CLINICIAN’S CORNER

CLINICAL CROSSROADS
CONFERENCES WITH PATIENTS AND DOCTORS

A 60-Year-Old Woman
With Mild Memory Impairment
Review of Mild Cognitive Impairment
James M. Ellison, MD, MPH, Discussant
DR LIBMAN: Ms E, a 60-year-old divorced woman living independently in active semiretirement, described her cognitive health as good until the summer of 2005. At that time,
she and her children noticed her difficulty recalling where
she placed objects, her forgetfulness about recent conversations, and her growing reliance on written reminders. As
part of an evaluation by her primary care physician, a magnetic resonance image (MRI) was obtained and revealed bilateral subcortical and periventricular discrete and confluent T2-enhancing white matter lesions with no significant
cortical atrophy (FIGURE and interactive eFigure, available
at http://www.jama.com). She was treated with paroxetine,
30 mg/d, to address concurrent symptoms of depression and
anxiety, and she was referred for further neurocognitive assessment. Her only other medication was low-dose aspirin.
She had no prior history of hypertension, diabetes mellitus, head trauma, or psychiatric illnesses. A history of tick
bites was elicited, and she had been smoking 1 pack of cigarettes per day for 30 years. She denied abuse of alcohol, illicit drugs, or prescription medications. Her family history
was negative for dementia. Physical examination showed a
blood pressure of 118/70 mm Hg and a regular pulse of 60/
min, and was noteworthy only for brisk symmetric reflexes
and a right-sided upgoing great toe. Her mental status examination showed a depressed and anxious mood. Attention and naming were intact. On a brief test of memory, she
recalled only 1 of 4 words after a delay but recognized the
other 3. She had some difficulty drawing a clock correctly.
Her complete blood cell count, erythrocyte sedimentation
rate, glucose, electrolytes, thyrotropin, and vitamin B12 levels were normal, and her Lyme disease and syphilis serologic studies were nonreactive. Her serum cholesterol was
mildly increased at 207 mg/dL (5.36 mmol/L) with a lowSee also Patient Page.
CME available online at www.jamaarchivescme.com
and questions on p 1598.
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Many older individuals experience or demonstrate cognitive impairment that is significantly abnormal for their
age and education yet beneath the threshold for a diagnosis of dementia. This mild cognitive impairment causes
minimal functional impairment and is often overlooked
in clinical settings, yet affected individuals are at heightened risk for a range of adverse outcomes including conversion to dementia. The case of Ms E, a 60-year-old
woman with mild memory impairment and white matter lesions on magnetic resonance imaging, provides
an opportunity to consider the questions that face patient, family, and clinicians when mild cognitive symptoms prompt a search for diagnosis and management
options. Discussion of her case reviews mild cognitive
impairment with emphasis on an evidence-based approach to evaluation and treatment, including management of comorbid medical conditions, lifestyle changes,
and pharmacotherapy.
JAMA. 2008;300(13):1566-1574

www.jama.com

density lipoprotein component of 120 mg/dL (3.11 mmol/L).
Lumbar puncture showed no abnormalities. Antinuclear antibody was present at 1:40 dilution with a speckled pattern. Apolipoprotein E (ApoE) genotype revealed the presence of a heterozygous state, e3/e4.
One year later, Ms E returned to her neurologist concerned that her memory impairment had worsened. In adThis conference took place at the Psychiatry Grand Rounds at Brigham and Women’s Hospital, Boston, Massachusetts, on April 13, 2007.
Author Affiliations: Dr Ellison is Associate Professor of Psychiatry, Harvard Medical School; Clinical Director, Geriatric Psychiatry Program, and Director, Memory
Diagnostic Clinic, McLean Hospital, Belmont, Massachusetts.
Corresponding Author: James M. Ellison, MD, MPH, McLean Hospital, SB 322,
115 Mill St, Belmont, MA 02478 (ellisonj@mcleanpo.mclean.org).
Clinical Crossroads at Beth Israel Deaconess Medical Center is produced and edited by Tom Delbanco, MD, Howard Libman, MD, Eileen E. Reynolds, MD, Amy
N. Ship, MD, and Anjala V. Tess, MD. Risa B. Burns, MD, is series editor.
Clinical Crossroads Section Editor: Margaret A. Winker, MD, Deputy Editor.

©2008 American Medical Association. All rights reserved.

