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Clinical Review & Education

Care of the Aging Patient: From Evidence to Action

The Diagnosis and Management


of Mild Cognitive Impairment
A Clinical Review
Kenneth M. Langa, MD, PhD; Deborah A. Levine, MD, MPH

Supplemental content at
IMPORTANCE Cognitive decline is a common and feared aspect of aging. Mild cognitive jama.com
impairment (MCI) is defined as the symptomatic predementia stage on the continuum of CME Quiz at
cognitive decline, characterized by objective impairment in cognition that is not severe jamanetworkcme.com and
enough to require help with usual activities of daily living. CME Questions 2567

OBJECTIVE To present evidence on the diagnosis, treatment, and prognosis of MCI and to
provide physicians with an evidence-based framework for caring for older patients with MCI
and their caregivers.

EVIDENCE ACQUISITION We searched PubMed for English-language articles in peer-reviewed


journals and the Cochrane Library database from inception through July 2014. Relevant
references from retrieved articles were also evaluated.

FINDINGS The prevalence of MCI in adults aged 65 years and older is 10% to 20%; risk
increases with age and men appear to be at higher risk than women. In older patients with Author Affiliations: Division of
General Medicine, Department of
MCI, clinicians should consider depression, polypharmacy, and uncontrolled cardiovascular Internal Medicine, University of
risk factors, all of which may increase risk for cognitive impairment and other negative Michigan, Ann Arbor (Langa, Levine);
outcomes. Currently, no medications have proven effective for MCI; treatments and Veterans Affairs Center for Clinical
Management Research, Ann Arbor,
interventions should be aimed at reducing cardiovascular risk factors and prevention of
Michigan (Langa, Levine); Institute
stroke. Aerobic exercise, mental activity, and social engagement may help decrease risk of for Social Research, University of
further cognitive decline. Although patients with MCI are at greater risk for developing Michigan, Ann Arbor (Langa);
dementia compared with the general population, there is currently substantial variation in Institute of Gerontology, University of
Michigan, Ann Arbor (Langa);
risk estimates (from <5% to 20% annual conversion rates), depending on the population Institute for Healthcare Policy and
studied. Current research targets improving early detection and treatment of MCI, Innovation, University of Michigan,
particularly in patients at high risk for progression to dementia. Ann Arbor (Langa, Levine);
Department of Neurology and Stroke
Program, University of Michigan, Ann
CONCLUSIONS AND RELEVANCE Cognitive decline and MCI have important implications for Arbor (Levine).
patients and their families and will require that primary care clinicians be skilled in identifying Corresponding Author: Kenneth M.
and managing this common disorder as the number of older adults increases in coming Langa, MD, PhD, Division of General
decades. Current evidence supports aerobic exercise, mental activity, and cardiovascular risk Medicine, University of Michigan,
2800 Plymouth Rd, Bldg 16, Room
factor control in patients with MCI.
430W, Ann Arbor, MI 48109-2800
(klanga@umich.edu).
JAMA. 2014;312(23):2551-2561. doi:10.1001/jama.2014.13806 Section Editor: Edward H.
Livingston, MD, Deputy Editor, JAMA.

do things on her computer and cell phone. Her husband reported


The Patients Story that she exhibited no initiative and that their home seemed more
disorganized. She had difficulty planning dinner and her cooking was
Mrs J, aged 81 years with hypertension and hyperlipidemia, re- simpler. Both reported no changes in language or speech. She con-
quested a referral to a neurologist, stating: I am forgetting things I tinued to drive locally without accidents but had difficulty remem-
just heard. bering directions to familiar places. Mrs J had no hallucinations or
Mrs J and her husband began noticing mild memory problems delusions. She slept well, her mood was fine, and she exhibited no
1.5 years earlier and reported slow progression since. Her husband behavioral problems or personality changes.
noticed changes in problem solving and time management. Mrs J Functionally, she remained independent in all activities of daily
was easily distracted and had difficulty remembering recent con- living (ADLs). She experienced urinary frequency and over the past
versations. She misplaced objects and spent time looking for them; couple of months has had a few incidents of urinary incontinence,
she read and wrote less than before. She repeatedly asked how to especially when awakening from a nap. In instrumental activities of

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Clinical Review & Education Care of the Aging Patient: From Evidence to Action Diagnosing and Managing Mild Cognitive Impairment

daily living (IADLs), Mr J had recently assumed the responsibility of


paying bills. Even with use of a compartmentalized pillbox, Mrs J oc- Box 1. Diagnosis Criteria for Mild Cognitive Impairment (MCI)
casionally forgot to take her medications (amlodipine, 5 mg daily; and MCI Due to Alzheimer Diseasea
losartan, 50 mg twice daily; and ergocalciferol, 1000 units daily).
Criteria for Diagnosing MCI
Concern regarding a change in cognition from the patient, knowl-
Perspectives
edgeable informant, or from a skilled clinician observing the patient
Mrs J (Asked when her memory first became a concern): Would you
Objective evidence of impairment (from cognitive testing) in 1 or more
believe Im about to say: I forget?Its just been gradual. I was asked
cognitive domains including memory, executive function, atten-
to play my monthly bridge gameand I declined. I thought: Ill never tion, language, or visuospatial skills
remember the cards.
Preservation of independence in functional abilities (although indi-
Mild cognitive impairment (MCI) is a clinical stage on the con- viduals may be less efficient and make more errors at performing ac-
tinuum of cognitive decline between what is considered normal ag- tivities of daily living and instrumental activities of daily living than
ing and dementia. MCI is characterized by impairment in cognition in the past)
that is not severe enough to require help with ADLs and IADLs. Mrs No evidence of a significant impairment in social or occupational func-
Js declining memory has clearly affected daily life in ways that both tioning (ie, not demented)
she and her husband have noticed, but she has remained generally
Clinical Characteristics Suggestive That MCI Is
independent and therefore has MCI. Due to Alzheimer Disease
Memory impairment present
Progressive decline in cognition over months to years (very rapid de-
Methods cline may suggest prion disease, neoplasm, or metabolic disorders)
Lack of parkinsonism and visual hallucinations (suggestive of demen-
We searched PubMed for English-language articles in peer- tia with Lewy bodies)
reviewed journals from inception through July 2014 using MeSH
Lack of vascular risk factors and extensive cerebrovascular disease
terms: mild cognitive impairment/diagnosis OR mild cognitive im- on brain imaging (suggestive of vascular cognitive impairment)
pairment/treatment OR mild cognitive impairment/therapy. We also
Lack of prominent behavioral or language disorders (suggestive of
searched the Cochrane Library database for mild cognitive impair- frontotemporal lobar degeneration)
ment; we reviewed the updated 2011 National Institute on Aging
a
Alzheimers Association (NIA-AA) diagnostic guidelines for dementia,1 Data are adapted from Albert et al.2

