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Alzheimer's disease (AD) is a neurodegenerative disorder associated with continual decline in cognition and ability to perform routine functions such as remembering familiar places or understanding speech. For decades, amyloid beta (Aβ) was viewed as the driver of AD, triggering neurodegenerative processes such as inflammation and formation of neurofibrillary tangles (NFTs). This approach has not yielded therapeutics that cure the disease or significant improvements in long-term cognition through removal of plaques and Aβ oligomers. Some researchers propose alternate mechanisms that drive AD or act in conjunction with amyloid to promote neurodegeneration. This review summarizes the status of AD research and examines research directions including and beyond Aβ, such as tau, inflammation, and protein clearance mechanisms. The effect of aging on microvasculature is highlighted, including its contribution to reduced blood flow that impairs cognition. Microvascular alterations observed in AD are outlined, emphasizing imaging studies of capillary malfunction. The review concludes with a discussion of two therapies to protect tissue without directly targeting Aβ for removal: (1) administration of growth factors to promote vascular recovery in AD; (2) inhibiting activity of a calcium-permeable ion channels to reduce microglial activation and restore cerebral vascular function.

Ex vivo 2-photon fluorescence microscopy (2PFM) with optical clearing enables vascular imaging deep into tissue. However, optical clearing may also produce spherical aberrations if the objective lens is not index-matched to the clearing material, while the perfusion, clearing, and fixation procedure may alter vascular morphology. We compared in vivo and ex vivo 2PFM in mice, focusing on apparent differences in microvascular signal and morphology. Following in vivo imaging, the mice (four total) were perfused with a fluorescent gel and their brains fructose-cleared. The brain regions imaged in vivo were imaged ex vivo. Vessels were segmented in both images using an automated tracing algorithm that accounts for the spatially varying PSF in the ex vivo images. This spatial variance is induced by spherical aberrations caused by imaging fructose-cleared tissue with a water-immersion objective. Alignment of the ex vivo image to the in vivo image through a non-linear warping algorithm enabled comparison of apparent vessel diameter, as well as differences in signal. Shrinkage varied as a function of diameter, with capillaries rendered smaller ex vivo by 13%, while penetrating vessels shrunk by 34%. The pial vasculature attenuated in vivo microvascular signal by 40% 300 μm below the tissue surface, but this effect was absent ex vivo. On the whole, ex vivo imaging was found to be valuable for studying deep cortical vasculature.

The 3D organization of cerebral blood vessels determines the overall capacity of the cerebral circulation to meet the metabolic requirements of the brain. Imaging methodologies which combine 3D microvascular structural imaging with blood flow quantification can shed light on the relationship between vascular structure and function, in health and disease. This study applies Arterial Spin Labeling (ASL) MRI with a hypercapnic challenge and ex vivo Serial Two-Photon Tomography (STPT) to examine the relationship between blood flow and vascular architecture following traumatic brain injury (TBI) in a mouse. Mice were exposed to a controlled cortical impact TBI and allowed to recover for either 1 day or 4 weeks. At each time point, ASL MRI was performed to quantify cerebral perfusion and the brain vasculature was imaged in 3D with STPT. Registration of ASL to STPT enabled flow changes to be related to the underlying microvascular structure in each ASL voxel. Hypoperfusion under rest and hypercapnia was observed both 1 day and 4 weeks post-TBI. Vessel density and vascular volume were reduced 1 day post-TBI, recovering by 4 weeks; however, the reorganized vasculature at the latter time point possessed an abnormal radial pattern. Our findings demonstrate functionally significant long-term changes in the vascular architecture following injury and illustrate why metrics beyond traditional measures of vessel density are required to understand the impact of vascular structure on function. •ASL MRI and microscopy were used to measure CBF and vascular structure in mouse TBI.•Patterns of vascular remodeling were observed that could only be described in 3D.•CBF is reduced up to 4-weeks post-TBI, despite recovery of vessel density.•Despite extensive remodeling, hierarchical structure of the network is maintained.•Vessels regrow radially but fail to fully restore CBF and vascular reactivity.

Physical activity has been correlated with a reduced risk of cognitive decline, including that associated with vascular dementia, mild cognitive impairment (MCI) and Alzheimer's disease (AD); recent literature suggests this may in part result from benefits to the cerebrovascular network. Using a transgenic (Tg) mouse model of AD, we evaluated the effect of running on cortical and hippocampal vascular morphology, cerebral amyloid angiopathy, amyloid plaque load, and spatial memory. TgCRND8 mice present with progressive amyloid pathology, advancing from the cortex to the hippocampus in a time-dependent manner. We postulated that the characteristic progression of pathology could lead to differential, time-dependent effects of physical activity on vascular morphology in these brain regions at 6 months of age. We used two-photon fluorescent microscopy and 3D vessel tracking to characterize vascular and amyloid pathology in sedentary TgCRND8 mice compared those who have a history of physical activity (unlimited access to a running wheel, from 3 to 6 months of age). In sedentary TgCRND8 mice, capillary density was found to be lower in the cortex and higher in the hippocampus compared to non-transgenic (nonTg) littermates. Capillary length, vessel branching, and non-capillary vessel tortuosity were also higher in the hippocampus of sedentary TgCRND8 compared to nonTg mice. Three months of voluntary running resulted in normalizing cortical and hippocampal microvascular morphology, with no significant difference between TgCRND8 and nonTg mice. The benefits of physical activity on cortical and hippocampal vasculature in 6-month old TgCRND8 mice were not paralleled by significant changes on parenchymal and cerebral amyloid pathology. Short-term spatial memory— as evaluated by performance in the Y-maze— was significantly improved in running compared to sedentary TgCRND8 mice. These results suggest that long-term voluntary running contributes to the maintenance of vascular morphology and spatial memory in TgCRND8 mice, even in the absence of an effect on amyloid pathology.

