Q: Recent research has defined mild cognitive impairment as a transitional state between the cognitive changes of normal aging and Alzheimer disease (AD) and other dementing illnesses. What criteria are used to differentiate mild cognitive impairment from more innocuous syndromes, such as benign senescent forgetfulness? Are patients with mild cognitive impairment considered to have incipient clinical AD? A: Benign senescent forgetfulness (age-associated memory impairment)-which results from the slowing of neural processes with age-is thought to be an extreme of normal aging. It does not significantly interfere with activities of daily living and is not a precursor of pathologic aging. As we age, we all notice an increase in "senior moments"- such as forgetting someone's name or why we went into a particular room. Benign senescent forgetfulness usually affects short-term memory rather than long-term or remote memory. Impaired learning ability manifests only in the setting of timed testing. Persons with benign forgetfulness are usually more concerned about this than family members. If a patient complains of being forgetful, he or she is less likely to have a dementia than if a family member reports it and the patient denies it. Mild cognitive impairment can be characterized as memory impairment without dementia (Table 1); that is, patients experience memory loss, but other higher cortical functions remain intact and none of the other features that suggest dementia (Table 2) are present. Patients may manifest memory impairment that is more extensive than would be expected for their age or have some minor word-finding difficulties. Mild cognitive impairment can be documented on objective tests of memory.1 However, general cognitive function is preserved and activities of daily living, social relationships, and occupational responsibilities are not affected. Therefore, patients with mild cognitive impairment do not meet criteria for clinically probable AD. It is not yet known whether mild cognitive impairment represents the earliest stages of AD or is a distinct clinical entity. Persons with benign senescent forgetfulness have a 1% to 2% per-year risk of progressing to dementia-the same as that for all persons 65 years or older. However, clinically probable AD develops in up to 25% of persons with mild cognitive impairment per year.2,3 Q: What is the best way to evaluate a patient who presents with memory impairment-or whose family is concerned about this? A: The first step is to rule out dementia, a condition that always involves a decline from a previous level of intellectual functioning.4 Dementia is a clinical diagnosis based on a history of cognitive decline and the absence of other conditions, such as delirium or depression. Screening tests-even if they are adjusted for educational level-are not diagnostic of dementia. The diagnosis of dementia is made following documentation of memory impairment (usually short-term memory), which typically manifests first, and at least one other cognitive disturbance, such as apraxia, agnosia, aphasia, or impaired executive function. Each of the cognitive deficits causes significant social or occupational dysfunction and affects activities of daily living. Early personality changes are more characteristic of AD, whereas early emotional lability is usually associated with multi-infarct dementias. Frontal lobe dementias typically present with depressive symptoms or excessive behaviors. Poor judgment can occur with all types of dementia; it may result from a combination of cognitive deficits or the patient's attempts to hide memory impairment. Q: How valuable are the screening tests used to evaluate patients with cognitive impairment? A: The Mini-Mental State Examination (MMSE) is probably the most commonly used instrument to screen for cognitive impairments. The MMSE (which also exists in shorter versions) is likely to be particularly useful for detecting early dementia, before the onset of functional and behavioral disturbances. However, screening instruments are not sufficient by themselves to make a diagnosis of dementia, in part because performance on such tests is a function of many factors, including education, age, cultural background, and comorbid conditions. Formal neuropsychological testing may be required to support a clinical diagnosis of dementia or mild cognitive impairment. Although a screening test cannot alone make a diagnosis of dementia, results can guide the investigation of other diagnostic possibilities. If a patient scores between 24 and 26 on the MMSE (the normal range is above 24, and 30 is the highest score), he may still meet the criteria for dementia. The MMSE primarily tests different aspects of orientation, language, and memory; the test of constructional abilities counts for only 1 of 30 points. The Clock Drawing Test further tests these abilities, as well as more complex higher cognitive functions, and is a useful adjunct to the MMSE (Figure). Persons with benign senescent forgetfulness should score in the normal range on screening cognitive tests (except for timed testing exercises), because their ability to learn new information is not impaired. Persons