MCI, 2 and preclinical Alzheimer disease. 3 Additionally, we re-


viewed a recent analysis of diagnostic testing for Alzheimer dis-
ease from the Institute for Clinical and Economic Review,4 and a Cen- The NIA-AA criteria define MCI due to Alzheimers disease as
ters for Medicare & Medicaid Services decision memo regarding those symptomatic but non-demented individuals whose pri-
-amyloid (A) positron emission tomography (PET) imaging for mary underlying pathophysiology is AD [Alzheimer disease].2 MCI
dementia.5 Our PubMed search yielded 4977 unique articles and our due to Alzheimer disease is characterized by memory impairment,
Cochrane Library search yielded 22 systematic reviewsthe titles longitudinal decline in cognitive function, and lack of evidence for
and abstracts of which were examined for relevance. For each of the vascular, traumatic, or other medical causes of cognitive decline
relevant articles identified, we then screened the references and (Box 1). The NIA-AA guidelines also proposed research criteria for
checked related citations in PubMed. Randomized double-blind pla- the use of biomarkersmeasures of A deposition and of neuronal
cebo-controlled trials with results reported as intention-to-treat injuryto further refine the likelihood that a patients MCI is due to
analyses were considered highest-quality data. Large prospective Alzheimer disease, but these tests are not yet recommended for rou-
cohort studies, meta-analyses, and systematic literature reviews tine clinical use.2
were also included as appropriate for supplementing the random- Two other recently developed clinical classification systems
ized-controlled trial results. Our results and discussion cite the ar- identify a symptomatic but nondemented stage of cognitive
ticles that both authors found most relevant to the diagnosis and decline, but use different terminology than the NIA-AA criteria.
management of MCI. We developed recommendations using evi- The International Working Group criteria use the terms prodromal
dence from these sources, as well as our clinical experience. AD or predementia AD to refer to individuals with cognitive
impairment that is not severe enough to significantly affect
Definitions and Diagnostic Criteria ADLs,7 while the new Diagnostic and Statistical Manual of Mental
In 2011, the NIA-AA convened workgroups to revise the 1984 diag- Disorders (Fifth Edition) (DSM-5) refers to this stage as mild neu-
nostic criteria for dementia, as well as dementia due to Alzheimer rocognitive disorder.8
disease. Diagnostic criteria for MCI, the symptomatic predementia
phase of the trajectory of cognitive decline, were subsequently es- Epidemiology and Risk Factors
tablished (Box 1).2 The key criteria that distinguish MCI from de- Recent clinical and population-based samples suggest an MCI preva-
mentia are preservation of independence in functional abilities (ADLs lence of 10% to 20% for adults aged 65 years and older,6,9 al-
and IADLs) and lack of significant impairment in social or occupa- though lack of standardized diagnostic criteria and differences in
tional functioning. MCI subtypes are sometimes defined by pres- sample characteristics across studies have led to significant uncer-
ence or absence of memory difficulties (amnestic vs nonamnestic tainty around these estimates. The likelihood that MCI will prog-
MCI)6 and the number of affected cognitive domains.2 ress to dementia depends on the specific diagnostic criteria used and

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Diagnosing and Managing Mild Cognitive Impairment Care of the Aging Patient: From Evidence to Action Clinical Review & Education

Figure. Suggested Approach for Diagnosing and Managing Mild


Cognitive Impairment Box 2. Descriptions of Cognitive Problemsa

Changes in memory (is the patient misplacing things more, using notes
Concern regarding a decline in cognition obtained from patient, informant, and reminders more, repeating questions, having trouble keeping
or clinician, or as the result of worsening performance on cognitive testing
track of dates and appointments?)
Perform history focused on the following: Changes in language (word-finding difficulties?)
Changes in cognitive function (onset, trajectory, examples) Changes in visuospatial function (new driving difficulties, including
Changes in functional status (activities of daily living and instrumental activities
being slow to identify roadway hazards, late to apply brakes, or dif-
of daily living, especially a change in ability to manage finances)
Current prescription and over-the-counter medications ficulty staying in lane?)
Neurological symptoms (vision, hearing, speech, sleep-disordered breathing, gait, Changes in attention/executive function (easily distracted, new dif-
and numbness and tingling)
ficulties preparing meals or using household appliances, new diffi-
Psychiatric symptoms (depression, anxiety, and behavioral or personality changes)
culty writing checks, new safety concerns from family members?)
a
Perform physical and neurological examination Data are adapted from McCarten14 and Holsinger et al.15

Perform laboratory testing including the following:


