Journal of the Neurological Sciences 349 (2015) 179184

Contents lists available at ScienceDirect

Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Olfactory identication in amnestic and non-amnestic mild cognitive

impairment and its neuropsychological correlates
Martin Vyhnalek a,b,, Hana Magerova b, Ross Andel c, Tomas Nikolai a,b, Alexandra Kadlecova a,b,
Jan Laczo a,b, Jakub Hort a,b
a
b
c

International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
Memory Clinic, Department of Neurology, Charles University in Prague, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
School of Aging Studies, University of South Florida, Tampa, FL, USA

a r t i c l e

i n f o

Article history:
Received 30 June 2014
Received in revised form 7 January 2015
Accepted 8 January 2015
Available online 14 January 2015
Keywords:
Mild cognitive impairment
Olfaction disorders
Smell
Alzheimer's disease
Cognition
Memory

a b s t r a c t
Background: Olfactory identication impairment in amnestic mild cognitive impairment (aMCI) patients is well
documented and considered to be caused by underlying Alzheimer's disease (AD) pathology, contrasting with
less clear evidence in non-amnestic MCI (naMCI). The aim was to (a) compare the degree of olfactory identication dysfunction in aMCI, naMCI, controls and mild AD dementia and (b) assess the relation between olfactory
identication and cognitive performance in aMCI compared to naMCI.
Methods: 75 patients with aMCI and 32 with naMCI, 26 patients with mild AD and 27 controls underwent the
multiple choice olfactory identication Motol Hospital Smell Test with 18 different odors together with a comprehensive neuropsychological examination.
Results: Controlling for age and gender, patients with aMCI and naMCI did not differ signicantly in olfactory
identication and both performed signicantly worse than controls (p b 0.001), albeit also better than patients
with mild AD (p b .001). In the aMCI group, higher scores on MMSE, verbal and non-verbal memory and visuospatial tests were signicantly related to better olfactory identication ability. Conversely, no cognitive measure
was signicantly related to olfactory performance in naMCI.
Conclusion: Olfactory identication is similarly impaired in aMCI and naMCI. Olfactory impairment is proportional to cognitive impairment in aMCI but not in naMCI.
2015 Published by Elsevier B.V.

1. Introduction
Olfactory impairment has been demonstrated in Alzheimer's disease
(AD) [10,20,36], presumably as a consequence of early degeneration of olfactory bulb, olfactory nerve and olfactory cortex situated predominantly
in the medial temporal lobe [1,2,3]. Among the three major types of olfactory ability (detection, discrimination and identication), the olfactory
identication is impaired earlier compared to the olfactory detection in
AD patients [50]. So far, most studies with cognitively impaired patients
have investigated only olfactory identication, which strongly correlates
with olfactory threshold and is easier to test [9, 11,12]. The olfactory identication decit seems to be specically linked mainly to the temporal
lobe including the amygdala, hippocampus and parahippocampal gyrus,

Abbreviations: MHST, Motol Hospital Smell Test.

Corresponding author at: Memory Clinic, Department of Neurology, Charles
University in Prague, 2nd Faculty of Medicine and Motol University Hospital, V valu 84,
150 06 Prague 5, Czech Republic. Tel.: +420 22443 6801; fax: +420 22443 6820.
E-mail address: martin.vyhnalek@fnmotol.cz (M. Vyhnalek).

http://dx.doi.org/10.1016/j.jns.2015.01.014
0022-510X/ 2015 Published by Elsevier B.V.

but even anterior temporal damage is sufcient to provoke olfactory identication impairment [21].
Dementia syndrome in AD and in other degenerative disorders is almost always preceded by mild cognitive impairment (MCI) syndrome
in which the patients have objective cognitive impairment on neuropsychological examination but do not show substantial decits in activities of daily living [43,45].
MCI patients with objective memory impairment are labeled
amnestic MCI (aMCI). These patients progress mainly to AD dementia
[15,42,44], aMCI patients with isolated memory (amnestic) impairment
are labeled as the single domain aMCI (aMCIsd), and aMCI patients with
an additional impairment in the other cognitive domains beyond memory (e.g., executive impairment, language, visuospatial) are called multiple domain aMCI (aMCImd) [42,44].
Among aMCI patients, olfactory identication impairment has been
demonstrated in a number of studies with a cross sectional design [8,
14,23,59]. To our best knowledge only one study also investigated
other olfactory modalities beyond olfactory identication in patients
with aMCI and it reported impaired olfactory detection and identication. There was also an olfactory discrimination decit but that was

