Abstract
Purpose
Vascular dysfunction is a major hallmark of Alzheimer’s disease (AD). However, studies that investigated vascular dysfunction in mice modeling AD using magnetic resonance angiography (MRA) are typically limited to qualitative and/or scoring-based paradigms, which are labor-intensive and observer-dependent.
Procedures
We developed and validated a semi-automatic MRA processing pipeline and applied this to high-resolution in vivo MRA images acquired on a 9.4T small animal MRI scanner. We assessed vascular morphology at 3, 6, and 12 months in wild-type (WT) and bigenic (APP.V717IxTau.P301L: biAT) mice.
Results
Vessel radius or length can increase with age regardless of genotype depending on the respective vessel. We also observed significantly lower internal carotid artery length in biAT mice compared to WT.
Conclusions
The results demonstrate that even subtle changes in vessel morphology can be noninvasively quantified. This is of great interest for AD, but also to other models of neurodegenerative diseases involving macrovascular dysfunction.
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References
Zhang B, Gu GJ, Jiang H, Guo Y, Shen X, Li B, Zhang W (2017) The value of whole-brain CT perfusion imaging and CT angiography using a 320-slice CT scanner in the diagnosis of MCI and AD patients. Eur Radiol 27:4756–4766
Lavina B (2016) Brain vascular imaging techniques. Int J Mol Sci 18:70
Schellong SM, Abolmaali N, Voigts B, Stelzner C (2017) Imaging of vessels supplying the brain. Internist (Berl) 58:758–765
Dorr A, Sled JG, Kabani N (2007) Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study. Neuroimage 35:1409–1423
Starosolski Z, Villamizar CA, Rendon D, Paldino MJ, Milewicz DM, Ghaghada KB, Annapragada AV (2015) Ultra high-resolution in vivo computed tomography imaging of mouse cerebrovasculature using a long circulating blood pool contrast agent. Sci Rep 5:10178
Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419–434
Iadecola C (2010) The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120:287–296
Montagne A, Nation DA, Pa J, Sweeney MD, Toga AW, Zlokovic BV (2016) Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol 131:687–707
El Tayara Nel T, Delatour B, Volk A, Dhenain M (2010) Detection of vascular alterations by in vivo magnetic resonance angiography and histology in APP/PS1 mouse model of Alzheimer’s disease. Magn Reson Mater Phys 23:53–64
Beckmann N, Schuler A, Mueggler T, Meyer EP, Wiederhold KH, Staufenbiel M, Krucker T (2003) Age-dependent cerebrovascular abnormalities and blood flow disturbances in APP23 mice modeling Alzheimer’s disease. J Neurosci 23:8453–8459
Kara F, Dongen ES, Schliebs R, Buchem MA, Groot HJ, Alia A (2012) Monitoring blood flow alterations in the Tg2576 mouse model of Alzheimer’s disease by in vivo magnetic resonance angiography at 17.6 T. Neuroimage 60:958–966
Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, van Leuven F (2008) Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol 172:786–798
Struys T, Govaerts K, Oosterlinck W, Casteels C, Bronckaers A, Koole M, van Laere K, Herijgers P, Lambrichts I, Himmelreich U, Dresselaers T (2017) In vivo evidence for long-term vascular remodeling resulting from chronic cerebral hypoperfusion in mice. J Cereb Blood Flow Metab 37:726–739
Chong SA, Benilova I, Shaban H, de Strooper B, Devijver H, Moechars D, Eberle W, Bartic C, van Leuven F, Callewaert G (2011) Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer’s disease: a multi-electrode array study. Neurobiol Dis 44:284–291
Kremer A (2012) Characterization and validation of transgenic mice as models for different pathological aspects of Alzheimer’s disease. Leuven university press, Leuven
Tustison NJ, Avants BB, Cook PA, Yuanjie Zheng, Egan A, Yushkevich PA, Gee JC (2010) N4ITK: improved N3 bias correction. IEEE Trans Med Imaging 29:1310–1320
Bates D, Machler M, Bolker BM, Walker SC (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48
Muyllaert D, Terwel D, Borghgraef P, Devijver H, Dewachter I, van Leuven F (2006) Transgenic mouse models for Alzheimer’s disease: the role of GSK-3B in combined amyloid and tau-pathology. Rev Neurol (Paris) 162:903–907
Van Dorpe J, Smeijers L, Dewachter I et al (2000) Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons. Am J Pathol 157:1283–1298
Van Broeck B, Vanhoutte G, Cuijt I et al (2008) Reduced brain volumes in mice expressing APP-Austrian mutation but not in mice expressing APP-Swedish-Austrian mutations. Neurosci Lett 447:143–147
Badhwar A, Lerch JP, Hamel E, Sled JG (2013) Impaired structural correlates of memory in Alzheimer’s disease mice. Neuroimage Clin 3:290–300
Hebert F, Grand'maison M, Ho MK et al (2012) Cortical atrophy and hypoperfusion in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging
Govaerts K, Lechat B, Struys T, Kremer A, Borghgraef P, van Leuven F, Himmelreich U, Dresselaers T (2019) Longitudinal assessment of cerebral perfusion and vascular response to hypoventilation in a bigenic mouse model of Alzheimer’s disease with amyloid and tau pathology. NMR Biomed 32:e4037
Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C (2001) A beta-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol 281:H2417–H2424
Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T (2008) Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer’s disease. Proc Natl Acad Sci U S A 105:3587–3592
Figueiredo G, Boll H, Kramer M, Groden C, Brockmann MA (2012) In vivo X-ray digital subtraction and CT angiography of the murine cerebrovasculature using an intra-arterial route of contrast injection. AJNR Am J Neuroradiol 33:1702–1709
Govaerts K, Dresselaers T, Struys T et al (2013) Towards quantitative evaluation of vascular alterations in mice using MR angiography. Front Neuroinform. https://doi.org/10.3389/conf.fninf.2013.10.00021
Yamamoto T, Okada T, Fushimi Y, Yamamoto A, Fujimoto K, Okuchi S, Fukutomi H, Takahashi JC, Funaki T, Miyamoto S, Stalder AF, Natsuaki Y, Speier P, Togashi K (2018) Magnetic resonance angiography with compressed sensing: an evaluation of moyamoya disease. PLoS One 13:e0189493
Funding
The European Commission supported the INMiND project (FP7, Health-F2-2011-278850) and the PANA project (H2020-NMP-12-2015-686009). The Flemish government (Innovation through Science and Technology) supported the IWT MIRIAD (SBO 130065) project. The Research Foundation Flanders supported KG (FWO scholarship 11N0714N) and TD (FWO-KaN 1.5.220.13N). University of Leuven supported the Program Financing IMIR (10/017).
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Experiments were performed in accordance with regional, national, and international standards on animal welfare, in particular European Union Directive 2010/63/EU, and approved and overseen by the Animal Care and Ethical Committees of the University of Leuven.
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Govaerts, K., Dresselaers, T., Van Leuven, F. et al. Quantitative Assessment of Age-Associated Alterations in Brain Vasculature in Wild-Type Mice and in Bigenic Mice that Model Alzheimer’s Disease. Mol Imaging Biol 22, 578–586 (2020). https://doi.org/10.1007/s11307-019-01402-w
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DOI: https://doi.org/10.1007/s11307-019-01402-w