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The disruption of the blood–brain barrier (BBB) in Alzheimer’s Disease (AD) is largely influenced by amyloid beta (Aβ). In this study, we developed a high-throughput microfluidic BBB model devoid of a physical membrane, featuring endothelial cells interacting with an extracellular matrix (ECM). This paper focuses on the impact of varying concentrations of Aβ1–42 oligomers on BBB dysfunction by treating them in the luminal. Our findings reveal a pronounced accumulation of Aβ1–42 oligomers at the BBB, resulting in the disruption of tight junctions and subsequent leakage evidenced by a barrier integrity assay. Additionally, cytotoxicity assessments indicate a concentration-dependent increase in cell death in response to Aβ1–42 oligomers (LC50 ~ 1 µM). This study underscores the utility of our membrane-free vascular chip in elucidating the dysfunction induced by Aβ with respect to the BBB. 

Abstract INTRODUCTIONVascular damage in Alzheimer's disease (AD) has shown conflicting findings particularly when analyzing longitudinal data. We introduce white matter hyperintensity (WMH) longitudinal morphometric analysis (WLMA) that quantifies WMH expansion as the distance from lesion voxels to a region of interest boundary. METHODSWMH segmentation maps were derived from 270 longitudinal fluid‐attenuated inversion recovery (FLAIR) ADNI images. WLMA was performed on five data‐driven WMH patterns with distinct spatial distributions. Amyloid accumulation was evaluated with WMH expansion across the five WMH patterns. RESULTSThe preclinical group had significantly greater expansion in the posterior ventricular WM compared to controls. Amyloid significantly associated with frontal WMH expansion primarily within AD individuals. WLMA outperformed WMH volume changes for classifying AD from controls primarily in periventricular and posterior WMH. DISCUSSIONThese data support the concept that localized WMH expansion continues to proliferate with amyloid accumulation throughout the entirety of the disease in distinct spatial locations. 

Multi-parametric photoacoustic microscopy (PAM) has emerged as a promising new technique for high-resolution quantification of hemodynamics and oxygen metabolism in the mouse brain. In this work, we have extended the scope of multi-parametric PAM to longitudinal, cortex-wide, awake-brain imaging with the use of a long-lifetime (24 weeks), wide-field (5 × 7 mm 2 ), light-weight (2 g), dual-transparency ( i.e., light and ultrasound) cranial window. Cerebrovascular responses to the window installation were examined in vivo, showing a complete recovery in 18 days. In the 22-week monitoring after the recovery, no dura thickening, skull regrowth, or changes in cerebrovascular structure and function were observed. The promise of this technique was demonstrated by monitoring vascular and metabolic responses of the awake mouse brain to ischemic stroke throughout the acute, subacute, and chronic stages. Side-by-side comparison of the responses in the ipsilateral (injury) and contralateral (control) cortices shows that despite an early recovery of cerebral blood flow and an increase in microvessel density, a long-lasting deficit in cerebral oxygen metabolism was observed throughout the chronic stage in the injured cortex, part of which proceeded to infarction. This longitudinal, functional-metabolic imaging technique opens new opportunities to study the chronic progression and therapeutic responses of neurovascular diseases.