scholarly journals Longitudinal Cognitive Decline in a Novel Rodent Model of Cerebral Amyloid Angiopathy Type-1

2020 ◽  
Vol 21 (7) ◽  
pp. 2348 ◽  
Author(s):  
Dominique L. Popescu ◽  
William E. Van Nostrand ◽  
John K. Robinson
Keyword(s):  
Transgenic Mouse ◽  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Reaction Times ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Delayed Reaction ◽  
Amyloid Aβ ◽  
Cerebral Amyloid ◽  
Speed Accuracy

Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by β-amyloid (Aβ) accumulation in and around the cerebral blood vessels and capillaries and is highly comorbid with Alzheimer’s disease (AD). Familial forms of CAA result from mutations within the Aβ domain of the amyloid β precursor protein (AβPP). Numerous transgenic mouse models have been generated around expression of human AβPP mutants and used to study cerebral amyloid pathologies. While behavioral deficits have been observed in many AβPP transgenic mouse lines, relative to rats, mice are limited in behavioral expression within specific cognitive domains. Recently, we generated a novel rat model, rTg-DI, which expresses Dutch/Iowa familial CAA Aβ in brain, develops progressive and robust accumulation of cerebral microvascular fibrillar Aβ beginning at 3 months, and mimics many pathological features of the human disease. The novel rTg-DI model provides a unique opportunity to evaluate the severity and forms of cognitive deficits that develop over the emergence and progression of CAA pathology. Here, we present an in-depth, longitudinal study aimed to complete a comprehensive assessment detailing phenotypic disease expression through extensive and sophisticated operant testing. Cohorts of rTg-DI and wild-type (WT) rats underwent operant testing from 6 to 12 months of age. Non-operant behavior was assessed prior to operant training at 4 months and after completion of training at 12 months. By 6 months, rTg-DI animals demonstrated speed–accuracy tradeoffs that later manifested across multiple operant tasks. rTg-DI animals also demonstrated delayed reaction times beginning at 7 months. Although non-operant assessments at 4 and 12 months indicated comparable mobility and balance, rTg-DI showed evidence of slowed environmental interaction. Overall, this suggests a form of sensorimotor slowing is the likely core functional impairment in rTg-DI rats and reflects similar deficits observed in human CAA.

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 Strictly Lobar Microbleeds Reflect Amyloid Angiopathy Regardless of Cerebral and Cerebellar Compartments

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3600-3607 ◽  
Author(s):  
Young Hee Jung ◽  
Hyemin Jang ◽  
Seong Beom Park ◽  
Yeong Sim Choe ◽  
Yuhyun Park ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Disease Burden ◽  
Dentate Nucleus ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Cerebral Microbleeds ◽  
Amyloid Angiopathy ◽  
Positron Emission ◽  
Aβ Amyloid ◽  
Cerebral Amyloid

Background and Purpose: We aimed to determine whether lobar cerebellar microbleeds or concomitant lobar cerebellar and deep microbleeds, in the presence of lobar cerebral microbleeds, attribute to underlying advanced cerebral amyloid angiopathy pathology or hypertensive arteriopathy. Methods: We categorized 71 patients with suspected cerebral amyloid angiopathy markers (regardless of the presence of deep and cerebellar microbleeds) into 4 groups according to microbleed distribution: L (strictly lobar cerebral, n=33), L/LCbll (strictly lobar cerebral and strictly lobar cerebellar microbleeds, n=13), L/Cbll/D (lobar, cerebellar, and deep microbleeds, n=17), and L/D (lobar and deep, n=8). We additionally categorized patients with cerebellar microbleeds into 2 groups according to dentate nucleus involvement: strictly lobar cerebellar (n=16) and dentate (n=14). We then compared clinical characteristics, Aβ (amyloid-β) positivity on PET (positron emission tomography), magnetic resonance imaging cerebral amyloid angiopathy markers, and cerebral small vessel disease burden among groups. Results: The frequency of Aβ positivity was higher in the L and L/LCbll groups (81.8% and 84.6%) than in the L/Cbll/D and L/D groups (37.5% and 29.4%; P <0.001), while lacune numbers were lower in the L and L/LCbll groups (1.7±3.3 and 1.7±2.6) than in the L/Cbll/D and L/D groups (8.0±10.3 and 13.4±17.7, P =0.001). The L/LCbll group had more lobar cerebral microbleeds than the L group (93.2±121.8 versus 38.0±40.8, P =0.047). The lobar cerebellar group had a higher Aβ positivity (75% versus 28.6%, P =0.011) and lower lacune number (2.3±3.7 versus 8.6±1.2, P =0.041) than the dentate group. Conclusions: Strictly lobar cerebral and cerebellar microbleeds are related to cerebral amyloid angiopathy, whereas any combination of concurrent lobar and deep microbleeds suggest hypertensive angiopathy regardless of cerebral or cerebellar compartments.

scholarly journals ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes

2020 ◽  
Vol 21 (12) ◽  
pp. 4371
Author(s):  
Abby Keable ◽  
Ronan O’Neill ◽  
Matthew MacGregor Sharp ◽  
Maureen Gatherer ◽  
Ho Ming Yuen ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Light And Electron Microscopy ◽  
Amyloid Β ◽  
Basement Membranes ◽  
Amyloid Angiopathy ◽  
Disease Spectrum ◽  
Arterial Drainage ◽  
Capillary Endothelial Cells ◽  
Cerebral Amyloid

The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage—IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy.

