Aging Clinical and Experimental Research

MINI REVIEW

Cognitive impairment: classification and open issues

Cristina Basso1, Federica Limongi1, Paola Siviero1, Giovanna Romanato1, Marianna Noale1,
Stefania Maggi1, Leontino Battistin2, and Gaetano Crepaldi1
1
CNR Aging Section, Institute of Neuroscience, Padova, 2IRCCS San Camillo, Lido di Venezia, Italy

ABSTRACT. Several clinically-defined cognitive im-

pairment syndromes, with differing diagnostic criteria
and nomenclature, have been proposed to describe
nondisabling symptomatic cognitive deficits.
Incidence and prevalence rates vary as a result of
different di- agnostic criteria and sampling
procedures across stud- ies. The incidence rates of
cognitive impairment in- crease with age; but no
consistent data have been re- ported on the
association with family history, age, sex, education,
Apo E4 genotype, depression, and other traditional
risk factors for dementia. Several studies have
suggested that most patients with cogni- tive
impairment clinically defined will progress to
Alzheimer Disease (AD), but rates of conversion vary
widely among studies. This review summarizes existing
definitions and related epidemiological data.
(Aging Clin Exp Res 2007; 19: 344-348)
©
2007, Editrice Kurtis
INTRODUCTION
Cognitive impairment without dementia has common-
ly been considered a normal consequence of brain
aging. Many attempts have been made to define the
clinical en- tity of cognitive decline associated with aging.
Prichard (1), at the beginning of the 19 th century,
identified the earliest stage of dementia as impairment of
recent memory with in- tact remote memory. A century
later, Kral (2) described be- nign senescent forgetfulness
(BSF), in which unimpor- tant parts of experiences of
the past are not recalled and in which the forgotten
data seem to belong to the remote past rather than the
recent past. The clinical features of BSF included
memory impairment, and particular attention was paid to
both the extent of the deficits and the patient’s
awareness of them, but no formal criteria were proposed.
BSF was characterized by an age-related decline, which
did not cross a disease threshold, although it was
probably a mild form of the same process giving rise to
malignant
senescent forgetfulness. So dementing disorders were
considered as disease processes distinct from aging, and
the term “senility” was rejected in favor of “dementia”.
DEFINITIONS
Age-associated memory impairment (AAMI)
A number of clinical labels have been proposed to
de- scribe subclinical cognitive deficits.
To characterize age-related changes in memory, the
National Institute of Mental Health (NIMH) working group
defined criteria for AAMI (3): age 50 years with
gradu- al onset of memory complaints substantiated by
psycho- logical performance tests [1.0 standard deviation
(SD) be- low the mean test value, normed on young
adults]. In AA- MI, memory impairment is not the
consequence of a specific neurological, psychiatric or
medical condition. Blackford and LaRue criticized
these criteria as being over-inclusive (4); difficult to
implement in epidemiologic studies (5); lacking construct
validity, in that people with higher intelligence; and
lacking predictive validity, in that subjective complaints
do not predict future decline. In ad- diction, it does not
contemplate and does not clearly discriminate between
subjects who will develop dementia and those who will
remain cognitively stable.
An alternative to viewing changes associated with ag-
ing as intrinsic to the aging process is to consider them
as harbingers of disease. Dementing diseases are more
common with age, and this point should be considered
in the effort to differentiate age-associated traits that
acquire disease status from those that do not. AAMI
prevalence estimates have ranged from 18.5% at age
greater than 50 to 38.4% between ages 60 and 78 (6).
Aging-associated cognitive decline (AACD)
In 1994, a task force of the International
Psychogeriatric Association (IPA), in collaboration with
the World Health Organisation (WHO) (7), proposed
diagnostic criteria for

Key words: Cognitive impairment, dementia.

Correspondence: Federica Limongi, CNR Aging Section, Institute of Neuroscience, Via Giustiniani 2, 35128 Padova,
Italy. E-mail: federica.limongi@in.cnr.it
Received August 10, 2006; accepted in revised form March 30, 2007.

