Short of mass screening of the elderly using a neuropsychological test or some yet-to-be-determined biomarker, persons with cognitive disorders come to the attention of the health care system only when symptoms are recognized. Occasionally, physicians identify cognitive deficit on routine examination or when they notice patients having trouble following instructions (eg, taking medications properly)
Dementia, of which Alzheimer disease (AD) isthe most common cause, is a major healthproblem confronting contemporary society.Because prompt (and, in the future, possiblypreclinical) initiation of treatment offers thegreatest hope for the successful managementof AD, early diagnosis is essential.
Short of mass screening of the elderly using a neuropsychological test or some yet-to-be-determined biomarker, persons with cognitive disorders come to the attention of the health care system only when symptoms are recognized. Occasionally, physicians identify cognitive deficit on routine examination or when they notice patients having trouble following instructions (eg, taking medications properly). In most cases, it is left to the patient or a family member or close friend of the patient to note the problems in cognition, memory, or behavior and report them to a health care provider. Thus, what might be termed "cognitive complaint" is a critical issue in dementia care. It determines, to a large extent, the timeliness of evaluation, diagnosis, and treatment.
EARLY AD OVERLOOKED
Unfortunately, delay in diagnosis and treatment is common. In a recent clinical trial that focused on very mild, early-stage AD in which a criterion for admission was diagnosis within 1 year of the start of the study, the mean estimated duration of dementia at entry into the study was almost 3 years.1 A major reason for the delayed diagnosis of AD, in general, is lack of awareness of cognitive problems on the part of patients and family members. For the latter, the delay in recognizing deficits in kin is often the result of simple psychological denial; for patients, it is more likely evidence of anosognosia, part of the brain disease itself. Some patients with AD flatly deny the existence of flagrant cognitive disabilities; others acknowledge a problem but minimize its significance, or their actions suggest that they do not fully appreciate the implications.2
MILD COGNITIVE IMPAIRMENT
Once AD is clinically manifest, it unfortunately may be too late to significantly influence the subsequent course of the disease. Preclinical detection and treatment are therefore the ideal.3 The population at maximum risk for AD-and for whom such intervention strategies should be targeted-are persons with mild cognitive impairment (MCI). This condition, which is intermediate between normal cognition and dementia, is characterized by significant cognitive deficit, most often in the domain of memory, but with satisfactory social and occupational functioning.4 More than 50% of persons with MCI-especially those with the amnestic subtype-will convert to frank dementia, usually AD, within 5 years.5
A diagnostic criterion for MCI has been cognitive complaint on the part of the patient, an informant, or both,6 but if AD is destined to develop in many persons with MCI and if AD involves some degree of anosognosia, then patients with MCI also might be expected to be less than fully aware of their symptoms. Indeed, Tabert and colleagues7 showed that patients with MCI with diminished awareness of their (comparatively minor) cognitive deficits were more likely to progress to dementia than were those who were more aware.
Other studies, using different experimental designs, also show the existence of anosognosia in MCI.8 It is for this reason that some authors9-11 advocate dropping "subjective memory complaint" (at least on the part of the patient) from the diagnostic criteria. In contrast, other studies suggest that while mild AD involves some degree of anosognosia, most patients with MCI are still capable of recognizing their deficits.12
As illustrated by Case in Point: Mild Cognitive Impairment, the issue of impaired self-awareness in MCI remains ambiguous. In fact, different ways of treating cognitive complaint as a diagnostic criterion for MCI probably account for some of the major differences between studies regarding the prevalence of MCI and its rate of progression to dementia.
There are a number of possible reasons for the divergent findings of the studies mentioned above that examined awareness of deficit in MCI. In the earliest stages of dementia, anosognosia may be a variable phenomenon. Some persons may retain the capacity to accurately appraise their cognitive performance.
Because impairment is mild, some of the methods for quantifying awareness, such as patient-caregiver discrepancy techniques, may not be sufficiently sensitive to detect subtle deficits. Other factors, such as intelligence, educational attainment, and capacity for introspection, might mediate the findings. It is also possible that awareness differs according to MCI subtype.
Because of preliminary evidence that impaired awareness is often associated with frontal lobe disease,13 awareness may be more impaired in the frontal/executive dysfunction form of MCI than in the amnestic type. This hypothesis, however, has never been tested. The dynamics between what patients with MCI complain about regarding perceived deficits and what their family members notice is another important issue that needs to be explored.
PURE Cognitive COMPLAINT
The obverse of impaired awareness of demonstrable cognitive deficit in AD and MCI is pure (subjective) cognitive complaint. Here the patient complains of memory or other cognitive disturbances, although no abnormalities are found on neuropsychological testing. Furthermore, there is no evidence that the complaint is significantly impacting social or occupational functioning.
In past clinical practice, significant organic disease was thought to be unlikely in persons who had explicit cognitive complaints but normal results on mental status testing. Indeed, anxiety and depression have long been known to significantly impair attention and concentration, leading indirectly to the subjective experience of memory complaint and other forms of cognitive impairment.
