There is no well-established in vivo marker of nigral degeneration in Parkinson's disease (PD). An ideal imaging marker would directly mirror the loss of substantia nigra dopaminergic neurones, which ...is most prominent in sub-regions called nigrosomes. High-resolution, iron-sensitive, magnetic resonance imaging (MRI) at 7T allows direct nigrosome-1 visualisation in healthy people but not in PD. Here, we investigated the feasibility of nigrosome-1 detection using 3T - susceptibility-weighted (SWI) MRI and the diagnostic accuracy that can be achieved for diagnosing PD in a clinical population. 114 high-resolution 3T - SWI-scans were reviewed consisting of a prospective case-control study in 19 subjects (10 PD, 9 controls) and a retrospective cross-sectional study in 95 consecutive patients undergoing routine clinical SWI-scans (>50 years, 9 PD, 81 non-PD, 5 non-diagnostic studies excluded). Two raters independently classified subjects into PD and non-PD according to absence or presence of nigrosome-1, followed by consensus reading. Diagnostic accuracy was assessed against clinical diagnosis as gold standard. Absolute inter- and intra-rater agreement was ≥94% (kappa≥0.82, p<0.001). In the prospective study 8/9 control and 8/10 PD; and in the retrospective study 77/81 non-PD and all 9 PD subjects were correctly classified. Diagnostic accuracy of the retrospective cohort was: sensitivity 100%, specificity 95%, NPV 1, PPV 0.69 and accuracy 96% which dropped to 91% when including non-diagnostic scans ('intent to diagnose'). The healthy nigrosome-1 can be readily depicted on high-resolution 3T - SWI giving rise to a 'swallow tail' appearance of the dorsolateral substantia nigra, and this feature is lost in PD. Visual radiological assessment yielded a high diagnostic accuracy for PD vs. an unselected clinical control population. Assessing the substantia nigra on SWI for the typical 'swallow tail' appearance has potential to become a new and easy applicable 3T MRI diagnostic tool for nigral degeneration in PD.
We have used magnetic resonance imaging (MRI) to provide important new insights into the function of the human placenta in utero. We have measured slow net flow and high net oxygenation in the ...placenta in vivo, which are consistent with efficient delivery of oxygen from mother to fetus. Our experimental evidence substantiates previous hypotheses on the effects of spiral artery remodelling in utero and also indicates rapid venous drainage from the placenta, which is important because this outflow has been largely neglected in the past. Furthermore, beyond Braxton Hicks contractions, which involve the entire uterus, we have identified a new physiological phenomenon, the 'utero-placental pump', by which the placenta and underlying uterine wall contract independently of the rest of the uterus, expelling maternal blood from the intervillous space.
Ingestion of poorly digested, fermentable carbohydrates (fermentable oligo-, di-, mono-saccharides and polyols; FODMAPs) have been implicated in exacerbating intestinal symptoms and the reduction of ...intake with symptom alleviation. Restricting FODMAP intake is believed to relieve colonic distension by reducing colonic fermentation but this has not been previously directly assessed. We performed a randomised controlled trial comparing the effect of a low FODMAP diet combined with either maltodextrin or oligofructose on colonic contents, metabolites and microbiota.
A parallel randomised controlled trial in healthy adults (n = 37). All subjects followed a low FODMAP diet for a week and supplemented their diet with either maltodextrin (MD) or oligofructose (OF) 7g twice daily. Fasted assessments performed pre- and post-diet included MRI to assess colonic volume, breath testing for hydrogen and methane, and stool collection for microbiota analysis.
The low FODMAP diet was associated with a reduction in Bifidobacterium and breath hydrogen, which was reversed by oligofructose supplementation. The difference in breath hydrogen between groups post-intervention was 27ppm (95% CI 7 to 50, P<0.01). Colonic volume increased significantly from baseline in both groups (OF increased 110ml (19.6%), 95% CI 30ml to 190ml, P = 0.01; MD increased 90ml (15.5%), 95% CI 6ml to 175ml, P = 0.04) with no significant difference between them. Colonic volumes correlated with total breath hydrogen + methane. A divergence in Clostridiales abundance was observed with increased abundance of Ruminococcaceae in the maltodextrin group, while in the oligofructose group, Lachnospiraceae decreased. Subjects in either group with high methane production also tended to have high microbial diversity, high colonic volume and greater abundance of methanogens.
A low FODMAP diet reduces total bacterial count and gas production with little effect on colonic volume.
The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is ...known about the time courses and distribution of water volumes in vivo in an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T 50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds.
To study whether maternal cigarette smoking during pregnancy is associated with alterations in the growth of fetal lungs, kidneys, liver, brain, and placenta.
A case-control study, with operators ...performing the image analysis blinded.