Complete blood cell count, electrolytes, glucose,
calcium, thyroid function, vitamin B12, and folate
Cognitive Function
Perform cognitive testing including the Montreal A history of cognitive changes over time, verified by knowledge-
Cognitive Assessment (MoCA) or the Mini-Cognitive
Assessment Instrument (Mini-Cog) able informants if available, is important for identifying the first di-
agnostic criteriondecline in cognitive function (Box 2).14,15 Criti-
No Evidence of mild cognitive Yes cal features that may elucidate a cause are onset, trajectory, time
impairment from evaluation? course, and nature of the cognitive symptoms. Very rapid cogni-
tive decline (weeks to months) is not typical of MCI due to Alzhei-
Reassure patient and family Optimize vascular risk factor control
Perform follow-up for Treat depression if present mer disease and should raise concerns for other causes such as neo-
reevaluation in approximately Address polypharmacy; stop medications plasm, metabolic disorders, or prion disease (Box 1). Patients and
6 months or with significant that negatively affect cognitive function
change in status informants (such as family members) may report conflicting views
Optimize vision, hearing, and
sleep-disordered breathing regarding the presence and severity of cognitive symptoms, either
Counsel patient and family on beneficial from lack of insight or because cognitive decline can be emotion-
behaviors, safety, finances, long-term
care, and prognosis (See Box 3) ally charged and symptom reporting may be minimized to avoid dif-
Perform follow-up for reevaluation in ficult or disrespectful discussions.14
approximately 6 months or with
significant change in status (See Box 3) Patients with suspected MCI should have cognitive function
assessments at baseline and at follow-up visits. A recent US Pre-
ventive Services Task Force systematic review on screening for
the setting in which the diagnosis is made (eg, primary care, spe- cognitive impairment in older adults examined a number of
cialist clinic, or general population).10 The prevalence of MCI in- instruments for primary care settings.16 The review concluded
creases with age and men appear to be at higher risk.9,11 Additional that brief cognitive assessments can successfully detect demen-
risk factors identified in some studies include lower educational level, tia in primary care, but the sensitivity of those instruments for
vascular risk factors (eg, diabetes and hypertension), Apolipopro- detecting MCI is generally lower, and it is still unclear whether
tein E (APOE) e4 genotype, vitamin D deficiency, sleep-disordered early diagnosis of cognitive impairment improves important
breathing,12 and prior critical illness (eg, sepsis).13 patient or caregiver outcomes.16
The Montreal Cognitive Assessment (MoCA) is a screening
tool that was developed specifically for detection of MCI and
takes approximately 10 minutes to administer.17 Using a cut point
Evaluation of the Patient With Suspected MCI
of 25/26 (lower scores indicate worse cognitive function), the
Dr F: Somebody who tells me that their memory has always been MoCA has a sensitivity of 80% to 100% and a specificity of 50%
bad[is] less worrying to me than a patient like [Mrs J] who told to 76% for detecting MCI.16 The Mini-Mental State Examination
me that over the past 1.5 years there's been a discrete and distinct (MMSE) has a sensitivity of 45% to 60% and a specificity of 65%
decline in her ability to remember things. And, she had an infor- to 90% for detecting MCI using cut points of 27 or 28 (lower
mantwho agreed with that. scores indicate worse cognitive function). 16 A recent study
All patients with suspected MCI should undergo a comprehen- directly comparing the MoCA and MMSE found the MoCA to be
sive history and physical examination focusing on cognitive func- more sensitive for accurately differentiating individuals with MCI
tion, functional status, medications, neurological or psychiatric ab- from those with normal cognition.18 Clinicians may also consider
normalities, and laboratory testing. The main goals are to distinguish the Mini-Cog test (which combines the Clock Drawing Test with a
MCI from normal aging or dementia and to identify potentially re- 3-word recall test) because it also has acceptable test perfor-
versible forms of MCI due to other conditions (eg, depression, medi- mance characteristics and can be performed in 3 minutes or
cation effects, thyroid disease, and vitamin B12/folate deficiency) less.16 Referral for formal neuropsychological testing may help
(Figure). diagnose MCI in patients with subtle cognitive decline. The eTable

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Clinical Review & Education Care of the Aging Patient: From Evidence to Action Diagnosing and Managing Mild Cognitive Impairment

in the Supplement contains more information on selected cogni- lar movements, vision, hearing, speech, focal weakness, ability to
tive tests. Although Mrs J scored in the normal range on the stand from a chair, and gait is useful for identifying potential con-
MMSE (29 of 30 points), her formal neuropsychological testing tributors to cognitive decline, including stroke, Parkinson disease,
showed objective deficits in memory function. normal-pressure hydrocephalus, or neuropathy due to toxins or vi-
Clinicians can collect standardized information on cognitive tamin deficiency.14
function from informants using the Informant Questionnaire on Depression is associated with cognitive impairment in older
Cognitive Decline in the Elderly (IQCODE),19 the Dementia Sever- adults and the relationship is likely bidirectional. Depression can be
ity Rating Scale (DSRS),20 and the AD8.21 The NIA-AA criteria for screened in older adults using assessment tools such as the Geri-
MCI note that scores on cognitive tests for individuals with MCI atric Depression Scale, on which a score of 6 or greater is sugges-
are typically 1 to 1.5 standard deviations below age- and tive of depression.30 Clinicians can query the informant about the
education- adjusted normative means. However, it is emphasized patients depressive and behavioral symptoms using the Neuropsy-
that these score ranges should be considered guidelines rather chiatric Inventory.31
than firm cut-offs for making an MCI diagnosis.2

