Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol.

INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Blood-Brain Barrier Permeability to Water Measured Using Multiple Echo Time Arterial Spin Labeling MRI in the Aging Human Brain.

BACKGROUND: The blood-brain barrier (BBB) plays a vital role in maintaining brain homeostasis, but the integrity of this barrier deteriorates slowly with aging. Noninvasive water exchange magnetic resonance imaging (MRI) methods may identify changes in the BBB occurring with healthy aging. PURPOSE: To investigate age-related changes in the BBB permeability to water using multiple-echo-time (multi-TE) arterial spin labeling (ASL) MRI. STUDY TYPE: Prospective, cohort. POPULATION: Two groups of healthy humans-older group (≥50 years, mean age = 56 ± 4 years, N = 13, females = 5) and younger group (≤20 years, mean age = 18 ± 1, N = 13, females = 7). FIELD STRENGTH/SEQUENCE: A 3T, multi-TE Hadamard pCASL with 3D Gradient and Spin Echo (GRASE) readout. ASSESSMENT: Two different approaches of variable complexity were applied. A physiologically informed biophysical model with a higher complexity estimating time ( T ex ) taken by the labeled water to move across the BBB and a simpler model of triexponential decay measuring tissue transition rate ( k lin ) . STATISTICS: Two-tailed unpaired Student t-test, Pearson's correlation coefficient and effect size. P < 0.05 was considered significant. RESULTS: Older volunteers showed significant differences of 36% lower T ex , 29% lower cerebral perfusion, 17% pronged arterial transit time and 22% shorter intra-voxel transit time compared to the younger volunteers. Tissue fraction ( f EV ) at the earliest TI = 1600 msec was significantly higher in the older group, which contributed to a significantly lower k lin compared to the younger group. f EV at TI = 1600 msec showed significant negative correlation with T ex (r = -0.80), and k lin and T ex showed significant positive correlation (r = 0.73). DATA CONCLUSIONS: Both approaches of Multi-TE ASL imaging showed sensitivity to detect age-related changes in the BBB permeability. High tissue fractions at the earliest TI and short T ex in the older volunteers indicate that the BBB permeability increased with age. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Subject-specific timing adaption in time-encoded arterial spin labeling imaging.

OBJECTIVES: One challenge in arterial spin labeling (ASL) is the high variability of arterial transit times (ATT), which causes associated arterial transit delay (ATD) artifacts. In patients with pathological changes, these artifacts occur when post-labeling delay (PLD) and bolus durations are not optimally matched to the subject, resulting in difficult quantification of cerebral blood flow (CBF) and ATT. This is also true for the free lunch approach in Hadamard-encoded pseudocontinuous ASL (H-pCASL). MATERIAL AND METHODS: Five healthy volunteers were scanned with a 3 T MR-system. pCASL-subbolus timing was adjusted individually by the developed adaptive Walsh-ordered pCASL sequence and an automatic feedback algorithm. The quantification results for CBF and ATT and the respective standard deviations were compared with results obtained using recommended timings and intentionally suboptimal timings. RESULTS: The algorithm individually adjusted the pCASL-subbolus PLD for each subject within the range of recommended timing for healthy subjects, with a mean intra-subject adjustment deviation of 47.15 ms for single-shot and 44.5 ms for segmented acquisition in three repetitions. DISCUSSION: A first positive assessment of the results was performed on healthy volunteers. The extent to which the results can be transferred to patients and are of benefit must be investigated in follow-up studies.

Robust Multi-TE ASL-Based Blood-Brain Barrier Integrity Measurements.

