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Effects of APOE ɛ4 on brain amyloid, lacunar infarcts, and white matter lesions: a study among patients with subcortical vascular cognitive impairment
Neurobiology of Aging 34 (2013) 2482e2487
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Effects of APOE ε4 on brain amyloid, lacunar infarcts, and white matter lesions: a study among patients with subcortical vascular cognitive impairment Hee Jin Kim a, Byoung Seok Ye a, Cindy W. Yoon b, Hanna Cho a, Young Noh c, Geon Ha Kim a, d, Yae Seul Choi a, Jung-Hyun Kim a, Seun Jeon e, Jong Min Lee e, Jae Seung Kim f, Yearn Seong Choe g, Kyung Han Lee g, Sung Tae Kim h, Changsoo Kim i, Dae Ryong Kang i, Chang-Seok Ki j, Jae Hong Lee k, David J. Werring l, Michael W. Weiner m, Duk L. Na a, Sang Won Seo a, * a
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Department of Neurology, Inha University College of Medicine, Korea c Department of Neurology, Gachon University Gil Medical Center, Incheon, Korea d Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea e Department of Biomedical Engineering, Hanyang University, Seoul, Korea f Department of Nuclear Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea g Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea h Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea i Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea j Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea k Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea l Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK m Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, California, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 December 2012 Received in revised form 22 April 2013 Accepted 8 May 2013 Available online 12 June 2013
The relationship between the apolipoprotein E ε4 allele (APOE4) and factors associated with vascular cognitive impairment (VCI) is unclear. We aimed to examine the effects of APOE4 on brain amyloid beta using Pittsburg compound B (PiB) and subcortical cerebrovascular disease, as assessed by lacunes and white matter hyperintensities (WMH) in subcortical VCI (SVCI) patients. We recruited 230 subjects with normal cognition, 111 subjects with cognitive impairment due to clinically defined Alzheimer’s disease (ADCI), and 134 subjects with clinically defined SVCI. A PiB retention ratio greater than 1.5 was considered to be PiB positive. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each cognitive impairment group. Multiple linear regression analysis was performed to investigate whether APOE4 was associated with brain amyloid beta, lacunes, and WMH. APOE4 did not increase the risk of PiB() SVCI (odds ratio [OR], 1.50; 95% confidence interval [CI], 0.79e2.84), whereas APOE4 increased the risk of PiB(þ) SVCI (OR, 4.52; 95% CI, 1.70e11.97) and PiB(þ) ADCI (odds ratio, 4.84; 95% CI, 2.54e7.91). In SVCI patients, APOE4 was positively associated with PiB retention ratio, whereas APOE4 was not associated with the number of lacunes or with WMH volume. Our results suggest that amyloid beta burden can occur in patients with and without subcortical cerebrovascular disease, and that it is associated with APOE4. However APOE4 might be independent of subcortical cerebrovascular disease. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Subcortical vascular cognitive impairment APOE White matter hyperintensity Lacune Amyloid beta burden
1. Introduction Subcortical vascular cognitive impairment (SVCI) refers to cognitive impairment due to subcortical cerebrovascular disease; * Corresponding author at: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel.: þ82-2-3410-1233; fax: þ82-2-3410-0052. E-mail address: [email protected] (S.W. Seo). 0197-4580/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.05.009
when sufficiently severe, such impairment is termed subcortical vascular dementia (SVaD). It is characterized by extensive white matter hyperintensities (WMH) and multiple lacunes on magnetic resonance imaging (MRI). However, pathological studies have suggested that patients clinically diagnosed with SVaD often have co-associated Alzheimer’s disease (AD) pathology (Jagust et al., 2008; Lim et al., 1999). It is well established that the apolipoprotein E epsilon 4 allele (APOE4) is an important risk factor in the development of AD
H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487
(Corder et al., 1993). APOE4 is associated with earlier age of onset of AD (Corder et al., 1993) and with increased amounts of brain amyloid beta (Ab) at any given age, measured with amyloid PET imaging (Drzezga et al., 2009). Furthermore, APOE4 is positively associated with vascular risk factors such as dyslipidemia and atherogenesis (Altamura et al., 2007; Lahoz et al., 2001), coronary atherosclerosis (Graner et al., 2008), and poor neuropsychological outcomes after subarachnoid hemorrhage (Martinez-Gonzalez and Sudlow, 2006). Recent studies have suggested that the APOE4 might contribute to increased risk of VaD (Chuang et al., 2010; Davidson et al., 2006). However, it is possible that the increased risk of VaD may be due to increased risk for the development of AD pathology, and not an increased risk of brain damage due to subcortical cerebrovascular disease. A previous study using Pittsburgh compound-B (PiB) PET, a sensitive method to detect brain Ab deposition (Klunk et al., 2004), showed that more than 30% of SVaD patients had significant Ab burden, representing AD pathology (Lee et al., 2011). However, the relationship between APOE4 and Ab burden in patients with SVCI has not previously been evaluated. We hypothesized that APOE4 genotype would be associated with increased risk of Ab burden (measured with PiB) in patients with SVCI. A preclinical study demonstrated that subcortical cerebrovascular disease may result in Ab accumulation in the brain through blockage of Ab clearance (Garcia-Alloza et al., 2011). This suggests that subcortical cerebrovascular disease might increase risk of Ab burden. This leads to the second hypothesis, namely, that the relationship between APOE4 and Ab burden might be weaker in patients with SVCI than in patients with cognitive impairment due to AD (ADCI), because some of the Ab burden in SVCI might result from mechanisms unrelated to APOE status.
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2011. Probable AD dementia patients fulfilled the criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 1984). Patients with SVaD met the diagnostic criteria for vascular dementia as determined by the Diagnostic and Statistical Manual of Mental DisorderseFourth Edition (DSM-IV), and the imaging criteria for SVaD proposed by Erkinjuntti et al. (Erkinjuntti et al., 2000). The amnestic MCI and subcortical vascular MCI patients met Petersen’s criteria (Petersen et al., 1999) for MCI with modifications as described previously (Seo et al., 2007). All subcortical vascular MCI and SVaD patients had subcortical vascular features, defined as focal neurological symptoms or signs suggestive of cerebrovascular disease, and severe WMH on their MRI scans. Severe WMH was defined as a cap or band (periventrivular WMH) 10 mm and deep white matter lesions (deep WMH) 25 mm, as modified from Fazekas’ ischemia criteria and as described in previous studies (Fazekas et al., 1987; Seo et al., 2009). The MRI findings of each patient with clinically diagnosed as SVCI are shown in the Supplementary Fig. 1. All amnestic MCI and AD were classified as having minimal (periventricular WMH <5 mm and deep WMH <5 mm) or moderate WMH (between minimal and severe grades). We excluded patients with territorial cortical infarctions and those with WMH resulting from radiation injury, multiple sclerosis, vasculitis, or leukodystrophy. All patients completed a clinical interview and neurological examination, as described previously (Lee et al., 2011). Blood tests included a complete blood count, blood chemistry test, vitamin B12/ folate measurements, syphilis serology, thyroid function test, and APOE genotyping. For the APOE genotype analyses, we enrolled a normal cognition (NC) group of 230 elderly subjects who had visited Samsung Medical Center during the same period as the patient group. Normal cognition was confirmed by extensive neuropsychological testing as described below (Ahn et al., 2010; Kang and Na, 2003).