Functional Status
Diagnostic Testing
Assessment of functional status determines whether a patient can
function independently (MCI), or whether cognitive decline is se- Neuroimaging
vere enough to require consistent help with ADLs or IADLs (demen- Structural
tia). The Functional Activities Questionnaire22 is a brief standard- The NIA-AA diagnostic guidelines do not recommend routine neu-
ized instrument for clinicians obtaining IADL information from an roimaging in the typical clinical assessment of MCI, but do propose
informant.6 When using the Functional Activities Questionnaire, pa- research criteria in which neuroimaging may help in determining MCI
tients with MCI have more IADLs that require assistance when com- etiology and prognosis.2 Some studies suggest that structural mag-
pared with those who have normal cognition (mean number of defi- netic resonance imaging (MRI) may be useful for identifying MCI and
cits, 2.7 vs 0.1; P < .01),23 and using a cut point of 6 points or greater those at greater risk for progression from MCI to dementia.6,32 Volu-
on the Functional Activities Questionnaire was found to have an 85% metric measures of the hippocampus that show atrophy, for in-
accuracy rate for distinguishing patients with MCI from those with stance, are suggestive of MCI and have been shown to correlate with
dementia.24 Mrs J was still generally independent, but had become likelihood of progression to dementia.33 However, lack of standard-
slower and less efficient with customary activities (eg, cooking and ization and validation for these measures limits their usefulness in
driving); increasing difficulties with finances may be another sen- clinical practice,34 and they are not currently recommended for in-
sitive indicator of early cognitive decline.25 forming prognosis. Structural brain MRI may rule out other poten-
tial causes for cognitive decline, such as subdural hematoma, stroke,
Medication Review NPH, or tumor, so should be considered if the history, physical, or
Certain classes and combinations of medications can contribute laboratory studies suggest one of these causes.35
to cognitive impairment26 so all current prescription and over-
the-counter medications should be reviewed. Drug classes most Functional and Amyloid Imaging
likely to contribute to cognitive impairment include anticholiner- Fludeoxyglucose PET can detect regions of hypometabolism in the
gics, opiates, benzodiazepines and nonbenzodiazepine hypnotics brain that may be characteristic of MCI due to Alzheimer disease, de-
(eg, zolpidem), digoxin, antihistamines, tricyclic antidepressants, mentia caused by Alzheimer disease, or other causes for cognitive
skeletal muscle relaxants, and antiepileptics. Hormonal therapy impairment.4,36 Most recently, PET imaging of the extent of A
(estrogen alone or estrogen plus progestin) for menopause has plaques in the brain has become more feasible with the radiophar-
been shown to increase risk for the combined end point of MCI or maceutical tracer florbetapir,37 and has been studied for its utility
dementia.27 In addition, hypotension related to intensive treat- in identifying individuals with, or at high risk for developing, Alzhei-
ment of hypertension28 and hypoglycemia related to intensive mer disease.38 A recent Centers for Medicare & Medicaid Services
treatment of diabetes29 may also contribute to cognitive decline. review of PET amyloid imaging noted that this technology accu-
rately identifies the presence of amyloid, but there is not yet suffi-
Neurological and Psychiatric Evaluation cient evidence that the imaging results will affect medical decision
Clinicians should perform a focused review of neurologic and psy- making or improve health outcomes for older adults with sus-
chiatric symptoms, a complete neurological examination, and a de- pected MCI or Alzheimer disease.5 Use of the technology is there-
pression assessment in patients with suspected MCI. Review of fore currently only recommended and covered by Medicare when
symptoms should probe vision and hearing problems, sleep- used in the context of a research study.5
disordered breathing, behavioral or personality changes (which may
suggest depression, thyroid disease, or frontotemporal dementia), Laboratory Testing
visual hallucinations (dementia with Lewy bodies or depression with Laboratory testing of complete blood count, electrolytes, glucose,
psychotic features), numbness or tingling in the extremities (neu- calcium, thyroid function, vitamin B12, and folate is recommended
ropathy), dizziness upon standing (orthostatic hypotension), to identify potentially reversible forms of MCI including infection,
changes in speech (stroke or Parkinson disease), and changes in gait renal failure, hypomagnesemia or hypermagnesemia, hyperglyce-
(stroke or normal-pressure hydrocephalus).14 A complete neuro- mia, hypocalcemia or hypercalcemia, hypothyroidism or hyperthy-
logical examination, including orthostatic hypotension, extraocu- roidism, and vitamin B12 or folate deficiency. Laboratory testing for

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Diagnosing and Managing Mild Cognitive Impairment Care of the Aging Patient: From Evidence to Action Clinical Review & Education

Table 1. Selected Randomized Controlled Trials of Pharmacologic Treatments and Behavioral Interventions for Mild Cognitive Impairment (MCI)

Patients
Mean Trial
Source No. Characteristics Age, y Intervention Length Primary Outcomes
Pharmacologic Treatmentsa
Salloway 270 Adults with MCI 72 Donepezil, 10 mg/d vs 24 wk No significant differences between treatment groups in the 2
et al,42 2004 placebo primary outcomes: New York University Paragraph Delayed
Recall test and the ADCS-CGIC-MCI.b
Petersen et al, 769 Adults with 73 Donepezil, 10 mg/d vs 2000 3y Compared with placebo, there were no significant
200543 amnestic MCI IU/d of vitamin E vs placebo differences in the probability of progression to Alzheimer
disease in the vitamin E group (HR, 1.02; 95% CI, 0.74-1.41;
P = .91) or the donepezil group (HR, 0.80; 95% CI,
0.57-1.13; P = .42).
Doody et al,44 821 Adults with 70 Donepezil, 10 mg/d vs 48 wk The dual primary efficacy end point was not reached. At 48
2009 amnestic MCI placebo weeks, there was a small, significant decrease in modified
ADAS-cogb (0.90 [SE, 0.37]) favoring donepezil (P = .01).
Changes in CDR-SB scoresb were minimal and not
significantly different between treatment groups.
Koontz and 19 Men with MCI 71 Galantamine, 12 mg twice 16 wk The primary outcome was the CANTAB.b At 16 weeks, only 1
Baskys,45 2005 daily vs placebo of the 6 subtests of the CANTAB (stockings of Cambridge
test)b differed significantly between galantamine and
placebo groups (mean [SD], 8.3 [1.9] vs 7.0 [1.4]; P = .02).
Cognitive Interventionc
Buschert 39 Adults with MCI 73 Group-based 6 mo There were significant improvements in the ADAS-cogb
et al,46 2011 or mild Alzheimer multicomponent cognitive (P = .02) and nonsignificant improvements in the MMSEb
disease intervention vs active (P= .07), favoring the intervention MCI group.
control
Barnes et al,47 37 Adults with MCI 74 Intensive, computer-based 6 wk RBANSb total scores improved 0.36 SDs in the intervention
2009 cognitive training vs passive group (P = .097) vs 0.03 SDs for controls (P = .88).
computer activities Between-group difference was 0.33 SDs (P = .26).
Barnes et al,48 126 Adults with 73 A 2 2 factorial design with 12 wk Global cognitive scores improved significantly over time
2013 memory concerns 4 groups: mental activity (mean, 0.16 standard deviations; P < .001) but did not differ
intervention (MA-I, between groups in the comparison between the mental
intensive computer) to activity groups (P = .17), the exercise groups (P = .74), or
exercise intervention (EX-I, across all 4 randomization groups (P = .26).
aerobic); MA-I to exercise
control (EX-C, stretching
and toning); mental activity
control (MA-C, educational
DVDs) to EX-1; and MA-C to
EX-C
Multidiciplinary Carec
Wolfs et al,49 235 Adults with a 78 Integrated multidisciplinary 52 wk At 12 mo, no significant difference between groups on
2008 suspected diagnostic clinic vs usual change in mean score on EQ-5D VASb (5.2 points; 95% CI,
diagnosis of care 0.58 to 10.94 points).
dementia or a
cognitive disorder
(>15% had MCI)

