Cortical superficial siderosis A marker of vascular amyloid in patients with cognitive impairment
Han Kyu Na, BS Jae-Hyun Park, MD Jung-Hyun Kim, MS Hee Jin Kim, MD Sung Tae Kim, MD David J. Werring, PhD, FRCP Sang Won Seo, MD Duk L. Na, MD
Correspondence to Dr. Duk L. Na: [email protected]
ABSTRACT
Objective: To investigate the prevalence and associations of cortical superficial siderosis (cSS) utilizing MRI markers of cerebral small vessel disease and amyloid burden assessed through in vivo amyloid imaging in a cognitively impaired population.
Methods: Gradient-recalled echo, T2*-weighted MRIs from 232 patients (Alzheimer disease– related cognitive impairment [ADCI], n 5 90; subcortical vascular cognitive impairment [SVCI], n 5 142) were reviewed for cSS. All subjects underwent in vivo amyloid imaging using [11C] Pittsburgh compound B (PiB)-PET. A multivariate logistic regression model was constructed to evaluate the predictive factors of cSS. A follow-up MRI was performed in 154 (66.4%) of 232 patients. Results: Twelve patients (5.2%) with cSS were equally distributed in ADCI (n 5 6) and SVCI (n 5 6) groups, but cSS was not present in any of the patients with a negative PiB scan. cSS was associated with markers of cerebral amyloid angiopathy, including higher global PiB retention ratio, APOE e2 allele presence, and a strictly lobar distribution of cerebral microbleeds. Of those patients with baseline cSS, 33% showed progression over time; there were 2 cases of symptomatic intracranial hemorrhage.
Conclusions: cSS occurred in both ADCI and SVCI groups, but not in patients with amyloidnegative SVCI, supporting the hypothesis that cSS reflects an amyloid rather than ischemic etiology. The associations with strictly lobar cerebral microbleeds and APOE e2 suggest that cerebral amyloid angiopathy, with increased vascular fragility related to APOE genotype, contributes to cSS in this population, with a high risk of progression over time and future intracranial hemorrhage. Neurology® 2015;84:849–855 GLOSSARY AD 5 Alzheimer disease; ADCI 5 Alzheimer disease–related cognitive impairment; ADL 5 activities of daily living; aMCI 5 amnestic mild cognitive impairment; CAA 5 cerebral amyloid angiopathy; CDR 5 Clinical Dementia Rating; CDR-SB 5 CDR– Sum of Boxes; CMB 5 cerebral microbleed; cSS 5 cortical superficial siderosis; FLAIR 5 fluid-attenuated inversion recovery; GRE 5 gradient-recalled echo; ICH 5 intracranial hemorrhage; PiB 5 Pittsburgh compound B; SPM 5 statistical parametric mapping; SS 5 superficial siderosis; SVaD 5 subcortical vascular dementia; SVCI 5 subcortical vascular cognitive impairment; SVD 5 small vessel disease; svMCI 5 subcortical vascular mild cognitive impairment; WMH 5 white matter hyperintensity.
Superficial siderosis (SS) describes hemosiderin deposits in the subpial layers of the cerebrum, cerebellum, brainstem, or spinal cord, leaving track-like linear residues of blood breakdown products, including hemosiderin, in the superficial layers.1 Cortical SS (cSS) refers to a subtype of SS in which SS is localized over the cortical surface of the supratentorial cerebral convexities.2–5 Although the understanding of underlying mechanisms of cSS remains elusive, cSS has been suggested as a characteristic neuroimaging marker of cerebral amyloid angiopathy (CAA),3,4,6 or as a risk factor for future intracranial hemorrhage (ICH) associated with CAA.5,7,8 However, cSS is also found in the general population of elderly without dementia (0.7%), in approximately 2% of patients in a memory clinic population, with a prevalence of 5% in those with Alzheimer disease (AD).9 Despite the recent increased interest in cSS, only a few studies have focused on Supplemental data at Neurology.org From Yonsei University College of Medicine (H.K.N.), Seoul; Departments of Neurology (J.-H.P., J.-H.K., H.J.K., S.W.S., D.L.N.) and Radiology (S.T.K.), Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea; and Department of Brain Repair and Rehabilitation (D.J.W.), UCL Institute of Neurology, Queen Square, London, UK. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2015 American Academy of Neurology
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the pathogenesis of cSS and have not yet evaluated the direct relationship between cSS and amyloid deposition because the studies were mainly based on MRIs.3–5 To our knowledge, studies investigating the pathogenesis of cSS in populations with cognitive impairment are limited to a few small reports.4,9 We tested the following hypotheses in a well-characterized population with cognitive impairment due to ischemia or Alzheimer pathology: (1) cSS is related to cerebral amyloid deposition; (2) cSS is related to strictly lobar cerebral microbleeds (CMBs), a marker of CAA; and (3) cSS is associated with APOE e2 genotype, which is known to be linked with increased vascular fragility in CAA. We also investigated the associations of cSS with imaging markers of subcortical small vessel disease (SVD) including CMBs, lacunes, and white matter hyperintensities (WMH). METHODS Standard protocol approvals, registrations, and patient consents. This study was approved by the institutional review board of Samsung Medical Center. Written informed consent was obtained from all study participants.
Patients and patient classification. Our initial sample consisted of a total of 257 consecutive patients who were clinically diagnosed with AD-related cognitive impairment (ADCI) or subcortical vascular cognitive impairment (SVCI) at Samsung Medical Center from July 2008 to April 2012 and underwent standardized [11C] Pittsburg compound B (PiB)PET and MRI. Patients who were clinically diagnosed with either amnestic mild cognitive impairment (aMCI) or dementia with AD were grouped as ADCI. Patients who were clinically diagnosed with either subcortical vascular mild cognitive impairment (svMCI) or subcortical vascular dementia (SVaD) were grouped as SVCI. The ADCI group (n 5 115) consisted of 46 patients with aMCI and 69 with probable AD. The SVCI group (n 5 142) consisted of 68 with svMCI and 74 with SVaD. We retrospectively reviewed the data collected previously,10 including detailed medical records and neuroimaging data. The diagnostic criteria11–14 used in this study are described in Methods e-1 on the Neurology® Web site at Neurology.org. All patients completed a clinical interview and neurologic examination. All participants underwent the Mini-Mental State Examination and a standardized neuropsychological battery called the Seoul Neuropsychological Screening Battery.15 All patients had blood tests including APOE genotyping. All patients underwent PiB-PET imaging and were classified as PiB-positive if the global PiB retention ratio was 2 SDs above the mean of normal controls,16 i.e., standardized uptake value ratios above 1.5. Among the 115 patients with presumed ADCI, 25 showed negative PiB scan, 18 had aMCI (18/46, 39.1%) and 7 probable AD (7/69, 10.1%), and were excluded because their cognitive impairment was considered unlikely to be due to AD. Consequently, our final study cohort consisted of 232 subjects: 90 patients with PiB1 ADCI, 48 patients with PiB1 SVCI, and 94 patients with PiB2 SVCI. 850
