Abstract
Background:
Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of cerebral amyloid angiopathy (CAA) and the mechanisms of their impact on cognition are poorly understood. We evaluated the cross-sectional association between CMB patterns and cerebral amyloid-β (Aβ) deposition, by florbetapir PET.
Methods:
The longitudinal ARIC study recruited individuals from 4 US communities from 1987–1989. In 2012–2014, the ARIC-PET ancillary recruited 322 nondemented ARIC participants who completed 3T brain MRI with T2*GRE as part of ARIC visit 5 to undergo florbetapir PET imaging. MRI images were read for CMBs and superficial siderosis (SS); on PET, global cortical standardized uptake value ratio >1.2 was considered a positive Aβ scan. Multivariable logistic regression models evaluated CMB characteristics in association with Aβ positivity. Effect modification by sex, race, APOE status, and cognition was evaluated.
Results:
CMBs were present in 24% of ARIC-PET participants. No significant associations were found between CMBs and Aβ positivity, but a pattern of isolated lobar CMBs or SS was associated with over 4-fold higher odds of elevated Aβ when compared to those with no CMBs (OR 4.72, 95% CI 1.16–19.16). A similar elevated risk was not observed in those with isolated subcortical or mixed subcortical and either lobar CMBs or SS. Although no significant interactions were found, effect estimates for elevated Aβ were nonsignificantly lower (p>0.10, OR 0.4–0.6) for a mixed CMB pattern, and odds ratios were nonsignificantly higher for lobar-only CMBs for four subgroups: women (vs men); Blacks (vs whites), APOE ε4 noncarriers (vs carriers), and cognitively normal (vs MCI).
Conclusions:
In this community-based cohort of nondemented adults, lobar-only pattern of CMBs or SS is most strongly associated with brain Aβ, with no elevated risk for a mixed CMB pattern. Further studies are needed to understand differences in CMB patterns and their meaning across subgroups.
INTRODUCTION
Cerebral amyloid angiopathy (CAA) is a condition in which amyloid-β (Aβ) deposits in the arterial walls, leading to macro- and micro-bleeds. Distribution of the microbleeds may point to this etiology, with most typical distribution in lobar/cortical, or cortico-subcortical regions,1 often indicative of probable or possible CAA. However, definite clinical diagnosis requires a full postmortem neuropathology examination. Typically, subcortical, or deep macro- or microbleeds, are associated with chronic hypertension.2 The relevance of these distinct microbleed distributions in the general population, especially without relevant clinical history, is less clear.
One consideration when determining the clinical relevance of microbleeds in the absence of other clinical criteria for CAA is the status of Aβ measured by PET.3 Although CAA-related Aβ distribution occurs in the vessel wall, as opposed to cortical tissue, several studies have also demonstrated higher cortical Aβ in individuals with CAA-related (cortical) hemorrhage compared to those with non-CAA-associated intracerebral hemorrhage,4–6 and thus it has been proposed that a negative Aβ PET scan can help rule out a potential diagnosis of CAA.7 Even though Aβ PET imaging has not been validated for diagnostic use in the revised Boston Criteria v2.0 for CAA,8 studies suggest that PET imaging can assist in differentiating those without CAA from those likely to be diagnosed as having probable or possible CAA.7 Studies are currently underway to evaluate the clinical use and specificity of this imaging modality for the clinical diagnosis of CAA. Likewise, the observation of additional imaging markers associated with CAA may further distinguish CAA-related clinical manifestations from non-CAA phenotypes. Superficial siderosis (SS), an imaging marker often associated with CAA, is characterized by hemosiderin deposition in the central nervous system due to persistent hemorrhage into the subarachnoid space,9, 10 and when evaluated in combination with Aβ PET imaging data, might provide additional insight into what imaging patterns might be most consistent with a diagnosis of CAA.
