Prevalence of cortical superficial siderosis in a memory clinic population
Hazel I. Zonneveld, MD Jeroen D.C. Goos, MD, PhD Mike P. Wattjes, MD, PhD Niels D. Prins, MD, PhD Philip Scheltens, MD, PhD Wiesje M. van der Flier, PhD Joost P.A. Kuijer, PhD Majon Muller, MD, PhD Frederik Barkhof, MD, PhD
Correspondence to Prof. Barkhof: [email protected]
ABSTRACT
Objective: To determine prevalence, topography, and severity of cortical superficial siderosis (SS), a recently recognized manifestation of cerebral amyloid angiopathy, and its possible association with Alzheimer disease (AD) in a memory clinic patient cohort.
Methods: We included 809 patients (56% men, aged 66 6 10 years) from the Amsterdam Dementia Cohort between November 2010 and November 2012 scanned on a 3-tesla MRI system. We analyzed prevalence and topography of cortical SS according to demographic, clinical, and MRI data. Agreement for SS detection between 2 neuroradiologists was calculated by using Cohen k.
Results: Agreement for detection of SS was excellent (unweighted k of 0.81). In 17 patients (2.1%), cortical SS was found without a known cause. The prevalence of idiopathic SS differed according to diagnostic groups (p , 0.001): nearly 5% (95% confidence interval [CI] 2.8%– 8.2%) in patients with AD (n 5 168) vs 2% (95% CI 0.7%–6.0%) in patients with mild cognitive impairment (n 5 143) and 2.5% (95% CI 0.7%–8.7%) in other types of dementia (n 5 80). By contrast, SS was not found in patients with subjective complaints (n 5 168) or in those with other disorders (n 5 157). Presence of SS was associated with APOE e4, microbleeds, and white matter hyperintensities (all p , 0.05) independent of diagnosis.
Conclusion: The prevalence of cortical SS in a memory clinic setting is higher than reported in the general population but lower than reported in cerebral amyloid angiopathy. The relatively high prevalence of SS in AD suggests that SS is a relevant radiologic manifestation of amyloid pathology in AD. Presence of SS does not seem to predict severity of AD. Further longitudinal research is needed to investigate clinical relevance. Neurology® 2014;82:698–704 GLOSSARY AD 5 Alzheimer disease; APT 5 antiplatelet therapy; CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; FSPGR 5 fast spoiled gradient recalled echo sequence; IQR 5 interquartile range; MB 5 microbleed; MCI 5 mild cognitive impairment; MMSE 5 Mini-Mental State Examination; MTA 5 medial temporal lobe atrophy; OR 5 odds ratio; rS 5 Spearman r; SAH 5 subarachnoid hemorrhage; SDH 5 subdural hematoma; SS 5 superficial siderosis; SWI 5 susceptibility-weighted imaging; TE 5 echo time; TR 5 repetition time; VaD 5 vascular dementia; WMH 5 white matter hyperintensities.
Superficial siderosis (SS) is a radiologic or pathologic finding of curvilinear hemosiderin deposits in the subpial layers of the CNS.1,2 SS can be seen on T2*-weighted or susceptibility-weighted imaging (SWI) as hypointense lines following the gyral surface.3–5 Cortical SS affects the convexity of the cerebral hemispheres, may be caused by recurrent nontraumatic focal convexity subarachnoid hemorrhages (SAHs),1,2 and has recently been linked to cerebral amyloid angiopathy (CAA), especially in patients older than 60 years.6 Cortical SS therefore differs from infratentorial SS in that it typically has no traumatic cause or discernible history.7 CAA is an agerelated disease caused by progressive deposition of b-amyloid in the media and adventitia of smaller to medium-sized cerebral arteries, arterioles and capillaries in the cerebral cortex, and the overlapping leptomeninges.7,8 These fragile amyloid-laden vessel walls may cause leakage, which may result in intracerebral hemorrhage and cerebral microbleeds (MBs).5 In addition to the ischemic consequences of CAA through reduced autoregulation, the hemorrhagic components From the Alzheimer Center and the Neuroscience Campus Amsterdam, and Departments of Radiology and Nuclear Medicine (H.I.Z., M.P.W., F.B.), Neurology (J.D.C.G., N.D.P., P.S., W.M.v.d.F.), Epidemiology and Biostatistics (W.M.v.d.F.), Physics and Medical Technology (J.P.A.K.), and Internal Medicine (M.M.), VU University Medical Center, Amsterdam, the Netherlands. 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. 698
© 2014 American Academy of Neurology
(especially MBs and SS) could potentially contribute to cognitive impairment in Alzheimer disease (AD) as well.8,9 Whether SS independently contributes to cognitive impairment is currently unknown. CAA is difficult to diagnose in vivo; the modified Boston criteria attempt to diagnose CAA with different degrees of certainty using radiologic (probable) and/or histopathologic (definitive) diagnoses.10–12 Research on the prevalence of SS so far focused on patients with histologically proven CAA (60.5%) and in the general elderly population without dementia (0.7%).12,13 Currently, systematic research on AD and other types of dementia is lacking. The aim of this study therefore was to assess the prevalence of cortical SS in a memory clinic population. Furthermore, we aimed to assess the relation between SS and clinical diagnosis and other clinical or radiologic characteristics. We hypothesized that in AD SS might be more prevalent than in the general population but less extensive than in patients with definite CAA. METHODS Patient population. In this single-center crosssectional study, we included 809 consecutive patients from the memory clinic–based Amsterdam Dementia Cohort studied between November 2010 and November 2012 and imaged using a whole-body MRI system operating at 3 tesla. All patients underwent standardized dementia screening, including medical history, physical, neurologic, neuropsychological examination, screening laboratory tests, and brain MRI. Dementia severity was assessed with the Mini-Mental State Examination (MMSE).14 Diagnoses were made in a multidisciplinary consensus meeting by a team of neurologists, neuropsychologists, a neurophysiologist, a psychiatrist, and a neuroradiologist. Diagnoses of (probable) AD were made according to the clinical criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association15 and patients fulfilled core clinical criteria according to National Institute on Aging–Alzheimer’s Association guidelines,16 diagnosis of vascular dementia (VaD) was based on National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherché et l’Enseignement en Neurosciences criteria,17 and a diagnosis of mild cognitive impairment (MCI) was based on Petersen criteria.18 If all clinical investigations were normal, patients were considered to have subjective memory complaints (i.e., criteria for MCI or major psychiatric disorder not fulfilled). The subgroup of “other dementia” entailed various diagnoses such as frontotemporal dementia19 and dementia with Lewy bodies (DLB).20 The subgroup of “other disorders” encompassed patients with other neurologic disorders such as psychiatric disorders, unclear diagnoses, or other diseases without dementia. We investigated whether there were identifiable causes for presence of SS such as stroke, aneurysmatic subarachnoid hemorrhage (SAH), subdural hematoma (SDH) due to head trauma, history of intradural surgery, or other SS mimics.1,2 We defined antiplatelet
therapy (APT) as use of thrombocyte aggregation inhibitors. Exclusion criteria were the following: no MRI available (e.g., only CT scan because of claustrophobia or metal objects), poor imaging quality (e.g., movement artifacts), or no SWI sequence available. Based on these criteria, we excluded 42 patients (5%) in total.
