The eye, the kidney, and cardiovascular disease: old concepts, better tools, and new horizons.

Chronic kidney disease (CKD) is common, with hypertension and diabetes mellitus acting as major risk factors for its development. Cardiovascular disease is the leading cause of death worldwide and the most frequent end point of CKD. There is an urgent need for more precise methods to identify patients at risk of CKD and cardiovascular disease. Alterations in microvascular structure and function contribute to the development of hypertension, diabetes, CKD, and their associated cardiovascular disease. Homology between the eye and the kidney suggests that noninvasive imaging of the retinal vessels can detect these microvascular alterations to improve targeting of at-risk patients. Retinal vessel-derived metrics predict incident hypertension, diabetes, CKD, and cardiovascular disease and add to the current renal and cardiovascular risk stratification tools. The advent of optical coherence tomography (OCT) has transformed retinal imaging by capturing the chorioretinal microcirculation and its dependent tissue with near-histological resolution. In hypertension, diabetes, and CKD, OCT has revealed vessel remodeling and chorioretinal thinning. Clinical and preclinical OCT has linked retinal microvascular pathology to circulating and histological markers of injury in the kidney. The advent of OCT angiography allows contrast-free visualization of intraretinal capillary networks to potentially detect early incipient microvascular disease. Combining OCT's deep imaging with the analytical power of deep learning represents the next frontier in defining what the eye can reveal about the kidney and broader cardiovascular health

A multifractal approach to space-filling recovery for PET quantification.

Purpose: A new image-based methodology is developed for estimating the apparent space-filling properties of an object of interest in PET imaging without need for a robust segmentation step and used to recover accurate estimates of total lesion activity (TLA). Methods: A multifractal approach and the fractal dimension are proposed to recover the apparent space-filling index of a lesion (tumor volume, TV) embedded in nonzero background. A practical implementation is proposed, and the index is subsequently used with mean standardized uptake value (SUVmean) to correct TLA estimates obtained from approximate lesion contours. The methodology is illustrated on fractal and synthetic objects contaminated by partial volume effects (PVEs), validated on realistic 18F-fluorodeoxyglucose PET simulations and tested for its robustness using a clinical 18F-fluorothymidine PET test-retest dataset. Results: TLA estimates were stable for a range of resolutions typical in PET oncology (4-6 mm). By contrast, the space-filling index and intensity estimates were resolution dependent. TLA was generally recovered within 15% of ground truth on postfiltered PET images affected by PVEs. Volumes were recovered within 15% variability in the repeatability study. Results indicated that TLA is a more robust index than other traditional metrics such as SUVmean or TV measurements across imaging protocols. Conclusions: The fractal procedure reported here is proposed as a simple and effective computational alternative to existing methodologies which require the incorporation of image preprocessing steps (i.e., partial volume correction and automatic segmentation) prior to quantification

Cerebrovascular Dysfunction and Degeneration in Alzheimer’s Disease Pathophysiology

