AD.
Differentiating Normal Cognitive Changes from Disease-Associated Impairment The process of distinguishing between different cognitive disorders for the purpose of diagnosis includes consideration of demographic and clinical factors such as age, family history, onset and course of symptoms, and presence of other signs of dysfunction (e.g., presence and symmetry of motor abnormalities). Factors such as an acute onset versus a slowly evolving disturbance in cognition can signal particular etiologies. Neuroimaging can be helpful in identifying tumors or vascular lesions, and although there are no specific neuroimaging signs associated with primary dementing disorders, imaging may identify greater than expected atrophy (brain cell loss) for one’s age. In some cases, it may be necessary to observe an individual over time to determine whether the disturbance is in fact progressive. The profile of cognitive functioning on neuropsychological measures (formal tests of cognitive abilities) can help inform diagnosis as well as treatment planning.
Neuropsychology: The Study of Brain Behavior Relationships The field of neuropsychology involves investigation of how developmental changes across the life span, diseases, and injury to the brain affect cognitive functioning. Clinical neuropsychology consists of administration of various types of tests of thinking abilities, and the resulting information is compared to age- and education-matched normative data and interpreted in the context of an individual’s demographic, medical, psychiatric, and social history. Many people are familiar with neuroimaging, structural assessment of the brain in the form of CT or MRI (magnetic resonance imaging), in which the structure of the brain is assessed at a given time point. Neuropsychology can be thought of as a functional assessment of the brain, putting the brain to work and measuring its functional abilities at a given point in time. In clinical practice, this information is used in conjunction with results of structural imaging, a physical exam, and a detailed medical history to explain cognitive and behavioral symptoms.
Cognitive Disorders Can Be Differentiated Based on Neuropsychological Profiles Differences in the profile of cognitive functioning on neuropsychological tests give clues to the etiology of the cognitive deficit. For example, the memory changes in AD differ from those associated with vascular dementia. AD is characterized by rapid forgetting of new information. Basic attention is typically intact in the early stages, and as a result, the AD patient may be able to demonstrate learning (albeit at a rate compromised relative to premorbid expectation). Despite learning of material, recall of this information after a delay is markedly impaired. The AD patient may not even remember being given the information to begin with. In comparison, individuals with vascular cognitive impairment tend to have significantly greater difficulty learning at the point of acquiring the new information, particularly when there is no inherent structure in the information to be remembered (e.g., lists of words as compared to story recall). Nevertheless, when questioned about the material after a delay period, these individuals tend to recall the information they initially learned. Certain cognitive disturbances that may be present in a variety of disorders may be the predominant presenting symptom distinguishing a particular type of dementia, such as marked aphasia in the patient with primary progressive aphasia, visuospatial deficits in patients with posterior cortical atrophy, or marked behavioral disturbances and social inappropriateness in patients with Pick’s disease.
Preservation of Cognitive Function with Aging The phrase ‘use it or lose it’ implies that engaging in challenging cerebral activity will stimulate the brain and help to maintain mental fitness, and failure to do so will have undesirable consequences. Research supports this notion, with studies showing that seniors who stay active, mentally as well as physically, perform better on tests of cognitive functioning. Further, people who engage in mentally stimulating behaviors throughout their life are believed to build cognitive reserve that may serve a protective role in preventing the development of late-life cognitive disorders. The literature suggests that other health and lifestyle factors may affect age-associated cognitive decline.