Multiple echo-time arterial spin labelling (multi-TE ASL) offers estimation of blood-tissue exchange dynamics by probing the T2 relaxation of the labelled spins. In this study, we provide a recipe for robust assessment of exchange time (Texch) as a proxy measure of blood-brain barrier (BBB) integrity based on a test-retest analysis. This includes a novel scan protocol and an extension of the two-compartment model with an "intra-voxel transit time" (ITT) to address tissue transit effects. With the extended model, we intend to separate the underlying two distinct mechanisms of tissue transit and exchange. The performance of the extended model in comparison with the two-compartment model was evaluated in simulations. Multi-TE ASL sequence with two different bolus durations was used to acquire in vivo data (n = 10). Cerebral blood flow (CBF), arterial transit time (ATT) and Texch were fitted with the two models, and mean grey matter values were compared. Additionally, the extended model also extracted ITT parameter. The test-retest reliability of Texch was assessed for intra-session, inter-session and inter-visit pairs of measurements. Intra-class correlation coefficient (ICC) and within-subject coefficient of variance (CoV) for grey matter were computed to assess the precision of the method. Mean grey matter Texch and ITT values were found to be 227.9 ± 37.9 ms and 310.3 ± 52.9 ms, respectively. Texch estimated by the extended model was 32.6 ± 5.9% lower than the two-compartment model. A significant ICC was observed for all three measures of Texch reliability (P < 0.05). Texch intra-session CoV, inter-session CoV and inter-visit CoV were found to be 6.6%, 7.9%, and 8.4%, respectively. With the described improvements addressing intra-voxel transit effects, multi-TE ASL shows good reproducibility as a non-invasive measure of BBB permeability. These findings offer an encouraging step forward to apply this potential BBB permeability biomarker in clinical research.

Nanomedicine and cancer immunotherapy: focus on indoleamine 2,3-dioxygenase inhibitors.

Nanomedicine application in cancer immunotherapy is currently one of the most challenging areas in cancer therapeutic intervention. Innovative solutions have been provided by nanotechnology to deliver cytotoxic agents to the cancer cells partially affecting the healthy cells of the body during the process. Nanoparticle-based drug delivery is an emerging approach to stimulate the immune responses against cancer. The inhibition of indoleamine 2,3-dioxygenase (IDO) is a pivotal area of research in cancer immunotherapy. IDO is a heme-containing immunosuppressive enzyme, which is responsible for the degradation of tryptophan while increasing the concentration of kynurenine metabolites. Various preclinical studies showed that IDO inhibition in certain diseases may result in significant therapeutic effects. Here, we provide a review of the natural and synthetic inhibitors of IDO. These inhibitors are classified according to their source, inhibitory concentrations, the chemical structure, and the mechanism of action. Tumor-targeted chemotherapy is an advanced technique and has more advantages as compared to the conventional chemotherapy. Search for more efficient and less toxic nanoparticles in conjunction with compounds to inhibit IDO is still an area of interest for several research groups worldwide, especially revealing to be an extensive and a promising area in cancer therapeutic innovations.

Indoleamine 2,3-dioxygenase expression and activity in patients with hepatitis C virus-induced liver cirrhosis.

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme. It plays a key role in various malignancies, infection and autoimmune diseases. IDO induces immunosuppression through the depletion of tryptophan and its downstream metabolites. Hepatitis C virus (HCV) has infected more than 12 million individuals in Pakistan. The aim of the present study was to assess the expression and activity of IDO in HCV-infected patients. The functional enzymatic activity of IDO was measured by colorimetric assay. Serum samples from 100 HCV-infected patients were taken to examine IDO activity and samples from 100 healthy volunteers were used as controls. Liver sections from patients with HCV (n=35) and healthy controls (n=5) were used for immunohistochemical studies. Immunohistochemical analysis revealed that IDO was overexpressed in 28 of 35 (80%) cirrhotic liver samples, whereas 5 of 35 (14.2%) cases presented moderate and 2 of 35 (5.7%) cases presented mild expression of IDO. The enzymatic activity of IDO was significantly higher in the serum samples of HCV-infected patients as compared with those in the control. These data indicate that the expression of IDO correlated with the pathogenesis of disease. In summary, it is suggested that the high expression of IDO in the progressively cirrhotic livers of HCV-infected patients might contribute to the development of hepatocellular carcinoma. IDO may characterize a novel therapeutic target against HCV.