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Imaging acquisition and analysis. The detailed protocols used to acquire magnetic resonance and PiB-PET images17 are described in Methods e-2 and e-3. Definition and assessment of cSS and SVD markers. cSS was defined as chronic blood linear residues in superficial layers of the cerebral cortex3 with the following characteristics: (1) bilinear track-like hypointensities on gradient-recalled echo (GRE) T2* images surrounding or within a cerebral sulcus1; (2) absence of corresponding hyperintense signals on fluidattenuated inversion recovery (FLAIR) images, which would indicate acute convexity subarachnoid hemorrhage3; (3) supratentorial location; and (4) exclusion of cSS associated with a previous MRI-defined ICH (i.e., a cSS right next to an ICH). cSS was classified as disseminated when affecting $4 sulci and as focal when affecting ,3 sulci.5 The MRI SVD markers investigated in this study were CMBs, WMH, and lacunes. The detailed definitions14,18,19 are described in Methods e-4. Two experienced clinicians, a neurologist, and a neuroradiologist who were blinded to patient clinical data reviewed the number and location of the cSS, CMBs, and lacunes on 20 or 22 axial slices of GRE T2* and 80 axial slices of FLAIR images. The k value between the 2 clinicians for the presence of cSS was 0.919. Consensus was sought in cases of discrepancy. Statistical parametric mapping. The detailed protocol for statistical parametric mapping (SPM) analyses of PiB-PET images is described in Methods e-5. Follow-up MRI. A total of 154 of 232 patients (66.4%) underwent a follow-up T1-weighted and GRE T2* MRI at least once, and the interval from the first MRI acquisition to the first followup was 1 to 50 months (median, 12 months). Of the 220 patients without cSS, the follow-up MRI was performed in 144 patients (65.4%), whereas 10 of 12 patients with cSS had follow-up MRIs 6 to 40 months (median, 12 months) after the first MRI acquisition: once in 6 patients, twice in 3 patients, and 3 times in 1 patient. Follow-up MRI was not available for the other 2 patients because of loss to follow-up (patient 2) and death as a result of ICH (patient 7). The same neurologist and neuroradiologist who blindly reviewed the cSS and small vessel MRI markers in the baseline MRI also rated the progression of cSS severity (decreased, unchanged, or increased) and the number of cSS in the follow-up MRI. Statistical analysis. Fisher exact test and global x2 were performed for categorical variables. The Mann–Whitney U test was performed for continuous variables. A logistic regression model using a 2-step approach was constructed to identify independent predictive factors associated with cSS. First, univariate analysis was performed with the potential predictive factors listed in table 1. Variables with a p value ,0.10 were entered into the multivariate logistic regression using a forward stepwise method. A 2-sided p value ,0.05 was considered statistically significant. All statistical analyses were performed with SPSS version 18.0 (SPSS, Chicago, IL). RESULTS Frequency,
demographic, and lesion characteristics of patients with cSS. A total of 12 patients
(5.2%) with cSS were identified in the cohort of 232 patients with cognitive impairment. The characteristics of patients with or without cSS are summarized in table 1. The underlying type of cognitive impairment in the 12 patients with cSS was heterogeneous (ADCI,
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Table 1
Basic characteristics of patients with and without cSS p Value
Total
cSS group
Non-cSS group
No. of patients
232
12
220
Age, y, mean 6 SD
72.2 6 8.1
75.5 6 8.3
72.0 6 8.1
0.099
Sex, male/female
97/135
6/6
91/129
0.563
MMSE score, mean 6 SD
22.0 6 5.7
23.0 6 3.3
22.0 6 5.8
0.853
CDR, mean 6 SD
0.78 6 0.49
0.71 6 0.45
0.78 6 0.45
0.469
CDR-SB, mean 6 SD
3.95 6 3.27
3.46 6 3.29
3.98 6 3.30
0.581
B-ADL,20 mean 6 SD
19.1 6 2.5
19.1 6 2.6
19.1 6 2.5
0.661
14.9 6 10.1
12.2 6 11.3
15.1 6 10.1
0.222
ADCI
90 (38.8)
6 (50.0)
84 (38.2)
SVCI
142 (61.2)
6 (50.0)
136 (61.8)
Hypertension
147 (63.4)
6 (50.0)
141 (64.1)
Diabetes mellitus
46 (19.8)
2 (16.7)
44 (20.0)
.0.999
Hyperlipidemia
70 (30.2)
1 (8.3)
69 (31.4)
0.113
Heart disease
33 (14.2)
2 (16.7)
31 (14.1)
0.682
37 (16.0)
0 (0.0)
37 (16.8)
0.222
APOE e2 allele carrier
24 (10.3)
4 (33.3)
20 (9.1)
0.025
APOE e4 allele carrier
85 (36.6)
7 (58.3)
78 (35.5)
0.130
S-IADL,
21
mean 6 SD
Diagnosis
0.545
Cardiovascular risk factor, n (%)
Stroke history, n (%)
0.364
APOE genotype, n (%)
Small vessel disease marker Distribution of CMBs,a n (%)
,0.001a
No CMBs
124 (53.4)
5 (41.7)
Strictly lobar CMBs
20 (8.6)
5 (41.7)
15 (6.8)
Mixed or strictly deep CMBs
88 (37.9)
2 (16.7)
86 (39.1)
23.1 (3.0–40.7)
22.8 (4.8–28.7)
23.1 (2.9–41.3)
0.986
2 (0–10)
0 (0–3)
2 (0–11)
0.063
1.81 6 0.54
2.22 6 0.43
1.79 6 0.54
0.004
WMH, mL, median (IQR) No. of lacunes, median (IQR) Global PiB retention ratio, mean 6 SD
119 (54.1)
Abbreviations: ADCI 5 Alzheimer disease–related cognitive impairment; B-ADL 5 Barthel activities of daily living index; CDR 5 Clinical Dementia Rating, CDR-SB 5 Clinical Dementia Rating–Sum of Boxes; CMB 5 cerebral microbleed; cSS 5 cortical superficial siderosis; IQR 5 interquartile range; MMSE 5 Mini-Mental State Examination; PiB 5 Pittsburgh compound B; S-IADL 5 Seoul instrumental activities of daily living; SVCI 5 subcortical vascular cognitive impairment; WMH 5 white matter hyperintensity. Mann–Whitney U test was used to compare continuous variables. Fisher exact test was used to compare nominal variables except for the distribution of CMBs. a Global x2 test was performed to compare the distribution of CMBs.
