Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications

Boulouis, Grégoire; Charidimou, Andreas; Greenberg, Steven M.

doi:10.1055/s-0036-1581993

Cited by 48 publications

(47 citation statements)

References 112 publications

(131 reference statements)

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“…We observed Aβ 1-42 plaques, mainly in the form of diffuse plaques, but some large compact plaques were also detected in the parenchyma. Aβ 1-40 diffuse plaques were present mainly around blood vessels as already described for cerebral amyloid angiopathy (CAA) in humans (Boulouis et al, 2016); however, Aβ 1-40 compact plaques were not observed. No Aβ staining was observed in younger animals.…”

Section: Discussionsupporting

confidence: 61%

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

Rodríguez-Callejas

Fuchs

Pérez-Cruz

2016

Front. Aging Neurosci.

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Common marmosets (Callithrix jacchus) have recently gained popularity in biomedical research as models of aging research. Basically, they confer advantages from other non-human primates due to their shorter lifespan with onset of appearance of aging at 8 years. Old marmosets present some markers linked to neurodegeneration in the brain such as amyloid beta (Aβ)1-42 and Aβ1-40. However, there are no studies exploring other cellular markers associated with neurodegenerative diseases in this non-human primate. Using immunohistochemistry, we analyzed brains of male adolescent, adult, old, and aged marmosets. We observed accumulation of Aβ1-40 and Aβ1-42 in the cortex of aged subjects. Tau hyperphosphorylation was already detected in the brain of adolescent animals and increased with aging in a more fibrillary form. Microglia activation was also observed in the aging process, while a dystrophic phenotype accumulates in aged subjects. Interestingly, dystrophic microglia contained hyperphosphorylated tau, but active microglia did not. These results support previous findings regarding microglia dysfunctionality in aging and neurodegenerative diseases as Alzheimer’s disease. Further studies should explore the functional consequences of these findings to position this non-human primate as animal model of aging and neurodegeneration.

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Section: Discussionsupporting

confidence: 61%

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

Rodríguez-Callejas

Fuchs

Pérez-Cruz

2016

Front. Aging Neurosci.

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“…Acquired and non-acquired disease states such as stroke, Alzheimer’s disease and others are associated with abnormal vascular function 19,20 . While extensive literature exists on stroke and its vascular effects/defects, there are scant reports related to traumatic brain injury (TBI).…”

Section: Discussionmentioning

confidence: 99%

Traumatic brain injury results in acute rarefication of the vascular network

Obenaus

Orantes

et al. 2017

Sci Rep

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The role of the cerebrovascular network and its acute response to TBI is poorly defined and emerging evidence suggests that cerebrovascular reactivity is altered. We explored how cortical vessels are physically altered following TBI using a newly developed technique, vessel painting. We tested our hypothesis that a focal moderate TBI results in global decrements to structural aspects of the vasculature. Rats (naïve, sham-operated, TBI) underwent a moderate controlled cortical impact. Animals underwent vessel painting perfusion to label the entire cortex at 1 day post TBI followed by whole brain axial and coronal images using a wide-field fluorescence microscope. Cortical vessel network characteristics were analyzed for classical angiographic features (junctions, lengths) wherein we observed significant global (both hemispheres) reductions in vessel junctions and vessel lengths of 33% and 22%, respectively. Biological complexity can be quantified using fractal geometric features where we observed that fractal measures were also reduced significantly by 33%, 16% and 13% for kurtosis, peak value frequency and skewness, respectively. Acutely after TBI there is a reduction in vascular network and vascular complexity that are exacerbated at the lesion site and provide structural evidence for the bilateral hemodynamic alterations that have been reported in patients after TBI.

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“…Sporadic cerebral amyloid angiopathy (CAA) is a very common small vessel disease (SVD) of the brain, a key cause of spontaneous lobar intracerebral haemorrhage (ICH) and a potential contributor to age- and Alzheimer pathology-related cognitive decline (Boulouis et al, 2016, Charidimou et al, 2012a, Viswanathan and Greenberg, 2011). CAA has thus received increasing attention in the both the Alzheimer and the stroke community for a number of additional important clinical reasons.…”

Section: Introductionmentioning

confidence: 99%

“…While the clinical-imaging spectrum of CAA has been expanded and refined substantially with the broad availability of brain MR imaging (Boulouis et al, 2016), imaging biomarkers of brain parenchymal microvascular lesions provide only indirect evidence for the disease. Since symptomatic or asymptomatic CAA presentations with or without ICH are becoming increasingly common clinical scenaria, additional non-invasive techniques and more direct biomarkers to diagnose CAA in vivo would have major clinical impact.…”

Section: Introductionmentioning

confidence: 99%

Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update

Farid

Charidimou

Baron

2017

NeuroImage: Clinical

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Sporadic cerebral amyloid angiopathy (CAA) is a very common small vessel disease of the brain, showing preferential and progressive amyloid-βdeposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. CAA now encompasses not only a specific cerebrovascular pathological trait, but also different clinical syndromes - including spontaneous lobar intracerebral haemorrhage (ICH), dementia and ‘amyloid spells’ - an expanding spectrum of brain parenchymal MRI lesions and a set of diagnostic criteria – the Boston criteria, which have resulted in increasingly detecting CAA during life. Although currently available validated diagnostic criteria perform well in multiple lobar ICH, a formal diagnosis is currently lacking unless a brain biopsy is performed. This is partly because in practice CAA MRI biomarkers provide only indirect evidence for the disease. An accurate diagnosis of CAA in different clinical settings would have substantial impact for ICH risk stratification and antithrombotic drug use in elderly people, but also for sample homogeneity in drug trials. It has recently been demonstrated that vascular (in addition to parenchymal) amyloid-βdeposition can be detected and quantified in vivo by positron emission tomography (PET) amyloid tracers. This non-invasive approach has the potential to provide a molecular signature of CAA, and could in turn have major clinical impact. However, several issues around amyloid-PET in CAA remain unsettled and hence its diagnostic utility is limited. In this article we systematically review and critically appraise the published literature on amyloid-PET (PiB and other tracers) in sporadic CAA. We focus on two key areas: (a) the diagnostic utility of amyloid-PET in CAA and (b) the use of amyloid-PET as a window to understand pathophysiological mechanism of the disease. Key issues around amyloid-PET imaging in CAA, including relevant technical aspects are also covered in depth. A total of six small-scale studies have addressed (or reported data useful to address) the diagnostic utility of late-phase amyloid PET imaging in CAA, and one additional study dealt with early PiB images as a proxy of brain perfusion. Across these studies, amyloid PET imaging has definite diagnostic utility (currently tested only in probable CAA): it helps rule out CAA if negative, whether compared to healthy controls or to hypertensive deep ICH controls. If positive, however, differentiation from underlying incipient Alzheimer's disease (AD) can be challenging and so far, no approach (regional values, ratios, visual assessment) seems sufficient and specific enough, although early PiB data seem to hold promise. Based on the available evidence reviewed, we suggest a tentative diagnostic flow algorithm for amyloid-PET use in the clinical setting of suspected CAA, combining early- and late-phase PiB-PET images. We also identified ten mechanistic amyloid-PET studies providing early but promising proof-of-concept data on CAA pathophysiology and its various manifestations incl...

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Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications

Cited by 48 publications

References 112 publications

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

Traumatic brain injury results in acute rarefication of the vascular network

Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update

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