The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice

Banerjee, Gargi; Carare, Roxana O.; Cordonnier, Charlotte; Greenberg, Steven M.; Schneider, Julie A.; Smith, Eric E.; Buchem, Mark A. van; Grond, Jeroen van der; Verbeek, Marcel M.; Werring, David J.

doi:10.1136/jnnp-2016-314697

Cited by 183 publications

(157 citation statements)

References 177 publications

(170 reference statements)

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“…Some degree of CAA is often present in patients with AD. CAA can also contribute to neurodegeneration and cognitive dysfunction through microbleeds 2. Our sample had considerable comorbid vascular pathology, but all patients with AD fulfilled both clinical and pathological criteria of AD.…”

Section: Discussionmentioning

confidence: 96%

Advanced cerebral amyloid angiopathy and small vessel disease are associated with psychosis in Alzheimer’s disease

Vik‐Mo

Bencze

Ballard

et al. 2018

J Neurol Neurosurg Psychiatry

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Section: Discussionmentioning

confidence: 96%

Advanced cerebral amyloid angiopathy and small vessel disease are associated with psychosis in Alzheimer’s disease

Vik‐Mo

Bencze

Ballard

et al. 2018

J Neurol Neurosurg Psychiatry

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“…The success of these drugs is still to be determined through ongoing trials, but it has become clear that amyloid-related imaging abnormalities (ARIA) [74,75] found on MRI indicating cerebrovascular edema are a potential adverse effect. ARIA in anti-Aβ monoclonal antibody trials is thought to result from the vascular accumulation of Aβ42 that is solubilized from plaques by the therapeutic antibodies and cleared from the brain via periarterial pathways [76]. The present work showing that apoA-I reduces vascular Aβ deposition and the recent work by our group with 3D engineered human arteries showing that HDL can specifically prevent Aβ42 vascular accumulation suggests that HDL may be a valuable companion therapeutic to administer in conjunction with anti-amyloid therapies to prevent or treat ARIA.…”

Section: Discussionmentioning

confidence: 99%

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

et al. 2019

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Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice . Methods APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice. Electronic supplementary material The online version of this article (10.1186/s13195-019-0497-9) contains supplementary material, which is available to authorized users.

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“…A prominent clinical feature of CAA in humans is the presence of cerebral microbleeds. 1,2 The presence of microbleeds was histochemically evaluated by Perl's staining for perivascular hemosiderin deposits in groups of progressively aged rTg-DI rats. Evidence of cerebral microbleeds was observed in the cortical and hippocampal regions of 12-montheold rTg-DI rats ( Figure 6, A and B).…”

Section: Robust Microhemorrhages and Small-vessel Occlusions Are Detementioning

confidence: 99%

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Davis

Hatfield

et al. 2018

The American Journal of Pathology

105

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Accumulation of fibrillar amyloid b protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid b protein in brain and faithfully recapitulates many of the pathologic aspects of human smallvessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions. (Am J Pathol 2018, 188: 2877e2889; https://doi.

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The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice

Cited by 183 publications

References 177 publications

Advanced cerebral amyloid angiopathy and small vessel disease are associated with psychosis in Alzheimer’s disease

Advanced cerebral amyloid angiopathy and small vessel disease are associated with psychosis in Alzheimer’s disease

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

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