Professional Documents
Culture Documents
Mild Cognitive
Address correspondence to
Dr Ronald C. Petersen, Mayo
Clinic, Department of
Neurology, 200 1st St SW,
Rochester, MN 55905-0001,
peter8@mayo.edu.
Relationship Disclosure:
Impairment
Dr Petersen serves on the Ronald C. Petersen, PhD, MD
board of directors for the
Alzheimer’s Association and
receives personal compensation
for serving as chair of the ABSTRACT
data monitoring committees
for Janssen Alzheimer Purpose of Review: As individuals age, the quality of cognitive function becomes
Immunotherapy and Pfizer an increasingly important topic. The concept of mild cognitive impairment (MCI) has
Inc. Dr Petersen receives evolved over the past 2 decades to represent a state of cognitive function between
personal compensation as a
consultant for Biogen, Eli Lilly that seen in normal aging and dementia. As such, it is important for health care
and Company, the Federal providers to be aware of the condition and place it in the appropriate clinical context.
Trade Commission, Genentech, Recent Findings: Numerous international population-based studies have been con-
Inc, Hoffmann la Roche, Inc,
and Merck & Company, Inc. ducted to document the frequency of MCI, estimating its prevalence to be between
Dr Petersen receives grant and 15% and 20% in persons 60 years and older, making it a common condition en-
funding support from the Mayo countered by clinicians. The annual rate in which MCI progresses to dementia varies
Foundation for Education and
Research, the National Institute between 8% and 15% per year, implying that it is an important condition to identify
on Aging, and the Patient and treat. In those MCI cases destined to develop Alzheimer disease, biomarkers are
Centered Outcomes Research emerging to help identify etiology and predict progression. However, not all MCI is due
Institute (PAT 206548).
Dr Petersen receives royalties to Alzheimer disease, and identifying subtypes is important for possible treatment and
from Oxford University Press. counseling. If treatable causes are identified, the person with MCI might improve.
Unlabeled Use of Summary: MCI is an important clinical entity to identify, and while uncertainties per-
Products/Investigational
Use Disclosure:
sist, clinicians need to be aware of its diagnostic features to enable them to counsel
Dr Petersen discusses the patients. MCI remains an active area of research as numerous randomized controlled
unlabeled/investigational trials are being conducted to develop effective treatments.
clinical trial results for mild
cognitive impairment.
* 2016 American Academy Continuum (Minneap Minn) 2016;22(2):404–418.
of Neurology.
Deterioration Scale as being MCI.5 In incipient AD nor did all patients have
1999, a group at the Mayo Clinic de- just a memory impairment. To address
scribed subjects in their community this situation, the Key Symposium was
aging study who had a memory con- held in Stockholm, Sweden, in 2003,
cern beyond what was expected for and criteria of a more broad scope were
age and who demonstrated a slight published in 2004.2,7 These criteria ac-
memory impairment yet did not meet complished two goals: (1) to broaden
criteria for dementia.6 The research the classification scheme beyond mem-
criteria used to characterize these sub- ory, and (2) to recognize that MCI could
jects were described, and the clinical result from a variety of etiologies and
outcomes were noted. not just AD. These criteria are outlined
in Figure 2-1,8 demonstrating the syn-
MULTIPLE TERMINOLOGIES dromic phenotypes and how they can
Over the years, several sets of termi- be paired with possible etiologies
nology for MCI and related conditions to assist the clinician in diagnosis. The
have evolved, many referring to similar Key Symposium characterization of
constructs in the general MCI range. MCI led to the distinction between the
The Mayo Clinic criteria previously noted amnestic form of MCI and the non-
focused on a memory disturbance and amnestic form of MCI, since these clin-
were developed to elucidate the earliest ical syndromes appeared to be aligned
symptomatic stages of AD. However, with etiologies in a differential fash-
it soon became apparent that not all ion and may have variable outcomes.
intermittent cognitive states represented Traditionally, amnestic MCI is the
FIGURE 2-1 Key Symposium criteria. First Key Symposium criteria demonstrating the syndromic phenotypes
and how they can be paired with possible etiologies to assist the clinician in making a diagnosis.
AD = Alzheimer disease; DLB = dementia with Lewy bodies; FTD = frontotemporal dementia;
MCI = mild cognitive impairment; VCI = vascular cognitive impairment.
Modified with permission from Petersen RC, Continuum (Minneap Minn).8 journals.lww.com/continuum/Fulltext/2004/02000/
MILD_COGNITIVE_IMPAIRMENT.3.aspx. B 2004, American Academy of Neurology.
