Diurnal variability of cerebral metabolites in healthy human brain with 2D localized correlation spectroscopy (2D L-COSY).

BACKGROUND: Two-dimensional localized correlation spectroscopy (2D L-COSY) is a research tool that has been applied to evaluate in vivo metabolic activity in many neurological and oncological disorders. Circadian mediators such as brain temperature, hydration, and osmotic regulation have been claimed to change metabolic profiles. PURPOSE: To evaluate the diurnal variability of neuro-metabolites with 2D L-COSY in healthy subjects using a 3 T scanner. STUDY TYPE: Crossover. POPULATION/PHANTOM: Ten healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino." Field Strength/Sequence: 3 T/2D L-COSY MRS. ASSESSMENT: In vivo 2D L-COSY measurements were performed on ten healthy subjects (5 M/5F, mean age 36.1 ± 7.7 years) repeatedly at three timepoints (0700, 1200, and 1700) on the same day. in vitro evaluations were performed in a similar fashion as in vivo on Braino containing selected brain metabolites at physiological concentrations and pH. 2D L-COSY was acquired from a 27 cm3 voxel located in the posterior cingulate cortex. A total of 75 resonances were included in the analysis and spectral peak volumes were normalized to creatine. STATISTICAL TEST: One-way repeated measured analysis of variance with Bonferroni post-hoc adjustment using SPSS software. RESULTS: In vitro data showed no statistically significant differences between different scans (P > 0.12). in vivo results showed statistically significant diurnal variations (P ≤ 0.05, F > 3.88) for 22 resonances. Bonferroni post-hoc testing showed there was statistically significant increases in metabolite ratios between 0700 and 1700 and these include different moieties of N-acetylaspartate, creatine, choline, myo-inositol, lipids, fucose, glutathione, and homocarnosine. DATA CONCLUSION: 2D L-COSY can detect diurnal physiological variability in neuro-metabolite levels. Thus, time of the day should be considered when planning MRS studies to avoid confounding results. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:592-601.

Reliability of neurometabolite detection with two-dimensional localized correlation spectroscopy at 3T.

BACKGROUND: Two-dimensional localized correlational spectroscopy (2D L-COSY) has been applied in vivo to investigate metabolic profiles in many disorders due to its ability to detect several metabolites simultaneously. Successful application of this technique depends on the reliability of the detection and understanding of the variability result from test-retest measurements. PURPOSE: To evaluate the test-retest repeatability/reliability of 2D L-COSY in detecting brain metabolites in a phantom and healthy subjects in a 3T scanner. STUDY TYPE: Test-retest. POPULATION/PHANTOM: Six healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino". FIELD STRENGTH/SEQUENCE: 3T/2D L-COSY MRS. ASSESSMENT: Healthy subjects underwent eight weekly experiments over a period of 3 months with an intersession delay of 1 month after the first four measurements. Twenty-nine neurometabolite resonances (8 diagonal, 14 cross, and 7 composite resonances) were studied using a 27 cm3 voxel from the posterior cingulate cortex. In vitro evaluations were performed in a similar manner as in vivo on a Braino phantom containing brain metabolites at physiological concentrations and pH. STATISTICAL TESTS: Intra- and intersubject variability were measured. Test-retest repeatability was calculated using coefficient of variation (CV), and reliability was assessed with standard error measurement (SEM) and intraclass correlation coefficient (ICC), using SPSS software. RESULTS: The intra/inter CV for in vitro and in vivo data ranged from 0.01-0.23%/0.02-0.29% and 0.03-0.23%/0.04-0.39%, respectively. The major diagonal peaks showed ICC ranging from 0.31 to 0.93, while the ICC for cross peaks were 0.09-0.87. The SEM for in vivo data ranged from 0.0016 to 0.08. The interweek interval may have a positive effect on metabolite ratios (P = 0.08; F = 1.78). DATA CONCLUSION: The low variability in metabolite concentration in this study shows a high level of reliability of 2D L-COSY in the human brain. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1559-1569.

Spinal multiparametric MRI and DEXA changes over time in men with prostate cancer treated with androgen deprivation therapy: a potential imaging biomarker of treatment toxicity.