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 C. Basso, F. Limongi, P. Siviero, et Aging Clin Exp Res 19: 344-348,
2007

AACD, in which patients score at least one SD below restric- tive definition, compared with 3% with the most
age and education-based standards (i.e., by reference to liberal
norms for elderly people) on neuropsychological tests
assessing multiple cognitive abilities (memory and
learning, attention and concentration, language and
visuospatial function- ing). The AACD criteria contain
no age restriction, al- though cognitive decline is more
prevalent in old age, and its onset may occur earlier in
life. Hanninen et al. (8) showed a prevalence of 26.6%
and Ritchie et al. (9) found a prevalence of 19.3% in
elderly subjects over 60.

Age-related cognitive decline (ARCD)

ARCD, defined by the Diagnostic and Statistical Man-
ual of mental disorders – Fourth Edition (DSM-IV) as
an objective decline in cognitive functioning consequent
up- on the aging process which is within normal limits,
given the person’s age, does not include diagnostic
criteria, and few epidemiological studies using this
definition have been conducted (10).

Mild cognitive disorder (MCD)

The International Statistical Classification of diseases
and related Health Problems, 10th Revision (ICD-10)
(6) included the definition of MCD, a diagnosis only
used when there are indications of a disease or
condition known to cause cerebral dysfunction.

Cognitive impairment, no dementia (CIND)

The category of CIND has been introduced to
classify all individuals with cognitive impairment falling
between healthy and demented states, but not meeting
criteria of dementia. It describes cognitive impairment
that may or may not progress to dementia, and
includes global cog- nitive impairment and deficits in
several cognitive do- mains. In the Canadian Study of
Health and Ageing (CSHA) (5), a nationally
representative epidemiologic study, the prevalence of
CIND was about 16%, twice that of dementia (8%). In
the Italian Longitudian Study on Ag- ing (ILSA) (11) a
prevalence rate of 10.7% was found.

Mild cognitive impairment (MCI)

The term MCI has received more attention
compared with the other terms still used. It identifies
subjects com- plaining of defective memory, is
preferably corroborated by an informant, includes
normal activities of daily living and normal general
cognitive functioning, but involves ab- normal memory
function for age and education; demen- tia is absent
(12, 13). Population-based studies estimate the
prevalence of MCI to be more than double that of de-
mentia (14) with prevalence rates ranging from 3% for age
60 years (9) to 15% for people aged 75 and older
(15). Fisk et al. (16) showed that changes in definition
changed the prevalence of MCI. The smallest preva-
lence (less than 3%) is also the result of the most
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 Aging Clin Exp Res 19: 344-348, Cognitive impairment: classification and open
2007
definition. However, these changes did not change the CIND remain sta-
proportion of subjects who progressed to dementia.
The heterogeneity of MCI required a subclassifica-
tion: amnestic MCI (a-MCI-single domain) which
focuses on the subjective memory complaint, ideally
corroborat- ed by an informant, with objective memory
impairment for age, and essentially preserved general
cognitive func- tion with largely intact functional
activities. MCI with slight impairment in multiple
domains represents a second type of MCI called md-MCI,
which involves various de- grees of impairment in
multiple cognitive domains such as language, executive
functions and visuospatial skills, with or without
memory impairment. Subjects with memory
impairment are called md-MCI+a and those without
are called md-MCI–a. The third and least common type
of MCI involves only the non-memory cognitive
domain, such as language, executive function or
visuospatial skills (non-amnestic MCI-single domain).
Other subtypes em- phasizing impairments in non-
memory domains, such as executive function and
visuospatial skills, may have a higher likelihood of
progressing to non-Alzheimer disease (AD) dementia,
such as dementia with Lewy bodies. The combination
of clinical subtypes and putative etiologies are also useful
in predicting the type of dementia which will evolve.
The clinical subtypes of MCI are defined partly by
the absence of impairment in activities of daily living
(ADL) and no more than “mild” impairment in instru-
mental activities of daily living (IADL) (17). Data shows
that IADL are lost before ADL, and there are even
hierarchi- cal patterns of functional losses within
these domains. IADL impairment may be associated
with changes in cognition and motor function, and
thus suggests that one or more items of IADL
impairment may serve as a better threshold for
cognitive decline diagnosis (17, 18).