Standard protocol approvals, registrations, and patient consents. The study was approved by the ethics review board of the VU University Medical Center Amsterdam, and all subjects gave written informed consent for their clinical data to be used for research purposes.
MRI protocol. MRI was performed on a 3T whole-body MR system (SignaHDxt; General Electric Medical Systems, Milwaukee, WI) using an 8-channel head coil. The protocol included the following pulse sequences: 1) axial, 2-dimensional, dual-echo, T2weighted, fast spin echo (echo time [TE] 5 20.9 and 111.4 milliseconds, repetition time [TR] 5 8,380 milliseconds, voxel size 3 3 0.5 3 0.5 mm); 2) sagittal, 3-dimensional, inversion-recovery fast spoiled gradient recalled echo sequence (FSPGR) (TE 5 3.2 milliseconds, TR 5 8.1 milliseconds, voxel size 1 3 0.9 3 0.9 mm) with oblique-coronal reconstructions perpendicular to the long axis of the hippocampus; 3) sagittal, 3-dimensional, fluid-attenuated inversion recovery (TE 5 127.9 milliseconds, TR 5 8,000 milliseconds, inversion time 5 2,344 milliseconds, echo train length 5 230, voxel size 1.2 3 1 3 1 mm) with 3-mm axial reformats; and 4) axial, 3-dimensional, T2*-weighted images (gradient echo, TE 5 25 milliseconds, TR 5 30.6 milliseconds, flip angle 15°, voxel size 3 3 0.63 3 0.63 mm). SWIs were computed from the magnitude and phase of the T2* acquisitions as previous described.21 Next, minimum intensity projections were computed over a sliding-slab of 3 SWIs. SS rating and other MRI measures. Each MRI scan was rated by 1 of 2 neuroradiologists blinded to all (para)clinical data. We defined cortical SS as a linear gyriform pattern of hypointense signal on SWIs.6 MBs were defined as small, homogeneous, round foci of low signal intensity in the brain parenchyma on SWIs less than 10 mm in diameter, using previously described exclusion criteria.22 All SWIs were systematically assessed for SS and MB number. We recorded whether there was at least one MB in close vicinity (,1 cm) of SS. For classification of SS distribution and to indicate severity, we scored their extent according to the recently published Amyloid Related Imaging Abnormalities with Edema of Effusion Scale on SWIs.23 This scale was used to measure the largest—in-plane—cross-sectional diameter of a sulcal hypointensity. These sulcal hypointensities were scored according to the anatomical location in terms of lobe and side, resulting in scores for 4 regions bilaterally: frontal lobe, parietal lobe, temporal lobe, and occipital lobe. Within each region, a score of 0 to 5 is given based on spatial extent and multifocality of the abnormality with a summary score of 0 to 40 (figure). Also, we categorized SS according to the modified Boston diagnostic criteria for CAA.12 SS was classified as focal (restricted to 3 sulci) and disseminated ($ 4 sulci). White matter hyperintensities (WMH) were assessed on fluid-attenuated inversion recovery images using the Fazekas scale with scores ranging from 0 to 3 (none, punctate, early confluent, and confluent).24 In addition, the presence of large-vessel infarcts and lacunar infarcts was determined. Medial temporal lobe atrophy (MTA) was rated using a 5-point rating scale (0–4)25 and oblique-coronal FSPGR reformats. In the analysis, we used the average of the bilateral MTA scores. Interrater reliability testing. Interrater agreement was examined by scoring patients in a test set that contained 22 patients in 4 categories: only SS, only MBs, no MBs or SS, or both SS Neurology 82
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Figure
Examples of brain MRIs in 1 patient with focal SS and 1 patient with diffuse SS and focal SS
Axial susceptibility-weighted images obtained from (A) a 68-year-old man diagnosed with Alzheimer disease presenting with focal superficial siderosis (SS) in the right frontal lobe (score 4), and (B) a 67-year-old woman diagnosed with Alzheimer disease presenting with diffuse SS in the right frontal (score 5) and parietal lobe (score 5) and focal SS in the left frontal lobe (score 3). Arrows indicate superficial siderosis. The patient also had multiple microbleeds (chevrons) in the parietal lobes.
and MBs by 2 neuroradiologists with 25 and 15 years of experience with analysis of cranial MRI. They were blinded to all (para) clinical information.
APOE genotyping. DNA was isolated from 10 mL of ethylenediaminetetraacetic acid/blood and was available from 610 of 809 patients (75%). APOE genotype was determined with the LightCycler APOE mutation detection method (Roche Diagnostics GmbH, Mannheim, Germany). Patients were categorized according to APOE e4 and APOE e2 status.
Statistical analysis. All statistical analyses were performed with SPSS version 20 (IBM Corp., Armonk, NY). The prevalence of SS was calculated as percentages of the total population and per diagnosis. Prevalences were compared by means of x² test or Fisher exact test where appropriate. Comparison between groups for continuous variables was performed using Student t tests or Mann-Whitney tests where appropriate. Binary logistic regression was performed with SS presence as outcome measure and WMH, lacunar infarcts, MBs, average MTA score, and infarcts as independent variables. Age and sex were entered as covariates. We performed nonparametric Spearman correlation analyses to assess a relation between SS severity and age, MB number, WMH scores, and MMSE score. Confidence interval (CI) was calculated with Confidence Interval Analysis by the method of Wilson.26,27 The degree of agreement was defined as k statistic calculated by the method of Landis and Koch.28 RESULTS The mean age at the time of MRI was 66 6 10 years, and 450 patients (56%) were men. The median MMSE score was 25 (interquartile range [IQR] 6). Distribution of patients over the 6 diagnostic groups was as follows: subjective complaints n 5 168 (21%), MCI n 5 143 (18%), AD n 5 249 (31%), VaD n 5 12 (1.4%), other types of dementia n 5 80 (10%), and other disorders n 5 157 (9%) (table 1). We found an unweighted Cohen k for interrater agreement of SS of 0.81, signifying excellent agreement. 700
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Prevalence, location, and severity of SS. Among 809 pa-