with mild cognitive impairment might get only 1 or 2 of 3 objects cor- rect on a 3-object recall but should be able to perform well on other areas of the MMSE. Screening tests can be administered at different points over the course of a dementing illness; thus, they can help track disease progression. Since the rate of cognitive decline varies greatly, these tests enable you to document changes objectively. A concomitant problem-such as an adverse effect of a medication-may escalate the rate of decline. When this effect is identified and the drug is withdrawn, the related cognitive changes may reverse themselves. Q: Does current research support an intervention- such as pharmacotherapy-early in the course of mild cognitive impairment? A: Some researchers advocate starting therapy with a cognitiveenhancing agent, such as a cholinesterase inhibitor, for patients with mild cognitive impairment. The reasoning is that since there is a high conversion rate from mild cognitive impairment to AD, it is likely that many patients with mild cognitive impairment have the underlying neuropathology of AD, even though they do not yet meet clinical diagnostic criteria.5 This question remains controversial, however. Some research suggests that cholinesterase inhibitors may slow the progression of the underlying pathology while providing symptomatic management for patients with dementia. However, there is no evidence that mild cognitive impairment can be successfully treated.1 Thus, I do not recommend that cholinesterase inhibitors be used until there is an actual diagnosis of dementia. In the case of a patient with mild cognitive impairment, I first rule out medication side effects and depression, document the cognitive changes, administer the appropriate screening tests, and have the patient return in 6 months to assess the progression of the documented changes. Q: There is some debate about the value of neuroimaging in patients with mild cognitive impairment. What is its role? A: In the absence of neurologic findings, initial neuroimaging studies in a patient with mild cognitive impairment are of limited value. Significant hippocampal and entorhinal cortex atrophy has been found in patients with mild cognitive impairment; such changes are not found in healthy persons. However, these changes do not have a high predictive value for individual patients.6 Consider CT or MRI for a patient with atypical features of dementia or for a patient with dementia who is experiencing a period of cognitive decline that is more rapid than would be expected. Atypical features or rapid decline may suggest another pathology-such as normal-pressure hydrocephalus, which is a treatable component of dementia. Q: What common causes of memory impairment are most likely to mimic dementia? How can I efficiently rule them out? A: Drug reactions, depression, and delirium must be ruled out before a diagnosis of dementia can be made. More than half of treatable dementias are attributable to either depression or an adverse effect of medication. Unfortunately, it is very tempting to prescribe a cognitive-enhancing drug if a patient complains of memory impairment. However, it is crucial to be absolutely certain of the diagnosis to ensure appropriate management. Even in a patient with diagnosed dementia, it is worth reviewing his medications and discontinuing those with adverse cognitive effects, to optimize the benefits of a cognitive-enhancing agent. Drug reactions. If your patient presents with a memory complaint, be sure that the history includes a complete list of medications he is taking, including over-the-counter remedies, complementary and alternative agents, and any "borrowed"drugs. The medications most closely associat- ed with memory impairment are benzodiazepines and narcotic analgesics. Agents that have anticholinergic side effects- including some harmless-seeming ones, such as allergy medications and H2 blockers like ranitidine(Drug information on ranitidine)-can also impair memory temporarily. In most cases, drug-related memory impairment develops gradually, as metabolites build up. This is particularly the case with benzodiazepines, such as lorazepam and alprazolam(Drug information on alprazolam), which are both fat-soluble; the changes can be fairly subtle and the patient may not be aware of them. If you suspect a drug reaction, taper and/or stop the suspected agent immediately. Memory function generally returns to normal within a week or so of drug discontinuation, and the change is very obvious both to the patient and to his family members or caregivers. Depression. Memory complaints can sometimes confuse the clinical picture in a patient with depression. Depressed elderly persons usually report low energy, loss of appetite, and sleep problems. They feel worst when they get up in the morning. Memory complaints in such patients are often subjective and reflect an impaired ability to concentrate, but may result in "I don't know" answers on objective tests. Even if you suspect coexisting dementia (documented depression in the early stages of dementia is common), it is wise to treat depression first in these persons. Delirium. Dementia is a risk factor