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Perspectives |
1 From the Department of Radiological Sciences, University of California, Irvine Medical Center, Orange. Received August 11, 2003; accepted August 18. Address correspondence to the author, 18961 Castlegate Ln, Santa Ana, CA 92705 (e-mail: rmfriede@uci.edu).
Index terms: Alzheimer disease, 10.83 • Dementia • Perspectives • Radiology and radiologists, socioeconomic issues
Correlating with the increase in life span is the increase in acquired dementia. The term dementia was introduced to American medical literature by Benjamin Rush in 1812. It was originally coined by Pinel, a French psychiatrist, who had used it to refer to patients with acquired idiocy (1). Dementia is an acquired impairment in our intellectual abilities; it affects memory, language, visuospatial skills, cognition, emotion, and personality (2). As we age, we all experience memory deficits. We do not remember where we put items, we forget appointments, and we temporarily forget names of individuals we know and names of places we have recently visited. To forget where we placed our keys is a memory deficit, but to forget what a key is used for is dementia.
What can be more frightening to individuals as they age than the thought of becoming demented in the near future? To many, the thought of becoming mentally incompetent is more frightening than the thought of physical disease. To be dependent on others for all of our needs, to be incapable of expressing our feelings, to be unable to recognize our family, and to lose our ability to reason is an utterly demoralizing concept for any individual. As we age, we all slow down. Our recall time increases, as does our forgetfulness. However, our basic wiring system in the brain remains intact—in dementia, the wires are cut. We are unable to reason, our memories are gone, and we are unable to function. We have lost the essence of being that makes us persons. John Jackson wrote in 1894 that a person with dementia does not have the use of his or her brain. He or she has no system of thinking; in the end, there is no person but only a living creature (3).
There are four main types of dementia that account for approximately 90% of the total cases. Alzheimer disease (AD) accounts for about 50% of cases; Lewy body dementia, for about 15%; frontotemporal dementia, for about 15%; and vascular dementia, for about 10%. Before discussing the problems of dementia, it might be interesting to briefly describe each type (1,2,4).
AD is characterized by difficulty in learning and retaining new information, with increasing problems that affect calculation, visuospatial skills, performance of purposeful acts, and language. The four hallmarks of AD are amnesia, apraxia, agnosia, and aphasia. Risk factors for AD include aging; family history; presence of APOE4 allele (apolipoprotein 
genotype); and in a small number of patients with early-onset AD, genetic inheritance from mutations on chromosomes 21, 14, and 1. Neuroprotective factors include higher education, challenging occupation, and presence of one or both APOE2 alleles. The neuropathologic hallmarks in the brain are considered to be neuritic plaques and neurofibrillary tangles.
Lewy body dementia is characterized by the Lewy body, a concentric hyaline cytoplasmic inclusion body. Symptoms at presentation may include dementia, fluctuating cognition, recurrent visual hallucinations, and features of parkinsonism.
Frontotemporal dementia is characterized by early onset of behavioral changes with intact visual and spatial skills. The individual may exhibit poor hygiene, lack of social tact, and lack of sexual inhibitions. These effects result from atrophy in the frontal and temporal lobes.
Vascular dementia results from lack of blood supply to the brain and may be the result of hemorrhage or ischemia from multiple infarcts. Symptoms at presentation vary, depending on the area affected. Focal neurologic signs are often present, suggesting stroke.
AD is the most common dementia and the one most feared by the aging population, and it is the main topic of this article. In 1907, neuropathologist Alois Alzheimer reported the clinical features and the pathologic findings of the senile plaques and neurofibrillary tangles of this illness that today bears his name. In his early writings, he wrote: "It is clear that there exists [sic] many more mental illnesses than our textbooks indicate. In many such cases a further histologic examination must be effected to determine the characteristics of each single case. We must reach the stage in which the vast, well-known disease groups must be subdivided into smaller groups, each with its own clinical and anatomic characteristics" (5).
