Vasomotion loss precedes impaired cerebrovascular reactivity and microbleeds in cerebral amyloid angiopathy

Kozberg, M.G.; Munting, L.P.; Hanlin, L.H.; Auger, C.A.; Berg, M.L. van den; Senneville, B.D. de; Hirschler, L.; Warnking, J.M.; Barbier, E.L.; Farrar, C.T.; Greenberg, S.M.; Bacskai, B.J.; Veluw, S.J. van

doi:doi:10.1093/braincomms/fcaf186

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-beta accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral haemorrhage 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-beta clearance, may be impaired in CAA. 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 (WT) littermates from 7 to 14 months of age, tracking amyloid-beta accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18- and 24-month-old...Show moreCerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-beta accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral haemorrhage 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-beta clearance, may be impaired in CAA. 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 (WT) littermates from 7 to 14 months of age, tracking amyloid-beta 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 WT littermates to detect microbleeds and to assess cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) with pseudo-continuous arterial spin labelling. We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in WT mice with age. This decline corresponded in timing to initial vascular amyloid-beta deposition (similar to 8-10 months of age), although it was more strongly correlated with age than with vascular amyloid-beta 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 the majority of APP23 mice by 18 months of age. Additionally, CBF and evoked CVR were intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. 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.In this multi-modal imaging study, Kozberg et al. report that the loss of spontaneous oscillations in arteriolar diameter (vasomotion) occurs early in CAA disease progression in the APP23 mouse model. The loss of vasomotion coincided with initial vascular amyloid-beta deposition and preceded the occurrence of microbleeds.Show less

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Vasomotion loss precedes impaired cerebrovascular reactivity and microbleeds in cerebral amyloid angiopathy