Impact of Apolipoprotein E4 Polymorphism on the Gray Matter Volume and the White Matter Integrity in Subjective Memory Impairment without White Matter Hyperintensities: Voxel-Based Morphometry and Tract-Based Spatial Statistics Study under 3-Tesla MRI Young-Min Lee, Ji-Kyung Ha, Je-Min Park, Byung-Dae Lee, EunSoo Moon, Young-In Chung, Ji-Hoon Kim, Hak-Jin Kim, Chi-Woong Mun, Tae-Hyung Kim, Young-Hoon Kim From the Department of Psychiatry, Pusan National University School of Medicine, Busan, Korea (YML, JKH, JMP, BDL, EM); Biomedical Research Institute, Pusan National University Hospital, Busan, Korea (YML, JMP, BDL, EM); Department of Psychiatry, Pusan National University School of Medicine, Yangsan, Korea (YIC, JHK); Department of Radiology, Pusan National University School of Medicine, Busan, Korea (HJK); Department of Biomedical Engineering and FIRST, Inje University, Gimhae, Korea (CWM,THK); and Department of Psychiatry, Medical School, Inje University, Haeundae Paik Hospital, Busan, Korea (YHK).
ABSTRACT OBJECTIVE: The aim of this study is to compare gray matter (GM) volume and white matter (WM) integrity in Apolipoprotein E4 (ApoE ε4) carriers with that of ApoE ε4 noncarriers using the voxel-based morphometry and diffusion tensor imaging (DTI) to investigate the effect of the ApoE ε4 on brain structures in subjective memory impairment (SMI) without white matter hyperintensities (WMH). METHODS: Altogether, 26 participants with SMI without WMH were finally recruited from the Memory impairment clinics of Pusan National University Hospital in Korea. All participants were ApoE genotyped (ApoE ε4 carriers: n = 13, matched ApoE ε4 noncarriers: n = 13) and underwent 3-tesla magnetic resonance imaging (MRI) including 3-dimensional volumetric images for GM volume and DTI for WM integrity. RESULTS: ApoE ε4 carriers compared with noncarriers in SMI without WMH showed the atrophy of GM in inferior temporal gyrus, inferior parietal lobule, anterior cingulum, middle frontal gyrus, and precentral gyrus and significantly lower fractional anisotropy WM values in the splenium of corpus callosum and anterior corona radiate. CONCLUSION: Our findings suggest that the ApoE ε4 is associated with both atrophy of GM volume and disruption of WM integrity in SMI without WMH.
Keywords: Apolipoprotein E4, subjective memory impairment, gray matter volume, white matter integrity. Acceptance: Received June 27, 2013, and in revised form October 22, 2014. Accepted for publication November 27, 2014. Correspondence: Address correspondence to Je-Min Park, MD, PhD, Department of Psychiatry, School of Medicine, Pusan National University, 305 Gudeok-Ro, Seo-Gu, Busan, Korea, 602-739. E-mail: [email protected]. J Neuroimaging 2016;26:144-149. DOI: 10.1111/jon.12207
Introduction Apolipoprotein E (ApoE) is a very low density lipoprotein that plays a major role in neuronal development, myelination, brain plasticity, and repair functions.1 Three alleles (ε2, ε3, and ε4) constitute the three major ApoE isoforms (ApoE ε2, ApoE ε3, ApoE ε4).1 ApoE ε4 among them is the only established susceptibility gene for late-onset Alzheimer’s disease (AD).2 It is known that ApoE ε4 affects gray matter (GM) volume and white matter (WM) integrity in AD.2–4 Changes in GM volume can be assessed by voxel-based morphometry (VBM)5 that is commonly used to investigate volume differences between groups. Many VBM studies have found that ApoE ε4 is associated with atrophy of GM in mild cognitive impairment (MCI)3,6 and AD.2–4 Disruption of WM integrity, caused by loss of the normal structure of myelin, can be assessed by diffusion tensor imaging (DTI).7 Recent DTI studies showed that ApoE ε4 is associated with disruption of WM integrity in healthy subjects8 and AD.9
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Subjective memory impairment (SMI) is defined by the sustained subjective memory complaints while the objective age-, gender-, and education-adjusted performance on neuropsychological tests is normal.10 SMI is fairly common in elderly people. Recent epidemiological studies have shown that SMI is predictive of unfavorable cognitive outcomes and is a risk factor for AD.11,12 Given the major role of ApoE in myelination, brain plasticity, and repair functions, it is quite probable that ApoE ε4 may affect structural brain changes (GM volume and WM integrity) in SMI. However, only a few studies have investigated the effects of ApoE ε4 on GM volume and WM integrity in SMI. Most studies have evaluated its role in healthy subject, MCI, and AD. Recent evidence13 suggests that vascular factors, such as cerebrovascular disease and white matter hyperintensities (WMH), contribute to the etiology of SMI. However, we are only concerned about the effect of ApoE ε4, not vascular factors, on GM volume and WM integrity in SMI. Therefore, it seems reasonable to exclude participants with moderate or
◦ 2015 by the American Society of Neuroimaging C
WMH on brain MRI to minimize the vascular etiologic impact on SMI. The aim of this study was two-fold. First, we compared GM volume in ApoE ε4 carriers with that of ApoE ε4 noncarriers using the VBM in SMI without WMH. Second, we compared WM integrity in ApoE ε4 carriers with that of ApoE ε4 noncarriers using DTI in SMI without WMH. Here, we expected negative effects of ApoE ε4 on GM volume and WM integrity.