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CLINICAL CROSSROADS

dition to forgetfulness, she newly reported increased difficulty balancing her checkbook. She described emotional
distress despite continuation of paroxetine. Her delayed recall appeared more impaired, with spontaneous recall of 0
of 4 words after a brief delay, recognition of only 2, and generation of 2 false positives. A formal test of memory, the California Verbal Learning Test, showed impaired learning of
new words, impaired delayed recall, and a number of false
positives among the words she recognized. Her clock drawing appeared more impaired, and she showed executive function deficits in her Trails B performance. Verbal fluency was
below expectation, with phonemic dysfunction greater than
semantic dysfunction. A single-photon emission computed tomographic scan showed no focal or regional cortical perfusion abnormalities. On the 30-item Geriatric Depression Scale she scored 12 points, which is consistent with
mild depression. She was given a diagnosis of early Alzheimer disease (AD). She continued paroxetine, 30 mg/d, and
began taking donepezil, which was titrated up to 10 mg/d.
MS E: HER VIEW
I have always been in good health, and I’ve prided myself
with my health. I walk 3 to 5 miles a day, and I’ve done so
for years. It was in 2005 that I first noticed I was forgetful.
I remember thinking, “This is not right.”
There were things that I couldn’t remember, and then I would
panic because that’s not like me. I began to take notes as to what
I did for the day and started keeping a journal, which helped.
But I was at the time in some sort of denial. I had had a viral
infection, and I thought it might be the aftereffect of that.
I had sold real estate, and then I decided to just chill a
little bit and work in a garden center. I have loved it. Last
summer, a couple times I would forget where I left my garden gloves or my scissors, or some plants, within the nursery. But that was my “little secret.” I never told anyone, and
I eventually found them.
I think it’s gotten worse. But I think what I struggle with
mostly is self-doubt now, because I know I have this condition. I don’t have the confidence within me that I used to
have in terms of taking my pills. So I check them off and I
make sure, and then I question whether I took them.
Just since my recent visit with my doctor, I’ve been very
concerned and upset about myself. He gave me a time frame,
and I refused to hear it.
Myfamilyhasbeenverysupportive.I’vesortofplayeditdown,
and I guess with this most recent diagnosis, I’m going to have
to make some decisions as to what I’m going to do. I just keep
hoping for a cure for this disease. I think my days are numbered.
I can’t imagine what will come; it’s frightening for me.
AT THE CROSSROADS:
QUESTIONS FOR DR ELLISON
How can mild cognitive impairment be distinguished from
normal cognitive aging? Should case-finding of sympto©2008 American Medical Association. All rights reserved.

Figure. T2-Weighted Fluid-Attenuated Inversion Recovery Magnetic
Resonance Image of Ms E’s Brain
Distribution of
white matter lesions

A

R

L

P

matic but undiagnosed elders be encouraged and if so, how
should case-finding be accomplished? When mild cognitive impairment is suspected, what diagnostic assessment
should be performed? Which conditions should be considered in the differential diagnosis of cognitive decline in older
adults? How do lifestyle, nutrition, and psychosocial or pharmacologic interventions affect cognition in aging? How
should concerns about driving, employment, financial issues, and residential arrangements be addressed? What would
you recommend for Ms E?
DR ELLISON: The clinical significance of cognitive changes
associated with aging or disease has attracted increasing attention in recent years. Baby boomers nearing retirement
share with neuroscientists and clinicians a desire to understand typical patterns of age-associated cognitive changes
and to improve techniques for earlier detection of pathological signs. Aging adults are encouraged by the media to
do crossword puzzles, to use software programs that claim
to offer beneficial cognitive stimulation, to attend groups
that teach memory skills, and to consult the many selfhelp books containing tips about physical and mental exercise, diet, and use of food supplements purported to enhance brain functioning and mitigate adverse consequences
of aging. Many vigorous older adults approach these activities with enthusiasm, even in the absence of strong evidence that these interventions effectively prevent or delay
cognitive decline. Within the medical system, memory diagnostic clinics that provide comprehensive evaluations have
become increasingly available.
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Normal Cognitive Aging, Mild Cognitive Impairment,
and Dementia