2. Methods 2.1. Participants
2.2. Patient classification We prospectively recruited 252 subjects with cognitive impairment who underwent standardized PiB-PET and brain MRI; these comprised 46 patients with amnestic mild cognitive impairment (MCI), 69 with probable AD dementia, 67 with subcortical vascular MCI, and 70 with SVaD, all of whom had been clinically diagnosed at Samsung Medical Center between September 2008 and May
Subjects who were clinically diagnosed with either amnestic MCI or dementia with AD were grouped together as ADCI. Subjects who were clinically diagnosed with either subcortical vascular MCI or SVaD were grouped together as SVCI. Patients were considered to be PiB positive if their global PiB retention ratio was 2 standard
Table 1 Characteristics of subjects with cognitive impairment and normal cognition NC
Patients (n) Demographics Age (y) Male:female, n Education (y) MCI: dementia, n MMSE Chronic disease, n (%) Hypertension Diabetes Hyperlipidemia MRI markers WMH, mL Lacunes, n PiB PET PiB retention ratio
230
SVCI
ADCI
Clinically defined
PiB(þ)
PiB()
Clinically defined
PiB(þ)
134
45
89
111
86
a
a
a
25
28.6 1.7
73.8 7.0 53:81a 9.0 5.3a 67:67 23.4 4.9a
77.5 5.3 16:29 9.6 5.7a 22:23 22.0 5.5a
72.0 7.0 37:52a 8.7 5.0a 45:44 24.1 4.4a
70.3 8.8 25:86a 11.3 5.3 44:67 21.5 6.0a
69.8 9.1 13:49a 11.4 5.1 26:60 20.4 6.0a
72.2 7.6a 11:14 10.9 6.2 18:7 25.7 3.3a
73 (31.7) 60 (26.1) 74 (32.2)
102 (76.1)a 34 (25.4) 45 (33.6)
30 (66.7)a 11 (24.4) 12 (26.7)
72 (80.9)a 23 (25.8) 33 (37.1)
52 (46.8)a 16 (14.4)a 26 (23.4)
37 (43.0) 10 (11.6)a 21 (24.4)
15 (60.0)a 6 (24.0) 5 (20.0)
39.1 18.4 11.6 13.6
41.3 21.0 6.4 7.2
37.9 16.9 14.2 15.3
4.9 6.8 0.5 1.6
5.3 7.4 0.3 0.9
3.4 3.3 1.1 3.0
1.5 0.4
2.1 0.3
1.2 0.1
2.0 0.5
2.3 0.3
1.3 0.1
65.1 7.7 50:131 11.5 4.9
a
PiB()
a
Data are presented as mean SD unless otherwise indicated. Key: ADCI, Alzheimer’s disease cognitive impairment; MCI, mild cognitive impairment; NC, normal cognition; PiB, Pittsburgh compound B; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PET, positon emission tomography; SVCI, subcortical vascular cognitive impairment; WMH, white matter hyperintensities. a p < 0.05; Student’s t test, Pearson’s c2 test, or Fisher’s exact test between NC and each of the cognitive impairment group.
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deviations (SUVR > 1.5) above the mean of the normal controls (Lee et al., 2011). We excluded 4 subjects with ADCI and 3 subjects with SVCI for whom APOE genotype data were not available. In summary, our final study cohort consisted of 230 subjects with NC and 245 subjects with cognitive impairment: 86 patients with PiB(þ) ADCI; 25 patients with PiB() ADCI; 45 patients with PiB(þ) SVCI; and 89 patients with PiB() SVCI. The demographic profiles of the patients and controls are shown in Table 1.
considered PiB(þ) if their global PiB retention ratio was >1.5 (Lee et al., 2011; Rowe et al., 2010). A voxel-based statistical analysis was performed using the Statistical Parametric Mapping program, version 2 (SPM2) and Matlab 6.5 for Windows (Math Works, Natick, MA), which are described in detail in the eMethods.
2.3. Neuropsychological tests
We obtained written consent from each patient, and the Institutional Review Board of Samsung Medical Center approved the study protocol.
All participants underwent neuropsychological tests using a standardized battery called the Seoul Neuropsychological Screening Battery (SNSB) (Ahn et al., 2010; Kang and Na, 2003). Activities of Daily Living scale, a modified version of Lawton’s Instrumental ADL (Lawton and Brody, 1969), was also completed. Based on subjects’ scores on these measures, they were classified into 3 categories: those who were cognitively normal, those with MCI, and those with dementia. 2.4. APOE genotyping Genomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification kit following the manufacturer’s instructions (Promega, Madison, WI). Two single nucleotide polymorphisms (SNP; rs429358 for codon 112 and rs7412 for codon 158) in the APOE gene were genotyped using TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA) on a 7500 Fast Real-Time PCR System (Applied Biosystems) according to the manufacturer’s instructions. 2.5. MRI techniques T2, T1, FLAIR, and T2 Fast Field Echo (FFE) MR images were acquired for all subjects at Samsung Medical Center using the same 3.0 T MRI scanner (Philips 3.0T Achieva, Eindhoven, Netherlands). The methods of MRI techniques and measurement of lacunes and WMH volume on MRI are described in detail in the eMethods. We quantified WMH volume (in milliliters) on FLAIR images using an automated method. 2.6. [11C] PiB-PET acquisition and analysis All patients completed the [11C] PiB-PET scan at Samsung or Asan Medical Center. The methods of PiB-PET acquisition and analysis are described in detail in the eMethods. To measure PiB retention, we used the cerebral cortical region to cerebellum uptake ratio, which is identical to the standardized uptake value ratios (SUVRs). The cerebellum was used as a reference region as it did not show group differences. Patients were classified as PiB(þ) or PiB() according to measured global PiB retention ratio. Patients were
2.7. Standard protocol approval, registration, and patient consent
2.8. Statistical analysis First, we used Student’s t test, Pearson’s c2 test, or Fisher’s exact test to compare general characteristics between NC and each of the cognitive impairment groups (ex, NC vs. clinically defined SVCI, NC vs. PiB(þ) SVCI, NC vs. PiB() SVCI). Second, Multiple logistic regression analysis was performed to evaluate the effect of APOE4 (carrier vs. non-carriers) on the risk of cognitive impairment in NC and each of the cognitive impairment group after adjustment for age, gender, education level, hypertension, diabetes, and hyperlipidemia. In each SVCI and ADCI group, the relationship of APOE4 to PiB retention ratio, number of lacunes, and WMH volume was examined using multiple linear regression analysis after adjustment for age, gender, education level, hypertension, diabetes, and hyperlipidemia. To evaluate whether there was an interactive effect of APOE4 and group (SVCI vs. ADCI) on PiB retention ratio, multiple linear regression was performed in the SVCI and ADCI subjects. We had age, gender, education level, hypertension, diabetes, hyperlipidemia, APOE4, group, and the interaction terms (APOE4 * group) as an independent variable and PiB retention ratio as a dependent variable. All analyses were performed with PASW Statistics 17 software (SPSS Inc, Chicago, IL). To examine the distribution of PiB retention in APOE4 carriers as compared to non-carriers, an SPM regression analysis was performed after adjusting for age, gender, education level, hypertension, diabetes, and hyperlipidemia. To evaluate whether there was an interactive effect of APOE4 and group (SVCI vs. ADCI) on the distribution of PiB retention, multiple linear regression was performed in the SVCI and ADCI subjects after additionally adjusting for APOE4 and group in the previous model. We defined statistical significance as p < 0.05 corrected for the false discovery rate (FDR). 3. Results 3.1. Participant demographics Characteristics of the study participants are shown in Table 1. In all, 86 (77.5%) of 111 patients with clinically defined ADCI (59.1% of
Table 2 APOE genotype frequencies by group
Patients, n APOE4 non-carrier APOE4 carrier Heterozygote (ε4/e) Homozygote (ε4/ε4)
NC
SVCI Clinically defined
PiB(þ)
PiB()
Clinically defined
PiB(þ)
PiB()
230 181 49 44 5
134 99 (73.9) 35 (26.1) 32 (23.9) 3 (2.2)
45 25 20 17 3
89 74 15 15 0
111 59 (53.2) 52 (46.8)a 39 (35.1) 13 (11.7)
86 37 49 36 13
25 22 3 3 0
(78.7) (21.3) (19.1) (2.2)
ADCI
(55.6) (44.4)a (37.8) (6.7)
(83.1) (16.9) (16.9) (0.0)
(43.0) (57.0)a (41.9) (15.1)
Data are presented as n (%) Key: ADCI, Alzheimer’s disease cognitive impairment; APOE4, Apolipoprotein E ε4 allele; NC, normal cognition; SVCI, subcortical vascular cognitive impairment. a p < 0.001 (Student’s t test between NC and each of the cognitive impairment groups).