Methods Participants All participants (n = 62) with SMI were recruited from the Memory impairment clinic cohort of Pusan National University Hospital in Korea from November 2011 to December 2012. Written informed consents were obtained from all participants, and this study was approved by the Pusan National University Hospital Institutional Review Board. All participants were right-handed and underwent MR scans of T1-weighted images (T1WI) and DTI. ApoE genotyping was performed using the restriction enzyme isoform genotyping method as previously described.14 The inclusion criteria for SMI were as follows: (1) sustained subjective memory complaints; (2) normal general cognition (within –1.5 SD of age- and education-adjusted norms on the Korean version of the Mini-Mental State Examination [K-MMSE]15 and a score higher than 25); (3) normal activities of daily living (ADL) as judged by both an interview with a clinician and the standardized ADL scale; and (4) no abnormality (within –1.5 SD of age- and education-adjusted norms) on a comprehensive neuropsychological battery. We applied the following exclusion criteria to all subjects: (1) other neurodegenerative diseases; (2) major depressive disorder or other psychiatric illness; (3) intracranial space occupying lesion; (4) aphasia or other language barrier; (5) MRI contraindications or known claustrophobia; (6) active substance abuse disorders; (7) severe systemic disease; (8) prominent visual or hearing impairment. We also excluded participants with moderate or severe WMH on brain MRI to minimize the vascular etiologic impact on SMI. The presence of moderate or severe WMH was defined as WMH on fluid-attenuated inversion recovery (FLAIR) images that fulfilled the following criteria: (1) periventricular WMH (caps or rim) longer than 5 mm, and (2) deep WMH consistent with extensive WM lesion or with diffusely confluent lesion ࣙ10 mm in maximum diameter. Eleven subjects out of all participants (n = 62) were excluded because eight subjects have moderate or severe WMH and three subjects have brain infarction on brain MRI. Among the rest of the participants (n = 51), for the analysis of this study, 13 subjects who were heterozygote for ApoE4 (ε3/ε4) were included into the ApoE ε4 carriers. 13 subjects, matched for age, gender, and education who were ε4 negative (ε3/ε3), were included into the ApoE ε4 noncarriers. This left a final group of 26 subjects with SMI.
Clinical Evaluation All patients underwent a comprehensive evaluation consisting of the following assessments: history taking from the patient and informant; medical and neurological examinations; K-MMSE15 for global cognitive evaluation; Geriatric Depression Scales (GDS)16 for the severity of depressive symptoms.
We also used the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-K)17 as comprehensive neuropsychological battery to examine the functional capacity of several cognitive domains: (1) memory (word list recall); (2) language (the Korean version of the Boston Naming Test [K-BNT]); and (3) visuospatial function (constructional apraxia). We also used the Korean version of the Frontal Assessment Battery (FAB-K)18 to examine the frontal or executive function: the FAB-K was known as a valid and reliable instrument for evaluating frontal lobe function in the elderly. We used Seoul instrumental activities of daily living (SIADL)19 which was validated in Korea as the standardized ADL scale. The SIADL consist of 15 items that address an individual’s ability to engage in more complex tasks, such as shopping or using the telephone, and impairment severity is scored from 1 (no impairment) to 3 for all items. Thus, the maximum score of SIADL is 45 and scores of ࣘ 7 indicate normal complex ADL.
Imaging Data Acquisition All participants underwent MR scans of T1WI and DTI on a Siemens (Erlangen, Germany) Trio TIM 3T scanner. T1WI were acquired using a 3D magnetization prepared rapid gradient echo (3D MP-RAGE) sequence with following parameters: repetition time (TR) = 1,800 ms, echo time (TE) = 2.07 ms, inversion time (TI) = 900 ms, flip angle = 12°, acquisition matrix = 256 × 256, field of view (FOV) = 250 × 250 mm2 , slice thickness = 1 mm, total number of slices = 256. DTI were acquired with the following echo planar acquisition parameters: diffusion-weighted gradients applied in 30 nonlinear directions, number of average = 2, TR = 6,200 ms, TE = 85 ms, flip angle = 90°, acquisition matrix = 128 × 128, FOV = 230 × 230 mm2 , slice thickness = 3 mm, b = 600 s/mm2 . All image acquisitions were ensured the same slice orientation paralleled to the anterior commissure and posterior commissure line.
MRI Data Analysis Image Preprocessing for VBM
The VBM 8 toolbox (http://dbm.neuro.uni-jena.de/vbm) which is incorporated in statistical parametric mapping 8 (SPM8, http://www.fil.ion.ucl.ac.uk/spm)20 was used to perform the analysis of brain structural imaging. In this process, all images were spatially normalized using combinations of affine linear transform and nonlinear registration to the standard MNI template (Montreal Neurological Institute) and segmented into GM, WM, and cerebrospinal fluid (CSF).21 Segmented GM images were modulated to compensate the volumetric effects of expansion or shrinking employed in spatial normalization by multiplying the voxel intensity with the Jacobian determinants reflecting the parameters for fitting a voxel in native space to corresponding voxel in template space. The modulated images were then smoothed with an 8-mm full width half maximum isotropic Gaussian kernel. Image Preprocessing for DTI
DTI were entirely processed with FMRIB Software Library (FSL, http://www.fmrib.ox.ac.uk/fsl) package.22 Image distortions induced by the effects of head movement and eddy currents was corrected by applying an affine alignment of diffusion-weighted images applied in different gradient Lee et al: ApoE ε4 and SMI
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Table 1. Demographic and Clinical Characteristics of All Participants with SMI
Age (years) Gender (female), N (%) Education (years) K-MMSE GDS CERAD-K Boston naming test Constructional apraxia Word list recall FAB SIADL
ApoE ε4 Carriers (N = 13)
ApoE ε4 Noncarriers (N = 13)
P Value
66.36 ± 6.34 7 (53.8) 9.73 ± 2.76 27.18 ± 1.88 11.36 ± 6.34
66.18 ± 7.83 7 (53.8) 8.45 ± 5.33 26.42 ± 2.48 14.27 ± 9.05
.953 1.000 .490 .249 .394
± ± ± ± ±
.526 .515 .382 .643 .740
10.54 9.63 4.54 13.45 3.18
± ± ± ± ±
1.36 1.50 1.43 2.54 2.31
10.18 9.18 5.27 13.81 3.36
2.13 1.72 2.10 2.96 2.69
Data are N (%) or means ± SD. SMI = subjective memory impairment; ApoE ε4 = Apolipoprotein E4; K-MMSE = Korean version of the Mini-Mental State Examination; GDS = Geriatric Depression Scale; CERAD-K = Korean version of Consortium to Establish a Registry for Alzheimer’s disease; FAB = Frontal Assessment Battery; SIADL = SeoulInstrumental Activities of Daily Living.