180

M. Vyhnalek et al. / Journal of the Neurological Sciences 349 (2015) 179184

accounted for by an abnormal olfactory threshold [8]. Finally, olfactory

impairment in aMCI represents a risk factor for subsequent cognitive
decline and conversion to AD dementia, as was demonstrated by some
longitudinal studies [6,53,54].
MCI patients with normal memory function but with cognitive impairment in non-memory domains (e.g. executive functions, visuospatial functions, language) are classied as non-amnestic MCI (naMCI).
Patients with naMCI may convert more frequently to non-AD dementias
[42,44], especially to frontotemporal lobar degeneration (FTLD),
Parkinson disease and Lewy body disease (LBD) in which olfactory identication impairment is frequently found [20,29,36,46].
However, there have been only a few studies investigating olfactory
functions in naMCI, which report inconsistent results [7,23,59]. Considering the evidence of olfactory identication impairment in these nonAD dementias, which are typically preceded by naMCI subtype, we
would expect large olfactory impairment in patients with naMCI that
may resemble that of patients with aMCI.
Association between olfactory and cognitive impairment in AD and
MCI patients is not yet fully understood. The association between memory and olfactory identication performance was demonstrated only in
a mixed cohort of healthy elderly and MCI patients and in a mixed cohort of MCI and dementia patients [7,8,23,48,60]. To our best knowledge
the relation between olfactory identication and cognitive performance
in MCI, specically in the amnestic versus non-amnestic MCI subtypes,
has not been assessed.
Because of anatomical and functional proximity of brain areas responsible for memory and olfaction (both situated predominantly in
the medial temporal lobe), we would expect proportional degree of olfaction and memory impairment in pre-dementia and dementia stages
of AD.
To build on previous research, the aim of this study was to:

Of the 75 broadly dened aMCI cases, only 18 had pure amnesia (all
other tests were within the normal range aMCIsd), while the remaining participants, labeled as aMCImd, suffered from other subtle semantic, visuoconstructive or attention-executive function decits (more
than 1.5 SD), or both.
Two other groups were used in this study:

1) Compare olfactory identication decit in patients with aMCI vs.

naMCI, as well as aMCI and naMCI vs. controls and mild AD.
2) Compare olfactory identication between patients with single vs.
multiple domain aMCI.
3) Analyze the association between olfactory identication and cognitive performance in aMCI vs. naMCI.

2.2. Exclusion criteria

The control group (n = 27) Reported no cognitive problems, which

was subsequently conrmed by neuropsychological testing and a CDR score
of 0.0. They were recruited from staff
and patient's relatives and were selected
to be as similar as possible to the other
groups in terms of age, education and
gender.
The mild probable AD group (n = 26) Met the Diagnostic and Statistical
Manual of Mental Disorders IV criteria for
dementia and the National Institute of
Neurological and Communicative Disorders and Stroke and Alzheimer Disease
and Related Disorders Association criteria
for probable AD [32]. Patients with
dementia had an impairment of memory
and another cognitive domain, impaired
functional activities, and their CDR
was 1.0 or higher. They didn't have significant vascular impairment on brain MRI
(Fazekas scale 0 or 1) [16]. All AD patients
were on a stable dose of cholinesterase
inhibitors for at least 3 months.

Subjects with history of smoking in past 10 years, acute or chronic

rhinitis or another ORL diagnosis causing potential hyposmia or subjects
with preexisting hyposmia of another etiology (posttraumatic, professional exposure to toxics) and subjects with depression (scoring more
than 5 on Geriatric Depression Scale) were excluded from the study.

2. Methods
2.3. Neuropsychological assessment
2.1. Subjects
All subjects were recruited from referrals to the Memory Disorders
Clinic at Motol Hospital, an afliate of Charles University in Prague,
and signed an informed consent approved by the local ethics committee. They underwent standard protocol which consisted of magnetic
resonance imaging, neurological, medical and laboratory evaluation,
questionnaires and complex neuropsychological assessment mentioned
below. A total of 160 participants were included in the analyses.
The MCI group subjects met the revised Petersen's criteria for MCI
[43]. The participants had cognitive complaints reported by themselves
or by their caregiver, they were impaired on objective cognitive tasks,
not demented with largely intact functional activities with CDR (Clinical
Dementia Rating scale) of 0.5.
The MCI patients (n = 107) were further classied into the following groups: (a) patients with naMCI (n = 32) or (b) patients with aMCI
(n = 75).
All aMCI patients had memory complaints and scored more than 1.5
of standard deviation (SD) lower than age matched controls in verbal
memory tests (Auditory Verbal Learning Test [AVLT] and Enhanced
Cued Recall [ECR] test).
Patients with naMCI had impairment only in the non-memory cognitive domains, manifesting in all patients as attentional-executive deficit, in addition 5 patients suffered from language decit and 3 patients
from visuospatial decit.