OBJECTIVES: To explore changes in bone mineral density (BMD) measured by DEXA and MRS fat fraction (FF), Dixon FF, and ADC in lower spinal vertebral bodies in men with prostate cancer treated with androgen deprivation therapy (ADT). METHODS: Twenty-eight men were enrolled onto a clinical trial. All received ADT. DEXA imaging was performed at baseline and 12 months. L-spine MRI was done at baseline and 6 months. RESULTS: The number of patients who underwent DEXA, Dixon, ADC, and MRS at baseline/follow-up were 28/27, 28/26, 28/26, and 22/20. An increase in FF was observed from T11 to S2 (average 1 %/vertebra). There was a positive correlation between baseline MRS FF and Dixon FF (r = 0.85, p < 0.0001) and a negative correlation between MRS FF and ADC (r = -0.56, p = 0.036). Over 6 months, MRS FF increased by a median of 25 % in relative values (p = 0.0003), Dixon FF increased (p < 0.0001) and ADC values decreased (p = 0.0014). Men with >5 % BMD loss after 1 year had triple the percentage increase in MRS FF at 6 months (61.1 % vs. 20.9 %, p = 0.19). CONCLUSIONS: Changes are observed on L-spine MRI after 6 months of ADT. Further investigation is warranted of MRS change as a potential predictive biomarker for later BMD loss. KEY POINTS: • Spinal marrow fat fraction increases after 6 months of androgen deprivation therapy. • More inferior vertebral bodies tend to have higher fat fractions. • MRS fat fraction changes were associated with later changes in DEXA BMD.

Lipid and Metabolite Deregulation in the Breast Tissue of Women Carrying BRCA1 and BRCA2 Genetic Mutations.

PURPOSE: To use localized correlated spectroscopy (COSY) to assess for an altered biochemical state or states in breast tissue of women with BRCA gene mutations that potentially constitute preinvasive conditions. MATERIALS AND METHODS: Institutional review board approval was obtained. Participants provided written informed consent. In vivo localized COSY images were recorded at 3 T in the breast tissue of women carrying BRCA1 (n = 9) or BRCA2 (n = 14) gene mutations and were compared with images in healthy control subjects with no family history of breast cancer (n = 10). All participants underwent contrast material-enhanced MR imaging and ultrasonography (US). Statistical significance was calculated with the Mann-Whitney two-sided nonparametric test. RESULTS: No abnormality was recorded with MR imaging or US. Metabolite levels in the BRCA1 cohort were reduced by 79% (P = .014) when compared with triglycerides level, and there was a 19% increase in lipid unsaturation and triglyceride levels (P = .027 and P = .086, respectively) when compared with cellular cholesterol level. Cholesterol level was reduced by 47% (P = .027) when compared with diallylic lipid level. Metabolite levels in the BRCA2 cohort showed increased unsaturation of 21% (P = .030) relative to triglycerides level. Comparison of the BRCA1 and BRCA2 cohorts showed a 47% (P = .002) increase in cholesterol level in the BRCA2 cohort when compared with diallylic lipid level and a 52% (P = .003) increase when compared with triglycerides level. Levels of diallylic lipid, unsaturated lipid, triglycerides, and terminal methyl on the acyl chain are reduced by 46% (P = .002), 57% (P = .003), 66% (P = .003), and 29% (P = .010), respectively, when compared with cholesterol level. CONCLUSION: Localized COSY recorded significant changes in women with BRCA1 and BRCA2 gene mutations when compared with control subjects. If these changes are ultimately proven to be a premalignant stage, this method may prove useful in screening.

Multiparametric MRI as an outcome predictor for anal canal cancer managed with chemoradiotherapy.