(88.0) (12.0) (12.0) (0.0)
H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487 Table 3 Odds ratios of cognitive impairment among APOE4 carriers as compared with noncarriers
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carriers, as compared to APOE4 non-carriers. Since there were only 3 APOE4 carriers among 25 PiB() ADCI patients, logistic regression was not performed in PiB() ADCI patients.
NC vs. SVCI Clinically defined SVCI
PiB(þ) SVCI
PiB() SVCI
n
n
n
OR (95% CI)
OR (95% CI)
OR (95% CI)
Non-carrier 99 Ref 25 Ref 74 Ref Carrier 35 1.50 (0.79e2.84) 20 4.52 (1.70e11.97) 15 0.96 (0.45e2.07) p 0.214 0.002 0.915 NC vs. ADCI
Non-carrier Carrier p
3.3. Association between APOE4 and PiB retention ratio, lacunes, or WMH in clinically defined SVCI and ADCI groups
Clinically defined ADCI
PiB(þ) ADCI
n
OR (95% CI)
n
OR (95% CI)
59 52
Ref 2.95 (1.73e5.01) <0.001
37 49
Ref 4.84 (2.54e7.91) <0.001
Adjusted for age, gender, education level, hypertension, diabetes, and hyperlipidemia. Because the frequency of APOE4 carriers in PiB() ADCI patients was too low to perform statistical analysis, the data are not shown in the above table. Key: APOE4, apolipoprotein E ε4 allele; ADCI, Alzheimer’s disease cognitive impairment; CI, confidence interval; OR, odds ratio; PiB, Pittsburgh compound B; Ref, reference; SVCI, subcortical vascular cognitive impairment.
amnestic MCI and 89.6% of probable AD dementia) were PiB(þ) and 45 (33.6%) of 134 patients with clinically defined SVCI (32.8% of subcortical vascular MCI and 34.3% of SVaD) were PiB(þ). 3.2. APOE4 and risk of groups with cognitive impairment compared to NC
Regarding the association of APOE4 and cerebrovascular disease, there was no association between APOE4 and WMH volume (b [SE] ¼ 0.095 [3.720], p ¼ 0.980 in clinically defined SVCI; b [SE] ¼ 2.133 [1.254], p ¼ 0.092 in clinically defined ADCI). APOE4 did not show significant association with lacunes in clinically defined SVCI (b [SE] ¼ 4.850 [2.536], p ¼ 0.058), whereas in clinically defined ADCI, APOE4 carriers showed significantly less lacunes than APOE4 non-carriers (b [SE] ¼ 0.719 [0.309], p ¼ 0.022). In contrast, APOE4 carriers had greater PiB retention ratio than APOE4 non-carriers in both clinically defined SVCI (b [SE] ¼ 0.237 [0.079], p ¼ 0.003) and clinically defined ADCI (b [SE] ¼ 0.420 [0.090], p < 0.001) patients (Fig. 1). There was no significant interactive effect of APOE4 and group (ADCI vs. SVCI) on PiB retention ratio (b [SE] ¼ 0.153 [0.122], p ¼ 0.211). Statistical parametric mapping showed that APOE4 carriers of clinically defined SVCI patients had stronger PiB retention in the bilateral frontal and temporoparietal cortices, and precuneus, as compared to APOE4 non-carriers. In clinically defined ADCI patients, a similar pattern was observed in more extensive areas (p < 0.05, FDR corrected) (Fig. 2). No interactive effect of APOE4 and group (SVCI vs. ADCI) on the distribution of PiB retention was observed. 4. Discussion
Compared to NC, APOE4 carriers were significantly more common in clinically defined ADCI (p < 0.001), PiB(þ) ADCI (p < 0.001), and PiB(þ) SVCI (p < 0.001) (Table 2). The associations between presence of APOE4 and the risk of each patient category compared to control subjects are shown in Table 3. The risk of clinically defined SVCI was not increased in APOE4 carriers. After stratification of clinically defined SVCI patients by PiB positivity, the risk of PiB(þ) SVCI was significantly increased in APOE4 carriers, as compared to APOE4 non-carriers. However, the risk of PiB() SVCI was not associated with APOE4. On the other hand, the risk of clinically defined ADCI was increased in APOE4 carriers, as compared to APOE4 non-carriers. After stratification of clinically defined ADCI patients by PiB positivity, the risk of PiB(þ) ADCI was significantly increased in APOE4
We determined the effects of APOE4 on the burden of Ab and subcortical cerebrovascular disease in a large cohort of carefully phenotyped patients with cognitive impairment using noninvasive amyloid imaging and structural MRI to assess markers of subcortical cerebrovascular disease. Our major findings were as follows. First, Ab deposition can occur in patients with and without subcortical cerebrovascular disease, and is associated with APOE4. Second, APOE4 might be independent of subcortical cerebrovascular disease. The first major findings are that Ab deposition can occur in patients with and without subcortical cerebrovascular disease, and that this deposition is associated with APOE4. The frequencies of PiB positivity in ADCI and SVCI were 77.5% and 33.6%, respectively,
Fig. 1. Association between APOE4 and PiB retention ratio in clinically defined SVCI and ADCI groupa. APOE4 carriers had greater PiB retention ratio in both SVCI (b (SE) ¼ 0.237 (0.079), p ¼ 0.003) and ADCI (b (SE) ¼ 0.420 (0.090), p < 0.001) patients. aMultiple linear regression analysis. Potential confounders such as age, gender, education level, hypertension, diabetes, and hyperlipidemia were included.
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Fig. 2. Association between APOE4 and PiB retention. Statistical parametric mapping showed that in clinically defined SVCI patients, APOE4 carriers had stronger PiB retention in the bilateral frontal and temporoparietal cortices, and precuneus. In clinically defined ADCI patients, similar pattern was observed in more extensive areas (p < 0.05, FDR corrected).
