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 DOI: 10.1177/1533317513495106

published online 2 July 2013AM J ALZHEIMERS DIS OTHER DEMENWu

Yan-Yan Liu, Zhong-Xian Yang, Zhi-Wei Shen, Ye-Yu Xiao, Xiao-Fang Cheng, Wei Chen, Yao-Wen Chen and Ren-HuaCognitive Impairment With No Dementia

Magnetic Resonance Spectroscopy Study of Amnestic Mild Cognitive Impairment and Vascular  

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Current Topics in Research

Magnetic Resonance Spectroscopy Studyof Amnestic Mild Cognitive Impairmentand Vascular Cognitive Impairment WithNo Dementia

Yan-Yan Liu, MD1, Zhong-Xian Yang, MD1, Zhi-Wei Shen, PhD1,Ye-Yu Xiao, MD1, Xiao-Fang Cheng, MD1, Wei Chen, MD2,Yao-Wen Chen, PhD1, and Ren-Hua Wu, PhD1,3

AbstractAmnestic mild cognitive impairment (aMCI) and vascular cognitive impairment with no dementia (VCIND) are highly predictive ofAlzheimer’s disease and vascular dementia. In this study, a 2-dimensional magnetic resonance spectroscopy was performed in 25patients with aMCI, 28 patients with VCIND, and 32 normal controls (NCs). The concentrations of N-acetyl aspartate (NAA),choline (Cho), myoinositol (MI), and creatine (Cr) were measured, and their ratios were calculated. The patients with aMCI dis-played significantly lower NAA/MI bilaterally in the posterior cingulate gyrus (PCG) and white matter of occipital lobe (OLWM)than NC participants or patients with VCIND , whereas patients with VCIND displayed markedly lower NAA/Cho bilaterally inthe white matter of frontal lobe (FLWM) and left OLWM, and right dorsal thalamus (DT) than patients with NC or aMCI. Com-pared with the controls, patients with aMCI displayed lower NAA and NAA/Cr in bilateral PCG, left precuneus, and DT, whereaspatients with VCIND displayed lower NAA/Cr in bilateral DT and FLWM. In addition, increased MI in right PCG of patients withaMCI and increased Cho in left FLWM of patients with VCIND were also observed. The results might help guide a clinical differ-entiation between the 2 disorders.

KeywordsMR spectroscopy, amnesic mild cognitive impairment, vascular cognitive impairment with no dementia

Introduction

Amnestic mild cognitive impairment (aMCI) refers to nonde-

mented individuals with memory complaints and objective

memory impairment, and has been shown consistently to have

a higher risk for developing Alzheimer’s disease (AD),1 with

almost 50% of these patients progressing to AD after 3 years.2

It is well known that AD is the most common cause of dem-

entia, with vascular dementia (VaD) being the second leading

cause.3 Vascular cognitive impairment with no dementia

(VCIND) describes those individuals whose symptoms are

associated with substantial functional impairment, but do not

meet the dementia criteria, and include a high proportion of

individuals with subcortical ischemia with cognitive impair-

ment of presumed cerebral vascular disease.4 Patients with

VCIND have a high risk of progression to dementia, mixed pri-

mary neurodegenerative dementia with vascular dementia, or

vascular dementia, particularly if they have recurrent stroke.5

Magnetic resonance (MR) spectroscopy (MRS) concurrently

measures brain metabolites, such as N-acetylaspartate (NAA),

myoinositol (MI), choline-containing compounds (Cho), and

total creatine. Previous studies performed with single-voxel

proton MRS on patients with mild cognitive impairment (MCI)

have demonstrated increases in the concentration of MI or the

MI/Cr ratio and decreases of NAA or the NAA/Cr ratio in the

hippocampus, posterior cingulate, occipital lobe white matter,

and parietotemporal cortex.6-8 Compared to patients with MCI

or AD, patients with VaD exhibit global reductions in NAA/Cr

ratio in the parietal gray and white matter, frontal white matter,

and the temporal lobe.9 Despite the etiologies of aMCI and

VCIND are different and a significant number of patients with

1 Department of Medical Imaging Center, the Second Affiliated Hospital,

Medical College of Shantou University, Shantou, China2 Department of Neurology, the Second Affiliated Hospital, Medical College of

Shantou University, Shantou, China3 Provincial Key Laboratory of Medical Molecular Imaging, Guangdong,

Shantou, China

Corresponding Author:

Ren-Hua Wu, PhD, Department of Medical Imaging Center, The Second

Affiliated Hospital, Medical College of Shantou University, Shantou 515041,

People’s Republic of China.

Email: rhwu@stu.edu.cn

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dementia may be with both etiologies, it is also important to

differentiate between aMCI and VCIND, because it could limit

the possible accuracy of research in prevention, risk factors,

and treatment of dementia.

The present study aimed to evaluate and characterize the

metabolic markers in patients with aMCI and VCIND compared

to normal control (NC) participants using 2-dimensional (2D)

chemical shift imaging proton MRS, and to assess proton MRS

(1H-MRS) alterations by positioning 10 volumes of interest in

the brain to study the metabolic changes.

