Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy

Kimberly, W. Taylor; Gilson, Aaron J.; Rost, Natalia S.; Rosand, Jonathan; Viswanathan, Anand; Smith, Eric E.; Greenberg, Steven M.

doi:10.1212/01.wnl.0000345666.83318.03

Cited by 216 publications

(184 citation statements)

References 30 publications

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“…54 However, the cytotoxic edema that occurs in the acute phase of the infarct (first 1 to 2 weeks), can be visible on MRI as hyperintense foci of restricted diffusion on diffusion-weighted imaging (DWI). Focal DWI lesions have shown to be more common in patients with CAA-related ICH (15% to 23%) than in patients with Alzheimer's disease and controls 59,60 and continue to occur in high frequency beyond the post-ICH period. 61 Importantly, DWI lesions have been found to be associated with other imaging markers of CAA (i.e., WMH volume and lobar microbleeds), but not with traditional vascular risk factors such as hypertension.…”

Section: Microinfarctsmentioning

confidence: 99%

Ischemic brain injury in cerebral amyloid angiopathy

Reijmer

Veluw

Greenberg

2015

J Cereb Blood Flow Metab

123

102

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Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA.

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Section: Microinfarctsmentioning

confidence: 99%

Ischemic brain injury in cerebral amyloid angiopathy

Reijmer

Veluw

Greenberg

2015

J Cereb Blood Flow Metab

123

102

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“…With disease progression, deposition of amyloid-β (Aβ) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), damages cerebrovascular cells, weakens vessel walls, and disrupts vascular function further (7). CAA also occurs independent of AD and has emerged as a frequent cause of brain hemorrhage, silent infarct, and cognitive impairment (8,9).…”

mentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

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Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions. T here is increasing evidence that alterations in the structure and function of cerebral blood vessels contribute to the brain dysfunction underlying Alzheimer's disease (AD) (1, 2). Whereas resting cerebral blood flow (CBF) is reduced early in course of AD (3, 4), the increase in CBF induced by brain activity (functional hyperemia), a vital mechanism matching the metabolic demands of active neurons with the delivery of nutrients through blood flow, is suppressed (5, 6). With disease progression, deposition of amyloid-β (Aβ) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), damages cerebrovascular cells, weakens vessel walls, and disrupts vascular function further (7). CAA also occurs independent of AD and has emerged as a frequent cause of brain hemorrhage, silent infarct, and cognitive impairment (8, 9).Studies in mice overexpressing mutated forms of the amyloid precursor protein (APP) have demonstrated that Aβ peptides, especially Aβ1-40, which accumulates preferentially in cerebral blood vessels, alter cerebrovascular function, resulting in vasoconstriction, impaired functional hyperemia, and inability of the endothelium to regulate vascular tone (10-12).These studies have raised the possibility that Aβ, in addition to damaging neurons and glia, also threatens the cerebral blood supply and increases the brain's susceptibility to hypoxia-ischemia (1, 13). Furthermore, considering that vascular transport is a key pathway for clearance of Aβ from the brain (14), these vascular alterations also may enhance the accumulation of Aβ in brain and cerebral blood vessels.Converging evidence indicates that Aβ exerts i...

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“…5 In addition, more recent MR imaging studies have suggested that subacute ischemic injury occurs in areas remote from the hematoma, including borderzone (BZ, also known as watershed) regions. [6][7][8][9][10][11] The etiology of these ischemic injuries has been postulated to be hemodynamic compromise secondary to BP reduction. 10 Studies of CBF in the perihematoma region indicate that this region is relatively hypoperfused, but not se-verely enough to result in ischemia.…”

Section: Abbreviationsmentioning

confidence: 99%

“…[6][7][8][9][10][11] The retrospective association shown between BP reduction in the setting of chronic hypertensive vasculopathy and these ischemic lesions raises the possibility that they are a consequence of hemodynamic compromise. Given that CPP has been shown to be more sensitive to slight variations in mean arterial pressure than individual measurements of CBF or CBV, 18 we postulated that subtle perfusion changes in the BZ regions may only become apparent by using this analysis.…”

Section: Borderzone Cerebral Perfusion Pressurementioning

confidence: 99%