n 5 6; SVCI, n 5 6). Six patients with cSS had focal cSS (patients 1–6) (50%); the other 6 patients had disseminated cSS (patients 7–12) (50%). Comparison of demographic, genetic, and SVD markers between cSS1 and cSS2 groups. The cSS1 and cSS2
groups did not show significant differences in age, sex, cardiovascular risk factors, Mini-Mental State Examination and activities of daily living (ADL) scores, scales such as Barthel ADL,20 and an instrumental ADL called Seoul ADL.21 We also investigated the prevalence of cSS as a function of
disease severity as assessed by Clinical Dementia Rating (CDR) and CDR–Sum of Boxes (CDR-SB): cSS and non-cSS groups did not differ regarding CDR and CDR-SB, and patients with cSS were evenly distributed among the 4 disease categories (aMCI, n 5 3; AD, n 5 3; svMCI, n 5 3; SVaD, n 5 3) (table e-1). There were no statistically significant associations of cSS with other SVD markers, including WMH and number of lacunes. However, the 2 groups differed on APOE genotype. Four of 12 patients with cSS were carriers of the APOE e2 allele (33.3%), and 7 of 12 were carriers Neurology 84
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of the APOE e4 allele (58.3%). The frequency of APOE e2 allele carrier status was higher in patients with cSS compared to that of patients without cSS (10.3%) (p 5 0.025). The frequency of APOE e4 allele carrier status was also higher in patients with cSS than that of patients without cSS (36.6%), which, however, did not reach statistical significance (p 5 0.130). The cSS1 and cSS2 groups differed significantly in CMB distribution patterns. The strictly lobar CMB distribution was associated with cSS (p , 0.001): the number of lobar CMBs was greater in the cSS1 group (p 5 0.046), especially in the parietal and occipital lobes. Deep CMBs did not differ between the groups (table 1). Comparison of amyloid burden and distribution between cSS1 and cSS2 groups. All 12 patients with cSS
showed positive PiB scans and a higher frequency than the non-cSS group (100% vs 57.3%, p 5 0.002). Moreover, the global PiB retention ratio was significantly higher in patients with cSS (2.22 6 0.43, mean 6 SD) than in those without cSS (1.79 6 0.54, mean 6 SD). The PiB retention ratio of each lobe was also remarkably higher in the cSS1 group,
Figure 1
Statistical parametric mapping of PiB retention in patients with or without cSS
except for the parietal lobe (see tables e-2 and e-3 for details). SPM analysis using age, sex, and education as covariates revealed that patients with cSS showed greater levels of PiB retention in all lobes, precuneus, and cingulate cortices when compared with that of normal controls or patients without cSS (figure 1). In a comparison of the cSS1 and cSS2 groups, the PiB retention ratio of the cSS1 group was significantly higher in all lobes, precuneus, and cingulate cortices. The above results, however, might have resulted from the fact that all subjects with cSS had positive PiB scans while only 57% of the subjects without cSS showed positive PiB scans. Therefore, we also compared amyloid burden and distribution between subjects with cSS and PiB-positive subjects without cSS, and the same analyses were performed within each group of ADCI and SVCI as well. We present these results in table e-3 (amyloid burden) and figure e-1 (amyloid distribution). In summary, analyses of both global PiB retention and SPM revealed that little difference was noted between cSS and PiB1 non-cSS in the combined and SVCI groups. However, for the patients with ADCI who had positive PIB scans, the global PiB retention ratio of cSS1 ADCI patients (2.53 6 0.22) was higher than that of cSS2 ADCI patients (2.24 6 0.33) (p 5 0.031). Moreover, the PiB retention ratio of cSS1 ADCI patients was higher than that of cSS2 ADCI patients in the frontal, temporal, and occipital lobes. Predictive factors for cSS. Results of the multivariate
logistic regression analysis are summarized in table 2. This analysis revealed that the global PiB retention ratio, APOE e2 allele positivity, and strictly lobar distribution of CMBs were significantly associated with cSS. Changes in imaging and clinical findings over time in patients with cSS. Of 144 patients without cSS who
When compared with the cSS2 group, the PiB retention of cSS1 group was significantly higher in all lobes, precuneus, and cingulate cortices (p , 0.05, false discovery rate–corrected). cSS 5 cortical superficial siderosis; PiB 5 Pittsburgh compound B. 852
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had follow-up GRE MRIs, not a single patient developed cSS. However, in 10 patients with cSS who had follow-up GRE images, cSS did not fade or disappear with time (no patients were rated as decreased in the cSS severity). Instead, 4 of the 12 patients with cSS (33.3%) exhibited either progression of cSS severity or an increase in the number of affected sulci (figure 2) (focal, n 5 2, patients 5 and 6; disseminated, n 5 2, patients 11 and 12). Two patients with focal cSS progressed to disseminated cSS (patients 5 and 6). cSS of the remaining 8 patients remained stable. Two patients experienced ICH after the detection of cSS, one in the contralateral hemisphere opposite the preexisting cSS (patient 12). The location of the hemorrhage in the other patient was unconfirmed because the patient died in another hospital and the
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Table 2
Results of multivariate logistic regression analysis 95% CI
Variable
Adjusted OR
p Value
Lower
Upper
Global PiB retention ratio
7.54
0.005
1.84
30.95
1.22
24.07
APOE e2 allele carrier Noncarrier
Reference
Carrier
5.42
0.026
Distribution of CMBs No CMBs
Reference
Strictly lobar CMBs
12.38
0.002
2.83
65.91
Mixed or strictly deep CMBs
1.22
0.833
0.20
7.62
Abbreviations: CI 5 confidence interval; CMB 5 cerebral microbleed; OR 5 odds ratio; PiB 5 Pittsburgh compound B.
family members did not grant access to the medical information (patient 7). Two patients with progressive cSS experienced recurrent transient neurologic symptoms: one with epilepsy-mimicking symptoms characterized by a brief loss of consciousness lasting from a few seconds to several minutes (patient 11), and the other with transient focal neurologic symptoms characterized by tingling sensation on the left arm along with dysarthria, which lasted for several hours, sometimes associated with dropping things held in the left hand (patient 12). There were no epileptiform discharges on EEG in either patient. Detailed clinical and neuroradiologic data of the 12 patients with cSS are shown in table e-1. DISCUSSION This study provides 4 major findings. First, cSS was detected by GRE T2*-weighted images in 12 of 232 patients (5.2%), a frequency much higher than the 0.7% that occurs in normal elderly,22 and similar to the previous report (6.1%) of subjects with cognitive impairment and patients with AD in a
Figure 2
Representative images of progressive, disseminated cSS (patient 11)
(A) Gradient-recalled echo T2* MRI of cSS baseline. (B) At 1-year follow-up, cSS showed progression in both the severity and the number of sulci involved. cSS 5 cortical superficial siderosis.
memory clinic population.4,9 Second, although the underlying clinically defined types of cognitive impairment among the 12 patients with cSS were heterogeneous (ADCI, n 5 6; SVCI, n 5 6), cSS was not found in patients with SVCI who had negative PiB scans (“pure” SVCI). Third, higher PiB retention ratio, existence of strictly lobar CMBs, and APOE e2 allele were independent predictive factors for cSS, supporting the hypothesis that cSS is associated with CAA, and with an increased vessel fragility related to APOE genotype. Fourth, onethird of patients with cSS exhibited progression of cSS in severity or in the number of affected sulci. Our findings demonstrated that cSS does not develop in patients with amyloid-negative SVCI, thus supporting the hypothesis that cSS is more suggestive of an amyloid than ischemic etiology. Our results also suggested that cSS is closely associated with vascular amyloid (CAA) for the following reasons. First, the amyloid burden of patients with cSS was significantly higher compared with that of patients without cSS. The same results were observed when subjects with cSS and PiB-positive subjects without cSS were compared, albeit only in ADCI not in SVCI and the combined groups. This discrepancy between the groups may have resulted from the fact that patients with SVCI have dual pathology (amyloid and ischemia) whereby ischemia may interfere with b-amyloid clearance, thus leading to greater amyloid burden than in patients with ADCI who have single amyloid pathology. Second, strictly lobar CMBs and APOE e2 allele were independent predictive factors for cSS. CMBs are often regarded as a neuroimaging marker of SVD with relevance to cerebrovascular disease, cognitive impairment, and normal aging.10,23–26 Several recent reports, however, have suggested that CMBs strictly restricted to lobar areas are more likely to be associated with CAA.10,22 APOE e2 is known to be a risk factor for CAA-related hemorrhage associated with weakening of amyloid-laden blood vessels.27 In this regard, extra caution may be required when using antiplatelets or anticoagulation agents in patients with cSS and APOE e2 allele, because they may have a higher risk of ICH.27–29 Previous imaging and pathology studies have suggested that amyloid distribution of CAA has an occipital predilection.30 Therefore, we expected that an SPM analysis of PiB-PET comparing patients with and without cSS would highlight occipital areas. In this study, however, the relative occipital to global cortical PiB retention of ADCI patients with cSS was not significantly higher than that of ADCI patients without cSS. Therefore, CAA cases might not entirely account for the development of cSS. In other words, our patients with cSS would not necessarily correspond to patients in a prehemorrhagic stage who Neurology 84
