Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy

Abstract

Objective: We aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA). Methods:We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/ macrobleeds identified on follow-up MRI and compared with PiB retention at "simulated" hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained.Results: Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, interquartile range [IQR] 1-9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23-1.46) than simulated lesions (1.14, 95% CI 1.07-1.22, p Ͻ 0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p Ͻ 0.0001). Mean DVR in a superior frontal/ parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p ϭ 0.003). Conclusions:Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA. Neurology ® 2012;79:320-326 GLOSSARY A␤ ϭ ␤-amyloid; CAA ϭ cerebral amyloid angiopathy; CI ϭ confidence interval; DVR ϭ distribution volume ratio; IQR ϭ interquartile range; PiB ϭ Pittsburgh compound B; ROI ϭ region of interest; SWI ϭ susceptibility-weighted imaging.Small vessel brain disease is associated with a range of brain lesions including white matter T2 hyperintensities, cerebral microbleeds, lacunar lesions, and cerebral microinfarcts.1-3 The precise relationship between location of the small vessel pathology and the resultant brain lesions has been difficult to establish, however, largely because of inability to image the small vessels during life. An important advance in this regard was the development of the thioflavin T derivative Pittsburgh compound B (PiB) for in vivo imaging of fibrillar ␤-amyloid (A␤). A series of studies have demonstrated that PiB labels not only parenchymal A␤ in senile plaques 4 but also the cerebrovascular A␤ deposits 5-9 that define cerebral amyloid angiopathy (CAA). A spatial relationship between vascular amyloid and lobar bleeds in CAA has been suggested by neuropathologic studies 10,11 and one cross-sectional radiologic analysis using PiB-PET imaging. 12 There are no prospective studies of patients with CAA followed over time, however, making it difficult...

Ischemic brain injury in cerebral amyloid angiopathy

“…Pittsburg compound B is a radiologic marker of amyloid plaques used to quantify cerebral amyloid load in vivo. [49][50][51] Results showed a positive correlation between WMH volume and cortical PiB uptake in patients with CAA, but not in patients with Alzheimer's disease or healthy elderly controls, 5 suggesting a direct relationship between subcortical WMH and cortical CAA pathology. Furthermore, two studies found that the distribution of WMH in patients with CAA is predominantly posterior, in line with the predominant posterior distribution of CAArelated vascular amyloid.…”

Florbetapir-PET to diagnose cerebral amyloid angiopathy

“…6 One of the exciting advances in CAA research has been the demonstration of the ability of Pittsburgh compound B (PiB), originally designed to detect plaque amyloid in Alzheimer disease (AD), to label vascular amyloid as well. [7][8][9][10] This PET tracer was shown to bind vascular amyloid by radiologic-pathologic correlation in both the common sporadic form of CAA and Iowa-type hereditary CAA, a form of the disorder with little or no plaque deposits of fibrillar Ab. 11,12 Amyloid imaging using PiB-PET has already made important contributions to our understanding of CAA-related hemorrhagic and ischemic disease mechanisms, 2,7,8,13,14 such as prediction of future hemorrhages.…”

Clinico-Radiological Characteristics and Pathological Diagnosis of Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage

“…1,3,29 On the other hand, several attempts using amyloid imaging, such as 11 C-Pittsburgh compound B positron emission tomography ( 11 C-PiB PET), have been made to detect CAA as an underlying disease in several pathological conditions such as dementia, cortical SAH, and cerebral angitis. [30][31][32][33][34] A positive relationship between local amyloid burden and a future risk for hemorrhage has been suggested based on the result of a longitudinal cohort study with 11 C-PiB PET and MRI. 31 However, the presence of vascular amyloid in the tissue sample is not perfectly specific for CAA-ICH because elderly people may incidentally present with asymptomatic vascular amyloid deposition.…”

“…[30][31][32][33][34] A positive relationship between local amyloid burden and a future risk for hemorrhage has been suggested based on the result of a longitudinal cohort study with 11 C-PiB PET and MRI. 31 However, the presence of vascular amyloid in the tissue sample is not perfectly specific for CAA-ICH because elderly people may incidentally present with asymptomatic vascular amyloid deposition. 3,4,11 For more definitive diagnosis of CAA-ICH, ruptured amyloid-laden blood vessels adjacent to the hematoma should be identified in postmortem study.…”