Rate of progression to dementia

Different progression rates have been reported, de-
pending on the definition of impairment and length of
fol- low-up: 12-38% over 1 year (10), 36% over 2
years
(19) , 18% over 3 years (20) and 42% over 5 years
(21). Hogan and Ebly reported that the highest rate of
pro- gression to dementia (51% of survivors) was seen
amongst those who met the ICD-10 F06 criteria for
MCI with re- spect to subjects with specific memory
impairment, in- tellectual decline or personality
change, without func- tional impairment. The
prevalence of all types of cogni- tive impairment,
including CIND and dementias accord- ing to the
CSHA, increased with age and affected 65% of those
aged 85 and older. Subjects with CIND were about
three times more likely to be living in an institution
than those who were cognitively unimpaired. Elderly
people with CIND also show a significant degree of
functional im- pairment and need of institutional care
(21). However, a substantial number of subjects with

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 C. Basso, F. Limongi, P. Siviero, et Aging Clin Exp Res 19: 344-348,
2007

ble, or may even improve in cognitive functioning over MCI to AD (10, 27, 30) vary widely across studies
time (11-21). ranging from
A Finnish study (22) demonstrated that 22% of
subjects with CIND improved after 3 years. Another
study (23) re- ported improvement in 15%, with an
additional 29% remaining stable after 3 years, but it is
not known whether the observed improvement is stable
over time.
In a prospective population-based study, the Kung-
sholmen Project (24), 35% of individuals with CIND
pro- gressed to dementia and 11% remained stable with
an es- timated improvement of 25% between baseline
and the 3- year follow-up. Those who improved within 3
years of fol- low-up did not have a significantly higher
risk of later pro- gressing to dementia than subjects
who had never been classified as cognitively impaired
(relative risk 1.4). It was then found that the absence of
a subjective memory complaint predicts improvement
(odds ratio 5.4), and progression to dementia appeared
to be time-depen- dent, occurring within 3 years. The
relative risk of pro- gressing to dementia was lower at
the 6-year follow-up, and a similar pattern was
described by Johansson and Zarit (25), who reported
rates of progression from MCD to dementia which
were higher over 2 years than over 7 years. Moreover,
the proportions of subjects who im- proved were
similar in severity. The improvement ob- served in the
3-year follow-up is similar to the 22% ob- served by
Schonknecht et al. (26) and slightly higher than the
15% described by Daly et al. (27). In the Kung-
sholmen Project, subjects improved after 3 years, and
re- turned to a cognitively unimpaired state without a
signif- icantly higher risk of dementia with respect to
unim- paired participants.
Longitudinal population studies, using various defini-
tions of MCD adapted to epidemiological studies, have
shown a prevalence in the elderly population between
3 and 19% in adults older 65 years, with an incidence of
8- 58 per 1000 per year, and a risk of developing
demen- tia of 11-33% over 2 years (28). Population-
based stud- ies have shown that up to 44% of patients
with MCI at their first evaluation were estimated to
return to normal a year later (28, 29). Nevertheless,
data shows conflicting conclusions about why not all
individuals identified with MCI appear to progress to
AD, and it has been sug- gested that MCI may represent
early AD which would be revealed with a sufficiently
long period of follow-up (14), or that it represents a
heterogeneous group of individuals within which there
are some at increased risk of demen- tia and others
who have a more non-progressive form of cognitive
impairment which is the reason why improve- ments
are observed.
Data have shown increased rates of progression to
AD in these individuals compared with those with no
cogni- tive impairment (14, 30), which is about 8-10%
per year over 5 years (16). Rates of conversion from

