Journal of Neuroimaging Vol 12 No 2 April 2002

Tanaka et al: Cerebral Blood Flow Abnormalities

Regional Cerebral Blood FlowAbnormalities in NondementedPatients With Memory Impairment

Makoto Tanaka, MD

Hidenao Fukuyama, MD

Hiroshi Yamauchi, MD

Minoru Narita, MD

Hidehiko Nabatame, MD

Masayuki Yokode, MD

Naoki Fujimoto, MD

Toru Kita, MD

Motonobu Murakami, MD

A B S T R A C T

Background. Patients with objective evidence of memoryimpairment have been considered to be at risk for developingAlzheimer’s disease (AD). However, little is known about pat-terns of regional cerebral blood flow abnormalities and theirprognostic significance in these patients. Methods. The authorsretrospectively studied 28 nondemented subjects with memoryloss and investigated patterns of blood flow abnormalities onsingle photon emission computed tomography (SPECT).Results. The patients were followed up for more than 2 years;during follow-up, 14 patients (50%) developed AD. The onset ofmemory impairment in patients who progressed to AD was sig-nificantly earlier than in those who remained in a nondementedcondition. SPECT data from the initial evaluation were analyzedby region of interest analysis and statistical parametric mapping.Interestingly, both groups of patients shared hypoperfusion inthe medial temporal regions and the posterior cingulate. In addi-tion to these regions, significant blood flow reduction in the pari-

etal and anterior cingulate cortices was detected in patients whoprogressed to AD. Conclusions. These results demonstrate that(1) subjects with an earlier onset of memory loss have anincreased risk for developing AD, (2) SPECT can be useful fordistinguishing subjects with memory loss who will rapidly prog-ress to AD from those who will not, and (3) perfusion impairmenttypical of AD was evident even in subjects with memory impair-ment who remained nondemented.

Key words: Memory loss, mild cognitive impairment, Alzhei-mer’s disease, single photon emission computed tomogra-phy (SPECT), prognosis.

Tanaka M, Fukuyama H, Yamauchi H, Narita M,Nabatame H, Yokode M, Fujimoto N, Kita T, Murakami M.

Regional cerebral blood flow abnormalities innondemented patients with memory impairment.

J Neuroimaging 2002;12:112–118.

Alzheimer’s disease (AD) is the most common cause of

dementia, affecting 15 million people worldwide.1 As the

incidence rate of AD increases with the growth of the

elderly population, the management of AD patients has

become a major medical issue. Although AD is a pro-

gressive degenerative disease, recent clinical trials

using acetylcholinesterase inhibitors have suggested

that early pharmacological intervention may slow the

loss of cognition, or even maintain cognitive functions.2,3

Therefore, preclinical or early diagnosis is critical for

effective treatment and management of AD.

Loss of memory is usually the first symptom of AD.

Once memory impairment has become apparent, other

cognitive functions such as speech, writing, compre-

hension, judgment, and abstract thinking start to

decline.4

It is thus important to identify those who will

112 Copyright © 2002 by the American Society of Neuroimaging

Received July 18, 2001, and in revised form October 2,

2001. Accepted for publication October 9, 2001.

From the Department of Geriatric Medicine (MT, MY,

TK) and the Department of Functional Brain Imaging,

Human Brain Research Center (HF), Graduate School

of Medicine, Kyoto University, Kyoto, Japan; the Depart-

ment of Geriatric Neurology (MT, MN, NF, MM) and the

Department of Neurology (HN), Shiga Medical Center;

and Shiga Medical Center Research Institute (HY),

Shiga, Japan.

