INTRODUCTION — Dementia is a disorder that is characterized by impairment of memory and at least one other cognitive domain (aphasia, apraxia, agnosia, executive function). These must represent a decline from previous level of function and be severe enough to interfere with daily function and independence [1].
Alzheimer's disease (AD) is the most common form of dementia in the elderly, accounting for 60 to 80 percent of cases, and it is estimated to affect more than 4 million Americans [2-5]. Between 2.4 and 3.1 million spouses, relatives, and friends take care of people with AD [6]. The cost of caring for one person with this disorder at home or in a nursing home is more than $47,000 per year [7]. Clinicians will need to accurately diagnose and manage the early cognitive manifestations of AD, particularly as new pharmacological agents are developed.
This topic will discuss the evaluation of cognitive impairment and dementia. The clinical, diagnostic, and pathologic aspects of specific dementia syndromes are discussed separately. (See "Dementia syndromes").
The treatment, risk factors, and prevention of dementia are also discussed separately. (See "Treatment of dementia", see "Risk factors for dementia" and see "Prevention of dementia"). The risk factors, treatment, and prevention of vascular dementia are specifically discussed separately. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and see "Treatment and prevention of vascular dementia").
DEFINITION OF DEMENTIA — Although a number of definitions exist for dementia, the DSM-IV definition is widely accepted and includes the following [1]:
Evidence from the history and mental status examination that indicates major impairment in learning and memory as well as at least one of the following:
- Impairment in handling complex tasks
- Impairment in reasoning ability
- Impaired spatial ability and orientation
- Impaired language
The cognitive symptoms must significantly interfere with the individual's work performance, usual social activities, or relationships with other people
This must represent a significant decline from a previous level of functioning
The disturbances are of insidious onset and are progressive, based on evidence from the history or serial mental-status examinations
The disturbances are not occurring exclusively during the course of
delirium
The disturbances are not better accounted for by a major psychiatric diagnosis
The disturbances are not better accounted for by a systemic disease or another brain disease
In a practice guideline published by the American Academy of Neurology (AAN), the DSM-IIIR definition of dementia (identical to the DSM-IV definition) was reported to have good to very good reliability and was recommended for routine use [8].
IDENTIFICATION OF DEMENTIA — Detecting dementia is a problem in routine, day-to-day medical practice [9]. One study found that the diagnosis was missed in 21 percent of demented or delirious patients on a general medical ward, while 20 percent of nondemented patients were misjudged as demented [10]. Nonetheless, the clinical diagnosis of dementia is reasonably accurate for those with experience in the evaluation of this disorder (show table 1) [11].
Most patients with dementia do not present with a complaint of memory loss; it is often a spouse or other informant who brings the problem to the physician's attention. Self-reported memory loss does not appear to correlate with the subsequent development of dementia, while informant-reported memory loss is a much better predictor of the current presence and future development of dementia [12,13]. Nevertheless, family members are often delayed in recognizing the signs of dementia, many of which are inaccurately ascribed to "aging."
The normal cognitive decline associated with aging consists primarily of mild changes in memory and the rate of information processing, which are not progressive and do not affect daily function. In a study of 161 community-dwelling, cognitively normal individuals ages 62 to 100 years, learning or acquisition performance declined uniformly with increasing age [14]. In contrast, delayed recall or forgetting remained relatively stable. Similarly, a second report found that aging was associated with a decline in the acquisition and early retrieval of new information but not in memory retention [15].
Patients with dementia may have difficulty with one or more of the following [16]:
Learning and retaining new information (eg, trouble remembering events)
Handling complex tasks (eg, balancing a checkbook)
Reasoning (eg, unable to cope with unexpected events)
Spatial ability and orientation (eg, getting lost in familiar places)
Language (eg, word finding)
Behavior
Patients and informants are often uncertain about the onset of symptoms since the appearance of dementia is insidious. The physician can usually date the onset of dementia by identifying when the patient stopped driving or managing finances. Useful questions for the patient and informant are, "When did you first notice the memory loss?" and "How has the memory loss progressed since then?"
The diagnosis of dementia must be distinguished from delirium and depression (show table 2) [17]. (See "Diagnosis of delirium and confusional states" and see "Depression: Clinical manifestations and diagnosis"):
Delirium is usually acute in onset and is associated with a clouding of the sensorium. Patients with delirium may have fluctuations in their level of consciousness and have difficulty with attention and concentration. Delirium and dementia can overlap, making the distinction difficult and sometimes impossible.
