Prevalence and Natural History of Superficial Siderosis: A Population-based Study

Abstract

Background and Purpose

Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during post-mortem examination or with iron-sensitive magnetic resonance imaging (MRI) techniques. The distribution of SS may predict the probable underlying etiology. This study aimed to report the prevalence and natural history of superficial siderosis (SS) in a population-based study.

Methods

Brain MRI scans from the Mayo Clinic Study of Aging, a population-based study of residents 50–89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid Positron Emission Tomography (PET), Apolipoprotein E (APOE) genotype, coexisting cerebral microbleeds, and extent of SS.

Results

A total of 1,412 participants had eligible MRI scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS (cSS) involving the cerebral convexities (7 focal and 6 disseminated). Only three of the participants with cSS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval [CI]: 0–0.45) in those 50 to 69 years old and 1.43% (CI 0.53–2.34) in those over 69 years old. APOE ε2 allele was more common in those with SS (57.1% vs 15.0%, p < 0.001). Compared to participants without SS, those with SS were also more likely to have a positive amyloid PET scan (76.9% vs 29.8%, p < 0.001)

Conclusions

SS may be encountered in the general elderly population. The association with increased amyloid burden and APOE ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS.

Introduction

Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during post-mortem examination or with iron-sensitive magnetic resonance imaging (MRI) techniques.^{1, 2}

The distribution of SS may predict the probable underlying etiology. In “classical” or infratentorial SS, hemosiderin deposition occurs in the posterior fossa, brain stem, and spinal cord with chronic intermittent bleeding into the subarachnoid space identified as a potential cause.³ Bleeding is often caused by dural or nerve root pathologies, prior surgeries, or tumors. These patients typically present with slowly progressive cerebellar ataxia and sensorineural hearing loss.⁴

In contrast, cortical superficial siderosis (cSS) refers to hemosiderin deposition restricted to the cerebral convexities and is associated with cerebral amyloid angiopathy (CAA), an age-related disease of cerebral vasculature caused by beta-amyloid deposition within the walls of small cortical and leptomeningeal arteries.^{2, 5} cSS has been suggested as a useful radiologic finding to establish a diagnosis of CAA.^{6, 7}

The prevalence and clinical significance of SS in the general elderly population remains unclear. The aim of this study was to report the prevalence of SS in a population-based study and to determine the clinical outcome of SS.

Materials and Methods

The Mayo Clinic Study of Aging (MCSA) is a population-based study in Olmsted County, Minnesota. Details of the MCSA have been published previously.⁸ Briefly, Olmsted County residents 50–89 years of age were enumerated using Rochester Epidemiology Project resources.⁹ Eligible subjects were sampled from the population and invited to participate. Recruitment started in 2004, with a subset undergoing a research MRI and Pittsburgh compound B (PiB) Positron Emission Tomography (PET) scans. MRI was performed on one of three 3T scanners from the same vendor (General Electric, Waukesha, WI, USA). MRI sequences sensitive to hemosiderin, a T2* Gradient Echo (GRE) (TR/TE = 200/20 ms; flip angle = 12°; FOV = 20 cm; in-plane matrix = 256 × 224; phase FOV = 1.00; slice thickness = 3.3 mm), were introduced in October 2011. Figure 1 demonstrates patient ascertainment.

Figure 1.

Algorithm of patient ascertainment.

Abbreviations: MCSA = Mayo Clinic Study of Aging; SS = superficial siderosis

The study protocols were approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards. All subjects provided signed informed consent to participate in the study and in the imaging protocols.

