The presence of insoluble aggregates of amyloid β (Aβ) in the form of neuritic plaques (NPs) is one of the main features that define Alzheimer’s disease. Studies have suggested that the accumulation of these peptides in the brain significantly contributes to extensive neuronal loss. Furthermore, the content and distribution of cholesterol in the membrane have been shown to have an important effect on the production and subsequent accumulation of Aβ peptides in the plasma membrane, contributing to dysfunction and neuronal death. The monomeric forms of these membrane-bound peptides undergo several conformational changes, ranging from oligomeric forms to beta-sheet structures, each presenting different levels of toxicity. Aβ peptides can be internalized by particular receptors and trigger changes from Tau phosphorylation to alterations in cognitive function, through dysfunction of the cholinergic system. The goal of this review is to summarize the current knowledge on the role of lipids in Alzheimer’s disease and their relationship with the basal cholinergic system, as well as potential disease-modifying therapies.

A rise in blood flow velocity variations (i.e. pulsatility) in the brain, caused by the stiffening of upstream arteries, is associated with cognitive impairment and neurodegenerative diseases. The study of this phenomenon requires brain-wide pulsatility measurements, with large penetration depth and high spatiotemporal resolution. The development of dynamic ultrasound localization microscopy (DULM), based on ULM, has enabled pulsatility measurements in the rodent brain in 2D. However, 2D imaging accesses only one slice of the brain and measures only 2D-projected and hence biased velocities . Herein, we present 3D DULM: using a single ultrasound scanner at high frame rate (1000–2000 Hz), this method can produce dynamic maps of microbubbles flowing in the bloodstream and extract quantitative pulsatility measurements in the cat brain with craniotomy and in the mouse brain through the skull, showing a wide range of flow hemodynamics in both large and small vessels. We highlighted a decrease in pulsatility along the vascular tree in the cat brain, which could be mapped with ultrasound down to a few tens of micrometers for the first time. We also performed an intra-animal validation of the method by showing consistent measurements between the two sides of the Willis circle in the mouse brain. Our study provides the first step towards a new biomarker that would allow the detection of dynamic abnormalities in microvessels in the brain, which could be linked to early signs of neurodegenerative diseases.

Ultrasound Localization Microscopy (ULM) has proven effective in resolving microvascular structures and local mean velocities at sub-diffraction-limited scales, offering high-resolution imaging capabilities. Dynamic ULM (DULM) enables the creation of angiography or velocity movies throughout cardiac cycles. Currently, these techniques rely on a Localization-and-Tracking (LAT) workflow consisting in detecting microbubbles (MB) in the frames before pairing them to generate tracks. While conventional LAT methods perform well at low concentrations, they suffer from longer acquisition times and degraded localization and tracking accuracy at higher concentrations, leading to biased angiogram reconstruction and velocity estimation. In this study, we propose a novel approach to address these challenges by reversing the current workflow. The proposed method, Tracking-and-Localization (TAL), relies on first tracking the MB and then performing localization. Through comprehensive benchmarking using both in silico and in vivo experiments and employing various metrics to quantify ULM angiography and velocity maps, we demonstrate that the TAL method consistently outperforms the reference LAT workflow. Moreover, when applied to DULM, TAL successfully extracts velocity variations along the cardiac cycle with improved repeatability. The findings of this work highlight the effectiveness of the TAL approach in overcoming the limitations of conventional LAT methods, providing enhanced ULM angiography and velocity imaging.

Objective: To assess the role of brain hemodynamics in neurodegenerative diseases, current imaging technologies remain insufficient due to limitations in spatial or temporal resolution for quantitative mapping of pulsatile flow in the whole brain. This study aims to demonstrate the feasibility of 3D transcranial Dynamic Ultrasound Localization Microscopy (DULM) for spatiotemporal blood flow measurements in the brain, addressing limitations of 2D imaging for velocity estimation within the 3D complex vascularized structures. Methods: We used a (128+128)-element, 12 MHz Row-Column Array (RCA) to perform transcranial DULM imaging in anesthetized mice (n = 7 in total). The RCA setup allows for reduced element count while maintaining a large field of view and high frame rate compared to matrix arrays. Transcranial images were acquired at a 750-Hz volume rate using an optimized microbubble concentration and a sequence of 42 tilted plane waves. Microbubbles were localized and tracked, enabling super-resolved dynamic density and velocity maps of the 3D brain vascular network. Results: Pulsatile flows were observed with 3D DULM in 7 mice. The segmentation of cortical vessels indicated that pulsatility in arteries was significantly higher than in veins, consistent across all mice and aligning with findings in existing literature. Conclusion: This study demonstrates for the first time the feasibility and reproducibility of obtaining high spatiotemporal resolution images of mouse brain vasculature using transcranial DULM with a RCA. Significance: This work highlights the potential of RCA 3D DULM for non-invasive cerebral hemodynamics studies, it might enable comprehensive vascular imaging suitable for research in early-stage neurodegenerative diseases.

While transcranial neuroimaging of individual capillary function holds transformative potential for diagnostics, it has proven difficult to achieve. Superresolution ultrasound, while capable of achieving micron-scale resolution, relies on the accumulation of multiple microbubble events, a method inherently limited by the exceedingly low probability of observing such events within capillaries. We present single capillary reporters (SCaRe), a paradigm-shifting approach that utilizes the complete flow trajectory information extracted from individual microbubbles to directly image single capillaries. This method allows for transcranial reconstruction and functional assessment of deep capillary networks in the entire brain. We employed computational simulations and pathological neuroinflammation models to quantify and validate metrics such as capillary transit-time and capillary stalling. Importantly, we demonstrated SCaRe’s ability to resolve immune responses to injury at the single capillary level, markedly broadening research avenues for exploring microvascular dysfunction across diverse neurological conditions.

The present study evaluated the risk effect of 12 Single Nucleotide Polymorphisms in the SORL1 gene in the Mexican population using Late-Onset Alzheimer’s Disease (LOAD) and control subjects. Considering APOE as the strongest genetic risk factor for LOAD, we conducted interaction analyses between single nucleotide polymorphisms (SNPs) and the APOE genotype. Methods: Patients were interviewed during their scheduled visits at neurologic and geriatric clinics from different institutions. The LOAD diagnosis included neurological, geriatric, and psychiatric examinations, as well as the medical history and neuroimaging. Polymorphisms in SORL1 were genotyped by real-time PCR in 156 subjects with LOAD and 221 controls. APOE genotype was determined in each study subject. Allelic, genotypic, and haplotypic frequencies were analyzed; an ancestry analysis was also performed. Results: The A/A genotype in rs1784933 might be associated with an increased LOAD risk. Two blocks with high degree linkage disequilibrium (LD) were identified. The first block composed by the genetic variants rs668387, rs689021 and rs641120 showed a positive interaction (mainly the rs689021) with rs1784933 polymorphism. Moreover, we found a significant association between the APOE ε4 allele carriers and the variant rs2070045 located in the second LD block. Conclusion: The rs1784933 polymorphism is associated with LOAD in Mexican patients. In addition, the presence of APOE ε4 allele and SORL1 variants could represent a genetic interaction effect that favors LOAD risk in the Mexican population. SNPs have been proposed as genetic markers associated with the development of LOAD that can support the clinical diagnosis. Future molecular studies could help understand sporadic Alzheimer’s Disease (AD) among the Mexican population, where currently there is a sub-estimate number in terms of disease frequency and incidence.