Abbreviation: HR, hazard ratio. to 18 with higher scores indicating greater dementia severity. MMSE
a
All studies used cholinesterase inhibitors. (Mini-Mental State Examination) scores range from 0 to 30, with higher scores
b
indicating better cognitive performance. The EQ-5D VAS score (EuroQol five
ADAS-cog (Alzheimer Disease Assessment Scale-Cognitive Subscale) scores
dimension visual analog scale) measures individuals ratings for health states
range from 0 to 70 and modified ADAS-cog scores range from 0 to 89; for
and ranges from 0 (worst imaginable state) to 100 (best imaginable health
both higher scores indicate worse cognitive performance. ADCS-CGIC-MCI
state). The RBANS (Repeatable Battery for Assessment of Neuropsychological
(Alzheimer Disease Cooperative Study Clinicians Global Impression of Change
Status) is a brief neurocognitive battery measuring immediate and delayed
for MCI) rates the clinician's impression of change from baseline on a 7-point
memory, attention, language, and visuospatial skills with higher scores
Likert-type scale from 1 indicating marked improvement to 4 indicating no
indicating better cognitive performance.
change to 7 marked worsening. CANTAB (Cambridge Automated
c
Neuropsychiatric Test Assessment Battery) stockings of Cambridge test scores Behavioral interventions were subcategorized as cognitive intervention,
represent the number of problems solved in the minimum number of possible physical activity, multidiciplinary care, or psychotherapeutic intervention
moves. CDR-SB (Clinical Dementia Rating Sum of Boxes) scores range from 0 studies.

liver function, syphilis, Lyme titers (Borrelia), and HIV may reveal rarer
causes for cognitive impairment.14 The proportion of dementia cases Medical Therapy
thought to be due to potentially reversible causes is about 9%.39
While studies have suggested that levels of biomarkers in the cere- WesummarizepotentialinterventionsforMCIfromrecentclinicaltrials
brospinal fluid (eg, A42 and protein) may help identify patients (Table 1 and Table 2), systematic reviews, meta-analyses, and obser-
with MCI who are more likely to progress to Alzheimer disease,40 vational studies. Participants in MCI clinical trials have often had more
routine lumbar puncture is not generally recommended for clinical education, healthier behaviors, and less comorbidity (including lower
evaluation.41 ratesofsmoking,hypertension,andheartdisease)comparedwithage-

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Clinical Review & Education Care of the Aging Patient: From Evidence to Action Diagnosing and Managing Mild Cognitive Impairment

Table 2. Selected Randomized Controlled Trials of Behavioral Interventions for Mild Cognitive Impairment (MCI)

Patients
Mean Trial
Source No. Characteristics Age, y Intervention Length Primary Outcomesa
b
Psychotherapeutic Interventions
Joosten-Weyn 93 Adults with MCI 70 Group cognitive behavioral 10 wk For patients, acceptance assessed using a subscale of the
Banningh therapy (patients) vs a waiting Illness Cognition Questionnaire increased more in the
et al,50 2011 list (controls) intervention group vs the waiting-list group (P = .03) with
an estimated between-group difference of 3.49 (95% CI,
6.21 to 0.73; P = .01).
Banningh 88 Significant 69 Group cognitive behavioral 10 wk For significant others, sense of competence assessed with
et al,51 2013 others of adults therapy (significant others) vs the Sense of Competence Questionnaire was not
with MCI a waiting list (controls) significantly different between the waiting list control
group vs the intervention group (P = .59).
Physical Activityb
Lautenschlager 170 Adults with 69 Home-based physical activity 24 wk At 18 mo, 0.73-point improvement on the ADAS-cog
et al,52 2008 memory program vs education and among patients in the intervention group vs a 0.04-point
concerns, 60% of usual care improvement for those receiving placebo (0.69-point
whom had MCI treatment difference; P = .04); at 6 mo, 0.26-point
improvement on the ADAS-cog among patients in the
intervention group vs a 1.04-point decrease for those
receiving placebo (1.3-point treatment difference,
P < .001). Results were similar in subgroup of patients with
MCI. The intervention group also showed modest
improvements in word list delayed recall (verbal memory)
and CDR-SB (functional impairment due to cognition).
Baker et al,53 2010 33 Adults with 70 High-intensity aerobic exercise 6 mo Compared with stretching, high-intensity aerobic exercise
amnestic MCI vs stretching (control group) significantly improved performance on tests of executive
function with stronger effects among women than men.
Suzuki et al,54 50 Adults with 75 Multicomponent exercise 12 mo Patients in the exercise group showed superior
2012 amnestic MCI program vs education improvements of cognitive function at treatment end for
(controls) the MMSE (group-by-time interaction, P = .04), the logical
memory subtest of the Wechsler Memory Scale-Revised
(group-by-time interaction, P = .03), and the Letter Verbal
Fluency Test (group-by-time interaction, P = .02).
Nagamatsu et al,55 86 Women with 75 Resistance training twice 26 wk Compared with the balance and tone training (control)
2012 subjective weekly, aerobic training twice group, the resistance training group significantly improved
memory weekly, or balance and tone performance on the Stroop test (executive function) (mean
concerns training twice weekly (control change, 1.4 seconds vs 9.1 seconds; P = .04). Changes in
group) Stroop performance scores did not differ significantly
between the aerobic training vs the balance and tone
training groups (mean change, 1.4 seconds vs 8.8 seconds;
P value not given).
Barnes et al,48 126 Adults with 73 A 2 2 factorial design with 4 12 wk Global cognitive scores improved significantly over time
2013 memory groups: mental activity (mean, 0.16 SD; P < .001) but did not differ between
concerns intervention (MA-I, intensive groups in the comparison between the mental activity
computer) to exercise groups (P = .17), the exercise groups (P = .74), or across
intervention (EX-I, aerobic); all 4 randomization groups (P = .26).
MA-I to exercise control (EX-C,
stretching and toning); mental
activity control (MA-C,
educational DVDs) to EX-1;
and MA-C to EX-C
a b
ADAS-cog (Alzheimer Disease Assessment Scale-Cognitive Subscale) scores Behavioral interventions were subcategorized as cognitive intervention,
range from 0 to 70 with higher scores indicating worse cognitive physical activity, multidiciplinary care, or psychotherapeutic intervention
performance. CDR-SB (Clinical Dementia Rating Sum of Boxes) scores range studies.
from 0 to 18 with higher scores indicating greater dementia severity. MMSE
(Mini-Mental State Examination) scores range from 0 to 30 with higher scores
indicating better cognitive performance.