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Late Life Cognitive Disorders
Studies have shown that higher fish consumption (at least once per week) in North Americans and Europeans was associated with reduced incidence of AD. Other studies have shown that eating fruits and vegetables high in antioxidants helps to fight off free radicals, which are detrimental to brain function. Alcohol consumption has been said to have an aging effect on the brain. While many sources cite benefits of modest consumption (particularly red wine) for cardiovascular health, excessive abuse has been associated with increased brain atrophy (wasting away of brain tissue) and cognitive dysfunction. Smoking is associated with changes in the cerebrovasculature, affecting blood flow to the brain and other vital organs. Numerous clinical trials have been conducted to assess possible neuroprotective effects of prescription medications, herbal supplements, and hormones. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen have been investigated as potential agents to ward off cognitive decline based on the theory that brain inflammation plays a role in the development of late life cognitive disorders. It is unclear whether the preventative benefit observed in some studies with NSAIDs was due to other extrinsic factors, and their use is not recommended for preventing cognitive decline at this time. These agents should not be taken without a doctor’s advice, since their use can cause severe bleeding and other complications. Early studies on estrogen were promising in terms of a protective effect on cognitive decline; however, later studies yielded contradictory findings. Given equivocal findings and the risks associated with use, more research needs to be done on hormones and cognition. There is no one substance that will prevent dementia; other agents such as statins (used to control cholesterol) and herbal supplements (such as Ginkgo biloba) are regarded by some as neuroprotective, but the results of controlled experimental investigations in these types of agents have been regarded as equivocal due to methodological limitations (e.g., lack of statistical power) or inconsistent findings across studies. Ginkgo biloba is widely used throughout Europe for treatment of cognitive decline. Although a systematic review of Gingko biloba revealed a positive effect over placebo, specific recommendations for use in treating cognitive disorders are deferred awaiting further investigations. The GEM trial (Ginkgo Evaluation of Memory) is a large-scale (>3000 participants), double-blind, randomized controlled trial designed to investigate Ginkgo biloba in the prevention of dementia that completed recruitment in 2002 (DeKosky et al., 2006). When the results of this well-designed 5-year trial are published, they may shed some light on the effectiveness of Ginkgo biloba in preventing late-life cognitive decline. Sensory changes can mistakenly present as or exacerbate cognitive decline; failure to accurately hear what has been said or see clearly interferes with one’s ability to process and retain information. Correcting hearing and vision as needed may improve one’s ability to engage in the environment and acquire what is needed to process information efficiently. Systemic illness and medications used can also influence how well a person engages in the environment, having an indirect effect on cognitive abilities. Given the known effects of cerebrovascular disease on mental status as well as the association of vascular risk and changes with the development of late life cognitive disorders, Alzheimer’s Disease International researchers advocate public health policies that address reducing modifiable risk factors for cerebrovascular disease (elevated cholesterol, tobacco use, diabetes). These risk factors not only are associated with diseases that threaten mental functioning, but have in and of themselves been associated with cognitive decline. Sleep and mood disturbances also influence how well an individual processes information and can present with changes in cognitive function that may be alleviated once the primary disturbance is treated. Perhaps the best plan for dementia prevention is consonant with recommendations to prevent other diseases: maintain your best health by paying attention to lifestyle factors that influence your physical and mental status (e.g., diet, exercise, alcohol/tobacco consumption, stress). In general, those that fare best tend to be those with a healthy attitude toward aging. Keeping active, both physically and mentally, may serve a protective role against cognitive decline associated with aging.
References DeKosky ST, Fitzpatrick A, Ives DG, et al. (2006) The Ginkgo Evaluation of Memory (GEM) study: Design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemporary Clinical Trials 27(3): 238–253.
Further Reading Attix DK and Welsh-Bohmer KA (2006) Geriatric neuropsychology: Assessment and intervention. New York: The Guilford Press. Fillit HM, Butler RN, O’Connell AW, et al. (2002) Achieving and maintaining cognitive vitality with aging. Mayo Clinic Proceedings 77(7): 681–696. Gauthier S, Reisberg B, Zaudig M, et al. (2006) International psychogeriatric association expert conference on mild cognitive impairment. Lancet 367: 1262–1270. Hayden KM, Zandi PP, Lyketsos CG, et al. (2006) Vascular risk factors for incident alzheimer disease and vascular dementia: The cache county study. Alzheimer Disease and Associated Disorders 20(2): 93–100. McKeith IG, Dickson DW, and Lowe J (2005) Diagnosis and management of dementia with lewy bodies: Third report of the DLB consortium. Neurology 65(12): 1863–1872. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, and Kokmen E (1999) Mild cognitive impairment: Clinical characteristics and outcome. Archives of Neurology 56(3): 303–308. Petersen RC, Doody R, Kurz A, et al. (2001) Current concepts in mild cognitive impairment. Archives of Neurology 58: 1985–1992. Rockwood K (2002) Vascular cognitive impairment and vascular dementia. Journal of the Neurological Sciences 203: 23–27.