KEY POINTS typical prodromal stage of dementia due posium criteria while making some of
h Traditionally, amnestic to AD, but other phenotypes can also the diagnostic features more explicit.
mild cognitive impairment lead to this type of dementia, such as These criteria also added biomarkers
is the typical prodromal
logopenic aphasia, posterior cortical at- for underlying AD pathophysiology in
stage of dementia due to
rophy (also known as the visual variant), an attempt to refine the underlying
Alzheimer disease, but
other phenotypes can
or a frontal lobeYdysexecutive presenta- etiology and, hence, predict outcome.
also lead to this type of tion of AD.9 The essential feature of this These criteria did not differentiate be-
dementia, such as portrayal is that not all MCI is early AD. tween amnestic and nonamnestic MCI.
logopenic aphasia, The Key Symposium criteria pre- At approximately the same time, the
posterior cortical atrophy vailed in the field and influenced the Diagnostic and Statistical Manual
(also known as the visual development of several randomized of Mental Disorders, Fifth Edition
variant), or a frontal controlled trials for possible interven- (DSM-5) was being developed.17 For
lobeYdysexecutive tion.10Y14 In 2011, the National Insti- the general category of neurocogni-
presentation of tute on Aging (NIA) and the Alzheimer’s tive disorders, the criteria now include
Alzheimer disease. Association convened workgroups to a predementia phase called mild
h Not all mild cognitive develop criteria for the entire AD spec- neurocognitive disorder. Once again,
impairment is early trum.1,9,15,16 The criteria for MCI due the construct is very similar to the
Alzheimer disease. to AD essentially adopted the Key Sym- Key Symposium criteria for MCI and
KEY POINTS
h The multiple sets of
criteria referring to mild
cognitive impairment
actually contain many of
the same elements and
are quite similar to the
original Key
Symposium criteria.
h Numerous international
studies have been
completed involving
several thousand
subjects, and these
studies tend to estimate
the overall prevalence
of mild cognitive
impairment in the
12% to 18% range in
persons over the age
of 60 years.
FIGURE 2-3 Comparison of common criteria used to characterize mild cognitive impairment
(MCI) in various publications. The biomarkers for amyloid-" (A") or tau could
be derived from either positron emission tomography (PET) imaging or CSF to
accompany the clinical syndromes described above.
AD = Alzheimer disease; CSF = cerebrospinal fluid; DSM-5 = Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition; FDG-PET = fluorodeoxyglucose positron emission tomography;
MRI = magnetic resonance imaging.
Reprinted with permission from Petersen RC, et al, J Intern Med.4 onlinelibrary.wiley.com/doi/10.1111/j.1365-
2796.2004.01388.x/full#b36. B 2014 The Association for the Publication of the Journal of Internal Medicine.
establish criteria prior to labeling the in persons over the age of 60 years.21Y26
participants as having MCI are more The Mayo Clinic Study of Aging, which
reliable and valid. Studies that apply is a population-based study in Olmsted
MCI criteria to previously collected data County, Minnesota, found the overall
can generate a variety of figures based prevalence of MCI to be 16% in resi-
on the cutoff scores that are used to dents age 70 years and older.27 MCI is
define MCI. Therefore, since MCI is a clearly an age-related condition, and
clinical diagnosis informed by neuro- to the extent that the evaluation sug-
psychological data, a prospective study gests a degenerative etiology, AD is
is preferred when interpreting epide- most likely.30
miologic data. A similar situation pertains to the
Numerous international studies have normal cognition to MCI transition,
been completed involving several with certain methodological issues
thousand subjects, and these studies lending themselves to some of the
tend to estimate the overall preva- variation. Several longitudinal epidemi-
lence of MCI in the 12% to 18% range ologic studies have followed cognitively
Case 2-1B
A mental status examination was performed on the 66-year-old patient
discussed in Case 2-1A, and while the patient did quite well, there was a
suggestion of memory impairment with impaired delayed recall of the
words. Neuropsychological testing was pursued, which showed a profile
that looked normal for his age, sex, and education in virtually all cognitive
domains except for memory. Here, his delayed recall of lists, paragraphs,
and nonverbal materials was mildly impaired.
Further interview of the patient and a family member revealed that
his function was largely preserved. In particular, he functioned in the
community quite well without difficulty, and while slightly more inefficient
at some tasks, he still completed everything quite well.