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otherwise fit with Boston CAA criteria. However, we cannot exclude the possibility that the absence of occipital predilection in our study may be partly attributable to the fact that our SPM analysis involved ADCI or SVCI patients with cSS whereas the prior study investigated patients with CAA without dementia. Given the fact that our patients with cSS harbored higher PiB burden than other typical patients with AD, we can assume that our patients with dementia and cSS are in advanced stages regarding amyloid deposition. Therefore, the occipital pattern that might have been shown in earlier stages may have progressed to a more global advanced amyloid depositing pattern of ADCI pathology. During the follow-up period of this study, several important characteristics of cSS were observed. First, we noticed that cSS did not fade or disappear with time. Instead, cSS progressed in one-third of patients with baseline cSS. Two of the 4 patients with progressive cSS were initially classified as focal, but subsequently developed disseminated cSS. Second, 2 patients experienced ICH after the detection of cSS. This is in line with previous studies suggesting that cSS increases the risk of future ICH.4,8 Third, cSS development did not necessarily have a direct relation to the severity of cognitive impairment. In this study, cSS and non-cSS groups did not differ in CDR and CDR-SB. Moreover, the final diagnosis was evenly distributed among the 4 disease categories in the patients with cSS (aMCI, n 5 3; AD, n 5 3; svMCI, n 5 3; SVaD, n 5 3) (table e-1). Lastly, 2 patients with progressive disseminated cSS experienced recurrent transient neurologic symptoms. The other 10 patients did not complain of any sudden focal neurologic symptoms, which may be interpreted as asymptomatic cSS. This finding was inconsistent with previous studies which reported that patients often present focal neurologic symptoms during cSS development.3,4 There are 3 possible explanations for this discrepancy. First, focal neurologic symptoms may occur only in patients with severe cSS, given that both patients had progressive, disseminated cSS. Second, we cannot exclude the possibility that the symptoms could not be detected because of underlying cognitive impairment, or the CSS in our patients spared eloquent areas such as central sulcus (e.g., only 1 of the 12 patients had cSS in the central sulcus). Lastly, previous studies were performed mainly in stroke clinics,3,8 whereas this study was performed in a memory disorder clinic. Further research is needed to investigate these possible interpretations. This study has several limitations. First, pathologic confirmation was not performed, which weakens our finding of the associations between cSS, and CAA or AD. Second, with only 12 patients with cSS, statistical power was limited. Third, we only repeated GRE 854
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MRIs in 66.4% and not all patients. Lastly, the patients in this study all had cognitive impairment, which may limit the generalizability of the results to other populations. However, this study has several strengths. Our study population was well characterized including full genotyping of APOE allele, standardized evaluations of cognitive impairment, standardized MRI, and in vivo amyloid imaging. Moreover, despite the limited number of patients with cSS, this study involved a fairly large population of patients with cognitive impairment, including patients with cSS, all of whom underwent in vivo amyloid imaging. AUTHOR CONTRIBUTIONS Han Kyu Na: drafting of manuscript, study concept and design, acquisition of data, analysis and interpretation. Jae-Hyun Park: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Jung-Hyun Kim: analysis and interpretation, critical revision of the manuscript for important intellectual content. Hee Jin Kim: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Sung Tae Kim: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. David J. Werring: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Sang Won Seo: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Duk L. Na: study concept and design, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision.
STUDY FUNDING This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020), and by the Samsung Medical Center Clinical Research Development Program grant (CRL108011).
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Received July 22, 2014. Accepted in final form November 5, 2014. REFERENCES 1.
2.
3.
4.
5.
6.
Linn J, Herms J, Dichgans M, et al. Subarachnoid hemosiderosis and superficial cortical hemosiderosis in cerebral amyloid angiopathy. AJNR Am J Neuroradiol 2008;29:184–186. Dhollander I, Nelissen N, Van Laere K, et al. In vivo amyloid imaging in cortical superficial siderosis. J Neurol Neurosurg Psychiatry 2011;82:469–471. Charidimou A, Jager RH, Fox Z, et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology 2013;81:626–632. Wollenweber FA, Buerger K, Mueller C, et al. Prevalence of cortical superficial siderosis in patients with cognitive impairment. J Neurol 2014;261:277–282. Linn J, Halpin A, Demaerel P, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010;74:1346–1350. Feldman HH, Maia LF, Mackenzie IRA, Forster BB, Martzke J, Woolfenden A. Superficial siderosis: a potential diagnostic marker of cerebral amyloid angiopathy in Alzheimer disease. Stroke 2008;39:2894–2897.
February 24, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Linn J, Wollenweber FA, Lummel N, et al. Superficial siderosis is a warning sign for future intracranial hemorrhage. J Neurol 2013;260:176–181. Charidimou A, Peeters AP, Jager R, et al. Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy. Neurology 2013;81:1666–1673. Zonneveld HI, Goos JD, Wattjes MP, et al. Prevalence of cortical superficial siderosis in a memory clinic population. Neurology 2014;82:698–704. Park JH, Seo SW, Kim C, et al. Pathogenesis of cerebral microbleeds: in vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol 2013;73:584–593. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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 1984;34:939–944. Erkinjuntti T, Inzitari D, Pantoni L, et al. Research criteria for subcortical vascular dementia in clinical trials. J Neural Transm Suppl 2000;59:23–30. Seo SW, Cho SS, Park A, Chin J, Na DL. Subcortical vascular versus amnestic mild cognitive impairment: comparison of cerebral glucose metabolism. J Neuroimaging 2009;19:213–219. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5-T in Alzheimer dementia and normal aging. Am J Roentgenol 1987;149:351–356. Ahn HJ, Chin J, Park A, et al. Seoul Neuropsychological Screening Battery–dementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients. J Korean Med Sci 2010;25: 1071–1076. Lee JH, Kim SH, Kim GH, et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology 2011;77:18–25. Seo SW, Lee JM, Im K, et al. Cortical thinning related to periventricular and deep white matter hyperintensities. Neurobiol Aging 2012;33:1156–1167.
18.
19.
20. 21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–174. Raposo N, Viguier A, Cuvinciuc V, et al. Cortical subarachnoid haemorrhage in the elderly: a recurrent event probably related to cerebral amyloid angiopathy. Eur J Neurol 2011;18:597–603. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965;14:61–65. Moon SY, Na DL, Seo SW, et al. Impact of white matter changes on activities of daily living in mild to moderate dementia. Eur Neurol 2011;65:223–230. Vernooij MW, Ikram MA, Hofman A, Krestin GP, Breteler MMB, van der Lugt A. Superficial siderosis in the general population. Neurology 2009;73:202–205. Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002;1:426–436. Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol 2011;70:871–880. Dierksen GA, Skehan ME, Khan MA, et al. Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol 2010;68:545–548. Werring DJ. Cerebral microbleeds: clinical and pathophysiological significance. J Neuroimaging 2007;17: 193–203. Love S, Nicoll JAR, Hughes A, Wilcock GK. APOE and cerebral amyloid angiopathy in the elderly. Neuroreport 2003;14:1535–1536. Rosand J, Hylek EM, O’Donnell HC, Greenberg SM. Cerebral amyloid angiopathy and warfarin-associated hemorrhage: a genetic and neuropathologic study. Neurology 1999;52:A503. Abstract. McCarron MO, Nicoll JAR, Ironside JW, Love S, Alberts MJ, Bone I. Cerebral amyloid angiopathy-related hemorrhage interaction of APOE epsilon 2 with putative clinical risk factors. Stroke 1999;30:1643–1646. Johnson KA, Gregas M, Becker JA, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 2007;62:229–234.