Patients with depression are more likely to complain about memory loss than those with dementia; the latter are frequently brought to physicians by their families, while depressed patients often present by themselves. Patients with depression may have signs of psychomotor slowing and produce a poor effort on testing, while those with dementia often try hard but respond with incorrect answers. Depression and dementia may occur in the same patient.
The pretest probability of dementia and of various causes of dementia depends upon patient characteristics such as age and race. Realizing that 5 percent of individuals over age 65 years and 35 to 50 percent of persons over age 85 years have dementia, the pretest probability of dementia in an older person with reported memory loss is estimated to be at least 60 percent.
The US Preventive Services Task Force has concluded that there is insufficient evidence to recommend for or against routine screening for dementia in older adults [18,19]. (See "USPSTF Guidelines: Screening for dementia: Recommendations and rationale").
Mild cognitive impairment — Mild cognitive impairment (MCI) is generally defined by the presence of memory difficulty and objective memory impairment but preserved ability to function in daily life. Patients with MCI appear to be at increased risk of dementia. This topic is discussed separately. (See "Mild cognitive impairment").
Dementia syndromes — The major dementia syndromes include [20-22]: (see "Dementia syndromes")
Alzheimer's disease (AD)
Dementia with Lewy bodies (DLB)
Frontotemporal dementia (FTD)
Vascular (multi-infarct) dementia (VaD)
Parkinson's disease with dementia (PDD)
Less common disorders such as progressive supranuclear palsy (PSP) can also be associated with dementia. Non-neurodegenerative dementias may be reversible, if the underlying cause can be identified and adequately treated [23].
Most elderly patients with chronic dementia have AD (approximately 60 to 80 percent). The vascular dementias account for 10 to 20 percent, and PD for 5 percent. The prevalence of VaD is relatively high in blacks, hypertensive persons, and patients with diabetes; some of the reversible dementias (eg, metabolic dementias) tend to occur in younger individuals. DLB may be as prevalent as VaD in older cohorts of patients [24]. FTD is much less common than AD, VaD, or DLB.
Alcohol-related dementia, medication side effects (eg, antihistamine use), depression, and other central nervous system illnesses are responsible for the remainder of the chronic dementias.
Dementia frequently has more than one cause, particularly as the condition progresses. In addition, medical illnesses exacerbating poor cognition are common in patients with dementia. The bedside evaluation combined with historical information from a reliable informant provides most of the information needed to ascertain the cause of dementia [17]. However, even with the addition of information from imaging studies, clinical criteria for VaD have relatively poor sensitivity [25].
DIAGNOSTIC APPROACH — The initial appointment in a patient with suspected dementia should focus upon the history. Preferably, family members are available to give an adequate history of cognitive and behavioral changes [21]. A drug history is particularly important; use of drugs that impair cognition (eg, analgesics, anticholinergics, psychotropic medications, and sedative-hypnotics) should be sought.
A full dementia evaluation can probably not be completed in a routine 30-minute visit; adequate time should be arranged as a follow-up appointment. The initial step at the follow-up visit is an assessment of cognitive function. This should be followed by a complete physical examination, including neurologic examination. The subsequent work-up may include laboratory and imaging studies (show algorithm 1) [26,27]. The DSM-IV criteria for the diagnosis of dementia are shown in Table three (show table 3).
Cognitive testing — Agreement between the history and the mental status examination is strongly suggestive of the diagnosis of dementia. When the history suggests cognitive impairment but the mental status examination is normal, possible explanations include mild dementia, high intelligence or education, depression, or rarely, misrepresentation on the part of the informants [28]. Conversely, when the mental status examination suggests cognitive impairment but the family and patient deny any problems, possible explanations include an acute confusional state, very low intelligence or education, or inadequate recognition by the family [28]. Neuropsychological assessment (psychometric testing) may be useful in difficult situations; re-evaluation at a later time is often helpful.
Mini-Mental State Examination — The Mini-Mental State Exam (MMSE) is the most widely used cognitive test for dementia in US clinical practice [29,30]. The examination takes approximately seven minutes to complete. It tests a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis.
The MMSE includes the following tasks [29]:
Orientation:
What is the date: (year)(season)(date)(day)(month) - 5 points
Where are we: (state)(county)(town)(hospital)(floor) - 5 points
Registration:
Name three objects: one second to say each. Ask the patient all three after you have said them. Give one point for each correct answer. Then repeat them until he/she learns all three. Count trials and record. The first repetition determines the score, but if the patient cannot learn the words after six trials then recall cannot be meaningfully tested. Maximum score - 3 points.
