P1-207: ENDOTHELIAL APP EXPRESSION LEADS TO CEREBRAL AMYLOID ANGIOPATHY IN VIVO

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.

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Abstract 62: Increased Monocyte/Macrophage Pro-Inflammatory Cytokines and Chemokines in Mice With Cerebral Amyloid Angiopathy

Stroke ◽

10.1161/str.52.suppl_1.62 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Carson Finger ◽

Juneyoung Lee ◽

Diego Morales ◽

Bharti Manwani

Keyword(s):

Inflammatory Cytokines ◽

Cerebral Amyloid Angiopathy ◽

Neuronal Damage ◽

Muscle Layer ◽

Amyloid Angiopathy ◽

Monocyte Chemoattractant Protein 1 ◽

Cerebral Amyloid ◽

The Brain ◽

Pro Inflammatory Cytokines

Introduction: Cerebral amyloid angiopathy (CAA) is one of the common causes of intracerebral hemorrhage in the elderly. It is caused by the deposition of amyloid-beta1-40 (Aβ1-40) deposition within cerebral blood vessels, especially the smooth muscle layer, that can cause cerebral microbleeds (CMBs) and cognitive impairment. We hypothesize Aβ deposition causes an innate inflammatory response characterized by an increase and activation of microglia and macrophages. This inflammation might cause CMBs, neuronal damage and cognitive decline CAA. Methods: C57BL6 Tg-SwDI male and female mice (18 months) were used as a mouse model for CAA. Age-matched wild-type (WT) mice were used as controls. Brain samples from these mice were fractionated and 23-plex cytokine multiplex was performed on the brain lysates. Data was analyzed using two sample t-test or GraphPad PRISM. Results: Our data showed that CAA increased levels of pro-inflammatory cytokines in the brain, as compared with WT mice. Multiplex analysis showed that Tg-SwDI mice had significantly higher levels of cytokines; tumor necrosis factor-α (TNF-α; 54.38 vs. 17.03 pg/ml, p=0.00207), IL-12 (70.81 vs. 53.95 pg/ml, p= 0.014), macrophage inflammatory protein-1α (MIP-1α, 113.92 vs. 16.81 pg/ml, p=3.85E-10), MIP-1β (86.15 vs. 53.43 pg/ml, p= 3.51E-09) and monocyte chemoattractant protein-1 (MCP-1, 109.46 vs. 118.53 pg/ml, p= 0.00033). Conclusion: This study highlights a monocyte/macrophage driven pro-inflammatory milieu in CAA. Recent studies using in vivo two-photon imaging and histology have found recruitment of microglia and monocytes/macrophages around induced 100 μm sized hemorrhage. The increase in these microglia is only found in Alzheimer’s patients who also had CAA and was not seen in patients with no CAA, suggesting the role of microglia in causing vascular frailty in CAA. Our study suggests that pro-inflammatory cytokines like TNF-a, IL-12, MIP-1α, MIP-1β and MCP-1 can be therapeutic targets for CAA.

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

Stroke ◽

10.1161/str.50.suppl_1.tmp109 ◽

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

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Analysis of Cerebral Amyloid Angiopathy in a Transgenic Mouse Model of Alzheimer Disease Using In Vivo Multiphoton Microscopy

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/60.3.274 ◽

2001 ◽

Vol 60 (3) ◽

pp. 274-279 ◽

Cited By ~ 27

Author(s):

E. Y. Kimchi ◽

S. Kajdasz ◽

B. J. Bacskai ◽

B. T. Hyman

Keyword(s):

Alzheimer Disease ◽

Mouse Model ◽

Transgenic Mouse ◽

Cerebral Amyloid Angiopathy ◽

Multiphoton Microscopy ◽

Transgenic Mouse Model ◽

Amyloid Angiopathy ◽

Cerebral Amyloid

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In vivo characterization of spontaneous microhemorrhage formation in mice with cerebral amyloid angiopathy

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19899377 ◽

2020 ◽

Vol 41 (1) ◽

pp. 82-91 ◽

Cited By ~ 2

Author(s):

Susanne J van Veluw ◽

Matthew P Frosch ◽

Ashley A Scherlek ◽

Daniel Lee ◽

Steven M Greenberg ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Spatial Relationship ◽

Amyloid Angiopathy ◽

Vascular Networks ◽

Complex Flow ◽

Wild Type Littermate ◽

Two Photon Microscopy ◽

Heparin Administration ◽

Cerebral Amyloid

The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls ( p = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.

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P1-460: Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.1043 ◽

2008 ◽

Vol 4 ◽

pp. T354-T355

Author(s):

Monica Garcia-Alloza ◽

Claudia Prada ◽

Elissa M. Robbins ◽

Rebecca A. Betensky ◽

Steven M. Greenberg ◽

...

Keyword(s):

Oxidative Stress ◽

Transgenic Mice ◽

Matrix Metalloproteinase ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Cerebral Amyloid

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

Stroke ◽

10.1161/str.48.suppl_1.211 ◽

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.

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