Cerebral Amyloid Angiopathy With Vascular Iron Accumulation and Calcification

Abstract

Background and Purpose— Previous studies of symptomatic and asymptomatic hereditary cerebral amyloid angiopathy (CAA) patients offered the possibility to study the radiological manifestations of CAA in the early stages of the disease. Recently, a striped cortex, observable as hypointense lines perpendicular to the pial surface on T 2 * -weighted 7T magnetic resonance imaging (MRI), was detected in 40% of the symptomatic hereditary CAA patients. However, the origin of these MRI contrast changes is unknown. This study aimed at defining the underlying pathology associated with the in vivo observed striped pattern. Methods— Formalin-fixed postmortem brain material including the occipital lobe of 4 hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) cases and 6 sporadic CAA cases were selected from local neuropathology tissue collections. Depending on the availability of the material, intact hemispheres or brain slabs including the occipital lobe of these patients were screened for the presence of a striped cortex. Regions containing the striped cortex were then subjected to high-resolution 7T MRI and histopathologic examination. Results— We found 2 hereditary cerebral hemorrhage with amyloidosis-Dutch type cases and 1 sporadic CAA case with striped patterns in the occipital cortex resembling the in vivo signal. Histopathologic examination showed that the striped pattern in the cortex at 7T MRI is because of iron accumulation and calcification of penetrating arteries. The presence of both nonheme iron and calcification on penetrating arteries causes signal loss and hence the abnormal striped patterns in the cortical ribbon on T 2 * -weighted MRI. Conclusions— We identified iron accumulation and calcification of the vessel wall in hereditary cerebral hemorrhage with amyloidosis-Dutch type as the histopathologic correlates of the striped cortex observed on in vivo 7T MRI.

Osteopontin and phospho‐SMAD2/3 are associated with calcification of vessels in D‐CAA, an hereditary cerebral amyloid angiopathy

“…Despite the spatial correlation between CAA load and vascular calcification, to date there is no proof for causality between the presence of the Aβ peptide per se, and calcification of the vessel wall . This is further supported by our previous finding where we observed calcification of non‐CAA vessels in a sCAA case . Furthermore, we observed in the present and in previous studies very heterogeneous patterns of calcification in areas with comparable CAA load, even within the same patient.…”

“…We observed different calcified vessel load between the D‐CAA cases, expressed as the number of fully calcified vessels per mm 2 , as shown in Figure . Within individuals, calcified vessels were clustering in specific part of the tissue section, and confined to the middle cortical layers (as also described in ). Calcified capillaries were Aβ‐laden capillaries (capCAA), restricted to areas where bigger calcified vessels were present (data not shown) and only observed in those cases with the most severe calcification load in the medium to large vessels (Figure ).…”

“…However, in our study, VSMCs are likely not responsible for the medial calcification. Firstly, VSMCs are not present in calcified, nor in pre‐calcified OPN‐positive vessels ( and this study) because CAA‐positive vessels usually do not have any VSMCs remaining. We also speculate that the increased OPN in D‐CAA may not have a vascular origin at all, be it from SMC or other cell types.…”

“…Brain tissue from eight D‐CAA patients, genetically tested for the presence of the mutation (NM_000484.3(APP):c.2077G>C), was used in this study as summarized in Table . In addition to the two cases previously described for the presence of calcifications (in ; cases H2 and H14), six additional patients presenting a known range of CAA severity (based on ) were selected (H5, H6, H7, H8, H9 and H10 as shown in Table ).…”

“…Recently, a striped pattern of hypointense lines perpendicular to the pial surface was observed on in vivo 7T MRI in the occipital cortex of symptomatic D-CAA patients (17). Histopathological examination showed that the striped pattern in the cortex on 7T MRI is caused by iron accumulation and calcification of penetrating arterioles (5,39).…”