Table 2. Regions of Gray Matter Atrophy in ApoE ε4 Carriers Compared to Noncarriers in SMI on VBM Analysis (P < .001, Uncorrected for Multiple Comparisons, Extent Threshold = 20 Voxel) MNI Coordinates (mm) Anatomical Region
Inferior temporal gyrus Inferior parietal lobule Anterior cingulum Middle frontal gyrus Precentral gyrus
Side
x
y
z
T Value
R R R L L
48 33 1 −16 −37
−48 −43 50 6 −9
−15 48 11 63 54
4.62 4.05 4.03 4.03 3.83
ApoE ε4 = Apolipoprotein E4; SMI = subjective memory impairment; VBM = voxel-based morphometry; MNI = Montreal Neurological Institute; L = left; R = right.
directions to nondiffusion-weighted image. After stripping the skull using brain extraction tool, diffusion tensor was calculated at each voxel and then fractional anisotropy (FA) was generated using Functional MRI of the Brain (fMRIB) diffusion toolbox.22 Voxel-wise statistical analysis of these DTI parameters was performed using tract-based spatial statistics (TBSS) v1.2.23,24 First, all individual FA images were nonlinearly aligned to FA template in 1 × 1 × 1 mm3 MNI space using FMRIB’s nonlinear registration tool.22 Second, aligned images were averaged and thinned to identify the mean FA skeleton represented as the center of common WM tracts.23 Third, mean FA skeleton was restricted with the thresholds .2 to exclude the voxels of GM, CSF in skeleton. All subject’s aligned FA images were projected onto the mean skeleton tracks and the resulting data fed into voxel-wise across subject statistics. The registration and projection vectors derived from DTI-FA processing were applied to other DTI parameters.
Statistical Analyses Pearson’s χ 2 for categorical data and Mann-Whitney U test for continuous variables were used to evaluate differences in demographic or clinical characteristics between ApoE ε4 carriers 146
and noncarriers in SMI using Statistical Package for the Social Sciences (SPSS) version 15.0. The VBM results were analyzed with using independent two-sample t-test with general linear model (GLM). Age, gender, and education were used as covariates to control these confusing factors. We also included GDS as covariates because depressive symptoms may affect cognitive symptoms of SMI and in this study, the subjects with SMI had comparatively high depressive symptoms. Statistical significant level was considered at P ࣘ .001 uncorrected at voxel level with the extent threshold of contiguous 20 voxels. Voxel-wise differences of DTI parameters were statistically analyzed by independent two-sample t-test with the GLM design controlling the effects of age, gender, education, and GDS as nuisance variables, setting the number of permutations at 5,000 based on the threshold-free cluster enhancement using randomize tools in FSL and take into account results to be significant at P < .05 with correction for multiple comparisons.25 Statistical power that is given in this study samples was 80% power.
Results Demographic or Clinical Characteristics Table 1 shows age, gender, educational level, K-MMSE, GDS, SIADL, and CERAD-K. No significant differences in demographic or clinical data were found between the ApoE ε4 carriers and the noncarriers.
VBM Analysis Table 2 describes the anatomical areas and T value for significantly different GM volumes between the ApoE ε4 carriers and the noncarriers (uncorrected P ࣘ .001, extent threshold = 20 voxel). ApoE ε4 carriers compared with noncarriers showed the atrophy of GM in inferior temporal gyrus, inferior parietal lobule, anterior cingulum, middle frontal gyrus, and precentral gyrus (Fig 1). No suprathreshold clusters of increased areas were found in ApoE ε4 carriers with respect to noncarriers.
TBSS Analysis Table 3 summarizes the results of DTI parameter maps within the maximum statistical thresholds. FA was significantly lowered (P < .05) in anterior corona radiata and splenium of corpus callosum in the ApoE ε4 carriers as compared to noncarriers (Fig 2).
Discussion We investigated the effect of the ApoE ε4 on GM volume and WM integrity in SMI without WMH, and found the ApoE ε4 is associated with both atrophy of GM volume and disruption of WM integrity in SMI without WMH. In more detail, we found that the ApoE ε4 carriers compared with noncarriers show the atrophy of GM in inferior temporal gyrus, inferior parietal lobule, anterior cingulum, middle frontal gyrus, and precentral gyrus (uncorrected P < .001, extent threshold = 20 voxel). Previous many studies have reported that the ApoE ε4 carriers compared with noncarriers show atrophy of hippocampus or other GM in AD.9,26–28 These results of dementia subjects are in overall agreement with our
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Fig 1. The results of voxel-based morphometry analysis showing the decreased gray matter volumes in ApoE ε4 carriers compared to noncarriers in subjective memory impairment without white matter hyperintensities (P < .001, uncorrected for multiple comparisons, extent threshold = 20 voxel). Table 3. Regions Showing Lower Degree of FA in ApoE ε4 Carriers Compared to Noncarriers in SMI on TBSS Analysis (P < .05 FDR Corrected with Multiple Comparisons, k > 100) MNI Coordinates (mm) Anatomical Region
Anterior corona radiata Splenium of corpus callosum
Side
Peak α -Value
x
y
z
Cluster Size (mm3 )
L
.97
106
155
60
4,745
R
.952
67
77
81
286
FA = fraction anisotropy; ApoE ε4 = Apolipoprotein E4; SMI = subjective memory impairment; TBSS = tract-based spatial statistics; FDR = false discovery rate; MNI = Montreal Neurological Institute; L = left; R = right.