Cognition, like other bodily functions, shows typical ageassociated decrements. The Diagnostic and Statistical Manual
of Mental Disorders, for example, defines age-related cognitive decline (ARCD) as impairment of cognitive functioning that is “within normal limits given the person’s age.”1
Episodic memory (recall of experiences and events) begins
to decline as early as the 20s,2 and spontaneous recall (of
names, for example), working memory, processing speed,
selective attention, and ability to multitask are among the
faculties that decline during the usual course of aging. Semantic memory (factual and conceptual knowledge), procedural memory, and language abilities can be preserved until late in life.3
Among older adults, memory complaints are reported by
as many as 56%.4 Even complaints without objectively demonstrable memory impairment may predict a mildly increased risk for later dementia.5 This subjective memory impairment (SMI)6 may also reflect the presence of depression,7
neuroticism,8 anxiety, fatigue, stress, chronic pain,9 disordered sleep, substance abuse, untoward effects of prescription medications, and/or other medical conditions.
Cognitive functioning abnormal for age and education
without meeting criteria for dementia, as seen in Ms E, should
not be attributed to normal aging. A syndrome of cognitive
impairment–no dementia (CIND) was estimated in one large
cross-sectional population study to affect 16.8% of an elderly population.10 A more restrictively defined syndrome
with lower expected prevalence, mild cognitive impair-

ment (MCI), has been defined to include a cognitive complaint, objectively impaired neuropsychological test performance, and essentially intact activities of daily living.11
Depending on whether a single or multiple areas of cognitive impairment can be demonstrated, and on whether
memory is or is not significantly impaired, MCI patients are
divided into 4 subgroups: amnestic single domain, amnestic multiple domain, nonamnestic single domain, and nonamnestic multiple domain.11 The characteristics of normal
cognitive aging (ARCD), subjective memory impairment,
mild cognitive impairment, and dementia are contrasted in
the TABLE.
By Diagnostic and Statistical Manual of Mental Disorders
criteria,1 the diagnosis of dementia requires that an acquired impairment of memory and an additional domain of
cognitive impairment (either aphasia, apraxia, agnosia, or
executive dysfunction) be demonstrated. These decrements must not be explained by delirium or other medical
or psychiatric disorders. In addition, memory and the other
abnormal cognitive function must each be associated with
significant social and/or occupational impairment.1 The clinician’s judgment about the degree of functional incapacitation of a patient, based in part on the reports of family members or others, will in many cases determine whether a
diagnosis of amnestic multiple-domain MCI or early dementia is made.
Detection and Assessment of MCI

A diagnosis of dementia sets in motion profound life changes
that affect self-esteem, autonomy, interpersonal relation-

Table. Clinical Features of Age-Related Cognitive Decline, Subjective Memory Impairment, Mild Cognitive Impairment (MCI), and Dementia

Subjective concern
Observer concern
Memory impairment

Nonmemory cognitive
dysfunction

Age-Related
Subjective
Cognitive Decline1
Memory Impairment6
Often present
Present
Typically not present
Typically not present
Present: mild (episodic
Subjectively present,
memory, spontaneous
not demonstrated
recall, working memory)
on testing
Preserved procedural
and semantic memory

Mild Cognitive
Impairment11
May be absent
Typically present

Present: mild (processing
speed, selective
attention)

Complaints on individual
tasks of daily living

Present in amnestic multiple
Present sufficiently to impair
domain and in
social and/or
nonamnestic MCI
occupational functioning
(executive dysfunction,
aphasia, apraxia, agnosia,
and/or impaired
visuospatial function)
Essentially intact basic
activities of daily living

Preserved attention span
and language

Present in amnestic MCI
(episodic memory)

Dementia1
May be absent
Present
Present sufficiently to impair
social and/or
occupational functioning

Functional impairment

Not present

Not present

Mild if present (may have
increased difficulty
performing more
complex instrumental
activities of daily living)

Present

Behavioral abnormalities

Not typically present

May be present
(depression or anxiety)

Often present (depression,
anxiety, apathy)

Often present (depression,
anxiety, apathy, agitation)

Neuroimaging abnormalities

May be present (mild age-related atrophy and/or
white matter disease)

Often present (mild to
moderate atrophy and/or
white matter disease)

Often present (atrophy and/or
white matter disease)