In the general population, the meaning of a mixed pattern of CMBs, where individuals have a combination of lobar and deep microbleeds, and, in some cases, also SS, is not fully understood.11, 12 Prior studies have shown associations between mixed distributions or higher amount of CMBs with cognitive decline in older populations,13, 14 suggesting that even in non-clinical samples, such imaging patterns could have prognostic value. The ability to separate out location and pattern of microbleeds (lobar vs. mixed vs. deep) allows further consideration of the meaning of these distinct patterns in relationship to cortical Aβ.
In this study, we tested the association of MRI-defined CMBs and SS with Aβ load (using brain florbetapir PET) in community-based, dementia-free participants without a history of intracerebral hemorrhage (ICH) to further explore the clinical relevance of these imaging findings in a community-based population. Specifically, we hypothesized that CMBs would be associated with elevated cortical brain Aβ, as indicated by florbetapir PET. Furthermore, we hypothesized that associations would be strongest in those with lobar microbleeds (and/or SS), weakest or absent in those with deep microbleeds only, and present but to a lesser extent in individuals with a mixed pattern of lobar and deep microbleeds. In addition, we evaluated whether these associations would be stronger in participants with mild cognitive impairment than those with normal cognition and evaluated interaction and effect modification by sex, race, and APOE status.
METHODS
All findings reported here are in accordance with the STROBE (Strengthening the Research of Observational Studies in Epidemiology) guidelines for cohort studies. Researchers trained in human subject confidentiality may request access to the data through ARICpub@unc.edu.
Participant inclusion
The Atherosclerosis Risk in Communities (ARIC) study recruited individuals from four U.S. communities between 1987 and 1989. These individuals were seen in-person at three subsequent visits through 1999, and then seen for the fifth visit, the first ARIC Neurocognitive study (ARIC-NCS) visit, in 2011–2013. The ARIC-NCS visit included a brain MRI scan for a subset of participants (N=1928) selected on the basis of having had a prior research MRI, having evidence of cognitive decline, or from an age-stratified random sample of normal controls.15 From those individuals seen at the ARIC-NCS visit and who completed a brain MRI, individuals from three of the ARIC communities (Forsyth County, NC; Jackson, MS; and Washington County, MD) and who were also without dementia were recruited into the ARIC-PET study, with a total of 346 individuals completing florbetapir PET brain imaging from 2012–2014. Additional inclusion criteria for the ARIC-PET study are provided elsewhere (Figure S1).16
From the 346 individuals recruited into ARIC-PET, participants missing microbleed data (based on poor image quality or incompleteness; N=6), who had dementia at the time of recruitment (N=1), or prior clinically diagnosed intracerebral hemorrhage (N=1) were excluded from the analytic sample. Non-white and non-Black participants (N=5) were also excluded due to very small numbers for comparison purposes. Additionally, those missing data for the covariates of hypertension (N=3), diabetes (N=5), and smoking status (N=3) were excluded, yielding an analytic population of 322.
The institutional review board for each institution approved this study and all participants provided informed consent.
Brain MRI imaging
All scans were conducted at each field center through the same MR protocol, using 3-Tesla MRI scanners, (including MP-RAGE, Axial T2*GRE, Axial T2 FLAIR, and Axial DTI sequences) and analyzed centrally at the Mayo Clinic MRI Reading Center. Microbleeds were rated using a T2* gradient echo sequence (repetition/ echo time =200/20 ms; slice thickness=3.3 mm) and defined as hypointense homogenous lesions no greater than 10 mm in diameter. Using previously described methods,15, 17 CMBs were localized, coded as appearing in gray or white matter, and based on their locations, assigned a label of lobar vs deep by trained image analysts and neuroradiologists. Superficial siderosis was identified as curvilinear areas of decreased signal intensity on the GRE images that followed the contour of sulci. Presence of SS, as defined, was marked and recorded.
MP-RAGE sequences were used for alignment and comparison of the MRI and florbetapir PET images. MRI and PET scans were acquired within one year of each other.