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 Aging Clin Exp Res 19: 344-348, Cognitive impairment: classification and open
2007
about 4% to 40% per year. Estimates are difficult to
in- terpret, because the few studies have methodological
lim- itations, such as small groups of highly selected
pa- tients, lack of similar comparison groups, short
and lim- ited cognitive function evaluation, and failure
to control for demographic variables. Data show that
the relative risk of AD increases between 3 and 8
times among persons with MCI, with estimates
depending on the length of follow-up (16, 31). Only
one study is available regarding the rate of cognitive
decline in subjects with MCI and without cognitive
impairment (31). Among highly educated Catholic
clergy members with MCI, the relative risk of
developing AD is about three times high- er over an
average of almost 5 years of follow-up. A non- linear or
accelerating rate of cognitive decline among per- sons
with MCI with respect to those without cognitive im-
pairment has been assumed, although previous studies
re- ported a period of accelerated cognitive decline
both be- fore (32) and after (33) the time of clinical
diagnosis, when subjects with MCI were not separated
from those without cognitive impairment. Thus, the
non-linear de- cline prior to the onset of dementia is
presumed to be as- sociated with MCI at the transition
phase from normal- ity to dementia. Data from the
Rush Memory and Aging Project (34), a longitudinal
study on 786 community- based persons with MCI
and without cognitive impair- ment, showed that both
groups had a non-linear accel- erating rate of cognitive
decline and that MCI subjects had an additional faster
linear rate of decline.
Various longitudinal studies show that subjects who
develop dementia had cognitive decline at baseline or
during follow-up when compared with individuals
who did not become demented, and various cognitive
test scores decline more precipitously in converters
than in non-converters (35, 36, 37).
Neuropsychological evaluation can discriminate the
transient nature of the early stage of MCI, when
impairment is defined solely by the results of
neuropsychological test scores. Thus, the probability
of performing poorly on the first evalua- tion does not
exclude good performance at the next vis- it. Kryscio
et al. (38) describe several risk factors which affect
transition from a cognitively normal state to amnestic
MCI or dementia. Many potential factors for disease
progression have been identified; no single one or a
combination of factors has yet emerged as a clear
predictor. The risk of a conversion from a cognitively
normal state to MCI and risk factors, which modify the
risk of progression from MCI to dementia (prognostic
factors), are two different classes of risk factors.
Prospec- tive studies beginning at midlife can identify
true risk fac- tors for developing MCI. Depression was
associated with MCI over a 3-year follow-up in the
Mayo prospec- tive cohort (39). The relationship
between depression, cognitive decline and dementia
has not clarified (40, 41). Lesser education and
greater age are associated with

Aging Clin Exp Res, Vol. 19, No. 5

 C. Basso, F. Limongi, P. Siviero, et
MCI (27, 42). The Cardiovascular Health Study shows
an association with depression, Apo E4 genotype, cor-
tical atrophy, and infarcts identified by magnetic reso-
nance imaging (42). No differences between MCI and
normal groups with respect to family history, age, sex,
education, cognitive scores, Apo E4 genotype, depres-
sion, medications, exposure to anesthesia, or hypop-
erfusion on single photon emission computed tomog-
raphy (SPECT) neuroimaging have been described
(43). However, there are data that support the strong
asso- ciation between Apo E4 genotype and the
progres- sion of MCI to AD (21), as well as specific
memory or language test scores, which predict
cognitive decline and or progression to AD. Daly et al.
(27) showed that functional impairment and
difficulties with specific dai- ly functions involving
judgment and problem-solving discriminated subjects
who would or would not progress to AD within 3 years.
In a Swedish community-based study (44, 45), anxiety
symptoms, interpreted as part of the
neurodegenerative process, predicted progression to
MCI, whereas depressive symptoms were considered
to be preclinical signs of AD. Changes in cognitive per-
formance, such as episodic memory, showed a signifi-
cantly greater rate of decline over the follow-up period
among converters; executive functions were lower at
baseline in converters to AD than in stable MCI and
nor- mal subjects (46, 47).
CONCLUSIONS
Data show that the risk of dementia increases with
in- creasing age for all MCI definitions. The time to
convert to dementia is longer in younger (7.8 years) than
in elderly subjects (4.5-5.7 years). Sex and level of
education do not appear to be associated with the risk
of transition to de- mentia. Studies investigating the
conversion from MCI to dementia should have a follow-
up of more than 5 years, in order to detect all subjects
with transition (48).
Most subjects with MCI are aged 40 to 85 years, and
do not progress to dementia in the long term. The risk
of dementia in MCI subjects is closely dependent on age
(49), and is low in subjects aged 40 to 50 and high in
those over 70. Despite what has been described in one
neu- rodegenerative study (28), MCI often represents
the pre- dementia stage of neurodegenerative disorders
in elderly but rarely in younger subjects.
Although risk factors for AD are probably also risk
factors for the development of MCI or progression to it,
no degree of correspondence has been found. This re-
flects the heterogeneity of MCI. Factors that predict no
progression, as well as improvement or cognitive sta-
bility, should be identified. Recent studies demonstrate
the importance of MCI as a clinical entity which not on-
ly predicts progression to dementia, but also functional
decline in activities that reflect autonomy and the qual-
ity of life (50).
348 Aging Clin Exp Res, Vol. 19, No.
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2007
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