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Cortical superficial siderosis: A marker of vascular amyloid in patients with cognitive impairment Han Kyu Na, Jae-Hyun Park, Jung-Hyun Kim, et al. Neurology 2015;84;849-855 Published Online before print January 28, 2015 DOI 10.1212/WNL.0000000000001288 This information is current as of January 28, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/8/849.full.html
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References
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Han Kyu Na, BS Jae-Hyun Park, MD Jung-Hyun Kim, MS Hee Jin Kim, MD Sung Tae Kim, MD David J. Werring, PhD, FRCP Sang Won Seo, MD Duk L. Na, MD
Correspondence to Dr. Duk L. Na: [email protected]
ABSTRACT
Objective: To investigate the prevalence and associations of cortical superficial siderosis (cSS) utilizing MRI markers of cerebral small vessel disease and amyloid burden assessed through in vivo amyloid imaging in a cognitively impaired population.
Methods: Gradient-recalled echo, T2*-weighted MRIs from 232 patients (Alzheimer disease– related cognitive impairment [ADCI], n 5 90; subcortical vascular cognitive impairment [SVCI], n 5 142) were reviewed for cSS. All subjects underwent in vivo amyloid imaging using [11C] Pittsburgh compound B (PiB)-PET. A multivariate logistic regression model was constructed to evaluate the predictive factors of cSS. A follow-up MRI was performed in 154 (66.4%) of 232 patients. Results: Twelve patients (5.2%) with cSS were equally distributed in ADCI (n 5 6) and SVCI (n 5 6) groups, but cSS was not present in any of the patients with a negative PiB scan. cSS was associated with markers of cerebral amyloid angiopathy, including higher global PiB retention ratio, APOE e2 allele presence, and a strictly lobar distribution of cerebral microbleeds. Of those patients with baseline cSS, 33% showed progression over time; there were 2 cases of symptomatic intracranial hemorrhage.
Conclusions: cSS occurred in both ADCI and SVCI groups, but not in patients with amyloidnegative SVCI, supporting the hypothesis that cSS reflects an amyloid rather than ischemic etiology. The associations with strictly lobar cerebral microbleeds and APOE e2 suggest that cerebral amyloid angiopathy, with increased vascular fragility related to APOE genotype, contributes to cSS in this population, with a high risk of progression over time and future intracranial hemorrhage. Neurology® 2015;84:849–855 GLOSSARY AD 5 Alzheimer disease; ADCI 5 Alzheimer disease–related cognitive impairment; ADL 5 activities of daily living; aMCI 5 amnestic mild cognitive impairment; CAA 5 cerebral amyloid angiopathy; CDR 5 Clinical Dementia Rating; CDR-SB 5 CDR– Sum of Boxes; CMB 5 cerebral microbleed; cSS 5 cortical superficial siderosis; FLAIR 5 fluid-attenuated inversion recovery; GRE 5 gradient-recalled echo; ICH 5 intracranial hemorrhage; PiB 5 Pittsburgh compound B; SPM 5 statistical parametric mapping; SS 5 superficial siderosis; SVaD 5 subcortical vascular dementia; SVCI 5 subcortical vascular cognitive impairment; SVD 5 small vessel disease; svMCI 5 subcortical vascular mild cognitive impairment; WMH 5 white matter hyperintensity.
Superficial siderosis (SS) describes hemosiderin deposits in the subpial layers of the cerebrum, cerebellum, brainstem, or spinal cord, leaving track-like linear residues of blood breakdown products, including hemosiderin, in the superficial layers.1 Cortical SS (cSS) refers to a subtype of SS in which SS is localized over the cortical surface of the supratentorial cerebral convexities.2–5 Although the understanding of underlying mechanisms of cSS remains elusive, cSS has been suggested as a characteristic neuroimaging marker of cerebral amyloid angiopathy (CAA),3,4,6 or as a risk factor for future intracranial hemorrhage (ICH) associated with CAA.5,7,8 However, cSS is also found in the general population of elderly without dementia (0.7%), in approximately 2% of patients in a memory clinic population, with a prevalence of 5% in those with Alzheimer disease (AD).9 Despite the recent increased interest in cSS, only a few studies have focused on Supplemental data at Neurology.org From Yonsei University College of Medicine (H.K.N.), Seoul; Departments of Neurology (J.-H.P., J.-H.K., H.J.K., S.W.S., D.L.N.) and Radiology (S.T.K.), Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea; and Department of Brain Repair and Rehabilitation (D.J.W.), UCL Institute of Neurology, Queen Square, London, UK. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2015 American Academy of Neurology
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the pathogenesis of cSS and have not yet evaluated the direct relationship between cSS and amyloid deposition because the studies were mainly based on MRIs.3–5 To our knowledge, studies investigating the pathogenesis of cSS in populations with cognitive impairment are limited to a few small reports.4,9 We tested the following hypotheses in a well-characterized population with cognitive impairment due to ischemia or Alzheimer pathology: (1) cSS is related to cerebral amyloid deposition; (2) cSS is related to strictly lobar cerebral microbleeds (CMBs), a marker of CAA; and (3) cSS is associated with APOE e2 genotype, which is known to be linked with increased vascular fragility in CAA. We also investigated the associations of cSS with imaging markers of subcortical small vessel disease (SVD) including CMBs, lacunes, and white matter hyperintensities (WMH). METHODS Standard protocol approvals, registrations, and patient consents. This study was approved by the institutional review board of Samsung Medical Center. Written informed consent was obtained from all study participants.