BACKGROUND: Organ-preserving chemo-radiotherapy (CRT) is the standard of care for non-metastatic anal squamous cell carcinoma (SCC). The optimal dosing schedules are yet to be determined. To improve local control rates, dose escalation has been investigated but found to not increase efficacy at the expense of increased toxicity for an unselected patient population. Diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) Magnetic Resonance Imaging (MRI) performed during CRT have early data suggesting it to be an effective tool in predicting later tumour response for SCC in related body sites. By performing multi-parametric MRI (mpmMRI) incorporating standard morphological, DWI and DCE sequences, we aim to determine whether the early changes in multi-parametric parameters during CRT can predict for later response in anal SCC. This may create opportunities to investigate treatment adaptation, either intensification or de-escalation, during CRT. METHODS/DESIGN: This protocol describes a prospective non-interventional multi-centre single-arm clinical trial. Twenty eligible patients with histologically confirmed non-metastatic anal SCC will receive standard definitive CRT and undergo multi-parametric MRI's at the following 4 time points; prior to treatment, during the second and fourth weeks of treatment and 6-8 weeks following treatment. Complete response will be defined by the absence of tumour persistence or recurrence as determined by clinical examination at 6 months. Images will be retrospectively analysed to determine the apparent diffusion coefficient and tumour perfusion coefficients (Ktrans and Kep) at each time point. The Mann-Whitney-Wilcoxon Test will be utilised to compare the change in these parameters for responder's verses non-responders. DISCUSSION: If validated, mpmMRI, along with other risk factors, can be used to stratify patients and guide radiation dosing in a prospective trial. Informed individualisation of treatment intensity should help us achieve our goals of improved efficacy and reduced toxicity. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614001219673 (19/11/2014).

Investigation on the performance of dedicated radiotherapy positioning devices for MR scanning for prostate planning.

The purpose of this study was to investigate performance of the couch and coil mounts designed for MR-simulation prostate scanning using data from ten volunteers. Volunteers were scanned using the standard MR scanning protocol with the MR coil directly strapped on the external body and the volunteer lying on the original scanner table. They also were scanned using a MR-simulation table top and pelvic coil mounts. MR images from both setups were compared in terms of body contour variation and image quality effects within particular organs of interest. Six-field conformal plans were generated on the two images with assigned bulk density for dose calculation. With the MR-simulation devices, the anterior skin deformation was reduced by up to 1.7 cm. The hard tabletop minimizes the posterior body deformation which can be up to 2.3 cm on the standard table, depending on the weight of volunteer. The image signal-to-noise ratio reduced by 14% and 25% on large field of view (FOV) and small FOV images, respectively, after using the coil mount; the prostate volume contoured on two images showed difference of 1.05 ± 0.66 cm3. The external body deformation caused a mean dose reduction of 0.6 ± 0.3 Gy, while the coverage reduced by 22% ± 13% and 27% ± 6% in V98 and V100, respectively. A dedicated MR simulation setup for prostate radiotherapy is essential to ensure the agreement between planning anatomy and treatment anatomy. The image signal was reduced after applying the coil mount, but no significant effect was found on prostate contouring.

Diffusion tensor imaging changes of the cortico-thalamic-striatal tracts correlate with fatigue and disability in people with relapsing-remitting MS.

PURPOSE: To investigate how the microstructural neural integrity of cortico-thalamic-striatal (CTS) tracts correlate with fatigue and disability over time. The primary outcome was diffusion tensor imaging (DTI) metrics change over time, and the secondary outcome was correlations with fatigue and disability in people with RRMS (pw-RRMS). METHODS: 76 clinically stable pw-RRMS and 43 matched healthy controls (HCs). The pw-RRMS cohort consisted of three different treatment subgroups. All participants underwent disability, cognitive, fatigue and mental health assessments. Structural and diffusion scans were performed at baseline (BL) and 2-year follow-up (2-YFU) for all participants. Fractional anisotropy (FA), mean, radial and axial diffusivities (MD, RD, AD) of normal-appearing white matter (NAWM) and white matter lesion (WML) in nine tracts-of-interests (TOIs) were estimated using our MRtrix3 in-house pipeline. RESULTS: We found significant BL and 2-YFU differences in most diffusion metrics in TOIs in pw-RRMS compared to HCs (pFDR ≤ 0.001; false-detection-rate (FDR)-corrected). There was a significant decrease in WML diffusivities and an increase in FA over the follow-up period in most TOIs (pFDR ≤ 0.001). Additionally, there were no differences in DTI parameters across treatment groups. AD and MD were positively correlated with fatigue scores (r ≤ 0.33, p ≤ 0.01) in NAWM-TOIs, while disability (EDSS) was negatively correlated with FA in most NAWM-TOIs (|r|≤0.31, p ≤ 0.01) at both time points. Disability scores correlated with all diffusivity parameters (r ≤ 0.29, p ≤ 0.01) in most WML-TOIs at both time points. CONCLUSION: Statistically significant changes in diffusion metrics in WML might be indicative of integrity improvement over two years in CTS tracts in clinically stable pw-RRMS. This finding represents structural changes within lesioned tracts. Measuring diffusivity in pw-RRMS affected tracts might be a relevant measure for future remyelination clinical trials.