which were consistent with previous studies (Klunk et al., 2004; Lee et al., 2011; Wolk et al., 2009). Our findings that APOE4 affects Ab burden in patients with and without subcortical cerebrovascular disease is supported by the following observations: first, the odds ratio of PiB(þ) SVCI in APOE4 carriers as compared to APOE4 noncarriers was similar to that of PiB(þ) ADCI; second, both SVCI and ADCI patients showed that APOE4 was associated with PiB retention ratio. Furthermore, there were no differences in the effects of APOE4 on Ab burden between patients with and without subcortical cerebrovascular disease, as there was no significant interactive effect of APOE4 and group (SVCI vs. ADCI) on the amount or distribution of PiB retention. Therefore, these findings do not support our hypothesis that the relationship between APOE4 and Ab burden is weaker in patients with SVCI than in patients with ADCI. On the contrary, our results suggest that subcortical cerebrovascular disease does not modify the relationship between APOE4 and Ab burden. The second major finding of our study was that APOE4 might to be independent of subcortical cerebrovascular disease. There was no significant difference in the frequency of APOE4 between NC and PiB() SVCI patients, which implies that APOE4 does not increase the risk of “pure” SVCI, as demonstrated by PiB PET. In addition, APOE4 was not associated with the number of lacunes or with WMH volume in patients with SVCI. APOE4 is known to be an important risk factor in the development of AD (Corder et al., 1993). In addition, APOE4 is suggested to be associated with the following: cerebral amyloid angiopathy (Premkumar et al., 1996); dementia after traumatic brain injury (Katzman et al., 1996; Mayeux et al., 1995); Down’s syndromeeassociated dementia (Deb et al., 2000); Creutzfeldt-Jakob disease (Amouyel et al., 1994); multiple sclerosis (Fazekas et al., 2001; Hogh et al., 2000); younger age of onset of amyotrophic lateral sclerosis (Zetterberg et al., 2008); and dementia with Lewy bodies (Harrington et al., 1994; Tsuang et al., 2012). Concerning effects of APOE4 on vascular disease, there are reports of an association between APOE4 and large artery disease such as atherogenesis (Altamura et al., 2007; Lahoz et al., 2001), coronary atherosclerosis (Graner et al., 2008), and large artery ischemic stroke. Furthermore, several studies have reported that APOE4 increases the risk of VaD (Chuang et al., 2010; Davidson et al., 2006), but others reported no association (Hong et al., 2011; Sulkava et al., 1996). We suggest that this inconsistency may result in part from the possibility that the subjects in the previously reported studies may have included patients with mixed vascular
and coexistent AD (Jagust et al., 2008). Therefore, our findings suggest that the previously observed increased risk of clinically defined SVCI in APOE4 carriers is due to the effects of APOE4 on AD pathology. The strengths of our study are its prospective setting, use of standardized PiB-PET and MRI imaging protocols, and standardized phenotyping of cognitive impairment. However, several limitations of our study must also be acknowledged. First, PiB() SVCI may not necessarily indicate pure SVCI, because PiB imaging detects fibrillar Ab, but no soluble Ab, and provides no information on tangle pathology. Second, PiB(þ) SVCI patients were older than NC and ADCI patients. Therefore, it is possible that if we had recruited an older ADCI group, there would have been less frequent APOE4 carriers. Third, to determine the true causal relationship between APOE4 and subcortical cerebrovascular disease or Ab burden throughout the population, large population-based longitudinal studies are needed. Finally, it is possible that we could not find any statistically significant relation of APOE4 on the risk of PiB() SVCI or interactive effect of APOE4 and group on the amount or distribution of PiB retention because of the relatively small sample size. Further investigation with a larger sample size is necessary to confirm our results. Nonetheless, this is the first study to demonstrate that Ab deposition can occur in patients with and without subcortical cerebrovascular disease, and is associated with APOE4, whereas APOE4 is independent of subcortical cerebrovascular disease. Disclosure statement Dr Seo and Dr Na receive research support from the Ministry of Health and Welfare, Korea. Acknowledgements This study was supported by grants from the Korean Healthcare Technology R&D Project, the Ministry for Health, Welfare & Family Affairs, the Republic of Korea (nos. A102065 and A070001), by the Korean Science and Engineering Foundation (KOSEF) NRL program grant funded by the Korean government (MEST; 2011-0028333), by Samsung Medical Center Clinical Research Development Program grants (CRL-108011 and CRS 110-14-1), and by the Converging Research Center Program through the Ministry of Education, Science and Technology (2010K001054).
H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neurobiolaging. 2013.05.009. References Ahn, H.J., Chin, J., Park, A., Lee, B.H., Suh, M.K., Seo, S.W., Na, D.L., 2010. Seoul Neuropsychological Screening Batteryddementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients. J. Korean Med. Sci. 25, 1071e1076. Altamura, C., Squitti, R., Pasqualetti, P., Tibuzzi, F., Silvestrini, M., Ventriglia, M.C., Cassetta, E., Rossini, P.M., Vernieri, F., 2007. What is the relationship among atherosclerosis markers, apolipoprotein E polymorphism and dementia? Eur. J. Neurol. 14, 679e682. Amouyel, P., Vidal, O., Launay, J.M., Laplanche, J.L., 1994. The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. The French Research Group on Epidemiology of Human Spongiform Encephalopathies. Lancet 344, 1315e1318. Chuang, Y.F., Hayden, K.M., Norton, M.C., Tschanz, J., Breitner, J.C., WelshBohmer, K.A., Zandi, P.P., 2010. Association between APOE epsilon4 allele and vascular dementia: the Cache County study. Dement. Geriatr. Cogn. Disord. 29, 248e253. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A., 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921e923. Davidson, Y., Gibbons, L., Purandare, N., Byrne, J., Hardicre, J., Wren, J., Payton, A., Pendleton, N., Horan, M., Burns, A., Mann, D.M., 2006. Apolipoprotein E epsilon4 allele frequency in vascular dementia. Dement. Geriatr. Cogn. Disord. 22, 15e19. Deb, S., Braganza, J., Norton, N., Williams, H., Kehoe, P.G., Williams, J., Owen, M.J., 2000. APOE epsilon 4 influences the manifestation of Alzheimer’s disease in adults with Down’s syndrome. Br. J. Psychiatry 176, 468e472. Drzezga, A., Grimmer, T., Henriksen, G., Muhlau, M., Perneczky, R., Miederer, I., Praus, C., Sorg, C., Wohlschlager, A., Riemenschneider, M., Wester, H.J., Foerstl, H., Schwaiger, M., Kurz, A., 2009. Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72, 1487e1494. Erkinjuntti, T., Inzitari, D., Pantoni, L., Wallin, A., Scheltens, P., Rockwood, K., Roman, G.C., Chui, H., Desmond, D.W., 2000. Research criteria for subcortical vascular dementia in clinical trials. J. Neur. Transm. Suppl. 59, 23e30. Fazekas, F., Chawluk, J.B., Alavi, A., Hurtig, H.I., Zimmerman, R.A., 1987. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am. J. Roentgenol. 149, 351e356. Fazekas, F., Strasser-Fuchs, S., Kollegger, H., Berger, T., Kristoferitsch, W., Schmidt, H., Enzinger, C., Schiefermeier, M., Schwarz, C., Kornek, B., Reindl, M., Huber, K., Grass, R., Wimmer, G., Vass, K., Pfeiffer, K.H., Hartung, H.P., Schmidt, R., 2001. Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology 57, 853e857. Garcia-Alloza, M., Gregory, J., Kuchibhotla, K.V., Fine, S., Wei, Y., Ayata, C., Frosch, M.P., Greenberg, S.M., Bacskai, B.J., 2011. Cerebrovascular lesions induce transient beta-amyloid deposition. Brain 134, 3697e3707. Graner, M., Kahri, J., Varpula, M., Salonen, R.M., Nyyssonen, K., Jauhiainen, M., Nieminen, M.S., Syvanne, M., Taskinen, M.R., 2008. Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease. Nutr. Metab. Cardiovasc. Dis. 18, 271e277. Harrington, C.R., Louwagie, J., Rossau, R., Vanmechelen, E., Perry, R.H., Perry, E.K., Xuereb, J.H., Roth, M., Wischik, C.M., 1994. Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer’s disease. Am. J. Pathol. 145, 1472e1484. Hogh, P., Oturai, A., Schreiber, K., Blinkenberg, M., Jorgensen, O.S., Ryder, L., Paulson, O.B., Sorensen, P.S., Knudsen, G.M., 2000. Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate. Mult. Scler. 6, 226e230. Hong, Y.J., Yoon, B., Shim, Y.S., Cho, A.H., Shin, H.E., Kim, Y.I., Kim, S.Y., Yang, D.W., 2011. APOE epsilon4 allele status in korean dementia patients with severe white matter hyperintensities. J. Alzheimers Dis. 24, 519e524. Jagust, W.J., Zheng, L., Harvey, D.J., Mack, W.J., Vinters, H.V., Weiner, M.W., Ellis, W.G., Zarow, C., Mungas, D., Reed, B.R., Kramer, J.H., Schuff, N., DeCarli, C., Chui, H.C.,