Methods

Participants

We recruited 85 elderly individuals comprised of 25 patients

with aMCI, 28 patients with VCIND, and 32 NC participants

through the Department of Neurological Clinic Service and

Medical Examination Center in our hospital. All participants

were right-handed, and demographic information for those

completing the study is shown in Table 1. This study was per-

formed with institutional review board approval. All partici-

pants and caregivers of the patients with aMCI, patients with

VCIND, and NC provided written informed consent prior to

MRS examination.

Criteria for aMCI, VCIND, and NC

Patients diagnosed with aMCI met the operational criteria pro-

posed by Petersen et al,10 which included: memory complaint,

confirmed by an informant; abnormal memory function, docu-

mented by extensive neuropsychological evaluation; normal

general cognitive function, as determined by both the clinical

dementia rating scale (CDR with at least 0.5 in the memory

domain) and mini-mental state examination (MMSE greater

than or equal to 24); no impairment in functional activities of

daily living, as determined by a clinical interview with the

patient and informant; insufficient impairment, cognitively and

functionally, to meet National Institute of Neurological and

Communicative Diseases and Stroke-Alzheimer’s Disease

and Related Disorders Association criteria for AD. Neuropsy-

chological testing included a Hachinski ischemic (HIS) score

(HIS score less than or equal to 4) and Montreal cognitive

assessment score (MoCA, Beijing Version, greater than or

equal to 24).

Diagnosis of VCIND depended on the following cri-

teria11,12: insufficient cognitive impairment to meet the Diag-

nostic and Statistical Manual of Mental Disorders (Fourth

Edition, Text Revision) criteria for dementia; vascular etiology

as follows: (a) cognitive impairment caused by cardiovascular

risk factors, (b) cognitive impairment caused by strategic

infarct or multiple infarcts indicated by a sudden onset or step-

wise progression and responsible lesions on MR imaging

(MRI) or computed tomography scans, and (c) cognitive

impairment due to subcortical small vessel disease suggested

by minor neurological signs (such as hemiparesis, lower facial

weakness, Babinski sign, sensory deficit, dysarthria, gait disor-

der, urine urgency, or motor slowness), moderate white matter

changes (at least 1 region score <2 according to the Wahlund

rating scale), and/or multiple lacunar infarcts (<2) on brain

imaging. Neuropsychological testings for aMCI, the MoCA

scoring, and HIS determination (HIS greater than 7) were also

performed.

The criteria for the selection of NC were no history of either

cognitive decline, neurological or psychiatric disorders, uncon-

trolled systemic medical disorders, or abnormal findings in

conventional brain MRI.

MR Spectroscopy

The 2D-CSI 1H-MRS studies were performed in all partici-

pants. All data were acquired on a standard 1.5 T GE scanner

(Signa; General Electric Medical Systems, HDx Twinspeed,

Wisconsin) using a standard eight-channel head coil. Axial fast

FSE T2-weighted images (slice thickness: 5 mm, field of view

[FOV]: 16 cm � 16 cm) were then acquired prior to spectro-

scopic acquisition at the basal ganglia level for MRS acquisi-

tion. The total regions of interest (ROIs) of the multivoxel

section were about 192 cm3 (12 cm � 8 cm � 2 cm: anterior

to posterior, left to right, thickness). A 2D-CSI 1H-MRS point

resolved spectroscopy (PRESS) pulse sequence (echo time ¼35 ms, repetition time ¼ 1500 ms, number of excitations ¼1, phase � frequency ¼ 18 � 18) was used for acquiring the

Table 1. Characteristics of Patients With aMCI and VCIND, and NC.a

Participants aMCI VCIND NC P value

Numbers 25 28 32 –Male/female 12/13 13/15 17/15 –Age, years 69.11 + 8.72 68.58 + 8.90 67.45 + 9.92 .863Education, years 9.24 + 3.14 8.97 + 2.36 9.41 + 2.67 .612MMSE score 26.13 + 1.78b 25.86 + 1.54b 28.08 + 1.38 .025MoCA score 24.36 + 1.82c 24.64 + 1.26c 27.86 + 1.17 .009

Abbreviations: aMCI, amnestic mild cognitive impairment; VCIND, vascular cognitive impairment with no dementia; NC, normal control; MMSE, mini-mental stateexamination; MoCA, Montreal cognitive assessment score; SD, standard deviation.a Values are expressed as mean + SD.b P < .05, aMCI versus NCs or VCIND versus NC.c P < .01, aMCI versus NCs or VCIND versus NC.

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spectroscopy data. Automatic prescanning was performed in all

participants until all spectra had good quality (<10 Hz of full

width at half height of the unsuppressed water peak and percen-

tages of water suppression �98%). The ROIs for 2D-CSI1H-MRS were then classified according to their location

assigned to 10 regions: bilateral posterior cingulate gyrus

(PCG), white matter of the occipital lobe (OLWM), inferior

precuneus (Pr), dorsal thalamus (DT), and white matter of the

frontal lobe (FLWM). These regions are at particular risk for

MCI or VCIND. The MRS acquisition scan time was 8 minutes

and 12 seconds.