Persons with these symptoms present in significant numbers to neurologists' offices and memory disorder clinics. However, mood disturbances are by no means the sole reason for subjective cognitive complaints. Among other persons who consult physicians with similar complaints are the relatives and friends of patients with AD, persons who have excessive intellectual expectations and place too many demands on their cognitive abilities (eg, those given to "multitasking"), and those who are especially introspective (the "worried well").
In cases such as that exemplified by Case in Point: Pure Cognitive Complaint, it would be premature to assume that pure sub- jective cognitive complaint (with or without depression) excludes the possibility of organic brain disease. First, the "purity" of the complaint depends on the thoroughness of the cognitive examination. Subtle changes in neuropsychological function are often missed.
In addition, recent studies suggest that after adjusting for depressed mood, anxiety, and other contributing factors, many elderly persons who have subjective memory complaint but apparently normal results on mental status testing may be detecting an incipient cognitive disorder such as MCI or mild AD.14,15 Indeed, some elderly persons with memory complaints alone have neuroimaging findings (eg, cortical atrophy and white matter hyperintensity patterns) that are qual- itatively similar to those seen in patients who have amnestic MCI and mild AD.16-18
How is a clinician to distinguish those persons with cognitive complaints who are likely to progress to MCI and dementia from those who will have a more benign course? Certain patterns of abnormalities on neuropsychological testing, such as deficits in verbal recall, psychomotor speed, and executive functioning, have been shown to predict the later development of dementia,3 but detailed testing of this type is not always feasible and some persons with apparently normal results may ultimately progress to AD.
The concomitant presence of depression or another mood disturbance is undoubtedly important because in many cases it underlies problems with concentration and attention. If cognitive complaints improve after a course of antidepressant therapy, the likelihood of such a diagnosis is increased.
However, depressed mood and cognitive complaints do not always respond to pharmacotherapy. In the elderly especially, it is also clear that the presence of depression (and other emotional symptoms), even without demonstrable cognitive deficits, by no means excludes the possibility of underlying organic disease. In some persons, depression either by itself or with cognitive symptoms can be the first sign of AD or another form of dementia.19,20
A factor that may help in the differential diagnosis is the patient's age. Younger persons with cognitive complaints are far less likely to have dementing illness than older persons with equivalent symptoms. On the other hand, cases of young-onset dementia undoubtedly exist, and some of the most difficult scenarios involve persons in late middle age (mid 50s) to 70 in whom a diagnosis of depression or dementia is plausible. Furthermore, there is no clear cutoff age to confidently predict that the cognitive symptoms are not related to an incipient progressive dementia.
Clinical experience suggests certain qualitative distinctions between cognitive complaints that are suggestive of incipient dementia and those that are more typically the result of impaired concentration, attention, and other factors. Thus, persons with neurologically benign forms of memory impairment frequently complain of periodic lapses of memory, with more or less intact cognition in between. They are more likely to endorse such items as "difficulty in focusing," "trouble with concentrating," and "problems in paying attention," when questioned about their symptoms. A typical complaint is that of starting to do something but then forgetting what was intended to be done.
Transient difficulty in remembering the names (but not other features) of persons and objects is another common complaint that in itself does not necessarily imply serious cognitive disturbance. However, failure to recognize a face that should be familiar or the correct name of an object when presented with multiple choices is far more ominous. In turn, forgetting some of the details of an event is less important than failing to remember the event itself. It must be stressed, however, that none of these clinical observations is infallible, nor is there much objective data to back them up.
The concordance between the complaints of the patient and those of an informant is probably important in making a differential diagnosis, but not without its own ambiguities. If the informant sees no evidence of cognitive symptoms despite complaints on the part of the patient, the neurological prognosis is often quite good. If, on the other hand, the informant notices problems that the patient is unaware of, the prognosis is more guarded. At the same time, however, it must be recognized that laypersons are not always astute observers of the mental state, and there may be a host of other factors that affect the objectivity of their observations.
The evaluation of cognitive complaints remains an important, but difficult, issue in neuropsychiatric diagnoses. Although objective demonstration of cognitive deficit is always helpful and is the gold standard against which other diagnostic methods must be measured, clinical mental status testing is often too brief to pick up subtle changes, and detailed neu- ropsychological testing is not available in many clinical settings. Furthermore, as discussed, there appear to be many instances in which subjective complaint is more sensitive than objective testing in predicting subsequent progression to organic dementia. The reverse situation, in which patients and sometimes caregivers are unaware of cognitive deficits that are plainly apparent on mental status testing, is another impediment to timely diagnosis.
The problem of delayed diagnosis of dementia probably can be overcome to some extent by better public awareness and by having general physicians routinely question patients and family members about cognition and by testing patients for cognitive symptoms. The problem of differentiating benign from pathological cognitive complaints is a much more difficult issue to resolve. There is a striking lack of hard data to confirm or disprove traditional clinical teachings regarding this issue.
Although numerous memory and cognitive questionnaires exist,21-23 these instruments typically provide an overall quantitative measure of cognitive complaint. Perhaps studies that examine qualitative patterns of memory complaint will provide the diagnostician with helpful information in distinguishing benign cognitive complaints from complaints heralding incipient dementia. Until reliable and predictive biomarkers of neurodegenerative diseases become available, it remains up to the clinician, using traditional clinical techniques, to make these important distinctions.
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