Relevant Websites http://www.alz.co.uk/
Alzheimer’s Disease International.
Late Life Cognitive Disorders
http://www.theaacn.org/links.html American Academy of Clinical Neuropsychology. http://www.the-ins.org/ International Neuropsychological Society. http://www.mayoclinic.com/ Mayo Clinic (for Mild Cognitive Impairment). http://www.ninds.nih.gov/ National Institutes of Health/National Institute of Neurological Disorders and Stroke. http://www.nia.nih.gov/ National Institutes of Health/National Institute on Aging. http://www.wpda.org/ World Parkinson’s Disease Association.
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Introduction Patterns of Age-Related Cognitive Decline and Cognitive Disorders Significant Loss of Mental Faculties Is Not a Normal Part of the Aging Process Mild Cognitive Impairment Is a Risk Factor for Dementia AD Is the Most Common Form of Dementia Mixed Dementia (Primary Dementia Plus Vascular Disease) Is Likely Underdiagnosed Cognitive Disorders Can Present Initially as Behavior or Personality Change Dementia Can Occur in Conjunction with Movement Disorders Not All Cognitive Disorders Are Progressive or Irreversible Differentiating Normal Cognitive Changes from Disease-Associated Impairment Neuropsychology: The Study of Brain Behavior Relationships Cognitive Disorders Can Be Differentiated Based on Neuropsychological Profiles Preservation of Cognitive Function with Aging References
1 1 2 2 2 3 4 4 4 5 5 5 5 6
Introduction As we age, changes in the physical aspects of our bodies have corresponding changes in function. Transformation in physical stature as a result of aging may be accompanied by reduced flexibility or decreased motor speed, and although it is not a welcome change, it is one with an observable correlate that is often understood or expected. In contrast, changes in cognition are not associated with any directly observable physical alteration, and as a result, they can be unexpected or a source of distress. However, there are in fact structural changes that occur in the brain as we age. These changes over time result from loss of neurons that occurs throughout the life span, resulting in decreased brain weight and volume. This is influenced in part by genetics, but is also affected by the environment and lifestyle factors, such as nutritional status, alcohol consumption, tobacco usage, level of education, and history of trauma. These lifestyle factors may be associated with one’s vulnerability to developing cognitive disorders with aging. For example, high levels of education have been associated with cognitive reserve, a concept that supposes that an individual’s education and other life experiences create a supply of skills or a knowledge base that can be called upon in situations when cognitive functioning is challenged (i.e., following neuronal loss from injury or disease). In theory, individuals with greater cognitive reserve (e.g., better educated) may be able to sustain greater cerebral insult before cognition becomes noticeably compromised. On the contrary, factors such as cerebral insult sustained in one’s lifetime (traumatic head injury) may increase risk for development of cognitive disorders in late life. Perhaps one of the most striking examples of this comes from the literature on professional boxers who, as a result of their occupation, sustain repeated blows to the head. Boxers with greater exposure to the sport have been found to be at increased risk for late life cognitive decline. More common everyday examples include increased vulnerability associated with the deleterious effects of a lifetime of chronic alcohol consumption, tobacco use, or prolonged nutritional deficiencies.