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

2012 ◽  
Vol 7 (2) ◽  
pp. 134 ◽  
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.

scholarly journals A practical approach to the management of cerebral amyloid angiopathy

2020 ◽  
pp. 174749302097446
Author(s):  
Mariel G Kozberg ◽  
Valentina Perosa ◽  
M Edip Gurol ◽  
Susanne J van Veluw
Keyword(s):  
Intracerebral Hemorrhage ◽  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Management Strategies ◽  
Immunosuppressive Treatment ◽  
Amyloid Β ◽  
Imaging Biomarkers ◽  
Amyloid Angiopathy ◽  
Age Related ◽  
Cerebral Amyloid

Cerebral amyloid angiopathy is a common small vessel disease in the elderly involving vascular amyloid-β deposition. Cerebral amyloid angiopathy is one of the leading causes of intracerebral hemorrhage and a significant contributor to age-related cognitive decline. The awareness of a diagnosis of cerebral amyloid angiopathy is important in clinical practice as it impacts decisions to use lifelong anticoagulation or nonpharmacological alternatives to anticoagulation such as left atrial appendage closure in patients who have concurrent atrial fibrillation, another common condition in older adults. This review summarizes the latest literature regarding the management of patients with sporadic cerebral amyloid angiopathy, including diagnostic criteria, imaging biomarkers for cerebral amyloid angiopathy severity, and management strategies to decrease intracerebral hemorrhage risk. In a minority of patients, the presence of cerebral amyloid angiopathy triggers an autoimmune inflammatory reaction, referred to as cerebral amyloid angiopathy-related inflammation, which is often responsive to immunosuppressive treatment in the acute phase. Diagnosis and management of cerebral amyloid angiopathy-related inflammation will be presented separately. While there are currently no effective therapeutics available to cure or halt the progression of cerebral amyloid angiopathy, we discuss emerging avenues for potential future interventions.

Cerebrovascular and Neurodegenerative Pathologies in Long-Term Stable Mild Cognitive Impairment

2021 ◽  
pp. 1-15
Author(s):  
Manu J. Sharma ◽  
Brandy L. Callahan
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cerebral Amyloid Angiopathy ◽  
Neurofibrillary Tangles ◽  
Small Vessel Disease ◽  
Significant Proportion ◽  
Amyloid Angiopathy ◽  
Prodromal Phase ◽  
Cerebral Amyloid

Background: Mild cognitive impairment (MCI) is considered by some to be a prodromal phase of a progressive disease (i.e., neurodegeneration) resulting in dementia; however, a substantial portion of individuals (ranging from 5–30%) remain cognitively stable over the long term (sMCI). The etiology of sMCI is unclear but may be linked to cerebrovascular disease (CVD), as evidence from longitudinal studies suggest a significant proportion of individuals with vasculopathy remain stable over time. Objective: To quantify the presence of neurodegenerative and vascular pathologies in individuals with long-term (>5-year) sMCI, in a preliminary test of the hypothesis that CVD may be a contributor to non-degenerative cognitive impairment. We expect frequent vasculopathy at autopsy in sMCI relative to neurodegenerative disease, and relative to individuals who convert to dementia. Methods: In this retrospective study, using data from the National Alzheimer’s Coordinating Center, individuals with sMCI (n = 28) were compared to those with MCI who declined over a 5 to 9-year period (dMCI; n = 139) on measures of neurodegenerative pathology (i.e., Aβ plaques, neurofibrillary tangles, TDP-43, and cerebral amyloid angiopathy) and CVD (infarcts, lacunes, microinfarcts, hemorrhages, and microbleeds). Results: Alzheimer’s disease pathology (Aβ plaques, neurofibrillary tangles, and cerebral amyloid angiopathy) was significantly higher in the dMCI group than the sMCI group. Microinfarcts were the only vasculopathy associated with group membership; these were more frequent in sMCI. Conclusion: The most frequent neuropathology in this sample of long-term sMCI was microinfarcts, tentatively suggesting that silent small vessel disease may characterize non-worsening cognitive impairment.

scholarly journals Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

2018 ◽  
Vol 135 (5) ◽  
pp. 671-679 ◽  
Author(s):  
Zane Jaunmuktane ◽  
Annelies Quaegebeur ◽  
Ricardo Taipa ◽  
Miguel Viana-Baptista ◽  
Raquel Barbosa ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

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

Stroke ◽  
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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