Postprocessing and metabolite quantification

Postprocessing was performed as follows: all subject initial

data (P file) would be created by the host machine and acquired

from the ADW4.5 workstation. All P files were then transferred

to a dedicated UNIX system and processed using spectroscopy

analysis by general electric software. Thus, every single vol-

ume of voxels was (FOV: 16.0 cm� 16.0 cm/phase, frequency:

18� 18)� 2.0 cm¼ 1.58 cm3. A standard phantom containing

detectable compounds was used as an external standard to

calibrate the metabolite concentrations. Absolute metabolite

concentrations with %standard deviation (SD; Cramer–Rao

lower bounds) of metabolite peaks of interest >20% were

excluded, thus indicating that these metabolites could be reli-

ably estimated. Absolute concentrations were then calculated

using a linear combination of model.13,14 Metabolite concen-

trations (mmol/L) of NAA, Cr, Cho, and MI were quantified,

and metabolite ratios (NAA/Cr, Cho/Cr, MI/Cr, NAA/MI, and

NAA/Cho) were calculated.

Data Analysis

Statistical analysis and graphics were performed with SPSS Ver-

sion 18.0 for Windows (SPSS, Chicago, Illinois). Group differ-

ences for age, education, MMSE and MoCA scores were

compared among the 3 groups using a 1-way analysis of var-

iance. As for absolute metabolite concentrations and metabolite

ratios, we used a nonparametric statistical analysis of covariance

Table 2. Absolute Concentrations of Metabolites (mmol/L) and the Ratio of Metabolites From NC Participants, Patients With aMCI andVCIND.a

Metabolites Group RPCG RPr ROLWM RDT RFLWM

Cho NC 1.24 + 0.35 1.10 + 0.25 1.39 + 0.33 1.54 + 0.31 1.47 + 0.25aMCI 1.38 + 0.43 1.19 + 0.33 1.51 + 0.34 1.67 + 0.34 1.61 + 0.33VCIND 1.47 + 0.32 1.26 + 0.40 1.61 + 0.37 1.70 + 0.46 1.67 + 0.38

Cr NC 5.31 + 0.51 5.33 + 0.56 5.61 + 0.76 5.74 + 0.92 5.66 + 0.87aMCI 5.57 + 0.69 5.66 + 0.80 6.02 + 0.84 5.96 + 0.48 5.87 + 0.82VCIND 5.65 + 0.37 6.70 + 0.45 5.81 + 0.55 5.76 + 0.85 5.90 + 0.49

NAA NC 8.37 + 1.65 8.53 + 1.03 8.34 + 1.43 8.39 + 1.05 8.49 + 1.45aMCI 7.01 + 1.39b 7.24 + 1.16 7.78 + 1.50 7.96 + 1.29 8.04 + 1.12VCIND 7.74 + 1.09 7.43 + 1.82 7.92 + 1.25 7.88 + 1.07 7.95 + 1.52

MI NC 5.01 + 0.88 4.06 + 0.74 4.68 + 1.01 4.46 + 0.78 4.57 + 0.91aMCI 6.25 + 1.13b 5.22 + 1.40 5.07 + 1.23 5.83 + 1.43 5.43 + 1.28VCIND 5.61 + 1.20 4.95 + 1.31 4.83 + 1.34 5.27 + 1.20 5.53 + 1.24

NAA/Cr NC 1.49 + 0.26 1.57 + 0.19 1.48 + 0.23 1.47 + 0.19 1.49 + 0.23aMCI 1.26 + 0.27b 1.20 + 0.32 1.35 + 0.27 1.27 + 0.26 1.46 + 0.21VCIND 1.29 + 0.43 1.29 + 0.33 1.39 + 0.45 1.35 + 0.25b 1.05 + 0.19b

Cho/Cr NC 0.25 + 0.07 0.21 + 0.05 0.25 + 0.06 0.27 + 0.06 0.26 + 0.05aMCI 0.26 + 0.03 0.25 + 0.04 0.26 + 0.05 0.30 + 0.04 0.35 + 0.11VCIND 0.30 + 0.09 0.27 + 0.07 0.31 + 0.08 0.32 + 0.07 0.38 + 0.18

MI/Cr NC 1.00 + 0.36 0.74 + 0.15 0.82 + 0.11 0.77 + 0.09 0.81 + 0.12aMCI 1.15 + 0.23 0.88 + 0.19 1.01 + 0.27 0.81 + 0.14 0.91 + 0.27VCIND 1.01 + 0.38 0.87 + 0.21 0.86 + 0.26 0.80 + 0.13 1.03 + 0.19

