Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study

Abstract

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer's disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, β-amyloid immunohistochemistry confirmed the presence of β-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged VirchowRobin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease.

The Spectrum of MR Detectable Cortical Microinfarcts: A Classification Study with 7-Tesla Postmortem MRI and Histopathology

“…One study 11 mentions that hemosiderin-containing macrophages in the basal ganglia were sometimes associated with minute areas of tissue necrosis. In another postmortem study of MRI detected microbleeds in the context of CAA, 12 some gliotic lesions with hemosiderin-laden macrophages were observed, which were interpreted as old, healed hemorrhage sites. However, it was noted that based on that study it could not be determined whether those lesions represent a primary ischemic pathology with secondary , and T2* (C) where it was enlarged due to the so-called 'blooming effect' .…”

In vivo iron quantification in collagenase‐induced microbleeds in rat brain

“…Although an established intracerebral hemorrhage rat model typically delivers 0.2 U of collagenase in 1 mL of saline (46,47), the smaller doses and volumes used in this study reflect an attempt to induce smaller and more focal hemorrhagic legions to better model BMB. However, it appears the collagenase injections caused bleeding that is more spatially diffuse than is characteristic of real BMB which generally originate from a single ruptured vessel (25). Refinements to the BMB induction technique leading to more concentrated lesions and distinct dipoles are possible.…”

“…BMB are visible in gradient recalled echo T 2 * magnetic resonance (MR) imaging as focal regions of signal loss (22,23) and have been histopathologically related to hemosiderin (7,24,25), the (paramagnetic) iron-protein complex associated with pathologic iron storage following hemorrhage (26) and ferritin breakdown (27). Thus, BMB represents a source of pathologic iron in the brain that is potentially cytotoxic (e.g., free radical production through the Fenton reaction).…”

“…A few studies have compared radiologic BMB with postmortem human tissue and have noted evidence of associated tissue damage (7,24,25). However, in vivo animal studies would allow the investigation of temporal relationships regarding tissue damage evolution following BMB and possible interventions.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Microbleeding due to microangiopathies may be a source of parenchymal iron deposition. It has been documented that extravasated erythrocytes may propagate along perivascular spaces, trigger inflammatory response and contribute to iron deposition in areas distant from the actual bleeding site [7]. Demyelinating lesions in multiple sclerosis are typically formed around a central vein, and extravasation of erythrocytes through venous walls damaged by perivascular inflammation may participate in iron deposition observed in some lesions [8].…”