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Q:Recent research has defined mild cognitiveimpairment as a transitional state between thecognitive changes of normal aging and Alzheimerdisease (AD) and other dementing illnesses. Whatcriteria are used to differentiate mild cognitiveimpairment from more innocuous syndromes, such asbenign senescent forgetfulness? Are patients with mildcognitive impairment considered to have incipientclinical AD?
Q: Recent research has defined mild cognitiveimpairment as a transitional state between thecognitive changes of normal aging and Alzheimerdisease (AD) and other dementing illnesses. Whatcriteria are used to differentiate mild cognitiveimpairment from more innocuous syndromes, such asbenign senescent forgetfulness? Are patients with mildcognitive impairment considered to have incipientclinical AD?A: Benign senescent forgetfulness (age-associated memoryimpairment)-which results from the slowing ofneural processes with age-is thought to be an extreme ofnormal aging. It does not significantly interfere with activitiesof 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 intoa particular room. Benign senescent forgetfulness usuallyaffects short-term memory rather than long-term or remotememory. Impaired learning ability manifests only in the settingof timed testing. Persons with benign forgetfulness areusually more concerned about this than family members. Ifa patient complains of being forgetful, he or she is less likelyto have a dementia than if a family member reports it andthe patient denies it.Mild cognitive impairment can be characterized asmemory impairment without dementia (Table 1); that is,patients experience memory loss, but other higher corticalfunctions remain intact and none of the other features thatsuggest dementia (Table 2) are present. Patients may manifestmemory impairment that is more extensive than wouldbe expected for their age or have some minor word-findingdifficulties. Mild cognitive impairment can be documentedon objective tests of memory.1 However, general cognitivefunction is preserved and activities of daily living, social relationships,and occupational responsibilities are not affected.Therefore, patients with mild cognitive impairment donot meet criteria for clinically probable AD. It is not yetknown whether mild cognitive impairment represents theearliest 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 sameas that for all persons 65 years or older. However, clinicallyprobable AD develops in up to 25% of persons with mildcognitive impairment per year.2,3Q: What is the best way to evaluate a patient whopresents with memory impairment-or whosefamily is concerned about this?A: The first step is to rule out dementia, a condition thatalways involves a decline from a previous level of intellectualfunctioning.4 Dementia is a clinical diagnosisbased on a history of cognitive decline and the absence ofother conditions, such as delirium or depression. Screeningtests-even if they are adjusted for educational level-arenot diagnostic of dementia.The diagnosis of dementia is made following documentationof memory impairment (usually short-termmemory), which typically manifests first, and at least oneother cognitive disturbance, such as apraxia, agnosia, aphasia,or impaired executive function. Each of the cognitivedeficits causes significant social or occupational dysfunctionand affects activities of daily living.Early personality changes are morecharacteristic of AD, whereas earlyemotional lability is usually associatedwith multi-infarct dementias. Frontallobe dementias typically present withdepressive symptoms or excessive behaviors.Poor judgment can occur withall types of dementia; it may resultfrom a combination of cognitive deficitsor the patient's attempts to hidememory impairment.Q: How valuable are the screening tests used toevaluate patients with cognitive impairment?A: The Mini-Mental State Examination (MMSE) is probablythe most commonly used instrument to screenfor cognitive impairments. The MMSE (which also exists inshorter versions) is likely to be particularly useful for detectingearly dementia, before the onset of functional andbehavioral disturbances. However, screening instrumentsare not sufficient by themselves to make a diagnosis of dementia,in part because performance on such tests is a functionof many factors, including education, age, cultural background,and comorbid conditions. Formal neuropsychologicaltesting may be required to supporta clinical diagnosis of dementia or mildcognitive impairment.Although a screening test cannotalone make a diagnosis of dementia,results can guide the investigation ofother diagnostic possibilities. If a patientscores between 24 and 26 on theMMSE (the normal range is above 24,and 30 is the highest score), he maystill meet the criteria for dementia. TheMMSE primarily tests different aspectsof orientation, language, and memory; the test of constructionalabilities counts for only 1 of 30 points. The ClockDrawing Test further tests these abilities, as well as morecomplex higher cognitive