Following neuropsychological tests and questionnaires were administered: Clinical Dementia Rating (CDR) [38], and 15-item Geriatric
Depression Scale [62]. Additional neuropsychological testing included
the Mini Mental State Examination (MMSE) [17], verbal memory
tests: Auditory Verbal Learning Test (AVLT) [51], 16-item version
Grober and Buschke's Test with Enhanced Cued Recall (ECR) procedure
[19], nonverbal memory test and visuospatial test: ReyOsterrieth
Complex Figure Test (ROCF) copy and reproduction [37], working
memory attention: digit span (DS) forward and reversed [58], Trail
Making Tests (TMT) A [47], executive functions: Category Fluency and
Initial Letter Fluency (FAS) tests [26] and TMT B.
2.4. Smell identication assessment
In all subjects, smell identication was assessed using the Motol
Hospital Smell Test (MHST) a multiple-choice smell identication
test developed and evaluated at our memory clinic [29,30]. MHST is
composed of 18 odors very well known among elderly Czech population
(pine-tree, peach, lemon, rose, cherry, grapefruit, clove, lavender, peppermint, orange, cinnamon, vanilla, coffee, honey, lilac, strawberry,
black currant, rum). Odors are presented as essential oils in special
phials in the amount of 200 l to both nostrils simultaneously. The essential oils are replaced every 2 months in the phials in order to prevent
degradation of the odor. After snifng the odor, subjects are asked to

M. Vyhnalek et al. / Journal of the Neurological Sciences 349 (2015) 179184

select one right answer from the four choices list. It was previously approved that MHST results correlate with the results of the University of
Pennsylvania Smell Identication Test (r = .68, p b .001) [11,30]. To exclude non-olfactory components of the smell identication failure, the
Picture Identication Test (PIT) was used [56].

181

regardless of age and gender. The relationship between better attention/working memory, executive function and olfactory ability
approached signicance. No cognitive measure was signicantly related
to olfactory performance in naMCI.
4. Discussion

2.5. Statistical analysis

All analyses were performed using SAS statistical software (SAS Institute, Cary, NC). All variables were examined for normality of distribution. No variable presented signicant deviation from normal score
distribution. Therefore, values are presented as average standard deviation or as percent. Controls were compared to aMCI, naMCI and AD
on the MHST using analysis of covariance (ANCOVA). As the group differed in age, education and gender, these variables were entered as covariates. The post hoc Tukey's Honestly Signicant Difference test was
used for group comparison. In an additional analysis, only aMCI patients
were used, allowing for a direct comparison between aMCIsd and
aMCImd subgroups. To address possible concerns regarding statistical
power in the main ANCOVA models, we estimated statistical power
using SAS procedure POWER, entering covariate-adjusted means and
using weighting to account for differences in sample size across groups.
We found that both ANCOVAs had upwards of 90% power to detect any
differences as statistically signicant. In addition, to help interpret
between-group differences, we also report effect sizes in the form of
Cohen's d (covariate-adjusted mean between-group difference over
pooled standard deviation) as this statistic is relatively independent of
sample size. Conventionally, Cohen's d is interpreted as small (about
0.2), medium (about 0.5) and large (about 0.8 or larger) [5].
In addition, we used ordinary least squares regression to examine
the relationship between olfactory ability and cognitive performance
both in the entire sample and separately across diagnostic groups, controlling for age and gender. The score for each cognitive domain (verbal
and nonverbal memory, executive, attention/working memory, visuospatial) was expressed as a unit-weighted composite z-score
(mean = 0, SD = 1) from the relevant neuropsychological tests to
more easily compare results across regression models. The values
from the TMT A and B tests, which are expressed in seconds to completion, were reversed before the z-scores were generated. The signicance
level was set at .05.
3. Results
Demographic and neuropsychological characteristics of the diagnostic groups and results of MHST are summarized in Table 1. All four
groups differed in age (F [3, 157] = 6.15, p = .001), years of education
(F [3, 157] = 4.65, p b . 004), gender (2 [3] = 11.53, p b .05), and MMSE
(F [3, 157] = 39.0, p b .0001). The subgroups of MCI did not differ in age,
years of education, or gender (F [1, 76] b 1.2, p N .27 in all analyses) but
they differed in MMSE (F [1, 76] = 6.72, p = .012), whereby AD patients
were signicantly older compared to controls and both aMCI subgroups.
There was a signicant main effect for group as a function of olfactory identication MHST scores (F [3, 157] = 11.17, p b .001). The post hoc
test revealed signicant impairment in aMCI (Cohen's d = 0.64), naMCI
(Cohen's d = 0.78) and AD (Cohen's d = 1.37) groups compared to controls (all ps b .001). In addition olfactory identication was signicantly
more impaired in AD group compared to both aMCI and naMCI subgroups (p b .001). No signicant difference was found between aMCI
and naMCI groups. Next, we compared olfactory identication in patients with aMCIsd vs. aMCImd, nding that aMCImd patients performed signicantly worse than those with aMCIsd (F [1, 76] = 7.21,
p = .009, Cohen's d = 0.63).
Finally, we used regression analyses to assess the relation between olfaction and cognitive performance (see Table 2). In the aMCI group,
higher MMSE, better visuospatial function, verbal memory, and nonverbal memory were all signicantly related to better olfactory ability