Attention and calculation:
Serial 7s, beginning with 100 and counting backward: one point for each correct; stop after five answers. Alternatively, spell WORLD backwards: one point for each letter that is in correct order. Maximum score - 5 points.
Ask for the three objects repeated above: one point for each correct. Maximum score - 3 points.
Show and ask patient to name a pencil and wrist watch - 2 points.
Repeat the following, "No ifs ands or buts." Allow only one trial - 1 point.
Follow a three stage command, "Take a paper in your right hand, fold it in half, and put it on the floor." Score one point for each task executed. Maximum score - 3 points.
On a blank piece of paper write "close your eyes," and ask the patient to read and do what it says - 1 point.
Give the patient a blank piece of paper and ask him/her to write a sentence. The sentence must contain a noun and verb and be sensible - 1 point.
Ask the patient to copy a design (eg, intersecting pentagons). All 10 angles must be present and two must intersect - 1 point.
A total maximal score on the MMSE is 30 points. Generally a score of less than 24 points is suggestive of dementia or delirium. Using a cutoff of 24 points, the MMSE had a sensitivity of 87 percent and a specificity of 82 percent in a large population based sample (show table 1) [31]. However, the test is not sensitive for mild dementia, and scores may be influenced by age and education, as well as language, motor, and visual impairments [32]. In one study, for example, the median MMSE score was 29 for individuals with at least nine years of schooling, 26 for those with five to eight years of schooling, and 22 for those with four years of schooling or less [31].
The use of higher cutoff scores on the MMSE improves sensitivity but lowers specificity. For research purposes, some investigators use a cutoff score of 26 or 27 in symptomatic populations in order to miss few true cases, while lower cutoffs would be necessary in populations where the expected prevalence is low [33]. Age-specific norms also have been established [31]; some groups have developed tools that incorporate age, gender, and education level (show figure 1) [34,35].
The MMSE also has utility in assessing competency in decision making. Studies suggest that high scores, 23, and low scores, <19, can be highly predictive in discriminating competency from incompetency. Intermediate scores warrant more detailed competency evaluation [36,37].
Other brief cognitive assessments — An ideal test for mental status screening should be brief and have good performance in populations with different cultural, linguistic, and educational backgrounds.
Mini-Cog. One such test is the "Mini-Cog," which consists of a clock drawing task (CDT) and an uncued recall of three unrelated words [38].
Scoring of the Mini-Cog is based on a simple decision tree with the following three rules:
Subjects recalling none of the words are classified as demented
Subjects recalling all three words are classified as non-demented
Subjects with intermediate (one to two) word recall are classified based on the CDT (abnormal = demented; normal = non-demented)
The CDT is considered normal if all numbers are present in the correct sequence and the hands readably display the correct time.
The advantages of the Mini-Cog include high sensitivity for predicting dementia status, short testing time relative to the MMSE, ease of administration, and diagnostic value not limited by the subject's education or language [38].
In a retrospective analysis of data from a random sample of 1119 older adults, the Mini-Cog was compared with the MMSE (at a cut point of 25); the Mini-Cog had similar sensitivity (76 versus 79 percent) and specificity (89 versus 88 percent) for dementia [39]. Although these results are promising, the Mini-Cog requires further validation with prospective data. These tests are also not appropriate for patients with aphasic or anomic disorders.
Informant interview — A brief, eight-item questionnaire for informants appears to be sensitive for detecting dementia and cognitive impairment [40]. Informants are asked whether the patient has exhibited any increase in the following deficits or behaviors:
- Problems with judgment
- Reduced interest in hobbies/activities
- Repeats questions, stories, or statements
- Trouble learning how to use a tool or appliance
- Forgetting the correct month or year
- Difficulty handling financial affairs (bill-paying, taxes)
- Difficulty remembering appointments
- Consistent problems with thinking and/or memory
A positive response to two or more questions had a sensitivity of 93 percent and a specificity of 46 percent. Increasing the cutoff score to three positive responses decreased the sensitivity to 90 percent and increased the specificity to 68 percent.
