Head-to-head comparison of amplified plasmonic exosome Aß42 platform and single-molecule array immunoassay in a memory clinic cohort.

BACKGROUND AND PURPOSE: Various blood biomarkers reflecting brain amyloid-ß (Aß) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. METHODS: Using the same cohort (n = 68), the performances of the single-molecule array (Simoa) Aß40, Aß42, Aß42/Aß40 and the amplified plasmonic exosome (APEX) Aß42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aß+) participants. RESULTS: Compared to Simoa biomarkers, APEX-Aß42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aß42 and 48.6% for Simoa-Aß42/Aß40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aß42 pre-screening does not increase the required number of initial participants. CONCLUSIONS: With its high diagnostic performance, APEX is an ideal candidate for Aß+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aß+ participants whilst halving recruitment costs.

Longitudinal trajectory of Amyloid-related hippocampal subfield atrophy in nondemented elderly.

Hippocampal atrophy and abnormal ß-Amyloid (Aß) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aß-associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aß correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET-Aß in AD-vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto-segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aß-related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aß correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal-to-widespread trajectory of Aß-associated hippocampal subfield atrophy over disease progression in nondemented elderly.

Improved quantification of amyloid burden and associated biomarker cut-off points: results from the first amyloid Singaporean cohort with overlapping cerebrovascular disease.

PURPOSE: The analysis of the [11C]PiB-PET amyloid images of a unique Asian cohort of 186 participants featuring overlapping vascular diseases raised the question about the validity of current standards for amyloid quantification under abnormal conditions. In this work, we implemented a novel pipeline for improved amyloid PET quantification of this atypical cohort. METHODS: The investigated data correction and amyloid quantification methods included motion correction, standardized uptake value ratio (SUVr) quantification using the parcellated MRI (standard method) and SUVr quantification without MRI. We introduced a novel amyloid analysis method yielding 2 biomarkers: AßL which quantifies the global Aß burden and ns that characterizes the non-specific uptake. Cut-off points were first determined using visual assessment as ground truth and then using unsupervised classification techniques. RESULTS: Subject's motion impacts the accuracy of the measurement outcome but has however a limited effect on the visual rating and cut-off point determination. SUVr computation can be reliably performed for all the subjects without MRI parcellation while, when required, the parcellation failed or was of mediocre quality in 10% of the cases. The novel biomarker AßL showed an association increase of 29.5% with the cognitive tests and increased effect size between positive and negative scans compared with SUVr. ns was found sensitive to cerebral microbleeds, white matter hyperintensity, volume, and age. The cut-off points for SUVr using parcellated MRI, SUVr without parcellation, and AßL were 1.56, 1.39, and 25.5. Finally, k-means produced valid cut-off points without the requirement of visual assessment. CONCLUSION: The optimal processing for the amyloid quantification of this atypical cohort allows the quantification of all the subjects, producing SUVr values and two novel biomarkers: AßL, showing important increased in their association with various cognitive tests, and ns, a parameter sensitive to non-specific retention variations caused by age and cerebrovascular diseases.

31 P magnetization transfer magnetic resonance spectroscopy: Assessing the activation induced change in cerebral ATP metabolic rates at 3 T.

PURPOSE: In vivo 31 P magnetic resonance spectroscopy (MRS) magnetization transfer (MT) provides a direct measure of neuronal activity at the metabolic level. This work aims to use functional 31 P MRS-MT to investigate the change in cerebral adenosine triphosphate (ATP) metabolic rates in healthy adults upon repeated visual stimuli. METHODS: A magnetization saturation transfer sequence with narrowband selective saturation of γ-ATP was developed for 31 P MT experiments at 3 T. RESULTS: Using progressive saturation of γ-ATP, the intrinsic T1 relaxation times of phosphocreatine (PCr) and inorganic phosphate (Pi) at 3 T were measured to be 5.1 ± 0.8 s and 3.0 ± 1.4 s, respectively. Using steady-state saturation of γ-ATP, a significant 24% ± 14% and 11% ± 7% increase in the forward creatine kinase (CK) pseudo-first-order reaction rate constant, k1 , was observed upon visual stimulation in the first and second cycles, respectively, of a paradigm consisting of 10-minute rest followed by 10-minute stimulation, with the measured baseline k1 being 0.35 ± 0.04 s-1 . No significant changes in forward ATP synthase reaction rate, PCr/γ-ATP, Pi/γ-ATP, and nicotinamide adenine dinucleotide/γ-ATP ratios, or intracellular pH were detected upon stimulation. CONCLUSION: This work demonstrates the potential of studying cerebral bioenergetics using functional 31 P MRS-MT to determine the change in the forward CK reaction rate at 3 T. Magn Reson Med 79:22-30, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Fat emulsion intragastric stability and droplet size modulate gastrointestinal responses and subsequent food intake in young adults.