Address correspondence to Dr Makoto Tanaka, Depart-

ment of Geriatric Medicine, Graduate School of Medi-

cine, Kyoto University, 54 Shogoin-Kawahara-cho,

Sakyo-ku, Kyoto 606-8507, Japan. E-mai l :

makoto@kuhp.kyoto-u.ac.jp.

progress to AD among patients complaining of mem-

ory loss. Several criteria for identifying groups of peo-

ple at risk for future cognitive decline have been pro-

posed, including age-associated memory impairment,5

mild cognitive impairment (MCI),6

and age-related cog-

nitive decline.7Petersen et al reported that subjects with

MCI converted to AD at a rate of 12% per year for 4

years.8

A structural imaging study using magnetic reso-

nance imaging (MRI) also showed that even subjects

with MCI who remained stable over a follow-up period

had a greater rate of hippocampal volume loss than con-

trol subjects.9

These results suggested that subjects

with memory impairment may be in preclinical phases of

AD, although this conclusion is under debate.10

As for

functional imaging techniques such as single photon

emission computed tomography (SPECT) and positron

emission tomography (PET), Minoshima et al11

demon-

strated that metabolic activity in the posterior cingulate

cortex was most significantly reduced in patients with

memory impairment who later developed AD. Mild met-

abolic reduction in the parietal and temporal cortices

was also detected. However, subjects with memory loss

who remained stable were not analyzed. Johnson et al12

showed that hypoperfusion in the hippocampal-

amygdaloid complex, the posterior cingulate, the ante-

rior thalamus, and the anterior cingulate was detected in

subjects with questionable AD at baseline who con-

verted to AD on follow-up using the singular value

decomposition method. Celsis et al13

examined regional

cerebral blood flow (rCBF) in nondemented subjects

with memory loss and found that temporoparietal asym-

metry in rCBF distinguished those who became

demented from others. In contrast, McKelvey et al14

reported that SPECT patterns examined by visual

inspection had no prognostic signif icance in

nondemented subjects with memory loss.

In this study, we investigated rCBF abnormalities in

patients with memory impairment and asked whether

SPECT data analysis could predict the prognosis of

nondemented subjects with memory loss. Interestingly,

we found significant perfusional reduction even in sub-

jects with memory loss who stayed clinically stable.

Moreover, we demonstrated that SPECT data could be

useful in distinguishing subjects who rapidly progressed

to AD from those who did not.

Materials and Methods

Patients

We retrospectively surveyed the medical records of pa-

tients who came to the memory clinic of the Department

of Geriatric Neurology, Shiga Medical Center, from Sep-

tember 1993, to September 1997. We found 41

nondemented subjects with memory loss. They were

examined by a neurologist, a psychiatrist, and a

neuropsychologist. Diagnoses of dementia and AD

were made by consensus using criteria of the Diagnos-

tic and Statistical Manual of Mental Disorders, 3rd edi-

tion revised15

(DMS-IIIR) and the National Institute of

Neurological and Communicative Disorders and

Stroke/the Alzheimer’s Disease and Related Disorders

Association (NINCDS/ADRDA),16

respectively.

Neuropsychological batteries including the Mini-Mental

Status Examination (MMSE),17

verbal fluency, Benton

visual memory test,18

and Kohs block-design test19

were

performed and interpreted by a neuropsychologist spe-

cializing in geriatrics. Although all of the patients were

documented to have memory impairment on

neurpsychological testing, they did not meet the DMS-

IIIR criteria for dementia because other cognitive im-

pairments were not present. Depression was excluded

by examination by a psychiatrist. Computed tomogra-

phy revealed that no patients had organic brain disease.

All 41 patients gave informed consent and underwent

SPECT for diagnostic purposes. (During this period,

351 patients with memory impairment underwent

SPECT: 259 cases with AD, 18 cases with

frontotemporal dementia, 32 cases with vascular de-

mentia, and 41 cases with memory impairment without

dementia.) These patients visited the clinic at least 4

times a year, and no patients received drugs during fol-

low-up that could affect cognitive functions. Within 1

year, 13 patients were lost during follow-up. The other

28 patients selected for this study were followed up for

at least 24 months (mean, 35.2 months). Some devel-

oped AD (Group 2), whereas others stayed at similar

levels of amnesic condition (Group 1). We selected 18

age-matched subjects who visited the clinic for cogni-

tive examination as a control group (Group 3). These

patients gave informed consent and underwent SPECT

as well as cognitive tests as part of their initial evaluation

but had no cognitive impairment, no active neurologic or

psychiatric disorders, and no ongoing medical prob-

lems.