Short portable mental status questionnaire. The short portable mental status questionnaire is another popular test of cognitive function [41]. It can be performed in approximately five minutes. This test contains items that test orientation, attention, immediate recall, arithmetic, abstraction, construction, information, and delayed (approximately three minutes) recall. It is reasonably sensitive and specific for the diagnosis of moderate to severe dementia, but similar to the MMSE, it is relatively insensitive in cases of mild dementia (show table 1).
Clock drawing. Asking the patient to draw a clock with a specific time is a quick examination that appears to correlate well with the MMSE score, although it has not undergone as rigorous an evaluation as the MMSE [42]. It is not a sensitive test for identifying very mild dementia [43,44].
Neuropsychologic testing — Neuropsychologic testing usually involves extensive evaluation of multiple cognitive domains (eg, attention, orientation, executive function, verbal memory, spatial memory, language, calculations, mental flexibility and conceptualization).
The AAN practice parameter for the early detection of dementia was published in 2001 [45]. The AAN reviewed a number of studies of neuropsychological testing for dementia; some were well designed observational controlled studies [46-49], and others were case series [50-52]. Most studies demonstrated a relatively high sensitivity (range 80 to 98 percent) and specificity (from 44 to 98 percent) for detection of dementia.
The AAN concluded that neuropsychologic batteries are useful instruments in identifying patients with dementia, particularly when administered to those at higher risk by virtue of memory impairment [45]. The neuropsychologic instruments that emphasize memory function were considered most useful. In particular, five subtests (Animal naming, Modified Boston Naming Test, MMSE, Constructional Praxis, and Word List Memory) were identified by a consortium of experts to be a valid, reliable measure of cognition in normal aging and AD. An aggregate total score accurately differentiated normals from those with MCI and AD [53]. However, it is important to recognize that scores can also be influenced by education and age and apply only to individuals whose primary language is English [54].
Assessment of premorbid ability — Estimating the premorbid mental ability is vital in order to assess the extent of dementia present. The National Adult Reading Test (NART) involves pronunciation of 50 irregular English words such as "ache" and "thyme" [55]. The more words a patient can read, the higher the estimate of premorbid functioning. The use of NART as an estimator of premorbid ability was validated in a case-control study of subjects about 80 years old; mean NART scores did not differ in those with and without mild to moderate dementia after controlling for actual premorbid IQ scores recorded at age 11 [56].
Physical examination — A thorough general physical examination to rule out an atypical presentation of a medical illness should be combined with a neurologic examination. The latter should focus upon focal neurologic deficits that may be consistent with prior strokes, signs of Parkinson's disease (PD) (eg, cogwheel rigidity and tremors), gait, and eye movements. In comparison, patients with Alzheimer's disease (AD) generally have no motor deficits at presentation. This examination, along with the medical and neurologic history, will allow tailoring of laboratory tests.
Laboratory testing — The American Academy of Neurology (AAN) recommends screening for B12 deficiency and hypothyroidism in patients with dementia [8]. (See "Neurologic manifestations of hypothyroidism" section on Screening for hypothyroidism in cognitive impairment). There are no clear data to support or refute ordering "routine" laboratory studies such as a complete blood count, electrolytes, calcium, glucose, blood urea nitrogen, creatinine, and liver function tests. Screening for neurosyphilis is not recommended unless there is a high clinical suspicion of neurosyphilis.
The cost-effectiveness of obtaining multiple laboratory studies in all patients has been questioned because the yield is low [57]. The prevalence of reversible dementia has fallen since 1972. In a 1994 study, this was less than one percent, and in a 2006 community-based series, none of the 560 patients with dementia screened had a treatable metabolic cause [57,58]. Some tests can be tailored to patients with a compatible history (eg, red blood cell folate in a patient with ethanol dependence, or ionized serum calcium in a patient with multiple myeloma, prostate cancer, or breast cancer).
The value of genetic testing for AD in patients with dementia is controversial. The apolipoprotein E epsilon 4 allele has been considered for use as a diagnostic test. As previously mentioned, however, many patients who are homozygotes for this allele will not develop AD [59]; thus, application of this test to large populations would lead to the overdiagnosis of AD, a practice with obvious potentially damaging consequences. For these reasons, genetic testing for the apolipoprotein E epsilon 4 allele is not currently recommended [60], nor is genetic testing for other potential causes of dementia [8].
While some studies suggest that increased levels of tau protein and decreased levels of beta-amyloid protein ending at amino acid 42 in cerebrospinal fluid may have predictive value for AD in nondemented patients and in patients with MCI, and may also distinguish AD from other forms of dementia [61-68], a role for these measurements in clinical practice has not been established [69,70].