Several authors have discussed the degree of dementia in our aging population. They have estimated that in the United States in our population aged 60 and older, the incidence of dementia approximately doubles every 5 years from 1% to 2% at age 60 to more than 40% at age 85 (2–4,6). Jorm and Jolley (6), in their meta-analysis, noted that occurrence of all dementia, including AD, increased exponentially to the age of 90 years, with no signs of leveling off. There was no sex difference in dementia, but women tended to have a higher incidence of AD; and men, a higher incidence of vascular dementia. In their meta-analysis, they noted that prevalence of dementia, including AD, was higher in Europe than it was in the United States and lower in Asia. Community-based study findings in Nigeria and India suggest that AD is uncommon, with a lower prevalence of about 1.1% in people 65 years of age, while results of studies in Shanghai, China, showed that the rate was 1% or less (5–7). This compares with a rate of 2% or more in most Western communities (6).
AD afflicts about 15 million people worldwide and about 4 million in the United States (3,8). When mild cases are included, the prevalence may be more than 10% of the population of whites older than 65 years and higher in blacks and Hispanics. The average yearly cost of care per person is more than $35,000 (3), with estimates of the total cost varying from $60 billion (8) to $200 billion (1) annually in the United States. In 2002, there were 4.9 million persons in the United States older than 85 years, and Clark and Karlawish (3) state that more than 40% may meet the clinical criteria for dementia. If we look to the future, the U.S. Census Bureau predicts that 6.6 million persons will be in the older-than-85-years category a decade from now (3). That could mean that almost half of this number may have dementia (4), primarily from AD, and the total number of individuals in the United States with dementia could reach 10 million in 50 years if current research does not discover how to prevent this scourge. Evans (9) used a cohort in the east Boston area in an effort to extrapolate the prevalence of AD in the United States. He estimated that the number of persons 65 years of age or older in the United States with probable AD in 1980 was 2.88 million. By using U.S. Census figures, he estimates that in 2050, the number of persons in the United States 65 years of age and older with AD will be approximately 10.3 million. Evans estimated that the percentage of people between 65 and 74 years of age with AD in the 1980 population was 3.9%, but for those older than 85 years of age, the number increased to 47.5%, representing about 1.25 million persons. In 2050, the number of individuals 85 years of age and older with AD will increase sevenfold to about 7.07 million. All authors stress that the increase in life span will produce dramatic increases in AD as our population ages (1,2,4,6,9).
The etiology of AD is still under investigation. Causative factors that have been described include gene mutations; abnormal processing of the amyloid precursor protein, which leads to amyloid plaques; oxidative damage; abnormal tau protein phosphorilization, which leads to neurofibrillary tangles; and environmental factors (3,4). Although the amyloid plaques and neurofibrillary tangles are considered the pathologic hallmark of AD, they are also present in other lesions, as well as in the brains of individuals without dementia.
Diagnostic criteria for the diagnosis of AD are far from exact, and there is probably a bias toward diagnosis of dementia cases as AD (10). Most diagnoses require the presence of memory loss, which is very nonspecific. The American Academy of Neurology recently concluded that none of the most widely used dementia diagnostic systems are particularly accurate because of the difficulty in distinguishing normal cognitive changes associated with aging from early AD (10). Memory loss, which includes the impairment of the ability to learn new information or to retrieve previously learned information, is among the most common cognitive changes normally noticed in elderly patients. In normal aging, these memory lapses usually do not affect our ability to function, whereas in AD, recognition of a progressive decline in memory usually is associated with a decrease in the patient’s ability to perform the activities of daily living, such as transporting oneself, managing money, and cooking. Mild to moderate changes in mood and behavior are common, as is word hesitancy, which progresses to a reluctance to initiate conversation. Patients often retain the ability to interpret and respond to the emotions of those around them, and usually language comprehension is less impaired than is the ability to talk. Even when moderate dementia is present, many individuals lack insight into their deficits. As dementia and confusion progress, depression is common among patients with dementia.
