Abstract P342: Histopathological Correlates of MRI-Visible Perivascular Spaces in Cerebral Amyloid Angiopathy

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Valentina Perosa ◽  
Leon P Munting ◽  
Whitney Freeze ◽  
Ashley A Scherlek ◽  
Anand Viswanathan ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Cerebral Amyloid Angiopathy ◽  
Ex Vivo ◽  
Histopathological Examination ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Cerebral Amyloid

Perivascular spaces (PVS) are fluid-filled spaces surrounding cerebral blood vessels. MRI-visible, supposedly enlarged, PVS in the centrum semiovale (CSO) have been associated with cerebral amyloid angiopathy (CAA). PVS enlargement may be due to perivascular clearance impairments, potentially caused by increased amyloid-β (Aβ) accumulation in the walls of vessels in the overlying cortex. We test this hypothesis, using MRI-guided histopathological examination of PVS in CAA autopsy cases. The cohort included 19 CAA (74.1±8.2y, 7F) and 5 non-CAA control cases (88.0±4.9y, 3F). Formalin-fixed hemispheres were scanned on a 3T MRI scanner, including a 500μm T2-weighted sequence. PVS enlargement was assessed in the CSO on in vivo and ex vivo MRI. In addition, local score of PVS enlargement was assessed in four pre-defined juxtacortical areas (Fig.A), using a semiquantitative score and on the corresponding histological sections (Fig.B). Severity of leptomeningeal and cortical CAA were assessed on adjacent Aβ-stained sections, using a semiquantitative scale.PVS enlargement was more severe in CAA cases compared to controls, both on in vivo and ex vivo MRI (p<0.05). PVS enlargement on ex vivo MRI positively correlated with the severity of PVS enlargement on the corresponding histopathological samples (Fig.C). Within CAA cases, the degree of PVS enlargement on ex vivo MRI was positively associated with leptomeningeal CAA severity (n=52 samples, ρ=0.35, p=0.011), but not cortical CAA severity (n=52 samples, ρ=0.10, p=0.472). These preliminary findings confirm that the degree of MRI-visible PVS in juxtacortical brain areas reflects enlargement on histopathology. Moreover, they suggest that PVS enlargement in cases with CAA corresponds to increased CAA severity in the overlying leptomeningeal vessels, possibly as a result of impaired perivascular clearance. Future directions include characterization of individual blood vessels associated with PVS enlargement.

scholarly journals Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces

2015 ◽  
Vol 36 (3) ◽  
pp. 576-580 ◽  
Author(s):  
Susanne J van Veluw ◽  
Geert Jan Biessels ◽  
Willem H Bouvy ◽  
Wim GM Spliet ◽  
Jaco JM Zwanenburg ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Resonance Imaging ◽  
Centrum Semiovale ◽  
Tissue Sections ◽  
Cortical Areas ◽  
Cerebral Amyloid

Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3–7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity.

scholarly journals Endothelial expression of human APP leads to cerebral amyloid angiopathy in mice

2020 ◽  
Author(s):  
Yuriko Tachida ◽  
Saori Miura ◽  
Rie Imamaki ◽  
Naomi Ogasawara ◽  
Hiroyuki Takuwa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Blood Levels ◽  
Amyloid Angiopathy ◽  
Disease Mechanisms ◽  
Age Dependent ◽  
Cerebral Amyloid ◽  
The Brain

AbstractThe deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in more than 90% of Alzheimer’s disease (AD) patients. The presence of such CAA pathology is not as evident, however, in most mouse models of AD, thereby making it difficult to examine the contribution of CAA to the pathogenesis of AD. Since blood levels of soluble amyloid precursor protein (sAPP) in rodents are less than 1% of those in humans, we hypothesized that endothelial APP expression would be markedly lower in rodents, thus providing a reason for the poorly expressed CAA pathology. Here we generated mice that specifically express human APP770 in endothelial cells. These mice exhibited an age-dependent robust deposition of Aβ in brain blood vessels but not in the parenchyma. Crossing these animals with APP knock-in mice led to an expanded CAA pathology as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results show that both neuronal and endothelial APP contribute cooperatively to vascular Aβ deposition, and suggest that this mouse model will be useful for studying disease mechanisms underlying CAA and for developing novel AD therapeutics.

scholarly journals Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways

2017 ◽  
Vol 114 (33) ◽  
pp. E6962-E6971 ◽  
Author(s):  
Aleksandra M. Wojtas ◽  
Silvia S. Kang ◽  
Benjamin M. Olley ◽  
Maureen Gatherer ◽  
Mitsuru Shinohara ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Fold Increase ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Clinical Complications ◽  
Perivascular Drainage

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood–brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu+/+ or Clu−/− background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu−/− mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu−/− mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.