matched general populations. More trials in MCI patients with less fa- (5149 participants).56 Consequently, cholinesterase inhibitors and
vorable demographic and health profiles are needed to increase gen- memantine are not recommended for MCI treatment and there are
eralizability, especially regarding prognosis. currently no FDA-approved medications for MCI.16,56 Ginkgo bi-
loba, a widely used herbal supplement to improve cognition and
Pharmacologic Treatment of MCI memory, has not been shown in randomized trials to prevent cog-
Currently, no drug has proven effective in treatment of MCI. Cho- nitive decline in those with MCI or normal cognition.57 Similarly, tes-
linesterase inhibitors have not been shown to decrease risk of pro- tosterone supplementation in older men showed no benefit for cog-
gression from MCI to dementia at 1 and 3 years.16 In addition, cho- nitive function in a randomized controlled trial.58
linesterase inhibitors have limited or no significant effects on
cognitive function over the short term (<12 months; Table 1) and may Vascular Risk Factor Control
substantially increase adverse effects, based on a meta-analysis of Stroke prevention and vascular risk factor control may reduce risk
4 trials (1960 participants)16 and another meta-analysis of 9 trials of progression from MCI to dementia, regardless of radiographic evi-

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Diagnosing and Managing Mild Cognitive Impairment Care of the Aging Patient: From Evidence to Action Clinical Review & Education

dence of cerebrovascular injury.59 An acute stroke and subclinical


infarcts can accelerate cognitive decline and precipitate dementia Box 3. Treating and Counseling Patients With Mild Cognitive
in patients with MCI.60,61 Vascular contributions to cognitive im- Impairment
pairment are common, and many MCI patients have pathological evi-
dence of neurodegenerative and cerebrovascular disease.62 Strat- Control of Vascular Risk Factors and Prevention of Stroke
and Subclinical Brain Injury
egies for primary or secondary stroke prevention include blood
Hypertension present
pressure control, smoking cessation, statin therapy, antiplatelet
Control blood pressure and avoid hypotension
therapy, and anticoagulation or antithrombotic therapy for atrial
fibrillation.63,64 Diabetes present
Independent of clinical stroke prevention, blood pressure con- Control severe hyperglycemia and avoid severe hypoglycemia
trol may reduce dementia risk. In the Systolic Hypertension in Primary or secondary stroke prevention
Europe (Syst-Eur) trial of 2418 adults (mean age 70 years), treat- Statin if indicated
ment of isolated systolic hypertension reduced incidence of demen- Atrial fibrillation present
tia by 50% (3.8 vs 7.7 cases per 1000 patient-years; P = .05) over 2 Initiate anticoagulant or antithrombotic therapy if no contraindi-
years.65 A meta-analysis of 4 placebo-controlled trials (16 595 pa- cations
tients) also suggested that antihypertensive treatment may re-
Beneficial Behaviors
duce incident dementia (HR, 0.87; 95% CI, 0.761.00; P = .045).66
Abstain from heavy alcohol or illicit drug use
The robustness of the evidence base for antihypertensive therapy
Engage in mental activity
to prevent cognitive decline, particularly in the oldest old, is de-
bated because several randomized controlled trials (RCTs; includ- Engage in physical activity
ing the HYVET-COG [Hypertension in the Very Elderly Trial cogni- Stop smoking
tive function assessment]) 66 and meta-analyses have shown Social Needsa
negative results. Elevated or worsening systolic blood pressure and Encourage and facilitate social interactions
cigarette smoking each increase the risk of cerebral white matter le- Discuss living will, durable power of attorney, financial and long-
sion progression, which is associated with cognitive decline in the term care plans
domains of information processing speed and executive Provide community resources for patient and caregivers
function.67,68 Trials have not established that statins or intensive gly-
Discuss driving safety
cemic control reduce the risk for dementia independent of stroke
Discuss home safety, including kitchen safety, firearms, poisons, and
prevention.
potential fall risks
The Eighth Joint National Committee (JNC 8) recently recom-
mended treating hypertensive adults aged 60 years and older to a Prognosis and Follow-up
blood pressure goal of less than 150/90 mm Hg.69 Given that higher Discuss current evidence and uncertainty regarding MCI prognosis
with patient and family
variability in systolic blood pressure is associated with stroke, cere-
bral white matter lesion progression, lower hippocampal volume, and Arrange follow-up approximately every 6 months to assess changes
in cognitive function and potential evolving needs for social support
cognitive impairment, clinicians may consider medications that re-
a
duce blood pressure variability (calcium channel blockers or thia- See the eBox in the Supplement for a list of web resources that may be
useful for patients and caregivers.
zide diuretics) when selecting antihypertensive regimens, particu-
larly in patients with marked variability in blood pressure,70,71
although this is unsettled.72 It is important to avoid overtreatment
of hypertension and diabetes because hypotension and hypogly- Although depressive and vegetative symptoms may cause or
cemia may increase the risk of cognitive decline and other patient contribute to MCI, there is mixed evidence as to whether treat-
harms.28,29 ment of depression improves cognitive impairment or decreases risk
of incident MCI or dementia. Given increasing evidence of the nega-
Treatment of the Patient tive impact of anticholinergic medications on cognitive function in
Although there are no drugs proven or approved to treat MCI, opti- older adults,76 treatment with antidepressants that have signifi-
mizing patients general medical and functional status, and provid- cant anticholinergic properties (eg, amitriptyline, nortriptyline, and
ing counseling regarding issues such as driving and home safety can paroxetine) should be avoided. A trial of withdrawing and simplify-
maximize patient and caregiver well-being, and reduce risk of nega- ing medication regimens in older adults may lead to improvements
tive outcomes (Box 3). Individuals with MCI are at increased risk for in cognitive function.26
gait dysfunction, mobility decline, and falls.73 Gait assessment, while
performing an attention-demanding task (dual-task testing), may
identify motor control and performance problems that could ben-
Counseling on Behaviors
efit from tailored interventions.73 Optimizing visual and auditory acu-
ity may enhance functioning because untreated vision and hearing Dr F: Sometimes a physical therapy referral to facilitate aerobic
problems are associated with cognitive decline.74,75 Use of a CPAP exercise is useful. I also suggested that she stay mentally
(continuous positive airway pressure machine) for patients with sleep- engagedbeing out of the house andaround other people is a
disordered breathing may also reduce risk of progression of cogni- very important way of stimulating the brainand helps preserve
tive decline,12 although definitive clinical trials are still necessary. brain function.