SPECT Examination

Patients were injected with 740 MBq (20 mCi) of [99m

Tc]

hexaemethyl-propylene amine oxime with eyes open

and ears unplugged in a quiet room. Ten minutes after

injection, scanning was performed parallel to the

canthomeatal line using a Triple-head Gamma Camera

GCA-9300A (Toshiba, Tokyo, Japan) with fanbeam

collimeter (full width half maximum : FWHM 7.5 mm).

The scanned data were reconstructed as axial images

Tanaka et al: Cerebral Blood Flow Abnormalities 113

using a Butterworth filter (order 4 and a cutoff at 0.26 cy-

cles/pixel) at 128 × 128 pixels with 40 slices (1.7 × 1.7 ×3.4 mm in actual size of voxel). A postreconstruction at-

tenuation correction was made (attenuation coefficient

0.09 cm–1

). Regions of interest (ROI) were determined

on appropriate axial images using an in-house image

analysis program (Fig 1). The radioactivity (RI) counts in

each region were divided by the mean RI counts in the

cerebellum for global normalization.

The SPECT data were also analyzed by Statistical

Parametric Mapping 99 (SPM99) (Wellcome Depart-

ment of Neurology, Institute of Neurology, University

College London, UK) and by MATLAB (Mathworks,

Sherborn, MA, USA) on a Sun Ultra-2 workstation (Sun

Microsystems, Mountain View, CA, USA). The SPECT

images were normalized to the standard brain atlas pro-

vided in the SPM99 template for SPECT, and we

applied a Gaussian filter of FWHM 20 mm to smooth the

images. This smoothing has been successfully applied

to SPECT data previously.20-23

The SPECT images were

sorted into 3 groups that corresponded to the 3 different

conditions: memory impairment–stable (Group 1),

memory impairment–AD (Group 2), and control (Group

3). The individual patients’ occipital RI counts were used

as the nuisance covariate to exclude individual variation

of the brain total counts. We therefore did not apply

global normalization of the RI counts. Statistical signifi-

cance was set at .05 without multiple comparisons. (We

adopted the lowest threshold because pathological

cases have no similar cerebral blood flow [CBF] reduc-

tion or large variance compared to activation studies.)

ANOVA with Bonferroni’s correction was applied to

analyze the regions of interest data among the 3 groups

using StatView IV (Abacus Concepts, Berkeley, CA,

USA).

Results

Twenty-eight patients with isolated memory loss were

followed up for a mean time of 35.3 months (range 24-

66 months). Age and sex did not differ between the

memory loss group and the control group; the average

age of the memory loss group was 71.0 ± 7.0 (Table 1).

The MMSE results for the memory loss group were sig-

nificantly lower than those for the control group (Table

1). For each item of the MMSE, the orientation for place

and delayed memory scores were significantly lower in

the memory loss group, whereas there were no signifi-

cant differences in the other items (Table 2). Although

the memory loss subjects on average scored less than 4

on the Benton visual memory test, there were no differ-

ences in the scores on the Kohs block-design test be-

tween the groups (Table 1). These results indicated that

cognitive functions other than memory were preserved

114 Journal of Neuroimaging Vol 12 No 2 April 2002

Fig 1. The regions of interest used for SPECT analysis. 1 =superior frontal cortex, 2 = parietal cortex, 3 = inferior frontalcortex, 4 = temporal cortex, 5 = basal ganglia, 6 = thala-mus, 7 = occipital cortex, 8 = medial temporal cortex, 9 =cerebellum.