BACKGROUND: Intragastric creaming and droplet size of fat emulsions may affect intragastric behavior and gastrointestinal and satiety responses. OBJECTIVES: We tested the hypotheses that gastrointestinal physiologic responses and satiety will be increased by an increase in intragastric stability and by a decrease in fat droplet size of a fat emulsion. METHODS: This was a double-blind, randomized crossover study in 11 healthy persons [8 men and 3 women, aged 24 ± 1 y; body mass index (in kg/m(2)): 24.4 ± 0.9] who consumed meals containing 300-g 20% oil and water emulsion (2220 kJ) with 1) larger, 6-µm mean droplet size (Coarse treatment) expected to cream in the stomach; 2) larger, 6-µm mean droplet size with 0.5% locust bean gum (LBG; Coarse+LBG treatment) to prevent creaming; or 3) smaller, 0.4-µm mean droplet size with LBG (Fine+LBG treatment). The participants were imaged hourly by using MRI and food intake was assessed by using a meal that participants consumed ad libitum. RESULTS: The Coarse+LBG treatment (preventing creaming in the stomach) slowed gastric emptying, resulting in 12% higher gastric volume over time (P < 0.001), increased small bowel water content (SBWC) by 11% (P < 0.01), slowed appearance of the (13)C label in the breath by 17% (P < 0.01), and reduced food intake by 9% (P < 0.05) compared with the Coarse treatment. The Fine+LBG treatment (smaller droplet size) slowed gastric emptying, resulting in 18% higher gastric volume (P < 0.001), increased SBWC content by 15% (P < 0.01), and significantly reduced food intake by 11% (P < 0.05, equivalent to an average of 411 kJ less energy consumed) compared with the Coarse+LBG treatment. These high-fat meals stimulated substantial increases in SBWC, which increased to a peak at 4 h at 568 mL (range: 150-854 mL; P < 0.01) for the Fine+LBG treatment. CONCLUSION: Manipulating intragastric stability and fat emulsion droplet size can influence human gastrointestinal physiology and food intake.

Methodology for improved detection of low concentration metabolites in MRS: optimised combination of signals from multi-element coil arrays.

State of the art magnetic resonance imaging (MRI) scanners are generally equipped with multi-element receive coils; 16 or 32 channel coils are common. Their development has been predominant for parallel imaging to enable faster scanning. Less consideration has been given to localized magnetic resonance spectroscopy (MRS). Multinuclear studies, for example (31)P or (13)C MRS, are often conducted with a single element coil located over the region of interest. (1)H MRS studies have generally employed the same multi-element coils used for MRI, but little consideration has been given as to how the spectroscopic data from the different channels are combined. In many cases it is simply co-added with detrimental effect on the signal to noise ratio. In this study, we derive the optimum method for combining multi-coil data, namely weighting with the ratio of signal to the square of the noise. We show that provided that the noise is uncorrelated, this is the theoretical optimal combination. The method is demonstrated for in vivo proton MRS data acquired using a 32 channel receive coil at 7T in four different brain areas; left motor and right motor, occipital cortex and medial frontal cortex.

tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: a 7 T magnetic resonance spectroscopy study.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and 'supervised' learning of internal 'forward' models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.

No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men.