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ships, employment, income, medical care, residential decisions, and plans for the future. Dementia, therefore, should
be diagnosed with considerable caution and on the basis of
appropriate evidence. Ms E, with relatively unimpaired function despite her subjective distress and objective neuropsychological findings, was prematurely given the diagnosis of
early AD. A diagnosis of amnestic multiple-domain MCI
would more accurately reflect her level of functioning at the
time of examination, which was below expectation for normal aging but not so impaired as to warrant a diagnosis of
dementia. Even the designation of MCI, however, is often a
distressing one.
Evidence suggests that amnestic MCI is often an intermediate-stage neurocognitive disorder between normal cognitive aging and AD. The brain of a patient with amnestic
MCI shows neuropathological changes12 and hippocampal
atrophy.13 Furthermore, the diagnosis of MCI is associated
with an increased lifetime risk for dementia,14 although many
patients with MCI do not progress to dementia over as long
as a decade of follow-up.15
Given the prognostic significance of MCI, the feasibility of identifying symptomatic individuals (“case finding”) has been explored.16 The familiar Mini-Mental State
Examination (MMSE)17 and Clock Drawing Test18 are
often used in primary care settings, although their sensitivities (75% and 51%, respectively) and specificities
(36% and 39%) are modest.19 Detecting asymptomatic
and mildly symptomatic individuals is most justified
when the detection process is unlikely to cause harm and
early recognition is likely to result in improved quality of
life. 20 Although more than half of older adults have
memory complaints,4 objective cognitive impairment is
found in a smaller number and MCI is by definition a
syndrome of minimal functional impairment. Therefore,
the modest clinical value of identifying individuals with
MCI using tests of limited sensitivity and specificity21
must be weighed against the possible harm associated
with the assignment of a diagnostic label that might
result in emotional stress or costly life consequences such
as a decrease in insurability.22 Furthermore, current suggestions for lifestyle modifications overlap substantially
with recommendations already made for healthier
aging.23,24 Because of these considerations, the clinical
value of large-scale case-finding for MCI remains
controversial.25-27
In contrast, even mild dementia is appropriate for casefinding. Unrecognized dementia is associated with such complications as an increased risk for motor vehicle crashes, delirium, and hip fracture.28,29 Dementia is often undiagnosed
by primary care physicians,30 perhaps related to patient denial, resistance to cognitive assessment, or the burden of other
tasks that must be completed during a medical encounter.
Increased recognition of dementia through proactive casefinding is justified by its frequency and severity in older
adults, the availability of brief cognitive assessment instru©2008 American Medical Association. All rights reserved.

ments with reasonable sensitivity and specificity,31 modestly but significantly effective interventions,32 and the potential for improving quality of life and safety. A review of
dementia screening tests validated in primary care and community samples reported sensitivities and specificities of commonly used tests as follows: MMSE (69% and 89%), General Practitioner Assessment of Cognition (85% and 86%),
Mini-COG (76% and 89%), and Memory Impairment Screen
(80% and 96%). Each would be suitable for use as an initial
screen for dementia case-finding in a primary care setting.33
Detection of MCI requires more sensitive brief instruments than detection of dementia. Failure to recall all 3 words
on the MMSE despite the total score being in the normal
range can suggest amnestic MCI.34 The Montreal Cognitive Assessment, a brief instrument, has been shown more
sensitive in detecting MCI than the MMSE (90% vs 18%),
although less specific (87% vs 100%).35 More extensive neuropsychological tests, when available, can add more precise characterization of cognitive deficits and establish a reference baseline.21
Although some individuals with MCI are improved at
follow-up, approximately 12% of patients with MCI in
some studies have progressed annually to dementia, compared with 1% to 2% of an elderly community population.11 Despite the absence of a consensus-based standardized disease management protocol, identification of
individuals with MCI can provide an opportunity to identify and address with them potentially remediable medical and lifestyle factors as well as other concerns they
may have. For Ms E, diagnostic questions are raised by
her white matter disease and upgoing toe, smoking and
hypercholesterolemia represent modifiable risk factors,
and her concerns and depressive symptoms suggest the
value of focused counseling in addition to her antidepressant treatment.
Laboratory tests and neuroimaging studies will not diagnose MCI but can help identify treatable causes, since cognitive impairment has a range of potential etiologies, including many treatable conditions such as depression,
delirium, nutritional deficiencies, sleep disorders, metabolic and endocrine disorders, autoimmune diseases, infections, neoplasms, adverse medication effects, misuse of
alcohol or drugs, and cardiopulmonary disorders (most are
addressed in 32). Tests such as antinuclear antibody and
single-photon emission computed tomography, administered early in the assessment of Ms E, are not a routine part
of the initial evaluation of MCI unless clinical history or
physical findings are atypical or suggest that these tests may
contribute to establishing the diagnosis. In patients whose
cognitive impairment is accompanied by symptoms suggesting seizures, infection, or delirium, an electroencephalogram and lumbar puncture may add diagnostic clarity.
Structural neuroimaging with computed tomography or MRI
is recommended in the assessment of individuals with dementia36 and may have value in the assessment of MCI.37 In
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Ms E’s case, the MRI-determined pattern of white matter disease suggests small-vessel disease. The concurrent finding
of a positive Babinski sign, which is frequently found in conjunction with small-vessel disease in patients with vascular
dementia,38 is consistent with that suggestion. The history
of tick bites, white matter disease, and changes in mood and
cognition made it important to consider Lyme disease.
Associated Lifestyle and Medical Factors