PET imaging
Aβ-PET imaging with florbetapir was conducted at 3 ARIC sites (Jackson, MS; Washington County, MD; and Forsyth County, NC) within 1 year of the brain MRI, using standardized procedures described elsewhere.16, 18 After intravenous injection of florbetapir, fifty to seventy-minute uptake scans were acquired and images transferred to the PET image analysis center, which at the time was located at Johns Hopkins University, where they were coregistered to the MRI, spatially normalized, and quantified for standardized uptake value ratios (SUVR) in distinct regions of interest, with the cerebellum as the reference region. Global cortical SUVR was calculated using a weighted average of the precuneus, orbitofrontal cortex, prefrontal cortex, superior frontal cortex, lateral temporal lobe, parietal lobe, occipital lobe, anterior cingulate, and posterior cingulate- regions most often associated with Aβ deposition in Alzheimer’s Disease pathogenesis.18 Like prior ARIC-PET studies,19 SUVR values were dichotomized using a sample median of 1.2, meaning a scan with a global cortical SUVR >1.2 was characterized as florbetapir positive.
Covariates
Demographic factors- sex, education level, and race were self-reported at study baseline, as was date of birth. Since microbleeds were evaluated on the visit 5 MRI, this was used as the study baseline for other covariates: participant age at visit 5 was included as a covariate. APOE genotype was determined based on measurement in the ARIC study (TaqMan assay; Applied Biosystems, Foster City, CA) and participants divided into ε4 carriers vs non-carriers. Cognitive status was attained through adjudicated research diagnoses from ARIC-NCS.20 Because no participants in this study had dementia at visit 5, by design, cognitive status was considered as mild cognitive impairment versus normal cognition.
Comorbidity covariates- diabetes, atrial fibrillation, hypertension, body mass index, and smoking status were recorded at visit 5. Based on an average comprised of the 2 final blood pressure recordings taken on the day of the visit out of 3 total recording times, hypertension was defined as systolic blood pressure > 140 mm Hg, diastolic blood pressure >90 mm Hg, or use of antihypertensive medications. Atrial fibrillation (AF) at visit 5 was defined as evidence of AF in a standard 12-lead ECG performed during the study exam, evidence of AF in any previous study ECG, or classification of AF in any hospitalization occurring during follow-up before visit 5. Diabetes was assessed based on laboratory results (fasting glucose of 126 mg/dL or higher, non-fasting glucose of 200 mg/dL or higher, and HbA1c of 6.5 or higher), self-report of physician-diagnosed diabetes, or use of oral diabetes medications or insulin. Weight (kg) and height (m) were measured and used to calculate body mass index (BMI). Smoking status (current vs not current) was self-reported.
Statistical Analysis
Stata/SE v17.0 was used for all analyses. We constructed logistic regression models with florbetapir uptake as the dependent variable, evaluated as a dichotomous measure of standardized uptake value ratio (SUVR>1.2) due to the variable being highly skewed; 1.2 represents the sample median as per earlier studies.16 Separate multivariable logistic regression models evaluated the effect of the presence (yes; no), number (0;1;2+), and pattern of microbleeds evaluated in association with global cortical SUVR positivity. To evaluate microbleed pattern, we first considered each location separately (lobar yes/ no; subcortical yes/no) and then created a variable to capture the overall pattern by microbleed distribution and location, considering: none (as the reference); subcortical only; mixed (lobar plus subcortical); and lobar only.
We further examined these same categories but considered the presence of SS grouped with lobar microbleeds as another potential indicator of past bleeding in a CAA-type pattern (comparing no microbleeds or siderosis as our reference; vs subcortical microbleeds only; mixed subcortical + either lobar microbleeds or siderosis; and either lobar microbleeds or siderosis). Based on a priori hypotheses, models incorporated the covariates described above including vascular risk factors and demographic information; model 1 included age, sex, race, education, and APOE e4 status, whereas model 2 incorporated hypertension, diabetes, obesity, smoking, and atrial fibrillation in addition to the covariates from model 1. We also tested for effect modification by sex, race, APOE, and cognitive status, each, in stratified analyses and with formal tests of interaction.