We assessed olfactory function in a relatively large sample of participants and considered analytically both diagnostic entities (normal,
aMCI, naMCI, AD) and neuropsychological assessment scores. Controlling for age and gender, we found that (a) olfactory identication impairment was similar in amnestic and non-amnestic MCI subgroups,
(b) aMCImd patients performed worse than those with aMCIsd, and
(c) olfactory identication impairment was related mainly to memory
and visuospatial function in aMCI but has no cognitive correlate in
naMCI.
In addition, the study conrms previous ndings of olfactory identication impairment early in the course of AD, already at the stage of
mild dementia [20,36] and in individuals with aMCI, an entity which is
often attributed to prodromal AD [8,14,23,59].
Impairment in aMCI subgroup was milder than in patients with mild
AD dementia, showing no oor effect for olfactory identication using
MHST in aMCI patients. Analogous results were found in other study
with UPSIT [8].
In a previous study of olfactory identication impairment in aMCI
using a relatively small sample, the authors reported a statistically
non-signicant tendency for patients with aMCImd to be more impaired than aMCIsd [23]. To our knowledge, the present study is the
rst to show the signicant difference between these 2 subgroups.
Our ndings of more severe olfactory impairment in aMCImd compared
to aMCIsd serve as indirect evidence for aMCIsd corresponding to
milder and more localized neuropathological changes compared to
aMCImd and it is in agreement with studies conrming higher conversion rate to AD in the latter group [31,55].
We found olfactory identication decits of similar extent in patients with naMCI compared to controls as in patients with aMCI compared to controls. This is in agreement with a study using brief 12
items test reporting modest impairment in MCI population as a whole
(amnestic and non-amnestic together) compared to control population
with no difference between MCI subtypes [59]. The direct comparison of
different MCI subtypes with controls was, however, not mentioned in
this paper. On the other hand, another study using UPSIT did not nd
any considerable impairment in olfactory identication in naMCI patients suggesting sparing of olfactory brain in this MCI subtype. However, naMCI group used in this study performed relatively well on the
MMSE scale; the control group was recruited from hospitalized patients
and their cognitive status was not conrmed with comprehensive neuropsychological testing [23]. Finally, conicting results have been found
in a large community based multi-ethnic study, in which MCI patients
were again impaired as a whole group in odor identication and aMCI
differed from cognitively intact elderly but no difference between
naMCI and controls nor between aMCI and naMCI was detected. However, this study was also community-based, thus using potentially less
impaired MCI patients compared to population from memory clinic [7].
There are several plausible explanations for profound olfactory identication impairment in naMCI found in our study. First, as stated above,
previous studies have found profound olfactory impairment in FTLD and
LBD [46,61] and inconsistent results in VD [13,18]. These dementia disorders are considered to be preceded typically by naMCI, so the olfactory impairment in this subgroup does not seem surprising [42,44].
Second, a recent publication revealed that in a population of participants 75 years of age, AD was the most common type of dementia following not only aMCI but also naMCI subgroup, although the risk of
developing AD dementia was lower in naMCI subgroup compared to
aMCI [22]. Similar results were found in previous studies [4,31]. Thus,
it is possible that at least in some of our naMCI patients, their olfactory

182

M. Vyhnalek et al. / Journal of the Neurological Sciences 349 (2015) 179184

Table 1
Descriptive characteristics of the sample.
aMCI

naMCI

Controls

Mild AD

(n = 57)

(n = 32)

(n = 27)

(n = 26)

6/12
70.61 8.40
14.56 3.63

30/27
73.32 9.25
13.73 3.32

15/17
69.25 9.87
15.47 2.73

6/21
69.15 8.50
15.22 2.73

6/26
74.2 7.98
12.05 2.97

28.06 1.89
7.29 3.35
14.35 3.20
36.33 8.58
4.83 3.55
12.96 6.50
32.07 2.70
18.82 5.57
99.65 23.7
47.33 9.01
6.11 1.32
9.17 2.33
4.78 .94
6.61 1.75
13.89 3.05

26.19 2.85
4.70 2.99
12.98 3.54
28.67 8.58
2.60 3.16
5.97 5.68
25.19 8.10
30.19 13.29
258.91 147
29.19 8.72
5.49 1.21
8.40 2.13
3.91 1.07
5.14 1.84
11.00 3.50

28.13 1.98
7.96 2.57
15.17 2.74
46 7.04
8.74 3.05
9.60 6.06
26.78 8.50
28.04 16.8
211.4 133
34.04 11.9
5.71 1.20
8.50 1.67
4.08 1.21
5.42 1.91
11.58 3.77

29.29 7.13
10.75 2.18
15.94 .250
50.06 10.1
10.56 3.25
15.25 6.58
30.00 40.3
18.94 4.49
75.31 36.0
44.00 8.9
6.69 1.14
10.81 2.17
4.88 1.09
6.94 2.05
15.19 1.47

21.15 4.11
2.28 2.53
7.92 4.42
19.96 71
.67 1.27
3.43 5.73
19.20 10.3
69.04 59.1
367.54 155
25.46 11.73
5.19 1.27
8.35 4.45
3.15 1.26
4.23 3.42
9.0 3.27

aMCI total

aMCIsd

aMCImd

(n = 75)

(n = 18)