After a provisional diagnosis is made, the patient is then evaluated for possible risk factors that include a family history of dementia, and assessment is performed for other possible causes that are treatable, such as medication, depression, head injury. To exclude physical problems, thyroid, liver, kidney, and endocrine function tests are performed (3). An overall evaluation of the patient is usually obtained from the involved person, as well as from relatives or caregivers. Patients who are suspected of having AD usually undergo a diagnostic work-up, which includes a history, physical examination, functional status assessment, and cognitive testing (performed either with oral questions or a prepared test such as the Mini-Mental State Examination). A problem with cognitive testing is that tests depend on a substantial amount of education, and individuals with less education may have low scores without having AD (7). Because of this, simple tests have been devised, such as remembering names of children and grandchildren or what an individual owns in terms of possessions, cars, or animals. At this stage, routine radiologic imaging probably is not necessary unless localizing neurologic signs or symptoms are noticed, although in about 5% of patients computed tomography (CT) and magnetic resonance (MR) imaging may help identify other clinically unexpected lesions that may contribute to the dementia (3).
The few patients with genetically induced AD present with symptoms in the 4th to 6th decades of life, which is 10–20 years earlier than do patients with acquired AD. One evaluation of 31 families with a history of AD before the age of 60 years revealed 31 patients with definite or probable AD, with a mean age of onset at 46.9 years (11). The majority of these patients belonged to families with multiple affected members, over at least two generations, and shared the criteria for autosomal dominant inheritance. Three causative genes have been identified: genes on chromosomes 21, 14, and 1. Early-onset AD is therefore a rare disease with an estimated prevalence of 5.3 persons per 100,000 (11).
The concept that some commonly occurring gene variations can modify the risk of acquired disease has been suggested. The 4 variation of the APOE gene is associated with an increased risk for sporadic late-onset AD, not for early-onset AD. However, more than 36% of cases clinically diagnosed as AD occur in patients lacking an 4 allele, and therefore its presence should not be considered a diagnostic test for AD (3).
AD pathologic changes consistently begin in or near the hippocampus and only later move out to affect the frontal, temporal, and parietal lobes. This sequence explains the consistent appearance of memory loss before other cognitive deficits. In one study in which volumetric MR imaging assessments of the brain were measured during intervals from 5 months to 6 years, the rate of global cerebral volume loss correlated strongly with the rate of change in the Mini-Mental State Examination score. Patients with AD, therefore, had a significant difference in rate of brain atrophy from that of the control group: a mean loss of 2.4% per year compared with 0.4% per year in the control group (12). It appeared that an early feature of AD was a decrease in brain volumes, averaging 25% more in patients with AD than in normal control subjects (ie, those with no known or clinically apparent abnormality), even in mild disease (12). In another series relating to the use of MR imaging in mild to moderate AD, the authors followed up 18 patients with mild to moderate AD and 18 control subjects, and each group underwent two sessions of brain MR imaging separated by 12 months. The mean rate of total brain atrophy in patients with AD was 2.37%, while in the control group it was 0.41% per year. The authors believe that serial volume MR imaging of the whole brain is an excellent method of quantification of brain atrophy to monitor progression of AD (13).
The greatest promise of MR imaging appears to lie in the ability to quantitate the degree of brain atrophy (3,12,13). The finding of cerebral atrophy in a patient with mild cognitive impairment may increase the certainty of a clinical diagnosis of AD, while monitoring the rate of cerebral atrophy may provide a measure of disease activity in response to therapy. Single photon emission CT is somewhat controversial, but the demonstration of the classic pattern of bilateral and asymmetric hypoperfusion in the parietal and temporal lobes in a patient with equivocal symptoms increases the likelihood of AD by about 20%, whereas a negative scan decreases the likelihood by about the same amount (14). Cerebrospinal fluid tau protein levels are elevated in most patients with AD, but apparently the level does not relate to the severity of the disease. Increased cerebrospinal fluid tau protein levels also are found in acquired immunodeficiency syndrome, multiple sclerosis, trauma, and other dementias. However, the presence of both an elevated tau protein level and a reduced ß42-amyloid (ie, amyloid beta protein) level does suggest AD (3). Despite these findings, the validity of the clinical diagnosis of AD has a poor track record of confirmation at autopsy, especially in advanced old age. The specificity at autopsy for a clinical diagnosis of AD after age 79 may be as low as 22% (10).