results. However, in studies of nondemented subjects, results have been mixed.29–31 For instances, Jack et al29 investigated the association between hippocampal volume and ApoE polymorphisms in 125 elderly healthy subjects. They found that hippocampal volumes did not differ significantly on the basis of ApoE genotype, neither did the study by Schmidt et al,30 which investigated hippocampal and parahippocampal volumes in subjects with normal cognition. In contrast to these negative findings, Plassman et al31 studied the association of ApoE ε4, hippocampal volume, and cognitive performance in 10 pairs of cognitively normal twins. They found that hippocampal volumes were smaller in ApoE ε4 carriers compared to noncarriers, despite the fact that the two groups did not differ in performance on neuropsychological test. Further studies
should be needed to clarify effect of ApoE ε4 on GM volume in SMI. We also found significantly reduced FA values in the ApoE ε4 carriers as compared to the noncarriers in the splenium of corpus callosum and anterior corona radiata, suggesting that the presence of ApoE ε4 may influence WM integrity before the onset of AD. These findings are in line with previous observations in healthy subjects8,32–34 and AD.9 Bhavani et al9 reported the impaired WM integrity in ApoE ε4 carriers. AD subjects were predominantly in the dominant cortex with involvement of the medial temporal lobe and limbic regions. Recent studies of healthy aging groups also showed that ApoE ε4 was associated with the impaired WM integrity in parahippocampal WM,8,32 and the corpus callosum.33,34 Braak and Braak35 have suggested that cognitive decline in AD is related to myelinopathy. ApoE ε4 could disrupt myelin sheath building or reduce the normal clearance of b-amyloid peptides. Considering SMI is a risk factor for AD, disruption of WM integrity, caused by loss of the normal structure of myelin by ApoE ε4, may affect cognitive decline in SMI. The results in this study have several limitations to be interpreted with caution. First, this study was limited by a relatively small sample size. Second, due to small sample size, uncorrected (P < .001) threshold at voxel level with the extent threshold of contiguous 20 voxels was applied to identify the atrophy of GM in the VBM analysis, instead of the correction for family-wise error or false discovery rate (FDR) corrected (P < .05) thresholds. This suggest that type I error may be higher in this study. Third, we considered isolated effects of ApoE ε4 allele on GM and WM in SMI. But, there might be other genes in linkage disequilibrium with ApoE ε4 that might affect Lee et al: ApoE ε4 and SMI
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Fig 2. The results of TBSS with mean FA skeleton (green) and significant regions (red) on a T1 template image in comparison between ApoE ε4 carriers and noncarriers among patients with SMI (P corrected < .05).
WM structure. For instance, APOC1 which is in strict linkage disequilibrium with ApoE ε4 plays an independent role in AD risk.36 Therefore, further studies with a larger sample size would be needed to investigate the contribution of other genes to brain structure. In conclusion, this study shows that the ApoE ε4 is associated with both atrophy of GM volume and disruption of WM integrity in SMI without WMH. This study was supported by Biomedical Research Institute Grant (2014–16), Pusan National University Hospital.
References 1. Zhong N, Weisgraber KH. Understanding the basis for the association of apoE4 with Alzheimer’s disease: opening the door for therapeutic approaches. Curr Alzheimer Res 2009;6(5):415-8. 2. Cosentino S, Scarmeas N, Helzner E, et al. APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease. Neurology 2008;70(19 Pt 2):1842-9. 3. Agosta F, Vossel KA, Miller BL, et al. Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc Natl Acad Sci U S A 2009;106(6):2018-22. 4. Boccardi M, Sabattoli F, Testa C, et al. APOE and modulation of alzheimer’s and frontotemporal dementia. Neurosci Lett 2004;356(3):167-70. 5. Wright IC, McGuire PK, Poline JB, et al. A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. Neuroimage 1995;2(4):244-52. 6. Farlow MR, He Y, Tekin S, et al. Impact of APOE in mild cognitive impairment. Neurology 2004;63(10):1898-901. 7. Moseley M. Diffusion tensor imaging and aging—a review. NMR Biomed 2002;15(7–8):553-60. 8. Nierenberg J, Pomara N, Hoptman MJ, et al. Abnormal white matter integrity in healthy apolipoprotein E epsilon4 carriers. Neuroreport 2005;16(12):1369-72. 9. Bagepally BS, Halahalli HN, John JP, et al. Apolipoprotein E4 and brain white matter integrity in Alzheimer’s disease: tractbased spatial statistics study under 3-Tesla MRI. Neurodegener Dis 2012;10(1-4):145-8. 10. Jonker C, Geerlings MI, Schmand B. Are memory complaints predictive for dementia? A review of clinical and population-based studies. Int J Geriatr Psychiatry 2000;15(11):983-91. 11. Jessen F, Wiese B, Bachmann C, et al. Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry 2010;67(4):414-22.
