Abstract
Background and Purpose
Prospective studies on cerebral microbleeds (CMB) have departed from individuals who already have CMB at baseline. Therefore, main outcomes have usually been the composite of new lesions appearing on the follow-up among patients who already had CMB together with those who de novo developed CMB. Using the Atahualpa Project Cohort, we aimed to assess correlates of incident CMB in community-dwelling older adults free of CMB at baseline.
Methods
Atahualpa residents aged ≥ 60 years received baseline clinical interviews and a brain MRI. Those who were free of CMB at baseline and received follow-up brain MRI at the end of the study were included. Multivariate logistic and Poisson regression models were fitted to assess the association and the incidence rate ratio (IRR) of incident CMB according to clinical and neuroimaging variables.
Results
The mean age of 241 study participants was 65.6 ± 6.1 years (57% women). After 6.5 years of follow-up, 25 subjects (10.4%) developed incident CMB. A total of 37 CMB were noticed in these 25 patients. A parsimonious logistic regression model demonstrated an association between the Edmonton Frail Scale (EFS) and incident CMB (p = .043). Multivariate logistic regression models showed an association between WMH progression and incident CMB (p = .011). Using Poisson regression models, the IRR for WMH progression at follow-up was increased in subjects with incident CMB (p = .029).
Conclusions
Study results show a significant relationship between the EFS, WMH progression, and incident CMB. This knowledge will allow the implementation of preventive policies to reduce incident CMB and its consequences.
Keywords: Microbleeds, prospective studies, neuroimaging, incidence, rural population, Ecuador
Introduction
Cerebral microbleeds (CMB) are small foci of hemosiderin-laden perivascular macrophages that result from extravasation of blood components probably related to mechanisms of arterial remodeling.1,2 According to their location (deep versus cortical), CMB have been mostly associated with either cerebral small vessel disease (cSVD) or cerebral amyloid angiopathy. However, other pathologies (traumatic brain injuries, chronic kidney disease, and chronic infections) may account for their occurrence.3–5 In addition, CMB have been reported after radiation therapy, certain endovascular procedures and with the use of some medications.6–8
Several cross-sectional studies have addressed CMB prevalence, which varies from 3% to >30% according to age and other characteristics of the study population.9–13 Common correlates of CMB include other neuroimaging biomarkers of cSVD and the apolipoprotein E (APOE) genotype. Traditional cardiovascular risk factors have been associated with CMB in some,10–12 but not all studies. 13 Cohort studies have focused on CMB incidence, but none of them departed exclusively with CMB-free individuals, and most incidents CMB were noticed in subjects who already had CMB at baseline.14–23 In the largest of these studies, individuals with baseline CMB had more than 5 times the odds of developing incident CMB than those without. 15 The same has been observed in other studies, where baseline CMB predicted the occurrence of incident CMB. Therefore, it is uncertain whether CMB may appear de novo in older adults who do not have CMB at baseline. Information on this subject mostly comes from White and Asian populations, and little is known about the incidence and correlates of CMB in other races/ethnic groups. Moreover, not all longitudinal studies are population-based but focused on incident CMB occurring in special conditions such as Alzheimer’s disease, 16 Moyamoya, 17 multiple sclerosis, 20 or infectious diseases. 21
Longitudinal studies on individuals free of CMB at baseline are of interest to determine the true incidence of CMB in older adults and factors predisposing to their occurrence. Also, more information is needed on CMB incidence from different ethnic groups. Taking the opportunity of the well-established Atahualpa Project Cohort, this study aimed to assess the burden and correlates of de novo appearing CMB in a population of older adults of Amerindian ancestry living in rural Ecuador.
Methods
Study population
The present study was conducted in community-dwelling older adults living in Atahualpa, a rural Ecuadorian village, where previous cross-sectional studies on CMB have been carried out. 24 As detailed elsewhere, the population of Atahualpa is homogenous regarding ethnicity (Amerindian ancestry), socio-economic status, living conditions, and dietary habits. 25
Study design
Participants were identified by means of door-to-door surveys and other overlapping sources. 25 Following a longitudinal prospective design, individuals aged ≥ 60 years who had a baseline brain MRI between 2012 and 2019, and were actively participating in the Atahualpa Project Cohort as of May 2021, were invited to receive a follow-up brain MRI (at the time of the last censoring date). A criterion for inclusion was that surveyed individuals must have been microbleed-free on baseline MRI. Participants signed informed consent forms at enrollment and before the practice of follow-up MRIs. The study was approved by the Ethics Committee of Hospital-Clínica Kennedy, Guayaquil (FWA 00030727). CMB presence at follow-up MRI was evaluated according to the different variables investigated (see below).