NAA/MI NC 1.94 + 0.28 2.15 + 0.51 1.84 + 0.33 1.88 + 0.27 1.90 + 0.29aMCI 1.18 + 0.35c,d 1.57 + 0.52 1.35 + 0.40b,d 1.36 + 0.38 1.59 + 0.31VCIND 1.74 + 0.46 1.64 + 0.30 1.76 + 0.54 1.61 + 0.31 1.71 + 0.25

NAA/Cho NC 6.31 + 1.37 8.13 + 1.07 6.34 + 1.06 5.97 + 1.26 6.10 + 1.13aMCI 5.89 + 0.71 7.95 + 1.22 5.97 + 1.33 5.58 + 1.05 5.75 + 1.04VCIND 5.78 + 1.04 7.49 + 1.08 5.75 + 1.21 5.42 + 1.35b,d 4.83 + 1.02c,d

Abbreviations: RPCG, right posterior cingulate gyrus; RPr, right inferior precuneus; ROLWM, right white matter of occipital lobe; RDT, right dorsal thalamus;RFLWM, right white matter of frontal lobe; Cho, choline; Cr, creatine; NAA, N-acetyl aspartate; MI, myoinositol; aMCI, amnestic mild cognitive impairment;VCIND, vascular cognitive impairment with no dementia; NC, normal control; SD, standard deviation.a Values are expressed as mean + SD.b P < 0.05, aMCI versus NCs or VCIND versus NCs.c P < 0.01, aMCI versus NCs or VCIND versus NCs.d P < 0.05, aMCI versus VCIND or VCIND versus aMCI.

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as covariates (influencing factors such as age, education, or men-

tal status scores) with a correction (Benjamin Hochberg) to do

multiple pairwise comparisons between these 3 groups. A P

value < .05 was considered to be statistically significant and the

values were presented as mean + SD.

Results

Table 1 describes the demographic characteristics and neurop-

sychological scores of the participants. Compared with NC par-

ticipants, the baseline MMSE scores (P < .05) and MoCA

scores (P < .01) were lower in patients with aMCI and VCIND,

No significant differences were found among the 3 groups in

regard to age and level of education (P > .05).

The absolute concentrations of NAA, MI, Cho, Cr, and the

metabolite ratios of NAA/Cr, Cho/Cr, MI/Cr, NAA/MI, and

NAA/Cho were obtained and we checked these metabolite con-

centrations, and metabolite ratios were examined for a normal

distribution. Concerning gender and education, there were no

differences among 3 groups for each metabolite concentration

and metabolite ratio in any ROIs. Table 2 shows the averaged

values of brain metabolites measured in the right side volumes

of interest (PCG, Pr, OLWM, DT, and FLWM) among the 3

groups. Decreased NAA/MI ratios in the right PCG (P < .01

vs NC or P < .05 vs VCIND group) and in the right OLWM

(P < .05 vs NC or vs VCIND group) along with decreases of

NAA concentration (P < .05) and NAA/Cr ratio (P < .05),

which were consistent with the elevation in the MI level (P <

.05), were observed in the right PCG in the patients with aMCI

(Figure 1: 1-4). Significantly decreased NAA/Cho ratios (P <

.05) in the right FLWM (P < .01 vs NC or P < .05 vs VCIND

group) and in the right DT (P < .05 vs NC or vs VCIND group),

along with a consistently decreased NAA/Cr ratio (P < .05) in

the left DT and FLWM were observed in the patients with

VCIND. However, we did not find any metabolic changes in

the right Pr in the 3 groups.

Figure 1. 1-4 are examples of attained multivoxel spectra of the bilateral posterior cingulate gyrus (PCG) by linear combination of modelevaluation of metabolite values: (1) normal control (NC) in left PCG) and (2) amnestic mild cognitive impairment (aMCI) in left PCG, (3) NC inright PCG, and (4) aMCI in right PCG. We could find myoinositol in the right PCG with aMCI increased, whereas the left may not be apparent.

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Table 3 compares the averaged brain metabolite levels in the

left of different regions in patients with aMCI and VCIND, and

NC participants. In the aMCI individuals, significant decreases

of NAA/MI ratio (P < .01 vs NC or P < .05 vs VCIND group)

and NAA level (P < .05), and NAA/Cr ratio (P < .05) were

found in the left PCG. The NAA/Cr ratio (P < .05) was found

to decrease in the left Pr and DT, and the ratio of NAA/MI (P <

.05) was also lower in the left OLWM than the NC participants

and patients with VCIND, whereas the concentration of Cho

(P < .05) was elevated in the left OLWM compared to NCs

(Figure 2: 5-8). Unlike the patients with aMCI, in the patients

with VCIND, elevated Cho and decreased NAA/Cho ratio were

observed in the left FLWM (P < .01 vs NC) and OLWM (P <

.05 vs NC). A decreased NAA/Cr ratio (P < .05) in the left DT

was also observed in our study. Tables 2 and 3 indicated that

patients with aMCI displayed significantly lower NAA/MI

bilaterally in PCG and OLWM than NC participants or patients

with VCIND, whereas patients with VCIND displayed mark-

edly lower NAA/Cho in bilateral FLWM, left OLWM, and

right DT than NC participants or patients with aMCI. These

results may carry independent value for discrimination

between patients with aMCI and VCIND.