Lifestyle, genetic, metabolic, and disease factors affect the
risk of dementia and probably the risk for the conversion
of MCI to dementia. One community sample showed an
odds ratio of 3.4 (95% confidence interval, 1.4-8.0) for the
development of AD among current smokers, while former
smokers’ risk of AD did not differ from that of nonsmokers.39 ApoE genotype is not routinely tested or recommended as a clinical assessment at present, although
patients with amnestic MCI and ApoE e4 genotype such as
Ms E have been found to have greater memory and functional impairment and hippocampal atrophy.40 Dyslipidemic states have been linked with dementia risk in some,
but not all, studies,41 and mild hypercholesterolemia has
been associated with increased Alzheimer amyloid pathology at autopsy.42 Few studies have evaluated the effects of
reducing hyperlipidemia with statins and their findings are
mixed.43 One randomized trial of atorvastatin (80 mg/d) in
patients who, like Ms E, had relatively mildly increased
cholesterol levels, a mild degree of cognitive impairment,
and an ApoE e4 allele showed modest but significant cognitive benefits.44
At least as important as treating Ms E’s hypercholesterolemia is smoking cessation, both to reduce her risk of progressive cognitive impairment and for stroke prevention.45
Other common modifiable risk factors, though not directly
relevant to Ms E’s care, include diabetes mellitus46 and hypertension.47 Treatment of type 2 diabetes has been linked
with amelioration of cognitive decline,48 and some but not
all studies find a reduced risk for developing dementia with
antihypertensive treatment.47
Ms E’s tick bite history and MRI findings of white matter
disease prompted evaluations for autoimmune and infectious disorders, but the white matter disease is not inconsistent with MCI. Milder white matter hyperintensities than
hers are found in many cognitively normal older individuals and white matter lesions are highly prevalent in individuals with vascular dementia or AD.49 Changes in the white
matter are associated with altered permeability of the bloodbrain barrier, ischemic damage, or demyelination. Confluent white matter intensities are associated with microvascular changes at autopsy.50 The constellation of findings that
include Ms E’s white matter disease, cigarette smoking, hypercholesterolemia, executive dysfunction, visuospatial difficulties, depressive symptoms, and relative lack of hippocampal atrophy on MRI all can be understood in the context
of an MCI syndrome reflecting vascular or mixed etiology.
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Depressive symptoms in individuals with MCI are frequent51 and are thought to represent neuropathological
change as well as a psychological reaction to impaired functioning. A history of depression was associated with greater
risk for dementia in a meta-analysis52 and a diagnosis of major depressive disorder in individuals with amnestic MCI
was associated with a relative risk of 2.6 for developing AD
in a prospective cohort study with a mean follow-up of 3
years.53
Special considerations are relevant to the use of an antidepressant in a patient with cognitive impairment. Anticholinergic medications such as paroxetine, the antidepressant Ms E takes, can adversely affect cognitive functioning.54
In one study, healthy nondepressed volunteers aged 30 to
50 years treated with paroxetine (20 to 40 mg/d), in contrast to those treated with sertraline (50 to 100 mg/d) or placebo, showed impaired delayed recall.55 For patients with
MCI, a selective serotonin reuptake inhibitor (SSRI) antidepressant such as citalopram or sertraline can provide a
nonanticholinergic, generically available treatment option
with once-daily dosing, minimal pharmacokinetic interactions with other medications, and significant evidence of
safety and efficacy in late-life depression.56 Interestingly, a
small randomized trial in which fluoxetine was given to nondepressed patients with MCI showed a statistical trend toward improvement in MMSE total score (P =.052, preintervention vs postintervention; MMSE changes for placebo and
fluoxetine, respectively, were 0.6 vs 2.8 points). The investigators attributed this to the promotion of hippocampal neurogenesis.57 Depressed, cognitively impaired patients who
experience SSRI adverse effects, such as fatigue, weight gain,
or sexual dysfunction, may find bupropion an acceptable
alternative drug.56 The safety and efficacy of nonserotonergic antidepressant medications in late-life depression are comparable with that of serotonergic antidepressants overall, but
early experience with bupropion prompted warning of an
increased seizure risk in patients with a history of a convulsive or eating disorder. In patients with no eating disorder and no prior risk factors for seizure, the seizure risk associated with sustained-release bupropion appears acceptably
close to that of other antidepressants.58
Nutritional and Pharmacologic Interventions