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2008. Neuropathological basis of magnetic resonance images in aging and dementia. Ann. Neurol. 63, 72e80. Kang, Y., Na, D.L., 2003. Seoul Neuropsychological Screening Battery. Human Brain Research & Consulting Co., Incheon. Katzman, R., Galasko, D.R., Saitoh, T., Chen, X., Pay, M.M., Booth, A., Thomas, R.G., 1996. Apolipoprotein-epsilon4 and head trauma: synergistic or additive risks? Neurology 46, 889e891. Klunk, W.E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D.P., Bergstrom, M., Savitcheva, I., Huang, G.F., Estrada, S., Ausen, B., Debnath, M.L., Barletta, J., Price, J.C., Sandell, J., Lopresti, B.J., Wall, A., Koivisto, P., Antoni, G., Mathis, C.A., Langstrom, B., 2004. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann. Neurol. 55, 306e319. Lahoz, C., Schaefer, E.J., Cupples, L.A., Wilson, P.W., Levy, D., Osgood, D., Parpos, S., Pedro-Botet, J., Daly, J.A., Ordovas, J.M., 2001. Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis 154, 529e537. Lawton, M.P., Brody, E.M., 1969. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9, 179e186. Lee, J.H., Kim, S.H., Kim, G.H., Seo, S.W., Park, H.K., Oh, S.J., Kim, J.S., Cheong, H.K., Na, D.L., 2011. Identification of pure subcortical vascular dementia using 11CPittsburgh compound B. Neurology 77, 18e25. Lim, A., Tsuang, D., Kukull, W., Nochlin, D., Leverenz, J., McCormick, W., Bowen, J., Teri, L., Thompson, J., Peskind, E.R., Raskind, M., Larson, E.B., 1999. Cliniconeuropathological correlation of Alzheimer’s disease in a community-based case series. J. Am. Geriatr. Soc. 47, 564e569. Martinez-Gonzalez, N.A., Sudlow, C.L., 2006. Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage. J. Neurol. Neurosurg. Psychiatry. 77, 1329e1335. Mayeux, R., Ottman, R., Maestre, G., Ngai, C., Tang, M.X., Ginsberg, H., Chun, M., Tycko, B., Shelanski, M., 1995. Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology 45, 555e557. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939e944. Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik, R.J., Tangalos, E.G., Kokmen, E., 1999. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 56, 303e308. Premkumar, D.R., Cohen, D.L., Hedera, P., Friedland, R.P., Kalaria, R.N., 1996. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer’s disease. Am. J. Pathol. 148, 2083e2095. Rowe, C.C., Ellis, K.A., Rimajova, M., Bourgeat, P., Pike, K.E., Jones, G., Fripp, J., TochonDanguy, H., Morandeau, L., O'Keefe, G., Price, R., Raniga, P., Robins, P., Acosta, O., Lenzo, N., Szoeke, C., Salvado, O., Head, R., Martins, R., Masters, C.L., Ames, D., Villemagne, V.L., 2010. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol. Aging 31, 1275e1283. Seo, S.W., Cho, S.S., Park, A., Chin, J., Na, D.L., 2009. Subcortical vascular versus amnestic mild cognitive impairment: comparison of cerebral glucose metabolism. J. Neuroimaging. 19, 213e219. Seo, S.W., Im, K., Lee, J.M., Kim, Y.H., Kim, S.T., Kim, S.Y., Yang, D.W., Kim, S.I., Cho, Y.S., Na, D.L., 2007. Cortical thickness in single- versus multiple-domain amnestic mild cognitive impairment. Neuroimage 36, 289e297. Sulkava, R., Kainulainen, K., Verkkoniemi, A., Niinisto, L., Sobel, E., Davanipour, Z., Polvikoski, T., Haltia, M., Kontula, K., 1996. APOE alleles in Alzheimer’s disease and vascular dementia in a population aged 85þ. Neurobiol. Aging 17, 373e376. Tsuang, D., Leverenz, J.B., Lopez, O.L., Hamilton, R.L., Bennett, D.A., Schneider, J.A., Buchman, A.S., Larson, E.B., Crane, P.K., Kaye, J.A., Kramer, P., Woltjer, R., Trojanowski, J.Q., Weintraub, D., Chen-Plotkin, A.S., Irwin, D.J., Rick, J., Schellenberg, G.D., Watson, G.S., Kukull, W., Nelson, P.T., Jicha, G.A., Neltner, J.H., Galasko, D., Masliah, E., Quinn, J.F., Chung, K.A., Yearout, D., Mata, I.F., Wan, J.Y., Edwards, K.L., Montine, T.J., Zabetian, C.P., 2013. APOE epsilon 4 Increases Risk for Dementia in Pure Synucleinopathies. Jama Neurol 70, 223e228. Wolk, D.A., Price, J.C., Saxton, J.A., Snitz, B.E., James, J.A., Lopez, O.L., Aizenstein, H.J., Cohen, A.D., Weissfeld, L.A., Mathis, C.A., Klunk, W.E., De-Kosky, S.T., 2009. Amyloid imaging in mild cognitive impairment subtypes. Ann. Neurol. 65, 557e568. Zetterberg, H., Jacobsson, J., Rosengren, L., Blennow, K., Andersen, P.M., 2008. Association of APOE with age at onset of sporadic amyotrophic lateral sclerosis. J Neurol. Sci. 273, 67e69.
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Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Effects of APOE ε4 on brain amyloid, lacunar infarcts, and white matter lesions: a study among patients with subcortical vascular cognitive impairment Hee Jin Kim a, Byoung Seok Ye a, Cindy W. Yoon b, Hanna Cho a, Young Noh c, Geon Ha Kim a, d, Yae Seul Choi a, Jung-Hyun Kim a, Seun Jeon e, Jong Min Lee e, Jae Seung Kim f, Yearn Seong Choe g, Kyung Han Lee g, Sung Tae Kim h, Changsoo Kim i, Dae Ryong Kang i, Chang-Seok Ki j, Jae Hong Lee k, David J. Werring l, Michael W. Weiner m, Duk L. Na a, Sang Won Seo a, * a
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Department of Neurology, Inha University College of Medicine, Korea c Department of Neurology, Gachon University Gil Medical Center, Incheon, Korea d Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea e Department of Biomedical Engineering, Hanyang University, Seoul, Korea f Department of Nuclear Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea g Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea h Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea i Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea j Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea k Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea l Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK m Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, California, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 December 2012 Received in revised form 22 April 2013 Accepted 8 May 2013 Available online 12 June 2013
The relationship between the apolipoprotein E ε4 allele (APOE4) and factors associated with vascular cognitive impairment (VCI) is unclear. We aimed to examine the effects of APOE4 on brain amyloid beta using Pittsburg compound B (PiB) and subcortical cerebrovascular disease, as assessed by lacunes and white matter hyperintensities (WMH) in subcortical VCI (SVCI) patients. We recruited 230 subjects with normal cognition, 111 subjects with cognitive impairment due to clinically defined Alzheimer’s disease (ADCI), and 134 subjects with clinically defined SVCI. A PiB retention ratio greater than 1.5 was considered to be PiB positive. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each cognitive impairment group. Multiple linear regression analysis was performed to investigate whether APOE4 was associated with brain amyloid beta, lacunes, and WMH. APOE4 did not increase the risk of PiB() SVCI (odds ratio [OR], 1.50; 95% confidence interval [CI], 0.79e2.84), whereas APOE4 increased the risk of PiB(þ) SVCI (OR, 4.52; 95% CI, 1.70e11.97) and PiB(þ) ADCI (odds ratio, 4.84; 95% CI, 2.54e7.91). In SVCI patients, APOE4 was positively associated with PiB retention ratio, whereas APOE4 was not associated with the number of lacunes or with WMH volume. Our results suggest that amyloid beta burden can occur in patients with and without subcortical cerebrovascular disease, and that it is associated with APOE4. However APOE4 might be independent of subcortical cerebrovascular disease. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Subcortical vascular cognitive impairment APOE White matter hyperintensity Lacune Amyloid beta burden