Patterns of Age-Related Cognitive Decline and Cognitive Disorders It is difficult to gauge whether the changes one experiences in thinking abilities can be attributable to normal aging, or if there is an issue of greater concern. Normal age-related changes in cognition are not disabling, and generally present as more of a nuisance than a real problem. They do not interfere with an individual’s ability to carry on conversations, manage finances, and coordinate other basic everyday activities. Differentiating normal age-related changes in cognition from disease-associated impairment can be a challenge, even for health-care practitioners. Not all aspects of thinking abilities decline with age. Studies show that over-learned verbal information, such as vocabulary, general fund of knowledge, and reasoning, tend to stay relatively intact until advanced old age. The degree to which these abilities do decline is relatively small and typically imperceptible by others. In comparison, performance-based skills, such as novel problem solving or tests that involve speed of information processing, tend to show more significant age-related declines. Perhaps the most frequent cognitive complaint of older adults is decreased memory, especially with advanced aging. Common complaints include entering a room and forgetting what you went in there for, forgetting names, and misplacing basic everyday ☆
Change History: August 2014: LD Ravdin has updated abstract and the section on Mild Cognitive Impairment Is a Risk Factor for Dementia.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.03086-5
1
2
Late Life Cognitive Disorders
Table 1
Common factors associated with changes in cognition
Lifestyle changes (retirement, residential move) Death of spouse, relatives, friends Diminution of social network Sleep disturbance Depression Chronic pain Sensory changes (i.e., reduced vision or hearing) Medication side effects
objects such as glasses or keys. Many have referred to this in jest as ‘senior moments,’ given their increased frequency in older adults. These types of forgetting are similar to difficulties encountered in the early stage of a cognitive disorder, yet they differ in terms of frequency and severity. Although forgetting where you put your car key can be distressing, it is something that may be regarded as a normal memory failure or result of inattention. However, forgetting that you need the key to start the car, or confusion about how to use it, would be a better indicator of an issue that warrants medical attention. Cognitive complaints can often signify other issues of clinical concern. Table 1 shows common conditions that may initially present with complaints of cognitive difficulties. It has been said that if you think you have Alzheimer’s disease (AD), you probably don’t. The reasoning here is that those with disease-associated impairments in cognition are often not the ones who complain about it most; it is typically family members that are more concerned. Individuals with early dementia may be aware of a change in cognition but tend to minimize the impact on their everyday functioning. Lack of complaint should not be erroneously assumed to be indicative of a lack of impairment.
Significant Loss of Mental Faculties Is Not a Normal Part of the Aging Process Years ago, it was generally accepted that losing one’s mental faculties was a normal part of the aging process referred to as senility. Many of those individuals previously identified as senile probably had what is now recognized as AD or some other form of dementia. The term senility has fallen out of favor because its use implies an unknown etiology, and as a result, no specified treatment or defined prognosis. Instead, the term dementia is used as a way to describe impairment in cognition, usually in the domain of memory plus some other aspect of cognition, that interferes with an individual’s ability to function independently. There have been major advances in the field of cognitive disorders in the past decade. Most notably, now there are treatment options for dementia, and although they were originally thought to simply delay disease progression, more recent evidence suggests that these agents may in fact be disease modifiers. In recent years, increasing efforts have focused on diagnosing dementia in its earliest stages, since treatment at the first indication of cognitive compromise may prove to be the most beneficial.
Mild Cognitive Impairment Is a Risk Factor for Dementia The term mild cognitive impairment (MCI) has been used to describe cognitive decline greater than expected as compared to age-matched peers, yet not at a level consistent with a dementing disorder. In its original conception, the term implied mild memory changes (now referred to as amnestic MCI), but the concept has evolved to include difficulties in other cognitive domains (nonamnestic MCI) as well as mild changes in more than one cognitive domain (MCI-multidomain). MCI reflects cognitive difficulties in the context of otherwise normal functioning (no interruption in activities of daily living). Individuals with MCI can be viewed as being in a transitional state between normal age-related decline and dementia, yet they may not necessarily progress to a dementing condition. Estimates vary, but numbers are as high as suggesting up to 40% of patients with MCI develop dementing conditions within three years of diagnosis. Figure 1 shows the annual rates of conversion from MCI to dementia over a 48-month period. The literature suggests that those with amnestic MCI are most likely to go on and develop AD at a rate of 15–25% per year. Those with MCI multidomain and nonamnestic MCI may progress to Alzheimer’s or some other form of dementia (e.g., frontotemporal dementia, vascular dementia, Lewy body dementia) or other conditions associated with cognitive compromise. More recently, researchers have used the term early MCI to describe a group of individuals who function at 1 standard deviation below the mean for their age group. Presumably, this is a precursor to MCI, which as been defined as 1.5 standard deviations below the mean on formal cognitive testing.
