Mapping of Microvascular Architecture in the Brain of an Alzheimer’s Disease Mouse Model using MRI

Abstract Purpose Growing evidence suggests that alterations of the cerebral microvasculature play a critical role in the pathogenesis of Alzheimer’s disease (AD). The objective of this study was to characterize and evaluate the cerebral microvascular architecture in the AD transgenic (Tg) mice model compared with non-Tg mice using brain microvascular indices obtained by MRI.Methods Seven non-Tg mice and ten 5xFAD Tg mice were scanned using a 7-T animal MRI system to measure the transverse relaxation rates of R2 and R2* before and after injection of the monocrystalline iron oxide nanoparticle contrast agent. After calculation of the relaxation rate difference of ΔR2* and ΔR2, the microvascular indices of the vessel size index (VSI), mean vessel diameter (mVD), mean vessel density (Q), mean vessel-weighted image (MvWI), and blood volume fraction (BVf) were mapped. The voxel-based analyses and regions-of-interest (ROIs)-based analyses were performed to compare the indices between the non-Tg and Tg groups.Results The BVf, mVD, VSI, and MvWI were greater in the Tg group than in the non-Tg group based on voxel comparisons. Additionally, the ROIs-based analysis showed that ΔR2*, BVf, mVD, MvWI, and VSI were increased in the Tg group compared to the non-Tg group in several brain regions. Most ROIs defined by the mouse brain atlas were not significantly different between the two groups.Conclusion We found increased microvascular indices of VSI and mVD in the Tg mice, reflecting microvascular disruption in the brain, which may be related to damages of the neurovascular unit in AD caused by cerebral amyloid angiopathy.Clinical Relevance / Application: To date, few studies have investigated the microvascular injuries of the AD brain using MRI. We suggest that investigation of cerebral microvasculature using a high-field MRI in AD would be worthwhile to elucidate the pathophysiology of cerebral amyloid angiopathy in this disease. Indeed, microvascular MRI can be a promising imaging tool for investigating early diagnosis and monitoring treatment in AD.

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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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Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Cells ◽

10.3390/cells10112903 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2903

Author(s):

Rebecca M. Parodi-Rullán ◽

Sabzali Javadov ◽

Silvia Fossati

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Amyloid Angiopathy ◽

Vascular Inflammation ◽

Neurovascular Unit ◽

Brain Parenchyma ◽

Amyloid Angiopathy ◽

Wide Range ◽

Cerebral Amyloid ◽

The Brain

Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid β (Aβ) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aβ also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood–brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aβ-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.

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Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease

Neuropathology and Applied Neurobiology ◽

10.1111/j.1365-2990.2005.00663.x ◽

2005 ◽

Vol 31 (4) ◽

pp. 414-421 ◽

Cited By ~ 27

Author(s):

S. Williams ◽

K. Chalmers ◽

G. K. Wilcock ◽

S. Love

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Neurofibrillary Pathology ◽

Cerebral Amyloid ◽

Relationship Of

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[ 18 F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer’s disease

European Journal of Neurology ◽

10.1111/ene.14743 ◽

2021 ◽

Author(s):

Sébastien Bergeret ◽

Mathieu Queneau ◽

Mathieu Rodallec ◽

Emmanuel Curis ◽

Julien Dumurgier ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Amyloid Angiopathy ◽

Fdg Pet ◽

Amyloid Angiopathy ◽

Cerebral Amyloid

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Abstract P418: Stroke Admissions and Outcomes Among Cerebral Amyloid Angiopathy and Alzheimer’s Disease in the National Inpatient Sample

Stroke ◽

10.1161/str.52.suppl_1.p418 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Nandakumar Nagaraja ◽

Urvish K Patel

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hospital Mortality ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Secondary Diagnosis ◽

National Inpatient Sample ◽

Admission Rates ◽

Secondary Outcomes ◽

Cerebral Amyloid

Background/Purpose: Although cerebral amyloid angiopathy (CAA) and Alzheimer’s Disease (AD) can manifest as separate diseases it can co-exist due to shared amyloid β pathogenic mechanisms. We assessed admission rates and outcomes of ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) among hospitalized patients with a secondary diagnosis of AD and CAA. Methods: Adult patients discharged with a secondary diagnosis of CAA or AD in National Inpatient Sample (NIS) in the years 2016 and 2017 were identified. Admission rates for IS, ICH, and SAH were primary outcomes. In-hospital mortality and discharge to home were secondary outcomes. Multivariate logistic regression analysis was performed to evaluate secondary outcomes with model adjusted for demographics, medical history, hospital characteristics, and Elixhauser comorbidity index. Results: Among 60,609,519 admissions in NIS, 893,834 (1.5%) patients had a secondary diagnosis of AD [mean age 82.1 years and 62% women] and 14,850 (0.02%) patients had CAA [mean age 76.2 years and 51% women]. Combined AD+CAA was present in 1,335 (0.002%) patients. Compared to AD and controls (non AD or CAA), patients with CAA had higher admission rates for IS (11.5% CAA vs 2.8% AD vs 1.7% control, p<0.0001), for ICH (29.5% CAA vs 0.4% AD vs 0.2% control, p<0.0001) and for SAH (3% CAA vs 0.1% AD vs 0.1% control, p<0.0001). Among patients admitted for IS, discharge to home was less likely in AD compared to controls (10.4% AD vs 36.3% control, OR=0.40; 95%CI=0.36-0.44). Among patients admitted for ICH, discharge to home was less likely in AD compared to controls (6.3% AD vs 18.5% control, OR=0.57; 95%CI=0.41-0.78) but higher in CAA (17.8% CAA vs 18.5% control, OR=1.35; 95%CI=1.11-1.63). In-hospital mortality was less likely in patients with CAA than controls among patients admitted for ICH (9.6% CAA vs 23% control, OR=0.33; 95%CI=0.26-0.41) and SAH (6.7% CAA vs 19.1% control, OR=0.27; 95%CI=0.11-0.62). Conclusion: Admissions for IS, ICH, and SAH were higher among CAA compared to AD in NIS. CAA patients had lower in-hospital mortality for ICH and SAH admissions and higher rates of home discharge for ICH admissions. AD patients were less likely to be discharged home for IS and ICH admissions.

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