Determination of hepatic extraction fraction with gadoxetate low-temporal resolution DCE-MRI-based deconvolution analysis: validation with ALBI score and Child-Pugh class.

INTRODUCTION: In this study, we aimed to investigate the feasibility of gadoxetate low-temporal resolution (LTR) DCE-MRI for voxel-based hepatic extraction fraction (HEF) quantification for liver sparing radiotherapy using a deconvolution analysis (DA) method. METHODS: The accuracy and consistency of the deconvolution implementation in estimating liver function was first assessed using simulation data. Then, the method was applied to DCE-MRI data collected retrospectively from 64 patients (25 normal liver function and 39 cirrhotic patients) to generate HEF maps. The normal liver function patient data were used to measure the variability of liver function quantification. Next, a correlation between HEF and ALBI score (a new model for assessing the severity of liver dysfunction) was assessed using Pearson's correlation. Differences in HEF between Child-Pugh score classifications were assessed for significance using the Kruskal-Wallis test for all patient groups and Mann-Whitney U-test for inter-groups. A statistical significance was considered at a P-value <0.05 in all tests. RESULTS: The results showed that the implemented method accurately reproduced simulated liver function; root-mean-square error between estimated and simulated liver response functions was 0.003, and the coefficient-of-variance of HEF was <20%. HEF correlation with ALBI score was r = -0.517, P < 0.0001, and HEF was significantly decreased in the cirrhotic patients compared to normal patients (P < 0.0001). Also, HEF in Child-Pugh B/C was significantly lower than in Child-Pugh A (P = 0.024). CONCLUSION: The study demonstrated the feasibility of gadoxetate LTR-DCE MRI for voxel-based liver function quantification using DA. HEF could distinguish between different grades of liver function impairment and could potentially be used for functional guidance in radiotherapy.

Neural diffusion tensor imaging metrics correlate with clinical measures in people with relapsing-remitting MS.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) can detect microstructural changes of white matter in multiple sclerosis (MS) and might clarify mechanisms responsible for disability. Thus, we aimed to compare DTI metrics in relapsing-remitting MS patients (RRMS) with healthy controls (HCs), and explore the correlations between DTI metrics, total brain white matter (TBWM) and white matter lesion (WML) with clinical parameters compared to volumetric measures. MATERIAL AND METHODS: 37 RRMS patients and 19 age/sex-matched HCs were included. All participants had clinical assessments, structural and diffusion scans on a 3T MRI. Volumetric and white matter DTI metrics; fractional anisotropy (FA), mean, radial and axial diffusivities (MD, RD and AD) were estimated and correlated with clinical parameters. The mean group differences were calculated using t-tests, and univariate correlations with Pearson correlation coefficients. RESULTS: Compared to HCs, statistically significant increases in MD (+3.6%), RD (+4.8%), AD (+2.7%) and a decrease in FA (-4.3%) for TBWM in RRMS was observed (p < .01). MD and RD in TBWM and AD in WML correlated moderately with disability status. Volumetric segmentation indicated a decrease in the total brain volume, GM and WM(-5%) with a reciprocal increase in CSF(+26%) in RRMS(p < .01). Importantly, DTI parameters showed a medium correlation with cognitive domains in contrast to white matter-related volumetric measurements in RRMS(Pearson correlation, p < .05). CONCLUSIONS: Our study shows a correlation of DTI metrics with clinical symptoms of MS, in particular cognition. More generally, these findings indicated that DTI is a useful and unique technique for evaluating the clinical features of white matter disease and warrants further investigation into its clinical role.

