Amyloid ß, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer's Disease.

The presence of insoluble aggregates of amyloid ß (Aß) 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 Aß 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. Aß 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.

Equivalent-time-active-cavitation-imaging enables vascular-resolution blood-brain-barrier-opening-therapy planning.

Objective. Linking cavitation and anatomy was found to be important for predictable outcomes in focused-ultrasound blood-brain-barrier-opening and requires high resolution cavitation mapping. However, cavitation mapping techniques for planning and monitoring of therapeutic procedures either (1) do not leverage the full resolution capabilities of ultrasound imaging or (2) place constraints on the length of the therapeutic pulse. This study aimed to develop a high-resolution technique that could resolve vascular anatomy in the cavitation map.Approach. Herein, we develop BandPass-sampled-equivalent-time-active-cavitation-imaging (BP-ETACI), derived from bandpass sampling and dual-frequency contrast imaging at 12.5 MHz to produce cavitation maps prior and during blood-brain barrier opening with long therapeutic bursts using a 1.5 MHz focused transducer in the brain of C57BL/6 mice.Main results. The BP-ETACI cavitation maps were found to correlate with the vascular anatomy in ultrasound localization microscopy vascular maps and in histological sections. Cavitation maps produced from non-blood-brain-barrier disrupting doses showed the same cavitation-bearing vasculature as maps produced over entire blood-brain-barrier opening procedures, allowing use for (1) monitoring focused-ultrasound blood-brain-barrier-opening (FUS-BBBO), but also for (2) therapy planning and target verification.Significance. BP-ETACI is versatile, created high resolution cavitation maps in the mouse brain and is easily translatable to existing FUS-BBBO experiments. As such, it provides a means to further study cavitation phenomena in FUS-BBBO.

Dynamic Ultrasound Localization Microscopy Without ECG-Gating.

OBJECTIVE: Dynamic Ultrasound Localization Microscopy (DULM) has first been developed for non-invasive Pulsatility measurements in the rodent brain. DULM relies on the localization and tracking of microbubbles (MBs) injected into the bloodstream, to obtain highly resolved velocity and density cine-loops. Previous DULM techniques required ECG-gating, limiting its application to specific datasets, and increasing acquisition time. The objective of this study is to eliminate the need for ECG-gating in DULM experiments by introducing a motion-matching method for time registration. METHODS: We developed a motion-matching algorithm based on tissue Doppler that leverages the cyclic tissue motion within the brain. Tissue Doppler was estimated for each group of frames in the acquisitions, at multiple locations identified as local maxima in the skin above the skull. Subsequently, each group of frames was time-registered to a reference group by delaying it based on the maximum correlation value between their respective tissue Doppler signals. This synchronization ensured that each group of frames aligned with the brain tissue motion of the reference group, and consequently, with its cardiac cycle. As a result, velocities of MBs could be averaged to retrieve flow velocity variations over time. RESULTS: Initially validated in ECG-gated acquisitions in a rat model (n = 1), the proposed method was successfully applied in a mice model in 2D (n = 3) and in a feline model in 3D (n = 1). Performing time-registration with the proposed motion-matching method or by using ECG-gating leads to similar results. For the first time, dynamic velocity and density cine-loops were extracted without the need for any information on the animal ECG, and complex dynamic markers such as the Pulsatility index were estimated. CONCLUSION: Results suggest that DULM can be performed without external gating, enabling the use of DULM on any ULM dataset where enough MBs are detectable. Time registration by motion-matching represents a significant advancement in DULM techniques, making DULM more accessible by simplifying its experimental complexity.

Quantitative pulsatility measurements using 3D dynamic ultrasound localization microscopy.

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.

SORL1 Polymorphisms in Mexican Patients with Alzheimer's Disease.

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.

Equivalent time active cavitation imaging.

Rationale. Despite the development of a large number of neurologically active drugs, brain diseases are difficult to treat due to the inability of many drugs to penetrate the blood-brain barrier. High-intensity focused ultrasound (HIFU) blood-brain barrier opening in a site-specific manner could significantly expand the spectrum of available drug treatments. However, without monitoring, brain damage and off-target effects can occur during these treatments. While some methods can monitor inertial cavitation, temperature increase, or passively monitor cavitation events, to the best of our knowledge none of them can actively and spatiotemporally map the HIFU pressure field during treatment.Methods. Here we detail the development of a novel ultrasound imaging modality called equivalent time active cavitation imaging (ETACI) capable of characterizing the HIFU pressure field through stable cavitation events across the field of view with an ultrafast active imaging setup. This work introduces (1) a novel plane wave sequence whose transmit delays increase linearly with transmit events enabling the sampling of high-frequency cavitation events, and (2) an algorithm allowing the processing of the microbubble signal for pressure field mapping. The pressure measurements with our modality were first carried outin vitrofor hydrophone comparison and thenin vivoduring blood-brain barrier opening treatment in mice.Results. This study demonstrates the capability of ETACI to spatiotemporally characterize a modulation pressure field with an active imaging setup. The resulting pressure field mapping reveals a good correlation with hydrophone measurements. Further results iareprovided experimentallyin vivowith promising results.Conclusion. This proof of concept establishes the first steps towards a novel ultrasound modality for monitoring focused ultrasound blood-brain barrier opening, allowing new possibilities for a safe and precise monitoring method.