fMRI and Voxel-based Morphometry in Detection of Early Stages of

Alzheimer's Disease

Andrey V. Sokolov

1,3

, Sergey V. Vorobyev

, Aleksandr Yu. Efimtcev

1,3

, Viacheslav S.

Dekan

1,3

Gennadiy E.

Trufanov

1,3

, Vladimir Yu. Lobzin

and Vladimir A. Fokin

1,3

Department of Radiology, Military Medical Academy n.a. S.M. Kirov, Klinicheskaya str., Saint-Petersburg, Russia

Department of Neurology, Military Medical Academy n.a. S.M. Kirov, Lesnoi pr., Saint-Petersburg, Russia

Department of Radiology, North-West Federal Medical Research Center n.a. V.A. Almazov, Akkuratova str.,

Saint-Petersburg, Russia

Keywords: Alzheimer’s Disease, Functional MRI, Voxel-based Morphometry.

Abstract: Alzheimer’s disease (AD) is the most common form of dementia in older adults. Loss of memory is the

usual first symptom and different brain regions are involved to this pathological process. The aim of the

study was to investigate the organization of cortical areas responsible for visual memory and determine

correlation between memory impairment and atrophy of memory specific brain regions in early stages of

AD. Voxel-based MR-morphometry was used to evaluate brain atrophy and functional MRI was used to

detect specific brain regions responsible to visual memory task in patients with Alzheimer's disease and in

control group. FMRI was performed on Siemens Magnetom Symphony (1.5 T ) with the use of Blood

Oxygenation Level Dependent technique (BOLD), based on distinctions of magnetic properties of

hemoglobin. For test stimuli we used blocks of 12 not related images for "Baseline" and 12 images with 6

presented before for "Active". Stimuli were presented 3 times with reduction of repeated images to 4 and 2.

For functional and morthometric data post-processing we used SPM8. Patients with Alzheimer's disease

showed less activation in hippocampal formation (HF) region and parahippocampal gyrus then the control

group (p<0.05). The study also showed reduced activation in posterior cingulate cortex (p<0.001). Voxel-

based morphometry showed significant atrophy of grey matter in Alzheimer’s disease patients, especially of

both temporal lobes (fusiform and parahippocampal gyri); frontal lobes (posterior cingulate and superior

frontal gyri). The study showed correlation between memory impairment and atrophy of memory specific

brain regions of frontal and medial temporal lobes. Reduced activation in hippocampal formation and

parahippocampal gyri, in posterior cingulate gyrus in patients with Alzheimer's disease correlates to

significant atrophy of these regions, detected by voxel-based morphometry. The use of functional MRI and

voxel-based morphometry provides the way to find alterations in brain function on early stages of AD

before the development of significant irreversible structural damage.

1 INTRODUCTION

Cognitive impairment is one of the most common

neurological disorders. Especially high prevalence

of neurological disease with clinical cognitive

impairment is among the senior people. 10-15% of

elderly people have severe cognitive impairment –

dementia. Dementia significantly reduces the quality

of life of patient and his family. Dementia causes

additional difficulties in the diagnosis and treatment

of opportunistic disease, and doctors have

difficulties in collecting anamnesis, assessment of

patient complaints. Alzheimer’s disease (AD) is the

most common form of dementia. Enormous number

of publications are devoted to cognitive disorders

research, based on the results of imaging studies.

Functional MRI (fMRI) and voxel-based

morphometry (VBM) open up new opportunities in

study of AD pathogenesis (Vasconcelos, L.G., 2011;

Odinak, M.M., 2011).

Different brain regions are involved to the

pathological process in AD irregularly. Primary

neuronal damage in the early stages of disease was

noted in the mediobasal parts of the frontal lobes of

the brain. Morphological changes are also defined in

the hippocampus, deep and posterior parts of

temporal and parietal lobes of the brain. The

Sokolov A., Vorobyev S., Eﬁmtcev A., Dekan V., Trufanov G., Lobzin V. and Fokin V.

fMRI and Voxel-based Morphometry in Detection of Early Stages of Alzheimer’s Disease.

DOI: 10.5220/0006109600670071

In Proceedings of the 10th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2017), pages 67-71

ISBN: 978-989-758-215-8

preferential involvement of mediobasal structures of

the temporal lobe in the pathological process have

been confirmed by numerous MRI studies, which

demonstrates significant hippocampus gray matter

atrophy in patients with Alzheimer's disease (Frisoni

G.B., 2008; Karas G.B., 2004; Zhang N., 2011).

More informative is to assess atrophy progression in

dynamics, and therefore morphometry of various

brain structures is used (Lobzin, V.Yu., 2013).