BACKGROUND & AIMS: Diets high in fructose have been proposed to contribute to nonalcoholic fatty liver disease. We compared the effects of high-fructose and matched glucose intake on hepatic triacylglycerol (TAG) concentration and other liver parameters. DESIGN: In a double-blind study, we randomly assigned 32 healthy but centrally overweight men to groups that received either a high-fructose or high-glucose diet (25% energy). These diets were provided during an initial isocaloric period of 2 weeks, followed by a 6-week washout period, and then again during a hypercaloric 2-week period. The primary outcome measure was hepatic level of TAG, with additional assessments of TAG levels in serum and soleus muscle, hepatic levels of adenosine triphosphate, and systemic and hepatic insulin resistance. RESULTS: During the isocaloric period of the study, both groups had stable body weights and concentrations of TAG in liver, serum, and soleus muscle. The high-fructose diet produced an increase of 22 ± 52 µmol/L in the serum level of uric acid, whereas the high-glucose diet led to a reduction of 23 ± 25 µmol/L (P < .01). The high-fructose diet also produced an increase of 0.8 ± 0.9 in the homeostasis model assessment of insulin resistance, whereas the high-glucose diet produced an increase of only 0.1 ± 0.7 (P = .03). During the hypercaloric period, participants in the high-fructose and high-glucose groups had similar increases in weight (1.0 ± 1.4 vs 0.6 ± 1.0 kg; P = .29) and absolute concentration of TAG in liver (1.70% ± 2.6% vs 2.05% ± 2.9%; P = .73) and serum (0.36 ± 0.75 vs 0.33 ± 0.38 mmol/L; P = .91), and similar results in biochemical assays of liver function. Body weight changes were associated with changes in liver biochemistry and concentration of TAGs. CONCLUSIONS: In the isocaloric period, overweight men who were on a high-fructose or a high-glucose diet did not develop any significant changes in hepatic concentration of TAGs or serum levels of liver enzymes. However, in the hypercaloric period, both high-fructose and high-glucose diets produced significant increases in these parameters without any significant difference between the 2 groups. This indicates an energy-mediated, rather than a specific macronutrient-mediated, effect. Clinical trials.gov no: NCT01050140.

Investigating the electrophysiological basis of resting state networks using magnetoencephalography.

In recent years the study of resting state brain networks (RSNs) has become an important area of neuroimaging. The majority of studies have used functional magnetic resonance imaging (fMRI) to measure temporal correlation between blood-oxygenation-level-dependent (BOLD) signals from different brain areas. However, BOLD is an indirect measure related to hemodynamics, and the electrophysiological basis of connectivity between spatially separate network nodes cannot be comprehensively assessed using this technique. In this paper we describe a means to characterize resting state brain networks independently using magnetoencephalography (MEG), a neuroimaging modality that bypasses the hemodynamic response and measures the magnetic fields associated with electrophysiological brain activity. The MEG data are analyzed using a unique combination of beamformer spatial filtering and independent component analysis (ICA) and require no prior assumptions about the spatial locations or patterns of the networks. This method results in RSNs with significant similarity in their spatial structure compared with RSNs derived independently using fMRI. This outcome confirms the neural basis of hemodynamic networks and demonstrates the potential of MEG as a tool for understanding the mechanisms that underlie RSNs and the nature of connectivity that binds network nodes.

Elevated brain temperature under severe heat exposure impairs cortical motor activity and executive function.

BACKGROUND: Excessive heat exposure can lead to hyperthermia in humans, which impairs physical performance and disrupts cognitive function. While heat is a known physiological stressor, it is unclear how severe heat stress affects brain physiology and function. METHODS: Eleven healthy participants were subjected to heat stress from prolonged exercise or warm water immersion until their rectal temperatures (Tre) attained 39.5°C, inducing exertional or passive hyperthermia, respectively. In a separate trial, blended ice was ingested before and during exercise as a cooling strategy. Data were compared to a control condition with seated rest (normothermic). Brain temperature (Tbr), cerebral perfusion, and task-based brain activity were assessed using magnetic resonance imaging techniques. RESULTS: Tbr in motor cortex was found to be tightly regulated at rest (37.3°C ± 0.4°C (mean ± SD)) despite fluctuations in Tre. With the development of hyperthermia, Tbr increases and dovetails with the rising Tre. Bilateral motor cortical activity was suppressed during high-intensity plantarflexion tasks, implying a reduced central motor drive in hyperthermic participants (Tre = 38.5°C ± 0.1°C). Global gray matter perfusion and regional perfusion in sensorimotor cortex were reduced with passive hyperthermia. Executive function was poorer under a passive hyperthermic state, and this could relate to compromised visual processing as indicated by the reduced activation of left lateral-occipital cortex. Conversely, ingestion of blended ice before and during exercise alleviated the rise in both Tre and Tbr and mitigated heat-related neural perturbations. CONCLUSION: Severe heat exposure elevates Tbr, disrupts motor cortical activity and executive function, and this can lead to impairment of physical and cognitive performance.