Comment. Based on examination findings, neuropsychological testing,
and discussions with the patient and his family member, he does not
appear to have dementia. A reasonable diagnosis at this point would be
amnestic mild cognitive impairment, but the etiology, given the patient’s
young age and negative family history, is uncertain. At this point, a
discussion with the patient might include possible etiologies and education
about lifestyle alterations, planning for the future, and consideration of
enrollment in randomized controlled trials.
does not add significantly to the diag- tia.42,43 The 2006 study by Hansson
nostic evaluation.34,40 and colleagues44 was most informative
The newest PET tracer that is emerg- with regard to these data and corrob-
ing allows investigators to evaluate the orates the suspicion that those indi-
role of tau in clinical progression, and viduals, particularly with amnestic
these data are evolving.41 It is quite MCI, who harbor low CSF levels of
likely that a tau PET scan that shows A"42 and elevated total tau and phos-
the spread of tau outside of the me- phorylated tau are at an increased risk
dial temporal lobe into lateral tempo- for progressing more rapidly than
ral lobe structures portends a poorer those subjects with the same clinical
prognosis and, more likely, a rapid phenotype but normal CSF biomarkers.
progression from MCI to AD demen- In general, these predictors all refer
tia, but these data need to be ampli- to individuals who are on the AD spec-
fied (Figure 2-4). trum. Biomarkers for other degenera-
Numerous studies have shown that tive disorders are less certain at this
the various CSF markers consistent with point and need to be fully evaluated.
AD predict progression to AD demen- As biomarkers for other disorders
levels of biomarker specificity for AD, etiology of the syndrome.17 As such, of biomarker specificity
conditions such as AD, frontotemporal for Alzheimer disease,
and AD dementia in which individuals and AD dementia in
lobar degeneration, dementia with Lewy
meet clinical criteria for dementia and which individuals meet
bodies, vascular cognitive impairment,
similarly have varying degrees of bio- clinical criteria for
human immunodeficiency (HIV)-related
marker support.1 These criteria have dementia and similarly
disorders, alcohol and substance abuse,
proved useful in characterizing the en- have varying degrees of
Parkinson disease, and a variety of other biomarker support.
tire spectrum of AD and expanding it
possible etiologies are explicated. As
beyond the dementia phase. Prior sets h The spectrum of
noted above, the process of combining
of criteria had focused only on the de- the clinical syndrome with patient his-
neurocognitive disorder,
mentia phase, but it has become ap- as defined by the
tory, clinical examination findings, and, Diagnostic and Statistical
parent in recent years that the AD while still evolving, biomarker informa- Manual of Mental
process likely begins years and per- tion is used to specify the clinical syn- Disorders, Fifth Edition, is
haps decades before clinical symp- drome. As is seen in DSM-5, there are divided into mild
toms appear.45 As such, the use of often degrees of certainty added to the neurocognitive disorder,
biomarkers has afforded an important clinical diagnoses based on the pre- which is very similar
tool for specificity for the clinician. It ponderance of evidence for a specific to mild cognitive
must be emphasized, however, that underlying disorder.17 impairment, and major
these criteria involving biomarkers are In 2007 and updated in 2010 and neurocognitive disorder,
still in the research phase, and specific 2013, investigators have proposed the which is very similar
recommendations regarding their use to dementia.
term prodromal AD as an alternative
in clinical practice remain to be deter- for characterizing individuals along
mined. However, based on the litera- the AD spectrum.18Y20 The most re-
ture cited above, it is apparent that the cent version of these criteria embod-
use of biomarkers is working its way ies the notion of amnestic MCI and
into clinical practice. embellishes it with evidence for amy-
In addition, the American Psychiatric loid deposition via PET scanning or
Association has recently published the amyloid and tau information using
DSM-5, and this set of criteria gives CSF.20 These investigators contend
consideration to the diagnosis of mild that the combination of amnestic MCI
neurocognitive disorder. In general, with specific biomarkers is highly
Continuum (Minneap Minn) 2016;22(2):404–418 www.ContinuumJournal.com 413
KEY POINTS
h Currently, there are no suggestive of the AD process and should ever, subsequent data suggest that
accepted pharmacologic be labeled as AD. These criteria have there may be some efficacy to be
treatments for mild been useful for randomized control gleaned from lifestyle modifications,
cognitive impairment trials for evaluation of pharmacologic and these need to be explored further.
approved by the US therapeutics intended to target under-
Food and Drug lying AD pathophysiology.46,47 CLINICAL ACCEPTANCE
Administration, the The construct of MCI has been in the
European Medicines TREATMENTS medical literature for many years and,
Agency, or the Currently, there are no accepted phar- over time, has been accepted in clin-
Pharmaceuticals and ical practice to certain degrees. The
macologic treatments for MCI ap-
Medical Devices Agency
proved by the FDA, the European American Academy of Neurology
in Japan.