tients, 26 (3.2%) had SS. In 9 cases, we found a cause for SS: 4 times known history of symptomatic SAH, 2 times SDH, once hemorrhagic stroke, once trauma, and once vasculitis. Our analyses thus identified 17 cases of SS (2.1%) without an identifiable cause. In the remainder, we focused on these “idiopathic” cases. SS was most often observed in the frontal lobes (59% [95% CI 36%–78%]; mean severity score 3.3), followed by parietal lobes (53% [95% CI 31%–74%]; mean severity score 3.3), occipital lobes (47% [95% CI 17%–52%]; mean severity score 1.9), and temporal lobes (24% [95% CI 10%–47%]; mean severity score 2.2). Total severity score per patient ranged from 1 to 26 with a mean of 6 6 8. Influence of diagnosis. The prevalence of SS varied according to the diagnosis (Fisher exact test p , 0.001) (table 1). Among the group of patients with subjective memory complaints, there were no cases of SS at all. The highest prevalence of 4.8% (95% CI 2.8%– 8.2%) was observed in patients with AD. Among patients with “other dementia,” 2 patients had SS (2.5% [95% CI 0.7%–8.7%]), of whom one patient had mixed pathology of DLB and VaD and the other mixed pathology of AD and VaD. Among the patients with SS, the mean severity score of SS did not differ according to the diagnosis (Kruskal-Wallis test p 5 0.32). Demographic findings and APOE status. The prevalence of idiopathic SS increased with age (p , 0.05). After adjusting for age and sex, there was an association with MMSE (SS1 median MMSE score 20 [IQR 9], SS2 median MMSE score 24 [IQR 6]; odds ratio [OR] 0.88 [95% CI 0.80–0.96], p , 0.05), and APOE e4 homozygosity vs nonhomozygosity (APOE e4/e41 5.7%, APOE e4/e42 1.1%; Fisher exact test p 5 0.02). SS prevalence did not differ by sex (women 2.8%, men 1.6%; x² 5 1.47, p 5 0.23), APOE e2 carriership (APOE e2/e21 1.7%, APOE e2/e22 1.5%; Fisher exact test p . 0.99), or APT (APT1 13%, APT2 21%; Fisher exact test p 5 0.55). There was only one patient carrying APOE e2/e2; therefore, we could not investigate the relationship between this variant and SS. Subsequently, we assessed Spearman correlations of SS severity with demographic, clinical, and radiologic characteristics. We found that SS severity increased with MB number (Spearman r [rS] 0.63, p 5 0.07). SS severity was not greater with increasing age (rS 0.023, p 5 0.93), decreasing MMSE score (rS 0.10, p 5 0.71), and WMH severity (rS 0.024, p 5 0.93). We repeated these analyses in an AD subgroup as a sensitivity analysis. All associations remained significant, except for the association between SS and MMSE (SS1 median MMSE score 19 [IQR 10],
Table 1
Baseline characteristics and imaging findings by diagnostic group Diagnostic groups
Characteristic
SMC (n 5 168)
MCI (n 5 143)
AD (n 5 249)
VaD (n 5 12)
Other types of dementia (n 5 80)
Other disorders (n 5 157)
Age, y, mean 6 SD
61 6 10
68 6 9
68 6 9
68 6 7
66 6 7
59 6 9
Men, n (%)
95 (57)
91 (64)
118 (47)
5 (48)
57 (71)
84 (54)
MMSE score, mean 6 SD
28 6 2
26 6 2
21 6 5
23 6 3
24 6 4
25 6 4
Prevalence antiplatelet use, n (%)
19 (13)
39 (31)
48 (21)
4 (44)
10 (15)
24 (18)
Prevalence idiopathic SS, n (%) [95% CI]
0 (0) [0–2.2]
0 (0) [0–24.3]
a
2 (2.5) [0.7–8.7]
3 (2.1) [0.7–6.0]
12 (4.8) [2.8–8.2]
SS focal (£3 sulci), n (%) [95% CI]
2 (1.4) [0.4–5.0]
9 (3.6) [2.0–6.7]
0 [0.0–4.6]
Disseminated (‡4 sulci), n (%) [95% CI]
1 (0.7) [0.1–3.4]
3 (1.2) [0.4–3.5]
2 (2.5) [0.7–8.7]
0 (0) [0–2.4]
WMH, n (%)
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Absent
71 (44)
32 (25)
41 (21)
0 (0)
22 (29)
50 (37)
Punctuate
71 (44)
53 (41)
105 (45)
1 (9)
33 (44)
61 (45)
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Early confluent
18 (11)
30 (23)
56 (24)
1 (9)
17 (23)
16 (12)
Confluent
3 (2)
14 (11)
25 (11)
9 (82)
3 (4)
8 (6)
Lacunar infarcts, n (%)
5 (3)
25 (9)
27 (12)
9 (82)
4 (5)
10 (7)
Lacunar infarcts BG, n (%)
2 (1)
15 (12)
19 (8)
8 (73)
2 (3)
8 (6)
Prevalence presence MBs, n (%)
36 (22)
40 (31)
79 (33)
9 (82)
19 (26)
31 (23)
Large infarcts, n (%)
1 (1)
7 (5)
8 (3)
0 (0)
0 (0)
4 (3)
MTA score, mean 6 SD
0.4 6 0.5
0.9 6 0.8
1.4 6 0.8
1.0 6 0.7
1.2 6 0.9
0.5 6 0.7
Abbreviations: AD 5 Alzheimer disease; BG 5 basal ganglia; CI 5 confidence interval; MBs 5 microbleeds; MCI 5 mild cognitive impairment; MMSE 5 Mini-Mental State Examination; MTA 5 medial temporal lobe atrophy; SMC 5 subjective memory complaints; SS 5 superficial siderosis; VaD 5 vascular dementia; WMH 5 white matter hyperintensities. Availability of complete data: WMH 747/809 (92%), lacunar infarcts 749/809 (93%), lacunar infarcts BG 748/809 (93%), MBs 749/809 (93%), large infarcts 752/809 (93%), and MTA 749/809 (93%). a One patient with mixed pathology of dementia with Lewy bodies and VaD; one patient with mixed pathology of AD and VaD.
701
SS2 median MMSE score 21 [IQR 6]; OR 0.93 [95% CI 0.83–1.05], p . 0.05) and between SS and age (p 5 0.19). Neuroimaging findings. Logistic regression analyses revealed that after adjustment for age and sex, the presence of SS was associated with presence of MBs, severity of WMH, and MTA. There was no association with presence of large infarcts, lacunar infarcts, or more specifically, lacunar infarcts in basal ganglia (table 2). When all MRI measures were entered simultaneously, associations with WMH (OR [95% CI] 2.4 [1.2–4.8]) for every step progression of WMH and presence of MBs (28 [3.5–226]) remained significant, whereas the association with MTA score did not (1.9 [1.0–3.7]). Microbleeds. Sixteen of the 17 patients with SS exhibited MBs, 13 (81%) of whom had at least one MB within 1 cm of the SS location. Among patients with MBs, the mean number of MBs was higher in patients with SS (n 5 16, median 24) than in patients without SS (n 5 198, median 2), a highly significant difference (Mann-Whitney U test p , 0.001). DISCUSSION In a memory clinic population, on average across diagnostic groups, 2.1% of patients (n 5 17) had idiopathic cortical SS on 3-tesla MRI, which is nearly twice the number of patients presenting with cortical SS secondary to a known cause such as SAH and SDH (1.1%, n 5 9). In a previous study of healthy elderly subjects, a very low prevalence of 0.7% was found,13 which is similar to our group with subjective memory complaints (n 5 168): 0% (95%
Table 2
Imaging findings in patients with and without idiopathic SS SS2 (n 5 783)
SS1 (n 5 17)
OR (95% CI) 2.7 (1.8–6.1)a
WMH, n (%) Absent
223 (31)
0 (0)
Punctuate
320 (44)
4 (24)
Early confluent
133 (18)
5 (29)
Confluent
54 (7)
8 (47)b
Lacunar infarcts, n (%)
77 (11)
3 (18)
Lacunar infarcts BG, n (%)
52 (7)
2 (12)
1.1 (0.3–4.2) 1.2 (0.3–5.5) b
Prevalence presence MBs, n (%)
197 (27)
16 (94)
34 (4.6–272)
Large infarcts, n (%)
19 (2.6)
1 (5.9)
1.6 (0.2–13.6)
MTA score, mean 6 SD
0.9 6 0.9
1.7 6 0.8b
1.9 (1.1–3.1)a
Abbreviations: BG 5 basal ganglia; CI 5 confidence interval; MBs 5 microbleeds; MTA 5 medial temporal lobe atrophy; OR 5 odds ratio; SS 5 superficial siderosis; WMH 5 white matter hyperintensities. Separate logistic regression analyses adjusted for age and sex were performed for each of the MRI variables. Availability of complete data: WMH 747/809 (92%), lacunar infarcts 749/809 (93%), lacunar infarcts BG 748/809 (93%), MBs 749/809 (93%), large infarcts 752/809 (93%), and MTA 749/809 (93%). a ORs were calculated for every step progression. b p , 0.01 (comparison within presence of SS). 702