Neuroimaging protocol
Both baseline and follow-up MRIs were performed with a Philips Intera 1.5T (Philips Medical Systems, Eindhoven, the Netherlands), following accepted standards for research on cSVD. 26 MRIs included two-dimensional multi-slice turbo spin echo T1-weighted (TR 594, TE 15), fluid attenuated inversion recovery (FLAIR) (TR 9000, TE 120, TI 2500), T2-weighted (TR 4500, TE 100), and T2*-weighted gradient-recalled echo (GRE) (TR 686, TE 23) sequences in the axial plane, as well as a FLAIR sequence oriented in the sagittal plane. The pre-established brain imaging package delivered by the manufacturer was used to homogenize applicability; slice thickness was 5 mm with 1 mm gap between slices. MRI readings focused on white matter hyperintensities (WMH) of presumed vascular, cerebral microbleeds (CMB), lacunes of presumed vascular origin, and enlarged basal ganglia perivascular spaces (BG-PVS). In addition, non-lacunar strokes were identified and tabulated.
Because of potential confusion between calcified parenchymal brain cysticerci (prevalent in about 10% of the study population) and CMB, 27 all individuals also received an unenhanced head CT scan (Philips Brilliance 64 CT scanner, Philips Medical Systems, Eindhoven, the Netherlands). Therefore, MRIs were read for CMB in the light of CT findings excluding calcified cysticerci.
WMH were identified as lesions appearing hyperintense on T2-weighted images that remained bright on FLAIR (without cavitation) and graded according to the modified Fazekas scale in none-to-mild and moderate-to-severe. 28 CMB were assessed on the T2*-weighted GRE sequence and rated according to the microbleed anatomical rating scale; only definite CMB were included (well-defined, small, rounded or circular, hypointense lesions). 29 Lacunes were defined in the T1-weighted sequence as fluid-filled cavities measuring 3–15 mm located in the territory of a perforating arteriole. 26 Enlarged BG-PVS were defined as small (<3 mm) structures of CSF intensity that followed the orientation of perforating arteries. 30 These lesions were assessed on the T2-weighted sequence and their burden was rated in the single slice with the highest number of these structures in one side; more than 10 of these structures were rated as abnormal. 31 MRIs were independently read by two study investigators blinded to clinical information. Overall, Kappa coefficients for interrater agreement were 0.93 for WMH, 0.82 for CMB, 0.88 for lacunes, 0.84 for the presence of >10 enlarged BG-PVS, and 0.91 for non-lacunar strokes; discrepancies were resolved by consensus.
Progression of each of these biomarkers was defined as a change from none-to-mild to moderate-to-severe for WMH, as the appearance of new lacunes (in subjects with or without baseline lacunes), as an increase in the burden of BG-PVS to more than 10, and as the presence of a new lacunar stroke in the follow-up MRI. As per protocol, CMB were not present at baseline MRIs (those individuals were excluded from the study) and their progression consisted in the appearance of these lesions at follow-up MRIs.
Clinical covariates
Demographics, cardiovascular risk factors, and levels of frailty were recorded at baseline as they have been associated with CMB in previous studies.15,32 Determinations of traditional cardiovascular risk factors followed the recommendations of the American Heart Association (AHA), which stratifies each of the following cardiovascular health metrics in the poor range according to well-defined cutoffs, including: (1) Poor smoking status if the subject is a current smoker or quit <1 year; (2) Poor body mass index if ≥ 30 kg/m2; (3) Poor physical activity if there is no moderate and vigorous activity; (4) Poor diet if there is none or only one of five AHA healthy dietary components; (5) Poor blood pressure if ≥ 140/90 mmHg; (6) Poor fasting glucose if ≥ 126 mg/dL; and (7) Poor total cholesterol blood levels if ≥ 240 mg/dL. 33 In addition, the pulse pressure (as an indicator of the pulsatile component of blood pressure)—characterized as increased if > 65 mmHg—was also taken into account. The Edmonton Frail Scale (EFS) was used to evaluate severity of cognitive frailty. This validated field instrument consists of 10 domains with 11 items including cognition, general health status, functional independence, social support, medication use, nutrition, mood, and balance and motility. 34 The maximum EFS score was 17 points, with higher scores corresponding to greater frailty levels. We did not use pre-defined cutoffs for categorizing a frail status due to lack of validation of these cutoffs in older adults living in remote rural communities. Instead, we considered the continuous EFS score for analyses.
