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Alzheimer’s disease has an increasing prevalence in the population world-wide, yet current diagnostic methods based on recommended biomarkers are only available in specialized clinics. Due to these circumstances, Alzheimer’s disease is usually diagnosed late, which contrasts with the currently available treatment options that are only effective for patients at an early stage. Blood-based biomarkers could fill in the gap of easily accessible and low-cost methods for early diagnosis of the disease. In particular, immune-based blood-biomarkers might be a promising option, given the recently discovered cross-talk of immune cells of the central nervous system with those in the peripheral immune system. Here, we give a background on recent advances in research on brain-immune system cross-talk in Alzheimer’s disease and review machine learning approaches, which can combine multiple biomarkers with further information (e.g. age, sex, APOE genotype) into predictive models supporting an earlier diagnosis. In addition, mechanistic modeling approaches, such as agent-based modeling open the possibility to model and analyze cell dynamics over time. This review aims to provide an overview of the current state of immune-system related blood-based biomarkers and their potential for the early diagnosis of Alzheimer’s disease.

Purpose. This pilot study aimed to explore the feasibility of scanning the human distal radius bone marrow in vivo to detect osteoporosis-related changes using magnetic resonance and evaluate whether the radius may serve as an accessible probing site for osteoporosis. This may lead in the future to the use of affordable means such as low-field MRI scanners for the monitoring of disease progression. Methods. A clinical trial was performed using a 3T MR scanner, including 26 women assigned into three study groups: healthy-premenopausal (n = 7; mean age 48.6 ± 3.5 years), healthy-postmenopausal (n = 10; mean age 54.5 ± 5.6 years), and osteoporotic-postmenopausal (n = 9; mean age 61.3 ± 5.6 years). Marrow fat composition was evaluated using T2 maps, a two-compartment model of T1, and a Dixon pulse sequence. Results. The osteoporotic group exhibited higher fat content than the other two groups and lower T2 values than the healthy-premenopausal group. Conclusions. Osteoporosis-related changes in the composition of the distal radius bone marrow may be detected in vivo using MRI protocols. The scanning protocols chosen here can later be repeated using low-field MRI scanners, thus offering the potential for early detection and treatment monitoring, using an accessible, affordable means that may be applied in small clinics. This trial is registered with MOH_2018-05-23_002247, NCT03742362.

Mechanical events and alterations in neuronal morphology that accompany neuronal activity have been observed for decades. However, no clear neurophysiological role, nor an agreed molecular mechanism relating these events to the electrochemical process, has been found. Here we hypothesized that intense, yet physiological, electrical activity in neurons triggers cytoskeletal depolymerization. We excited the sciatic nerve of anesthetized mice with repetitive electric pulses (5, 10, and 100 Hz) for 1 and 2 min and immediately fixed the excised nerves. We then scanned the excised nerves with high-resolution transmission electron microscopy, and quantified cytoskeletal changes in the resulting micrographs. We demonstrate that excitation with a stimulation frequency that is within the physiological regime is accompanied by a significant reduction in the density of cytoskeletal proteins relative to the baseline values recorded in control nerves. After 10 Hz stimulation with durations of 1 and 2 min, neurofilaments density dropped to 55.8 and 51.1% of the baseline median values, respectively. In the same experiments, microtubules density dropped to 23.7 and 38.5% of the baseline median values, respectively. These changes were also accompanied by a reduction in the cytoskeleton-to-cytoplasm contrast that we attribute to the presence of depolymerized electron-dense molecules in the lumen. Thus, we demonstrate with an in vivo model a link between electrical activity and immediate cytoskeleton rearrangement at the nano-scale. We suggest that this cytoskeletal plasticity reduces cellular stiffness and allows cellular homeostasis, maintenance of neuronal morphology and that it facilitates in later stages growth of the neuronal projections.

The field of computer modeling and simulation of biological systems is rapidly advancing, backed by significant progress in the fields of experimentation techniques, computer hardware, and programming software. The result of a simulation may be delivered in several ways, from numerical results, through graphs of the simulated run, to a visualization of the simulation. The vision of an in-silico experiment mimicking an in-vitro or in-vivo experiment as it is viewed under a microscope is appealing but technically demanding and computationally intensive. Here, we report “Cell Studio,” a generic, hybrid platform to simulate an immune microenvironment with biological and biophysical rules. We use game engines—generic programs for game creation which offer ready-made assets and tools—to create a visualized, interactive 3D simulation. We also utilize a scalable architecture that delegates the computational load to a server. The user may view the simulation, move the “camera” around, stop, fast-forward, and rewind it and inject soluble molecules into the extracellular medium at any point in time. During simulation, graphs are created in real time for a broad view of system-wide processes. The model is parametrized using a user-friendly Graphical User Interface (GUI). We show a simple validation simulation and compare its results with those from a “classical” simulation, validated against a “wet” experiment. We believe that interactive, real-time 3D visualization may aid in generating insights from the model and encourage intuition about the immunological scenario.

