Different microvascular alterations underlie microbleeds and microinfarcts

Abstract

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. Methods: We scanned intact formalin-fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. Results: In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ-positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). Interpretation: These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways.

Hereditary cerebral amyloid angiopathy, Piedmont-type mutation

“…We examined vessels associated with cortical microbleeds and observed no β-amyloid in the vessels at the bleeding site. This finding is consistent with previous observations in sporadic CAA, 8,9 suggesting a mechanism in which severely affected vessel segments undergo remodeling entailing loss of β-amyloid deposits before hemorrhage. 8 Determining the exact rupture site for leptomeningeal bleeds is more challenging because these hemorrhages are often larger and more dispersed with significant damage to the surrounding tissue.…”

“…This finding is consistent with previous observations in sporadic CAA, 8,9 suggesting a mechanism in which severely affected vessel segments undergo remodeling entailing loss of β-amyloid deposits before hemorrhage. 8 Determining the exact rupture site for leptomeningeal bleeds is more challenging because these hemorrhages are often larger and more dispersed with significant damage to the surrounding tissue. It is therefore unclear whether leptomeningeal vessel hemorrhages follow the same proposed pathophysiologic mechanism as smaller cortical microbleeds, a topic for future investigations.…”

“…Qualitative assessment of H&E-stained sections suggested fewer chronic microinfarcts than typical in sporadic CAA. 8 Similar to observations in sporadic CAA, the vessels feeding the infarcted tissue demonstrated increased local β-amyloid burden. 8 These findings suggest that the relative sparing of the cortical vasculature from CAA may lead to fewer microinfarcts in patients with the Piedmont mutation, a factor likely contributing to the lack of cognitive impairment in these patients (in addition to the absence of plaques and tangles).…”

“…Four cortical microinfarcts were identified in total (across all 4 sections), fewer than typically observed in cases with sporadic CAA using similar methodology. 8 The cortical vessels associated with each microinfarct had substantial β-amyloid in their walls ( figure 2B). Serial sectioning of MRI-guided samples yielded 3 microbleeds (2 recent, one old).…”

Utility of shape evolution and displacement in the classification of chronic multiple sclerosis lesions

“…The more spherical deformations observed with SVD, along with the lack of changes in lesion positioning, may point to the underlying pathophysiology of lesion development as hyaline degeneration of the subcortical arteries and arterioles along with resulting micro-ischemia, gliosis, and tissue degeneration dominate 21 . Alterations in endothelial shear stress, decreased vessel wall compliance, impaired vasodilation, changes in vessel thickness, perivascular enlargement, and amyloid ß peptide within vessels have also been implicated 2,[22][23][24] . These mechanisms of injury differ substantially with chronic autoimmune demyelinating events where persistent inflammation related to aberrant microglia or macrophage behavior may occur along with endogenous remyelination and secondary degenerative changes 25,26 .…”