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12. Reisberg B, Shulman MB, Torossian C, et al. Outcome over seven years of healthy adults with and without subjective cognitive impairment. Alzheimers Dement. 2010;6(1):11-24. 13. de Groot JC, de Leeuw FE, Oudkerk M, et al. Cerebral white matter lesions and subjective cognitive dysfunction: the Rotterdam Scan Study. Neurology 2001;56(11):1539-45. 14. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31(3):545-8. 15. Kang Y, Na DL, Hahn S. A validity study on the Korean MiniMental State Examination (K-MMSE) in dementia patients. J Korean Neurol Assoc 1997;15:300-8. 16. Bae JN, Cho MJ. Development of the Korean version of the Geriatric Depression Scale and its short form among elderly psychiatric patients. J Psychosom Res 2004;57(3):297305. 17. Lee JH, Lee KU, Lee DY, et al. Development of the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K): clinical and neuropsychological assessment batteries. J Gerontol B Psychol Sci Soc Sci 2002;57(1):P47-P53. 18. Kim TH, Huh Y, Choe JY, et al. Korean version of frontal assessment battery: psychometric properties and normative data. Dement Geriatr Cogn Disord 2010;29(4):363-70. 19. Ku HM, Kim JH, Kwon EJ, et al. A study on the reliability and validity of seoul instrumental activities of daily living (SIADL). Neuropsychiatr Assoc 2014;43:189-99. 20. Ashburner J, Friston KJ. Voxel-based morphometry—the methods. Neuroimage 2000;11(6 Pt 1):805-21. 21. Mazziotta J, Toga A, Evans A, et al. A probabilistic atlas and reference system for the human brain: International consortium for brain mapping (ICBM). Philos Trans R Soc Lond B Biol Sci 2001;356(1412):1293-322. 22. Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23:S208-S219. 23. Smith SM, Jenkinson M, Johansen-Berg H, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 2006;31(4):1487-505. 24. Smith SM, Johansen-Berg H, Jenkinson M, et al. Acquisition and voxelwise analysis of multi-subject diffusion data with tract-based spatial statistics. Nat Protoc 2007;2(3):499-503. 25. Smith SM, Nichols TE. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 2009;44(1):83-98. 26. Lehtovirta M, Laakso MP, Soininen H, et al. Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes. Neuroscience 1995;67(1): 65-72. 27. Juottonen K, Lehtovirta M, Helisalmi S, et al. Major decrease in the volume of the entorhinal cortex in patients with Alzheimer’s disease
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carrying the apolipoprotein E epsilon4 allele. J Neurol Neurosurg Psychiatry 1998;65(3):322-7. Geroldi C, Pihlajamaki M, Laakso MP, et al. APOE-epsilon4 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology 1999;53(8):1825-32. Jack CR Jr, Petersen RC, Xu YC, et al. Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Ann Neurol 1998;43(3):30310. Schmidt H, Schmidt R, Fazekas F, et al. Apolipoprotein E e4 allele in the normal elderly: neuropsychologic and brain MRI correlates. Clin Genet 1996;50(5):293-9. Plassman BL, Welsh-Bohmer KA, Bigler ED, et al. Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition. Neurology 1997;48(4):985-9.
32. Honea RA, Vidoni E, Harsha A, et al. Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. J Alzheimers Dis 2009;18(3):553-64. 33. Persson J, Lind J, Larsson A, et al. Altered brain white matter integrity in healthy carriers of the APOE epsilon4 allele: a risk for AD? Neurology 2006;66(7):1029-33. 34. Smith CD, Chebrolu H, Andersen AH, et al. White matter diffusion alterations in normal women at risk of Alzheimer’s disease. Neurobiol Aging 2010;31(7):1122-31. 35. Braak H, Braak E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol 1996;92(2):197-201. 36. Scacchi R, Gambina G, Ruggeri M, et al. Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer’s disease. Neurosci Lett 1999;259(1):33-6.
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ABSTRACT OBJECTIVE: The aim of this study is to compare gray matter (GM) volume and white matter (WM) integrity in Apolipoprotein E4 (ApoE ε4) carriers with that of ApoE ε4 noncarriers using the voxel-based morphometry and diffusion tensor imaging (DTI) to investigate the effect of the ApoE ε4 on brain structures in subjective memory impairment (SMI) without white matter hyperintensities (WMH). METHODS: Altogether, 26 participants with SMI without WMH were finally recruited from the Memory impairment clinics of Pusan National University Hospital in Korea. All participants were ApoE genotyped (ApoE ε4 carriers: n = 13, matched ApoE ε4 noncarriers: n = 13) and underwent 3-tesla magnetic resonance imaging (MRI) including 3-dimensional volumetric images for GM volume and DTI for WM integrity. RESULTS: ApoE ε4 carriers compared with noncarriers in SMI without WMH showed the atrophy of GM in inferior temporal gyrus, inferior parietal lobule, anterior cingulum, middle frontal gyrus, and precentral gyrus and significantly lower fractional anisotropy WM values in the splenium of corpus callosum and anterior corona radiate. CONCLUSION: Our findings suggest that the ApoE ε4 is associated with both atrophy of GM volume and disruption of WM integrity in SMI without WMH.