Regular blood pressure (BP) monitoring enables earlier detection of hypertension and reduces cardiovascular disease. Cuff-based BP measurements require equipment that is inconvenient for some individuals and deters regular home-based monitoring. Since smartphones contain sensors such as video cameras that detect arterial pulsations, they could also be used to assess cardiovascular health. Researchers have developed a variety of image processing and machine learning techniques for predicting BP via smartphone or video camera. This review highlights research behind smartphone and video camera methods for measuring BP. These methods may in future be used at home or in clinics, but must be tested over a larger range of BP and lighting conditions. The review concludes with a discussion of the advantages of the various techniques, their potential clinical applications, and future directions and challenges. Video cameras may potentially measure multiple cardiovascular metrics including and beyond BP, reducing the risk of cardiovascular disease.

Cerebral blood vessels play an important role in brain metabolic activity in general and following traumatic brain injury (TBI) in particular. However, the extent to which TBI alters microvessel structure is not well understood. Specifically, how intracranial mechanical responses produced during impacts relate to vascular damage needs to be better studied. Therefore, the objective of this study was to investigate the biomechanical mechanisms and thresholds of brain microvascular injury. Detailed microvascular damage of mouse brain was quantified using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) and ex vivo Serial Two-Photon Tomography (STPT) in seven mice that had undergone controlled cortical impact. Mechanical strains were investigated through finite element (FE) modeling of the mouse brain. We then compared the post-injury vessel density map with FE-predicted strain and found a moderate correlation between the vessel length density and the predicted peak maximum principal strains (MPS) (R2 = 0.52). High MPS was observed at the impact regions with low vessel length density, supporting the mechanism of strain-triggered microvascular damage. Using logistic regression, the MPS corresponding to a 50% probability of injury was found to be 0.17. Given the literature reporting MPS of over 0.2 in the human brain for mild TBI/concussion cases, it is highly recommended to consider microvascular damage when investigating mild TBI/concussion in the future.

Traumatic brain injury (TBI) can induce changes in vascular architecture. Although ultrasound metrics such as pulsatility index (PI) are sensitive to changes in hemodynamic resistance downstream from major arteries, these metrics depend on features unrelated to vessel architecture, such as blood pressure and heart rate. In contrast, input impedance and reflection coefficient that are derived from wave reflection theory seek to minimize the effects of altered cardiac output or heart rate. In this article, we investigate the use of ultrasound to assess changes in vascular impedance and wave reflection in the common carotid arteries of mice exposed to a controlled cortical impact. Focusing on the first harmonics of the reflected waves, the impedance phase was increased ipsilaterally in impacted mice compared with shams, whereas the magnitude of the impedance was unchanged. In contrast, PI was reduced bilaterally. Interestingly, PI and the first harmonic magnitude of input impedance in the carotid artery were correlated on the contralateral but not ipsilateral side. We investigated the use of these metrics to classify mice as sham or TBI, finding an area under the receiver operating characteristic curve ipsilaterally of 0.792 (confidence interval [CI]: 0.648–0.936) for correct classification with first harmonic impedance magnitude and phase as predictors and 0.716 (CI: 0.553–0.879) using carotid artery PI and diameter as predictors. Overall, the findings support the use of wave reflection analysis as a more specific measure of vascular changes following TBI and motivate the translation of this approach for monitoring vascular changes in humans affected by TBI.

This thesis describes a novel imaging methodology for visualization and quantitative analysis of the vascular topology of different cortical regions of the mouse brain in 3D. The brain is perfused with a fluorescent contrast agent, and rendered fully transparent via optical clearing. This procedure enables images through the whole cortical depth to be obtained with a 2-photon microscope without sectioning. The Allen Reference Atlas (ARA) (Lein et al., 2007) is registered to the 2-photon data for delineation of the cortical regions. Quantitative metrics are then extracted from the different regions using an automatic vessel segmentation algorithm. These metrics are compared with those obtained by other investigators to validate this technique, and are found to be in agreement. Since this methodology possesses the resolution to visualize vessels of all sizes, and provides reasonable estimates of quantitative parameters, it shows strong potential for quantitative analysis of normal and abnormal cortical vascular architecture.

The 3D organization of cerebral blood vessels determines the overall capacity of the cerebral circulation to meet the metabolic requirements of the brain. This study used Arterial Spin Labeling (ASL) MRI with a hypercapnic challenge and ex vivo Serial Two-Photon Tomography (STPT) to examine the relationship between blood flow and 3D microvascular structure following traumatic brain injury (TBI) in a mouse. Mice were exposed to a controlled cortical impact TBI and allowed to recover for either 1 day or 4 weeks. At each time point, ASL MRI was performed to quantify cerebral perfusion and the brain vasculature was imaged in 3D with STPT. Registration of ASL to STPT enabled flow changes to be related to the underlying microvascular structure in each ASL voxel. Hypoperfusion under rest and hypercapnia was observed both 1 day and 4 weeks post-TBI. Vessel density and vascular volume were reduced 1 day post-TBI, recovering by 4 weeks; however, the reorganized vasculature at the latter time point possessed an abnormal radial pattern. Our findings demonstrate functionally significant long-term changes in the vascular architecture following injury and illustrate why metrics beyond traditional measures of vessel density are required to understand the impact of vascular structure on function.

[MEL MARTINEZ], 53, earned a bachelor's degree from Florida State University and went to law school there before joining a prominent Orlando law firm. He has a net worth of roughly $3 million. Martinez is a Roman Catholic and he and his wife, Kitty, have three children.