Journal of the Neurological Sciences 349 (2015) 179–184

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Olfactory identification 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 identification 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 identification dysfunction in aMCI, naMCI, controls and mild AD dementia and (b) assess the relation between olfactory identification 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 identification 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 significantly in olfactory identification and both performed significantly 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 significantly related to better olfactory identification ability. Conversely, no cognitive measure was significantly related to olfactory performance in naMCI. Conclusion: Olfactory identification 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 identification), the olfactory identification is impaired earlier compared to the olfactory detection in AD patients [50]. So far, most studies with cognitively impaired patients have investigated only olfactory identification, which strongly correlates with olfactory threshold and is easier to test [9, 11,12]. The olfactory identification deficit seems to be specifically 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 Úvalu 84, 150 06 Prague 5, Czech Republic. Tel.: +420 22443 6801; fax: +420 22443 6820. E-mail address: [email protected] (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 sufficient to provoke olfactory identification 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 deficits 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 identification 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 identification in patients with aMCI and it reported impaired olfactory detection and identification. There was also an olfactory discrimination deficit but that was

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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 classified 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 identification 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 identification 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 identification 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 identification and cognitive performance in MCI, specifically 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 defined 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 deficits (more than 1.5 SD), or both. Two other groups were used in this study:

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

2.2. Exclusion criteria

–The control group (n = 27) Reported no cognitive problems, which was subsequently confirmed 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 affiliate 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 classified 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 deficit and 3 patients from visuospatial deficit.

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: Rey–Osterrieth 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 identification assessment In all subjects, smell identification was assessed using the Motol Hospital Smell Test (MHST) — a multiple-choice smell identification 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 μl to both nostrils simultaneously. The essential oils are replaced every 2 months in the phials in order to prevent degradation of the odor. After sniffing the odor, subjects are asked to

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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 Identification Test (r = .68, p b .001) [11,30]. To exclude non-olfactory components of the smell identification failure, the Picture Identification Test (PIT) was used [56].

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regardless of age and gender. The relationship between better attention/working memory, executive function and olfactory ability approached significance. No cognitive measure was significantly 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 significant 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 Significant 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 significant. 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 significance 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 (χ2 [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 significantly older compared to controls and both aMCI subgroups. There was a significant main effect for group as a function of olfactory identification MHST scores (F [3, 157] = 11.17, p b .001). The post hoc test revealed significant 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 identification was significantly more impaired in AD group compared to both aMCI and naMCI subgroups (p b .001). No significant difference was found between aMCI and naMCI groups. Next, we compared olfactory identification in patients with aMCIsd vs. aMCImd, finding that aMCImd patients performed significantly 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 significantly 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 identification impairment was similar in amnestic and non-amnestic MCI subgroups, (b) aMCImd patients performed worse than those with aMCIsd, and (c) olfactory identification impairment was related mainly to memory and visuospatial function in aMCI but has no cognitive correlate in naMCI. In addition, the study confirms previous findings of olfactory identification 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 floor effect for olfactory identification using MHST in aMCI patients. Analogous results were found in other study with UPSIT [8]. In a previous study of olfactory identification impairment in aMCI using a relatively small sample, the authors reported a statistically non-significant tendency for patients with aMCImd to be more impaired than aMCIsd [23]. To our knowledge, the present study is the first to show the significant difference between these 2 subgroups. Our findings 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 confirming higher conversion rate to AD in the latter group [31,55]. We found olfactory identification deficits 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 find any considerable impairment in olfactory identification 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 confirmed with comprehensive neuropsychological testing [23]. Finally, conflicting 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 identification 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 identification 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

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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 1–5 AVLT 30 ROCF-R ROCF-C TMT A TMT B COWAT F-DigitSpan—NM F-DigitSpan—SC R-DigitSpan—NM R-DigitSpan—SC 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 1–5, 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-DigitSpan—NM, forward Digit Span — numbers; F-DigitSpan—SC, forward Digit Span — score; RDigitSpan—NM, reversed Digit Span — numbers; R-DigitSpan—SC, reversed Digit Span — score; COWAT, Czech version with “N”, “K”, “P” letters, MHST — Motol Hospital Smell test.

deficit 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 confirm 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 identification 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 identification scores in our sample (26% and 40% respectively). These results correspond to earlier findings 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 identification 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 confirms that olfaction and memory in aMCI share the common neuroanatomical substrate and underlies the importance of medial temporal lobes for olfactory identification in this group. Table 2 Association between cognitive scores and olfactory identification in aMCI. Cognitive domain/variable

Estimate

Standard error of the estimate

P

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

a

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

We found olfactory identification 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 identification to the right hemisphere [27,49]. In our aMCI sample, a significant 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 identification. There are several possible explanations: ROCF task performance reflects the influence of many brain networks, which may preclude precise interpretation of neuropsychological test scores [24]. Alternatively, copy of ROCF may reflect 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 find any significant contribution of cognitive function to the variability in olfactory identification 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 identification impairment in non-AD dementias are not fully understood. For example, olfactory identification impairment in FTLD is explained by impairment of brain centers relevant to olfactory identification in frontal and temporal lobes [33,40,46], while other studies speculated about the olfactory identification impairment being caused by cognitive impairment [28,41]. Olfactory deficit 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 identification in LBD. However, the only autopsy study linked anosmia to Lewy body pathology present in olfactory brain (mainly cingulum),

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with no influence of concomitant AD pathology [34]. There is conflicting 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 deficits 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 identification impairment in naMCI: disease specific 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 findings 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 identification test was used and the olfactory threshold and discrimination were not assessed. Therefore, the detected deficits in olfactory identification could be at least partly due to a deficit 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 identification 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 identification 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 identification 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 reflect more advanced stage of the AD-related pathological process. On the other hand, the absence of a link between cognition and olfactory identification 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 confirm 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.

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