Table 1. Characteristics and Cognitive Testing at Initial

Evaluation

Memory Loss Cases Control Cases

Group 1 Group 2 Group 3

Subjects 14 14 18

Age 74.4 ± 5.2* 67.6 ± 7.1 74.2 ± 4.2*

Male/female 5/9 5/9 7/11

MMSE 24.1 ± 2.8 23.8 ± 2.5 26.3 ± 1.5*

Word fluency

Letter 6.7 ± 4.0 5.7 ± 2.8 6.7 ± 2.3

Category 7.4 ± 2.5 6.1 ± 1.9 7.5 ± 2.6

Benton visual

memory test18

3.8 ± 1.4 3.8 ± 1.5 n.d.

Kohs block-

design test19

71.8 ± 14.3 70.9 ± 12.5 73.5 ± 12.0

N-ADL 47.3 ± 2.5 47.7 ± 1.8 n.d.

MMSE = Mini-Mental Status Examination, N-ADL = N scale for activityof daily living, a scale commonly used in Japan, n.d. = not determined.A significant correlation was shown between N-ADL and Gottfries-Brane-Steen (GBS) scores.

24

*P < .01.

in the subjects of the memory loss group. In addition, N

scale for activity of daily living (N-ADL) scores24

re-

vealed normal daily life activity in these subjects (Table

1).

During follow-up, 14 patients (50%) became

demented (Group 2, Table 1, Fig 2). All 14 met the

NINCDS/ADRDA criteria for probable AD. On the other

hand, the other 14 patients remained nondemented for

at least 2 years (Group 1, Table 1, Fig 2).

Neuropsychological test scores at the initial evaluation

did not predict which patients would progress to AD

(Table 1). However, the average age of Group 2 was sig-

nificantly lower than that of Group 1 (Table 1). Because

there were no differences in the duration of reported

memory loss prior to presentation between the groups

(data not shown), this result suggested that patients

with earlier onset of memory loss had an increased risk

of developing AD.

We examined SPECT data to reveal whether

regional hypoperfusion could predict rapid progression

to AD or not. We first performed a ROI analysis (Fig 1).

Because no significant asymmetry was observed, we

analyzed the mean values of the right and left hemi-

spheres in each region. Compared with those in the

control group (Group 3), the patients in Group 2 had sig-

nificantly lower values in the parietal and medial tempo-

ral lobes (Table 3). The values in the medial temporal

cortex tended to be lower in Group 1 than those in

Group 3, but the differences did not reach statistical sig-

nificance (Table 3).

We also performed SPM analysis. As shown in Figure

3, hypoperfusion in the medial temporal lobe

(hippocampal-amygdaloid complex) was observed in

both Group 1 and Group 2 (Fig 3C, D). Moreover,

hypoperfusion in the parietal and anterior cingulate cor-

tices was observed in Group 2 but not in Group 1 (Fig

3A, B, Fig 4), indicating that reduction in these areas

could differentiate Groups 1 and 2. Blood flow in the

posterior cingulate cortex was reduced in both Group 1

and Group 2 (Fig 4).

Tanaka et al: Cerebral Blood Flow Abnormalities 115

Table 2. Comparison of Mini-Mental Status Examination

(MMSE) Items

MMSE Memory Loss Cases Control Cases

Orientation (time) 4.0 ± 1.1 4.5 ± 0.5

Orientation (place) 3.8 ± 1.0* 4.6 ± 0.6

Immediate memory 3.0 ± 0.0 3.0 ± 0.0

Attention and calculation 3.9 ± 1.5 3.6 ± 1.5

Delayed memory 0.7 ± 1.0* 1.8 ± 0.6

Naming 2.0 ± 0.0 2.0 ± 0.0

Repetition 0.9 ± 0.4 0.9 ± 0.2

Three-stage verbal command 2.8 ± 0.5 2.9 ± 0.3

Written command 0.96 ± 0.2 1.0 ± 0.0

Writing 1.0 ± 0.0 1.0 ± 0.0

Copy a design 1.0 ± 0.0 0.9 ±0.2

*P < .01.