Variation in maternal sensitivity and the development of memory biases in preschoolers.

Introduction: Links between maternal sensitivity, hippocampal development, and memory abilities suggests early life insensitive care may shape structures and schemas influencing future decisions and stress management, biasing children to negative information. While it is possible that this pattern of neurodevelopment may have adaptive consequences, for example, preventing children from encountering untoward experience with future adversity, it may also leave some children at risk for the development of internalizing problems. Methods: Here, in a Two Wave Study, we examine whether insensitive care predicts sub sequentially assessed memory biases for threatening (but not happy) stimuli in preschoolers (n = 49), and if such relations cut across different forms of relational memory, i.e., memory for relations between two "items," between an "item" and its spatial location, and an "item" and its temporal sequence. In a subset (n = 18) we also examine links between caregiving, memory, and hippocampal subregion volume. Results: Results indicate no main or interactive influence of gender on relational memory. However, insensitive caregiving predicted the difference between Angry and Happy memory during the Item-Space condition (B = 2.451, se = 0.969, p = 0.014, 95% CI (0.572, 4.340)], as well as memory for Angry (but not Happy) items [B = -2.203, se = 0.551, p < 0.001, 95% CI (-3.264,-1.094)]. Memory for the difference between Angry and Happy stimuli in the Space condition associated with larger right hippocampal body volumes (Rho = 0.639, p = 0.004). No relations were observed with internalizing problems. Discussion: Results are discussed with reference to developmental stage and in consideration of whether negative biases may serve as an intermediate factor linking early life insensitive care and later socioemotional problems including an increased incidence of internalizing disorders.

Evidence for inefficient contraction and abnormal mitochondrial activity in sarcopenia using magnetic resonance spectroscopy.

BACKGROUND: Mitochondrial dysfunction has been implicated in sarcopenia. 31 P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function. METHODS: Twenty Chinese men with sarcopenia (SARC, age = 73.1 ± 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 ± 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations. RESULTS: Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 ± 0.59 vs. 0.57 ± 0.22, moderate: 0.93 ± 0.43 vs. 0.58 ± 0.68, high: 0.70 ± 0.57 vs. 0.43 ± 0.51 mmol L-1  min-1  bar-1  cm-2 , P = 0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3 ± 6.4 vs. 14.6 ± 6.5 mmol L-1  min-1 , P = 0.2). However, relative increases in end-exercise ADP in SARC (31.8 ± 9.9 vs. 24.0 ± 7.3 mmol L-1 , P = 0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho = -0.42, P = 0.03] and end-exercise ADP (complex III, rho = -0.52, P = 0.01; CS rho = -0.45, P = 0.02; SDH rho = -0.45, P = 0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho = -0.47, P = 0.02), and the cost of contraction at high intensity (rho = -0.54, P = 0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho = 0.5, P = 0.03), CS (rho = 0.47, P = 0.02) and SDH (rho = 0.46, P = 0.03), linking increased mitochondrial complex activity with increased ability to generate energy through oxidative pathways. CONCLUSIONS: This study used 31 P MRS to assess ATP utilization and resynthesis in sarcopenic muscle and demonstrated abnormal increases in the energy cost during exercise and perturbed mitochondrial energetics in recovery. Associations between mitochondrial complex activity and the fractional contribution to energy requirement during exercise indicate increased ability to generate energy oxidatively in those with better mitochondrial complex activity.

Comparison of quantitative parameters and radiomic features as inputs into machine learning models to predict the Gleason score of prostate cancer lesions.