Demographic characteristics
Gender (male/female)
Age
Education

36/39
72.67 9.07
13.96 3.40

Test scores
MMSE
ECR-IR
ECR-TR
AVLT 15
AVLT 30
ROCF-R
ROCF-C
TMT A
TMT B
COWAT
F-DigitSpanNM
F-DigitSpanSC
R-DigitSpanNM
R-DigitSpanSC
MHST score

26.64 2.76
5.30 3.25
13.30 3.50
30.51 9.13
3.13 3.38
7.66 6.57
26.85 7.74
27.5 12.86
222.3 146
33.6 11.70
5.64 1.26
8.59 2.19
4.12 1.10
5.49 1.91
11.69 3.60

Abbreviations: aMCI, amnestic mild cognitive impairment; naMCI, non-amnestic mild cognitive impairment; sd, single domain; md, multiple domain; MMSE, total score; AVLT 15, sum of
trials 1 to 5; AVLT 30, recall after 30 min; ECR-FR, Enhanced Cued Recall test free recall; ECR-TR, Enhanced Cued Recall test total recall after cueing; ROCF-R, visual reproduction after 3
min; ROCF-C, copy score; TMT A, given in seconds; TMT B, time given in seconds; F-DigitSpanNM, forward Digit Span numbers; F-DigitSpanSC, forward Digit Span score; RDigitSpanNM, reversed Digit Span numbers; R-DigitSpanSC, reversed Digit Span score; COWAT, Czech version with N, K, P letters, MHST Motol Hospital Smell test.

decit could be attributable to underlying AD pathology. Third, with the

naMCI group largely overlapping with both the aMCI group and the
controls in our study, the results conrm the established notion from
longitudinal studies that naMCI is probably etiologically a very heterogeneous group [4,22,31].
Finally, the reason for more profound olfactory identication impairment found in our study compared to the previous ones is that, contrary
to other studies, we used clinically based groups of patients referred by
families and primary care physicians for cognitive impairment and their
impairment was greater than in population based studies [7].
As expected, the degree of olfactory impairment in aMCI was related
mainly to memory performance, where the scores in verbal and nonverbal memory tests explained a large part of variance in olfactory identication scores in our sample (26% and 40% respectively). These results
correspond to earlier ndings in non-demented elderly associating anosmia with AD-like memory impairment as assessed by a Qualitative
Evaluation of Dementia checklist [48]. Other studies have demonstrated
moderate to strong correlation of olfactory identication impairment
with memory scores and only weak to moderate correlation with
other cognitive domains in non-demented subjects (aMCI, naMCI and
controls together) [7,23]. Similar results were noted in a pooled sample
of healthy controls, MCI and demented patients [8,60]. The strongest relation with memory domains conrms that olfaction and memory in
aMCI share the common neuroanatomical substrate and underlies the
importance of medial temporal lobes for olfactory identication in this
group.
Table 2
Association between cognitive scores and olfactory identication in aMCI.
Cognitive
domain/variable

Estimate

Standard error of
the estimate

Adjusted
r-squarea

MMSE
Verbal memory
Non-verbal memory
Visuospatial function
Executive function
Working memory

1.37
1.44
1.71
1.44
0.01
0.06

0.56
0.63
0.47
0.45
0.01
0.45

.017
.026
b.001
.002
NS
NS

.26
.25
.40
.37
.21
.20

Note that adjusted r-square for age and gender alone was .21.

We found olfactory identication more closely related to nonverbal

memory as opposed to verbal memory. This may be the result of suggested lateralization of nonverbal memory as well as odor identication
to the right hemisphere [27,49].
In our aMCI sample, a signicant contribution to olfaction scores was
found with visuospatial functions, but not with working memory and
executive functions. To our knowledge only one study has examined
the relation between visuospatial functions and olfaction and found an
association between olfaction and copy of ROCF using a sample of cognitively impaired patients similar to ours [60]. The reason for this association is not very well understood as visuospatial functions are
dependent mainly on the parietal and occipital cortexes which do not
play a crucial role in olfactory identication. There are several possible
explanations: ROCF task performance reects the inuence of many
brain networks, which may preclude precise interpretation of neuropsychological test scores [24]. Alternatively, copy of ROCF may reect
hippocampal atrophy, as demonstrated in our recent study in
nondemented older adults [57]. Finally, the early concomitant degeneration of posterior part of the brain in aMCI patients could be another underlying cause.
Contrary to results in aMCI patients, we did not nd any signicant
contribution of cognitive function to the variability in olfactory identication ability in naMCI group. One plausible explanation may be that, as
stated earlier, contrary to aMCI, which is caused mainly by AD pathology,
naMCI is an etiologically heterogeneous condition caused by different
processes leading to dementia including vascular and neurodegenerative
diseases like FTLD, DLB and AD [3, 15,42,44].
Pathways to olfactory identication impairment in non-AD dementias are not fully understood. For example, olfactory identication impairment in FTLD is explained by impairment of brain centers relevant
to olfactory identication in frontal and temporal lobes [33,40,46],
while other studies speculated about the olfactory identication impairment being caused by cognitive impairment [28,41]. Olfactory decit in
LBD has been explained by Lewy body pathology in olfactory brain regions as well as by concomitant AD pathology which is very common
in this disease [25,35,39,52]. There is no pathological study with odor
identication in LBD. However, the only autopsy study linked anosmia
to Lewy body pathology present in olfactory brain (mainly cingulum),