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CI 0%–2.2%). The prevalence of SS previously reported in patients with pathologically confirmed CAA was 60.5%,12 still higher than our subgroup of patients with AD with 10 or more MBs and SS (37%), who are likely to harbor CAA as well. The prevalence of SS differed according to diagnosis. Nearly 5% of patients with AD exhibited SS. The relatively high prevalence of SS in this group and the 2 patients with dementias (one patient with mixed pathology of DLB and VaD and one patient with mixed pathology of VaD and AD) provides further evidence that SS is a manifestation of amyloid pathology. Another proof that amyloid is involved in the development of SS is the occurrence of amyloidrelated imaging abnormalities including cerebral MBs and sulcal hemosiderin deposition in patients participating in clinical trials with therapeutic agents to lower b-amyloid burden in AD.29 Our finding that SS is found preferentially in the frontal, followed by parietal and occipital lobes, and is underrepresented in the temporal lobes, is largely consistent with a previous study that described the topographical distribution of SS in the general population.12 Notably, the total number of patients with SS included in that study was only 7. The study that described prevalence of SS in patients with CAA did not describe the topographical distribution of SS.12 Topographical distribution of SS seems to differ from the distribution of lobar MBs despite the fact that both conditions are amyloid-related. Previous studies revealed that lobar MBs are mainly found in the posterior regions of the brain and seem to spare the frontal lobes.30–32 While topography of MBs was not analyzed in detail in this study, we did notice that MBs occurred in proximity of SS, which might suggest focally active CAA-related angiopathy. Disseminated SS was found in only 25% of AD patients with SS. Therefore, we think that disseminated SS may be more suggestive for CAA than for AD, despite the fact that both conditions are amyloid-related.33 We hypothesize that there are different types of amyloid deposition (parenchymal vs leptomeningeal), which are responsible for different patterns in distribution between SS and MBs. The distribution of SS seems to be more in line with PET data in AD, showing highest uptake of amyloid in the frontal and parietal lobes.34 The mean MMSE score in patients with SS differed significantly from the group of patients without SS; however, this was mostly driven by the diagnosis of AD than by its severity. In our study, the strongest independent radiologic predictors for SS were the presence of one or more MBs and WMH severity. Furthermore, we found a correlation between SS severity and MB number. Earlier studies reporting on prevalence of lobar MBs in AD were not able to show any relation between MB occurrence and
cognitive performance.14,32,35,36 One study, however, demonstrated that patients with AD with multiple MBs presented with more severe cognitive impairment.37 Whether SS itself contributes to cognitive decline thus remains uncertain. APOE e4/e4 status and APOE e2 status genotypes have been associated with CAA and macrohemorrhages.38 CAA is strongly associated with lobar MBs.39,40 Some studies showed associations of APOE e4 homozygosity with lobar MBs.30,41 We found a similar association between APOE e4 homozygosity and SS presence. This again reinforces the notion that both phenomena share pathophysiologic mechanisms and are amyloid-related. Limitations of our study include the crosssectional design and the retrospective nature of the study. Although our total population was large, the group of patients with SS was still relatively small. Another limitation is the lack of histopathologic confirmation of the underlying small-vessel pathology— CAA. A possible selection bias might stem from the fact that SS is a relatively new phenomenon, resulting in an underestimation of the presence of SS; however, we saw a good interobserver agreement. Conversely, small blood vessels may resemble SS, potentially leading to overestimation; this is likely to be a minor effect because no SS was scored in a large number of subjective memory complaint cases. In general, there is a lack of longitudinal studies of SS. Further studies should investigate whether the presence of SS affects the prognosis of a patient and whether there is an accelerated cognitive decline in patients with SS. We do not know whether resolution of SS can occur over time; this has been shown to be a minor effect for MBs. Currently, the clinical symptomatology of SS remains unclear and further longitudinal research needs to be conducted to investigate these; transient focal neurologic episodes or “amyloid spells” have been described in 15% of patients with CAA. Exact pathophysiology (spreading cortical depression, seizurelike activity, or ischemic/bleeding) remains unclear. However, they may relate to MBs or SS.42 This study showed that the prevalence of SS in a large cohort of patients attending a memory clinic is higher than previously described in a communitybased sample and lower than reported in patients with CAA. The finding of a relatively high proportion of SS in patients with AD provides further evidence that SS is a manifestation of amyloid pathology. Although our results indicate that SS is not a sensitive AD marker, idiopathic SS seems to be more specific for AD than the presence of lobar MBs. AUTHOR CONTRIBUTIONS Hazel Zonneveld, Dr. Goos, Dr. Wattjes, Dr. van der Flier, and Dr. Barkhof designed the study. Dr. Goos collected the data. Hazel Zonneveld, Dr. Goos, Dr. Wattjes, Dr. Barkhof, and Dr. van der Flier analyzed and interpreted the
data. Hazel Zonneveld and Dr. Goos, Dr. Wattjes, Dr. van der Flier, Dr. Barkhof wrote the manuscript. Dr. Prins, Dr. Scheltens, Dr. Kuijer, and Dr. Muller revised the manuscript. Hazel Zonneveld and Dr. van der Flier completed the statistical analysis.
ACKNOWLEDGMENT The authors thank Dr. P.J. Kostense for his statistical assistance.
STUDY FUNDING Research of the VUmc Alzheimer Center is part of the neurodegeneration research program of the Neuroscience Campus Amsterdam. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte.
DISCLOSURE H. Zonneveld and J. Goos report no disclosures. M. Wattjes received payment for consultancy for Biogen Idec, and has received payment for lectures for Biogen Idec, Bayer Healthcare, Roche, and Janssen-Cilag. N. Prins serves on the advisory board of Boehringer Ingelheim and Envivo. He has been a speaker at symposia organized by Janssen and Novartis. N.D.P. has a senior fellowship at the Alzheimer Center VUmc partly supported by Vereniging AEGON and receives research support from the Brain Foundation of the Netherlands and Alzheimer Nederland. N.D.P. receives no personal compensation for the activities mentioned above. P. Scheltens receives grant support (for the institution) from GE Healthcare, Danone Research, and Merck. In the past 2 years, he has received speaker’s fees (paid to the institution) from Lilly, GE Healthcare, Lundbeck, Danone, and Janssen AI-Pfizer. W. van der Flier, J. Kuijer, and M. Muller report no disclosures. F. Barkhof received grant funds from the Dutch MS Society and EU-FP7, and received payment for consultancy from Bayer Schering Pharma, Sanofi-Aventis, Biogen Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, and Janssen Research, and received payment for development of educational presentations for the Serono Symposium Foundation. Go to Neurology.org for full disclosures.