INTRODUCTION: The classification of prostate cancer (PCa) lesions using Prostate Imaging Reporting and Data System (PI-RADS) suffers from poor inter-reader agreement. This study compared quantitative parameters or radiomic features from multiparametric magnetic resonance imaging (mpMRI) or positron emission tomography (PET), as inputs into machine learning (ML) to predict the Gleason scores (GS) of detected lesions for improved PCa lesion classification. METHODS: 20 biopsy-confirmed PCa subjects underwent imaging before radical prostatectomy. A pathologist assigned GS from tumour tissue. Two radiologists and one nuclear medicine physician delineated the lesions on the mpMR and PET images, yielding 45 lesion inputs. Seven quantitative parameters were extracted from the lesions, namely T2-weighted (T2w) image intensity, apparent diffusion coefficient (ADC), transfer constant (KTRANS), efflux rate constant (Kep), and extracellular volume ratio (Ve) from mpMR images, and SUVmean and SUVmax from PET images. Eight radiomic features were selected out of 109 radiomic features from T2w, ADC and PET images. Quantitative parameters or radiomic features, with risk factors of age, prostate-specific antigen (PSA), PSA density and volume, of 45 different lesion inputs were input in different combinations into four ML models - Decision Tree (DT), Support Vector Machine (SVM), k-Nearest-Neighbour (kNN), Ensembles model (EM). RESULTS: SUVmax yielded the highest accuracy in discriminating detected lesions. Among the 4 ML models, kNN yielded the highest accuracies of 0.929 using either quantitative parameters or radiomic features with risk factors as input. CONCLUSIONS: ML models' performance is dependent on the input combinations and risk factors further improve ML classification accuracy.

Magnetic field therapy enhances muscle mitochondrial bioenergetics and attenuates systemic ceramide levels following ACL reconstruction: Southeast Asian randomized-controlled pilot trial.

Background: Metabolic disruption commonly follows Anterior Cruciate Ligament Reconstruction (ACLR) surgery. Brief exposure to low amplitude and frequency pulsed electromagnetic fields (PEMFs) has been shown to promote in vitro and in vivo murine myogeneses via the activation of a calcium-mitochondrial axis conferring systemic metabolic adaptations. This randomized-controlled pilot trial sought to detect local changes in muscle structure and function using MRI, and systemic changes in metabolism using plasma biomarker analyses resulting from ACLR, with or without accompanying PEMF therapy. Methods: 20 patients requiring ACLR were randomized into two groups either undergoing PEMF or sham exposure for 16 weeks following surgery. The operated thighs of 10 patients were exposed weekly to PEMFs (1 â€‹mT for 10 â€‹min) for 4 months following surgery. Another 10 patients were subjected to sham exposure and served as controls to allow assessment of the metabolic repercussions of ACLR and PEMF therapy. Blood samples were collected prior to surgery and at 16 weeks for plasma analyses. Magnetic resonance data were acquired at 1 and 16 weeks post-surgery using a Siemens 3T Tim Trio system. Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) was utilized to monitor changes in high-energy phosphate metabolism (inorganic phosphate (Pi), adenosine triphosphate (ATP) and phosphocreatine (PCr)) as well as markers of membrane synthesis and breakdown (phosphomonoesters (PME) and phosphodiester (PDE)). Quantitative Magnetization Transfer (qMT) imaging was used to elucidate changes in the underlying tissue structure, with T1-weighted and 2-point Dixon imaging used to calculate muscle volumes and muscle fat content. Results: Improvements in markers of high-energy phosphate metabolism including reductions in ΔPi/ATP, Pi/PCr and (Pi â€‹+ â€‹PCr)/ATP, and membrane kinetics, including reductions in PDE/ATP were detected in the PEMF-treated cohort relative to the control cohort at study termination. These were associated with reductions in the plasma levels of certain ceramides and lysophosphatidylcholine species. The plasma levels of biomarkers predictive of muscle regeneration and degeneration, including osteopontin and TNNT1, respectively, were improved, whilst changes in follistatin failed to achieve statistical significance. Liquid chromatography with tandem mass spectrometry revealed reductions in small molecule biomarkers of metabolic disruption, including cysteine, homocysteine, and methionine in the PEMF-treated cohort relative to the control cohort at study termination. Differences in measurements of force, muscle and fat volumes did not achieve statistical significance between the cohorts after 16 weeks post-ACLR. Conclusion: The detected changes suggest improvements in systemic metabolism in the post-surgical PEMF-treated cohort that accords with previous preclinical murine studies. PEMF-based therapies may potentially serve as a manner to ameliorate post-surgery metabolic disruptions and warrant future examination in more adequately powered clinical trials. The Translational Potential of this Article: Some degree of physical immobilisation must inevitably follow orthopaedic surgical intervention. The clinical paradox of such a scenario is that the regenerative potential of the muscle mitochondrial pool is silenced. The unmet need was hence a manner to maintain mitochondrial activation when movement is restricted and without producing potentially damaging mechanical stress. PEMF-based therapies may satisfy the requirement of non-invasively activating the requisite mitochondrial respiration when mobility is restricted for improved metabolic and regenerative recovery.