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Clinical Review & Education Care of the Aging Patient: From Evidence to Action Diagnosing and Managing Mild Cognitive Impairment

There is modest evidence from RCTs and clinical studies that local department of motor vehicles, but some states have manda-
various behavioral interventions, particularly aerobic exercise and tory reporting for patients with diagnosed dementia (see eBox in
mental activity, may have small but beneficial effects on cognitive the Supplement).80
function in older adults with MCI (Tables 1 and 2).16 Several RCTs
of community-dwelling adults with or at risk for MCI have shown
that home-based or professionally-supervised programs of aero-
Follow-up
bic exercise or resistance training modestly improve cognition,
particularly executive function, over 18-month follow-up Serial assessments of cognition are recommended because pro-
(Table 2). The combination of aerobic exercise and mental activity gressive cognitive decline provides additional evidence that the
may benefit patients with MCI. The Mental Activity and eXercise individual has MCI due to AD.2 Longitudinal follow-up and serial
(MAX) RCT of 126 inactive older adults with memory concerns cognitive assessments are also useful since they allow a clearer
demonstrated that a 12-week program of combined physical and assessment of a patients true baseline and trajectory of cognitive
mental activity was associated with small significant improve- function over time, and decrease the risk that poor performance
ments in global cognitive function, regardless of the types of on a single assessment due to anxiety, fatigue, or acute illness
physical activity (aerobic vs stretching and toning) and mental leads to a false positive diagnosis of MCI. However, the optimal
activity (intensive vs educational videos).48 Observational studies timing, choice, and cost effectiveness of longitudinal cognitive
suggest that the Mediterranean diet also may reduce the risk of assessments are unclear. Tests of episodic memory identify MCI
converting from MCI to dementia.77 patients with high likelihood of progressing to Alzheimer disease
Other observational studies suggest that social engagement within a few years. 2 General cognitive screening instruments
may reduce the risk of cognitive decline and preserve memory, (eg, MoCA) are recommended for detecting dementia in individu-
particularly in adults with less than 12 years of education or those als with suspected MCI.82 Serial assessments of daily functioning
with vascular disease.78 Little is known about the effectiveness of may identify MCI patients who are more likely to develop
multidisciplinary care programs or supportive care interventions dementia,83 may indicate incident dementia, and may identify
(eg, counseling, education, support groups) for patients with MCI need for additional resources.
or their families because well-designed RCTs are lacking16 and one No neuroimaging or laboratory test is currently recommended
RCT that included many patients with dementia showed negative for predicting MCI progression to dementia in clinical practice.2 Al-
results (Table 1).49 A few, small RCTs found that psychotherapy though specific brain imaging findings (eg, A deposition, medial
may modestly increase patients acceptance of an MCI diagnosis temporal lobe atrophy, hippocampal atrophy, or hypoperfusion or
and also provide knowledge, insight, acceptance, and coping hypometabolism in the temporoparietal cortex) are associated with
skills for significant others (Table 2), 50,51 but larger RCTs are an increased risk of progression, these findings currently lack speci-
needed. ficity. Cerebrospinal fluid tests showing low levels of A42, el-
Small RCTs46-48 and clinical studies suggest that cognitive in- evated levels of , or a low A42 to ratio confer an increased like-
terventions may improve cognitive function moderately over 6 to lihood of progressing to dementia; however, results may be
12 months for persons with MCI or mild dementia; however, im- ambiguous or contradictory for a given patient, may vary across sites,
provements are often specific to targeted cognitive domains, may and diagnostic accuracy and positive predictive value are
not be greater than active controls, and may not improve daily func- suboptimal.40,84 It is not recommended to perform routine ge-
tioning (Table 1).16,79 Moreover, it is difficult to recommend specific netic testing for mutations in amyloid precursor protein, presenilin
components of cognitive interventions because of heterogeneity 1, or presenilin 2 in adults with cognitive changes presenting before
across studies. age 65 years, or the APOE e4 allele in older adults.
An issue that often arises in patients with MCI is driving A common question is whether patients with suspected MCI re-
safety.80 Although there is general consensus among medical and quire specialist consultations. Given the current limited evidence for
transportation societies that those with moderate to severe effective MCI treatments, consultation would serve primarily to con-
dementia should not drive due to significantly increased risk of firm the diagnosis and help identify reversible causes.
crashes, evidence of driving impairment for patients with MCI is
less clear.80,81 The clinician should probe the patient and family
for indicators of driving impairment, including recent motor
Prognosis
vehicle accidents or near misses, changes in the patients driving
behaviors (eg, speed, ability to stay in lane, road sign comprehen- Mr J: You're worried[whether] this thing is going to get worse,
sion), or episodes of getting lost in familiar areas.80 Testing for which it probably will, but at what rate? It's uncertainty of the
deficits in visuospatial and executive function (Clock Drawing Test future regarding all of these things, whether it's safety or whether
and Trail-making tests), cognitive domains thought to be impor- it's decision making. . And doctors don't seem to know either. It's
tant for driving safely, or formal driving evaluation may provide very frustrating.
useful information.81 Patients are often reluctant to stop driving Prognosis is uncertain for patients with MCI and, as articu-
even on recommendations by their physician, family, or both, so lated by Mr J, uncertainty about the future is a major source of
early and repeated discussions suggesting that driving cessation worry. Although patients with MCI have a greater risk of develop-
may be necessary and referral to public transportation or other ing dementia compared with the general population, studies
options may be useful in early counseling sessions. There is no report substantial variability. Reported annual rates of MCI con-
legal requirement for physicians to report a patient with MCI to a version to dementia span from less than 5%83 to 12% to 20%,9