Statistical analysis
STATA software package version 17 (College Station, TX, USA) was used for data analysis. Continuous variables were compared by linear models and categorical variables by the chi-square or Fisher exact test in unadjusted analyses. To compute person-years of follow-up, we considered the time from baseline to follow-up MRIs, which was the last administrative censoring date (end of study). Separate logistic and Poisson regression models were respectively fitted to estimate the Odds Ratio (OR) and the incidence rate ratio (IRR) of CMB at follow-up according to clinical and neuroimaging variables at baseline, as well as to neuroimaging variables at follow-up. Parsimonious models (using variables reaching p < .1 significance in unadjusted analyses) were fitted as needed. Poisson regression models took into account the effect of time on CMB at follow-up according to the other variables. Diet was not included as a variable in any of these models because the few individuals with a poor diet were allocated to the group of individuals without CMB progression (collinearity).
Results
Figure 1 depicts enrollment and the reasons for not including study participants at each stage of this process. A total of 403 (84%) out of 478 individuals aged ≥ 60 years enrolled in the Atahualpa Project cohort from 2012 to 2019 received baseline brain MRIs, head CTs, and clinical interviews. Thirty-six of the 75 excluded individuals died or emigrated before the practice of neuroimaging exams, 19 declined consent, 17 were severely disabled or had contraindications for MRI, and 3 had missing clinical information. Of 403 candidates, 263 (65%) had a follow-up brain MRI and were eligible for this study. Ninety of 140 non-eligible participants died, and the remaining 50 either declined further consent, became disabled over the study years, or emigrated between baseline and follow-up MRI. In addition, 22 participants had CMB at baseline MRIs and were not included. There were no significant differences in unadjusted analyses across demographics, CVH metrics, and the EFS across the 22 individuals excluded because of having CMB at baseline and the 241 included participants. However, moderate-to-severe WMH (p = .009) and lacunes (p < .001) were more frequent among the former.
Figure 1.
Flow chart depicting enrollment and the reasons for not including study participants at each stage of this process.
The follow-up time between baseline and follow-up brain MRIs was 1576 person-years (95% C.I.: 1553–1619 years), and the median follow-up was 6.5 years (interquartile range: 2.3–7.8 years).
The mean (±SD) age at baseline of 241 study participants was 65.6 ± 6.1 years (median age: 63.6 years; age range: 60–91 years) and 137 (57%) were women. Individual cardiovascular health metrics in the poor range included: smoking status: 10 (4%); body mass index: 55 (23%); physical activity: 10 (4%); diet: 10 (4%); blood pressure: 93 (39%); fasting glucose: 68 (28%); and total cholesterol blood levels: 38 (16%). The pulse pressure was elevated in 81 (37%) participants, and the mean score in the EFS was 4 ± 2.3 points.
At baseline MRI, 33 (14%) participants had moderate-to-severe WMH. Lacunes were noticed in 10 (4%) subjects, >10 enlarged BG-PVS in 48 (20%), and non-lacunar strokes in seven (3%), six of which were ischemic and the other hemorrhagic. At follow-up MRI, moderate-to-severe WMH were noticed in 84 (35%) individuals, lacunes in 23 (10%), >10 enlarged BG-PVS in 86 (36%), and non-lacunar strokes in 17 (7%), two of which were hemorrhagic. Overall, progression of WMH was recognized in 51 cases (21%), lacunes in 13 (5%), >10 enlarged BG-PVS in 36 (15%), and non-lacunar strokes in ten (4%).
As previously mentioned, all individuals were CMB-free at baseline MRI. After a median follow-up of 6.5 years, 25 subjects (10.4%; 95% C.I.: 7.1–14.9%) with incident CMB were identified. A total of 37 de novo CMB were noticed in these 25 patients (Figure 2). CMB were single in 19 cases (76%), from 2–3 in four, and ≥ 4 in two. Regarding location, CMB were deep in 19 cases, cortical in four, and located both deep and cortical in the remaining two.
Figure 2.
T2*-weighted gradient-recalled echo MRI showing de novo appearance of cerebral microbleeds when baseline (left) and follow-up (right) images were compared (Images taken from one study participant).