AD Is the Most Common Form of Dementia One hundred years ago, there was not as much concern about late life dementing disorders, mainly because people were not living long enough to get them. AD is an age-related disorder, and as a result the incidence has dramatically increased over the years as the
Late Life Cognitive Disorders
MCI
3
Alzheimer disease
100
MCI, %
80 60 40 20 0 Initial examination
12
24 mo
36
48
Figure 1 Annual rates of conversion from mild cognitive impairment (MCI) to dementia over 48 months. Reproduced from Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, and Kokmen E (1999) Mild cognitive impairment: Clinical characteristics and outcome. Archives of Neurology 56(3): 303–308. Copyright © (1999) American Medical Association. All rights reserved. Table 2
Common forms of dementia
Alzheimer’s disease Vascular dementia (also referred to as multi-infarct dementia, Binswanger’s disease) Primary progressive aphasia Dementia with Lewy bodies Corticobasal degeneration Posterior cortical atrophy Infectious diseases (HIV dementia, syphilis, Creutzfeldt-Jakob disease) Structural abnormalities (hydrocephalus, tumors) Toxic substances (alcohol, exposure to heavy metals)
population throughout the world is living longer. Numbers of affected individuals will differ across countries as a function of life expectancy. World-wide estimates suggest over 25 million people have dementia, and this estimate is expected to double every 20 years. These staggering projections are likely the result of numerous factors, including increased life expectancies, greater awareness, as well as the availability of treatments that are delaying the disease process and possibly extending the lives of affected individuals. AD is the most common form of dementia. The neuropathology of senile plaques and neurofibrillary tangles that are characteristic of the disease are also found to a much lesser degree in the brains of healthy older adults. Aside from age, other hypothesized risk factors for development of AD include female gender, history of head trauma, and low levels of education. There are rare forms of AD that are associated with genetic risk factors, but the most common form of the disease is likely a result of a combination of genes and the environment. Genetic risk associated with the most common form of the disorder has been associated with the presence of a particular type of gene that makes a form of a protein present in all individuals. Presence of a specific form of this gene (Apolipoprotein-e4 allele; APOE-e4) has been associated with increased chance of developing late-onset sporadic AD. APOE is a susceptibility factor for development of AD; its presence does not determine who will get the disease. Given its low sensitivity and specificity as well as equivocal predictive value for an individual patient, testing for APOE (APOE genotyping) is not recommended for clinical purposes. In AD, the primary symptoms of memory decline tend to come on slowly. It often takes a year or longer before these symptoms come to medical attention. Symptoms of forgetfulness and confusion are often observed by family members, since the affected individual typically has diminished insight, and even if they admit to memory problems, they tend to minimize the impact on their everyday life. In its most common manifestation, AD is slowly progressive, and cognitive decline may occur over a period of 8 to 10 years or longer before death. AD is just one type of dementia. Table 2 lists common forms of dementia. In the advanced stages, all progressive dementias present with very similar clinical manifestations, and it is difficult to distinguish among them.
Mixed Dementia (Primary Dementia Plus Vascular Disease) Is Likely Underdiagnosed Perhaps the second most common form of dementia is that attributable to vascular disease. Aging of the cerebrovasculature (blood vessels in the brain) can result in cognitive difficulties ranging from mild deficits to a full-blown dementia (vascular dementia, also referred to as multi-infarct dementia or Binswanger’s disease). These changes frequently occur in conjunction with Alzheimer’s-like plaques and tangles, resulting in a mixed dementia (i.e., neuropathology of both AD and vascular dementia). Given the prevalence of age-related changes in the cerbrovasculature, and the fact that vascular disease risk factors have also been found to be associated
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with increased risk for AD, mixed dementias likely occur more frequently than they are recognized. In fact, some investigators have reasonably argued that mixed dementias may be the most common cause of late-life cognitive disorders. Although initially used to describe AD symptoms in the presence of cognitive impairment attributable to vascular disease, the term mixed dementia is also used to represent the combination of other primary dementing disorders and evidence of cerebrovascular compromise.