Comparison of metrics for the evaluation of medical segmentations using prostate MRI dataset.

Nine previously proposed segmentation evaluation metrics, targeting medical relevance, accounting for holes, and added regions or differentiating over- and under-segmentation, were compared with 24 traditional metrics to identify those which better capture the requirements for clinical segmentation evaluation. Evaluation was first performed using 2D synthetic shapes to highlight features and pitfalls of the metrics with known ground truths (GTs) and machine segmentations (MSs). Clinical evaluation was then performed using publicly-available prostate images of 20 subjects with MSs generated by 3 different deep learning networks (DenseVNet, HighRes3DNet, and ScaleNet) and GTs drawn by 2 readers. The same readers also performed the 2D visual assessment of the MSs using a dual negative-positive grading of -5 to 5 to reflect over- and under-estimation. Nine metrics that correlated well with visual assessment were selected for further evaluation using 3 different network ranking methods - based on a single metric, normalizing the metric using 2 GTs, and ranking the network based on a metric then averaging, including leave-one-out evaluation. These metrics yielded consistent ranking with HighRes3DNet ranked first then DenseVNet and ScaleNet using all ranking methods. Relative volume difference yielded the best positivity-agreement and correlation with dual visual assessment, and thus is better for providing over- and under-estimation. Interclass Correlation yielded the strongest correlation with the absolute visual assessment (0-5). Symmetric-boundary dice consistently yielded good discrimination of the networks for all three ranking methods with relatively small variations within network. Good rank discrimination may be an additional metric feature required for better network performance evaluation.

Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation.

Transcranial direct current stimulation (tDCS) modulates cortical excitability and is being used for human studies more frequently. Here we probe the underlying neuronal mechanisms by measuring polarity-specific changes in neurotransmitter concentrations using magnetic resonance spectroscopy (MRS). MRS provides evidence that excitatory (anodal) tDCS causes locally reduced GABA while inhibitory (cathodal) stimulation causes reduced glutamatergic neuronal activity with a highly correlated reduction in GABA, presumably due to the close biochemical relationship between the two neurotransmitters.

Evaluation of Multimodal Algorithms for the Segmentation of Multiparametric MRI Prostate Images.

Prostate segmentation in multiparametric magnetic resonance imaging (mpMRI) can help to support prostate cancer diagnosis and therapy treatment. However, manual segmentation of the prostate is subjective and time-consuming. Many deep learning monomodal networks have been developed for automatic whole prostate segmentation from T2-weighted MR images. We aimed to investigate the added value of multimodal networks in segmenting the prostate into the peripheral zone (PZ) and central gland (CG). We optimized and evaluated monomodal DenseVNet, multimodal ScaleNet, and monomodal and multimodal HighRes3DNet, which yielded dice score coefficients (DSC) of 0.875, 0.848, 0.858, and 0.890 in WG, respectively. Multimodal HighRes3DNet and ScaleNet yielded higher DSC with statistical differences in PZ and CG only compared to monomodal DenseVNet, indicating that multimodal networks added value by generating better segmentation between PZ and CG regions but did not improve the WG segmentation. No significant difference was observed in the apex and base of WG segmentation between monomodal and multimodal networks, indicating that the segmentations at the apex and base were more affected by the general network architecture. The number of training data was also varied for DenseVNet and HighRes3DNet, from 20 to 120 in steps of 20. DenseVNet was able to yield DSC of higher than 0.65 even for special cases, such as TURP or abnormal prostate, whereas HighRes3DNet's performance fluctuated with no trend despite being the best network overall. Multimodal networks did not add value in segmenting special cases but generally reduced variations in segmentation compared to the same matched monomodal network.