RESULTS
A total of 322 individuals enrolled in the ARIC-PET study were included in our analytic sample. The descriptive statistics for the included participants are shown in Table 1. Of the 322 participants analyzed, 75 had CMBs present; of those with CMBs present, 45 had deep microbleeds only, 15 had mixed deep and lobar microbleeds, and 15 had only lobar microbleeds. Only 3 (0.9%) had SS. Although the majority of the 75 individuals with microbleeds had only 1 (Q1, Q3, 1,7), the range was up to 21.
Table 1.
Characteristics of analytic sample, by microbleed status (N=322)
| Variables | No microbleeds (N=247) | Deep microbleeds only (N=45) | Mixed (deep + lobar) microbleeds (N=15) | Lobar microbleeds only (N=15) |
|---|---|---|---|---|
| Age (y) (mean (SD)) | 75.9 (5.3) | 74.5 (5.2) | 77.5 (6.1) | 75.0 (4.5) |
| Female sex | 146 (59%) | 24 (53%) | 4 (27%) | 9 (60%) |
| Black race | 98 (40%) | 24 (53%) | 7 (47%) | 9 (60%) |
| Education < HS High school / GED >HS |
33 (13%) 107 (43%) 107 (43%) |
10 (22%) 20 (44%) 15 (33%) |
4 (27%) 5 (33%) 6 (40%) |
4 (27%) 6 (40%) 5 (33%) |
| APOE e4 carrier* | 65 (27%) | 17 (39%) | 7 (47%) | 9 (60%) |
| Hypertension | 178 (72%) | 32 (71%) | 10 (67%) | 10 (67%) |
| Diabetes | 98 (40%) | 19 (42%) | 6 (40%) | 4 (27%) |
| Obesity (BMI≥30) | 96 (39%) | 17 (38%) | 6 (40%) | 2 (13%) |
| Current smoking | 12 (5%) | 5 (11%) | 0 (0%) | 1 (7%) |
| Global Cortical SUVR (mean (SD)) | 1.28 (0.24) | 1.29 (0.26) | 1.36 (0.37) | 1.42 (0.23) |
| Mild cognitive impairment | 66 (27%) | 7 (16%) | 6 (40%) | 5 (33%) |
N (%) unless otherwise specified
5 individuals missing APOE data, coded as “missing” for analyses (not excluded)
Observed prevalences of cerebral microbleeds were similar in distribution across racial categories, although slightly more common in Blacks, who had more deep-only and lobar-only CMBs. Of the 138 Black participants in the study, 40 had CMBs present (24 deep, 7 mixed deep and lobar, 9 strictly lobar) and of the 184 white participants, 35 had CMBs present (21 deep, 8 mixed deep and lobar, 6 strictly lobar). Differences in covariates were also evident across microbleed type, particularly in sex and APOE e4 carrier status. Women were overrepresented in the strictly lobar group (60%) as well as the no microbleed group (59%) but under-represented in the mixed CMB group (27%). In addition, the strictly lobar group had the highest proportion of APOE e4 carriers as well as the highest mean global cortical SUVR (1.42).
Cerebral Amyloid-β in relation to presence and number of cerebral microbleeds
There was no association between presence of microbleeds and SUVR when demographic covariates and vascular risk were included in the analysis (Table 2; OR 1.38, 95% CI 0.76–2.48). Likewise, there was no association between the number of CMBs and SUVR (Table 2).