Table 1 depicts characteristics of participants across categories of CMB at follow-up. In unadjusted analyses, the frequency of individuals with high pulse pressure (p = .014) and progression of WMH (p = .006) was higher among those with CMB than in those without; in addition, the EFS score was higher in the former (p = .003).
Table 1.
Characteristics of 241 community-dwelling older adults free of cerebral microbleeds (CMB) at baseline, according to the presence of incident CMB at follow-up (unadjusted analyses).
| Variable | Total series (n = 241) | CMB (n = 25) | No CMB (n = 216) | p value |
|---|---|---|---|---|
| Age (in years) at baseline, mean ± SD. | 65.6 ± 6.1 | 67.1 ± 6.6 | 65.4 ± 6 | 0.186 |
| Women, n (%) | 137 (57) | 16 (64) | 121 (56) | 0.446 |
| Current smoker, n (%) | 10 (4) | 1 (4) | 9 (4) | 0.968 |
| Body mass index ≥30 kg/m2, n (%) | 55 (23) | 6 (24) | 49 (23) | 0.882 |
| Poor physical activity, n (%) | 10 (4) | 2 (8) | 8 (4) | 0.278 |
| Poor diet, n (%) | 10 (4) | 0 | 10 (5) | — |
| Blood pressure ≥140/90 mmHg, n (%) | 93 (39) | 14 (56) | 79 (37) | 0.059 |
| Fasting glucose ≥126 mg/dL, n (%) | 68 (28) | 9 (36) | 59 (27) | 0.361 |
| Total cholesterol ≥240 mg/dL, n (%) | 38 (16) | 4 (16) | 34 (16) | 0.973 |
| Pulse pressure >65 mmHg, n (%) | 81 (34) | 14 (56) | 68 (31) | 0.014* |
| Edmonton frail scale (points), mean ± SD | 4 ± 2.3 | 5.2 ± 2.2 | 3.9 ± 2.2 | 0.006* |
| Moderate-to-severe WMH‡ at baseline, n (%) | 33 (14) | 5 (20) | 28 (13) | 0.333 |
| Lacunes at baseline, n (%) | 10 (4) | 2 (8) | 8 (4) | 0.278 |
| >10 enlarged BG-PVS§ at baseline, n (%) | 48 (20) | 7 (28) | 41 (19) | 0.285 |
| Non-lacunar strokes at baseline, n (%) | 7 (3) | 1 (4) | 6 (3) | 0.540 |
| WMH progression, n (%) | 51 (21) | 11 (44) | 40 (19) | 0.003* |
| Lacunes progression, n (%) | 13 (5) | 3 (12) | 10 (5) | 0.140 |
| Enlarged BG-PVS progression, n (%) | 38 (16) | 4 (16) | 34 (16) | 0.973 |
| Non-lacunar stroke progression, n (%) | 10 (4) | 1 (4) | 9 (4) | 0.968 |
*Statistically significant result.
‡White matter hyperintensities.
§Basal ganglia-perivascular spaces.
A multivariate logistic regression showed no significant association between any of the investigated clinical variables (at baseline) and CMB progression at follow-up; the most parsimonious model that included high pulse pressure and EFS scores, however, demonstrated a significant association between the EFS score and CMB at follow-up (Supplemental File, Table 1S). Separate logistic regression models, adjusted for demographics and neuroimaging variables at baseline and follow-up, showed a significant association between WMH progression and CMB at follow-up (Supplemental File, Table 2S).
Poisson regression models adjusted for clinical variables showed no significant associations between any of the investigated variables and CMB progression at follow-up, nor in the fully-adjusted model or in the most parsimonious model, with the exception of a marginal non-significant association between the EFS score and CMB at follow-up (Supplemental File, Table 3S). In separate Poisson regression models, adjusted for demographics and neuroimaging variables, the IRR for WMH progression at follow-up was increased in subjects with CMB at follow-up (Supplemental file, Table 4S).
Discussion
This longitudinal prospective study, conducted in CMB-free community-dwelling older adults of Amerindian ancestry, shows a direct relationship between baseline increased EFS scores (as an indicator of frailty) as well as an increased progression of WMH in individuals who develop CMB at follow-up. There was not, however, association of incident CMB with demographics, traditional cardiovascular risk factors and other neuroimaging biomarkers of cerebrovascular damage at baseline, and with lacunes and BG-PVS at follow-up.