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Prevalence of cortical superficial siderosis in a memory clinic population Hazel I. Zonneveld, Jeroen D.C. Goos, Mike P. Wattjes, et al. Neurology 2014;82;698-704 Published Online before print January 29, 2014 DOI 10.1212/WNL.0000000000000150 This information is current as of January 29, 2014 Updated Information & Services
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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 © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Hazel I. Zonneveld, MD Jeroen D.C. Goos, MD, PhD Mike P. Wattjes, MD, PhD Niels D. Prins, MD, PhD Philip Scheltens, MD, PhD Wiesje M. van der Flier, PhD Joost P.A. Kuijer, PhD Majon Muller, MD, PhD Frederik Barkhof, MD, PhD
Correspondence to Prof. Barkhof: [email protected]
ABSTRACT
Objective: To determine prevalence, topography, and severity of cortical superficial siderosis (SS), a recently recognized manifestation of cerebral amyloid angiopathy, and its possible association with Alzheimer disease (AD) in a memory clinic patient cohort.
Methods: We included 809 patients (56% men, aged 66 6 10 years) from the Amsterdam Dementia Cohort between November 2010 and November 2012 scanned on a 3-tesla MRI system. We analyzed prevalence and topography of cortical SS according to demographic, clinical, and MRI data. Agreement for SS detection between 2 neuroradiologists was calculated by using Cohen k.
Results: Agreement for detection of SS was excellent (unweighted k of 0.81). In 17 patients (2.1%), cortical SS was found without a known cause. The prevalence of idiopathic SS differed according to diagnostic groups (p , 0.001): nearly 5% (95% confidence interval [CI] 2.8%– 8.2%) in patients with AD (n 5 168) vs 2% (95% CI 0.7%–6.0%) in patients with mild cognitive impairment (n 5 143) and 2.5% (95% CI 0.7%–8.7%) in other types of dementia (n 5 80). By contrast, SS was not found in patients with subjective complaints (n 5 168) or in those with other disorders (n 5 157). Presence of SS was associated with APOE e4, microbleeds, and white matter hyperintensities (all p , 0.05) independent of diagnosis.
Conclusion: The prevalence of cortical SS in a memory clinic setting is higher than reported in the general population but lower than reported in cerebral amyloid angiopathy. The relatively high prevalence of SS in AD suggests that SS is a relevant radiologic manifestation of amyloid pathology in AD. Presence of SS does not seem to predict severity of AD. Further longitudinal research is needed to investigate clinical relevance. Neurology® 2014;82:698–704 GLOSSARY AD 5 Alzheimer disease; APT 5 antiplatelet therapy; CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; FSPGR 5 fast spoiled gradient recalled echo sequence; IQR 5 interquartile range; MB 5 microbleed; MCI 5 mild cognitive impairment; MMSE 5 Mini-Mental State Examination; MTA 5 medial temporal lobe atrophy; OR 5 odds ratio; rS 5 Spearman r; SAH 5 subarachnoid hemorrhage; SDH 5 subdural hematoma; SS 5 superficial siderosis; SWI 5 susceptibility-weighted imaging; TE 5 echo time; TR 5 repetition time; VaD 5 vascular dementia; WMH 5 white matter hyperintensities.
Superficial siderosis (SS) is a radiologic or pathologic finding of curvilinear hemosiderin deposits in the subpial layers of the CNS.1,2 SS can be seen on T2*-weighted or susceptibility-weighted imaging (SWI) as hypointense lines following the gyral surface.3–5 Cortical SS affects the convexity of the cerebral hemispheres, may be caused by recurrent nontraumatic focal convexity subarachnoid hemorrhages (SAHs),1,2 and has recently been linked to cerebral amyloid angiopathy (CAA), especially in patients older than 60 years.6 Cortical SS therefore differs from infratentorial SS in that it typically has no traumatic cause or discernible history.7 CAA is an agerelated disease caused by progressive deposition of b-amyloid in the media and adventitia of smaller to medium-sized cerebral arteries, arterioles and capillaries in the cerebral cortex, and the overlapping leptomeninges.7,8 These fragile amyloid-laden vessel walls may cause leakage, which may result in intracerebral hemorrhage and cerebral microbleeds (MBs).5 In addition to the ischemic consequences of CAA through reduced autoregulation, the hemorrhagic components From the Alzheimer Center and the Neuroscience Campus Amsterdam, and Departments of Radiology and Nuclear Medicine (H.I.Z., M.P.W., F.B.), Neurology (J.D.C.G., N.D.P., P.S., W.M.v.d.F.), Epidemiology and Biostatistics (W.M.v.d.F.), Physics and Medical Technology (J.P.A.K.), and Internal Medicine (M.M.), VU University Medical Center, Amsterdam, the Netherlands. 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. 698
© 2014 American Academy of Neurology
(especially MBs and SS) could potentially contribute to cognitive impairment in Alzheimer disease (AD) as well.8,9 Whether SS independently contributes to cognitive impairment is currently unknown. CAA is difficult to diagnose in vivo; the modified Boston criteria attempt to diagnose CAA with different degrees of certainty using radiologic (probable) and/or histopathologic (definitive) diagnoses.10–12 Research on the prevalence of SS so far focused on patients with histologically proven CAA (60.5%) and in the general elderly population without dementia (0.7%).12,13 Currently, systematic research on AD and other types of dementia is lacking. The aim of this study therefore was to assess the prevalence of cortical SS in a memory clinic population. Furthermore, we aimed to assess the relation between SS and clinical diagnosis and other clinical or radiologic characteristics. We hypothesized that in AD SS might be more prevalent than in the general population but less extensive than in patients with definite CAA. METHODS Patient population. In this single-center crosssectional study, we included 809 consecutive patients from the memory clinic–based Amsterdam Dementia Cohort studied between November 2010 and November 2012 and imaged using a whole-body MRI system operating at 3 tesla. All patients underwent standardized dementia screening, including medical history, physical, neurologic, neuropsychological examination, screening laboratory tests, and brain MRI. Dementia severity was assessed with the Mini-Mental State Examination (MMSE).14 Diagnoses were made in a multidisciplinary consensus meeting by a team of neurologists, neuropsychologists, a neurophysiologist, a psychiatrist, and a neuroradiologist. Diagnoses of (probable) AD were made according to the clinical criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association15 and patients fulfilled core clinical criteria according to National Institute on Aging–Alzheimer’s Association guidelines,16 diagnosis of vascular dementia (VaD) was based on National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherché et l’Enseignement en Neurosciences criteria,17 and a diagnosis of mild cognitive impairment (MCI) was based on Petersen criteria.18 If all clinical investigations were normal, patients were considered to have subjective memory complaints (i.e., criteria for MCI or major psychiatric disorder not fulfilled). The subgroup of “other dementia” entailed various diagnoses such as frontotemporal dementia19 and dementia with Lewy bodies (DLB).20 The subgroup of “other disorders” encompassed patients with other neurologic disorders such as psychiatric disorders, unclear diagnoses, or other diseases without dementia. We investigated whether there were identifiable causes for presence of SS such as stroke, aneurysmatic subarachnoid hemorrhage (SAH), subdural hematoma (SDH) due to head trauma, history of intradural surgery, or other SS mimics.1,2 We defined antiplatelet
therapy (APT) as use of thrombocyte aggregation inhibitors. Exclusion criteria were the following: no MRI available (e.g., only CT scan because of claustrophobia or metal objects), poor imaging quality (e.g., movement artifacts), or no SWI sequence available. Based on these criteria, we excluded 42 patients (5%) in total.
Standard protocol approvals, registrations, and patient consents. The study was approved by the ethics review board of the VU University Medical Center Amsterdam, and all subjects gave written informed consent for their clinical data to be used for research purposes.