Four medications have been approved for the symptomatic treatment of patients with AD (3,4). They are as follows: tacrine hydrochloride (Cognex; First Horizon, Alpharetta, Ga), donepezil hydrochloride (Aricept; Pfizer, New York, NY), rivastigmine (Exelon; Novartis Consumer Health, Parsippany, NJ), and galantamine hydrobromide (Reminyl; Janssen Pharmaceutica, Titusville, NJ). All of these are cholinesterase inhibitors that produce essentially the same degree of modest improvements in approximately 30%–40% of patients with mild to moderate AD. All have various organ toxic side effects and different dosing frequencies. Their major effect seems to be the potential to slow the rate of progression of AD, without modifying the basic pathologic findings of the disease. High-dose vitamin E has been suggested by some to have a similar effect, and the American Academy of Neurology now recommends 1,000 IU of vitamin E twice daily as a standard of care in patients with AD. Newer treatments such as N-methyl-D-aspartate (NMDA) receptor antagonists are being studied (3). Glutamate, the most prevalent excitatory neurotransmitter in the brain, is involved in the pathways that lead toward cell death in AD. Use of an NMDA receptor antagonist to block the action of the glutamate may prevent the cell death that results from the increased activity. Memantine, which has been used as an NMDA receptor antagonist, is a promising drug with possible neuroprotective effects (15). Investigators in a number of European studies have reported substantial cognitive improvement in patients, even in many with moderately severe AD, treated with memantine. Findings of a study recently published in the New England Journal of Medicine suggested that memantine did alleviate the symptoms of AD in patients with moderately severe AD (15). The authors thought that a study should be performed in the future with memantine together with cholinergic treatments to see whether they could be complementary or synergistic. Other investigational studies are progressing with selegiline and vitamin E versus a placebo in an effort to delay clinical progression and delay the time for nursing home placement. In the past, results of studies with estrogen and cholesterol-lowering drugs have been positive, but the use of these agents is controversial (16).
Findings in recent publications have suggested that nonsteroidal antiinflammatory drugs (NSAIDS) bind to plaques and have antiaggregational effects on the brains of people with AD (17). It has been suggested that naproxen and ibuprofen bind selectively to the plaques associated with AD and appear to dissolve them. Large doses of NSAIDS, of course, have their own secondary effects, and their effects on AD still have to be proved in the future (18). Ginkgo biloba as a treatment for oxidative damage has been tried in Europe, with some positive effects reported, but similar to the results with NSAIDS, overall results have been somewhat disappointing (16). In the Canadian study on health and aging, investigators found an apparent protective effect of NSAIDS, but further study is being conducted (16). A current AD antiinflammatory prevention trial with two antiinflammatory agents, naproxen and celecoxib, will enroll 2,500 individuals aged 70 and older with a family history of AD and will follow up these individuals for 7 years (16). There has been some suggestion that some nonsteroidal agents may reduce amyloid formation in a variety of cell culture models.
In the July 14, 2003, issue of Newsweek, findings were reported about research being conducted with the use of statins in AD (19). Dr Robert Green, associate professor of neurology at Boston University School of Medicine, Mass, performed a study that showed a 39% reduction in AD in persons who had been taking statins for at least 6 months. Dr Larry Sparks, at the Sun Health Research Institute, Sun City, Ariz, believes that an elevated cholesterol level augments the production of amyloid plaques in the brain (19). They are both hopeful that statins will delay or even prevent the development of AD.
Our society is aging, with the greatest growth in our population in those older than 85 years. Dementia affects approximately 2% of individuals at age 65 and then doubles approximately every 5 years, affecting more than 40% of individuals at age 85, and appears to continue to increase at older ages (6,20).
Increasing dementia together with increasing physical infirmities as we age does not bode well for the "golden years." Today, as many as two-thirds of our citizens older than the age of 90 may be physically or mentally incapacitated (21,22). As our life span increases, the medical, social, and financial problems will become staggering unless future research finds the means to mitigate this problem.
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