Medicines Agency, or the Pharmaceu- (AAN) completed an evidence-based
h Lifestyle modifications ticals and Medical Devices Agency in medicine review of the literature and
and other
Japan. Numerous randomized control concluded that the construct of MCI is
nonpharmacologic
trials have been conducted in the MCI useful for clinicians to identify since
therapies have also
been investigated, and spectrum, but none has been success- the condition does lead to a higher
there is a suggestion ful at demonstrating effectiveness at risk of progression to dementia.50
that some of these delaying the progression from MCI to Numerous epidemiologic studies have
modifications or AD dementia.10Y14 One of the first been done around the world that have
therapies, such as trials, conducted by the Alzheimer’s suggested the utility of the identi-
aerobic exercise, may Disease Cooperative Study, evaluated fication of MCI as a clinical entity.
be effective at reducing donepezil and high-dose vitamin E in Roberts and colleagues51 evaluated
the rate of progression amnestic MCI.13 This study indicated members of the Behavioral Neurology
from mild cognitive that donepezil may be effective at section and the Geriatric Neurology
impairment to dementia. section of the AAN and documented
slowing the rate of progression in all
h Criticism has been subjects with amnestic MCI for the that MCI is used frequently in clinical
raised regarding the first year of the trial and perhaps up to practice and that practitioners find the
boundaries of the construct useful. There were concerns
2 years in subjects with amnestic MCI
condition of mild about its specificity and the lack of
who were positive for the APOE4 iso-
cognitive impairment treatments, but, nevertheless, it was
with respect to
form. However, since the study was
designed to continue for 36 months, believed to be useful.
differentiating it from
no treatments demonstrated effective- Recently, a similar exercise was done
changes of cognitive
aging and also ness at that time and, as such, the trial in Europe assessing the utility of the
differentiating it was negative. Other studies involving construct of MCI in clinical practice and
from dementia. cholinesterase inhibitors that have the outcome was quite similar to that
been used for the treatment of AD found in polling members of the AAN.
dementia were also unsuccessful.10,11,13 As such, it appears that the construct of
Lifestyle modifications and other MCI is accepted in clinical practice and
nonpharmacologic therapies have also serves a function for clinicians in com-
been investigated, and there is a municating clinical diagnoses to pa-
suggestion that some of these modifi- tients. It has also been a useful construct
cations or therapies, such as aerobic for research as literally thousands of
exercise, may be effective at reducing studies have been generated in the
the rate of progression from MCI to past decade assessing various aspects
dementia.48 However, a state-of-the- of the condition.
science report from the National Insti- This is not to say, however, that there
tutes of Health (NIH) in 2010 failed to is not controversy surrounding the con-
document any successful interventions struct. Criticism has been raised regard-
for progression to dementia.49 How- ing the boundaries of the condition
6. Petersen RC, Smith GE, Waring SC, et al. 16. Sperling RA, Aisen PS, Beckett LA, et al.
Mild cognitive impairment: clinical Toward defining the preclinical stages of
characterization and outcome. Arch Neurol Alzheimer’s disease: recommendations from
1999;56(3):303Y308. doi:10.1001/ the National Institute on Aging-Alzheimer’s
archneur.56.3.303. Assocation workgroups on diagnostic
guidelines for Alzheimer’s disease.
7. Winblad B, Palmer K, Kivipelto M, et al.
Alzheimers Dement 2011;7(3):280Y292.
Mild cognitive impairmentVbeyond doi:10.1016/j.jalz.2011.03.003.
controversies, towards a consensus: report
of the International Working Group on 17. American Psychiatric Association. Diagnostic
Mild Cognitive Impairment. J Intern Med and statistical manual of mental disorders,
2004;256(3):240Y246. doi:10.1111/ fifth edition. Washington, DC: American
j.1365-2796.2004.01380.x. Psychiatric Publishing, 2013.
8. Petersen RC. Mild Cognitive Impairment. 18. Dubois B, Feldman HH, Jacova C, et al. Research
Continuum (Minneap Minn) 2004; criteria for the diagnosis of Alzheimer’s
10(1 Dementia):9Y28. doi:10.1212/ disease: revising the NINCDS-ADRDA criteria.