Alzheimer's disease is characterized by

progressive decline in memory. Functional MRI

allows to investigate alterations in brain function

before development of significant structural damage

(Bassett, S.S., 2006). Golby A. et al. (2005)

examined the functional competency of certain brain

regions and their relationship with specific

behavioural memory deficit in Alzheimer’s disease.

Results of fMRI resting state studies have so far

relatively consistently pointed to the early

involvement of posteromedial grey matter, such as

the posterior cingulum and precuneus (Pihlajamaki

M., 2008).

The purpose of this study was to evaluate brain

activation by visual memory task in patients with

Alzheimer's disease and to determine correlation

between memory impairment and atrophy of

memory specific brain regions of frontal and medial

temporal lobes.

2 MATERIALS AND METHODS

2.1 Participants

We studied 27 patients with Alzheimer's disease

(mean age 69,6±8,9 years), 22 matched by age

(68,8±4,3 years) volunteers without evidence of

brain lesions for VBM, and 20 healthy volunteers

(35±5,1 years) for fMRI as a control group. Young

volunteers were chosen as a control group for fMRI

due to the absence of significant differences in

healthy individuals of different ages according to our

previous study (Odinak M.M. et al, 2011). Patients

with Alzheimer's disease underwent a course of

medical treatment in the neurological department of

Military Medical Academy. Their evaluation

included physical and neurological examination,

brain imaging (MRI), blood analysis, including

markers of inflammation, hormones, cholesterol and

APOE. All of them underwent neuropsychological

assessment to determine memory impairment,

attention, thinking, speech and visual-spatial

functions, using the following methods: Mini-

Mental State Examination (MMSE), Frontal

Assessment Battery (FAB), Free and Cued Selective

Reminding Test with Immediate Recall (FCSRT-

IR), Clock Drawing Test, Montreal Cognitive

Assessment (MoCA), Trail Making Test (TMT),

Digit-span task (forward and backward), Luria´s

Memory Words test (10 words), Digit Symbol

Substitution Test. The study included patients with

mild cognitive impairment or mild dementia. The

diagnosis of Alzheimer's disease was established

according to the NIA criteria (2011).

Each participant gave written informed consent

to participate in the study. The study was approved

by Ethics Committee of Military Medical Academy.

2.2 fMRI and VBM Data Acquisition

To investigate the organization of memory and

localize cortical areas activated by visual memory

task we used functional magnetic resonance imaging

and to evaluate brain atrophy of patients with

Alzheimer's disease voxel-based MRI morphometry

was performed. Conventional T1- and T2-weighted

images in three orthogonal planes were obtained

also.

fMRI was performed on 1.5 T MR-scanner

(Magnetom Symphony) with BOLD (Blood

Oxygenation Level Dependent) technique, that is

based on distinctions of magnetic properties of

haemoglobin. Functional MR images were acquired

using echo-planar imaging (EPI) with repetition time

(TR) = 3700 ms, echo time (TE) = 50 ms, flip angle

= 90º, field of view (FOV) = 230 mm and matrix

size 128*128. For test stimuli we used series of 12

not related images for "baseline" and 12 images with

for "active". 6 images in “active” period have been

already presented in “baseline”. Stimuli were

presented 3 times with reduction of repeated images

to 4 and 2. A finger switch response system was

used to collect patient responses.

To obtain high resolution images of whole brain

for Talairach coregistration and reslicing along

different planes, we used 3D MPRAGE

(Magnetization Prepared Rapid Acquisition Gradient

Echo) – T1-sequence with the following parameters:

repetition time (TR) = 2000 ms, echo time (TE) =

4,38 ms, flip angle = 10º, field of view (FOV) = 250

mm, 160 slices and matrix size 256*256.

2.3 fMRI and VBM Data

Post-processing

For functional data post-processing we used SPM8

(Welcome Department of Imaging Neuroscience,

University College, London, UK) software package

BIOIMAGING 2017 - 4th International Conference on Bioimaging

running under MATLAB R2010a (The Mathworks,

Sherborn, MA, USA) programming. For voxel-

based morphometry we used VBM toolbox of

SPM8. Template space was defined by standard EPI

template data in SPM (MNI coordinates - Montreal

neurologic Institute, McGill University, Montreal,

Canada).

VBM data were visualized with MRICron

(http://www.mccauslandcenter.sc.edu/mricro/mricro

n/), using Talairach atlas masks (Talairach and

Tournoux, 1988).

3 RESULTS

Examining each group separately, we found that

group of healthy volunteers showed activation of

cingulated gyrus (p<0.001). Cingulate gyrus plays

an essential role in memory formation and provide

intercommunications between brain regions.

