Loss of spontaneous vasomotion precedes impaired cerebrovascular reactivity and microbleeds in a mouse model of cerebral amyloid angiopathy

Background Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-β accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral hemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-β clearance, may be impaired in CAA. Methods To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using in vivo 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype littermates from 7 to 14 months of age, tracking amyloid-β accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18-, and 24-month-old APP23 transgenic mice and wildtype littermates to detect microbleeds and to assess cerebral blood flow and cerebrovascular reactivity with pseudo-continuous arterial spin labeling. Results We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in wildtype mice with age. This decline corresponded in timing to initial vascular amyloid-β deposition (∼8-10 months of age), although was more strongly correlated with age than with vascular amyloid-β burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in APP23 mice by 18 months of age. Additionally, evoked cerebrovascular reactivity was intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. Conclusions Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target. ### Competing Interest Statement The authors have declared no competing interest. * CAA : cerebral amyloid angiopathy ICH : intracerebral hemorrhage VSMC : vascular smooth muscle cells CSF : cerebrospinal fluid MGE : multi-gradient echo pCASL : pseudo-Continuous Arterial Spin Labeling Tg : transgenic WT : wildtype CBF : cerebral blood flow CVR : cerebrovascular reactivity TOF : time-of-flight SMA : smooth muscle actin MRI : magnetic resonance imaging BOLD : blood oxygen level dependent TR : repetition time TE : echo time RARE : Rapid Acquisition with Relaxation Enhancement EPI : echo-planar imaging fc-FLASH : flow-compensated, fast low angle shot RBC : red blood cell FOV : field of view ROI : region of interest PBS : phosphate buffered saline TBS : tris buffered saline DAB : 3,3’-diaminobenzidine LME : linear mixed effects AIC : Akaike information criterion BIC : Bayesian information criterion AUC : area under the curve