Brain MRI scans were reviewed and documented by a board-certified neuroradiologist for abnormalities. The radiologic report was searched for the terms “superficial siderosis” or “hemosiderin” deposition. All MRI scans were also systemically reviewed by a trained-image analyst and areas of hemosiderin deposition including superficial siderosis were identified. Findings from the radiology report and analyst review were confirmed by a vascular neurologist. Participants with SS were identified with the following inclusion criteria: 1) initial head MRI from October 2011 through June 2016 showing linear pattern of hypointensity on GRE imaging consistent with SS. Participants with an alternative explanation for MRI findings, such as aneurysmal subarachnoid hemorrhage, intracranial surgery, or significant head trauma were not counted as SS. Additional data abstracted included age at time of MRI, cognitive status, medications, PiB-PET imaging, Apolipoprotein E (APOE) genotype, number and location of coexisting cerebral microbleeds (CMBs), and extent of cSS. Cognitive status was categorized as normal, mild cognitive impairment (MCI), or dementia based on consensus diagnosis from clinician, neuropsychologist and study coordinator. The details of the cognitive evaluation have previously been published.⁸ PiB-PET findings were classified as PiB-positive if the standardized uptake value ratio (SUVr) was >1.42.¹⁰ CMBs were defined according to consensus criteria¹¹ as homogenous hypointense lesions in the gray matter or white matter distinct from iron or calcium deposits and vessel flow voids on T2* GRE. Location of CMBs was classified as lobar, deep, or combination. Similar to prior publications,⁶ the extent of cSS was defined as focal if restricted to three or fewer sulci or disseminated if affecting more than three sulci. Cases of SS were further categorized as either infratentorial SS or cSS based on distribution of hemosiderin deposition. Cases involving only the posterior fossa (cerebellum and/or brainstem) were considered infratentorial SS, while those with hemosiderin deposition restricted to supratentorial locations (superficial layers of cerebral cortex) were defined as cSS.² In participants with a diagnosis of SS, serial MRI scans were reviewed when available to evaluate for progression of SS, CMBs, or hemorrhage. However, only the initial MRI scan obtained during the study period was used when calculating prevalence. The electronic medical record was reviewed to evaluate for interval events such as symptomatic hemorrhage or stroke.

Statistical analysis

Descriptive statistics including the median and interquartile range (IQR) for continuous variables and the frequency and percent for categorical variables were used to summarize participant characteristics by the presence of SS. When comparing those with SS to those without SS, Kruskal-Wallis tests were performed for continuous measures while chi-square tests (or Fisher’s exact test where appropriate) were performed for categorical measures.

Logistic regression models were used to determine whether age at imaging, MCI or dementia status at imaging, presence of an APOE ε2 allele, or abnormal PiB-PET scan was associated with SS. Each covariate was considered individually with age to explore confounding as well as in multivariable models. Our final multivariate model included adjustment for age, abnormal PiB-PET, and presence of an APOE ε2 allele.

Frequencies of SS were calculated following the original sampling scheme by dividing the number of observed SS by the number of imaged participants per age/sex strata. A two-stage inverse probability weighting (IPW) approach was used to adjust observed frequencies for two possible causes for bias: study non-participation and imaging non-participation.^{12, 13} We derived weights from a logistic regression model adjusting for age, sex and education for whether an individual recruited ultimately had an in-person MCSA study visit during the time-period studied. Further covariates abstracted from the medical record were also considered for inclusion into the logistic models with very little effect so the weights derived using age, sex and education were used. Similarly, weights were derived amongst those who had an in-person MCSA study visit on whether or not they had a usable MRI scan for SS ascertainment adjusting for age, sex, education and MCI/dementia prevalence at recruitment for imaging. These two sets of weights were then multiplied to give each imaged participant a single weight to adjust their observation. The frequency of SS was then standardized to the Olmsted County population (2010 Census) directly by age and sex according to our population-based sampling to give population prevalence estimates.^{14, 15} All statistical testing presented was performed at the conventional 2-tailed alpha level of 0.05. All analyses were performed using SAS, version 9.4 (SAS Institute, Cary, NC).

Results

Among a total of 1,412 participants who had eligible MRI scans, 1,381 (98%) had APOE data, and 1,239 (88%) had PiB/PET. Eleven participants were identified through the radiology report with an additional four identified through the trained analysts. Two participants had infratentorial SS (0.14%) and 13 had cSS (0.92%). When stratified by age, the observed frequency of SS was 0.39% in those 50 to 69 years old, with estimated population prevalence 0.21% [95% confidence interval (CI) 0–0.45]. The observed frequency was 1.89% in those over 69 years old, with estimated prevalence 1.43% (CI 0.53–2.34). The overall estimated population prevalence in those 50–89 years old was 0.56% (CI 0.25–0.86).

Demographics of participants with and without SS are shown in Table 1. The presence of an APOE ε4 allele did not differ between those with and without SS (28.6% vs 28.5%, p = 0.99). Presence of an APOE ε2 allele was more common in those with SS (57.1% vs 15.0%, p < 0.001). Participants with SS were also more likely to be PiB-positive (76.9% vs 29.8%, p < 0.001). In logistic regression models (Table 2), SS was associated with an elevated (positive) PiB SUVr (odds ratio [OR] 5.68; 95% CI 1.33–24.22, p = 0.019) and the APOE ε2 allele (OR 10.67; 95% CI 3.23–35.28, p < 0.001) after adjusting for age at imaging.