Assessing the impact of magnetic resonance treatment simulation (MRSIM) on target volume delineation and dose to organs at risk for oropharyngeal radiotherapy.

INTRODUCTION: Assessing the use of a radiation therapy (RT) planning MRI performed in the treatment position (pMRI) on target volume delineation and effect on organ at risk dose for oropharyngeal cancer patients planned with diagnostic MRI (dMRI) and CT scan. METHODS: Diagnostic MRI scans were acquired for 26 patients in a neutral patient position using a 3T scanner (dMRI). Subsequent pMRI scans were acquired on the same scanner with a flat couch top and the patient in their immobilisation mask. Each series was rigidly registered to the patients planning CT scan and volumes were first completed with the CT/dMRI. The pMRI was then made available for volume modification. For the group with revised volumes, two IMRT plans were developed to demonstrate the impact of the modification. Image and registration quality was also evaluated. RESULTS: The pMRI registration led to the modification of target volumes for 19 of 26 participants. The pMRI target volumes were larger in absolute volume resulting in reduced capacity for organ sparing. Predominantly, modifications occurred for the primary gross tumour volume (GTVp) with a mean Dice Similarity Coefficient (DSC) of 0.7 and the resulting high risk planning target volume, a mean DSC of 0.89. Both MRIs scored similarly for image quality, with the pMRI demonstrating improved registration quality and efficiency. CONCLUSIONS: A pMRI provides improvement in registration efficiency, quality and a higher degree of oncologist confidence in target delineation. These results have led to a practice change within our department, where a pMRI is acquired for all eligible oropharyngeal cancer patients.

Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue.

PURPOSE: Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as  γ-aminobutyric acid (GABA) and glutamine + glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients. METHODS: 24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices. Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS). RESULTS: RRMS patients had higher fatigue scores relative to HC (p ≤  0.05). Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p =  0.04). Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p =  0.008) and Glx (r = 0.511, p =  0.018) in PFC. Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p ≤  0.04) and positively with PFC Glx (r = 0.480, p =  0.028). CONCLUSION: The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.

Biochemical Correlations with Fatigue in Multiple Sclerosis Detected by MR 2D Localized Correlated Spectroscopy.

BACKGROUND AND PURPOSE: Fatigue is the common symptom in patients with multiple sclerosis (MS), yet its pathophysiological mechanism is poorly understood. We investigated the metabolic changes in fatigue in a group of relapsing-remitting MS (RRMS) patients using MR two-dimensional localized correlated spectroscopy (2D L-COSY). METHODS: Sixteen RRMS and 16 healthy controls were included in the study. Fatigue impact was assessed with the Modified Fatigue Impact Scale (MFIS). MR 2D L-COSY data were collected from the posterior cingulate cortex. Nonparametric statistical analysis was used to calculate the changes in creatine scaled metabolic ratios and their correlations with fatigue scores. RESULTS: Compared to healthy controls, the RRMS group showed significantly higher fatigue and lower metabolic ratios for tyrosine, glutathione, homocarnosine (GSH+Hca), fucose-3, glutamine+glutamate (Glx), glycerophosphocholine (GPC), total choline, and N-acetylaspartate (NAA-2), while increased levels for isoleucine and glucose (P ≤ .05). Only GPC showed positive correlation with all fatigue domains (r = .537, P ≤ .05). On the other hand, Glx-upper, NAA-2, GSH+Hca, and fucose-3 showed negative correlations with all fatigue domains (r = -.345 to -.580, P ≤ .05). While tyrosine showed positive correlation with MFIS (r = .499, P ≤ .05), cognitive fatigue was negatively correlated with total GSH (r = -.530, P ≤ .05). No correlations were found between lesion load or brain volumes with fatigue score. CONCLUSIONS: Our results suggest that fatigue in MS is strongly correlated with an imbalance in neurometabolites but not structural brain measurements.

A prospective, multi-centre trial of multi-parametric MRI as a biomarker in anal carcinoma.