Table 2:
Associations between microbleeds, their distribution and number, and global cortical SUVR >1.2
| Model 1 (OR, 95% CI) |
Model 2 (OR, 95% CI) |
|
|---|---|---|
| Any microbleeds (yes/no) | 1.33 (0.74, 2.37) | 1.38 (0.76, 2.48) |
| Any lobar microbleeds | 1.67 (0.70, 4.00) | 1.86 (0.76, 4.55) |
| Any subcortical microbleeds | 1.03 (0.55, 1.92) | 1.02 (0.54, 1.92) |
| Number of microbleeds 0 1 2+ |
1 (ref) 1.47 (0.72, 2.99) 1.14 (0.48, 2.66) |
1 (ref) 1.56 (0.76, 3.21) 1.14 (0.48, 2.70) |
| Number of subcortical microbleeds 0 1 2+ |
1 (ref) 0.95 (0.46, 1.96) 1.23 (0.43, 3.52) |
1 (ref) 0.98 (0.47, 2.05) 1.12 (0.39, 3.23) |
| Number of lobar microbleeds 0 1 2+ |
1 (ref) 2.00 (0.72, 5.58) 1.06 (0.23, 4.82) |
1 (ref) 2.42 (0.84, 6.97) 0.96 (0.20, 4.54) |
Model 1: Adjusted for age, sex, race, educational level, APOE ε4 (including dummy variable for missing APOE)
Model 2: Model 1 + hypertension, diabetes, obesity, smoking, atrial fibrillation
Cerebral Amyloid-β in relation to pattern of microbleed location and superficial siderosis
Amyloid-β positivity did not significantly differ in individuals who had any lobar microbleeds, (67%) vs those without lobar microbleeds (which included individuals with no microbleeds and individuals with subcortical-only microbleeds (49% Aβ positive; p=0.07)), nor in adjusted models (Table 2; adjusted OR 1.86, 95% CI 0.76–4.55). However, when a lobar-only microbleed pattern was considered (compared to all other distributions), a univariate association was seen (80% of those with a lobar-only pattern had Aβ positivity vs 50% of those with any other microbleed patterns, p=0.03). When we further considered the overall pattern of the distributions (only lobar, mixed, or only subcortical) separately, with no microbleeds as a reference, there was an elevated odds ratio of Aβ compared to the no microbleed group for those with lobar-only microbleeds, but again only in the univariate analysis (unadjusted OR 4.23, 95% CI 1.17, 15.37; see Table 3).
Table 3.
Associations between microbleed patterns, superficial siderosis, and elevated (>1.2) global cortical SUVR.
| Unadjusted (OR, 95% CI) | Model 1 (OR, 95% CI) | Model 2 (OR, 95% CI) | |
|---|---|---|---|
| No microbleeds | 1 (ref) | 1 (ref) | 1 (ref) |
| Only subcortical microbleeds | 1.21 (0.64, 2.29) | 1.14 (0.57, 2.30) | 1.14 (0.56, 2.32) |
| Mixed (subcortical + lobar microbleeds) | 1.21 (0.43, 3.44) | 0.99 (0.31, 3.17) | 1.01 (0.31, 3.32) |
| Only lobar microbleeds | 4.23 (1.17, 15.37) | 3.30 (0.83, 13.07) | 4.07 (0.99, 16.71) |
| Unadjusted (OR, 95% CI) | Model 1 (95%CI) | Model 2 (95% CI) | |
| No microbleeds or siderosis | 1 (ref) | 1 (ref) | 1 (ref) |
| Only subcortical microbleeds | 1.17 (0.61, 2.22) | 1.14 (0.56, 2.31) | 1.15 (0.56, 2.34) |
| Mixed (subcortical microbleeds + either lobar microbleeds or superficial siderosis) | 1.37 (0.50, 3.80) | 1.07 (0.34, 3.33) | 1.06 (0.33, 3.45) |
| Only lobar microbleeds or superficial siderosis | 4.62 (1.29, 16.63) | 3.72 (0.95, 14.53) | 4.72 (1.16, 19.16) |
Model 1: Adjusted for age, sex, race, educational level, APOE ε4 (including dummy variable for missing APOE)
Model 2: Model 1 + hypertension, diabetes, obesity, smoking, atrial fibrillation
Because SS is also indicative of CAA, we analyzed microbleed location but added SS as an alternative to lobar microbleeds as another CAA-type marker. Results were similar but significant when we expanded the definition to include SS. Those with a pattern of only lobar microbleeds and/or SS (but without any subcortical microbleeds) had the highest risk of elevated global cortical Aβ compared to those without cerebral microbleeds (Table 3; adjusted OR 4.72, 95% CI 1.16–19.16).