1. Introduction Subcortical vascular cognitive impairment (SVCI) refers to cognitive impairment due to subcortical cerebrovascular disease; * Corresponding author at: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel.: þ82-2-3410-1233; fax: þ82-2-3410-0052. E-mail address: [email protected] (S.W. Seo). 0197-4580/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.05.009
when sufficiently severe, such impairment is termed subcortical vascular dementia (SVaD). It is characterized by extensive white matter hyperintensities (WMH) and multiple lacunes on magnetic resonance imaging (MRI). However, pathological studies have suggested that patients clinically diagnosed with SVaD often have co-associated Alzheimer’s disease (AD) pathology (Jagust et al., 2008; Lim et al., 1999). It is well established that the apolipoprotein E epsilon 4 allele (APOE4) is an important risk factor in the development of AD
H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487
(Corder et al., 1993). APOE4 is associated with earlier age of onset of AD (Corder et al., 1993) and with increased amounts of brain amyloid beta (Ab) at any given age, measured with amyloid PET imaging (Drzezga et al., 2009). Furthermore, APOE4 is positively associated with vascular risk factors such as dyslipidemia and atherogenesis (Altamura et al., 2007; Lahoz et al., 2001), coronary atherosclerosis (Graner et al., 2008), and poor neuropsychological outcomes after subarachnoid hemorrhage (Martinez-Gonzalez and Sudlow, 2006). Recent studies have suggested that the APOE4 might contribute to increased risk of VaD (Chuang et al., 2010; Davidson et al., 2006). However, it is possible that the increased risk of VaD may be due to increased risk for the development of AD pathology, and not an increased risk of brain damage due to subcortical cerebrovascular disease. A previous study using Pittsburgh compound-B (PiB) PET, a sensitive method to detect brain Ab deposition (Klunk et al., 2004), showed that more than 30% of SVaD patients had significant Ab burden, representing AD pathology (Lee et al., 2011). However, the relationship between APOE4 and Ab burden in patients with SVCI has not previously been evaluated. We hypothesized that APOE4 genotype would be associated with increased risk of Ab burden (measured with PiB) in patients with SVCI. A preclinical study demonstrated that subcortical cerebrovascular disease may result in Ab accumulation in the brain through blockage of Ab clearance (Garcia-Alloza et al., 2011). This suggests that subcortical cerebrovascular disease might increase risk of Ab burden. This leads to the second hypothesis, namely, that the relationship between APOE4 and Ab burden might be weaker in patients with SVCI than in patients with cognitive impairment due to AD (ADCI), because some of the Ab burden in SVCI might result from mechanisms unrelated to APOE status.
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2011. Probable AD dementia patients fulfilled the criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 1984). Patients with SVaD met the diagnostic criteria for vascular dementia as determined by the Diagnostic and Statistical Manual of Mental DisorderseFourth Edition (DSM-IV), and the imaging criteria for SVaD proposed by Erkinjuntti et al. (Erkinjuntti et al., 2000). The amnestic MCI and subcortical vascular MCI patients met Petersen’s criteria (Petersen et al., 1999) for MCI with modifications as described previously (Seo et al., 2007). All subcortical vascular MCI and SVaD patients had subcortical vascular features, defined as focal neurological symptoms or signs suggestive of cerebrovascular disease, and severe WMH on their MRI scans. Severe WMH was defined as a cap or band (periventrivular WMH) 10 mm and deep white matter lesions (deep WMH) 25 mm, as modified from Fazekas’ ischemia criteria and as described in previous studies (Fazekas et al., 1987; Seo et al., 2009). The MRI findings of each patient with clinically diagnosed as SVCI are shown in the Supplementary Fig. 1. All amnestic MCI and AD were classified as having minimal (periventricular WMH <5 mm and deep WMH <5 mm) or moderate WMH (between minimal and severe grades). We excluded patients with territorial cortical infarctions and those with WMH resulting from radiation injury, multiple sclerosis, vasculitis, or leukodystrophy. All patients completed a clinical interview and neurological examination, as described previously (Lee et al., 2011). Blood tests included a complete blood count, blood chemistry test, vitamin B12/ folate measurements, syphilis serology, thyroid function test, and APOE genotyping. For the APOE genotype analyses, we enrolled a normal cognition (NC) group of 230 elderly subjects who had visited Samsung Medical Center during the same period as the patient group. Normal cognition was confirmed by extensive neuropsychological testing as described below (Ahn et al., 2010; Kang and Na, 2003).
2. Methods 2.1. Participants
2.2. Patient classification We prospectively recruited 252 subjects with cognitive impairment who underwent standardized PiB-PET and brain MRI; these comprised 46 patients with amnestic mild cognitive impairment (MCI), 69 with probable AD dementia, 67 with subcortical vascular MCI, and 70 with SVaD, all of whom had been clinically diagnosed at Samsung Medical Center between September 2008 and May
Subjects who were clinically diagnosed with either amnestic MCI or dementia with AD were grouped together as ADCI. Subjects who were clinically diagnosed with either subcortical vascular MCI or SVaD were grouped together as SVCI. Patients were considered to be PiB positive if their global PiB retention ratio was 2 standard
Table 1 Characteristics of subjects with cognitive impairment and normal cognition NC
Patients (n) Demographics Age (y) Male:female, n Education (y) MCI: dementia, n MMSE Chronic disease, n (%) Hypertension Diabetes Hyperlipidemia MRI markers WMH, mL Lacunes, n PiB PET PiB retention ratio
230
SVCI
ADCI
Clinically defined
PiB(þ)
PiB()
Clinically defined
PiB(þ)
134
45
89
111
86
a
a
a
25
28.6 1.7
73.8 7.0 53:81a 9.0 5.3a 67:67 23.4 4.9a
77.5 5.3 16:29 9.6 5.7a 22:23 22.0 5.5a
72.0 7.0 37:52a 8.7 5.0a 45:44 24.1 4.4a
70.3 8.8 25:86a 11.3 5.3 44:67 21.5 6.0a
69.8 9.1 13:49a 11.4 5.1 26:60 20.4 6.0a
72.2 7.6a 11:14 10.9 6.2 18:7 25.7 3.3a
73 (31.7) 60 (26.1) 74 (32.2)
102 (76.1)a 34 (25.4) 45 (33.6)
30 (66.7)a 11 (24.4) 12 (26.7)
72 (80.9)a 23 (25.8) 33 (37.1)
52 (46.8)a 16 (14.4)a 26 (23.4)
37 (43.0) 10 (11.6)a 21 (24.4)
15 (60.0)a 6 (24.0) 5 (20.0)
39.1 18.4 11.6 13.6
41.3 21.0 6.4 7.2
37.9 16.9 14.2 15.3
4.9 6.8 0.5 1.6
5.3 7.4 0.3 0.9
3.4 3.3 1.1 3.0
1.5 0.4
2.1 0.3
1.2 0.1
2.0 0.5
2.3 0.3
1.3 0.1
65.1 7.7 50:131 11.5 4.9
a
PiB()
a
Data are presented as mean SD unless otherwise indicated. Key: ADCI, Alzheimer’s disease cognitive impairment; MCI, mild cognitive impairment; NC, normal cognition; PiB, Pittsburgh compound B; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PET, positon emission tomography; SVCI, subcortical vascular cognitive impairment; WMH, white matter hyperintensities. a p < 0.05; Student’s t test, Pearson’s c2 test, or Fisher’s exact test between NC and each of the cognitive impairment group.
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deviations (SUVR > 1.5) above the mean of the normal controls (Lee et al., 2011). We excluded 4 subjects with ADCI and 3 subjects with SVCI for whom APOE genotype data were not available. In summary, our final study cohort consisted of 230 subjects with NC and 245 subjects with cognitive impairment: 86 patients with PiB(þ) ADCI; 25 patients with PiB() ADCI; 45 patients with PiB(þ) SVCI; and 89 patients with PiB() SVCI. The demographic profiles of the patients and controls are shown in Table 1.
considered PiB(þ) if their global PiB retention ratio was >1.5 (Lee et al., 2011; Rowe et al., 2010). A voxel-based statistical analysis was performed using the Statistical Parametric Mapping program, version 2 (SPM2) and Matlab 6.5 for Windows (Math Works, Natick, MA), which are described in detail in the eMethods.