The Mediterranean diet—high in vegetables, legumes, fruits,
nuts, cereals, fish, and olive oil and low in saturated fats—
has been linked with a lower risk for AD.59 Daily administration of the omega-3 fatty acids docosahexaenoic acid and
eicosapentaenoic acid (0.6 g) for 6 months was associated
with a significant decrease (P =.02) in expected decline of
MMSE scores in a subgroup of individuals with very mild
AD (baseline MMSE ⬎27); their scores declined only 0.5
points during that interval as compared with a 2.6-point decline for placebo-treated individuals.60 Folate supplementation for 3 years conferred benefits in memory, processing
speed, and sensorimotor speed in a Netherlands commu©2008 American Medical Association. All rights reserved.

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nity cohort,61 but similar benefits were not found with a folate-B12-B6 supplement administered for 2 years to a cohort
studied in the United States, where folate fortification of flour
is mandated.62 Use of antioxidants or anti-inflammatory
drugs, such as ginkgo biloba extract,63 vitamin E,64 aspirin,65 or rofecoxib,66 is not consistently supported by evidence, and a possible risk of cognitive impairment was associated with use of estrogen/progestin hormone treatment
in the Women’s Health Initiative’s cognitive study.67 Consistent physical exercise has been advocated for dementia
risk reduction68 and shown to improve cognitive function
in older adults with subjective memory impairment or MCI,69
and it merits further investigation in MCI cohorts.
No medication has been approved by the US Food and
Drug Administration (FDA) for the treatment of MCI, and
pharmacotherapy recommendations are based on limited evidence. Individuals with amnestic MCI who took donepezil, but not those in comparison groups treated with placebo or vitamin E, showed a relative risk reduction for
conversion to AD of 58% at 12 months and 36% at 24 months
but no risk reduction for conversion at 36 months.64 A possible 3-year benefit of unclear significance was noted for carriers of 1 or more ApoE e4 alleles. Adverse effects led to discontinuation of donepezil in 36% of participants compared
with 25% of those receiving placebo.63 The time-limited improvement and significant incidence of adverse effects in this
study suggest donepezil to be a poorly supported pharmacotherapy for MCI in general, though specific patients might
be appropriate for treatment. Rivastigmine for MCI was not
better than placebo in decreasing progression to dementia.70 Galantamine was associated with greater improvement on a secondary measure of cognition in each of 2 controlled MCI treatment trials, without significant differences
noted on the cognitive items of the Alzheimer Disease Assessment Scale (ADAS-cog) or in the rate of conversion to
dementia measured after 24 months of treatment.71 Increased mortality of unclear significance was observed with
galantamine.72
Memantine, a glutamatergic cognitive enhancer indicated by the FDA for treatment of moderate to severe AD,
was tested on a small group of patients with age-associated
memory impairment, a condition that, like MCI, lies between normal cognitive aging and dementia but differs in
that cognitive impairment is defined based on younger adult
normative values. Compared with placebo, memantine produced a statistically nonsignificant trend toward improvement on a computerized battery of tests of attention and information processing speed. However, no significant change
was observed on measures of memory performance.73
As the population ages, more treatments for MCI will be
developed. Pharmaceuticals currently being investigated for
this diagnosis include a selective metabotropic glutamate receptor antagonist, a novel L-type calcium channel blocker, a
phosphodiesterase inhibitor, a ␥-aminobutyric acid receptor antagonist, and a serotonin 5HT6 antagonist, among oth©2008 American Medical Association. All rights reserved.

ers.74 Furthermore, it is possible that one or more of the antiamyloid therapies currently under investigation for the
treatment of AD75 may prove efficacious when administered
for MCI or the earliest recognizable stage of dementia.
Psychosocial Interventions

