Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Abstract

Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and light sheet microscopy) and in vivo imaging (wide field optical spectroscopy and two-photon imaging) to determine detailed changes in aged cerebrovascular networks. Whole-brain vascular tracing showed an overall ~10% decrease in vascular length and branching density, and light sheet imaging with 3D immunolabeling revealed increased arteriole tortuosity in aged brains. Vasculature and pericyte densities showed significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. Moreover, in vivo imaging in awake mice identified delays in neurovascular coupling and disrupted blood oxygenation. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.

Impaired drainage through capillary-venous networks contributes to age-related white matter loss

“…Further, our data emphasizes the importance of gaining a holistic view of blood flow changes across cortical layers, since a limited view of the upper cortex results in an incomplete understanding of blood flow deficit. Coupled with the broad view provided by light-sheet microscopy 18 , in vivo studies can now hone into specific brain regions most vulnerable during aging and disease.…”

“…15 Reduction in vascular density during aging, particularly in white matter, is widely reported and may be the basis for tissue deterioration. [16][17][18] The etiology of these changes is difficult to understand in the human brain because of limitations in resolution of clinical imaging. This has emphasized a need for in vivo preclinical imaging studies that can provide insight on the pathophysiological basis of age-related white matter loss.…”

“…15 Reduction in vascular density during aging, particularly in white matter, is widely reported and may be the basis for tissue deterioration. [16][17][18] The etiology of these changes is difficult to understand in the human brain because of limitations in resolution of clinical imaging. This has emphasized a need for in vivo preclinical imaging studies that can provide insight on the pathophysiological basis of age-related white matter loss.To better understand age-related changes in the brain microvasculature, we leveraged recent advances in deep multi-photon imaging that substantially increase imaging depths beyond conventional two-photon imaging by reducing light scattering and out-of-focus excitation.…”

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

“…Molecular studies in Col4a1 -mutant mice suggest that arterial SMC loss is driven by increased TGF-β activity, whereas the hypermuscularization of the ACT zone arises from increased NOTCH3 activity ( 65 , 68 ). Regarding the capillary bed, 2D and 3D imaging in rodents revealed a small reduction in vascular length, branching density, and pericyte number, particularly in deep cortical layers and WM, in aged brains ( 59 , 60 ). Pericyte coverage is reduced in Htra1 -KO mice but, in striking contrast, pericyte density and/or coverage are preserved in Notch3 -KO mice, Col4a1 -mutant mice, and mice carrying an Arg169Cys mutation in NOTCH3 (hereafter referred to as CADASIL mice) ( 64 , 67 , 73 , 74 ).…”

“…Brain arteries of aged rodents exhibit increased tortuosity ( 59 – 61 ). Age-related focal loss and degeneration of arterial SMCs can be detected in the superficial vascular network of the retina, a developmental extension of the brain that enables robust quantification at cellular resolution thanks to its stereotypical and planar angioarchitecture ( 62 ).…”