Dementia, broadly defined, incurs devastating individual human cost with an increasingly substantial societal burden. AD represents the clinically most diagnosed form of dementia, seconded by vascular dementia (Masters et al., 2015). With regard to TBI and AD, Schaffert et al. (2018) found in their epidemiological study that a history of TBI with loss of consciousness represented a meaningful risk factor for the onset of AD – importantly, as confirmed by autopsy. As reviewed in Van Den Heuvel et al. (2007), these epidemiological observations comport with the observed rapid (hours to days) accumulation of excessive amyloid precursor proteins (APP), then Aß in soluble and plaque forms, within and around traumatically injured axons after moderate to severe TBI. Roberts et al. (1994) is an early example of an autopsy-based study demonstrating this rapid onset after severe TBI in 30% (13/40) patients, days to about a week after injury, with more Aß accumulation in older patients. Marklund et al. (2014) also observed rapid production of APP and Aß using cerebral microdialysis in 10/10 severe head injury patients up to 14 days after injury.
Motivation: Ultrasound can address AD histopathology and behavior, in vivo. We note that there exists recently evolving literature demonstrating that transcranially delivered ultrasound can temporarily and safely activate central neural circuits, shown in rodents, sheep, primates, and humans (reviewed in Bobola et al., 2018; Blackmore et al., 2019). Motivated by this literature and by Iaccarino et al., our preliminary data demonstrate that transcranial, pulsed, and focused ultrasound, delivered with a PRF of 40 Hz, can activate 5XFAD (C57BL6) mouse brain acutely at 40 Hz and activate microglia to co-localize with Aß plaque relative to sham after one hour of ultrasound plus an additional hour of sedation. Moreover, daily exposure for one week of each hemisphere of 5XFAD (C57BL6) mouse brains to the same ultrasound protocol shows a quantitative reduction in Aß plaque in each hemisphere relative to sham application.
Anticipated impact on the care of TBI patients: Here we seek to determine whether or not ultrasound applied transcranially to the brains of mouse models of AD after TBI can improve memory-related behavior, through induction of a combination of activated microglia into a phagocytotic rather than pro-inflammatory state, and cerebral vasodilation (where vasodilation would likely produce additional benefits) that reduce Aß burden. We anticipate that the useful ultrasound protocols we identify will have the same effect on humans, subject to further study, of course.
Anticipated Tasks and Time to Clinical Trials: Our approach uses near diagnostic intensity levels of ultrasound shown safe in mouse, rat, sheep, rabbit, non-human primate, and human brains. Therefore, successful completion of the proposed work could lead relatively rapidly to preclinical human trials for safety and then efficacy of our approach applied to AD and, possibly, to other dementias, after TBI. While these ultrasound protocols have a history of safety as tested with healthy brain tissue, prudence suggests it reasonable to perform further safety studies of the favored protocols using AD mouse brain after TBI, and more extensive behavioral studies, before human application. Given sufficient funding, two years beyond the completion of this proposed work, we think it reasonable to consider human trials for this approach.
Sponsor: Department of Defense