Psychosocial interventions play a prominent role in the management of cognitive impairment. For Ms E, individual counseling and cognitive training might alleviate distress associated with self-esteem and lifestyle changes while offering
strategies for memory optimization. Problem-solving therapy,
which can improve generation of alternatives and decisionmaking skills, reduced disability and diminished depressive symptoms (75% remission with problem-solving therapy
vs 22% remission with supportive therapy) in a group of elderly adults with major depression and significant executive dysfunction.76 Cognitive training interventions have been
explored both in adults with normal cognition and in those
with dementia, and to a lesser degree in individuals with
MCI. A recent review distinguished between the goals of cognitive training (teaching strategies and skills to optimize cognitive functioning) and those of cognitive rehabilitation
(which focuses on specific activities of daily living) or cognitive stimulation (involvement in activities designed to increase cognitive and social functioning in a nonspecific
manner).77 Current data are limited but suggest that a combination of these approaches may be useful in at least some
MCI patients, for example, creating an appropriate environment for learning or for activities that require concentration, learning to organize information more efficiently by
categorizing, combining, or using mnemonics, and adopting memory aids such as a memory notebook to organize
reminders and other notes in a single location.78 Printed or
computerized exercises for attention and memory may be
combined with advice regarding diet, exercise, and stress
reduction. One recent small study evaluated the effects of a
4-week structured group cognitive rehabilitation program
with components such as these in 18 individuals with MCI,
comparing them with the outcomes of 10 individuals with
MCI on a waitlist. Among those receiving the intervention,
performance on activities of daily living improved, depression score on the Beck Depression Inventory decreased by
50%, and verbal memory as measured by the California Verbal Learning Test increased by a mean of 2.8 points (P⬍.001)
while these measures showed no significant change among
controls.78
Lifestyle Modifications

Over time, an individual with MCI will need to address issues of driving, employment, finances, long-term residential planning, and decision-making autonomy. Discussion
of driving becomes important at an early stage because impaired visual perception and executive function are strongly
associated with an increased risk for at-fault involvement
in a motor vehicle collision.79 Although the optimal time
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for intervention and the ideal interval for driver reassessment remain unclear,80 active monitoring and intervention
by family or caregivers is often appropriate because the majority of cognitively impaired elders may otherwise continue driving until a collision occurs.81 It is common for patients and families to resist a suggestion to cease driving, a
limitation that may greatly interfere with independence and
autonomy, and physicians are not mandated reporters of impaired drivers in most states.82 Options that are available to
a concerned clinician include a frank discussion of risks and,
in the United States, a recommendation to seek retesting
through the Registry of Motor Vehicles or from a Driver Rehabilitation Specialist, or a letter to the Registry of Motor
Vehicles requesting that the patient’s license be suspended
pending mandatory testing.82
For patients with MCI who continue to work or perform
other duties that require intact executive function and
memory, additional supports or role modifications should
be considered. If the diagnosis of MCI results in a change
in employment status, however, the effects on both selfesteem and income can be distressing to the patient.
Because of attentional and executive function impairment, MCI is associated with an increased error rate in financial transactions and an overall decrease in capacity to
understand and manage monetary affairs.83 Denial, desire
to protect a loved one’s self-esteem, and practical considerations may postpone family action in this area. Failure to
address financial capacity in a cognitively impaired individual can have costly consequences. When necessary and
with appropriate safeguards, family members eventually may
need to obtain power of attorney or guardianship in order
to assume control of an incapacitated person’s financial decisions and transactions.
Patients and families may require assistance in decisions
regarding medical care and residential plans. A health care
proxy should be identified and advance directives prepared while an individual is still competent. For residential planning, discussions should be individualized. Some
families and patients prefer to preserve a current living arrangement for as long as possible by addressing safety issues, simplifying the demands associated with maintenance activities, addressing transportation needs, and
assisting with shopping and other activities outside the home.
Other families feel that moving patients to an assisted living facility at an earlier stage facilitates an easier transition
to a new environment. Referral to appropriate professionals such as elder law attorneys or geriatric care managers
may aid families during a stressful and confusing transition.
Adjustment to the cognitive decline of a loved one who
may previously have been a highly responsible and competent member of a family is disruptive at best and can be devastating. Both the patient and his/her support system will
often require a considerable amount of psychoeducational
and emotional assistance while they adjust to the implications of a diagnosis of cognitive impairment at risk for pro1572

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gression. Aside from emergencies, however, a competent patient’s agreement should be obtained before discussing
diagnostic, prognostic, and treatment issues with others. The
patient may prefer to limit the discussion to specific areas
and/or participants. Topics of importance for a family discussion include clarification of roles, advice on dealing with
a person’s repetitive questioning or irritability, ways to communicate more effectively, understanding prognostic issues, accessing resources, addressing safety issues, and confronting denial regarding the patient’s level of ability and
appropriate degree of autonomy. If dementia develops and
a patient’s ability to make safe and appropriate decisions is
in doubt, discussion of guardianship may become appropriate. When an integrated care team is available, the family may find the team’s collaborative treatment and advice
increasingly useful over time.
Recommendations for Ms E