2.3. Neuropsychological tests
We obtained written consent from each patient, and the Institutional Review Board of Samsung Medical Center approved the study protocol.
All participants underwent neuropsychological tests using a standardized battery called the Seoul Neuropsychological Screening Battery (SNSB) (Ahn et al., 2010; Kang and Na, 2003). Activities of Daily Living scale, a modified version of Lawton’s Instrumental ADL (Lawton and Brody, 1969), was also completed. Based on subjects’ scores on these measures, they were classified into 3 categories: those who were cognitively normal, those with MCI, and those with dementia. 2.4. APOE genotyping Genomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification kit following the manufacturer’s instructions (Promega, Madison, WI). Two single nucleotide polymorphisms (SNP; rs429358 for codon 112 and rs7412 for codon 158) in the APOE gene were genotyped using TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA) on a 7500 Fast Real-Time PCR System (Applied Biosystems) according to the manufacturer’s instructions. 2.5. MRI techniques T2, T1, FLAIR, and T2 Fast Field Echo (FFE) MR images were acquired for all subjects at Samsung Medical Center using the same 3.0 T MRI scanner (Philips 3.0T Achieva, Eindhoven, Netherlands). The methods of MRI techniques and measurement of lacunes and WMH volume on MRI are described in detail in the eMethods. We quantified WMH volume (in milliliters) on FLAIR images using an automated method. 2.6. [11C] PiB-PET acquisition and analysis All patients completed the [11C] PiB-PET scan at Samsung or Asan Medical Center. The methods of PiB-PET acquisition and analysis are described in detail in the eMethods. To measure PiB retention, we used the cerebral cortical region to cerebellum uptake ratio, which is identical to the standardized uptake value ratios (SUVRs). The cerebellum was used as a reference region as it did not show group differences. Patients were classified as PiB(þ) or PiB() according to measured global PiB retention ratio. Patients were
2.7. Standard protocol approval, registration, and patient consent
2.8. Statistical analysis First, we used Student’s t test, Pearson’s c2 test, or Fisher’s exact test to compare general characteristics between NC and each of the cognitive impairment groups (ex, NC vs. clinically defined SVCI, NC vs. PiB(þ) SVCI, NC vs. PiB() SVCI). Second, Multiple logistic regression analysis was performed to evaluate the effect of APOE4 (carrier vs. non-carriers) on the risk of cognitive impairment in NC and each of the cognitive impairment group after adjustment for age, gender, education level, hypertension, diabetes, and hyperlipidemia. In each SVCI and ADCI group, the relationship of APOE4 to PiB retention ratio, number of lacunes, and WMH volume was examined using multiple linear regression analysis after adjustment for age, gender, education level, hypertension, diabetes, and hyperlipidemia. To evaluate whether there was an interactive effect of APOE4 and group (SVCI vs. ADCI) on PiB retention ratio, multiple linear regression was performed in the SVCI and ADCI subjects. We had age, gender, education level, hypertension, diabetes, hyperlipidemia, APOE4, group, and the interaction terms (APOE4 * group) as an independent variable and PiB retention ratio as a dependent variable. All analyses were performed with PASW Statistics 17 software (SPSS Inc, Chicago, IL). To examine the distribution of PiB retention in APOE4 carriers as compared to non-carriers, an SPM regression analysis was performed after adjusting for age, gender, education level, hypertension, diabetes, and hyperlipidemia. To evaluate whether there was an interactive effect of APOE4 and group (SVCI vs. ADCI) on the distribution of PiB retention, multiple linear regression was performed in the SVCI and ADCI subjects after additionally adjusting for APOE4 and group in the previous model. We defined statistical significance as p < 0.05 corrected for the false discovery rate (FDR). 3. Results 3.1. Participant demographics Characteristics of the study participants are shown in Table 1. In all, 86 (77.5%) of 111 patients with clinically defined ADCI (59.1% of
Table 2 APOE genotype frequencies by group
Patients, n APOE4 non-carrier APOE4 carrier Heterozygote (ε4/e) Homozygote (ε4/ε4)
NC
SVCI Clinically defined
PiB(þ)
PiB()
Clinically defined
PiB(þ)
PiB()
230 181 49 44 5
134 99 (73.9) 35 (26.1) 32 (23.9) 3 (2.2)
45 25 20 17 3
89 74 15 15 0
111 59 (53.2) 52 (46.8)a 39 (35.1) 13 (11.7)
86 37 49 36 13
25 22 3 3 0
(78.7) (21.3) (19.1) (2.2)
ADCI
(55.6) (44.4)a (37.8) (6.7)
(83.1) (16.9) (16.9) (0.0)
(43.0) (57.0)a (41.9) (15.1)
Data are presented as n (%) Key: ADCI, Alzheimer’s disease cognitive impairment; APOE4, Apolipoprotein E ε4 allele; NC, normal cognition; SVCI, subcortical vascular cognitive impairment. a p < 0.001 (Student’s t test between NC and each of the cognitive impairment groups).
(88.0) (12.0) (12.0) (0.0)
H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487 Table 3 Odds ratios of cognitive impairment among APOE4 carriers as compared with noncarriers
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carriers, as compared to APOE4 non-carriers. Since there were only 3 APOE4 carriers among 25 PiB() ADCI patients, logistic regression was not performed in PiB() ADCI patients.
NC vs. SVCI Clinically defined SVCI
PiB(þ) SVCI
PiB() SVCI
n
n
n
OR (95% CI)
OR (95% CI)
OR (95% CI)
Non-carrier 99 Ref 25 Ref 74 Ref Carrier 35 1.50 (0.79e2.84) 20 4.52 (1.70e11.97) 15 0.96 (0.45e2.07) p 0.214 0.002 0.915 NC vs. ADCI
Non-carrier Carrier p
3.3. Association between APOE4 and PiB retention ratio, lacunes, or WMH in clinically defined SVCI and ADCI groups
Clinically defined ADCI
PiB(þ) ADCI
n
OR (95% CI)
n
OR (95% CI)
59 52
Ref 2.95 (1.73e5.01) <0.001
37 49
Ref 4.84 (2.54e7.91) <0.001
Adjusted for age, gender, education level, hypertension, diabetes, and hyperlipidemia. Because the frequency of APOE4 carriers in PiB() ADCI patients was too low to perform statistical analysis, the data are not shown in the above table. Key: APOE4, apolipoprotein E ε4 allele; ADCI, Alzheimer’s disease cognitive impairment; CI, confidence interval; OR, odds ratio; PiB, Pittsburgh compound B; Ref, reference; SVCI, subcortical vascular cognitive impairment.
