Cerebral amyloid angiopathy: an underdiagnosed cause of recurrent neurological symptoms

Cerebral amyloid angiopathy (CAA) is a common, yet frequently underdiagnosed pathology characterised by accumulation of amyloid β proteins in the small blood vessels of the brain. As a result, cerebrovascular dysregulation follows, leading to cerebral microbleeds, lobar intracerebral haematomas and sulcal subarachnoid haemorrhages. Gradual motor and cognitive decline due to these brain injuries leads to significant functional limitation in patients. We describe the case of a 69-year-old man requiring multiple hospital admissions with a variety of neurological symptoms. Following imaging of the brain, he was eventually diagnosed with CAA. We present a brief up-to-date literature review on epidemiology, pathophysiology, clinical features, diagnosis and treatment options for CAA.

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

10.1101/2020.07.22.215418 ◽

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.

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SYMPOSIUM: Clearance of Aβ from the Brain in Alzheimer's Disease: Perivascular Drainage of Amyloid-β Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer's Disease

Brain Pathology ◽

10.1111/j.1750-3639.2008.00133.x ◽

2007 ◽

Vol 18 (2) ◽

pp. 253-266 ◽

Cited By ~ 366

Author(s):

Roy O. Weller ◽

Malavika Subash ◽

Stephen D. Preston ◽

Ingrid Mazanti ◽

Roxana O. Carare

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Β ◽

Amyloid Angiopathy ◽

Cerebral Amyloid ◽

The Brain ◽

Perivascular Drainage

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Advances in our Understanding of the Pathophysiology, Detection and Management of Cerebral Amyloid Angiopathy

European Neurological Review ◽

10.17925/enr.2012.07.02.134 ◽

2012 ◽

Vol 7 (2) ◽

pp. 134 ◽

Cited By ~ 12

Author(s):

Octavio M Pontes-Neto ◽

Eitan Auriel ◽

Steven M Greenberg ◽

◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Small Vessel Disease ◽

Specific Treatment ◽

Amyloid Β ◽

Amyloid Angiopathy ◽

Amyloid Β Peptide ◽

Small Vessels ◽

The Media ◽

Cerebral Amyloid ◽

The Brain

Cerebral amyloid angiopathy (CAA) is pathologically defined as the deposition of amyloid protein, most commonly the amyloid β peptide (Aβ), primarily within the media and adventitia of small and medium-sized arteries of the leptomeninges, cerebral and cerebellar cortex. This deposition likely reflects an imbalance between Aβ production and clearance within the brain and leads to weakening of the overall structure of brain small vessels, predisposing patients tolobar intracerebral haemorrhage (ICH), brain ischaemia and cognitive decline. CAA is associated with markers of small vessel disease, like lobar microbleeds and white matter hyperintensities on magnetic resonance imaging. Therefore, it can be now be diagnosed during life with reasonable accuracy by clinical and neuroimaging criteria. Despite the lack of a specific treatment for this condition, the detection of CAA may help in the management of patients, regarding the prevention of major haemorrhagic complications and genetic counselling. This review discusses recent advances in our understanding of the pathophysiology, detection and management of CAA.

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Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1901659116 ◽

2019 ◽

Vol 116 (20) ◽

pp. 10031-10038 ◽

Cited By ~ 10

Author(s):

Takayuki Inoue ◽

Satoshi Saito ◽

Masashi Tanaka ◽

Hajime Yamakage ◽

Toru Kusakabe ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Amyloid Angiopathy ◽

Apoptotic Cell ◽

Amyloid Β ◽

Myeloid Cell ◽

Low Permeability ◽

Amyloid Angiopathy ◽

Neuroprotective Effects ◽

Cerebral Amyloid ◽

The Brain

Cerebral amyloid angiopathy (CAA) results from amyloid-β deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer’s disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-β removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-β through suppressing the ApoE–ERK1/2–amyloid-β precursor protein axis, despite the low permeability of the blood–brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-β production and beneficially modulating proinflammatory microglial phenotypes.

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The Role of Basement Membranes in Cerebral Amyloid Angiopathy

Frontiers in Physiology ◽

10.3389/fphys.2020.601320 ◽

2020 ◽

Vol 11 ◽

Author(s):

Matthew D. Howe ◽

Louise D. McCullough ◽

Akihiko Urayama

Keyword(s):

Risk Factors ◽

Cognitive Decline ◽

Cerebral Amyloid Angiopathy ◽

Functional Impairment ◽

Amyloid Β ◽

Basement Membranes ◽

Amyloid Angiopathy ◽

Transport Pathways ◽

Cerebral Amyloid ◽

The Brain

Dementia is a neuropsychiatric syndrome characterized by cognitive decline in multiple domains, often leading to functional impairment in activities of daily living, disability, and death. The most common causes of age-related progressive dementia include Alzheimer’s disease (AD) and vascular cognitive impairment (VCI), however, mixed disease pathologies commonly occur, as epitomized by a type of small vessel pathology called cerebral amyloid angiopathy (CAA). In CAA patients, the small vessels of the brain become hardened and vulnerable to rupture, leading to impaired neurovascular coupling, multiple microhemorrhage, microinfarction, neurological emergencies, and cognitive decline across multiple functional domains. While the pathogenesis of CAA is not well understood, it has long been thought to be initiated in thickened basement membrane (BM) segments, which contain abnormal protein deposits and amyloid-β (Aβ). Recent advances in our understanding of CAA pathogenesis link BM remodeling to functional impairment of perivascular transport pathways that are key to removing Aβ from the brain. Dysregulation of this process may drive CAA pathogenesis and provides an important link between vascular risk factors and disease phenotype. The present review summarizes how the structure and composition of the BM allows for perivascular transport pathways to operate in the healthy brain, and then outlines multiple mechanisms by which specific dementia risk factors may promote dysfunction of perivascular transport pathways and increase Aβ deposition during CAA pathogenesis. A better understanding of how BM remodeling alters perivascular transport could lead to novel diagnostic and therapeutic strategies for CAA patients.

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The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy

International Journal of Molecular Sciences ◽

10.3390/ijms21041225 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1225

Author(s):

Raisah Owasil ◽

Ronan O’Neill ◽

Abby Keable ◽

Jacqui Nimmo ◽

Matthew MacGregor Sharp ◽

...

Keyword(s):

White Matter ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Β ◽

Basement Membranes ◽

Amyloid Angiopathy ◽

Aqp4 Expression ◽

Fluid Uptake ◽

Arterial Drainage ◽

Cerebral Amyloid ◽

The Brain

In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries—the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15620434 ◽

2015 ◽

Vol 36 (3) ◽

pp. 576-580 ◽

Cited By ~ 33

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.

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Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

Acta Neuropathologica ◽

10.1007/s00401-018-1822-2 ◽

2018 ◽

Vol 135 (5) ◽

pp. 671-679 ◽

Cited By ~ 38

Author(s):

Zane Jaunmuktane ◽

Annelies Quaegebeur ◽

Ricardo Taipa ◽

Miguel Viana-Baptista ◽

Raquel Barbosa ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Amyloid Β ◽

Amyloid Angiopathy ◽

Cerebral Amyloid

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Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab

Stroke ◽

10.1161/strokeaha.121.036873 ◽

2021 ◽

Author(s):

Lukas Sveikata ◽

Andreas Charidimou ◽

Anand Viswanathan

Keyword(s):

Clinical Trials ◽

Alzheimer Disease ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Β ◽

High Rate ◽

Amyloid Angiopathy ◽

Cerebrovascular Pathology ◽

Cerebral Amyloid

We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy’s efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.

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