Fig 2. Changes in Mini-Mental Status Examination(MMSE) scores in patients who progressed to AD and thosewho remained nondemented.

Table 3. Regions of Interest (ROI) Analysis of Single Photon

Emission Computed Tomography (SPECT) Data

Group 1 Group 2 Group 3

Superior frontal 0.83 ± 0.05 0.83 ± 0.04 0.85 ± 0.07

Inferior frontal 0.81 ± 0.08 0.79 ± 0.06 0.80 ± 0.07

Parietal 0.82 ± 0.05 0.78 ± 0.05* 0.85 ± 0.08

Temporal 0.86 ± 0.07 0.81 ± 0.07 0.84 ± 0.07

Occipital 0.94 ± 0.06 0.92 ± 0.07 0.95 ± 0.07

Basal ganglion 1.15 ± 0.06 1.15 ± 0.07 1.17 ± 0.10

Thalamus 1.22 ± 0.08 1.21 ± 0.11 1.24 ± 0.11

Hypocampus 0.86 ± 0.04 0.82 ± 0.05* 0.89 ± 0.07

*Statistically significant (Group 2 vs Group 3).

Discussion

In this study, we demonstrated that patients with mem-

ory impairment shared hypoperfusion in the medial tem-

poral cortex (corresponding to the hippocampal-

amygdaloid complex) and posterior cingulate cortex. It

is of interest that even amnesic patients who stayed

nondemented showed CBF abnormalities in the areas

known to be affected by AD.11,12

This result is in line with

the result of a recent MRI study showing that rates of

hippocampal volume loss were more severe in patients

with MCI than in control subjects.9

These results sug-

gested that even stable MCI patients may eventually

progress to AD and that intervention.

Notably, blood flow reduction in the parietal and ante-

rior cingulate cortices could discriminate patients who

rapidly progressed to AD from those who did not. The

length of an initial plateau phase has been shown to be

variable among AD patients.25

The present study dem-

onstrated that blood flow reduction in the parietal and

anterior cingulate cortices could be a critical marker for

identifying patients who will rapidly progress to AD

among elderly patients complaining of memory loss.

Decreased blood flow and activation deficit in the

anterior cingulate cortex have been described in sev-

eral pathological conditions including depression,26,27

anorexia nervosa,28

schizophrenia,29

posttraumatic

stress disorder,30

and psychosis associated with AD.31,32

However, al though Johnson et al1 2

reported

hypoperfusion in the anterior cingulate cortex in early

stage AD, few studies have focused on this area in the

development of AD. Functional imaging, electrical stim-

ulation, and lesion studies have shown that the anterior

cingulate cortex has an important role in attention, emo-

tional self-control, focused problem-solving, error rec-

ognition, and adaptive responses to changing condi-

tions.33

Deficits in these cognitive areas are all major

symptoms of AD. The finding that dysfunction of this

area was a critical marker for rapid progression to AD is

of great interest.

Patients of Group 1 and Group 2 scored almost

equally to control subjects on the Kohs block-design test

(visuospatial function), verbal fluency (frontal circuit),

and MMSE items on attention, language ability, calcula-

tion, and construction, suggesting that these patients

had normal functions in these cognitive areas. More-

over, normal ADL scores indicated that common social

activities were not affected in these patients. However,

detailed cognitive tests, such as the Wechsler Adult

Intelligence Scale and test batteries on aphasia and

apraxia, were not performed at initial evaluation.

Recently, Bozoki et al34

reported that among

nondemented elderly patients, memory loss alone

rarely progressed to dementia in the subsequent 2

years. However, the risk of developing dementia was

116 Journal of Neuroimaging Vol 12 No 2 April 2002

Fig 3. Statistical parametric mapping analysis of SPECTdata between Groups 1 and 3 (A, C), and between Groups 2and 3 (B, D). Analyzed data were rendered onto a single stan-dard magnetic resonance image. Statistical significance levelwas set at P < .05 without multiple comparisons. Note thathippocampal perfusion is reduced in the patients of Group 1(C) (X, Y, Z = [36, –19, –11, z = 3.05],[–36, –25, –13, z = 2.67]in Talairach coordinate and z score) whereas parietal cerebralblood flow reduction is also observed in the patients of Group2 (arrow in B) ([–27, –63, 47, z = 2.3], [20, –58, 62, z = 2.2]).