Frailty, a geriatric condition characterized by reduced functional reserve and vulnerability, has been related to CMB in cross-sectional studies.32,35 In one of them, only brainstem CMB were associated with physical frailty, which suggested that the location of CMB in a highly eloquent area for motor pathways was responsible for this association. 32 Another study found that the above-mentioned association could be related to reduce expression of platelet-induced impaired endothelial repair since the association was limited to individuals with low platelet counts. 35 The present study is the first to demonstrate that higher levels of the EFS at baseline predict de novo CMB appearance. Further studies are warranted to confirm pathogenetic mechanisms involved in the relation between frailty and CMB.
WMH progression was significantly associated with incident CMB, but at baseline it was not. This means that WMH and CMB progress together, which is biologically plausible since both are biomarkers of cSVD. It is important to note, however, that other biomarkers of cSVD, namely, lacunes and enlarged BG-PVS, were not predictors of incident CMB. Our results differ from those of other longitudinal studies on CMB incidence, probably because the present study included a population of CMB-free individuals at baseline.
Of interest, incident CMB were not associated with traditional cardiovascular risk factors at baseline, suggesting that CMB may appear independently of arterial hypertension, diabetes mellitus, and hypercholesterolemia. This lack of association has also been reported in the Northern Manhattan Study, 13 and this concordance is probably related to ethnicity of participants, since both (The Northern Manhattan and the Atahualpa Project Cohort) are the only studies that include populations with different ethnic backgrounds. Much remains to be learned on CMB correlates in diverse ethnic groups. In contrast to that reported by others,22,23 incident CMB were not more frequent with advanced baseline age. The explanation for this lack of association is that we departed from a CMB-free population of older adults and it is possible that after a given age incident CMB are not more frequent across age subgroups.
It must be noticed that in a cross-sectional study assessing CMB prevalence in the Atahualpa population, we found a significant association between CMB and increasing age, arterial hypertension and lacunes. 24 However, those associations vanished in this longitudinal study. This probably means that after a certain age, de novo CMB appearance may be related to other—yet unexplored—risk factors.
This study has limitations. The SARS-CoV-2 pandemic severely struck the village from April 2020, resulting in a mortality rate of more than 60 per 1000 among older adults. 36 In addition, several individuals left the village because of fears related to the pandemic or declined to receive a follow-up MRI. These events reduced the number of study participants with follow-up MRIs and probably contributed to a small amount of selection bias. CVH metrics were measured at baseline and they may have changed during follow-up, leading to over or underestimation of our findings. However, the population has been closely followed and almost all individuals had repeated CVH metrics determinations over the study years. We did not identify relevant changes in CVH metrics with the exception of a transient decline in physical activity and dietary habits among older adults during the past year as a result of the SARS-CoV-2 pandemic. 37 We relied on a 2-dimensional T2*-weighted GRE sequence for identifying CMB and not in 3-dimensional T2*-weighted GRE or susceptibility-weighted sequences, which have been proven to be more sensitive for recognizing these lesions. 3 We did not determine the presence of apolipoprotein E (APOE) genotype, which has been found to be associated with CMB, in particular those located within cerebral lobes.12,15 Also, the interquartile range of follow-up varied widely, which was related to the fact that study participants were recruited during door-to-door surveys conducted from 2012 to 2019 and the last administrative censoring date was the same for the entire population. In addition, it is possible that some unmeasured covariates may have played a role in the investigated relationship. These limitations are counterbalanced by the major strengths of our study, which include the population-based longitudinal prospective design, the homogeneity of the study population regarding race/ethnicity, socio-economic status and lifestyles, and the practice of baseline and follow-up MRIs using the same equipment and protocols in all cases.
In conclusion, study results show a significant relationship between incident CMB, the EFS score and WMH progression. This knowledge will allow implementation of cost-effective preventive policies to reduce the de novo appearance of CMB in older adults and its associated consequences.
Supplemental Material
Supplemental Material for De novo appearance of cerebral microbleeds in community-dwelling older adults. Neuroimaging and clinical correlates by Oscar H Del Brutto, Bettsy Y Recalde, Denisse A Rumbea and Robertino M Mera in The Neuroradiology Journal
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Universidad Espiritu Santo - Ecuador.
Supplemental material: Supplemental material for this article is available online.
ORCID iD
Oscar H Del Brutto https://orcid.org/0000-0003-1917-8805
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Supplementary Materials
Supplemental Material for De novo appearance of cerebral microbleeds in community-dwelling older adults. Neuroimaging and clinical correlates by Oscar H Del Brutto, Bettsy Y Recalde, Denisse A Rumbea and Robertino M Mera in The Neuroradiology Journal