Neurobiology of Aging 30 (2009) 838841

Brief communication

Reduced olfactory bulb and tract volume in early

Alzheimers diseaseA MRI study
Philipp A. Thomann a, , Vasco Dos Santos a , Pablo Toro a ,
Peter Schonknecht a , Marco Essig b , Johannes Schroder a
a

Section of Geriatric Psychiatry, University of Heidelberg, Vostr. 4, 69115 Heidelberg, Germany

b German Cancer Research Center, Heidelberg, Germany
Received 26 April 2007; received in revised form 10 June 2007; accepted 6 August 2007
Available online 17 September 2007

Abstract
Olfactory dysfunction has been reported to occur already in the early stages of Alzheimers disease (AD) and to increase with disease
severity. In neuropathological research, the deposition of neurofibrillary tangles and neuritic plaques in the olfactory bulb and tract (OBT) of
AD patients has been consistently demonstrated. We used high-resolution magnetic resonance imaging (MRI) to determine the volume of the
OBT in 21 patients with early AD and in 21 healthy comparison subjects. The OBT was manually traced on consecutive coronal slices. When
compared to healthy controls, right, left and mean OBT volumes were significantly reduced in patients with AD (p < 0.01). In AD patients,
the mean OBT volume was significantly correlated with global cognitive performance as determined by the mini-mental state examination
(r = 0.605; p = 0.004). Manual tracing on MRI images revealed OBT atrophy to be present early in the course of AD. Since the respective
findings were associated with cognitive impairment, they may contribute to early recognition and diagnosis of the disease.
2007 Elsevier Inc. All rights reserved.
Keywords: Alzheimers disease (AD); Olfactory bulb and tract; Magnetic resonance imaging (MRI)

1. Introduction
Alzheimers disease (AD) is the most frequent dementia beyond the age of 65 years, affecting an eminent and
increasing part of the population. Neuropathologically, AD
is characterized by neuronal loss and deposition of neurofibrillary tangles (NFTs) and amyloid plaques in the brain.
Post-mortem studies demonstrated that three main stages can
be differentiated during the clinical course of AD (Braak
stages, Braak et al., 1993), with parahippocampal regions
the earliest to be affected (Braak stages 1 and 2), before the
pathological alterations spread into additional structures of

Corresponding author. Tel.: +49 6221 56 38091; fax: +49 6221 56 1742.
E-mail addresses: philipp thomann@med.uni-heidelberg.de
(P.A. Thomann), dossantosvasco@med.uni-heidelberg.de (V. Dos Santos),
pablo toro@med.uni-heidelberg.de (P. Toro),
peter schoenknecht@med.uni-heidelberg.de(P. Schonknecht),
m.essig@dkfz.de (M. Essig),
johannes schroeder@med.uni-heidelberg.de (J. Schroder).
0197-4580/$ see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.neurobiolaging.2007.08.001

the medial temporal lobe/limbic system (Braak stages 3 and

4) and then encroach major parts of the temporal, parietal,
and frontal cortical areas (Braak stages 5 and 6).
Limbic structures, early involved in the course of the
AD, have olfactory connections. Olfactory dysfunction in
AD has consistently been reported by a number of independent research groups (Larsson et al., 1999; Mesholam et al.,
1998; Murphy et al., 1990; Nordin et al., 1997). Following
the results of neuropathological studies (Attems and Jellinger,
2006; Kovacs et al., 1999; Tsuboi et al., 2003) impaired olfaction in AD seems to refer to the deposition of amyloid plaques
and neurofibrillary tangles in the olfactory bulb which constitutes the first synaptic relay in the olfactory pathway (e.g.,
Nieuwenhuys et al., 1988).
The majority of magnetic resonance imaging (MRI)
studies investigating morphological alterations in early AD
revealed according to the above mentioned main stages of
the disease predominantly the substructures of the medial
temporal lobe to undergo atrophic processes (for review see

P.A. Thomann et al. / Neurobiology of Aging 30 (2009) 838841

839

Chetelat and Baron, 2003). Interestingly, MRI studies on

potential structural changes of the olfactory bulb and tract
(OBT) in AD have not been performed yet, although this
structure can be reliably delineated on adequate MR images
(Abolmaali et al., 2002; Rombaux et al., 2006; Turetsky et
al., 2003; Yousem et al., 1998).
In the present study, we therefore ascertained the volumes of the OBT in patients with mild AD and in healthy
controls by using high-resolution MRI under the hypothesis that AD patients would show significantly lower OBT
volumes than healthy comparison subjects, referring to an
early accumulation of NFTs and amyloid plaques in this
area.

2. Materials and methods

2.1. Subjects
Twenty-one patients with mild AD (according to the
NINCDS-ADRDA criteria (McKhann et al., 1984), with
all patients fulfilling the criteria of probable AD) and 21
healthy controls were included in this study. Both patients
and controls were consecutively recruited through the section of geriatric psychiatry at the University of Heidelberg,
Germany. The clinical evaluation of all subjects included
ascertainment of personal and family history as well as
physical, neurological and neuropsychological examination.
Global cognitive deficits were assessed using the mini-mental
state examination (MMSE, Folstein et al., 1975). All investigations were approved by the local ethics committee. Written
informed consent was obtained from all participants.

Fig. 1. Coronal T1-weighted MRI scans showing (a) rostral- and (b) caudalmost part of the olfactory bulb and tract.

ranged from 0.914 to 0.937 for intraobserver, and from 0.917

to 0.929 for interobserver variation.

