Discussion
comorbidity, tissue injury, edema, amyloid-related imaging abnormalities, AD, ARIA
EXTRAVASATION, EDEMA, EFFUSIONS
In this study, we explored the physiological responses to FUS-mediated BBB opening targeting various brain regions of individuals with early AD. Using in vivo MRI, we show that FUS-mediated BBB opening results in perivenous contrast tracer distribution patterns that support the existence of a brain-wide network of functionally compartmentalized spaces around cerebral veins. Concentration of gadobutrol tracer within this perivenous network suggests that these neurofluid channels likely serve as low-resistance pathways for intracerebral fluid flow and convective efflux in humans. Additional post-FUS MRI enhancement effects indicate prominent reactive venous permeabilization involving both intraparenchymal and downstream extraparenchymal veins. These findings, along with post-FUS sulcal effusions, shown for the first time in this study, correlate spatially and temporally with post-FUS immunological response patterns that have been documented in preclinical animal models [Two prior studies documented contrast tracer accumulation along perivenous brain regions following clinical FUS procedures, however these prior works were limited in scope to the hippocampal region [Differential hyperenhancement is demonstrated within this network upon BBB opening. The enhancement effects are unassociated with parenchymal edema or evidence of tissue injury. Moreover, the perivenous enhancement changes are invariably followed by rapid tracer clearance. This transient hyperenhancement phenomenon around cerebral veins is not explainable by tracer diffusion, pathological contrast enhancement, or retrograde flow of contrast tracer which has previously been suggested following FUS procedures [Remarkably, the patterns of contrast agent pooling described here are reproducible across persons and across brain regions, though the subtle fluid shift is not appreciable in preclinical models nor by postmortem histology in humans. While the perivenous tracer distribution phenomena were not described prospectively following FUS in animal models, retrospective review suggests that they may have manifested in non-human primates [In this study, we further demonstrate reactive changes along the perivenous network following FUS. Enhanced venous permeability is shown along the entire course of this perivenous system, both within the brain parenchyma and along downstream meningeal veins following BBB opening. These imaging data suggest that fluid enters the perivenous network via two routes, both through efflux from adjacent upstream brain interstitium and via extravasation, or exudation, from the intravenous compartment. This proposed physiology differs, in part, from the proposed glymphatic hypothesis [Notably, post-FUS effusions and T2* susceptibility effects share some features with amyloid-related imaging abnormalities (ARIA) that have been described following administration of anti-amyloid immunotherapies [Limitations of the present study should be noted and include small sample size of eight participants who underwent treatment at a single institution and were part of an ongoing multicenter clinical trial. Future studies assessing FUS imaging responses in larger cohorts are needed. Expanded datasets are also necessary to draw more definitive conclusions on possible cavitation dose-related responses and to understand influences of specific sonication parameters, microbubble factors, and individual patient-related and comorbidity factors on physiological effects of FUS-mediated BBB opening, as well as differences in patterns across brain regions. Furthermore, MRI data presented here were acquired serially, but at fixed time points. Future MRI analyses incorporating real-time dynamic imaging would contribute to knowledge of post-FUS intracerebral fluid flow in live humans and associated pathophysiologic abnormalities in AD [