MRI protocol. MRI was performed on a 3T whole-body MR system (SignaHDxt; General Electric Medical Systems, Milwaukee, WI) using an 8-channel head coil. The protocol included the following pulse sequences: 1) axial, 2-dimensional, dual-echo, T2weighted, fast spin echo (echo time [TE] 5 20.9 and 111.4 milliseconds, repetition time [TR] 5 8,380 milliseconds, voxel size 3 3 0.5 3 0.5 mm); 2) sagittal, 3-dimensional, inversion-recovery fast spoiled gradient recalled echo sequence (FSPGR) (TE 5 3.2 milliseconds, TR 5 8.1 milliseconds, voxel size 1 3 0.9 3 0.9 mm) with oblique-coronal reconstructions perpendicular to the long axis of the hippocampus; 3) sagittal, 3-dimensional, fluid-attenuated inversion recovery (TE 5 127.9 milliseconds, TR 5 8,000 milliseconds, inversion time 5 2,344 milliseconds, echo train length 5 230, voxel size 1.2 3 1 3 1 mm) with 3-mm axial reformats; and 4) axial, 3-dimensional, T2*-weighted images (gradient echo, TE 5 25 milliseconds, TR 5 30.6 milliseconds, flip angle 15°, voxel size 3 3 0.63 3 0.63 mm). SWIs were computed from the magnitude and phase of the T2* acquisitions as previous described.21 Next, minimum intensity projections were computed over a sliding-slab of 3 SWIs. SS rating and other MRI measures. Each MRI scan was rated by 1 of 2 neuroradiologists blinded to all (para)clinical data. We defined cortical SS as a linear gyriform pattern of hypointense signal on SWIs.6 MBs were defined as small, homogeneous, round foci of low signal intensity in the brain parenchyma on SWIs less than 10 mm in diameter, using previously described exclusion criteria.22 All SWIs were systematically assessed for SS and MB number. We recorded whether there was at least one MB in close vicinity (,1 cm) of SS. For classification of SS distribution and to indicate severity, we scored their extent according to the recently published Amyloid Related Imaging Abnormalities with Edema of Effusion Scale on SWIs.23 This scale was used to measure the largest—in-plane—cross-sectional diameter of a sulcal hypointensity. These sulcal hypointensities were scored according to the anatomical location in terms of lobe and side, resulting in scores for 4 regions bilaterally: frontal lobe, parietal lobe, temporal lobe, and occipital lobe. Within each region, a score of 0 to 5 is given based on spatial extent and multifocality of the abnormality with a summary score of 0 to 40 (figure). Also, we categorized SS according to the modified Boston diagnostic criteria for CAA.12 SS was classified as focal (restricted to 3 sulci) and disseminated ($ 4 sulci). White matter hyperintensities (WMH) were assessed on fluid-attenuated inversion recovery images using the Fazekas scale with scores ranging from 0 to 3 (none, punctate, early confluent, and confluent).24 In addition, the presence of large-vessel infarcts and lacunar infarcts was determined. Medial temporal lobe atrophy (MTA) was rated using a 5-point rating scale (0–4)25 and oblique-coronal FSPGR reformats. In the analysis, we used the average of the bilateral MTA scores. Interrater reliability testing. Interrater agreement was examined by scoring patients in a test set that contained 22 patients in 4 categories: only SS, only MBs, no MBs or SS, or both SS Neurology 82
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Figure
Examples of brain MRIs in 1 patient with focal SS and 1 patient with diffuse SS and focal SS
Axial susceptibility-weighted images obtained from (A) a 68-year-old man diagnosed with Alzheimer disease presenting with focal superficial siderosis (SS) in the right frontal lobe (score 4), and (B) a 67-year-old woman diagnosed with Alzheimer disease presenting with diffuse SS in the right frontal (score 5) and parietal lobe (score 5) and focal SS in the left frontal lobe (score 3). Arrows indicate superficial siderosis. The patient also had multiple microbleeds (chevrons) in the parietal lobes.
and MBs by 2 neuroradiologists with 25 and 15 years of experience with analysis of cranial MRI. They were blinded to all (para) clinical information.
APOE genotyping. DNA was isolated from 10 mL of ethylenediaminetetraacetic acid/blood and was available from 610 of 809 patients (75%). APOE genotype was determined with the LightCycler APOE mutation detection method (Roche Diagnostics GmbH, Mannheim, Germany). Patients were categorized according to APOE e4 and APOE e2 status.
Statistical analysis. All statistical analyses were performed with SPSS version 20 (IBM Corp., Armonk, NY). The prevalence of SS was calculated as percentages of the total population and per diagnosis. Prevalences were compared by means of x² test or Fisher exact test where appropriate. Comparison between groups for continuous variables was performed using Student t tests or Mann-Whitney tests where appropriate. Binary logistic regression was performed with SS presence as outcome measure and WMH, lacunar infarcts, MBs, average MTA score, and infarcts as independent variables. Age and sex were entered as covariates. We performed nonparametric Spearman correlation analyses to assess a relation between SS severity and age, MB number, WMH scores, and MMSE score. Confidence interval (CI) was calculated with Confidence Interval Analysis by the method of Wilson.26,27 The degree of agreement was defined as k statistic calculated by the method of Landis and Koch.28 RESULTS The mean age at the time of MRI was 66 6 10 years, and 450 patients (56%) were men. The median MMSE score was 25 (interquartile range [IQR] 6). Distribution of patients over the 6 diagnostic groups was as follows: subjective complaints n 5 168 (21%), MCI n 5 143 (18%), AD n 5 249 (31%), VaD n 5 12 (1.4%), other types of dementia n 5 80 (10%), and other disorders n 5 157 (9%) (table 1). We found an unweighted Cohen k for interrater agreement of SS of 0.81, signifying excellent agreement. 700
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Prevalence, location, and severity of SS. Among 809 pa-
tients, 26 (3.2%) had SS. In 9 cases, we found a cause for SS: 4 times known history of symptomatic SAH, 2 times SDH, once hemorrhagic stroke, once trauma, and once vasculitis. Our analyses thus identified 17 cases of SS (2.1%) without an identifiable cause. In the remainder, we focused on these “idiopathic” cases. SS was most often observed in the frontal lobes (59% [95% CI 36%–78%]; mean severity score 3.3), followed by parietal lobes (53% [95% CI 31%–74%]; mean severity score 3.3), occipital lobes (47% [95% CI 17%–52%]; mean severity score 1.9), and temporal lobes (24% [95% CI 10%–47%]; mean severity score 2.2). Total severity score per patient ranged from 1 to 26 with a mean of 6 6 8. Influence of diagnosis. The prevalence of SS varied according to the diagnosis (Fisher exact test p , 0.001) (table 1). Among the group of patients with subjective memory complaints, there were no cases of SS at all. The highest prevalence of 4.8% (95% CI 2.8%– 8.2%) was observed in patients with AD. Among patients with “other dementia,” 2 patients had SS (2.5% [95% CI 0.7%–8.7%]), of whom one patient had mixed pathology of DLB and VaD and the other mixed pathology of AD and VaD. Among the patients with SS, the mean severity score of SS did not differ according to the diagnosis (Kruskal-Wallis test p 5 0.32). Demographic findings and APOE status. The prevalence of idiopathic SS increased with age (p , 0.05). After adjusting for age and sex, there was an association with MMSE (SS1 median MMSE score 20 [IQR 9], SS2 median MMSE score 24 [IQR 6]; odds ratio [OR] 0.88 [95% CI 0.80–0.96], p , 0.05), and APOE e4 homozygosity vs nonhomozygosity (APOE e4/e41 5.7%, APOE e4/e42 1.1%; Fisher exact test p 5 0.02). SS prevalence did not differ by sex (women 2.8%, men 1.6%; x² 5 1.47, p 5 0.23), APOE e2 carriership (APOE e2/e21 1.7%, APOE e2/e22 1.5%; Fisher exact test p . 