Keywords: Apolipoprotein E4, subjective memory impairment, gray matter volume, white matter integrity. Acceptance: Received June 27, 2013, and in revised form October 22, 2014. Accepted for publication November 27, 2014. Correspondence: Address correspondence to Je-Min Park, MD, PhD, Department of Psychiatry, School of Medicine, Pusan National University, 305 Gudeok-Ro, Seo-Gu, Busan, Korea, 602-739. E-mail: [email protected]. J Neuroimaging 2016;26:144-149. DOI: 10.1111/jon.12207
Introduction Apolipoprotein E (ApoE) is a very low density lipoprotein that plays a major role in neuronal development, myelination, brain plasticity, and repair functions.1 Three alleles (ε2, ε3, and ε4) constitute the three major ApoE isoforms (ApoE ε2, ApoE ε3, ApoE ε4).1 ApoE ε4 among them is the only established susceptibility gene for late-onset Alzheimer’s disease (AD).2 It is known that ApoE ε4 affects gray matter (GM) volume and white matter (WM) integrity in AD.2–4 Changes in GM volume can be assessed by voxel-based morphometry (VBM)5 that is commonly used to investigate volume differences between groups. Many VBM studies have found that ApoE ε4 is associated with atrophy of GM in mild cognitive impairment (MCI)3,6 and AD.2–4 Disruption of WM integrity, caused by loss of the normal structure of myelin, can be assessed by diffusion tensor imaging (DTI).7 Recent DTI studies showed that ApoE ε4 is associated with disruption of WM integrity in healthy subjects8 and AD.9
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Subjective memory impairment (SMI) is defined by the sustained subjective memory complaints while the objective age-, gender-, and education-adjusted performance on neuropsychological tests is normal.10 SMI is fairly common in elderly people. Recent epidemiological studies have shown that SMI is predictive of unfavorable cognitive outcomes and is a risk factor for AD.11,12 Given the major role of ApoE in myelination, brain plasticity, and repair functions, it is quite probable that ApoE ε4 may affect structural brain changes (GM volume and WM integrity) in SMI. However, only a few studies have investigated the effects of ApoE ε4 on GM volume and WM integrity in SMI. Most studies have evaluated its role in healthy subject, MCI, and AD. Recent evidence13 suggests that vascular factors, such as cerebrovascular disease and white matter hyperintensities (WMH), contribute to the etiology of SMI. However, we are only concerned about the effect of ApoE ε4, not vascular factors, on GM volume and WM integrity in SMI. Therefore, it seems reasonable to exclude participants with moderate or
◦ 2015 by the American Society of Neuroimaging C
WMH on brain MRI to minimize the vascular etiologic impact on SMI. The aim of this study was two-fold. First, we compared GM volume in ApoE ε4 carriers with that of ApoE ε4 noncarriers using the VBM in SMI without WMH. Second, we compared WM integrity in ApoE ε4 carriers with that of ApoE ε4 noncarriers using DTI in SMI without WMH. Here, we expected negative effects of ApoE ε4 on GM volume and WM integrity.
Methods Participants All participants (n = 62) with SMI were recruited from the Memory impairment clinic cohort of Pusan National University Hospital in Korea from November 2011 to December 2012. Written informed consents were obtained from all participants, and this study was approved by the Pusan National University Hospital Institutional Review Board. All participants were right-handed and underwent MR scans of T1-weighted images (T1WI) and DTI. ApoE genotyping was performed using the restriction enzyme isoform genotyping method as previously described.14 The inclusion criteria for SMI were as follows: (1) sustained subjective memory complaints; (2) normal general cognition (within –1.5 SD of age- and education-adjusted norms on the Korean version of the Mini-Mental State Examination [K-MMSE]15 and a score higher than 25); (3) normal activities of daily living (ADL) as judged by both an interview with a clinician and the standardized ADL scale; and (4) no abnormality (within –1.5 SD of age- and education-adjusted norms) on a comprehensive neuropsychological battery. We applied the following exclusion criteria to all subjects: (1) other neurodegenerative diseases; (2) major depressive disorder or other psychiatric illness; (3) intracranial space occupying lesion; (4) aphasia or other language barrier; (5) MRI contraindications or known claustrophobia; (6) active substance abuse disorders; (7) severe systemic disease; (8) prominent visual or hearing impairment. We also excluded participants with moderate or severe WMH on brain MRI to minimize the vascular etiologic impact on SMI. The presence of moderate or severe WMH was defined as WMH on fluid-attenuated inversion recovery (FLAIR) images that fulfilled the following criteria: (1) periventricular WMH (caps or rim) longer than 5 mm, and (2) deep WMH consistent with extensive WM lesion or with diffusely confluent lesion ࣙ10 mm in maximum diameter. Eleven subjects out of all participants (n = 62) were excluded because eight subjects have moderate or severe WMH and three subjects have brain infarction on brain MRI. Among the rest of the participants (n = 51), for the analysis of this study, 13 subjects who were heterozygote for ApoE4 (ε3/ε4) were included into the ApoE ε4 carriers. 13 subjects, matched for age, gender, and education who were ε4 negative (ε3/ε3), were included into the ApoE ε4 noncarriers. This left a final group of 26 subjects with SMI.
Clinical Evaluation All patients underwent a comprehensive evaluation consisting of the following assessments: history taking from the patient and informant; medical and neurological examinations; K-MMSE15 for global cognitive evaluation; Geriatric Depression Scales (GDS)16 for the severity of depressive symptoms.
We also used the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-K)17 as comprehensive neuropsychological battery to examine the functional capacity of several cognitive domains: (1) memory (word list recall); (2) language (the Korean version of the Boston Naming Test [K-BNT]); and (3) visuospatial function (constructional apraxia). We also used the Korean version of the Frontal Assessment Battery (FAB-K)18 to examine the frontal or executive function: the FAB-K was known as a valid and reliable instrument for evaluating frontal lobe function in the elderly. We used Seoul instrumental activities of daily living (SIADL)19 which was validated in Korea as the standardized ADL scale. The SIADL consist of 15 items that address an individual’s ability to engage in more complex tasks, such as shopping or using the telephone, and impairment severity is scored from 1 (no impairment) to 3 for all items. Thus, the maximum score of SIADL is 45 and scores of ࣘ 7 indicate normal complex ADL.
