The primary findings from this study were small DWI-hyperintense lesions suggestive of subacute ischemic infarction in 12 of 78 (15%) patients with a diagnosis of advanced CAA. Such lesions were absent from a slightly older AD/MCI control group. Their presence was unrelated to conventional vascular risk factors such as HTN, diabetes, or coronary artery disease and was instead associated with number of hemorrhagic lesions on GRE MRI, a marker of CAA severity.23
As we excluded subjects with symptoms of ischemic stroke, these lesions appear to be clinically silent events that occur as part of the ongoing pathogenesis of CAA. These lesions appear similar to small silent infarcts identified in two patients with another small vessel disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.27
The signal characteristics, size, and location of the DWI-positive lesions suggest they may represent the neuroimaging correlates of the neuropathologic infarctions described in association with CAA.2-7
Analyses of autopsied brains with advanced CAA have identified lesions described as perivascular scars, microinfarcts, or small infarctions at frequencies ranging from 37%3
to close to 100%.2,7
These pathologically observed infarctions are frequently multiple and located in the cortical ribbon or underlying subcortical white matter. The observation that CAA in cortical vessels can cause infarction of subcortical white matter presumably reflects the anatomy of blood flow to the white matter, by which penetrating vessels traverse the cortex before supplying the white matter.28
Although one neuropathologic analysis found a possible synergistic relationship between severe CAA and HTN,3
these lesions appear generally to occur independently of atherosclerosis or arteriolosclerosis of cerebral or systemic vessels. Blood pressure did not appear to be a major contributor to DWI-positive lesions in the current study, though this study did not include direct blood pressure measurements at the time of MRI.
Given the transience of DWI changes after stroke, the finding of lesions in 15% of subjects suggests these small infarctions may occur very frequently. Assuming a 10-day poststroke period when restricted diffusion remains detectable,13
their estimated annual prevalence would be calculated as (17/78) x (365/10) or 8.0 new infarctions per person-year. This estimate is strikingly high relative to the estimated incidence of new microbleeds (~1.4 per year) or symptomatic ICH (~0.14 per year) calculated from other cohorts with advanced CAA23
and suggests that the lifetime burden of ischemic infarction in advanced CAA could be substantial.
This surprisingly high frequency of DWI lesions raises important questions about our study’s limitations and possible sources of overestimation. The number of scans examined was relatively small, yielding wide confidence intervals for the true prevalence of DWI-positive lesions (exact 95% confidence intervals 8.2% to 25.3%). Also, there was no pathologic confirmation that the DWI-positive lesions indeed represent infarctions, although their signal characteristics and location correlate reasonably well with the neuropathologic studies of CAA. We further note possible bias toward identifying lesions in the CAA cases, particularly as the scans could not be analyzed blinded to the accompanying presence of hemorrhage. It is reassuring in this regard that independent analysis of a subset of scans showed no evidence for substantial interrater variability. Finally, scans were generally obtained at only a single time point in each subject. Only 10 of the 78 MRI scans were performed without any reference to clinical events, and the majority were performed during the days (38 scans) or months (18 scans) after acute ICH. We did not, however, see an increased frequency of DWI lesions on scans performed shortly after ICH relative to the remainder of the study group, indicating that the timing of infarction and ICH may be independent of each other.
The association between DWI-positive lesions and number of total hemorrhages or microbleeds suggests that infarction and microbleed formation may share common pathophysiologic steps. Previous pathologic studies have identified vasculopathic changes specifically linked to CAA-related bleeding such as fibrinoid necrosis and microaneurysm formation29
; the association of these pathologic changes with small infarction remains to be determined. The absence of association between DWI lesions and WMH is somewhat unexpected, as one might have predicted a close relationship between the occurrence of true infarction and the incomplete infarction hypothesized to underlie WMH.28
Our data instead suggest that processes besides microinfarction may be key determinants of WMH burden, one example being impaired cerebrovascular reactivity12
(which is associated with volume of WMH). We also found no association between MRI evidence of chronic infarcts and the DWI-positive lesions, which may be too small to leave an area of MRI signal recognizable as a chronic infarct.
The suggestion of relatively frequent ischemic infarction in CAA subjects extends the spectrum of CAA-related pathophysiology, which previously included hemorrhage and impaired cerebrovascular reactivity. Our cross-sectional data provide no information on the effect of these lesions on future clinical course, clearly an important subject for future investigation. Determining the contribution of small ischemic infarction to cognitive impairment in CAA will likely require multivariable analysis in larger cohorts, controlling for other radiographic markers of microstructural damage in CAA such as white matter lesions30
and increased global mean diffusivity.22
If these lesions are found to contribute substantially to the clinical impact of CAA, they may ultimately be considered as radiographic markers for candidate treatments of this disorder.