Brain amyloid ß, cerebral small vessel disease, and cognition: A memory clinic study.

OBJECTIVE: To evaluate the association between brain amyloid ß (Aß) and cerebral small vessel disease (CSVD) markers, as well as their joint effect on cognition, in a memory clinic study. METHODS: A total of 186 individuals visiting a memory clinic, diagnosed with no cognitive impairment, cognitive impairment no dementia (CIND), Alzheimer dementia (AD), or vascular dementia were included. Brain Aß was measured by [11C] Pittsburgh compound B-PET global standardized uptake value ratio (SUVR). CSVD markers including white matter hyperintensities (WMH), lacunes, and cerebral microbleeds (CMBs) were graded on MRI. Cognition was assessed by neuropsychological testing. RESULTS: An increase in global SUVR is associated with a decrease in Mini-Mental State Examination (MMSE) in CIND and AD, as well as a decrease in global cognition Z score in AD, independent of age, education, hippocampal volume, and markers of CSVD. A significant interaction between global SUVR and WMH was found in relation to MMSE in CIND (P for interaction: 0.009), with an increase of the effect size of Aß (ß = -6.57 [-9.62 to -3.54], p < 0.001) compared to the model without the interaction term (ß = -2.91 [-4.54 to -1.29], p = 0.001). CONCLUSION: Higher global SUVR was associated with worse cognition in CIND and AD, but was augmented by an interaction between global SUVR and WMH only in CIND. This suggests that Aß and CSVD are independent processes with a possible synergistic effect between Aß and WMH in individuals with CIND. There was no interaction effect between Aß and lacunes or CMBs. Therefore, in preclinical phases of AD, WMH should be targeted as a potentially modifiable factor to prevent worsening of cognitive dysfunction.

Subtyping of circulating exosome-bound amyloid ß reflects brain plaque deposition.

Despite intense interests in developing blood measurements of Alzheimer's disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid ß (Aß) proteins - exosome-bound vs. unbound - directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aß aggregates preferentially bind with exosomes. We thus define a population of Aß as exosome-bound (Aß42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aß, the exosome-bound Aß measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.

Development of a Dedicated Rebinner with Rigid Motion Correction for the mMR PET/MR Scanner, and Validation in a Large Cohort of 11C-PIB Scans.

Head motion occurring during brain PET studies leads to image blurring and to bias in measured local quantities. The objective of this work was to implement a correction method for PET data acquired with the mMR synchronous PET/MR scanner. Methods: A list-mode-based motion-correction approach has been designed. The developed rebinner chronologically reads the recorded events from the Siemens list-mode file, applies the estimated geometric transformations, and frames the detected counts into sinograms. The rigid-body motion parameters were estimated from an initial dynamic reconstruction of the PET data. We then optimized the correction for 11C-Pittsburgh compound B (11C-PIB) scans using simulated and actual data with well-controlled motion. Results: An efficient list-mode-based motion correction approach has been implemented, fully optimized, and validated using simulated and actual PET data. The average spatial resolution loss induced by inaccuracies in motion parameter estimates and by the rebinning process was estimated to correspond to a 1-mm increase in full width at half maximum with motion parameters estimated directly from the PET data with a temporal frequency of 20 s. The results show that the rebinner can be safely applied to the 11C-PIB scans, allowing almost complete removal of motion-induced artifacts. The application of the correction method to a large cohort of 11C-PIB scans led to the following observations: first, that more than 21% of the scans were affected by motion greater than 10 mm (39% for subjects with Mini-Mental State Examination scores below 20), and second, that the correction led to quantitative changes in Alzheimer-specific cortical regions of up to 30%. Conclusion: The rebinner allows accurate motion correction at a cost of minimal resolution reduction. Application of the correction to a large cohort of 11C-PIB scans confirmed the necessity of systematically correcting for motion to obtain quantitative results.