Osteoporosis is characterized by reduction in trabecular bone in conjunction with increased marrow cell adiposity. While these changes occur within weeks, monitoring of treatment efficacy as performed by DEXA is sensitive only to long-term changes. MRI is sensitive to bone marrow changes but is less affordable. In a recent study, we have shown that a stray-field NMR can monitor bone marrow cellular changes that are related to osteoporosis. Objectives. To demonstrate sensitivity of a low-field tabletop NMR scanner to bone marrow dynamics following hormonal treatment in rats. Methods. Two-month-old female rats (n=36) were ovariectomized (OVX) and dosed for the ensuing 3 or 5 weeks with 20 mg/kg of PTH(1-34). Hind limbs femurs and tibiae were isolated and underwent ex vivo microradiography and histology and NMR relaxometry at 6 weeks (preventive experiment) and 11 weeks (therapeutic treatment experiment) after OVX. Results. OVX rats developed osteoporotic changes including adipogenic marrow compared to Sham and PTH treated rats. T2 and ADC NMR relaxation coefficients were found to correlate with marrow composition. Conclusions. This study suggests that stray-field NMR, an affordable method that is sensitive to the rapid cellular changes in bone marrow, may have a clinical value in monitoring hormonal treatment for osteoporosis.

Immune tolerance toward “self” is critical in multiple immune disorders. While there are several mechanisms to describe the involvement of immune cells in the process, the role of peripheral tissue cells in that context is not yet clear. The theory of ecoimmunity postulates that interactions between immune and tissue cells represent a predator–prey relationship. A lifelong interaction, shaped mainly during early ontogeny, leads to selection of nonimmune cell phenotypes. Normally, therefore, nonimmune cells that evolve alongside an intact immune system would be phenotypically capable of evading immune responses, and cells whose phenotype falls short of satisfying this steady state would expire under hostile immune responses. This view was supported until recently by experimental evidence showing an inferior endurance of severe combined immunodeficiency (SCID)-derived pancreatic islets when engrafted into syngeneic immune-intact wild-type (WT) mice, relative to islets from WT. Here we extend the experimental exploration of ecoimmunity by searching for the presence of the phenotypic changes suggested by the theory. Immune-related phenotypes of islets, spleen, and bone marrow immune cells were determined, as well as SCID and WT nonlymphocytic cells. Islet submass grafting was performed to depict syngeneic graft functionality. Islet cultures were examined under both resting and inflamed conditions for expression of CD40 and major histocompatibility complex (MHC) class I/II and release of interleukin-1α (IL-1α), IL-1β, IL-6, tumor necrosis factor-α (TNF-α), IL-10, and insulin. Results depict multiple pathways that appear to be related to the sculpting of nonimmune cells by immune cells; 59 SCID islet genes displayed relative expression changes compared with WT islets. SCID cells expressed lower tolerability to inflammation and higher levels of immune-related molecules, including MHC class I. Accordingly, islets exhibited a marked increase in insulin release upon immunocyte depletion, in effect resuming endocrine function that was otherwise suppressed by resident immunocytes. This work provides further support of the ecoimmunity theory and encourages subsequent studies to identify its role in the emergence and treatment of autoimmune pathologies, transplant rejection, and cancer.

BACKGROUND:Regulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM). METHODS:Twelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation. RESULTS:We found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded. CONCLUSIONS:These results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation. TRIAL REGISTRATION:ClinicalTrials.gov NCT02727790.

The goal of this study was to examine the use of diffusion-weighted magnetic resonance imaging (DW-MRI) for the assessment of early progression of photodamage induced by Pd-bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT). TOOKAD is a novel second-generation photosensitizer for PDT of solid tumors developed in our laboratory and presently under clinical trials for prostate cancer (PC) therapy. Using the subcutaneous human prostate adenocarcinoma WISH-PC14 xenografts in nude mice as a model, a unique biphasic change in the apparent diffusion coefficient (ADC) was observed within the first 24 hours post-PDT, with initial decrease followed by an increase in ADC. Using DW-MRI, this phenomenon enables the detection of successful tumor response to PDT within 7 hours posttreatment. This process was validated by direct, histological, immunohistochemical examinations and also by evaluation of serum prostate-specific antigen (PSA) levels that decreased significantly already 7 hours posttreatment. In vitro studies of multicellular cell spheroids confirmed a PDT-induced decrease in ADC, suggesting that lipid peroxidation (LPO) significantly contributes to ADC decline observed after PDT. These results demonstrate that TOOKAD-based PDT successfully eradicates prostate adenocarcinoma xenografts and suggests DW-MRI to be useful for the detection of early tumor response and treatment outcome in the clinical setting.

Insulin resistance (IR) is one of the most widespread health problems in modern times. The gold standard for quantification of IR is the hyperinsulinemic-euglycemic glucose clamp technique. During the test, a regulated glucose infusion is delivered intravenously to maintain a constant blood glucose concentration. Current control algorithms for regulating this glucose infusion are based on feedback control. These models require frequent sampling of blood, and can only partly capture the complexity associated with regulation of glucose. Here we present an improved clamp control algorithm which is motivated by the stochastic nature of glucose kinetics, while using the minimal need in blood samples required for evaluation of IR. A glucose pump control algorithm, based on artificial neural networks model was developed. The system was trained with a data base collected from 62 rat model experiments, using a back-propagation Levenberg-Marquardt optimization. Genetic algorithm was used to optimize network topology and learning features. The predictive value of the proposed algorithm during the temporal period of interest was significantly improved relative to a feedback control applied at an equivalent low sampling interval. Robustness to noise analysis demonstrates the applicability of the algorithm in realistic situations.