0.99), or APT (APT1 13%, APT2 21%; Fisher exact test p 5 0.55). There was only one patient carrying APOE e2/e2; therefore, we could not investigate the relationship between this variant and SS. Subsequently, we assessed Spearman correlations of SS severity with demographic, clinical, and radiologic characteristics. We found that SS severity increased with MB number (Spearman r [rS] 0.63, p 5 0.07). SS severity was not greater with increasing age (rS 0.023, p 5 0.93), decreasing MMSE score (rS 0.10, p 5 0.71), and WMH severity (rS 0.024, p 5 0.93). We repeated these analyses in an AD subgroup as a sensitivity analysis. All associations remained significant, except for the association between SS and MMSE (SS1 median MMSE score 19 [IQR 10],
Table 1
Baseline characteristics and imaging findings by diagnostic group Diagnostic groups
Characteristic
SMC (n 5 168)
MCI (n 5 143)
AD (n 5 249)
VaD (n 5 12)
Other types of dementia (n 5 80)
Other disorders (n 5 157)
Age, y, mean 6 SD
61 6 10
68 6 9
68 6 9
68 6 7
66 6 7
59 6 9
Men, n (%)
95 (57)
91 (64)
118 (47)
5 (48)
57 (71)
84 (54)
MMSE score, mean 6 SD
28 6 2
26 6 2
21 6 5
23 6 3
24 6 4
25 6 4
Prevalence antiplatelet use, n (%)
19 (13)
39 (31)
48 (21)
4 (44)
10 (15)
24 (18)
Prevalence idiopathic SS, n (%) [95% CI]
0 (0) [0–2.2]
0 (0) [0–24.3]
a
2 (2.5) [0.7–8.7]
3 (2.1) [0.7–6.0]
12 (4.8) [2.8–8.2]
SS focal (£3 sulci), n (%) [95% CI]
2 (1.4) [0.4–5.0]
9 (3.6) [2.0–6.7]
0 [0.0–4.6]
Disseminated (‡4 sulci), n (%) [95% CI]
1 (0.7) [0.1–3.4]
3 (1.2) [0.4–3.5]
2 (2.5) [0.7–8.7]
0 (0) [0–2.4]
WMH, n (%)
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Absent
71 (44)
32 (25)
41 (21)
0 (0)
22 (29)
50 (37)
Punctuate
71 (44)
53 (41)
105 (45)
1 (9)
33 (44)
61 (45)
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Early confluent
18 (11)
30 (23)
56 (24)
1 (9)
17 (23)
16 (12)
Confluent
3 (2)
14 (11)
25 (11)
9 (82)
3 (4)
8 (6)
Lacunar infarcts, n (%)
5 (3)
25 (9)
27 (12)
9 (82)
4 (5)
10 (7)
Lacunar infarcts BG, n (%)
2 (1)
15 (12)
19 (8)
8 (73)
2 (3)
8 (6)
Prevalence presence MBs, n (%)
36 (22)
40 (31)
79 (33)
9 (82)
19 (26)
31 (23)
Large infarcts, n (%)
1 (1)
7 (5)
8 (3)
0 (0)
0 (0)
4 (3)
MTA score, mean 6 SD
0.4 6 0.5
0.9 6 0.8
1.4 6 0.8
1.0 6 0.7
1.2 6 0.9
0.5 6 0.7
Abbreviations: AD 5 Alzheimer disease; BG 5 basal ganglia; CI 5 confidence interval; MBs 5 microbleeds; MCI 5 mild cognitive impairment; MMSE 5 Mini-Mental State Examination; MTA 5 medial temporal lobe atrophy; SMC 5 subjective memory complaints; SS 5 superficial siderosis; VaD 5 vascular dementia; WMH 5 white matter hyperintensities. Availability of complete data: WMH 747/809 (92%), lacunar infarcts 749/809 (93%), lacunar infarcts BG 748/809 (93%), MBs 749/809 (93%), large infarcts 752/809 (93%), and MTA 749/809 (93%). a One patient with mixed pathology of dementia with Lewy bodies and VaD; one patient with mixed pathology of AD and VaD.
701
SS2 median MMSE score 21 [IQR 6]; OR 0.93 [95% CI 0.83–1.05], p . 0.05) and between SS and age (p 5 0.19). Neuroimaging findings. Logistic regression analyses revealed that after adjustment for age and sex, the presence of SS was associated with presence of MBs, severity of WMH, and MTA. There was no association with presence of large infarcts, lacunar infarcts, or more specifically, lacunar infarcts in basal ganglia (table 2). When all MRI measures were entered simultaneously, associations with WMH (OR [95% CI] 2.4 [1.2–4.8]) for every step progression of WMH and presence of MBs (28 [3.5–226]) remained significant, whereas the association with MTA score did not (1.9 [1.0–3.7]). Microbleeds. Sixteen of the 17 patients with SS exhibited MBs, 13 (81%) of whom had at least one MB within 1 cm of the SS location. Among patients with MBs, the mean number of MBs was higher in patients with SS (n 5 16, median 24) than in patients without SS (n 5 198, median 2), a highly significant difference (Mann-Whitney U test p , 0.001). DISCUSSION In a memory clinic population, on average across diagnostic groups, 2.1% of patients (n 5 17) had idiopathic cortical SS on 3-tesla MRI, which is nearly twice the number of patients presenting with cortical SS secondary to a known cause such as SAH and SDH (1.1%, n 5 9). In a previous study of healthy elderly subjects, a very low prevalence of 0.7% was found,13 which is similar to our group with subjective memory complaints (n 5 168): 0% (95%
Table 2
Imaging findings in patients with and without idiopathic SS SS2 (n 5 783)
SS1 (n 5 17)
OR (95% CI) 2.7 (1.8–6.1)a
WMH, n (%) Absent
223 (31)
0 (0)
Punctuate
320 (44)
4 (24)
Early confluent
133 (18)
5 (29)
Confluent
54 (7)
8 (47)b
Lacunar infarcts, n (%)
77 (11)
3 (18)
Lacunar infarcts BG, n (%)
52 (7)
2 (12)
1.1 (0.3–4.2) 1.2 (0.3–5.5) b
Prevalence presence MBs, n (%)
197 (27)
16 (94)
34 (4.6–272)
Large infarcts, n (%)
19 (2.6)
1 (5.9)
1.6 (0.2–13.6)
MTA score, mean 6 SD
0.9 6 0.9
1.7 6 0.8b
1.9 (1.1–3.1)a
Abbreviations: BG 5 basal ganglia; CI 5 confidence interval; MBs 5 microbleeds; MTA 5 medial temporal lobe atrophy; OR 5 odds ratio; SS 5 superficial siderosis; WMH 5 white matter hyperintensities. Separate logistic regression analyses adjusted for age and sex were performed for each of the MRI variables. Availability of complete data: WMH 747/809 (92%), lacunar infarcts 749/809 (93%), lacunar infarcts BG 748/809 (93%), MBs 749/809 (93%), large infarcts 752/809 (93%), and MTA 749/809 (93%). a ORs were calculated for every step progression. b p , 0.01 (comparison within presence of SS). 702