amnestic MCI and 89.6% of probable AD dementia) were PiB(þ) and 45 (33.6%) of 134 patients with clinically defined SVCI (32.8% of subcortical vascular MCI and 34.3% of SVaD) were PiB(þ). 3.2. APOE4 and risk of groups with cognitive impairment compared to NC
Regarding the association of APOE4 and cerebrovascular disease, there was no association between APOE4 and WMH volume (b [SE] ¼ 0.095 [3.720], p ¼ 0.980 in clinically defined SVCI; b [SE] ¼ 2.133 [1.254], p ¼ 0.092 in clinically defined ADCI). APOE4 did not show significant association with lacunes in clinically defined SVCI (b [SE] ¼ 4.850 [2.536], p ¼ 0.058), whereas in clinically defined ADCI, APOE4 carriers showed significantly less lacunes than APOE4 non-carriers (b [SE] ¼ 0.719 [0.309], p ¼ 0.022). In contrast, APOE4 carriers had greater PiB retention ratio than APOE4 non-carriers in both clinically defined SVCI (b [SE] ¼ 0.237 [0.079], p ¼ 0.003) and clinically defined ADCI (b [SE] ¼ 0.420 [0.090], p < 0.001) patients (Fig. 1). There was no significant interactive effect of APOE4 and group (ADCI vs. SVCI) on PiB retention ratio (b [SE] ¼ 0.153 [0.122], p ¼ 0.211). Statistical parametric mapping showed that APOE4 carriers of clinically defined SVCI patients had stronger PiB retention in the bilateral frontal and temporoparietal cortices, and precuneus, as compared to APOE4 non-carriers. In clinically defined ADCI patients, a similar pattern was observed in more extensive areas (p < 0.05, FDR corrected) (Fig. 2). No interactive effect of APOE4 and group (SVCI vs. ADCI) on the distribution of PiB retention was observed. 4. Discussion
Compared to NC, APOE4 carriers were significantly more common in clinically defined ADCI (p < 0.001), PiB(þ) ADCI (p < 0.001), and PiB(þ) SVCI (p < 0.001) (Table 2). The associations between presence of APOE4 and the risk of each patient category compared to control subjects are shown in Table 3. The risk of clinically defined SVCI was not increased in APOE4 carriers. After stratification of clinically defined SVCI patients by PiB positivity, the risk of PiB(þ) SVCI was significantly increased in APOE4 carriers, as compared to APOE4 non-carriers. However, the risk of PiB() SVCI was not associated with APOE4. On the other hand, the risk of clinically defined ADCI was increased in APOE4 carriers, as compared to APOE4 non-carriers. After stratification of clinically defined ADCI patients by PiB positivity, the risk of PiB(þ) ADCI was significantly increased in APOE4
We determined the effects of APOE4 on the burden of Ab and subcortical cerebrovascular disease in a large cohort of carefully phenotyped patients with cognitive impairment using noninvasive amyloid imaging and structural MRI to assess markers of subcortical cerebrovascular disease. Our major findings were as follows. First, Ab deposition can occur in patients with and without subcortical cerebrovascular disease, and is associated with APOE4. Second, APOE4 might be independent of subcortical cerebrovascular disease. The first major findings are that Ab deposition can occur in patients with and without subcortical cerebrovascular disease, and that this deposition is associated with APOE4. The frequencies of PiB positivity in ADCI and SVCI were 77.5% and 33.6%, respectively,
Fig. 1. Association between APOE4 and PiB retention ratio in clinically defined SVCI and ADCI groupa. APOE4 carriers had greater PiB retention ratio in both SVCI (b (SE) ¼ 0.237 (0.079), p ¼ 0.003) and ADCI (b (SE) ¼ 0.420 (0.090), p < 0.001) patients. aMultiple linear regression analysis. Potential confounders such as age, gender, education level, hypertension, diabetes, and hyperlipidemia were included.
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H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487
Fig. 2. Association between APOE4 and PiB retention. Statistical parametric mapping showed that in clinically defined SVCI patients, APOE4 carriers had stronger PiB retention in the bilateral frontal and temporoparietal cortices, and precuneus. In clinically defined ADCI patients, similar pattern was observed in more extensive areas (p < 0.05, FDR corrected).
which were consistent with previous studies (Klunk et al., 2004; Lee et al., 2011; Wolk et al., 2009). Our findings that APOE4 affects Ab burden in patients with and without subcortical cerebrovascular disease is supported by the following observations: first, the odds ratio of PiB(þ) SVCI in APOE4 carriers as compared to APOE4 noncarriers was similar to that of PiB(þ) ADCI; second, both SVCI and ADCI patients showed that APOE4 was associated with PiB retention ratio. Furthermore, there were no differences in the effects of APOE4 on Ab burden between patients with and without subcortical cerebrovascular disease, as there was no significant interactive effect of APOE4 and group (SVCI vs. ADCI) on the amount or distribution of PiB retention. Therefore, these findings do not support our hypothesis that the relationship between APOE4 and Ab burden is weaker in patients with SVCI than in patients with ADCI. On the contrary, our results suggest that subcortical cerebrovascular disease does not modify the relationship between APOE4 and Ab burden. The second major finding of our study was that APOE4 might to be independent of subcortical cerebrovascular disease. There was no significant difference in the frequency of APOE4 between NC and PiB() SVCI patients, which implies that APOE4 does not increase the risk of “pure” SVCI, as demonstrated by PiB PET. In addition, APOE4 was not associated with the number of lacunes or with WMH volume in patients with SVCI. APOE4 is known to be an important risk factor in the development of AD (Corder et al., 1993). In addition, APOE4 is suggested to be associated with the following: cerebral amyloid angiopathy (Premkumar et al., 1996); dementia after traumatic brain injury (Katzman et al., 1996; Mayeux et al., 1995); Down’s syndromeeassociated dementia (Deb et al., 2000); Creutzfeldt-Jakob disease (Amouyel et al., 1994); multiple sclerosis (Fazekas et al., 2001; Hogh et al., 2000); younger age of onset of amyotrophic lateral sclerosis (Zetterberg et al., 2008); and dementia with Lewy bodies (Harrington et al., 1994; Tsuang et al., 2012). Concerning effects of APOE4 on vascular disease, there are reports of an association between APOE4 and large artery disease such as atherogenesis (Altamura et al., 2007; Lahoz et al., 2001), coronary atherosclerosis (Graner et al., 2008), and large artery ischemic stroke. Furthermore, several studies have reported that APOE4 increases the risk of VaD (Chuang et al., 2010; Davidson et al., 2006), but others reported no association (Hong et al., 2011; Sulkava et al., 1996). We suggest that this inconsistency may result in part from the possibility that the subjects in the previously reported studies may have included patients with mixed vascular
and coexistent AD (Jagust et al., 2008). Therefore, our findings suggest that the previously observed increased risk of clinically defined SVCI in APOE4 carriers is due to the effects of APOE4 on AD pathology. The strengths of our study are its prospective setting, use of standardized PiB-PET and MRI imaging protocols, and standardized phenotyping of cognitive impairment. However, several limitations of our study must also be acknowledged. First, PiB() SVCI may not necessarily indicate pure SVCI, because PiB imaging detects fibrillar Ab, but no soluble Ab, and provides no information on tangle pathology. Second, PiB(þ) SVCI patients were older than NC and ADCI patients. Therefore, it is possible that if we had recruited an older ADCI group, there would have been less frequent APOE4 carriers. Third, to determine the true causal relationship between APOE4 and subcortical cerebrovascular disease or Ab burden throughout the population, large population-based longitudinal studies are needed. Finally, it is possible that we could not find any statistically significant relation of APOE4 on the risk of PiB() SVCI or interactive effect of APOE4 and group on the amount or distribution of PiB retention because of the relatively small sample size. Further investigation with a larger sample size is necessary to confirm our results. Nonetheless, this is the first study to demonstrate that Ab deposition can occur in patients with and without subcortical cerebrovascular disease, and is associated with APOE4, whereas APOE4 is independent of subcortical cerebrovascular disease. Disclosure statement Dr Seo and Dr Na receive research support from the Ministry of Health and Welfare, Korea. Acknowledgements This study was supported by grants from the Korean Healthcare Technology R&D Project, the Ministry for Health, Welfare & Family Affairs, the Republic of Korea (nos. A102065 and A070001), by the Korean Science and Engineering Foundation (KOSEF) NRL program grant funded by the Korean government (MEST; 2011-0028333), by Samsung Medical Center Clinical Research Development Program grants (CRL-108011 and CRS 110-14-1), and by the Converging Research Center Program through the Ministry of Education, Science and Technology (2010K001054).
H.J. Kim et al. / Neurobiology of Aging 34 (2013) 2482e2487
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