Discussion

Using 2D-CSI MRS, a reduction in the NAA concentration and

NAA/MI and NAA/Cr ratios was detected in the bilateral PCG

and OLWM in the patients with aMCI. In the left inferior Pr

and left DT of patients with aMCI, the NAA/Cr ratio is reduced

whereas the NAA levels did not significantly change. How-

ever, significantly decreased NAA/Cho ratio in the bilateral

FLWM, right DT, and left OLWM, along with NAA/Cr in the

bilateral FLWM and DT, was observed in the VCIND group.

So lower NAA/MI and NAA/Cr ratios, as well as concentration

of NAA, were more pronounced in aMCI compared to the

patients with VCIND. The posterior cingulate gyrus is a default

network system which experiences neuronal and synaptic loss,

as well as cognitive dysfunction in AD,15 and the thalamus

plays a crucial role in relaying sensation, spatial sense, and

motor signals to the cerebral cortex, along with the regulation

Table 3. Absolute Concentrations of Metabolites (mmol/L) and the Ratio of Metabolites From NC Participants, Patients With aMCI andVCIND.

Metabolites Group LPCG LPr LOLWM LDT LFLWM

Cho NC 1.42 + 0.24 1.18 + 0.20 1.44 + 0.13 1.47 + 0.31 1.50 + 0.26aMCI 1.52 + 0.22 1.31 + 0.16 1.61 + 0.23b 1.53 + 0.32 1.68 + 0.32VCIND 1.54 + 0.26 1.33 + 0.25 1.54 + 0.29 1.65 + 0.28 1.88 + 0.39c

Cr NC 5.20 + 0.92 4.92 + 0.64 5.51 + 0.74 5.67 + 0.79 5.49 + 1.04aMCI 5.39 + 1.08 5.27 + 0.83 5.57 + 1.07 5.72 + 0.90 5.59 + 0.83VCIND 5.52 + 1.13 5.31 + 0.52 5.73 + 1.16 5.84 + 0.71 5.76 + 0.99

NAA NC 8.23 + 1.32 7.84 + 1.62 8.62 + 0.93 8.51 + 0.74 8.57 + 0.86aMCI 6.89 + 1.05b 7.14 + 1.27 7.73 + 1.41 7.87 + 1.14 7.94 + 1.03VCIND 7.14 + 1.80 7.66 + 1.52 7.90 + 1.28 7.78 + 1.30 7.98 + 1.25

MI NC 4.76 + 0.32 4.25 + 0.96 4.54 + 0.93 4.43 + 0.63 4.98 + 0.78aMCI 5.33 + 0.29 4.92 + 1.35 5.32 + 1.29 5.13 + 1.08 5.16 + 1.05VCIND 5.08 + 0.41 4.86 + 1.31 4.93 + 0.98 4.66 + 1.21 4.85 + 0.96

NAA/Cr NC 1.58 + 0.27 1.50 + 0.27 1.54 + 0.15 1.52 + 0.20 1.48 + 0.20aMCI 1.22 + 0.24b 1.15 + 0.29b 1.37 + 0.28 1.23 + 0.22b 1.36 + 0.36VCIND 1.44 + 0.31 1.32 + 0.32 1.29 + 0.16 1.33 + 0.34b 1.32 + 0.24b

Cho/Cr NC 0.26 + 0.05 0.23 + 0.06 0.27 + 0.03 0.26 + 0.05 0.28 + 0.05aMCI 0.32 + 0.07 0.22 + 0.07 0.32 + 0.07 0.28 + 0.02 0.29 + 0.08VCIND 0.35 + 0.08 0.24 + 0.10 0.33 + 0.10 0.34 + 0.09 0.32 + 0.07

MI/Cr NC 0.76 + 0.18 0.90 + 0.21 0.75 + 0.14 0.79 + 0.11 0.75 + 0.13aMCI 0.92 + 0.21 1.23 + 0.28 0.83 + 0.28 0.88 + 0.17 1.01 + 0.24VCIND 0.85 + 0.29 0.96 + 0.33 0.79 + 0.33 0.76 + 0.15 0.90 + 0.17

NAA/MI NC 1.80 + 0.38 2.20 + 0.20 2.04 + 0.29 1.94 + 0.27 1.90 + 0.32aMCI 1.16 + 0.27c,d 1.89 + 0.23 1.53 + 0.33b,d 1.68 + 0.32 1.73 + 0.38VCIND 1.56 + 0.21 1.92 + 0.16 1.90 + 0.25 1.86 + 0.31 1.89 + 0.27