functions, and is a useful adjunctto the MMSE (Figure).Persons with benign senescent forgetfulness shouldscore in the normal range on screening cognitive tests (exceptfor timed testing exercises), because their ability tolearn new information is not impaired. Persons with mildcognitive impairment might get only 1 or 2 of 3 objects cor-rect on a 3-object recall but should be able to perform wellon other areas of the MMSE.Screening tests can be administered at different pointsover the course of a dementing illness; thus, they can helptrack disease progression. Since the rate of cognitive declinevaries greatly, these tests enable you to document changesobjectively. A concomitant problem-such as an adverse effectof a medication-may escalate the rate of decline. Whenthis effect is identified and the drug is withdrawn, the relatedcognitive changes may reverse themselves.Q: Does current researchsupport an intervention-such as pharmacotherapy-early inthe course of mild cognitiveimpairment?A: Some researchers advocatestarting therapy with a cognitiveenhancingagent, such as a cholinesteraseinhibitor, for patients with mildcognitive impairment. The reasoning is that since there is ahigh conversion rate from mild cognitive impairment toAD, it is likely that many patients with mild cognitive impairmenthave the underlying neuropathology of AD, eventhough they do not yet meet clinical diagnostic criteria.5This question remains controversial, however. Someresearch suggests that cholinesterase inhibitors may slowthe progression of the underlying pathology while providingsymptomatic management for patients with dementia.However, there is no evidence that mild cognitive impairmentcan be successfully treated.1 Thus, I do not recommendthat cholinesterase inhibitors be used until there is anactual diagnosis of dementia. In the case of a patient withmild cognitive impairment, I first ruleout medication side effects and depression,document the cognitivechanges, administer the appropriatescreening tests, and have the patientreturn in 6 months to assess the progressionof the documented changes.Q: There is some debate aboutthe value of neuroimaging inpatients with mild cognitiveimpairment. What is its role?A: In the absence of neurologicfindings, initial neuroimagingstudies in a patient with mild cognitiveimpairment are of limited value. Significanthippocampal and entorhinalcortex atrophy has been found in patients with mild cognitiveimpairment; such changes are not found in healthy persons.However, these changes do not have a high predictivevalue for individual patients.6Consider CT or MRI for a patient with atypical featuresof dementia or for a patient with dementia who is experiencinga period of cognitive decline that is more rapid thanwould be expected. Atypical features or rapid decline maysuggest another pathology-such as normal-pressure hydrocephalus,which is a treatable component of dementia.Q: What common causes ofmemory impairment aremost likely to mimic dementia?How can I efficiently rule them out?A: Drug reactions, depression, anddelirium must be ruled out beforea diagnosis of dementia can bemade. More than half of treatable dementiasare attributable to either depressionor an adverse effect of medication. Unfortunately,it is very tempting to prescribe a cognitive-enhancing drugif a patient complains of memory impairment. However, itis crucial to be absolutely certain of the diagnosis to ensureappropriate management. Even in a patient with diagnoseddementia, it is worth reviewing his medications and discontinuingthose with adverse cognitive effects, to optimizethe benefits of a cognitive-enhancing agent.Drug reactions. If your patient presents with a memorycomplaint, be sure that the history includes a completelist of medications he is taking, including over-the-counterremedies, complementary and alternative agents, and any"borrowed"drugs. The medications most closely associat-ed with memory impairment are benzodiazepines and narcoticanalgesics. Agents that have anticholinergic side effects-including some harmless-seeming ones, such as allergymedications and H2 blockers like ranitidine-can alsoimpair memory temporarily.In most cases, drug-related memory impairment developsgradually, as metabolites build up. This is particularlythe case with benzodiazepines, such as lorazepam and alprazolam,which are both fat-soluble; the changes can befairly subtle and the patient may not be aware of them. Ifyou suspect a drug reaction, taper and/or stop the suspectedagent immediately. Memory function generally returnsto normal within a week or so of drug discontinuation, andthe change is very obvious both to the patient and to hisfamily members or caregivers.Depression. Memory complaintscan sometimes confuse the clinical picturein a patient with depression. Depressedelderly persons usually reportlow energy, loss of appetite, and sleepproblems. They feel worst when theyget up in the morning. Memory complaintsin such patients are often subjectiveand reflect an impaired abilityto concentrate, but may result in "Idon't