Neuroimaging — The use of neuroimaging in patients with dementia is controversial. A number of guidelines on the clinical evaluation of dementia have been published, many of which do not recommend imaging studies routinely, but include clinical prediction rules to identify patients who might have reversible causes of dementia that can be diagnosed with imaging studies (eg, subdural hematoma, normal pressure hydrocephalus, treatable cancer) [8,58,71-77]. The prediction rules vary, including factors such as young age (<60), focal signs, short duration of symptoms (less than two years), among others. However, the sensitivity and specificity of these prediction rules is low [78]. The AAN recommends structural neuroimaging with either a noncontrast head CT or MRI in the routine initial evaluation of all patients with dementia [8].
MRI findings in AD include both generalized and focal atrophy as well as white matter lesions [79]. In general, these findings are nonspecific. However, a number of investigators have correlated changes in hippocampal volume with cognitive decline in patients with and without preexisting dementia [80-82]. Because hippocampal volumes decline in normal aging, age-specific criteria are needed; however, both young and old patients with AD have abnormal hippocampal atrophy for age [83]. In the future, if found to have sufficient specificity, these findings may be useful in detecting AD at an early or even preclinical stage and in following the course of the disease, thereby guiding treatment decisions [80,84].
Demented patients with significant atherosclerotic risk factors may harbor silent cerebrovascular disease. Obtaining a head CT in these selected cases may lead to more aggressive management of the patient's hypertension, diabetes, lipid disorders, alcohol consumption, and smoking cessation, and may prompt one to prescribe aspirin. A head CT scan is important for patients with acute onset of cognitive impairment and rapid neurologic deterioration. Neuroimaging is also indicated when there are historical features or findings on physical examination suggestive of a subdural hematoma, thrombotic stroke, or cerebral hemorrhage.
AD and other neurodegenerative diseases can cause serious alterations in brain metabolism, providing the rationale for the use of positron emission tomography (PET) to assist in the diagnosis of dementia. In one of the largest studies of PET for this purpose to date, PET studies in 146 patients presenting with cognitive symptoms of dementia were sensitive indicators of the presence of AD and of neurodegenerative disease in general [85]. A negative PET scan indicated that pathologic progression of cognitive impairment was unlikely to occur over the next three years. The clinical application of PET scanning remains to be determined [86]. New techniques, such as the use of 11C-labeled Pittsburgh compound-B tracer, which binds to fibrillar amyloid beta plaques, are under investigation [87,88].
Brain biopsy — Brain biopsy has a very limited role in the diagnosis of dementia; the diagnostic yield is low, and the test is invasive with a significant risk of serious complications. Typically, it is used in younger patients and those with atypical clinical presentations in which a treatable cause of dementia (eg, inflammatory disorders such as vasculitis or multiple sclerosis) is considered plausible. In one series of 90 consecutive biopsies undertaken for the investigation of dementia, 57 percent were diagnostic, although biopsy obtained information led to specific treatment interventions in only 11 percent [89]. Only a raised cerebrospinal fluid cell count predicted the finding of a potentially treatable disease. In another series of similar size, the diagnostic yield was 47 percent [90].
SUMMARY AND RECOMMENDATIONS — Recommendations for the evaluation of cognitive impairment and dementia are derived from our clinical experience as well as from the American Academy of Neurology (AAN) practice guidelines [8,45].
The initial step in the evaluation of a patient with suspected dementia should focus upon the history. Family members or other informants who know the patient well are invaluable resources for providing an adequate history of cognitive and behavioral changes.
Adequate time should be arranged for a full assessment of cognitive function, followed by a complete physical examination, including neurologic examination.
The Mini-Mental State Exam is a useful screening test for dementia; a score of less than 24 points is suggestive of dementia or delirium.
Neuropsychologic testing batteries are useful in identifying patients with dementia, particularly when administered to those who may be at increased risk of cognitive impairment.
Screening for B12 deficiency and hypothyroidism is recommended for patients being evaluated for dementia.
Screening for depression in patients with dementia is recommended because depression is a common treatable comorbidity that may also masquerade as dementia.
Genetic testing for the apolipoprotein E epsilon 4 allele is not currently recommended, nor is genetic testing for other potential causes of dementia.
Structural neuroimaging with either a noncontrast head CT or MRI is recommended in the routine initial evaluation of all patients with dementia.
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