NAA/Cho NC 5.84 + 0.52 6.41 + 0.59 6.43 + 0.71 5.99 + 1.17 5.41 + 1.16aMCI 5.42 + 0.47 6.05 + 0.83 5.49 + 0.49 5.21 + 1.11 5.17 + 1.18VCIND 5.17 + 0.49 5.94 + 1.04 4.44 + 0.95b,d 4.53 + 1.45 4.26 + 1.05c,d

Abbreviations: LPCG, left posterior cingulate gyrus; LPr, left inferior precuneus; LOLWM, left white matter of occipital lobe; LDT, left dorsal thalamus; RFLWM,left white matter of frontal lobe; Cho, choline; Cr, creatine; NAA, N-acetyl aspartate; MI, myoinositol; aMCI, amnestic mild cognitive impairment; VCIND, vascularcognitive impairment with no dementia; NC, normal control; SD, standard deviation.a Values are expressed as mean + SD.b P < .05, aMCI versus NCs or VCIND versus NCs.c P < .01, aMCI versus NCs or VCIND versus NCs.d P < .05, aMCI versus VCIND or VCIND versus aMCI.

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of consciousness, sleep, and alertness. People have paid atten-

tion to the role of thalamus injury in cognitive impairment gra-

dually, and relationship between lower NAA/Cr ratio and DT

has been demonstrated in several studies.16,17 In agreement

with these studies, patients with VCIND displaying thalamo-

cortical dysfunction are associated with neuronal and axonal

injury. The NAA is not only used as a measure of neuronal den-

sities but of neuronal function, and our findings of decreased

NAA levels may be related to lower brain glucose metabolism

in the PCG and has been proposed as a marker of the early

reflection of an impaired energetic metabolism.18 In our study,

the finding that patients with aMCI exhibit decreases in NAA/

MI and NAA/Cr ratios in the bilateral PCG and OLWM was

consistent with previous reports.7,19 In the left inferior Pr, the

decrease in NAA was found in patients with aMCI, which had

also been measured by fluid-registered serial MRI to have the

highest rates of atrophy.20 Likewise, the reduction in NAA/Cr

ratio in the left FLWM is also indicative of an energy deficit

that might result from a defect in oxidative metabolism in neu-

ronal mitochondria in patients with the VCIND group.21-23

Elevated MI/Cr in the PCG and OLWM of patients with

MCI has been previously reported.24 Instead of observing ele-

vated MI/Cr, we found that the MI level was higher in the PCG

and in the left OLWM in patients with aMCI when compared to

the patients with VCIND and NC participants. Increased MI

might indicate elevated neuroglial concentration.25 Even

though there have been some reports to suggest that the MI/

Cr ratio was significant in different brain regions,26 we did not

find evidence for alterations in the MI level, or MI/Cr or NAA/

MI ratios in patients with VCIND. According to Tables 2 and 3,

the reduction of NAA/MI in the PCG and OLWM was more

significant than other areas in the aMCI group. Our findings

and previous studies might provide an effective criterion in evi-

dence of MCI pathological progression.27,28 It is more mean-

ingful to find that NAA/MI ratios have a higher sensitivity

than NAA/Cr ratios or NAA concentrations in the bilateral

PCG and OLWM in patients with aMCI (Table 2 and Table

3). So, the decreased NAA/MI bilaterally in the PCG and

OLWM might be a valuable marker to distinguish patients with

aMCI from patients with VCIND or NCparticipants.

The Cho represents a constituent of cell membranes of choli-

nergic neurons to maintain their function and integrity, so

increased Cho levels might be related to increased cell mem-

brane phospholipid turnover.29 The paratrigonal white matter

areas, included in the OLWM and FLWM, are rich in choliner-

gic fibres deriving from the nucleus basalis of Meynert, which

innervates large areas of the frontal and parietal neocortex,30 and

we showed increases in Cho in the left OLWM of patients with

Figure 2. 1-4 are examples of attained multivoxel spectra of the bilateral white matter of frontal lobe (FLWM) by linear combination of modelevaluation of metabolite values: (1) normal control (NC) in left FLWM and (2) vascular cognitive impairment with no dementia (VCIND) in leftFLWM, (3) NC in right FLWM and (4) VCIND in right FLWM. We could find choline in the left FLWM with VCIND significantly increased.

6 American Journal of Alzheimer’s Disease & Other Dementias® 00(0)

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aMCI and left FLWM in the VCIND group compared to other

regions. Hence, increased Cho may reflect damaged cholinergic

neurons and increased membrane synthesis or phospholipid turn-

over in neurological diseases.31 Thus a significant decrease in

NAA/Cho in the bilateral FLWM regions in this study is sugges-

tive of occurring a higher membrane turnover and decrease in

NAA in these regions. The results showed that an increased Cho

level is correlated with a decreased NAA/Cho ratio in the bilat-

eral FLWM and left OLWM in patients with VCIND. The MRS

data suggest that patients with VCIND probably have more

severe damage in the FLWM and OLWM than the aMCI group

and the NC group, and it also indicates that the NAA/Cho ratio

(as well as the NAA/MI ratio in patients with aMCI) measured

with MRS furnishes a means to quantify brain metabolic dam-

age, allowing for the possibility of an effective criterion and a

higher sensitivity than other metabolite markers. Thus, we

believe that future longitudinal studies aiming to determine

MR spectroscopic changes in absolute concentrations and rela-

tive concentrations will provide a more reliable and sensitive

indicator of metabolic abnormalities in patients with aMCI and

VCIND.