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CI 0%–2.2%). The prevalence of SS previously reported in patients with pathologically confirmed CAA was 60.5%,12 still higher than our subgroup of patients with AD with 10 or more MBs and SS (37%), who are likely to harbor CAA as well. The prevalence of SS differed according to diagnosis. Nearly 5% of patients with AD exhibited SS. The relatively high prevalence of SS in this group and the 2 patients with dementias (one patient with mixed pathology of DLB and VaD and one patient with mixed pathology of VaD and AD) provides further evidence that SS is a manifestation of amyloid pathology. Another proof that amyloid is involved in the development of SS is the occurrence of amyloidrelated imaging abnormalities including cerebral MBs and sulcal hemosiderin deposition in patients participating in clinical trials with therapeutic agents to lower b-amyloid burden in AD.29 Our finding that SS is found preferentially in the frontal, followed by parietal and occipital lobes, and is underrepresented in the temporal lobes, is largely consistent with a previous study that described the topographical distribution of SS in the general population.12 Notably, the total number of patients with SS included in that study was only 7. The study that described prevalence of SS in patients with CAA did not describe the topographical distribution of SS.12 Topographical distribution of SS seems to differ from the distribution of lobar MBs despite the fact that both conditions are amyloid-related. Previous studies revealed that lobar MBs are mainly found in the posterior regions of the brain and seem to spare the frontal lobes.30–32 While topography of MBs was not analyzed in detail in this study, we did notice that MBs occurred in proximity of SS, which might suggest focally active CAA-related angiopathy. Disseminated SS was found in only 25% of AD patients with SS. Therefore, we think that disseminated SS may be more suggestive for CAA than for AD, despite the fact that both conditions are amyloid-related.33 We hypothesize that there are different types of amyloid deposition (parenchymal vs leptomeningeal), which are responsible for different patterns in distribution between SS and MBs. The distribution of SS seems to be more in line with PET data in AD, showing highest uptake of amyloid in the frontal and parietal lobes.34 The mean MMSE score in patients with SS differed significantly from the group of patients without SS; however, this was mostly driven by the diagnosis of AD than by its severity. In our study, the strongest independent radiologic predictors for SS were the presence of one or more MBs and WMH severity. Furthermore, we found a correlation between SS severity and MB number. Earlier studies reporting on prevalence of lobar MBs in AD were not able to show any relation between MB occurrence and
cognitive performance.14,32,35,36 One study, however, demonstrated that patients with AD with multiple MBs presented with more severe cognitive impairment.37 Whether SS itself contributes to cognitive decline thus remains uncertain. APOE e4/e4 status and APOE e2 status genotypes have been associated with CAA and macrohemorrhages.38 CAA is strongly associated with lobar MBs.39,40 Some studies showed associations of APOE e4 homozygosity with lobar MBs.30,41 We found a similar association between APOE e4 homozygosity and SS presence. This again reinforces the notion that both phenomena share pathophysiologic mechanisms and are amyloid-related. Limitations of our study include the crosssectional design and the retrospective nature of the study. Although our total population was large, the group of patients with SS was still relatively small. Another limitation is the lack of histopathologic confirmation of the underlying small-vessel pathology— CAA. A possible selection bias might stem from the fact that SS is a relatively new phenomenon, resulting in an underestimation of the presence of SS; however, we saw a good interobserver agreement. Conversely, small blood vessels may resemble SS, potentially leading to overestimation; this is likely to be a minor effect because no SS was scored in a large number of subjective memory complaint cases. In general, there is a lack of longitudinal studies of SS. Further studies should investigate whether the presence of SS affects the prognosis of a patient and whether there is an accelerated cognitive decline in patients with SS. We do not know whether resolution of SS can occur over time; this has been shown to be a minor effect for MBs. Currently, the clinical symptomatology of SS remains unclear and further longitudinal research needs to be conducted to investigate these; transient focal neurologic episodes or “amyloid spells” have been described in 15% of patients with CAA. Exact pathophysiology (spreading cortical depression, seizurelike activity, or ischemic/bleeding) remains unclear. However, they may relate to MBs or SS.42 This study showed that the prevalence of SS in a large cohort of patients attending a memory clinic is higher than previously described in a communitybased sample and lower than reported in patients with CAA. The finding of a relatively high proportion of SS in patients with AD provides further evidence that SS is a manifestation of amyloid pathology. Although our results indicate that SS is not a sensitive AD marker, idiopathic SS seems to be more specific for AD than the presence of lobar MBs. AUTHOR CONTRIBUTIONS Hazel Zonneveld, Dr. Goos, Dr. Wattjes, Dr. van der Flier, and Dr. Barkhof designed the study. Dr. Goos collected the data. Hazel Zonneveld, Dr. Goos, Dr. Wattjes, Dr. Barkhof, and Dr. van der Flier analyzed and interpreted the
data. Hazel Zonneveld and Dr. Goos, Dr. Wattjes, Dr. van der Flier, Dr. Barkhof wrote the manuscript. Dr. Prins, Dr. Scheltens, Dr. Kuijer, and Dr. Muller revised the manuscript. Hazel Zonneveld and Dr. van der Flier completed the statistical analysis.
ACKNOWLEDGMENT The authors thank Dr. P.J. Kostense for his statistical assistance.
STUDY FUNDING Research of the VUmc Alzheimer Center is part of the neurodegeneration research program of the Neuroscience Campus Amsterdam. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte.
DISCLOSURE H. Zonneveld and J. Goos report no disclosures. M. Wattjes received payment for consultancy for Biogen Idec, and has received payment for lectures for Biogen Idec, Bayer Healthcare, Roche, and Janssen-Cilag. N. Prins serves on the advisory board of Boehringer Ingelheim and Envivo. He has been a speaker at symposia organized by Janssen and Novartis. N.D.P. has a senior fellowship at the Alzheimer Center VUmc partly supported by Vereniging AEGON and receives research support from the Brain Foundation of the Netherlands and Alzheimer Nederland. N.D.P. receives no personal compensation for the activities mentioned above. P. Scheltens receives grant support (for the institution) from GE Healthcare, Danone Research, and Merck. In the past 2 years, he has received speaker’s fees (paid to the institution) from Lilly, GE Healthcare, Lundbeck, Danone, and Janssen AI-Pfizer. W. van der Flier, J. Kuijer, and M. Muller report no disclosures. F. Barkhof received grant funds from the Dutch MS Society and EU-FP7, and received payment for consultancy from Bayer Schering Pharma, Sanofi-Aventis, Biogen Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, and Janssen Research, and received payment for development of educational presentations for the Serono Symposium Foundation. Go to Neurology.org for full disclosures.
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Prevalence of cortical superficial siderosis in a memory clinic population Hazel I. Zonneveld, Jeroen D.C. Goos, Mike P. Wattjes, et al. Neurology 2014;82;698-704 Published Online before print January 29, 2014 DOI 10.1212/WNL.0000000000000150 This information is current as of January 29, 2014 Updated Information & Services
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