Imaging Data Acquisition All participants underwent MR scans of T1WI and DTI on a Siemens (Erlangen, Germany) Trio TIM 3T scanner. T1WI were acquired using a 3D magnetization prepared rapid gradient echo (3D MP-RAGE) sequence with following parameters: repetition time (TR) = 1,800 ms, echo time (TE) = 2.07 ms, inversion time (TI) = 900 ms, flip angle = 12°, acquisition matrix = 256 × 256, field of view (FOV) = 250 × 250 mm2 , slice thickness = 1 mm, total number of slices = 256. DTI were acquired with the following echo planar acquisition parameters: diffusion-weighted gradients applied in 30 nonlinear directions, number of average = 2, TR = 6,200 ms, TE = 85 ms, flip angle = 90°, acquisition matrix = 128 × 128, FOV = 230 × 230 mm2 , slice thickness = 3 mm, b = 600 s/mm2 . All image acquisitions were ensured the same slice orientation paralleled to the anterior commissure and posterior commissure line.
MRI Data Analysis Image Preprocessing for VBM
The VBM 8 toolbox (http://dbm.neuro.uni-jena.de/vbm) which is incorporated in statistical parametric mapping 8 (SPM8, http://www.fil.ion.ucl.ac.uk/spm)20 was used to perform the analysis of brain structural imaging. In this process, all images were spatially normalized using combinations of affine linear transform and nonlinear registration to the standard MNI template (Montreal Neurological Institute) and segmented into GM, WM, and cerebrospinal fluid (CSF).21 Segmented GM images were modulated to compensate the volumetric effects of expansion or shrinking employed in spatial normalization by multiplying the voxel intensity with the Jacobian determinants reflecting the parameters for fitting a voxel in native space to corresponding voxel in template space. The modulated images were then smoothed with an 8-mm full width half maximum isotropic Gaussian kernel. Image Preprocessing for DTI
DTI were entirely processed with FMRIB Software Library (FSL, http://www.fmrib.ox.ac.uk/fsl) package.22 Image distortions induced by the effects of head movement and eddy currents was corrected by applying an affine alignment of diffusion-weighted images applied in different gradient Lee et al: ApoE ε4 and SMI
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Table 1. Demographic and Clinical Characteristics of All Participants with SMI
Age (years) Gender (female), N (%) Education (years) K-MMSE GDS CERAD-K Boston naming test Constructional apraxia Word list recall FAB SIADL
ApoE ε4 Carriers (N = 13)
ApoE ε4 Noncarriers (N = 13)
P Value
66.36 ± 6.34 7 (53.8) 9.73 ± 2.76 27.18 ± 1.88 11.36 ± 6.34
66.18 ± 7.83 7 (53.8) 8.45 ± 5.33 26.42 ± 2.48 14.27 ± 9.05
.953 1.000 .490 .249 .394
± ± ± ± ±
.526 .515 .382 .643 .740
10.54 9.63 4.54 13.45 3.18
± ± ± ± ±
1.36 1.50 1.43 2.54 2.31
10.18 9.18 5.27 13.81 3.36
2.13 1.72 2.10 2.96 2.69
Data are N (%) or means ± SD. SMI = subjective memory impairment; ApoE ε4 = Apolipoprotein E4; K-MMSE = Korean version of the Mini-Mental State Examination; GDS = Geriatric Depression Scale; CERAD-K = Korean version of Consortium to Establish a Registry for Alzheimer’s disease; FAB = Frontal Assessment Battery; SIADL = SeoulInstrumental Activities of Daily Living.
Table 2. Regions of Gray Matter Atrophy in ApoE ε4 Carriers Compared to Noncarriers in SMI on VBM Analysis (P < .001, Uncorrected for Multiple Comparisons, Extent Threshold = 20 Voxel) MNI Coordinates (mm) Anatomical Region
Inferior temporal gyrus Inferior parietal lobule Anterior cingulum Middle frontal gyrus Precentral gyrus
Side
x
y
z
T Value
R R R L L
48 33 1 −16 −37
−48 −43 50 6 −9
−15 48 11 63 54
4.62 4.05 4.03 4.03 3.83
ApoE ε4 = Apolipoprotein E4; SMI = subjective memory impairment; VBM = voxel-based morphometry; MNI = Montreal Neurological Institute; L = left; R = right.
directions to nondiffusion-weighted image. After stripping the skull using brain extraction tool, diffusion tensor was calculated at each voxel and then fractional anisotropy (FA) was generated using Functional MRI of the Brain (fMRIB) diffusion toolbox.22 Voxel-wise statistical analysis of these DTI parameters was performed using tract-based spatial statistics (TBSS) v1.2.23,24 First, all individual FA images were nonlinearly aligned to FA template in 1 × 1 × 1 mm3 MNI space using FMRIB’s nonlinear registration tool.22 Second, aligned images were averaged and thinned to identify the mean FA skeleton represented as the center of common WM tracts.23 Third, mean FA skeleton was restricted with the thresholds .2 to exclude the voxels of GM, CSF in skeleton. All subject’s aligned FA images were projected onto the mean skeleton tracks and the resulting data fed into voxel-wise across subject statistics. The registration and projection vectors derived from DTI-FA processing were applied to other DTI parameters.
Statistical Analyses Pearson’s χ 2 for categorical data and Mann-Whitney U test for continuous variables were used to evaluate differences in demographic or clinical characteristics between ApoE ε4 carriers 146
and noncarriers in SMI using Statistical Package for the Social Sciences (SPSS) version 15.0. The VBM results were analyzed with using independent two-sample t-test with general linear model (GLM). Age, gender, and education were used as covariates to control these confusing factors. We also included GDS as covariates because depressive symptoms may affect cognitive symptoms of SMI and in this study, the subjects with SMI had comparatively high depressive symptoms. Statistical significant level was considered at P ࣘ .001 uncorrected at voxel level with the extent threshold of contiguous 20 voxels. Voxel-wise differences of DTI parameters were statistically analyzed by independent two-sample t-test with the GLM design controlling the effects of age, gender, education, and GDS as nuisance variables, setting the number of permutations at 5,000 based on the threshold-free cluster enhancement using randomize tools in FSL and take into account results to be significant at P < .05 with correction for multiple comparisons.25 Statistical power that is given in this study samples was 80% power.