It is also worth noting that the prognostic value of VCIND as

a diagnostic entity has not been fully determined.32 In our study,

we examined the neuroimaging differences of individuals with

VCIND and aMCI by 2D-CSI 1H MRS. Our study found a dif-

ferent distribution of metabolite changes in different brain

regions between the 2 groups. To address this need, it would

be of interest to perform further studies with longer follow-up

of these individuals to establish the long-term rate of conver-

sion, which includes measures with MRS and structural MRI

studies.33

In this study, although the 2D-CSI MRS technique offers the

ability to provide extensive data from multiple contiguous vox-

els and enable us to detect the metabolic changes in different

brain regions at the same time, the study is limited by the fact

that the MRS technique was performed from a single slice

(from the frontal to occipital regions of the brain). The hippo-

campus, which is not covered in the ROI in this study, is

another important region that is known to be affected in

patients with aMCI. We must improve the level of MRS tech-

nique, especially 3D-CSI MRS. In conclusion, the present

study demonstrates MRS abnormalities in particular regions

of the brain of patients with aMCI and VCIND and provides

further evidence that the absolute and relative concentrations

is useful for detection of the characteristic patterns of metabolic

concentration in patients with dementia. Further research pro-

spectively in evaluating the effect of new drugs proposed for

the prevention and treatment of dementia is required.

Acknowledgments

We thank Dr Stanley Lin for helpful discussions and for checking the

language.

Authors Note

Yan-Yan Liu and Zhong-Xian Yang contributed equally to this manu-

script and should be considered as cofirst authors.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the

research, authorship and/or publication of this article: the National

Natural Science Foundation of China (key project No. 30930027) and

the National Natural Science Foundation of China (general project No.

60971075).

References

1. Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impair-

ment. Lancet. 2006;367(9518):1262-1270.

2. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild

cognitive impairment. Arch Neurol. 2001;58(12):1985-1992.

3. Neuropathology Group. Pathological correlates of late-onset

dementia in a multicentre, community-based population in Eng-

land and Wales. Neuropathology Group of the Medical Research

Council Cognitive Function and Ageing Study (MRCCFAS).

Lancet. 2001;357(9251):169-175.

4. Pantoni L, Gorelick P. Advances in vascular cognitive impair-

ment 2010. Stroke. 2011;42(2):291-293.

5. Narasimhalu K, Ang S, De Silva DA, et al. The prognostic effects

of poststroke cognitive impairment no dementia and domain-

specific cognitive impairments in nondisabled ischemic stroke

patients. Stroke. 2011;42(4):883-888.

6. Siger M, Schuff N, Zhu X, Miller BL, Weiner MW. Regional

myo-inositol concentration in mild cognitive impairment using

1H magnetic resonance spectroscopic imaging. Alzheimer Dis

Assoc Disord. 2009;23(1):57-62.

7. Fayed N, Modrego PJ, Rojas-salinas G, Aguilar K. Brain gluta-

mate leves are decreased in Alzheimer’s disease. A Magnetic

Resonance Spectroscopy study. Am J Alzheimers Dis Other

Demen. 2011;26(6):450-456.

8. Rami L, Gomez-Anson B, Bosch B, et al. Cortical brain metabo-

lism as measured by proton spectroscopy is related to memory

performance in patients with amnestic mild cognitive impairment

and Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;

24(4):274-279.

9. Herminghaus S, Frolich L, Gorriz C, et al. Brain metabolism in

Alzheimer disease and vascular dementia assessed by in vivo

proton magnetic resonance spectroscopy. Psychiatry Res. 2003;

123(3):183-190.

10. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kok-

men E. Mild cognitiveimpairment: clinical characterization and

outcome. Arch Neurol. 1999;56(3):303-308.

11. Ingles JL, Wentzel C, Fisk JD, Rockwood K. Neuropsychological

predictors of incident dementia in patients with vascular cognitive

impairment, without dementia. Stroke. 2002;33(8):1999-2002.

12. Garrett KD, Browndyke JN, Whelihan W, et al. The neuropsycho-

logical profile of vascular cognitive impairment-no dementia:

comparisons to patients at risk for cerebrovascular disease and

vascular dementia. Arch Clin Neuropsychol. 2004;19(6):745-757.

13. Yang ZX, Huo SS, Cheng XF, et al. Quantitative multivoxel pro-

ton MR spectroscopy study of brain metabolites in patients with

Liu et al. 7

at UNIV ARIZONA LIBRARY on July 5, 2014aja.sagepub.comDownloaded from

amnestic mild cognitive impairment: a pilot study. Neuroradiol-

ogy. 2012;54(5):451-458.