Group differences for elevated global cortical SUVR by sex, race, APOE, and cognitive status
We evaluated subgroup differences in risk of elevated global cortical SUVR (>1.2) associated with microbleeds by sex, race, APOE ε4, and cognitive status in our demographics-adjusted model. We did not find any significant interactions between CMB pattern and our subgroups, nor any significant associations within most subgroups. However, although not statistically significant, a mixed pattern of cerebral microbleeds for those with normal cognition, women, Blacks, and APOE ε4 negative participants was associated with a nonsignificant decrease in odds of elevated Aβ (Figure 1, Table S1; OR estimates 0.42 – 0.66) when compared to those with mild cognitive impairment, men, whites, and APOE ε4 carriers, respectively, all of whom had a qualitative nonsignificant increase in odds of elevated Aβ. APOE-negative status was associated with a nonsignificantly elevated risk for high global cortical Aβ amongst those who had either only lobar microbleeds or SS (Figure 1; OR 6.44, 95% CI 0.67–62.28) with a similar nonsignificant trend shown for those who were women, Black, or rated as having normal cognitive status.
Figure 1.
Forest plot of associations between microbleed patterns and odds of elevated global cortical SUVR (>1.2) by sex, race, APOE, and cognitive status, compared to no microbleeds. Odds ratios from Model 1 adjusted for age, sex, race, education, and APOE e4 status. 1Mixed CMBs refer to presence of subcortical cerebral microbleeds and either lobar microbleeds or superficial siderosis. Each odds ratio refers to the effects in each group and distribution of CMBs when compared to those without CMBs.
DISCUSSION
In this community-based study of nondemented older adults, primarily subcortical or mixed microbleed patterns were not associated with elevated brain Aβ by PET, but a pattern of isolated lobar microbleeds or SS was. Additionally, we did not find specific subgroups in whom other microbleed patterns were significantly associated with elevated Aβ, although most of these subgroups were too small to allow meaningful inferences.
Our findings are consistent with other studies that have compared CAA-related microbleeds with non-CAA CMBs using florbetapir PET methods. In one such study, using florbetapir PET, patients with intracerebral microbleeds who met criteria for CAA had higher global cortical Aβ (as well as occipital cortical Aβ) than did patients with CMBs associated with a hypertensive etiology (standardized uptake value ratios of 1.41 vs 1.15, p=0.001). In this sample of 19 adults, florbetapir PET had a 100% sensitivity and 89% specificity for probable CAA among CMB patients with normal cognition.5 Our SUVR estimates are similar to these, even though our findings were not in a CAA clinical cohort, with our observed SUVR of 1.42 in participants with lobar-only microbleeds and 1.44 in participants with only lobar microbleeds or SS (Table S2). Other authors have reported elevated global cortical florbetapir uptake in CAA vs hypertensive CMB patients but with lower sensitivities.6 In the current study, the presence of lobar microbleeds and SS,21, 22 a pattern usually related to CAA, was also associated with a greater risk of elevated cortical Aβ by florbetapir PET. A recent Aβ PET autopsy study demonstrated that the association between CAA and Aβ PET may be driven by co-occurring Aβ plaques rather than vascular Aβ, suggesting Aβ PET could be a surrogate biomarker for CAA.23
While the association between CAA and cortical Aβ has been established in prior studies, the combination of both lobar (or SS) and deep microbleeds is less clearly associated with Aβ imaging markers. Prior studies have shown associations between a mixed microbleed pattern and cognitive decline in older populations,13 emphasizing the potential clinical importance of this pattern. In the Mayo Clinic Study of Aging, lobar microbleeds were associated with elevated PET Pittsburgh compound B measured Aβ deposition, but subcortical microbleeds and mixed microbleeds were not, though such patterns were relatively infrequent in this population.5 In a similar study, Raposo et al. (2017) also showed that individuals with mixed lobar and deep microbleeds did not have a significantly higher risk of elevated cortical Aβ by florbetapir PET. Raposo et al. (2017) and Gurol et al. (2016) evaluated patients with clinically diagnosed probable CAA who survived at least 6 months after intracerebral hemorrhage, increasing the likelihood that the patients evaluated had less severe CAA.5,6 Such survivorship bias could decrease the generalizability of these results in the broader population. However, in this non-clinical sample with incidentally found microbleeds, we observed consistent results indicating that the presence of a mixed pattern of CMBs was not significantly associated with elevated global cortical Aβ.