Alzheimer’s disease (AD) is a terminal illness and the most common form of dementia, which disproportionately affects the aged population. The pathophysiology of AD is characterized by neurodegeneration that slowly progresses, affecting regions of the brain that are involved in learning, memory, language, and executive function. In patients with the disease, early symptoms include non-disruptive forgetfulness that evolves into the inability to form new memories and ultimately the loss of autonomy at late stages. Histopathological hallmarks in the brain from patients with AD is the presence of amyloid-β (Aβ)-plaques and neurofibrillary tangles (NFT) deposited in the parenchyma. Since the discovery of these hallmarks, the majority of AD research has disproportionately focused on Aβ -plaques and NFT. Although the etiology of AD remains unknown, considerable advances have been made describing the cellular, molecular, and genetic contributions to the disease. Aging is the important risk factor for the development of AD, many other factors that increase the risk of developing AD later in life are vascular in nature. The function of the cardiovascular system is known to decline during healthy aging, and the same is true for the cerebrovasculature. Empirical evidence has demonstrated a decline cerebrovascular function in AD that exceeds the decline that occurs in healthy aging. Cerebrovascular dysfunction is the major contributor to the development of hypoperfusion and hypometabolism in patients diagnosed with AD. Cerebral amyloid angiopathy (CAA) is a neuropathological condition defined by the abnormal accumulation of Aβ on the walls of the cerebrovasculature. CAA occurs in as many as 90% of patients with AD and is implicated in the weakening of the walls of cerebral blood vessels. The occurrence of microhemorrhages, aneurysms, and microinfarctions are pathological manifestations associated with weakened walls of cerebral blood vessels in the brains of patients with confirmed AD. Noteworthy, cerebrovascular dysfunction, hypoperfusion, and hypometabolism occur before the onset of Aβ-plaque and NFT deposition in the brain of patients and animal models with AD. These findings provide a compelling basis that suggest a prominent role of dysfunctional cerebrovasculature in the etiology and for the progression of AD. Although the overwhelming evidence that implicates cerebrovascular dysfunction in AD, a thorough account of the changes that occur to the cerebrovasculature nor the mechanisms that drive these changes during the development and progression of AD has not been previously reported. The overarching goal(s) of this work are to; (1) provide a thorough description of the changes that occur to the cerebrovasculature during age and the progression of AD; (2) describe the mechanisms involved in cerebrovascular damage in AD; and (3) characterize the degeneration that results from cerebrovascular hypoperfusion. These overarching goals were achieved by completing five separate studies. Described in study 1, we investigated the effects of hypoxia on astrocytic mitochondria by assessing mitochondrial fission-fusion dynamics, reactive oxygen species production, synthesis of ATP, and mitophagy. Overall, we found a drastic mitochondrial network change that is triggered by metabolic crisis during hypoxia; these changes are followed by mitochondrial degradation and retraction of astrocytic extensions during reoxygenation. In study 2, we provide a novel model for the gradual development of cerebrovascular hypoperfusion in mice. Cerebrovascular hypoperfusion developed over 34-days by inserting an ameroid constrictor ring and microcoil bilaterally around the external carotid arteries. We investigated the neurodegenerative effects of hypoperfusion in mice by assessing both gray and white matter pathology. Histopathological analyses of the brain revealed neuronal and axonal degeneration as well as necrotic lesions. The most severely affected regions were located in the hippocampus and corpus callosum. Described in study 3, we performed a series of experiments to investigate the effects of Aβ on cerebrovascular endothelial cells. In this study, we focused on characterizing the changes to mitochondrial oxidative phosphorylation, superoxide production, mitochondrial calcium, ATP synthesis, and endothelial cell death. These results describe a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which was driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. In study 4, we developed a method to evaluate the cerebrovasculature of the whole-brain and constructed analyses to assess the angioarchitecture. We used vascular corrosion casting method to replicate the cerebrovasculature in adult mice and used MicroCT to acquire volumetric imaging data of the cerebrovascular network at a resolution required to investigate the microvasculature. Our analyses of the cerebrovasculature evaluated the morphology, topology, and organization of the angioarchitecture. With these developments, we investigated the effects of age and progression of disease on the cerebrovasculature in wild type mice and the triple transgenic mouse model of AD. Study 5 provides data describing degenerative changes to the microvascular network that progress with age in the triple transgenic mouse model of AD. These changes to the microvasculature occurred early, before the onset of Aβ-plaque deposition and NFT development. Overall, this body of work provides evidence of an early cerebrovascular disruption in the etiology of AD that progresses with age. Aβ mediates early cerebrovascular damage through direct interaction with vascular endothelial cells. Microvascular degeneration can lead to hypoperfusion which damages both gray and white matter. Hypoperfusion-associated hypoxia may mediate parenchymal damage by disrupting mitochondrial fission-fusion dynamics and enhancing mitophagy. These data provide a basis for the development of novel therapeutic strategies that target the changes to the cerebrovasculature for the treatment of AD. These observations may substantiate a prophylactic strategy for the treatment of AD by preventing the initial factors that lead to compromised cerebrovasculature

Analysis of contrast-enhanced medical images.