Controls also showed statistically significant

activation in hippocampal formation (HF) and

parahippocampal gyrus and Broadman area 6 (BA6).

The function of BA6 is to organize complex motor

response while carrying out the instructions, in

particular the definition of "right" or "wrong"

stimulus. 80% of controls showed activation of

BA40, which plays the role in recognition of visual

images.

Group comparison analysis allows to identify

certain brain regions with different activation

patterns. Patients with Alzheimer's disease showed

less activation in hippocampal formation (HF) and

parahippocampal gyri comparing to healthy controls

group (p<0.05). The study also showed reduced

activation in posterior cingulate gyrus (p<0.001).

Figure 1: Reduced activation in posterior cingulated gyrus

and in hippocampal formation region in AD patients

(p<0.001).

The results demonstrate that a lot of different

brain regions participating in the differentiation of

the stimuli are involved. This corresponds to the

opinion, that the morphological substratum of higher

cortical functions is a set of combined functional

centers (Luria A., 1962), thereby confirming the

concept of dynamic functional localization.

Figure 2: Differences in activation between AD group and

healthy controls (three-dimensional volume-rendered

display).

Voxel-based morphometry showed significant

general atrophy of grey matter in AD patients,

especially of both temporal lobes (fusiform and

parahippocampal gyri), frontal lobes (and superior

frontal gyri), parietal lobes and cingulate gyrus.

However, the most significant changes were found

in mediobasal temporal lobe (up to 3.6 cm

at p

<0,01) and thalamuses (up to 4.5 cm

at p = 0,02).

Table 1: The values of volumes (cm

) of different brain

regions, based on MRICron analysis.

Cerebral

Region

patients

group

Control

group

p-value

Frontal lobes 365,9±18,0 382,4±6,3 <0,01

Temporal

lobes

217,4±3,9 225,7±3,2 <0,01

Parietal

lobes

179,0±5,3 181,9±3,6 0,03

Hippocampal

region

3,6±0,5 3,9±0,1 <0,01

fMRI and Voxel-based Morphometry in Detection of Early Stages of Alzheimer’s Disease

Figure 3: Brain atrophy in Alzheimer's disease patients

comparing to the control group (p<0.001).

In this study we identified patterns of cognitive

deficits of varying severity in accordance to the

volume changes of certain brain structures. For this

purpose, a correlation analysis was performed

comparing the results of neuropsychological

assessment and identified brain volumes. The most

significant correlations are shown in Table 2.

Table 2: Correlations between brain atrophy and

neuropsychological assessment.

Cerebral

Region

Neuropsychological

scale

Spearman's

rank

correlation

coefficient

(r),

p<0,05

Total gray

matter volume

MMSE orientation

subtest

0,56

Temporal lobe

MMSE total,

FCSRT-IR

0,57

0,56

Parietal lobe

MMSE

Luria´s Memory

Words test

0,44

0,53

Cingulate cortex

Luria´s Memory

Words test,

FCSRT-IR

0,85

0,86

Frontal lobe

MMSE total,

categorical verbal

fluency

0,51

0,43

Occipital lobe

TMT «А»

TMT «В»

– 0,86

– 0,78

Hippocampal

formation region

MMSE orientation

subtest,

FCSRT-IR

0,52

0,65

Thalamus

MMSE attention

subtest,

0,70

According to the correlation analysis there is a

decrease of certain brain structures volume

accompanied by deterioration of specific cognitive

functions. This was true for such intellectual-mental

functions such as memory, attention and thinking.

Atrophy of temporal and parietal lobes associated

with a reduction of scale results: MMSE (r = 0,57

and r = 0,54, respectively, at p <0,05) and 5 words

test (r = 0,53, p <0,05).

4 CONCLUSION

In summary, combined application of fMRI and

VBM allows to assess brain atrophy along with

functional component of memory impairment and

can help to detect Alzheimer's disease related

changes in early stages before they may be revealed

by means of conventional MRI study. The study

showed correlation between memory impairment

and atrophy of memory specific brain regions of

frontal and medial temporal lobes. Thus, reduced

activation in hippocampal formation and

parahippocampal gyri, in posterior cingulate gyrus in

patients with Alzheimer's disease correlates to

significant atrophy of these regions, detected by

voxel-based morphometry, and to deterioration of

specific cognitive functions. Obtained data

correspond to comprehensive conceptions of

pathogenesis and general clinical features of AD.

Combined fMRI and voxel-based morphometry

study can be used in clinical practice in patients with

AD and cognitive disorders.

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fMRI and Voxel-based Morphometry in Detection of Early Stages of Alzheimer’s Disease