Study performed on a research-dedicated magnetic resonance imaging (MRI) scanner (1.5 T) with participants recruited from a large teaching hospital in the United Kingdom.
A total of 26 pregnant women (13 current smokers, 13 non smokers) were recruited; 18 women (10 current smokers, 8 nonsmokers) returned for the second scan later in their pregnancy.
Each fetus was scanned with MRI at 22-27 weeks and 33-38 weeks gestational age (GA).
Images obtained with MRI were used to measure volumes of the fetal brain, kidneys, lungs, liver and overall fetal size, as well as placental volumes.
Exposed fetuses showed lower brain volumes, kidney volumes, and total fetal volumes, with this effect being greater at visit 2 than at visit 1 for brain and kidney volumes, and greater at visit 1 than at visit 2 for total fetal volume. Exposed fetuses also demonstrated lower lung volume and placental volume, and this effect was similar at both visits. No difference was found between the exposed and nonexposed fetuses with regards to liver volume.
Magnetic resonance imaging has been used to show that maternal smoking is associated with reduced growth of fetal brain, lung and kidney; this effect persists even when the volumes are corrected for maternal education, gestational age, and fetal sex. As expected, the fetuses exposed to maternal smoking are smaller in size. Similarly, placental volumes are smaller in smoking versus nonsmoking pregnant women.
Objective
Although the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such ...as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood–brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD.
Methods
We used 3‐ and 7‐Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy.
Results
We found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction‐associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients.
Interpretation
Taken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications. Ann Neurol 2015;78:160–177
Oral dosage forms are the most widely and frequently used formulations to deliver active pharmaceutical ingredients (APIs), due to their ease of administration and noninvasiveness. Knowledge of ...intragastric release rates and gastric mixing is crucial for predicting the API release profile, especially for immediate release formulations. However, knowledge of the intragastric fate of oral dosage forms
to date is limited, particularly for dosage forms administered when the stomach is in the fed state. An improved understanding of gastric food processing, dosage form location, disintegration times, and food effects is essential for greater understanding for effective API formulation design.
standard and controlled modeling has played a significant role in predicting the behavior of dosage forms
. However, discrepancies are reported between
and
disintegration times, with these discrepancies being greatest in the fed state. Studying the fate of a dosage form
is a challenging process, usually requiring the use of invasive methods, such as intubation. Noninvasive, whole body imaging techniques can however provide unique insights into this process. A scoping review was performed systematically to identify and critically appraise published studies using MRI to visualize oral solid dosage forms
in healthy human subjects. The review identifies that so far, an all-purpose robust contrast agent or dosage form type has not been established for dosage form visualization and disintegration studies in the gastrointestinal system. Opportunities have been identified for future studies, with particular focus on characterizing dosage form disintegration for development after the consumption food, as exemplified by the standard Food and Drug Administration (FDA) high fat meal.
The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of ...existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method.
Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later.
Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence.
Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes.
This trial was registered at ClinicalTrials.gov as NCT03191045.
The objective of this study was to investigate whether ingestion of fructose and fructans (such as inulin) can exacerbate irritable bowel syndrome (IBS) symptoms. The aim was to better understand the ...origin of these symptoms by magnetic resonance imaging (MRI) of the gut.
A total of 16 healthy volunteers participated in a four-way, randomized, single-blind, crossover study in which they consumed 500 ml of water containing 40 g of either glucose, fructose, inulin, or a 1:1 mixture of 40 g glucose and 40 g fructose. MRI scans were performed hourly for 5 h, assessing the volume of gastric contents, small bowel water content (SBWC), and colonic gas. Breath hydrogen (H2) was measured and symptoms recorded after each scan.
Data are reported as mean (s.d.) (95% CI) when normally distributed and median (range) when not. Fructose increased area under the curve (AUC) from 0-5 h of SBWC to 71 (23) l/min, significantly greater than for glucose at 36 (11-132) l/min (P<0.001), whereas AUC SBWC after inulin, 33 (17-106) l/min, was no different from that after glucose. Adding glucose to fructose decreased AUC SBWC to 55 (28) l/min (P=0.08) vs. fructose. Inulin substantially increased AUC colonic gas to 33 (20) l/min, significantly greater than glucose and glucose+fructose (both P<0.05). Breath H2 rose more with inulin than with fructose. Glucose when combined with fructose significantly reduced breath H2 by 7,700 (3,121-12,300) p.p.m./min relative to fructose alone (P<0.01, n=13).
Fructose but not inulin distends the small bowel with water. Adding glucose to fructose reduces the effect of fructose on SBWC and breath hydrogen. Inulin distends the colon with gas more than fructose, but causes few symptoms in healthy volunteers.
PDF