Table 1.

Characteristics of participants with and without superficial siderosis

Characteristic*	Negative SS n=1397	Positive SS n=15	Total n=1412	p value
Age, years	68 (62, 77)	79 (74, 85)	68 (62, 78)	0.0021
Male	736 (52.7)	10 (66.7)	746 (52.8)	0.282
Education, years	15 (12, 16)	15 (13, 17)	15 (12, 16)	0.601
MCI/dementia at MRI	134 (9.6)	4 (26.7)	138 (9.8)	0.0272
Presence of APOE ε4 allele†	389 (28.5)	4 (28.6)	393 (28.5)	0.992
Presence of APOE ε2 allele†	205 (15.0)	8 (57.1)	213 (15.4)	<0.0012
Global PiB ratio‡	1.35 (1.28, 1.47)	1.96 (1.54, 2.19)	1.35 (1.28, 1.48)	0.0021
Abnormal PiB§	365 (29.8)	10 (76.9)	375 (30.3)	<0.0012

¹Kruskal Wallis

²Chi-Square

Abbreviations: SS = superficial siderosis; MCI = mild cognitive impairment; APOE = apolipoprotein E; PiB = Pittsburgh compound B

^*Data are presented as n (%), except for age, education, and global PiB ratio, which are presented as median (Q1, Q3)

^†APOE status unavailable in 30 participants with negative SS and 1 with positive SS

^‡Standardized Uptake Value Ratio (SUVR) determined by voxel-size weighted average, gray matter + white matter sharpening, no partial volume correction, cerebellar crus reference

^§Abnormal PiB defined as PiB ratio > 1.42; information unavailable in 171 participants with negative SS and 2 with positive SS

Table 2.

Multivariate logistic model for superficial siderosis

	Odds Ratio	95% Confidence Interval	p Value
Age at MRI	1.06	0.98 – 1.14	0.13
Abnormal PiB ratio*	5.68	1.33 – 24.22	0.019
Any APOE ε2 allele†	10.67	3.23 – 35.28	<0.001

^*PiB data unavailable in 171 participants with negative SS and 2 with positive SS

^†APOE status unavailable in 30 participants with negative SS and 1 with positive SS

Estimates reported from a single multivariate logistic model for SS adjusting for age at MRI, abnormal PiB ratio and APOE ε2 presence

APOE and PiB-PET results were reviewed further based on location of SS. Seven of 12 participants with cSS and APOE data available (58.3%) were APOE ε2 positive; neither of the participants with infratentorial SS had an APOE ε2 allele. Of those with PiB-PET results available, nine participants with cSS (75%) and one participant (50%) with infratentorial SS were PiB-positive. Table 3 describes the clinical, genetic, and imaging features for participants with SS. Of the 13 participants with cSS, 9 (69%) were on aspirin at the time of diagnosis and none were on anticoagulation. Seven participants had focal cSS and six had disseminated involvement. None of the participants with focal cSS had associated CMBs, but three of the six (50%) with disseminated cSS had associated CMBs (range 1 to 90).

Table 3.

Characteristics of participants with superficial siderosis (SS)

	Age (years)	Sex	Antithrombotic use	# of cerebral microbleeds on initial scan (location)	Any APOE ε2 allele	Abnormal PiB-PET
Focal cSS*	86	M	Aspirin 81 mg	0	No	Yes
	82	F	None	0	No	No
	79	F	Aspirin 81 mg	0	Yes	Yes
	78	M	Aspirin 81 mg	0	No	Yes
	74	M	Aspirin 81 mg	0	Yes	Yes
	71	F	Aspirin 81 mg	0	No	No
	62	M	None	0	Yes	No
Disseminated cSS*	88	M	None	0	No	Unavailable
	87	F	Aspirin 81 mg	0	Yes	Yes
	82	M	Aspirin 325 mg	0	Yes	Yes
	80	M	Aspirin 325 mg	1 (lobar)	Yes	Yes
	79	F	Aspirin 81 mg	16 (lobar)	Yes	Yes
	76	M	None	90 (lobar)	Unavailable	Yes
Infratentorial SS	61	F	None	0	No	No
	85	M	None	0	No	Yes

Abbreviations: SS = superficial siderosis; cSS = cortical superficial siderosis; APOE = apolipoprotein E; PiB-PET = Pittsburgh compound B Positron Emission Tomography

^*Extent of cSS involvement was defined as focal (restricted to ≤ 3 sulci) or disseminated (> 3 sulci).