M. Vyhnalek et al. / Journal of the Neurological Sciences 349 (2015) 179184

with no inuence of concomitant AD pathology [34]. There is conicting

evidence about the extent and cause of olfactory impairment in VD and
the impairment of olfaction in this group has been considered mainly as
a consequence of cognitive decits and concomitant AD pathology
which is common in VD [18,52].
The lack of an association between olfactory performance and cognition could therefore be due to the presence of various factors leading to
olfactory identication impairment in naMCI: disease specic neuropathological changes in the olfactory brain regions, concomitant AD
neuropathological changes in olfactory bulb and nerve and cognitive
impairment [28,33,40,41,46,18,25,52].
Our results correspond to the earlier ndings in non-AD dementias,
where no relation between cognition and olfaction was found in FTLD
and LBD [29,34].
The limitations of the study are that (as most other olfactory studies)
only olfactory identication test was used and the olfactory threshold
and discrimination were not assessed. Therefore, the detected decits
in olfactory identication could be at least partly due to a decit at a
more basic level of olfactory processing. The cross-sectional design of
the study did not allow us to make precise conclusions regarding the etiology of MCI in our patients. Furthermore, the lack of an association between olfaction and cognitive performance in the naMCI group suggests
that olfactory performance may not predict dementia conversion in that
group.
The heterogeneity of olfactory identication results in naMCI group
(with some patients scoring as high as controls) and the absence of relation to cognitive decline in this subgroup depend probably on the underlying pathology leading to conversion into the various types of
dementia which could also explain different results of naMCI in various
studies.
Olfactory impairment in aMCI together with strong relationship
with memory scores points to the relative clinical and neuropathological uniformity of this subgroup proposed in other MCI studies [42].
As postulated in previous studies, olfactory identication impairment is more pronounced in aMCImd compared to aMCIsd patients
consistent with the fact that the former subtype may represent a more
advanced pathological stage than the latter.
We conclude that olfactory identication impairment is present not
only in aMCI but also in naMCI patients. Unlike in naMCI, we found a
proportional impairment between cognition and olfaction in aMCI.
This may be explained by probable underlying AD; and the more pronounced impairment in aMCImd compared to aMCIsd may reect
more advanced stage of the AD-related pathological process. On the
other hand, the absence of a link between cognition and olfactory identication in naMCI patients may be caused by known clinical and etiological heterogeneity of this group.
Longitudinal studies and studies with neuropathological correlations are necessary to conrm this hypothesis.

Acknowledgment
Supported by the FNUSA-ICRC project (no. CZ.1.05/1.1.00/02.0123)
from the European Regional Development Fund, by the European Social
Fund within the project Young Talent Incubator II (reg. no. CZ.1.07/
2.3.00/20.0117), and by the MH CZ DRO, Motol University Hospital,
Prague, Czech Republic 00064203.

References
[1] Attems J, Lintner F, Jellinger KA. Olfactory involvement in aging and Alzheimer's
disease: an autopsy study. J Alzheimers Dis 2005;7(2):14958.
[2] Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta
Neuropathol 1991;82(4):23959.
[3] Braak H, Braak E. Staging of Alzheimer's disease-related neurobrillary changes.
Neurobiol Aging 1995;16(3):2718 discussion 278284.

