Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated

F o r S t r o k Background and PurposeThe pro-inflammatory cytokine interleukin-1 (IL-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6 (IL-6), which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous (SC) IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. MethodsSCIL-STROKE was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of SC IL-1Ra (100mg administered twice daily for three days) in patients presenting within 5h of ischemic stroke onset. Randomization was stratified for baseline NIHSS score and thrombolysis. Measurement of plasma IL-6 and other peripheral inflammatory markers was undertaken at five time points. The primary outcome was difference in concentration of log(IL-6) as area under the curve to Day 3. Secondary outcomes included exploratory effect of IL-1Ra on three month outcome with the modified Rankin Scale (mRS). ResultsWe recruited 80 patients (mean age 72, median NIHSS 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma and plasma C-reactive protein (p<0.001). IL-1Ra was well-tolerated with no safety concerns.Allocation to IL-1Ra was not associated with a favorable outcome on mRS: OR (95% CI) = 0.67 (0.29 to 1.52); p=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. ConclusionsIL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. SC IL-1Ra is safe and well-tolerated. Further 3

SummaryNLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.

The development of effective therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many bloodborne therapies, and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5 and 4 h) and delayed (24 and 48 h) time points, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains longterm liposomal colocalization within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischemic region late after experimental stroke (2−3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages toward brain repair. These findings demonstrate the capability of liposomes to maximize selective translocation into the brain after stroke and identify two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of stroke treatments.