Background: Alzheimer's disease (AD) is a neurodegenerative disorder with progressive cognitive decline in aging individuals that poses a significant challenge to patients due to an incomplete understanding of its etiology and lack of effective interventions. While "the Amyloid Cascade Hypothesis," the abnormal accumulation of amyloid-β in the brain, has been the most prevalent theory for AD, mounting evidence from clinical and epidemiological studies suggest that defects in cerebral vessels and hypoperfusion appear prior to other pathological manifestations and might contribute to AD, leading to "the Vascular Hypothesis." However, assessment of structural and functional integrity of the cerebral vasculature in vivo in the brain from AD rodent models has been challenging owing to the limited spatiotemporal resolution of conventional imaging technologies.
Methods: We employed two in vivo imaging technologies, i.e., Dual-Wavelength Imaging (DWI) and Optical Coherence Tomography (OCT), to evaluate cerebrovascular reactivity (CVR; responsiveness of blood vessels to vasoconstriction as triggered by cocaine) in a relatively large field of view of the cortex in vivo, and 3D quantitative cerebrovascular blood flow (CBF) imaging in living transgenic AD mice at single vessel resolution.
Results: Our results showed significantly impaired CVR and reduced CBF in basal state in transgenic AD mice compared to non-transgenic littermates in an early stage of AD progression. Changes in total hemoglobin (Δ[HbT]) in response to vasoconstriction were significantly attenuated in AD mice, especially in arteries and tissue, and the recovery time of Δ[HbT] after vasoconstriction was shorter for AD than WT in all types of vessels and cortical tissue, thereby indicating hypoperfusion and reduced vascular flexibility. Additionally, our 3D OCT images revealed that CBF velocities in arteries were slower and that the microvascular network was severely disrupted in the brain of AD mice.
Conclusions: These results suggest significant vascular impairment in basal CBF and dynamic CVR in the neurovascular network in a rodent model of AD at an early stage of the disease. These cutting-edge in vivo optical imaging tools offer an innovative venue for detecting early neurovascular dysfunction in relation to AD pathology and pave the way for clinical translation of early diagnosis and elucidation of AD pathogenesis in the future.
Keywords: Alzheimer’s disease; Amyloid; Blood-Brain Barrier; Early diagnosis; Neurodegenerative diseases; Neurovascular dysfunction; Neurovascular unit; OCT; Sex difference.