Abstract TMP109: Loss of Gray-White Contrast in Cerebral Amyloid Angiopathy: An in-vivo and Ex-Vivo Exploratory Approach

Stroke ◽  
2019 ◽  
Vol 50 (Suppl_1) ◽  
Author(s):  
Panagiotis Fotiadis ◽  
Susanne van Veluw ◽  
David Salat ◽  
Andrew Warren ◽  
Sarah Grill ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Ex Vivo ◽  
Amyloid Angiopathy ◽  
Exploratory Approach ◽  
Cerebral Amyloid

Abstract 211: The Role of Vascular Amyloid β in the Formation of Microhemorrhages in Cerebral Amyloid Angiopathy

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Susanne J van Veluw ◽  
Andreas Charidimou ◽  
Anand Viswanathan ◽  
Matthew Frosch ◽  
Brian Bacskai ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Direct Consequence ◽  
Transgenic Animals ◽  
Diagnostic Feature ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Cerebral Amyloid

Introduction: Cerebral microhemorrhages are a key diagnostic feature of advanced cerebral amyloid angiopathy (CAA), but the underlying mechanisms remain poorly understood. We investigate the role of vascular Amyloid β (Aβ) in the formation of microhemorrhages in CAA, examining both human tissue and mouse models. Methods: First, we examined the histopathology of microhemorrhages, targeted with post-mortem MRI in humans. Brain slabs from nine cases with moderate/severe CAA were subjected to 7 T MRI. Samples were taken from representative MRI-observed microhemorrhages. On the corresponding histopathological sections we assessed the presence of Aβ in the walls of involved vessels, as well as number of Aβ-positive cortical vessels in areas (<2 mm) surrounding the rupture site. Second, to evaluate microhemorrhage formation in real-time in 3D, we performed in vivo two-photon microscopy in aged APP/PS1 mice with advanced CAA. Mice with previously installed cranial windows were injected with fluorescently labeled anti-fibrin, dextran, and methoxy-XO4 to study clot formation (i.e. microhemorrhages) and their spatial localization in relation to Aβ-positive vessels. Results: Human data: in 7/19 microhemorrhages the involved vessels were preserved. Only one of these vessels was positive for Aβ. Moreover, the density of Aβ-positive cortical vessels was lower close to the site of microhemorrhage (~1 positive vessel/mm 2 ), compared to control areas (~2 positive vessels/mm 2 ). Mouse data: we studied six transgenic ~21 month old APP/PS1 mice and two age-matched wild-type littermates. Mean number of in vivo observed microhemorrhages did not differ between groups (Tg: 1.3 / WT: 1), but the transgenic mice tended to have bigger microhemorrhages (mean size 4706 μm 3 ) than their wild-type controls (2505 μm 3 ). Interestingly, in the transgenic animals only one microhemorrhage was found in close proximity to vascular Aβ deposits. Conclusions: These findings question the widely held assumption that microhemorrhages in CAA are a direct consequence of Aβ deposition in the walls of responsible vessels. Our observations suggest that microhemorrhage formation may not be a direct consequence of more severe CAA locally, but may occur preferentially in areas of relatively low CAA.

scholarly journals Neuropathological correlates of cortical superficial siderosis in cerebral amyloid angiopathy

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3343-3351
Author(s):  
Andreas Charidimou ◽  
Valentina Perosa ◽  
Matthew P Frosch ◽  
Ashley A Scherlek ◽  
Steven M Greenberg ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Ex Vivo ◽  
Superficial Siderosis ◽  
Amyloid Angiopathy ◽  
Age At Death ◽  
Cortical Layers ◽  
Ischaemic Injury ◽  
Cerebral Amyloid ◽  
Cortical Superficial Siderosis

Abstract Cortical superficial siderosis is an established haemorrhagic neuroimaging marker of cerebral amyloid angiopathy. In fact, cortical superficial siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial siderosis. Fourteen autopsy cases with cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and eosin and Perls’ Prussian blue, and immunohistochemistry was performed against amyloid-β and GFAP. Cortical superficial siderosis was present on ex vivo MRI in 8/14 cases (57%) and 0/3 controls (P = 0.072). Histopathologically, cortical superficial siderosis corresponded to iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial siderosis was assessed on a total of 65 Perls’-stained sections from MRI-targeted and untargeted sampling combined in cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial siderosis was associated with concentric splitting of the vessel wall (an advanced form of cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P &lt; 0.0001), but reduced cerebral amyloid angiopathy severity in cortical vessels (P = 0.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial siderosis was associated with the presence of microinfarcts (P = 0.025), though not microbleeds (P = 0.973). Collectively, these data suggest that cortical superficial siderosis on MRI corresponds to iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. Cortical superficial siderosis appears to be the result of predominantly advanced cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas.

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