BACKGROUND AND PURPOSE: To investigate the role of multi-parametric magnetic resonance imaging (MP-MRI) as a biomarker for squamous cell carcinoma of the anal canal (SCCAC). MATERIALS AND METHODS: From January 2013 to January 2017, 25 patients with non-metastatic SCCAC were enrolled in a multi-centre prospective clinical trial, of whom 20 completed protocol treatment. MP-MRIs, incorporating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) sequences, were performed before (baseline), during the second and fourth weeks of chemo-radiotherapy (CRT), and 8 weeks following treatment completion. Histogram analysis of multi-parametric maps generated maximum, mean, median, minimum, skewness, kurtosis, and standard deviation metrics. Exact logistic regression and ROC AUC analyses were performed for each metric at every timepoint. An elastic net LASSO logistic regression was also performed using all measures at each timepoint. RESULTS: With a median follow up of 17.1 months, 3/20 patients had a local recurrence, and 5/20 had any recurrence. Several apparent diffusion coefficient (ADC) metrics extracted from DW-MRIs correlated with local recurrence and demonstrated excellent discrimination: baseline skewness (p = 0.04, ROC AUC 0.90) and standard deviation (SD) (p = 0.02, ROC AUC 0.90), week 2 skewness (p = 0.02, ROC AUC 0.91) and SD (p = 0.01, ROC AUC 0.94), week 4 kurtosis (p = 0.01, AUC 0.92) and SD (p = 0.01, ROC AUC 0.96). Changes in minimum ADC between baseline and week 2 (p = 0.02, ROC AUC 0.94) and baseline and week 4 (p = 0.02, ROC AUC 0.94) were prognostic for local recurrence. For prediction of any recurrence, ADC minimum (p = 0.02, ROC AUC 0.87) and SD (p = 0.01, ROC AUC 0.85) at baseline, and ADC maximum (p = 0.03, ROC AUC 0.77) and SD (p = 0.02, ROC AUC 0.81) at week 4 were significant. On LASSO logistic regression, ADC minimum and SD at baseline were retained for any recurrence. The only significant finding for DCE-MRI was a correlation of k-trans min at the second follow-up with local recurrence (p = 0.05, AUC 0.84). CONCLUSION: Several ADC parameters at various time points correlate with recurrence suggesting DW-MRI is a potential biomarker for SCCAC.

Evaluation of MS related central fatigue using MR neuroimaging methods: Scoping review.

BACKGROUND: Fatigue is a common and debilitating symptom in multiple sclerosis (MS). Over the past decade, a growing body of research has focussed on the pathophysiological mechanisms underlying central (cognitive and physical) fatigue in MS. The precise mechanisms causing fatigue in MS patients are complex and poorly understood, and may differ between patients. Advanced quantitative magnetic resonance imaging (MRI) techniques allow for objective assessment of disease pathology and have been used to characterise the pathophysiology of central fatigue in MS. OBJECTIVE: To systematically review the existing literature of MRI-based studies assessing the pathophysiological mechanisms of MS-related central fatigue. METHODS: A systematic literature search of four major databases (PubMed, Medline, Embase, Scopus and Google Scholar) was conducted to identify MRI-based studies of MS-related fatigue published in the past 20 years. Studies using the following MRI-based methods were included: structural (lesion load/atrophy), T1 relaxation time/magnetisation transfer ratio (MTR), diffusion tensor imaging (DTI), functional MRI (fMRI) and magnetic resonance spectroscopy (MRS). RESULTS: A total of 92 studies were identified as meeting the search criteria and included for review. Structurally, regional gray/white matter atrophy, cortical thinning, decreased T1 relaxation times and reduced fractional anisotropy were associated with central fatigue in MS. Functionally, hyperactivity and reduced functional connectivity in several regional areas of frontal, parietal, occipital, temporal and cerebellum were suggested as causes of central fatigue. Biochemically, a reduction in N-acetyl aspartate/creatine and increased (glutamine+glutamate)/creatine ratios were correlated with fatigue severity in MS. CONCLUSION: Several advanced quantitative MRI methods have been employed in the study of central fatigue in MS. Central fatigue in MS is associated with macro/microstructural and functional changes within specific brain regions (frontal, parietal, temporal and deep gray matter) and specific pathways/networks (cortico-cortical and cortico-subcortical). Alternations in the cortico-striatal-thalamocortical (CSTC) loop are correlated with the development of fatigue in MS patients.