Cognitive Disorders Can Present Initially as Behavior or Personality Change Not all cognitive disorders will present with complaints about memory or thinking as the primary symptom. Frontal systems dementias, such as Pick’s disease or frontotemporal dementia, may initially present as changes in behavior or personality. In some cases, there may be an exacerbation of premorbid personality characteristics, or behavior may be uncharacteristic of the individual. Cognition may be affected, but deficits may be secondary to behavioral disturbances such as impulsivity, poor judgment, reduced initiative and planning, and impaired ability to organize. The individual is unable to engage and interact effectively with the environment, resulting in difficulties learning and conducting everyday activities independently. For example, someone with a frontal systems dementia may be able to conduct each element of food preparation in isolation, but because they are unable to plan, organize, and sequence the events appropriately, they cannot prepare a meal. Presence of these types of symptoms can help in determining the etiology of the cognitive disturbance. Visual hallucinations and misidentification syndromes (e.g., Capgras syndrome, the belief that loved ones have been replaced by imposters) in the early stages of a dementia may be of diagnostic significance. For example, these behaviors are more likely to be seen in the early stages of dementia with Lewy bodies (DLB) than some of the other forms of dementia. Patients with DLB also present with confusion and cognitive difficulties not unlike that observed in AD, although their symptoms may fluctuate throughout the day between periods of lucidness and confusion. In addition, patients with DLB can be differentiated from AD by the presence of motor symptoms similar to those observed in Parkinson’s disease.
Dementia Can Occur in Conjunction with Movement Disorders Cognitive disturbances associated with movement disorders can progress to a global dementia. In movement disorders such as Parkinson’s disease, Huntington’s disease, corticobasal degeneration, and progressive supranuclear palsy, cognitive difficulties can occur in conjunction with or following initial symptoms of a disturbance in motor systems. In keeping with slowing of motor functions (bradykinesia) often found in these disorders, the cognitive disturbance typically reflects slowing of thought processes referred to as bradyphrenia. Performance on timed tasks is often particularly affected, as are skills generally referred to executive functions, which require organization and planning, rapid generation of responses, and task persistence. Cognitive deficits can be relatively mild but can advance to a full-blown dementia as the disease progresses, such that the cognitive disturbance may be indistinguishable from an Alzheimer’s-type dementia in the advanced stages.
Not All Cognitive Disorders Are Progressive or Irreversible The dementing disorders described thus far have generally referred to progressive and irreversible disturbances in cognition, the majority of which have a slow, insidious onset. Those characteristics do not appropriately describe all late-life cognitive disorders. Perhaps the best example of an acute alteration in mental status that is also reversible is delirium, which can closely follow medical illness and present as a sudden change in thinking abilities, reduced alertness, and confusion. This transient deficit has a fluctuating course throughout the day, but eventually resolves shortly after the disturbance that provoked it is alleviated. Delirium can be differentiated from dementia by several factors relating to the onset, course, and presentation (see Table 3). Delirium does not Table 3
Differential diagnosis of delirium versus dementia based on presenting features
Feature
Delirium
Dementia
Onset Arousal
Acute onset Reduced consciousness (drowsy, semicomatose) Clouded attention Fluctuating symptoms throughout the day
Insidious onset Alert
Attention Symptom fluctuation Behavioral changes a
Agitation and aggression
Dementia with Lewy bodies can present with fluctuating cognitive symptoms.
Intact attention Insignificant daily fluctuationsa Agitation and aggression usually not present until moderate to advanced stages
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necessarily negate a subsequent diagnosis of dementia, and all else being equal, those with even mild symptoms of dementia are at greater risk for developing delirium relative to cognitively intact individuals. There are several types of dementias generally referred to as reversible dementias (e.g., normal pressure hydrocephalus, depression, metabolic/endocrine disturbances), but it is important to note that cognitive decline associated with these conditions is not always completely reversible. For example, if unrecognized, untreated, or subject to significant delays in treatment, the cognitive disturbance in patients with normal pressure hydrocephalus can evolve into a dementing disorder indistinguishable from other dementias (e.g., AD). The dementia syndrome of depression is typically regarded as a reversible condition; however, late life depression may be a warning signaling the earliest stages of a dementing disorder. There is a substantial literature describing a relationship between depression and cerebrovascular disease, and depression has been regarded as a prodrome to dementia and a risk factor for development of cognitive disorders such as AD.
Differentiating Normal Cognitive Changes from Disease-Associated Impairment The process of distinguishing between different cognitive disorders for the purpose of diagnosis includes consideration of demographic and clinical factors such as age, family history, onset and course of symptoms, and presence of other signs of dysfunction (e.g., presence and symmetry of motor abnormalities). Factors such as an acute onset versus a slowly evolving disturbance in cognition can signal particular etiologies. Neuroimaging can be helpful in identifying tumors or vascular lesions, and although there are no specific neuroimaging signs associated with primary dementing disorders, imaging may identify greater than expected atrophy (brain cell loss) for one’s age. In some cases, it may be necessary to observe an individual over time to determine whether the disturbance is in fact progressive. The profile of cognitive functioning on neuropsychological measures (formal tests of cognitive abilities) can help inform diagnosis as well as treatment planning.