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Diagnosing and Managing Mild Cognitive Impairment Care of the Aging Patient: From Evidence to Action Clinical Review & Education

depending on the country and population studied. Patients can Competing risks are another important consideration
be counseled that a minority will progress to dementia annually, although patients with MCI have an increased risk of dementia,
however many patients with MCI (40%-70%) may not progress they also have greater mortality. Risk-prediction models should
to dementia even after 10 years. 85 Importantly, some MCI estimate the likelihood that MCI patients will develop dementia
patients (15%-20%) will have improved cognition 1 to 2 years prior to dying from competing causes, especially cardiovascular
later, although the latter group likely remains at increased risk of disease and cancer. Unfortunately, clinicians currently have insuf-
future cognitive decline.9,86 ficient information regarding Mrs Js absolute risk of developing
Risk factors for MCI progression include older age, fewer years dementia compared with her risks of dying from a nondementia
of education, stroke, diabetes, and amnestic MCI subtype.9,87 The cause or experiencing stable or improved cognition in the next
presence of an APOE e4 allele may modestly increase the risk of pro- few years.
gressing from MCI to Alzheimer disease dementia.88 Conversely, fac-
tors associated with increased likelihood of reverting from MCI to
normal cognition include younger age, more years of education,
Future Directions
higher baseline cognitive function, and non-amnestic single MCI
type.86 Ongoing research aims to identify those MCI patients most Older adults fear cognitive decline and most patients prefer testing
likely to progress to dementia, particularly Alzheimer disease de- that would indicate future Alzheimer disease risk.91 These factors,
mentia, in order to target interventions. combined with changes in diagnostic technologies for risk stratifi-
It is important to counsel that clinicians cannot confidently cation, portend that guidelines for the diagnosis and management
predict Mrs Js individual risk of progressing to dementia. Guide- of MCI will likely be in flux and debated over the next decade.
lines recommend using deficit type (amnestic or nonamnestic The limited efficacy of currently available interventions to pre-
MCI)6 and ruling out other causes of cognitive impairment (vascu- vent or delay progression of MCI to dementia90 increases the
lar, trauma, depression, medical comorbidity)2 to estimate risk for importance of clinicians discussing the balance of benefits and risks
progression. However, MCI is a clinical diagnosis that has variable of interventions, as well as patients goals and preferences regard-
predictive accuracy for Alzheimer disease dementia depending ing medical interventions in later life. Given that there can be sig-
on the patients age and the definition of MCI used. Moreover, nificant financial costs associated with diagnostic testing for MCI, as
MCI subtype classification may not accurately predict brain well as emotional distress and social stigma, some patients and
pathology. Although amnestic MCI is thought to be a prodrome of families may prefer to forego the diagnostic evaluation.92 Clinical
Alzheimer disease dementia, 30% of patients with amnestic MCI decision-making regarding when and how to diagnose and treat
who develop dementia have a primary brain pathology that is not MCI (and preclinical Alzheimer disease) will likely change signifi-
Alzheimer disease.89 cantly if and when a safe and effective disease-modifying agent for
Existing models to predict risk of MCI progression have limita- preclinical Alzheimer disease and dementia is identified. In the
tions, including poor discrimination and low positive predictive val- meantime, primary care clinicians can support patients like Mrs J in
ues. Overall, better prognostic models are needed that account for practicing healthy lifestyle behaviors, minimizing risks from poly-
demographic, clinical, neuropsychiatric, biological, and pathologi- pharmacy and comorbidities, and counseling patients and families
cal heterogeneity in elders at risk for cognitive decline.90 about how best to plan for the future.

ARTICLE INFORMATION 2. Albert MS, DeKosky ST, Dickson D, et al. The 6. Petersen RC. Clinical practice: mild cognitive
Funding/Support: Dr Langa reports receipt of diagnosis of mild cognitive impairment due to impairment. N Engl J Med. 2011;364(23):2227-2234.
support, in part, by National Institutes of Health Alzheimers disease: recommendations from the 7. Dubois B, Feldman HH, Jacova C, et al. Revising
(NIH) grant U01 AG009740. Dr Levine reports National Institute on Aging-Alzheimers Association the definition of Alzheimers disease. Lancet Neurol.
receipt of support from NIH grant K23 AG040278. workgroups on diagnostic guidelines for 2010;9(11):1118-1127.
The Care of the Aging Patient series is made Alzheimers disease. Alzheimers Dement. 2011;7(3):
270-279. 8. American Psychiatric Association. Diagnostic
possible by funding from The SCAN Foundation. and Statistical Manual of Mental Disorders. 5th ed.
Care of the Aging Patient Series: Authors 3. Sperling RA, Aisen PS, Beckett LA, et al. Toward Washington, DC: American Psychiatric Association;
interested in contributing Care of the Aging Patient defining the preclinical stages of Alzheimers 2013.
articles may contact the section editor Dr disease: recommendations from the National
Institute on Aging-Alzheimers Association 9. Plassman BL, Langa KM, Fisher GG, et al.
Livingston at edward.livingston@jamanetwork.org. Prevalence of cognitive impairment without
workgroups on diagnostic guidelines for
Care of the Aging Patient: From Evidence to Alzheimers disease. Alzheimers Dement. 2011;7(3): dementia in the United States. Ann Intern Med.
Action is produced and edited at the University of 280-292. 2008;148(6):427-434.
California, San Francisco, by Kenneth Covinsky, MD, 10. Matthews FE, Stephan BC, McKeith IG, et al.
Louise Walter, MD, Louise Aronson, MD, MFA, and 4. Institute for Clinical and Economic Review.
Diagnostic tests for Alzheimers disease: defining Two-year progression from mild cognitive
Anna Chang, MD; Amy J. Markowitz, JD, is impairment to dementia. J Am Geriatr Soc. 2008;
managing editor. evidence standards for insurance coverage of
diagnostic tests for Alzheimers Disease: 2012. 56(8):1424-1433.

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Clinical Review & Education Care of the Aging Patient: From Evidence to Action Diagnosing and Managing Mild Cognitive Impairment

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Diagnosing and Managing Mild Cognitive Impairment Care of the Aging Patient: From Evidence to Action Clinical Review & Education

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