We report two lines of evidence suggesting that CAA-related microbleeds and macrobleeds, though arising from a common vascular disease, represent distinct pathophysiologic events. Findings supporting this inference are that 1) hemorrhage volumes appear to fall into a bimodal distribution best modeled as a mixture of two separate populations, and 2) CAA subjects with many microbleeds demonstrate significantly thicker amyloid-positive vessels than those with few microbleeds. These essentially independent observations support a model by which symptomatic macrobleeding and asymptomatic microbleeding are distinct entities with characteristic pathophysiologies.
It is notable that the cut-point between the two hemorrhage volume populations determined by ROC analysis of the estimated two-component mixture model () corresponded to a spherical diameter of 0.57 cm, a value very close to the upper size limits of 0.5 to 1 cm traditionally chosen to define microbleeds.1-3
The reasonably wide separation of the two peaks (plotted on a logarithmic scale in ) suggests that the precise cut-point chosen probably has little effect on whether a given lesion will be classified as a microbleed or macrobleed. We note that the measurements on GRE MRI overestimate the true size of the microbleeds because of the susceptibility (“blooming”) artifact. A recent comparison of hemorrhage volumes on GRE MRI and CT suggested a correction factor of 0.8.15
The overall relationship between microbleeds and macrobleeds remains an active area of investigation. Some previous studies have suggested that the number of microbleeds predicts risk of future symptomatic ICH.13, 16
In the case of symptomatic hemorrhage following thrombolytic treatment for ischemic stroke, however, the presence of microbleeds appears not to be predictive.17, 18
The observation of increased vessel wall thickness among high relative to low microbleed-count subjects suggests that thicker vessels may render vessels more likely to produce microbleeding when they rupture. Thickening of the vessel wall and narrowing of the vascular lumen has long been noted as characteristic of CAA,14, 19
but the factors determining degree of wall thickness are largely unknown. Severe wall thickening occurs in Iowa-type hereditary CAA,20
a familial form of CAA also characterized by multiple microbleeds without symptomatic hemorrhage among 10 affected members of the originally identified pedigree. Whether similar considerations of microbleeding and vessel wall thickness apply to vasculopathies other than CAA, such as hypertensive hemorrhage,11
remains to be determined. In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), another vascular pathology associated with severe thickening of the arterial wall and loss of normal wall elements, microbleeds are common but symptomatic macrobleeds are rare,9, 21-23
suggesting possible similarities to the CAA high microbleed group.
There are important limitations to the current analysis. Hemorrhages and hemorrhage volumes were measured by MRI (using relatively thick slices) rather than neuropathologically, yielding potential radiographic artifacts and mismeasurements, but also allowing systematic detection of hemorrhage throughout the full cerebral cortices. Also, since most of our CAA subjects are identified following presentation to a tertiary referral center with symptomatic ICH, our study cohort was likely biased to have more and larger macrobleeds than would be observed in a community-based analysis. Recent data from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) study, for example, found a 25th
percentile for ICH volumes of 3 cm3
, indicating a substantial number of smaller ICHs.24
It is nonetheless unlikely that a bias towards more and larger macrobleeds would account for the overall bimodal distribution of hemorrhage volumes (), which is caused by relatively underpopulated bins at even smaller volumes (approximately 0.14 to 2.7 cm3
) than those detected in the BASIC study. We also note that the volumes of the presenting ICH were similar between subjects with and without accompanying microbleeds (p=0.62 by Wilcoxon rank sum test) and that there was no association between number of microbleeds and the volume of the presenting macrobleed (Kendall’s tau=−0.065, p=0.57), suggesting that the observed bimodal distribution was not the result of combining two separate subtypes of ICH patients. Finally, our neuropathologic analysis involved only a small number of subjects, though with a large enough number of vessel segments to allow robust statistical comparisons using a mixed-effects model to account for correlations within subjects and tissue sections. As this analysis was performed at a single time point for each subject, we cannot exclude the possibility that proportional wall thickness changes with increasing disease duration.