Neuropsychology: The Study of Brain Behavior Relationships The field of neuropsychology involves investigation of how developmental changes across the life span, diseases, and injury to the brain affect cognitive functioning. Clinical neuropsychology consists of administration of various types of tests of thinking abilities, and the resulting information is compared to age- and education-matched normative data and interpreted in the context of an individual’s demographic, medical, psychiatric, and social history. Many people are familiar with neuroimaging, structural assessment of the brain in the form of CT or MRI (magnetic resonance imaging), in which the structure of the brain is assessed at a given time point. Neuropsychology can be thought of as a functional assessment of the brain, putting the brain to work and measuring its functional abilities at a given point in time. In clinical practice, this information is used in conjunction with results of structural imaging, a physical exam, and a detailed medical history to explain cognitive and behavioral symptoms.
Cognitive Disorders Can Be Differentiated Based on Neuropsychological Profiles Differences in the profile of cognitive functioning on neuropsychological tests give clues to the etiology of the cognitive deficit. For example, the memory changes in AD differ from those associated with vascular dementia. AD is characterized by rapid forgetting of new information. Basic attention is typically intact in the early stages, and as a result, the AD patient may be able to demonstrate learning (albeit at a rate compromised relative to premorbid expectation). Despite learning of material, recall of this information after a delay is markedly impaired. The AD patient may not even remember being given the information to begin with. In comparison, individuals with vascular cognitive impairment tend to have significantly greater difficulty learning at the point of acquiring the new information, particularly when there is no inherent structure in the information to be remembered (e.g., lists of words as compared to story recall). Nevertheless, when questioned about the material after a delay period, these individuals tend to recall the information they initially learned. Certain cognitive disturbances that may be present in a variety of disorders may be the predominant presenting symptom distinguishing a particular type of dementia, such as marked aphasia in the patient with primary progressive aphasia, visuospatial deficits in patients with posterior cortical atrophy, or marked behavioral disturbances and social inappropriateness in patients with Pick’s disease.
Preservation of Cognitive Function with Aging The phrase ‘use it or lose it’ implies that engaging in challenging cerebral activity will stimulate the brain and help to maintain mental fitness, and failure to do so will have undesirable consequences. Research supports this notion, with studies showing that seniors who stay active, mentally as well as physically, perform better on tests of cognitive functioning. Further, people who engage in mentally stimulating behaviors throughout their life are believed to build cognitive reserve that may serve a protective role in preventing the development of late-life cognitive disorders. The literature suggests that other health and lifestyle factors may affect age-associated cognitive decline.
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Studies have shown that higher fish consumption (at least once per week) in North Americans and Europeans was associated with reduced incidence of AD. Other studies have shown that eating fruits and vegetables high in antioxidants helps to fight off free radicals, which are detrimental to brain function. Alcohol consumption has been said to have an aging effect on the brain. While many sources cite benefits of modest consumption (particularly red wine) for cardiovascular health, excessive abuse has been associated with increased brain atrophy (wasting away of brain tissue) and cognitive dysfunction. Smoking is associated with changes in the cerebrovasculature, affecting blood flow to the brain and other vital organs. Numerous clinical trials have been conducted to assess possible neuroprotective effects of prescription medications, herbal supplements, and hormones. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen have been investigated as potential agents to ward off cognitive decline based on the theory that brain inflammation plays a role in the development of late life cognitive disorders. It is unclear whether the preventative benefit observed in some studies with NSAIDs was due to other extrinsic factors, and their use is not recommended for preventing cognitive decline at this time. These agents should not be taken without a doctor’s advice, since their use can cause severe bleeding and other complications. Early studies on estrogen were promising in terms of a protective effect on cognitive decline; however, later studies yielded contradictory findings. Given equivocal findings and the risks associated with use, more research needs to be done on hormones and cognition. There is no one substance that will prevent dementia; other agents such as statins (used to control cholesterol) and herbal supplements (such as Ginkgo biloba) are regarded by some as neuroprotective, but the results of controlled experimental investigations in these types of agents have been regarded as equivocal due to methodological limitations (e.g., lack of statistical power) or inconsistent findings across studies. Ginkgo biloba is widely used throughout Europe for treatment of cognitive decline. Although a systematic review of Gingko biloba revealed a positive effect over placebo, specific recommendations for use in treating cognitive disorders are deferred awaiting further investigations. The GEM trial (Ginkgo Evaluation of Memory) is a large-scale (>3000 participants), double-blind, randomized controlled trial designed to investigate Ginkgo biloba in the prevention of dementia that completed recruitment in 2002 (DeKosky et al., 2006). When the results of this well-designed 5-year trial are published, they may shed some light on the effectiveness of Ginkgo biloba in preventing late-life cognitive decline. Sensory changes can mistakenly present as or exacerbate cognitive decline; failure to accurately hear what has been said or see clearly interferes with one’s ability to process and retain information. Correcting hearing and vision as needed may improve one’s ability to engage in the environment and acquire what is needed to process information efficiently. Systemic illness and medications used can also influence how well a person engages in the environment, having an indirect effect on cognitive abilities. Given the known effects of cerebrovascular disease on mental status as well as the association of vascular risk and changes with the development of late life cognitive disorders, Alzheimer’s Disease International researchers advocate public health policies that address reducing modifiable risk factors for cerebrovascular disease (elevated cholesterol, tobacco use, diabetes). These risk factors not only are associated with diseases that threaten mental functioning, but have in and of themselves been associated with cognitive decline. Sleep and mood disturbances also influence how well an individual processes information and can present with changes in cognitive function that may be alleviated once the primary disturbance is treated. Perhaps the best plan for dementia prevention is consonant with recommendations to prevent other diseases: maintain your best health by paying attention to lifestyle factors that influence your physical and mental status (e.g., diet, exercise, alcohol/tobacco consumption, stress). In general, those that fare best tend to be those with a healthy attitude toward aging. Keeping active, both physically and mentally, may serve a protective role against cognitive decline associated with aging.
References DeKosky ST, Fitzpatrick A, Ives DG, et al. (2006) The Ginkgo Evaluation of Memory (GEM) study: Design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemporary Clinical Trials 27(3): 238–253.
Further Reading Attix DK and Welsh-Bohmer KA (2006) Geriatric neuropsychology: Assessment and intervention. New York: The Guilford Press. Fillit HM, Butler RN, O’Connell AW, et al. (2002) Achieving and maintaining cognitive vitality with aging. Mayo Clinic Proceedings 77(7): 681–696. Gauthier S, Reisberg B, Zaudig M, et al. (2006) International psychogeriatric association expert conference on mild cognitive impairment. Lancet 367: 1262–1270. Hayden KM, Zandi PP, Lyketsos CG, et al. (2006) Vascular risk factors for incident alzheimer disease and vascular dementia: The cache county study. Alzheimer Disease and Associated Disorders 20(2): 93–100. McKeith IG, Dickson DW, and Lowe J (2005) Diagnosis and management of dementia with lewy bodies: Third report of the DLB consortium. Neurology 65(12): 1863–1872. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, and Kokmen E (1999) Mild cognitive impairment: Clinical characteristics and outcome. Archives of Neurology 56(3): 303–308. Petersen RC, Doody R, Kurz A, et al. (2001) Current concepts in mild cognitive impairment. Archives of Neurology 58: 1985–1992. Rockwood K (2002) Vascular cognitive impairment and vascular dementia. Journal of the Neurological Sciences 203: 23–27.
Relevant Websites http://www.alz.co.uk/
Alzheimer’s Disease International.
Late Life Cognitive Disorders
http://www.theaacn.org/links.html American Academy of Clinical Neuropsychology. http://www.the-ins.org/ International Neuropsychological Society. http://www.mayoclinic.com/ Mayo Clinic (for Mild Cognitive Impairment). http://www.ninds.nih.gov/ National Institutes of Health/National Institute of Neurological Disorders and Stroke. http://www.nia.nih.gov/ National Institutes of Health/National Institute on Aging. http://www.wpda.org/ World Parkinson’s Disease Association.
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