Three participants with cSS (1 focal, 2 disseminated) had follow up MRI scans a mean of 31.3 months after the initial scan. There was no further hemorrhage in the participant with focal cSS. However, both of the participants with disseminated cSS and follow up MRI experienced additional hemorrhage: one with multiple new asymptomatic CMBs and one with multiple new CMBs as well as symptomatic lobar intracerebral hemorrhage (ICH) distant to the site of cSS.

Discussion

Our findings indicate that cSS can be seen in approximately 1% of persons over age 70 in the general population. The subset of individuals with disseminated cSS and associated microbleeds may be at risk of developing additional hemorrhage, including lobar hematomas but future studies will be necessary to confirm this increased risk. The association of cSS with APOE ε2 allele, which is a risk factor lobar hemorrhage, further supports an increased risk of hemorrhage among these individuals.

The overall prevalence of SS in our study was similar to another epidemiological study, the Rotterdam study, which focused only on those with cSS. That study found cSS in 0.7% of non-demented elderly individuals, all with coexisting lobar CMBs suggestive of CAA.¹⁶ Unlike the Rotterdam study, the majority (10 out of 13) of our cSS cases occurred in the absence of CMBs. Our study extends the findings of the Rotterdam study by including (1) PiB-PET and APOE profiles, and (2) including participants with infratentorial SS. The association of cSS with increased brain beta-amyloid burden and the APOE ε2 genotype in our study provides supportive evidence of CAA as a possible cause of cSS in older patients, but none of the participants with cSS had pathologic confirmation.¹⁷ APOE ε2 has previously been associated with both focal and disseminated cSS in patients with pathologically proven CAA.^{18, 19}

The finding that cSS occurs in the absence of CMBs is not surprising. Among patients with CAA, the presence of cSS has been associated with a lower CMB burden.¹⁹ Increased CMB count has been associated with APOE ε4.¹⁹ The variations in clinical and imaging characteristics among patients with CAA suggest that although APOE ε2 and ε4 are both risk factors for CAA, they present with different phenotypes and may contribute to CAA-related hemorrhage through distinct mechanisms.^{19, 20} The APOE ε2 allele is associated with a reduced risk of AD but a higher risk of clinical ICH, whereas the APOE ε4 allele is a risk factor for both AD and CAA.²⁰

cSS is a risk factor for CAA-related hemorrhage, independent of CMB burden.^{21, 22} The ability to determine which patients are at increased risk of hemorrhage may influence decisions regarding antithrombotic medications. CAA is an important cause of warfarin-associated lobar ICH in the elderly, and APOE ε2 status is overrepresented among these patients.²³ The two participants with interval hemorrhage during follow-up had disseminated cSS and CMBs at the time of the initial MRI. This finding supports prior studies demonstrating extent of cSS and number of CMBs as important risk factors for future hemorrhage.^{21, 24}

The prevalence of SS is low, and associations of SS with APOE status and PiB-PET results must be interpreted cautiously in the setting of such small numbers which limits the generalizability. Additionally, some participants were missing information such as APOE status, PiB-PET results, and cognitive profile. Lack of follow up data in a majority of eligible participants with SS is another limitation and limits our ability to estimate the risk of subsequent hemorrhage. Although most participants with siderosis had multiple MRI scans, a minority had subsequent scans after diagnosis of SS since GRE imaging was introduced in October 2011. While a strength of this study is that we were able to account for two potentially large sources of bias, study non-participation and imaging non-participation bias, through IPW, unmeasured bias not accounted for by this technique remains a possibility.

Summary

CAA exists on a continuum with additional factors such as APOE status influencing disease progression. Asymptomatic cases of focal cSS may represent an early manifestation of CAA and more extensive longitudinal follow-up is needed to determine whether these participants develop CMBs, disseminated cSS, or ICH. Detecting imaging changes while still asymptomatic is an important way to track the disease course and to identify risk factors for progression.

MCSA Data.

• U01 AG006786: (Petersen) Mayo Clinic Study of Aging (MCSA)

• P50 AG016574: (Petersen) Alzheimer’s Disease Research Center (ADRC)

• R01 AG034676: (Rocca) Rochester Epidemiology Project (REP)

• R01 AG011378: (Jack) Evaluating and Extending Our Hypothetical Model of Alzheimer’s Biomarkers

• R01 AG041851: (Jack/Knopman) Validating the New Criteria for Preclinical Alzheimer’s disease

• R01 NS097495: (Vemuri) Development, Validation, and Application of an Imaging based CVD Scale