Results Demographic or Clinical Characteristics Table 1 shows age, gender, educational level, K-MMSE, GDS, SIADL, and CERAD-K. No significant differences in demographic or clinical data were found between the ApoE ε4 carriers and the noncarriers.
VBM Analysis Table 2 describes the anatomical areas and T value for significantly different GM volumes between the ApoE ε4 carriers and the noncarriers (uncorrected P ࣘ .001, extent threshold = 20 voxel). ApoE ε4 carriers compared with noncarriers showed the atrophy of GM in inferior temporal gyrus, inferior parietal lobule, anterior cingulum, middle frontal gyrus, and precentral gyrus (Fig 1). No suprathreshold clusters of increased areas were found in ApoE ε4 carriers with respect to noncarriers.
TBSS Analysis Table 3 summarizes the results of DTI parameter maps within the maximum statistical thresholds. FA was significantly lowered (P < .05) in anterior corona radiata and splenium of corpus callosum in the ApoE ε4 carriers as compared to noncarriers (Fig 2).
Discussion We investigated the effect of the ApoE ε4 on GM volume and WM integrity in SMI without WMH, and found the ApoE ε4 is associated with both atrophy of GM volume and disruption of WM integrity in SMI without WMH. In more detail, we found that the ApoE ε4 carriers compared with noncarriers show the atrophy of GM in inferior temporal gyrus, inferior parietal lobule, anterior cingulum, middle frontal gyrus, and precentral gyrus (uncorrected P < .001, extent threshold = 20 voxel). Previous many studies have reported that the ApoE ε4 carriers compared with noncarriers show atrophy of hippocampus or other GM in AD.9,26–28 These results of dementia subjects are in overall agreement with our
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Fig 1. The results of voxel-based morphometry analysis showing the decreased gray matter volumes in ApoE ε4 carriers compared to noncarriers in subjective memory impairment without white matter hyperintensities (P < .001, uncorrected for multiple comparisons, extent threshold = 20 voxel). Table 3. Regions Showing Lower Degree of FA in ApoE ε4 Carriers Compared to Noncarriers in SMI on TBSS Analysis (P < .05 FDR Corrected with Multiple Comparisons, k > 100) MNI Coordinates (mm) Anatomical Region
Anterior corona radiata Splenium of corpus callosum
Side
Peak α -Value
x
y
z
Cluster Size (mm3 )
L
.97
106
155
60
4,745
R
.952
67
77
81
286
FA = fraction anisotropy; ApoE ε4 = Apolipoprotein E4; SMI = subjective memory impairment; TBSS = tract-based spatial statistics; FDR = false discovery rate; MNI = Montreal Neurological Institute; L = left; R = right.
results. However, in studies of nondemented subjects, results have been mixed.29–31 For instances, Jack et al29 investigated the association between hippocampal volume and ApoE polymorphisms in 125 elderly healthy subjects. They found that hippocampal volumes did not differ significantly on the basis of ApoE genotype, neither did the study by Schmidt et al,30 which investigated hippocampal and parahippocampal volumes in subjects with normal cognition. In contrast to these negative findings, Plassman et al31 studied the association of ApoE ε4, hippocampal volume, and cognitive performance in 10 pairs of cognitively normal twins. They found that hippocampal volumes were smaller in ApoE ε4 carriers compared to noncarriers, despite the fact that the two groups did not differ in performance on neuropsychological test. Further studies
should be needed to clarify effect of ApoE ε4 on GM volume in SMI. We also found significantly reduced FA values in the ApoE ε4 carriers as compared to the noncarriers in the splenium of corpus callosum and anterior corona radiata, suggesting that the presence of ApoE ε4 may influence WM integrity before the onset of AD. These findings are in line with previous observations in healthy subjects8,32–34 and AD.9 Bhavani et al9 reported the impaired WM integrity in ApoE ε4 carriers. AD subjects were predominantly in the dominant cortex with involvement of the medial temporal lobe and limbic regions. Recent studies of healthy aging groups also showed that ApoE ε4 was associated with the impaired WM integrity in parahippocampal WM,8,32 and the corpus callosum.33,34 Braak and Braak35 have suggested that cognitive decline in AD is related to myelinopathy. ApoE ε4 could disrupt myelin sheath building or reduce the normal clearance of b-amyloid peptides. Considering SMI is a risk factor for AD, disruption of WM integrity, caused by loss of the normal structure of myelin by ApoE ε4, may affect cognitive decline in SMI. The results in this study have several limitations to be interpreted with caution. First, this study was limited by a relatively small sample size. Second, due to small sample size, uncorrected (P < .001) threshold at voxel level with the extent threshold of contiguous 20 voxels was applied to identify the atrophy of GM in the VBM analysis, instead of the correction for family-wise error or false discovery rate (FDR) corrected (P < .05) thresholds. This suggest that type I error may be higher in this study. Third, we considered isolated effects of ApoE ε4 allele on GM and WM in SMI. But, there might be other genes in linkage disequilibrium with ApoE ε4 that might affect Lee et al: ApoE ε4 and SMI
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Fig 2. The results of TBSS with mean FA skeleton (green) and significant regions (red) on a T1 template image in comparison between ApoE ε4 carriers and noncarriers among patients with SMI (P corrected < .05).
WM structure. For instance, APOC1 which is in strict linkage disequilibrium with ApoE ε4 plays an independent role in AD risk.36 Therefore, further studies with a larger sample size would be needed to investigate the contribution of other genes to brain structure. In conclusion, this study shows that the ApoE ε4 is associated with both atrophy of GM volume and disruption of WM integrity in SMI without WMH. This study was supported by Biomedical Research Institute Grant (2014–16), Pusan National University Hospital.
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