for delirium. In general, delirium has a relatively sudden onset (over days to a couple of weeks in outpatients), is usually reversible, and is often associated with medication use or withdrawal or with an acute illness. Dementia is characterized by insidious onset and gradual decline over a long period (typically more than 6 months); it is not usually associated with a pharmacologic agent or an acute illness. If a patient's family reports that he had an acute episode of confusion during hospitalization and relates this to the onset of cognitive decline, it may be difficult to be certain of the underlying diagnosis. The first step is to manage any factors that might cause delirium; the next is to treat suspected depression before moving on to confirm a diagnosis of dementia and initiating cognitive-enhancing therapy. Q: Can you recommend any guidelines for helping a patient withdraw from a drug, such as a benzodiazepine, that may be responsible for memory impairment? A: It can, of course, be difficult to wean patients off certain agents-particularly the benzodiazepines, such as alprazolam. These agents can be quite addictive, and patients can experience withdrawal symptoms, such as insomnia, anxiety, or even seizures.7 The taper needs to be done quite slowly to ensure compliance; the process may take as long as 3 to 6 months for patients who have been using elevated dosages. It is essential to have the patient's cooperation in the withdrawal process. I have had good results by assigning the patient the responsibility of determining the rate of the taper, using goal setting as an incentive. In some of my patients who have been taking a benzodiazepine (particularly alprazolam), I taper the dosage down to lower levels and then substitute oxazepam(Drug information on oxazepam). Because this agent is water-soluble rather than lipid-soluble, its onset is slower, its duration of action is predictable, it has no active metabolites, and it is less addictive. Temazepam(Drug information on temazepam) is an alternative water-soluble benzodiazepine that is a particularly effective replacement for nighttime sedatives for insomnia. Q: We've all had patients who insist that without their benzodiazepines they have unacceptable levels of anxiety or insomnia. How do you address these concerns? A: I explain to patients that although they may have been taking a particular drug without any apparent side effects for a long time, aging of the brain diminishes the ability to tolerate the medication as before. I tell them that these drugs can cause cognitive impairment and also increase the risk of depression or delirium. I emphasize that rather than concentrating on the loss of the insomnia medication or anxiolytic, they should view the process as an investment in the recovery of their memory. Q: What is a good substitute if patients require a sleep aid during the period in which a benzodiazepine is being withdrawn? A: I initially prescribe a nightly dose of trazodone, a mild antidepressant with very good sedative properties. I start with 25 mg for the first 4 days and then titrate up to 50 or 100 mg if necessary, over a period of a few weeks. This strategy ensures efficacy without daytime somnolence. Ultimately, the goal is to have the patient discontinue all sleep- ing medications, but it's a lot easier-and probably safer- to wean a patient off trazodone than some of the other agents; for example, benzodiazepine withdrawal symptoms do not occur with trazodone. Some patients find that alcohol(Drug information on alcohol) helps induce sleep, but alcohol disrupts sleep architecture and may also contribute to cognitive impairment. Alcohol use is best discouraged in patients with this condition. Q: Is there evidence that supports (or refutes) the use of ginkgo biloba(Drug information on ginkgo biloba) to prevent or treat memory disorders? Some of my patients start taking it when they notice that they are becoming forgetful. A: A recent randomized, double-blind, placebo-controlled 6-week trial of a ginkgo product found that it did not improve memory or related cognitive function in cognitively normal adults older than 60 years.8 A recent metaanalysis by Birks and colleagues9 found that there was some evidence of improvement in cognition and function associated with ginkgo among patients with cognitive impairment. However, these authors noted that many of the trials were small and methodologically flawed and that publication bias could not be ruled out. They also observed that the results of more recent trials have been ambiguous. Certainly one concern about using ginkgo biloba is the lack of batch-to-batch consistency. Some of my patients who have taken ginkgo seem to derive real benefit from it, although the objective evidence of benefit is anecdotal at best. The powerful placebo effect of this agent (as high as 50% in some trials) has been demonstrated repeatedly and may result from changes at the neurotransmitter level. Some research suggests that a change in a patient's environment or the way he feels about himself can be as effective as medication. Such psychological factors have very powerful effects that we don't completely understand.