Ms E appears to have amnestic MCI of the multiple domain
type with a probable vascular or mixed etiology and she may
be at increased risk for future progression to dementia. However, she should be reassured that her current limitations are
mild and conversion may be delayed or may not occur. Serial visits and periodic neuropsychological reassessment should
be performed to monitor her cognitive status and functional
autonomy. For further diagnostic assessment, it is reasonable to check her vitamin B12 and folate levels and to obtain
carotid ultrasound studies to determine whether blood flow
is compromised to the point of requiring intervention for
stroke prevention. Continuation of donepezil treatment at this
stage is discretionary and this option can be discussed with
Ms E, taking into account a recent report of cognitive deterioration following cholinesterase inhibitor discontinuation
in individuals with MCI.84 Adopting a Mediterranean diet and
taking an appropriate omega-3 fatty acid dietary supplement could be considered as possibly helpful interventions
that are unlikely to harm. Ms E’s mild depressive syndrome,
in the context of her stressful circumstances, should benefit
from psychotherapeutic treatment. If her evolving symptoms suggest that she should continue to receive antidepressant treatment, paroxetine likely should be replaced by a less
anticholinergic agent.
Ms E should assess her lifestyle to make sure that her current living arrangements and activities are appropriate. She
should quit smoking through a smoking cessation program as soon as possible, modify her diet as needed, and
participate in a regular physical exercise program. If her mild
hypercholesterolemia does not improve with these interventions, treatment with a statin should be considered. A
cognitive training program may be beneficial now or in the
future to improve her mnemonic and organizational strategies. She may wish to consult an elder-law attorney and/or
a geriatric care manager to begin to address planning for the
future including financial planning, power of attorney, health
care proxy, driving, and residential supports. Ms E’s life has
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CLINICAL CROSSROADS

clearly been made more complicated by her cognitive difficulties, but these interventions may help her continue functioning optimally and maximize her level of autonomy and
quality of life for a significant number of years.
QUESTIONS AND DISCUSSION
QUESTION: I’m wondering about the psychosocial piece of
this. For example, if her marriage had not broken up and
she was with somebody, could there have been a delay in
some of the symptoms?
DR ELLISON: That’s an important question but as yet there
is no definitive answer with respect to patients with MCI.
One study found that marriage decreased the risk of developing AD,85 while others have reported no benefit86 or even
a trend toward increased risk.87 Whether or not the patient
is benefited, however, it’s clear that a demented person’s caregiving spouse experiences very significant stress. Mittleman and colleagues88 have shown the efficacy of psychoeducation in reducing caregiver stress and delaying nursing
home placement.
QUESTION: Could you say something about the specific
guidelines for when you would consider a PET (positron
emission tomography) scan in comparison to MRI data that
you have on hand in this case?
DR ELLISON: The PET scan is an expensive test and should
not be used clinically unless the results will contribute meaningfully to a patient’s treatment planning. In research settings, abnormal PET findings are significantly linked with conversion to dementia,89 but the clinical role of PET in the
management of MCI and dementia is limited at present. As
more effective early stage interventions are identified or developed, the use of PET may become more clinically relevant. The PET scan, incidentally, is covered by Medicare when
considered medically necessary, which is currently defined as
when it is used to aid in the differential diagnosis between AD
and frontotemporal dementia. Experimental PET ligands hold
promise for improving the early identification of AD.
Financial Disclosures: Dr Ellison reports serving on the speakers bureau for Eli Lilly
& Co, Forest Laboratories, Wyeth, and Pfizer and reports receiving grant funding
from GlaxoSmithKline. He also reports pending grants from Elan and Eisai.
Funding/Support: This Clinical Crossroads is made possible in part by a grant from
the Sidney R. Rabb Charitable Trust and the Sidney and Esther Rabb Charitable
Foundation.
Role of the Sponsor: The funding organization did not participate in collection,
management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
Additional Contributions: We thank the patient for sharing her story and we thank
Bruce Price, MD, Chief of Neurology, McLean Hospital, Belmont, Massachusetts,
and Harvard Medical School; and Manjola Ujkaj, MD, PhD, research associate,
McLean Hospital, for helpful comments during the preparation of this article. Neither received compensation for their comments.
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