In previous ARIC studies, lobar microbleeds were more frequently associated with APOE e4, as well as smaller brain regions typically affected in Alzheimer’s disease, both of which are more likely to co-occur with CAA, whereas deep microbleeds more frequently co-occurred with lacunar infarcts and white matter hyperintensities, both markers of small vessel disease.17 Our current findings, showing elevated brain Aβ in nondemented participants with an isolated lobar or SS pattern (but not with a mixed microbleed pattern), are consistent with these earlier findings and further emphasize the importance of studying such differences in pathogenic processes in non-clinical cohorts. Future studies could employ methods such as pooled analyses of these distinct patterns to validate these findings in a larger sample.
When comparing differences in risk of elevated Aβ deposition based on prevalence of cerebral microbleeds, we did not find an elevated risk for those with more than one CMB regardless of microbleed distribution when compared to those with only 1 microbleed within the same respective group. This finding perhaps suggests that cortical Aβ levels are more related to distribution rather than density of microbleeds, such that lobar-only microbleeds or SS are associated with higher levels of global cortical Aβ.
In our assessment of subgroup differences, we did not find any significant interactions between CMB pattern and race, sex, APOE, or cognitive status. Although numbers in subgroups were quite small, it is interesting and hypothesis-generating to note the qualitative differences for certain subgroups, where for some groups mixed microbleeds appeared protective and for others perhaps with increased risk. Even though the findings are underpowered to make any conclusions, it is possible that survivorship might also impact associations between microbleeds and Aβ in some subgroups. It is also important to note that participants in this study who had a mixed pattern of CMBs were on average older and male in comparison to other CMB patterns (Table 1). In this study sample, our findings suggest that the presence of a mixed microbleed pattern independent of subgroup was not primarily driven by CAA as shown by the lack of association with Aβ, although even the associations with CMB patterns in the total sample may have been underpowered due to small numbers.
Our findings are limited because of the use of observational, cross-sectional data, and because of the relatively small sample size. Over time, the microbleed patterns observed here may change or may be associated with a different pattern of global cortical Aβ that our study cannot capture. Likewise, there may be residual confounding whereby factors that contribute to microbleeds or global cortical Aβ are not well captured here. In this sample, we only had 3 participants with SS, so these results may be more reflective of the impact of lobar CMBs rather than a mixed effect between lobar CMBs and SS. Additionally, the recruitment of only nondemented adults could increase the likelihood of survivorship bias where most of the population observed may have less severe pathologies due to the longitudinal nature of ARIC/ARIC-PET. The use of binarized SUVR for PET positivity may decrease our ability to show correlations between these CMB patterns and amyloid, but this measure is highly skewed and plateaus such that additions to SUVR no longer make a meaningful difference to cortical brain amyloid at a certain point.24 Also, no formal partial volume methodology was employed that could be useful if there was atrophy or spillover of radioactivity from areas of microbleeds and CMBs. Even with these limitations, this study extends the current literature by evaluating CAA-related microbleeds in a community-based cohort, where we can begin to understand the meaning of these microbleed patterns in the general population.