know" answers on objectivetests. Even if you suspect coexistingdementia (documented depression inthe early stages of dementia is common),it is wise to treat depression firstin these persons.Delirium. Dementia is a risk factorfor delirium. In general, deliriumhas a relatively sudden onset (over days to a couple ofweeks in outpatients), is usually reversible, and is often associatedwith medication use or withdrawal or with an acuteillness. Dementia is characterized by insidious onset andgradual decline over a long period (typically more than 6months); it is not usually associated with a pharmacologicagent or an acute illness.If a patient's family reports that he had an acute episodeof confusion during hospitalization and relates this to theonset of cognitive decline, it may be difficult to be certain ofthe underlying diagnosis. The first step is to manage any factorsthat might cause delirium; the next is to treat suspecteddepression before moving on to confirm a diagnosis of dementiaand initiating cognitive-enhancing therapy.Q: Can you recommend any guidelines for helpinga patient withdraw from a drug, such as abenzodiazepine, that may be responsible for memoryimpairment?A: It can, of course, be difficult to wean patients off certainagents-particularly the benzodiazepines, such asalprazolam. These agents can be quite addictive, and patientscan experience withdrawal symptoms, such as insomnia,anxiety, or even seizures.7 The taper needs to be done quiteslowly to ensure compliance; the process may take as longas 3 to 6 months for patients who have been using elevateddosages. It is essential to have the patient's cooperation inthe withdrawal process. I have had good results by assigningthe patient the responsibility of determining the rate ofthe taper, using goal setting as an incentive.In some of my patients who have been taking a benzodiazepine(particularly alprazolam), I taper the dosagedown to lower levels and then substitute oxazepam. Becausethis agent is water-soluble ratherthan lipid-soluble, its onset is slower,its duration of action is predictable, ithas no active metabolites, and it is lessaddictive. Temazepam is an alternativewater-soluble benzodiazepine that is aparticularly effective replacement fornighttime sedatives for insomnia.Q: We've all had patients whoinsist that without theirbenzodiazepines they haveunacceptable levels of anxiety orinsomnia. How do you addressthese concerns?A: I explain to patients that althoughthey may have beentaking a particular drug without anyapparent side effects for a long time, aging of the brain diminishesthe ability to tolerate the medication as before.I tell them that these drugs can cause cognitive impairmentand also increase the risk of depression or delirium.I emphasize that rather than concentrating on the loss ofthe insomnia medication or anxiolytic, they should viewthe process as an investment in the recovery of theirmemory.Q: What is a good substitute if patients require asleep aid during the period in which abenzodiazepine is being withdrawn?A: I initially prescribe a nightly dose of trazodone, a mildantidepressant with very good sedative properties. Istart with 25 mg for the first 4 days and then titrate up to 50or 100 mg if necessary, over a period of a few weeks. Thisstrategy 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 otheragents; for example, benzodiazepine withdrawal symptomsdo not occur with trazodone.Some patients find that alcohol helps induce sleep, butalcohol disrupts sleep architecture and may also contributeto cognitive impairment. Alcohol use is best discouraged inpatients with this condition.Q: Is there evidence that supports (or refutes) theuse of ginkgo biloba to prevent or treatmemory disorders? Some of my patients start taking itwhen they notice that they are becoming forgetful.A: A recent randomized, double-blind, placebo-controlled6-week trial of a ginkgo product found that it did notimprove memory or related cognitivefunction in cognitively normal adultsolder than 60 years.8 A recent metaanalysisby Birks and colleagues9 foundthat there was some evidence of improvementin cognition and function associatedwith ginkgo among patientswith cognitive impairment. However,these authors noted that many of thetrials were small and methodologicallyflawed and that publication bias couldnot be ruled out. They also observedthat the results of more recent trialshave been ambiguous.Certainly one concern about using ginkgo biloba is thelack of batch-to-batch consistency. Some of my patients whohave taken ginkgo seem to derive real benefit from it, althoughthe objective evidence of benefit is anecdotal at best.The powerful placebo effect of this agent (as high as 50% insome trials) has been demonstrated repeatedly and may resultfrom changes at the neurotransmitter level.Some research suggests that a change in a patient'senvironment or the way he feels about himself can be as effectiveas medication. Such psychological factors have verypowerful effects that we don't completely understand.
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