14. Fayed N, Modrego PJ, Medrano J. Comparative test-retest relia-

bility of metabolite values assessed with Magnetic Resonance

Spectroscopy of the brain. The LCModel versus the manufacturer

software. Neurol Res. 2009;31(5):472-477.

15. Huang C, Wahlund LO, Svensson L, Winblad B, Julin P. Cingu-

late cortex hypoperfusion predicts Alzheimer’s disease in mild

cognitive impairment. BMC Neurol. 2002;2:9.

16. Pattany PM, Yezierski RP, Widerstrom-Noga EG, et al. Proton

magnetic resonance spectroscopy of the thalamus in patients with

chronic neuropathic pain after spinal cord injury. AJNR Am J Neu-

roradiol. 2002;23(6):901-905.

17. Ben Salem D, Walker PM, Bejot Y, et al. N-acetylaspartate/crea-

tine and choline/creatine ratios in the thalami, insular cortex and

white matter as markers of hypertension and cognitive impair-

ment in the elderly. Hypertens Res. 2008;31(10):1851-1857.

18. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM.

N-Acetylaspartate in the CNS: from neurodiagnostics to neuro-

biology. Prog Neurobiol. 2007;81(2):89-131.

19. Modrego PJ, Fayed N, Pina MA. Conversion from mild cogni-

tive impairment to probable Alzheimer’s disease predicted

by brain magnetic resonance spectroscopy. Am J Psychiatry.

2005;162(4):667-675.

20. Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. Mapping

the evolution of regional atrophy in Alzheimer’s disease:

unbiased analysis of fluid-registered serial MRI. Proc Natl Acad

Sci U S A. 2002;99(7):4703-4707.

21. Gasparovic C, Prestopnik J, Thompson J, et al. 1H-MR spectro-

scopy metabolite levels correlate with executive function in vas-

cular cognitive impairment. J Neurol Neurosurg Psychiatry.

2013;84(7):715-721.

22. Black S, Gao F, Bilbao J. Understanding white matter disease:

imaging-pathological correlations in vascular cognitive impair-

ment. Stroke. 2009;40(suppl 3):S48-S52.

23. Nitkunan A, Charlton RA, Barrick TR, McIntyre DJ, Howe FA,

Markus HS. Reduced N-acetylaspartate is consistent with axonal

dysfunction in cerebral small vessel disease. NMR Biomed. 2009;

22(3):285-291.

24. Schott JM, Frost C, MacManus DG, Ibrahim F, Waldman AD,

Fox NC. Short echo time proton magnetic resonance spectroscopy

in Alzheimer’s disease: a longitudinal multiple time point study.

Brain. 2010;133(11):3315-3322.

25. Modrego PJ, Fayed N, Sarasa M. Magnetic resonance spectroscopy

in the prediction of early conversion from amnestic Mild Cognitive

Impairment to dementia. BMJ Open. 2011;1(1):e000007.

26. Watanabe T, Shiino A, Akiguchi I. Absolute quantification in pro-

ton magnetic resonance spectroscopy is useful to differentiate

amnesic mild cognitive impairment from Alzheimer’s disease and

healthy aging. Dement Geriatr Cogn Disord. 2010;30(1):71-77.

27. Fayed N, Davila J, Oliveros A, Castillo J, Medrano JJ. Utility of

different MR modalities in mild cognitive impairment and its use

as a predictor of conversion to probable dementia. Acad Radiol.

2008;15(9):1089-1098.

28. Olson BL, Holshouser BA, Britt W3rd, et al. Longitudinal meta-

bolic and cognitive changes in mild cognitive impairment

patients. Alzheimer Dis Assoc Disord. 2008;22(3):269-277.

29. Subhawong TK, Wang X, Durand DJ, et al. Proton MR spectro-

scopy in metabolic assessment of musculoskeletal lesions. AJR

Am J Roentgenol. 2012;198(1):162-172.

30. Swartz RH, Sahlas DJ, Black SE. Strategic involvement of choli-

nergic pathways and executive dysfunction: does location of

white matter signal hyperintensities matter? J Stroke Cerebrovasc

Dis. 2003;12(1):29-36.

31. Alvarez-Sabın J, Roman GC. Citicoline in vascular cognitive

impairment and vascular dementia after stroke. Stroke. 2011;

42(suppl 1):S40-S43.

32. Stephan BC, Matthews FE, Khaw KT, Dufouil C, Brayne C.

Beyond mild cognitive impairment: vascular cognitive impair-

ment, no dementia (VCIND). Alzheimers Res Ther. 2009;1(1):4.

33. Modrego PJ, Fayed N. Longitudinal magnetic resonance spec-

troscopy as marker of cognitive deterioration in mild cognitive

impairment. Am J Alzheimers Dis Other Demen. 2011;26(8):

631-636.

8 American Journal of Alzheimer’s Disease & Other Dementias® 00(0)

at UNIV ARIZONA LIBRARY on July 5, 2014aja.sagepub.comDownloaded from