183

[4] Busse A, Hensel A, Guhne U, Angermeyer MC, Riedel-Heller SG. Mild cognitive impairment: long-term course of four clinical subtypes. Neurology 2006;67(12):
217685. http://dx.doi.org/10.1212/01.wnl.0000249117.23318.e1.
[5] Cohen JA. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale:
Lawrence Erlbaum Associates; 1988.
[6] Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla M, Marder K, et al. Olfactory decits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up. Am J Psychiatry 2000;157(9):1399405.
[7] Devanand DP, Tabert MH, Cuasay K, Manly JJ, Schupf N, Brickman AM, et al. Olfactory
identication decits and MCI in a multi-ethnic elderly community sample.
Neurobiol Aging 2010;31(9):1593600. http://dx.doi.org/10.1016/j.neurobiolaging.
2008.09.008.
[8] Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H. Olfaction in patients with
mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 2008;29(5):
693706. http://dx.doi.org/10.1016/j.neurobiolaging.2006.11.014.
[9] Doty RL. Ofce procedures for quantitative assessment of olfactory function. Am J
Rhinol 2007;21(4):46073.
[10] Doty RL, Reyes PF, Gregor T. Presence of both odor identication and detection deficits in Alzheimer's disease. Brain Res Bull 1987;18(5):597600. http://dx.doi.org/
10.1016/0361-9230(87)90129-8.
[11] Doty RL, Shaman P, Dann M. Development of the University-Of-Pennsylvania smell
identication test a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32(3):489502. http://dx.doi.org/10.1016/0031-9384(84)90269-5.
[12] Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell
Identication Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984;94(2 Pt 1):1768.
[13] Duff K, McCaffrey RJ, Solomon GS. The pocket smell test successfully discriminating
probable Alzheimer's dementia from vascular dementia and major depression. J
Neuropsychiatry Clin Neurosci 2002;14(2):197201.
[14] Eibenstein A, Fioretti AB, Simaskou MN, Sucapane P, Mearelli S, Mina C, et al. Olfactory screening test in mild cognitive impairment. Neurol Sci 2005;26(3):15660.
http://dx.doi.org/10.1007/s10072-005-0453-2.
[15] Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild cognitive impairment to dementia in clinic-vs community-based cohorts. Arch Neurol 2009;
66(9):1151.
[16] Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities
at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol 1987;
149(2):3516. http://dx.doi.org/10.2214/ajr.149.2.351.
[17] Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for
grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):
18998.
[18] Gray AJ, Staples V, Murren K, Dhariwal A, Bentham P. Olfactory identication is impaired in clinic-based patients with vascular dementia and senile dementia of
Alzheimer type. Int J Geriatr Psychiatry 2001;16(5):5137.
[19] Grober E, Buschke H. Genuine memory decits in dementia. Dev Neuropsychol
1987;3(1):1336.
[20] Hawkes C. Olfaction in neurodegenerative disorder. Mov Disord 2003;18(4):
36472.
[21] Jones-Gotman M, Zatorre RJ, Cendes F, Olivier A, Andermann F, McMackin D, et al.
Contribution of medial versus lateral temporal-lobe structures to human odour
identication. Brain 1997;120(10):184556.
[22] Jungwirth S, Zehetmayer S, Hinterberger M, Tragl KH, Fischer P. The validity of
amnestic MCI and non-amnestic MCI at age 75 in the prediction of Alzheimer's dementia and vascular dementia. Int Psychogeriatr 2012;24(6):95966. http://dx.doi.
org/10.1017/s1041610211002870.
[23] Lehrner J, Pusswald G, Gleiss A, Auff E, Dal-Bianco P. Odor identication and selfreported olfactory functioning in patients with subtypes of mild cognitive impairment. Clin Neuropsychol 2009;23(5):81830. http://dx.doi.org/10.1080/
13854040802585030.
[24] Lezak MD, Black HD, W., L. D. Neuropsychological assessment. V ed. Oxford: Oxford
University Press; 2004.
[25] Liberini P, Parola S, Spano P, Antonini L. Olfactory dysfunction in dementia associated with Lewy bodies. Parkinsonism Relat Disord 1999;5:30.
[26] Loonstra AS, Tarlow AR, Sellers AH. COWAT metanorms across age, education, and
gender. Appl Neuropsychol 2001;8(3):1616.
[27] Loring DW, Lee GP, Meador KJ. Revising the ReyOsterrieth: rating right hemisphere
recall. Arch Clin Neuropsychol 1988;3(3):23947.
[28] Luzzi S, Snowden JS, Neary D, Coccia M, Provinciali L, Lambon Ralph MA. Distinct
patterns of olfactory impairment in Alzheimer's disease, semantic dementia,
frontotemporal dementia, and corticobasal degeneration. Neuropsychologia 2007;
45(8):182331.
[29] Magerova H, Vyhnalek M, Laczo J, Andel R, Rektorova I, Kadlecova A, et al. Odor identication in frontotemporal lobar degeneration subtypes. Am J Alzheimers Dis Other
Demen 2014. http://dx.doi.org/10.1177/1533317514539033.
[30] Magerova H, Vyhnalek M, Laczo J, Bojar M, Hort J. Smell perception testing in early
diagnosis of neurodegenerative dementia. Ceska Slov Neurol Neurochir 2008;
71(3):298302.
[31] Manly JJ, Tang MX, Schupf N, Stern Y, Vonsattel JP, Mayeux R. Frequency and course
of mild cognitive impairment in a multiethnic community. Ann Neurol 2008;63(4):
494506. http://dx.doi.org/10.1002/ana.21326.
[32] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the
auspices of Department of Health and Human Services Task Force on Alzheimer's
Disease. Neurology 1984;34(7):93944.
[33] McLaughlin NCR, Westervelt HJ. Odor identication decits in frontotemporal dementia: a preliminary study. Arch Clin Neuropsychol 2008;23(1):11923.