Although these findings are incidental, this information could help clinicians with patients who have microbleeds but are not diagnosed with CAA, especially those who may have MCI or show signs of executive decline. Our findings suggest further evaluation to determine pathogenic sources beyond CAA contributing to cognitive deficits. Other imaging markers of cerebrovascular disease such as white matter hyperintensities, lacunes, and perivascular spaces could be evaluated, and vascular risk factors for subcortical CMBs, like hypertension, may prove especially important to control in such patients. If a PET scan cannot be obtained for a patient, markers and vascular risk factors that are associated with CAA and/or the CMB and SS patterns of interest may be used. Risk factors like APOE e4 are highly associated with these CMB patterns and could be used as a surrogate marker. Using these measures in replacement of the diagnostic criteria for CAA is not recommended but may provide predictive value in determining patients whose cognitive decline may be related to possible CAA.
This study focused on two characteristics of CMBs which have been attributed to different pathogenic processes in neuropathology. Here, we show that distribution of CMBs consistent with cerebral amyloid angiopathy, although in the absence of other clinical signs of CAA and in a community-based cohort, are associated with global cortical Aβ levels. A mixed pattern changes this association, perhaps suggesting that a mixed pattern of CMBs may be attributed to a non-CAA-related mechanism. While our study does not look at clinical outcomes or mechanisms through which mixed patterns of CMBs affect cognitive decline, our findings suggest that these effects are mediated through processes beyond elevated global cortical Aβ. Therefore, future studies may be needed to investigate associations between mixed patterns of CMBs and/or SS and mechanisms through which these patterns affect neuropathology.
Supplementary Material
Figure S1- Flowchart of ARIC-PET inclusion and exclusion criteria
Table S1 – Associations between patterns of Cerebral Microbleeds and global cortical SUVR by sex, race, APOE, and cognitive status
Table S2 – Participant characteristics for subgroups defined by microbleed pattern, including superficial siderosis
Acknowledgements
The authors thank the staff and participants of the ARIC study for their important contributions.
Sources of Funding
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The ARIC Neurocognitive Study is supported by U01HL096812, U01HL096814, U01HL096899, U01HL096902, and U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD). Brain MRI examinations performed in the 2004-06 Brain MRI study were funded by R01HL70825. Brain PET scans in 2011-14 were funded by R01AG040282. This research was also supported by the Intramural Research Program of the National Institute on Aging (KW) and the National Institute of Neurological Disorders and Stroke (RG, DO).
Non-standard Abbreviations and Acronyms
- Aβ
Amyloid β
- ARIC
Atherosclerosis Risk in Communities (study)
- CAA
Cerebral amyloid angiopathy
- CMB
Cerebral microbleeds
- SS
Superficial siderosis
- SUVR
Standardized uptake value ratios
Footnotes
Disclosures
Dr. Kantarci consults for Biogen, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly and funding from NIH and Alzheimer’s Drug Discovery Foundation. Dr. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He has served as a consultant for Roche, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for lecanemab on December 2, 2022, but received no compensation. ongoing unpaid consulation relationship with Biogen regarding secondary analyses of the double blind and open label trials. He receives funding from the NIH. Dr. Wong reports a consultation with Engrail Therapautics and grants through his university with Eisai and Anavex, and previous grants with Hoffman-LaRoche. Dr. Gottesman served as Chair of the American Neurological Association Annual Meeting Programming committee but receives no personal compensation, and previously received research support from the NIH that supported this work.
None of the other authors have any disclosures relevant to this manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1- Flowchart of ARIC-PET inclusion and exclusion criteria
Table S1 – Associations between patterns of Cerebral Microbleeds and global cortical SUVR by sex, race, APOE, and cognitive status
Table S2 – Participant characteristics for subgroups defined by microbleed pattern, including superficial siderosis