Fig 4. Statistical parametric mapping analysis projectedonto the sagittal image for Group 1 versus Group 3 (A), andGroup 2 versus Group 3 (B).Note that the anterior (1, 36, 33, z= 2.04) (arrowhead in B) and posterior cingulate cortices (–4,–36, 37, z = 1.96) (arrow in B) show cerebral blood flow reduc-tion in Group 2 compared to Group 3. It was disclosed that theposterior cingulate cortex (–6, –59, 27, z = 1.86) (arrow in A)had lower perfusion in the patients of Group 1 compared toGroup 3.

significantly increased in patients with impairment in at

least 1 cognitive area beyond memory loss.34

The

patients who progressed to dementia in this study may

have had mild cognitive deficits at the first examination,

and a more detailed examination with sensitive tests

might have been able to show differences between the 2

groups.

Group 1 and Group 2 differed significantly by age,

with the group that progressed to dementia being youn-

ger. Younger individuals with AD have more severe met-

abolic abnormalities than older individuals.35,36

Thus, it

is possible that the difference in age might have affected

rCBF in the 2 groups. However, it is unlikely that the

results of this study were solely due to this age differ-

ence between the groups. First, although some groups

have reported lower activity in associative and posterior

cingulate cortices of early compared with late onset AD

patients, lower activity in the anterior cingulate cortex in

early onset AD has never been reported. Moreover,

CBF in the anterior cingulate cortex was shown to

decrease with aging.37,38

Second, earlier studies were

undertaken to compare metabolic activity between

presenile versus senile AD. In our study, the average

age of Group 1 was 68 years old. To our knowledge,

there is no evidence that age affects brain metabolism

among senile AD patients. Furthermore, at the initial

evaluation all the patients of this study were not AD, but

MCI patients. It is not known whether younger MCI

patients have lower brain metabolic activity.

In longitudinal studies, attrition invariably introduces

a bias related to the loss of more severely affected indi-

viduals. We examined SPECT findings of the 13

patients lost during follow-up in this study. Compared to

the control group, we found significant hypoperfusion in

the medial temporal and posterior cingulate cortices but

not in other areas. There were no significant differences

in blood flow when compared to Group 1 or Group 2

(data not shown). Presumably, the 13 cases who

dropped out of this study were composed not only of

individuals who progressed to dementia but also of indi-

viduals who remained stable.

In this study, we employed 2 methods commonly

used by the many institutes which analyze SPECT data.

ROI analyses successfully differentiated the patients

who rapidly progressed to AD from the others by parietal

and medial temporal blood flow reduction. Moreover,

SPM analyses clearly showed the differences in pari-

etal, medial temporal, and anterior and posterior

cingulate cortices among the 3 groups. Thus, ROI anal-

yses may be sufficient in daily clinical settings, but SPM

analyses could provide more useful information and

improve the discrimination among the different groups,

even if time-consuming off-line analyses were required.

This study demonstrated that SPECT data analyzed

by ROI and SPM could be applied to the assessment of

the prognoses of patients with memory impairment.

Moreover, it was shown that even patients with memory

impairment who stayed nondemented had CBF abnor-

malities similar to AD.

This work was supported by grants from the Ministry of Health and

Welfare, Japan (Comprehensive Research on Aging and Health,

Research on Specific Diseases, Research on Health Services, and

Analysis of Aged Brain Function with Neuroimaging Techniques) and

by a grant from the Japan Society for Promotion of Science (Research

for the Future Program JSPS-RFTF 97L Ø Ø 2 Ø 1).

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118 Journal of Neuroimaging Vol 12 No 2 April 2002