Patients and patient classification. Our initial sample consisted of a total of 257 consecutive patients who were clinically diagnosed with AD-related cognitive impairment (ADCI) or subcortical vascular cognitive impairment (SVCI) at Samsung Medical Center from July 2008 to April 2012 and underwent standardized [11C] Pittsburg compound B (PiB)PET and MRI. Patients who were clinically diagnosed with either amnestic mild cognitive impairment (aMCI) or dementia with AD were grouped as ADCI. Patients who were clinically diagnosed with either subcortical vascular mild cognitive impairment (svMCI) or subcortical vascular dementia (SVaD) were grouped as SVCI. The ADCI group (n 5 115) consisted of 46 patients with aMCI and 69 with probable AD. The SVCI group (n 5 142) consisted of 68 with svMCI and 74 with SVaD. We retrospectively reviewed the data collected previously,10 including detailed medical records and neuroimaging data. The diagnostic criteria11–14 used in this study are described in Methods e-1 on the Neurology® Web site at Neurology.org. All patients completed a clinical interview and neurologic examination. All participants underwent the Mini-Mental State Examination and a standardized neuropsychological battery called the Seoul Neuropsychological Screening Battery.15 All patients had blood tests including APOE genotyping. All patients underwent PiB-PET imaging and were classified as PiB-positive if the global PiB retention ratio was 2 SDs above the mean of normal controls,16 i.e., standardized uptake value ratios above 1.5. Among the 115 patients with presumed ADCI, 25 showed negative PiB scan, 18 had aMCI (18/46, 39.1%) and 7 probable AD (7/69, 10.1%), and were excluded because their cognitive impairment was considered unlikely to be due to AD. Consequently, our final study cohort consisted of 232 subjects: 90 patients with PiB1 ADCI, 48 patients with PiB1 SVCI, and 94 patients with PiB2 SVCI. 850
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Imaging acquisition and analysis. The detailed protocols used to acquire magnetic resonance and PiB-PET images17 are described in Methods e-2 and e-3. Definition and assessment of cSS and SVD markers. cSS was defined as chronic blood linear residues in superficial layers of the cerebral cortex3 with the following characteristics: (1) bilinear track-like hypointensities on gradient-recalled echo (GRE) T2* images surrounding or within a cerebral sulcus1; (2) absence of corresponding hyperintense signals on fluidattenuated inversion recovery (FLAIR) images, which would indicate acute convexity subarachnoid hemorrhage3; (3) supratentorial location; and (4) exclusion of cSS associated with a previous MRI-defined ICH (i.e., a cSS right next to an ICH). cSS was classified as disseminated when affecting $4 sulci and as focal when affecting ,3 sulci.5 The MRI SVD markers investigated in this study were CMBs, WMH, and lacunes. The detailed definitions14,18,19 are described in Methods e-4. Two experienced clinicians, a neurologist, and a neuroradiologist who were blinded to patient clinical data reviewed the number and location of the cSS, CMBs, and lacunes on 20 or 22 axial slices of GRE T2* and 80 axial slices of FLAIR images. The k value between the 2 clinicians for the presence of cSS was 0.919. Consensus was sought in cases of discrepancy. Statistical parametric mapping. The detailed protocol for statistical parametric mapping (SPM) analyses of PiB-PET images is described in Methods e-5. Follow-up MRI. A total of 154 of 232 patients (66.4%) underwent a follow-up T1-weighted and GRE T2* MRI at least once, and the interval from the first MRI acquisition to the first followup was 1 to 50 months (median, 12 months). Of the 220 patients without cSS, the follow-up MRI was performed in 144 patients (65.4%), whereas 10 of 12 patients with cSS had follow-up MRIs 6 to 40 months (median, 12 months) after the first MRI acquisition: once in 6 patients, twice in 3 patients, and 3 times in 1 patient. Follow-up MRI was not available for the other 2 patients because of loss to follow-up (patient 2) and death as a result of ICH (patient 7). The same neurologist and neuroradiologist who blindly reviewed the cSS and small vessel MRI markers in the baseline MRI also rated the progression of cSS severity (decreased, unchanged, or increased) and the number of cSS in the follow-up MRI. Statistical analysis. Fisher exact test and global x2 were performed for categorical variables. The Mann–Whitney U test was performed for continuous variables. A logistic regression model using a 2-step approach was constructed to identify independent predictive factors associated with cSS. First, univariate analysis was performed with the potential predictive factors listed in table 1. Variables with a p value ,0.10 were entered into the multivariate logistic regression using a forward stepwise method. A 2-sided p value ,0.05 was considered statistically significant. All statistical analyses were performed with SPSS version 18.0 (SPSS, Chicago, IL). RESULTS Frequency,
demographic, and lesion characteristics of patients with cSS. A total of 12 patients
(5.2%) with cSS were identified in the cohort of 232 patients with cognitive impairment. The characteristics of patients with or without cSS are summarized in table 1. The underlying type of cognitive impairment in the 12 patients with cSS was heterogeneous (ADCI,
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Table 1
Basic characteristics of patients with and without cSS p Value
Total
cSS group
Non-cSS group
No. of patients
232
12
220
Age, y, mean 6 SD
72.2 6 8.1
75.5 6 8.3
72.0 6 8.1
0.099
Sex, male/female
97/135
6/6
91/129
0.563
MMSE score, mean 6 SD
22.0 6 5.7
23.0 6 3.3
22.0 6 5.8
0.853
CDR, mean 6 SD
0.78 6 0.49
0.71 6 0.45
0.78 6 0.45
0.469
CDR-SB, mean 6 SD
3.95 6 3.27
3.46 6 3.29
3.98 6 3.30
0.581
B-ADL,20 mean 6 SD
19.1 6 2.5
19.1 6 2.6
19.1 6 2.5
0.661
14.9 6 10.1
12.2 6 11.3
15.1 6 10.1
0.222
ADCI
90 (38.8)
6 (50.0)
84 (38.2)
SVCI
142 (61.2)
6 (50.0)
136 (61.8)
Hypertension
147 (63.4)
6 (50.0)
141 (64.1)
Diabetes mellitus
46 (19.8)
2 (16.7)
44 (20.0)
.0.999
Hyperlipidemia
70 (30.2)
1 (8.3)
69 (31.4)
0.113
Heart disease
33 (14.2)
2 (16.7)
31 (14.1)
0.682
37 (16.0)
0 (0.0)
37 (16.8)
0.222
APOE e2 allele carrier
24 (10.3)
4 (33.3)
20 (9.1)
0.025
APOE e4 allele carrier
85 (36.6)
7 (58.3)
78 (35.5)
0.130
S-IADL,
21
mean 6 SD
Diagnosis
0.545
Cardiovascular risk factor, n (%)
Stroke history, n (%)
0.364
APOE genotype, n (%)
Small vessel disease marker Distribution of CMBs,a n (%)
,0.001a
No CMBs
124 (53.4)
5 (41.7)
Strictly lobar CMBs
20 (8.6)
5 (41.7)
15 (6.8)
Mixed or strictly deep CMBs
88 (37.9)
2 (16.7)
86 (39.1)
23.1 (3.0–40.7)
22.8 (4.8–28.7)
23.1 (2.9–41.3)
0.986
2 (0–10)
0 (0–3)
2 (0–11)
0.063
1.81 6 0.54
2.22 6 0.43
1.79 6 0.54
0.004
WMH, mL, median (IQR) No. of lacunes, median (IQR) Global PiB retention ratio, mean 6 SD
119 (54.1)
Abbreviations: ADCI 5 Alzheimer disease–related cognitive impairment; B-ADL 5 Barthel activities of daily living index; CDR 5 Clinical Dementia Rating, CDR-SB 5 Clinical Dementia Rating–Sum of Boxes; CMB 5 cerebral microbleed; cSS 5 cortical superficial siderosis; IQR 5 interquartile range; MMSE 5 Mini-Mental State Examination; PiB 5 Pittsburgh compound B; S-IADL 5 Seoul instrumental activities of daily living; SVCI 5 subcortical vascular cognitive impairment; WMH 5 white matter hyperintensity. Mann–Whitney U test was used to compare continuous variables. Fisher exact test was used to compare nominal variables except for the distribution of CMBs. a Global x2 test was performed to compare the distribution of CMBs.