2.2. Image acquisition

2.4. Statistical analysis

The MRI-data were obtained at the German Cancer

Research Center with a 1.5-T Magnetom Symphony
MR scanner (Siemens Medical Solutions, Erlangen,
Germany) by using a T1-weighted 3D magnetization
prepared rapid gradient echo sequence (MP-RAGE,
126 coronar slices, image matrix = 256 256, voxel
size = 0.98 mm 0.98 mm 1.8 mm,
TR = 10 ms,
TE = 4 ms).

The SPSS for Windows version 14 was used for statistical

analysis. To address inter-individual differences in head size,
the OBT volumes were corrected by dividing them by each
subjects intracranial volume. The latter was estimated by the
sum of gray matter, white matter and cerebrospinal fluid after
segmentation of the T1-weighted data sets by applying the
iterative a-prior knowledge based algorithm implemented in
SPM2 software (http://www.fil.ion.ucl.ac.uk/spm). Students
two-tailed t-test procedure was used to evaluate significant
differences between AD patients and controls. In the patient
group, the relationship between mean OBT volume and
global cognitive performance (as determined by the MMSE
score) was assessed by using Pearsons correlation coefficient.

2.3. Manual segmentation

Manual OBT measurement was performed using the manual segmentation function of BRAINS2 software (Magnotta
et al., 2002). In coronal view, the olfactory bulb was identified at the anterior cribriform plate and traced on a mean of
24.43 2.25 (mean standard deviation; S.D.) consecutive
slices (Fig. 1); posteriorly, the olfactory tract extends to enter
the brain below the rostral part of the corpus callosum. The
rater (P.A.T.) was blinded to the diagnosis. Twenty randomly
selected scans were retraced twice by the same as well as
by a second rater (V.D.S.); intraclass correlation coefficients

3. Results
According to statistical analysis there were no significant differences with respect to age, gender distribution, and
level of school education. As expected, the mean MMSE

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P.A. Thomann et al. / Neurobiology of Aging 30 (2009) 838841

Table 1
Subject demographics and morphometric measures
Variable

Controls

AD

T-value

d.f.

p-Value

Sex
Age (years)
Education (years)
MMSE
ICV (dm3 )
Right OBT (mm3 )
Left OBT (mm3 )
Mean OBT (mm3 )
Right OBTb
Left OBTb
Mean OBTb

13 F/8 M
70.38 7.14
9.67 1.74
29.05 0.81
1.38 0.10
127.41 16.73
124.21 13.00
125.81 14.12
95.80 13.75
93.23 9.63
94.52 11.26

14 F/7 M
71.76 4.94
9.81 1.94
22.10 1.87
1.33 0.10
112.85 14.01
114.10 14.99
113.47 14.01
82.91 9.09
83.82 9.77
83.36 9.01

0.73
0.251
15.66
1.57
3.06
2.34
2.84
3.58
3.15
3.55

40
40
40
40
40
40
40
40
40
40

n.sig.a
0.470
0.803
0.000
0.125
0.004
0.025
0.007
0.001
0.003
0.001

Mean S.D.; d.f., degrees of freedom; n.sig., not significant; MMSE, mini-mental state examination; ICV, intracranial volume; OBT, olfactory bulb and tract.
a 2 -Test.
b Corrected by intracranial volume.

score in AD patients was significantly lower when compared

to controls (p < 0.001). Subject demographics and volumetric measures are reported in Table 1. Students two-tailed
t-test yielded no significant difference for the intracranial
volume, but for the right (p = 0.001), left (p = 0.003) and
mean (p = 0.001) OBT volume with lower values in AD
patients.
In patients with AD, the mean OBT volume was found to
be significantly associated with the MMSE score according
to Pearsons moment correlation (r = 0.605, p = 0.004).
4. Discussion
Our study yielded two major findings: (i) in patients with
mild AD, the OBT volume was significantly reduced when
compared to healthy controls and (ii) in the patients group,
the OBT volume was significantly correlated with global
cognitive performance as determined by the MMSE.
Recently, neuropathological research described the OBT
to undergo degenerative alterations in AD; in their study
on 15 autopsy AD cases and 15 healthy controls, Kovacs
et al. (1999) detected NFT pathology in the OBT in the
very early Braak stages, even before an affection of the
entorhinal cortex could be observed. By Tsuboi et al. (2003)
NFTs were also found to be present in the OBT early in the
course of AD as indicated by the fact that, in their study
sample of 93 individuals, one-third of the cases with Braak
stage 2 already showed tau pathology in this area. And most
recently, Attems and Jellinger (2006) reported a comparable
result from their examination of a large number of autopsy
cases (n = 273), where 36.4% of the Braak stages 2 showed
olfactory tau pathology. Additionally, the latter study demonstrated a strong association between rate of NFT deposition
and disease severity. Taken together, these results clearly
emphasize an involvement of the OBT in AD that occurs
very early in the course of the disease. Hence, we assume
that our result of significantly smaller OBTs in patients with
mild AD compared to cognitively unaffected control subjects
reflects the degenerative processes described above.

In AD patients, smaller mean OBT volumes were significantly correlated with lower MMSE scores. This result
suggests that the OBT atrophy increases with progression of
the disease, likely reflecting the neuropathological finding of
NFT density increasing with higher Braak stages (Attems and
Jellinger, 2006; Kovacs et al., 1999; Tsuboi et al., 2003).
Further research is needed to clarify whether our finding of a significantly reduced OBT volume in patients with
mild AD also applies to individuals with mild cognitive
impairment, the assumed preclinical stage of AD. Moreover, future studies should also correlate OBT atrophy with
olfactory function and changes of other cerebral structures to
enhance our understanding of how these factors relate to each
other.

Disclosure statement
No conflicts of interest to declare by any of the authors.

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