Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease : additional results from the AMBAR study

This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) were performed. MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18 FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG. (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053). The online version contains supplementary material available at 10.1007/s00259-022-05915-

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer’s disease: additional results from the AMBAR study

Albumin; Intravenous immunoglobulin; PlasmapheresisAlbúmina; Inmunoglobulina intravenosa; PlasmaféresisAlbúmina; Immunoglobulina intravenosa; PlasmafèresiPurpose This study was designed to detect structural and functional brain changes in Alzheimer’s disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. Methods Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) were performed. Results MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. Conclusions PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG.The AMBAR study is sponsored by Grifols, a manufacturer of therapeutic human serum albumin and intravenous immune globulin. GC-B, IR, JC-C, DP, MBo, and OLL received direct or indirect funding from Grifols to carry out the study and the preparation of the manuscript

Mapping the Impact and Plasticity of Cortical-Cardiovascular Interactions in Vascular Disease Using Structural and Functional MRI

There is growing interest in the role of vascular disease in accelerating age-related decline in cerebrovascular structural and functional integrity. Since an increased number of older adults are surviving chronic diseases, of which cardiovascular disease (CVD) is prevalent, there is an urgent need to understand relationships between cardiovascular dysfunction and brain health. It is unclear if CVD puts the brains of older adults, already experiencing natural brain aging, at greater risk for degeneration. In this thesis, the role of CVD in accelerating brain aging is explored. Because physical activity is known to provide neuroprotective benefits to brains of older adults, the role of physical activity in mediating disease effects were also explored. Using novel neuroimaging techniques, measures of gray matter volume and cerebrovascular hemodynamics were compared between groups of coronary artery disease patients and age-matched controls, to describe regional effects of CVD on the brain. In a sub-set of patients, imaging measures were repeated after completion of a 6-month exercise training, part of a cardiac rehabilitation program, to examine exercise effects. Differences in cerebrovascular hemodynamics were measured as changes in resting cerebral blood flow (CBF) and changes in cerebrovascular reactivity (CVR) to hypercapnia (6% CO2) using a non-invasive perfusion magnetic resonance imaging technique, arterial spin labelling (ASL). We found decreased brain volume, CBF and CVR in several regions of the brains of coronary artery disease patients compared to age-matched healthy controls. The reductions in CBF and CVR were independent of underlying brain atrophy, suggesting that changes in cerebrovascular function could precede changes in brain structure. In addition, increase in brain volume and CBF were observed in some regions of the brain after exercise training, indicating that cardiac rehabilitation programs may have neurorehabiliation effects as well. Since, CBF measured with ASL is not the [gold] standard measure of functional brain activity, we examined the regional correlation of ASL-CBF to glucose consumption rates (CMRglc) measured with positron emission tomography (PET), a widely acceptable marker of brain functional activity. Simultaneous measurements of ASL-CBF and PET-CMRglc were performed in a separate study in a group of older adults with no neurological impairment. Across brain regions, ASL-CBF correlated well with PET-CMRglc, but variations in regional coupling were found and demonstrate the role of certain brain regions in maintaining higher level of functional organization compared to other regions. In general, the results of the thesis demonstrate the impact of CVD on brain health, and the neurorehabiliation capacity of cardiac rehabilitation. The work presented also highlights the ability of novel non-invasive neuroimaging techniques in detecting and monitoring subtle but robust changes in the aging human brain

Longitudinal Evaluation of Fatty Acid Metabolism in Normal and Spontaneously Hypertensive Rat Hearts with Dynamic MicroSPECT Imaging

The goal of this project is to develop radionuclide molecular imaging technologies using a clinical pinhole SPECT/CT scanner to quantify changes in cardiac metabolism using the spontaneously hypertensive rat (SHR) as a model of hypertensive-related pathophysiology. This paper quantitatively compares fatty acid metabolism in hearts of SHR and Wistar-Kyoto normal rats as a function of age and thereby tracks physiological changes associated with the onset and progression of heart failure in the SHR model. The fatty acid analog, 123I-labeled BMIPP, was used in longitudinal metabolic pinhole SPECT imaging studies performed every seven months for 21 months. The uniqueness of this project is the development of techniques for estimating the blood input function from projection data acquired by a slowly rotating camera that is imaging fast circulation and the quantification of the kinetics of 123I-BMIPP by fitting compartmental models to the blood and tissue time-activity curves

Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2

Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on β-adrenergic versus Angiotensin II (Ang II)-dependent (Gs vs. Gαq mediated) modulation of Ca2+i-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca2+ currents and Ca2+i transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca2+ currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, β-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca2+-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca2+i-dependent hypertrophic growth response to Ang II, but not to β-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT1 signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for β-adrenergic Ca2+i-stimulation in adult myocytes

Relevance of cannabinoids in preclinical models of psychiatric disorders

Throughout this thesis, we are going to navigate through the history of cannabis, from its first use thousands of years ago, to its exponential growth in use and knowledge during the last third of the last century. The endocannabinoid system was a cutting-edge discovery, which initiated interest in cannabinoids both in their effects on the human body, and in their interaction with other neural systems, such as the dopaminergic reward system. Not much later, the implications of cannabis in adolescence were postulated, opening a wide range of possibilities in the study of cannabinoids. Consequently, researchers began to wonder whether cannabinoids might influence the consumption of other drugs and, the possible interactions with other endogenous systems, such as the opioid system, and their association with the onset of psychiatric disorders, such as schizophrenia. In this sense, preclinical models have provided a great impulse for the understanding of such processes and effects of cannabinoids. Nevertheless, it is important to note that the field of cannabinoid research is rapidly evolving, and although substantial progress has been made, many questions remain to be answered.Programa de Doctorado en Ciencia y Tecnología Biomédica por la Universidad Carlos III de MadridPresidente: Juan Nàcher Roselló.- Secretaria: Raquel Abalo Delgado.- Vocal: Miguel Ángel Morcillo Alons

NNeMo (Neonatal NeuroMonitor) - a hybrid optical system to characterize perfusion and metabolism in the newborn brain

Premature birth, defined as a gestational period less than 37 weeks, occurs in 8% of infants born in Canada. These births are associated with a higher risk of developing neurological complications. Infants born with very low birth weights (VLBW, \u3c 1500 g) experience cognitive or behavioural deficits at a rate of 40-50%, while a further 5-10% develop major disorders such as cerebral palsy. The likelihood of injury increases with a shorter gestational period and/or a lower birthweight. Intraventricular hemorrhaging (IVH) occurs in 20-25% of VLBW infants, characterized by bleeding in the germinal matrix and surrounding white matter. This highly vascularized region is particularly susceptible to bleeds due to underdeveloped cerebrovascular structures. Severe IVH causes an inflammatory response and subsequent obstruction of cerebrospinal fluid (CSF) drainage, resulting in enlargement of the brain’s ventricles, referred to as post-hemorrhagic ventricular dilatation (PHVD). PHVD increases intracranial pressure and can result in compression/damage of brain tissue. Diagnosis of IVH and PHVD is regularly performed using cranial ultrasound. Clinicians can visually assess and grade hemorrhaging/ventricle dilatation. Ultrasound, however, is limited in its ability to continuously monitor and only detects irreversible damage. NNeMo (Neonatal NeuroMonitor) is a hybrid optical device combining diffuse correlation (DCS) and near-infrared spectroscopy (NIRS) to simultaneous monitor cerebral blood flow (CBF) and metabolism at the bedside. DCS analyzes light scatter from red blood cells to infer their motion and calculate CBF while NIRS exploits light absorption properties to quantify changes in oxidized cytochrome c oxidase (oxCCO), a direct marker of energy metabolism. System validation was presented in a piglet model of neonatal hypoxia-ischemia. Clinical translation of NNeMo was demonstrated in PHVD infants during ventricular taps (i.e., CSF drainage). Changes in perfusion and metabolism are presented in premature infants at high risk of IVH within the first 72 hours of life. Lastly, NNeMo was translated to the cardiac operating room, in patients undergoing surgery with cardiopulmonary bypass, to observe metabolic response to large intraoperative changes in CBF. Optical measures of perfusion and metabolism show potential to act as prognostic markers of injury and could aid clinicians in patient management before significant damage persists