n 5 6; SVCI, n 5 6). Six patients with cSS had focal cSS (patients 1–6) (50%); the other 6 patients had disseminated cSS (patients 7–12) (50%). Comparison of demographic, genetic, and SVD markers between cSS1 and cSS2 groups. The cSS1 and cSS2
groups did not show significant differences in age, sex, cardiovascular risk factors, Mini-Mental State Examination and activities of daily living (ADL) scores, scales such as Barthel ADL,20 and an instrumental ADL called Seoul ADL.21 We also investigated the prevalence of cSS as a function of
disease severity as assessed by Clinical Dementia Rating (CDR) and CDR–Sum of Boxes (CDR-SB): cSS and non-cSS groups did not differ regarding CDR and CDR-SB, and patients with cSS were evenly distributed among the 4 disease categories (aMCI, n 5 3; AD, n 5 3; svMCI, n 5 3; SVaD, n 5 3) (table e-1). There were no statistically significant associations of cSS with other SVD markers, including WMH and number of lacunes. However, the 2 groups differed on APOE genotype. Four of 12 patients with cSS were carriers of the APOE e2 allele (33.3%), and 7 of 12 were carriers Neurology 84
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of the APOE e4 allele (58.3%). The frequency of APOE e2 allele carrier status was higher in patients with cSS compared to that of patients without cSS (10.3%) (p 5 0.025). The frequency of APOE e4 allele carrier status was also higher in patients with cSS than that of patients without cSS (36.6%), which, however, did not reach statistical significance (p 5 0.130). The cSS1 and cSS2 groups differed significantly in CMB distribution patterns. The strictly lobar CMB distribution was associated with cSS (p , 0.001): the number of lobar CMBs was greater in the cSS1 group (p 5 0.046), especially in the parietal and occipital lobes. Deep CMBs did not differ between the groups (table 1). Comparison of amyloid burden and distribution between cSS1 and cSS2 groups. All 12 patients with cSS
showed positive PiB scans and a higher frequency than the non-cSS group (100% vs 57.3%, p 5 0.002). Moreover, the global PiB retention ratio was significantly higher in patients with cSS (2.22 6 0.43, mean 6 SD) than in those without cSS (1.79 6 0.54, mean 6 SD). The PiB retention ratio of each lobe was also remarkably higher in the cSS1 group,
Figure 1
Statistical parametric mapping of PiB retention in patients with or without cSS
except for the parietal lobe (see tables e-2 and e-3 for details). SPM analysis using age, sex, and education as covariates revealed that patients with cSS showed greater levels of PiB retention in all lobes, precuneus, and cingulate cortices when compared with that of normal controls or patients without cSS (figure 1). In a comparison of the cSS1 and cSS2 groups, the PiB retention ratio of the cSS1 group was significantly higher in all lobes, precuneus, and cingulate cortices. The above results, however, might have resulted from the fact that all subjects with cSS had positive PiB scans while only 57% of the subjects without cSS showed positive PiB scans. Therefore, we also compared amyloid burden and distribution between subjects with cSS and PiB-positive subjects without cSS, and the same analyses were performed within each group of ADCI and SVCI as well. We present these results in table e-3 (amyloid burden) and figure e-1 (amyloid distribution). In summary, analyses of both global PiB retention and SPM revealed that little difference was noted between cSS and PiB1 non-cSS in the combined and SVCI groups. However, for the patients with ADCI who had positive PIB scans, the global PiB retention ratio of cSS1 ADCI patients (2.53 6 0.22) was higher than that of cSS2 ADCI patients (2.24 6 0.33) (p 5 0.031). Moreover, the PiB retention ratio of cSS1 ADCI patients was higher than that of cSS2 ADCI patients in the frontal, temporal, and occipital lobes. Predictive factors for cSS. Results of the multivariate
logistic regression analysis are summarized in table 2. This analysis revealed that the global PiB retention ratio, APOE e2 allele positivity, and strictly lobar distribution of CMBs were significantly associated with cSS. Changes in imaging and clinical findings over time in patients with cSS. Of 144 patients without cSS who
When compared with the cSS2 group, the PiB retention of cSS1 group was significantly higher in all lobes, precuneus, and cingulate cortices (p , 0.05, false discovery rate–corrected). cSS 5 cortical superficial siderosis; PiB 5 Pittsburgh compound B. 852
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had follow-up GRE MRIs, not a single patient developed cSS. However, in 10 patients with cSS who had follow-up GRE images, cSS did not fade or disappear with time (no patients were rated as decreased in the cSS severity). Instead, 4 of the 12 patients with cSS (33.3%) exhibited either progression of cSS severity or an increase in the number of affected sulci (figure 2) (focal, n 5 2, patients 5 and 6; disseminated, n 5 2, patients 11 and 12). Two patients with focal cSS progressed to disseminated cSS (patients 5 and 6). cSS of the remaining 8 patients remained stable. Two patients experienced ICH after the detection of cSS, one in the contralateral hemisphere opposite the preexisting cSS (patient 12). The location of the hemorrhage in the other patient was unconfirmed because the patient died in another hospital and the
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Table 2
Results of multivariate logistic regression analysis 95% CI
Variable
Adjusted OR
p Value
Lower
Upper
Global PiB retention ratio
7.54
0.005
1.84
30.95
1.22
24.07
APOE e2 allele carrier Noncarrier
Reference
Carrier
5.42
0.026
Distribution of CMBs No CMBs
Reference
Strictly lobar CMBs
12.38
0.002
2.83
65.91
Mixed or strictly deep CMBs
1.22
0.833
0.20
7.62
Abbreviations: CI 5 confidence interval; CMB 5 cerebral microbleed; OR 5 odds ratio; PiB 5 Pittsburgh compound B.
family members did not grant access to the medical information (patient 7). Two patients with progressive cSS experienced recurrent transient neurologic symptoms: one with epilepsy-mimicking symptoms characterized by a brief loss of consciousness lasting from a few seconds to several minutes (patient 11), and the other with transient focal neurologic symptoms characterized by tingling sensation on the left arm along with dysarthria, which lasted for several hours, sometimes associated with dropping things held in the left hand (patient 12). There were no epileptiform discharges on EEG in either patient. Detailed clinical and neuroradiologic data of the 12 patients with cSS are shown in table e-1. DISCUSSION This study provides 4 major findings. First, cSS was detected by GRE T2*-weighted images in 12 of 232 patients (5.2%), a frequency much higher than the 0.7% that occurs in normal elderly,22 and similar to the previous report (6.1%) of subjects with cognitive impairment and patients with AD in a
Figure 2
Representative images of progressive, disseminated cSS (patient 11)
(A) Gradient-recalled echo T2* MRI of cSS baseline. (B) At 1-year follow-up, cSS showed progression in both the severity and the number of sulci involved. cSS 5 cortical superficial siderosis.
memory clinic population.4,9 Second, although the underlying clinically defined types of cognitive impairment among the 12 patients with cSS were heterogeneous (ADCI, n 5 6; SVCI, n 5 6), cSS was not found in patients with SVCI who had negative PiB scans (“pure” SVCI). Third, higher PiB retention ratio, existence of strictly lobar CMBs, and APOE e2 allele were independent predictive factors for cSS, supporting the hypothesis that cSS is associated with CAA, and with an increased vessel fragility related to APOE genotype. Fourth, onethird of patients with cSS exhibited progression of cSS in severity or in the number of affected sulci. Our findings demonstrated that cSS does not develop in patients with amyloid-negative SVCI, thus supporting the hypothesis that cSS is more suggestive of an amyloid than ischemic etiology. Our results also suggested that cSS is closely associated with vascular amyloid (CAA) for the following reasons. First, the amyloid burden of patients with cSS was significantly higher compared with that of patients without cSS. The same results were observed when subjects with cSS and PiB-positive subjects without cSS were compared, albeit only in ADCI not in SVCI and the combined groups. This discrepancy between the groups may have resulted from the fact that patients with SVCI have dual pathology (amyloid and ischemia) whereby ischemia may interfere with b-amyloid clearance, thus leading to greater amyloid burden than in patients with ADCI who have single amyloid pathology. Second, strictly lobar CMBs and APOE e2 allele were independent predictive factors for cSS. CMBs are often regarded as a neuroimaging marker of SVD with relevance to cerebrovascular disease, cognitive impairment, and normal aging.10,23–26 Several recent reports, however, have suggested that CMBs strictly restricted to lobar areas are more likely to be associated with CAA.10,22 APOE e2 is known to be a risk factor for CAA-related hemorrhage associated with weakening of amyloid-laden blood vessels.27 In this regard, extra caution may be required when using antiplatelets or anticoagulation agents in patients with cSS and APOE e2 allele, because they may have a higher risk of ICH.27–29 Previous imaging and pathology studies have suggested that amyloid distribution of CAA has an occipital predilection.30 Therefore, we expected that an SPM analysis of PiB-PET comparing patients with and without cSS would highlight occipital areas. In this study, however, the relative occipital to global cortical PiB retention of ADCI patients with cSS was not significantly higher than that of ADCI patients without cSS. Therefore, CAA cases might not entirely account for the development of cSS. In other words, our patients with cSS would not necessarily correspond to patients in a prehemorrhagic stage who Neurology 84