Early detection of human organ diseases is of great importance for the accurate diagnosis and institution of appropriate therapies. This can potentially prevent progression to end-stage disease by detecting precursors that evaluate organ functionality. In addition, it also assists the clinicians for therapy evaluation, tracking diseases progression, and surgery operations. Advances in functional and contrast-enhanced (CE) medical images enabled accurate noninvasive evaluation of organ functionality due to their ability to provide superior anatomical and functional information about the tissue-of-interest. The main objective of this dissertation is to develop a computer-aided diagnostic (CAD) system for analyzing complex data from CE magnetic resonance imaging (MRI). The developed CAD system has been tested in three case studies: (i) early detection of acute renal transplant rejection, (ii) evaluation of myocardial perfusion in patients with ischemic heart disease after heart attack; and (iii), early detection of prostate cancer. However, developing a noninvasive CAD system for the analysis of CE medical images is subject to multiple challenges, including, but are not limited to, image noise and inhomogeneity, nonlinear signal intensity changes of the images over the time course of data acquisition, appearances and shape changes (deformations) of the organ-of-interest during data acquisition, determination of the best features (indexes) that describe the perfusion of a contrast agent (CA) into the tissue. To address these challenges, this dissertation focuses on building new mathematical models and learning techniques that facilitate accurate analysis of CAs perfusion in living organs and include: (i) accurate mathematical models for the segmentation of the object-of-interest, which integrate object shape and appearance features in terms of pixel/voxel-wise image intensities and their spatial interactions; (ii) motion correction techniques that combine both global and local models, which exploit geometric features, rather than image intensities to avoid problems associated with nonlinear intensity variations of the CE images; (iii) fusion of multiple features using the genetic algorithm. The proposed techniques have been integrated into CAD systems that have been tested in, but not limited to, three clinical studies. First, a noninvasive CAD system is proposed for the early and accurate diagnosis of acute renal transplant rejection using dynamic contrast-enhanced MRI (DCE-MRI). Acute rejection–the immunological response of the human immune system to a foreign kidney–is the most sever cause of renal dysfunction among other diagnostic possibilities, including acute tubular necrosis and immune drug toxicity. In the U.S., approximately 17,736 renal transplants are performed annually, and given the limited number of donors, transplanted kidney salvage is an important medical concern. Thus far, biopsy remains the gold standard for the assessment of renal transplant dysfunction, but only as the last resort because of its invasive nature, high cost, and potential morbidity rates. The diagnostic results of the proposed CAD system, based on the analysis of 50 independent in-vivo cases were 96% with a 95% confidence interval. These results clearly demonstrate the promise of the proposed image-based diagnostic CAD system as a supplement to the current technologies, such as nuclear imaging and ultrasonography, to determine the type of kidney dysfunction. Second, a comprehensive CAD system is developed for the characterization of myocardial perfusion and clinical status in heart failure and novel myoregeneration therapy using cardiac first-pass MRI (FP-MRI). Heart failure is considered the most important cause of morbidity and mortality in cardiovascular disease, which affects approximately 6 million U.S. patients annually. Ischemic heart disease is considered the most common underlying cause of heart failure. Therefore, the detection of the heart failure in its earliest forms is essential to prevent its relentless progression to premature death. While current medical studies focus on detecting pathological tissue and assessing contractile function of the diseased heart, this dissertation address the key issue of the effects of the myoregeneration therapy on the associated blood nutrient supply. Quantitative and qualitative assessment in a cohort of 24 perfusion data sets demonstrated the ability of the proposed framework to reveal regional perfusion improvements with therapy, and transmural perfusion differences across the myocardial wall; thus, it can aid in follow-up on treatment for patients undergoing the myoregeneration therapy. Finally, an image-based CAD system for early detection of prostate cancer using DCE-MRI is introduced. Prostate cancer is the most frequently diagnosed malignancy among men and remains the second leading cause of cancer-related death in the USA with more than 238,000 new cases and a mortality rate of about 30,000 in 2013. Therefore, early diagnosis of prostate cancer can improve the effectiveness of treatment and increase the patient’s chance of survival. Currently, needle biopsy is the gold standard for the diagnosis of prostate cancer. However, it is an invasive procedure with high costs and potential morbidity rates. Additionally, it has a higher possibility of producing false positive diagnosis due to relatively small needle biopsy samples. Application of the proposed CAD yield promising results in a cohort of 30 patients that would, in the near future, represent a supplement of the current technologies to determine prostate cancer type. The developed techniques have been compared to the state-of-the-art methods and demonstrated higher accuracy as shown in this dissertation. The proposed models (higher-order spatial interaction models, shape models, motion correction models, and perfusion analysis models) can be used in many of today’s CAD applications for early detection of a variety of diseases and medical conditions, and are expected to notably amplify the accuracy of CAD decisions based on the automated analysis of CE images

Cerebral Circulation

Diagnostics and diseases related to the cerebrovascular system are constantly evolving and updating. 3D augmented reality or quantification of cerebral perfusion are becoming important diagnostic tools in daily practice and the role of the cerebral venous system is being constantly revised considering new theories such as that of “the glymphatic system.” This book provides updates on models, diagnosis, and treatment of diseases of the cerebrovascular system

On the Indeterminates of Glaucoma:the Controversy of Arterial Blood Pressure and Retinal Perfusion

Glaucoma is a chronic eye disease characterized by thinning of the retina, death of ganglion cells, and progressive loss of vision, eventually leading to blindness. The prevalence of glaucoma is estimated at 1-3% of those over 40 years old. With a constantly aging population, this number is expected to increase significantly over the next 10 years. Even with treatment, about 15% of people with glaucoma currently develop residual vision or tunnel vision and eventually become blind or partially sighted. The mechanisms behind ganglion cell death are poorly understood. Elevated eye pressure is the main risk factor for glaucoma, but treatment in the form of medication, laser, or surgery can only slow the decline, not stop it. In addition, high intraocular pressure is neither necessary nor sufficient for the development of glaucoma, indicating the existence of other unknown risk factors. It has been established that the death of ganglion cells results in a decreased oxygen demand and a concomitant decrease in blood flow. However, there is also a hypothesis that reduced or unstable blood supply is not only a consequence, but also a cause of glaucoma. This is known as the ‘chicken-egg’ dilemma in glaucoma. It is supported by the observation that the risk of developing glaucoma is higher in people with very low blood pressure (sometimes even as a result of overtreatment of high blood pressure).This dissertation is an attempt to methodically examine whether blood pressure can be linked to changes in the retina that could suggest susceptibility to glaucoma. For this purpose, we analyze epidemiological data from the Groningen Longitudinal Glaucoma Study, we use advanced imaging techniques to model the microcirculation, and we describe its relationship with the neural structure and oxygen consumption of the retina. We provide evidence leaning towards the existence of a vascular component, likely pertinent to glaucoma