184

M. Vyhnalek et al. / Journal of the Neurological Sciences 349 (2015) 179184

[34] McShane RH, Nagy Z, Esiri MM, King E, Joachim C, Sullivan N, et al. Anosmia in dementia is associated with Lewy bodies rather than Alzheimer's pathology. J Neurol
Neurosurg Psychiatry 2001;70(6):73943.
[35] Merdes AR, Hansen LA, Jeste DV, Galasko D, Hofstetter CR, Ho GJ, et al. Inuence of
Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies.
Neurology 2003;60(10):158690.
[36] Mesholam RI, Moberg PJ, Mahr RN, Doty RL. Olfaction in neurodegenerative disease:
a meta-analysis of olfactory functioning in Alzheimer's and Parkinson's diseases.
Arch Neurol 1998;55(1):84.
[37] Meyers JE, Meyers KR. Rey complex gure test and recognition trial: professional
manual. Odessa, FL: Psychological Assessment Resources; 1995.
[38] Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules.
Neurol Neurol 1993;43(11):24124.
[39] Nedelska Z, Ferman TJ, Boeve BF, Przybelski SA, Lesnick TG, Murray ME, et al. Pattern
of brain atrophy rates in autopsy-conrmed dementia with Lewy bodies. Neurobiol
Aging 2014. http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.005.
[40] Omar R, Mahoney CJ, Buckley AH, Warren JD. Flavour identication in frontotemporal
lobar degeneration. J Neurol Neurosurg Psychiatry 2013;84(1):8893.
[41] Pardini M, Huey ED, Cavanagh AL, Grafman J. Olfactory function in corticobasal syndrome and frontotemporal dementia. Arch Neurol 2009;66(1):926.
[42] Petersen RC. Mild cognitive impairment. N Engl J Med 2011;364(23):222734.
[43] Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;
256(3):18394.
[44] Petersen RC. Clinical practice. Mild cognitive impairment. N Engl J Med 2011;
364(23):222734. http://dx.doi.org/10.1056/NEJMcp0910237.
[45] Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;
56(3):303.
[46] Rami L, Loy CT, Hailstone J, Warren JD. Odour identication in frontotemporal lobar
degeneration. J Neurol 2007;254(4):4315.
[47] Reitan Rm WD. The HalsteadReitan neuropsychological test battery. Theory and
clinical interpretation. South Tucson: Neuropsychology Press; 1993.
[48] Royall DR, Chiodo LK, Polk MS, Jaramillo CJ. Severe dysosmia is specically associated with Alzheimer-like memory decits in nondemented elderly retirees.
Neuroepidemiology 2002;21(2):6873 [doi: 48619].
[49] Royet JP, Plailly J. Lateralization of olfactory processes. Chem Senses 2004;29(8):
73145. http://dx.doi.org/10.1093/chemse/bjh067.

[50] Serby M, Larson P, Kalkstein D. The nature and course of olfactory decits in
Alzheimer's disease. Am J Psychiatry 1991;148(3):35760.
[51] Schmidt M. Rey auditory verbal learning test: a handbook. Los Angeles, LA: Western
Psychological Services; 1996.
[52] Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account
for most dementia cases in community-dwelling older persons. Neurology 2007;
69(24):2197204. http://dx.doi.org/10.1212/01.wnl.0000271090.28148.24.
[53] Swan GE, Carmelli D. Impaired olfaction predicts cognitive decline in nondemented
older adults. Neuroepidemiology 2002;21(2):5867 [doi: 48618].
[54] Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, et al. A 10-item smell
identication scale related to risk for Alzheimer's disease. Ann Neurol 2005;58(1):
15560. http://dx.doi.org/10.1002/ana.20533.
[55] Tabert MH, Manly JJ, Liu X, Pelton GH, Rosenblum S, Jacobs M, et al. Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive
impairment. Arch Gen Psychiatry 2006;63(8):91624. http://dx.doi.org/10.1001/
archpsyc.63.8.916.
[56] Vollmecke TA, Doty RL. Development of the Picture Identication Test (PIT) a research companion to the University-of-Pennsylvania Smell Identication Test
(UPSIT). Chem Senses 1985;10(3):4134.
[57] Vyhnalek M, Nikolai T, Andel R, Nedelska Z, Rubinova E, Markova H, et al. Neuropsychological correlates of hippocampal atrophy in memory testing in nondemented
older adults. J Alzheimers Dis 2014. http://dx.doi.org/10.3233/jad-132642.
[58] Wechsler D. Wechsler memory scale. San Antonio; Toronto: The Psychological
Corporation; 1997.
[59] Westervelt HJ, Bruce JM, Coon WG, Tremont G. Odor identication in mild cognitive
impairment subtypes. J Clin Exp Neuropsychol 2008;30(2):1516. http://dx.doi.org/
10.1080/13803390701287408.
[60] Westervelt HJ, Ruffolo JS, Tremont G. Assessing olfaction in the neuropsychological
exam: the relationship between odor identication and cognition in older adults.
Arch Clin Neuropsychol 2005;20(6):7619.
[61] Westervelt HJ, Stern RA, Tremont G. Odor identication decits in diffuse Lewy body
disease. Cogn Behav Neurol 2003;16(2):93.
[62] Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. Development and
validation of a geriatric depression screening scale: a preliminary report. J Psychiatr
Res 1983;17(1):3749.