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ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
otherwise fit with Boston CAA criteria. However, we cannot exclude the possibility that the absence of occipital predilection in our study may be partly attributable to the fact that our SPM analysis involved ADCI or SVCI patients with cSS whereas the prior study investigated patients with CAA without dementia. Given the fact that our patients with cSS harbored higher PiB burden than other typical patients with AD, we can assume that our patients with dementia and cSS are in advanced stages regarding amyloid deposition. Therefore, the occipital pattern that might have been shown in earlier stages may have progressed to a more global advanced amyloid depositing pattern of ADCI pathology. During the follow-up period of this study, several important characteristics of cSS were observed. First, we noticed that cSS did not fade or disappear with time. Instead, cSS progressed in one-third of patients with baseline cSS. Two of the 4 patients with progressive cSS were initially classified as focal, but subsequently developed disseminated cSS. Second, 2 patients experienced ICH after the detection of cSS. This is in line with previous studies suggesting that cSS increases the risk of future ICH.4,8 Third, cSS development did not necessarily have a direct relation to the severity of cognitive impairment. In this study, cSS and non-cSS groups did not differ in CDR and CDR-SB. Moreover, the final diagnosis was evenly distributed among the 4 disease categories in the patients with cSS (aMCI, n 5 3; AD, n 5 3; svMCI, n 5 3; SVaD, n 5 3) (table e-1). Lastly, 2 patients with progressive disseminated cSS experienced recurrent transient neurologic symptoms. The other 10 patients did not complain of any sudden focal neurologic symptoms, which may be interpreted as asymptomatic cSS. This finding was inconsistent with previous studies which reported that patients often present focal neurologic symptoms during cSS development.3,4 There are 3 possible explanations for this discrepancy. First, focal neurologic symptoms may occur only in patients with severe cSS, given that both patients had progressive, disseminated cSS. Second, we cannot exclude the possibility that the symptoms could not be detected because of underlying cognitive impairment, or the CSS in our patients spared eloquent areas such as central sulcus (e.g., only 1 of the 12 patients had cSS in the central sulcus). Lastly, previous studies were performed mainly in stroke clinics,3,8 whereas this study was performed in a memory disorder clinic. Further research is needed to investigate these possible interpretations. This study has several limitations. First, pathologic confirmation was not performed, which weakens our finding of the associations between cSS, and CAA or AD. Second, with only 12 patients with cSS, statistical power was limited. Third, we only repeated GRE 854
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MRIs in 66.4% and not all patients. Lastly, the patients in this study all had cognitive impairment, which may limit the generalizability of the results to other populations. However, this study has several strengths. Our study population was well characterized including full genotyping of APOE allele, standardized evaluations of cognitive impairment, standardized MRI, and in vivo amyloid imaging. Moreover, despite the limited number of patients with cSS, this study involved a fairly large population of patients with cognitive impairment, including patients with cSS, all of whom underwent in vivo amyloid imaging. AUTHOR CONTRIBUTIONS Han Kyu Na: drafting of manuscript, study concept and design, acquisition of data, analysis and interpretation. Jae-Hyun Park: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Jung-Hyun Kim: analysis and interpretation, critical revision of the manuscript for important intellectual content. Hee Jin Kim: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Sung Tae Kim: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. David J. Werring: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Sang Won Seo: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Duk L. Na: study concept and design, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision.
STUDY FUNDING This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020), and by the Samsung Medical Center Clinical Research Development Program grant (CRL108011).
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Received July 22, 2014. Accepted in final form November 5, 2014. REFERENCES 1.
2.
3.
4.
5.
6.
Linn J, Herms J, Dichgans M, et al. Subarachnoid hemosiderosis and superficial cortical hemosiderosis in cerebral amyloid angiopathy. AJNR Am J Neuroradiol 2008;29:184–186. Dhollander I, Nelissen N, Van Laere K, et al. In vivo amyloid imaging in cortical superficial siderosis. J Neurol Neurosurg Psychiatry 2011;82:469–471. Charidimou A, Jager RH, Fox Z, et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology 2013;81:626–632. Wollenweber FA, Buerger K, Mueller C, et al. Prevalence of cortical superficial siderosis in patients with cognitive impairment. J Neurol 2014;261:277–282. Linn J, Halpin A, Demaerel P, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010;74:1346–1350. Feldman HH, Maia LF, Mackenzie IRA, Forster BB, Martzke J, Woolfenden A. Superficial siderosis: a potential diagnostic marker of cerebral amyloid angiopathy in Alzheimer disease. Stroke 2008;39:2894–2897.
February 24, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Linn J, Wollenweber FA, Lummel N, et al. Superficial siderosis is a warning sign for future intracranial hemorrhage. J Neurol 2013;260:176–181. Charidimou A, Peeters AP, Jager R, et al. Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy. Neurology 2013;81:1666–1673. Zonneveld HI, Goos JD, Wattjes MP, et al. Prevalence of cortical superficial siderosis in a memory clinic population. Neurology 2014;82:698–704. Park JH, Seo SW, Kim C, et al. Pathogenesis of cerebral microbleeds: in vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol 2013;73:584–593. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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 1984;34:939–944. Erkinjuntti T, Inzitari D, Pantoni L, et al. Research criteria for subcortical vascular dementia in clinical trials. J Neural Transm Suppl 2000;59:23–30. Seo SW, Cho SS, Park A, Chin J, Na DL. Subcortical vascular versus amnestic mild cognitive impairment: comparison of cerebral glucose metabolism. J Neuroimaging 2009;19:213–219. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5-T in Alzheimer dementia and normal aging. Am J Roentgenol 1987;149:351–356. Ahn HJ, Chin J, Park A, et al. Seoul Neuropsychological Screening Battery–dementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients. J Korean Med Sci 2010;25: 1071–1076. Lee JH, Kim SH, Kim GH, et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology 2011;77:18–25. Seo SW, Lee JM, Im K, et al. Cortical thinning related to periventricular and deep white matter hyperintensities. Neurobiol Aging 2012;33:1156–1167.
18.
19.
20. 21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–174. Raposo N, Viguier A, Cuvinciuc V, et al. Cortical subarachnoid haemorrhage in the elderly: a recurrent event probably related to cerebral amyloid angiopathy. Eur J Neurol 2011;18:597–603. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965;14:61–65. Moon SY, Na DL, Seo SW, et al. Impact of white matter changes on activities of daily living in mild to moderate dementia. Eur Neurol 2011;65:223–230. Vernooij MW, Ikram MA, Hofman A, Krestin GP, Breteler MMB, van der Lugt A. Superficial siderosis in the general population. Neurology 2009;73:202–205. Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002;1:426–436. Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol 2011;70:871–880. Dierksen GA, Skehan ME, Khan MA, et al. Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol 2010;68:545–548. Werring DJ. Cerebral microbleeds: clinical and pathophysiological significance. J Neuroimaging 2007;17: 193–203. Love S, Nicoll JAR, Hughes A, Wilcock GK. APOE and cerebral amyloid angiopathy in the elderly. Neuroreport 2003;14:1535–1536. Rosand J, Hylek EM, O’Donnell HC, Greenberg SM. Cerebral amyloid angiopathy and warfarin-associated hemorrhage: a genetic and neuropathologic study. Neurology 1999;52:A503. Abstract. McCarron MO, Nicoll JAR, Ironside JW, Love S, Alberts MJ, Bone I. Cerebral amyloid angiopathy-related hemorrhage interaction of APOE epsilon 2 with putative clinical risk factors. Stroke 1999;30:1643–1646. Johnson KA, Gregas M, Becker JA, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 2007;62:229–234.
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Cortical superficial siderosis: A marker of vascular amyloid in patients with cognitive impairment Han Kyu Na, Jae-Hyun Park, Jung-Hyun Kim, et al. Neurology 2015;84;849-855 Published Online before print January 28, 2015 DOI 10.1212/WNL.0000000000001288 This information is current as of January 28, 2015 Updated Information & Services
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