01.CON.0000293545.39683.cc. Lancet Neurol 2007;6(8):734Y746. doi:10.1016/
S1474-4422(07)70178-3.
9. Albert MS, DeKosky ST, Dickson D, et al.
The diagnosis of mild cognitive impairment 19. Dubois B, Feldman HH, Jacova C, et al. Revising
due to Alzheimer’s disease: recommendations the definition of Alzheimer’s disease: a new
from the National Institute on Aging-Alzheimer’s lexicon. Lancet Neurol 2010;9(11):1118Y1127.
Association workgroups on diagnostic doi:10.1016/S1474-4422(10)70223-4.
guidelines for Alzheimer’s disease. Alzheimers 20. Dubois B, Feldman HH, Jacova C, et al.
Dement 2011;7(3):270Y279. doi:10.1016/ Advancing research diagnostic criteria for
j.jalz.2011.03.008. Alzheimer’s disease: the IWG-2 criteria.
10. Doody RS, Ferris SH, Salloway S, et al. Lancet Neurol 2014;13(6):614Y629.
Donepezil treatment of patients with MCI: a doi:10.1016/S1474-4422(14)70090-0.
48-week randomized, placebo-controlled 21. Busse A, Hensel A, Gühne U, et al. Mild
trial. Neurology 2009;72(18):1555Y1561. cognitive impairment: long-term course of
doi:10.1212/01.wnl.0000344650.95823.03. four clinical subtypes. Neurology
2006;67(12):2176Y2185. doi:10.1212/
11. Feldman HH, Ferris S, Winblad B, et al.
01.wnl.0000249117.23318.e1.
Effect of rivastigmine on delay to diagnosis
of Alzheimer’s disease from mild cognitive 22. Di Carlo A, Lamassa M, Baldereschi M, et al.
impairment: the InDDEx study. Lancet CIND and MCI in the Italian elderly:
Neurol 2007;6(6):501Y512. doi:10.1016/ frequency, vascular risk factors, progression
S1474-4422(07)70109-6. to dementia. Neurology 2007;68(22):
1909Y1916. doi:10.1212/01.wnl.
12. Thal LJ, Ferris SH, Kirby L, et al. A randomized,
0000263132.99055.0d.
double-blind, study of rofecoxib in patients
with mild cognitive impairment. 23. Ganguli M, Chang CC, Snitz BE, et al.
Neuropsychopharmacology 2005;30(6): Prevalence of mild cognitive impairment
1204Y1215. doi:10.1038/sj.npp.1300690. by multiple classifications: The
Monongahela-Youghiogheny Healthy Aging
13. Winblad B, Gauthier S, Scinto L, et al.
Team (MYHAT) project. Am J Geriatr
Safety and efficacy of galantamine in
Psychiatry 2010;18(8):674Y683. doi:10.1097/
subjects with mild cognitive impairment.
JGP.ob013e3181cdee4f.
Neurology 2008;70(22):2024Y2035.
doi:10.1212/01.wnl.0000303815. 24. Larrieu S, Letenneur L, Orgogozo JM, et al.
69777.26. Incidence and outcome of mild cognitive
impairment in a population-based prospective
14. Petersen RC, Thomas RG, Grundman M,
cohort. Neurology 2002;59(10):1594Y1599.
et al. Vitamin E and donepezil for the
doi:10.1212/01.WNL.0000034176.07159.F8.
treatment of mild cognitive impairment. N
Engl J Med 2005;352(23):2379Y2388. 25. Lopez OL, Jagust WJ, DeKosky ST, et al.
doi:10.1056/NEJMoa050151. Prevalence and classification of mild cognitive
impairment in the Cardiovascular Health
15. McKhann GM, Knopman DS, Chertkow H,
Study Cognition Study: part 1. Arch Neurol
et al. The diagnosis of dementia due to
2003;60(10):1385Y1389. doi:10.1001/
Alzheimer’s disease: recommendations from
archneur.60.10.1385.
the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic 26. Manly JJ, Tang MX, Schupf N, et al. Frequency
guidelines for Alzheimer’s disease. and course of mild cognitive impairment in
Alzheimers Dement 2011;7(3):263Y269. a multiethnic community. Ann Neurol
doi:10.1016/j.jalz.2011.03.005. 2008;63(4):494Y506. doi:10.1002/ana.21326.