Assessment and predictors of fatigue in men with prostate cancer receiving radiotherapy and androgen deprivation therapy.

INTRODUCTION: Fatigue is a commonly reported symptom in men receiving radiation therapy and androgen deprivation therapy (ADT) for prostate cancer. Despite this, the complex mechanisms remain unclear. This study aims to investigate factors which correlate with development of fatigue. METHODS: Twenty-seven men with high-risk prostate cancer undergoing radiation therapy and 18 months of ADT were assessed for fatigue, haemoglobin (Hb), testosterone, magnetic resonance imaging (MRI) fat fraction (FF) and apparent diffusion coefficient (ADC), at baseline and at intervals after radiotherapy. Changes from baseline were analysed using paired t-tests. Linear time trends were assessed using linear mixed effect models. RESULTS: Overall, mean fatigue score increased from baseline to the 18-month time interval (difference 4.5, P = 0.0114). The mean value for Hb significantly decreased (P < 0.001) from baseline to 18 months. The mean value for testosterone significantly decreased (P < 0.001) from baseline to 12 months, and remained low. Mean for MRI FF showed a significant increase (P < 0.001) from baseline to 6 months. MRI ADC showed a non-significant decrease from baseline to 6 months (P = 0.4416). CONCLUSION: Radiotherapy and ADT resulted in a significant increase in fatigue scores. Statistically significant changes were noted in Hb, testosterone and MRI FF and ADC, however, none were shown to have a strong association with worsening fatigue. Further investigation in a larger cohort is required to assess the interaction between fatigue and possible biological factors.

2D in-vivo L-COSY spectroscopy identifies neurometabolite alterations in treated multiple sclerosis.

BACKGROUND: We have applied in vivo two-dimensional (2D) localized correlation spectroscopy (2D L-COSY), in treated relapsing relapsing-remitting multiple sclerosis (RRMS) to identify novel biomarkers in normal-appearing brain parenchyma. METHODS: 2D L-COSY magnetic resonance spectroscopy (MRS) spectra were prospectively acquired from the posterior cingulate cortex (PCC) in 45 stable RRMS patients undergoing treatment with Fingolimod, and 40 age and sex-matched healthy control (HC) participants. Average metabolite ratios and clinical symptoms including, disability, cognition, fatigue, and mental health parameters were measured, and compared using parametric and nonparametric tests. Whole brain volume and MRS voxel morphometry were evaluated using SIENAX and the SPM LST toolbox. RESULTS: Despite the mean whole brain lesion volume being low in this RRMS group (6.8 ml) a significant reduction in PCC metabolite to tCr ratios were identified for multiple N-acetylaspartate (NAA) signatures, gamma-aminobutyric acid (GABA), glutamine and glutamate (Glx), threonine, and isoleucine/lipid. Of the clinical symptoms measured, visuospatial function, attention, and memory were correlated with NAA signatures, Glx, and isoleucine/lipid in the brain. CONCLUSIONS: 2D L-COSY has the potential to detect metabolic alterations in the normal-appearing MS brain. Despite examining only a localised region, we could detect metabolic variability associated with symptoms.

A Modified Reach-to-Grasp Task in a Supine Position Shows Coordination Between Elbow and Hand Movements After Stroke.

Objective: A modified reach-to-grasp task has been developed for the purpose of investigating arm-hand coordination in a supine position in the functional magnetic resonance imaging environment. The objective of this study was to investigate the kinematics of the reach-to-grasp task, in stroke and healthy participants. Design: Observational cohort study. Setting: Movement laboratory. Participants: Ten stroke participants and 10 age-matched healthy participants performed 10 repetitions of the modified reach-to-grasp task in two conditions-a natural condition and a standardized condition in a splint. Intervention: Not applicable. Main Outcome Measures: Kinematic variables of start time of transport, start time of aperture, movement duration, time of peak velocity (PV), percentage time of PV, peak deceleration (PD), percentage time of PD, peak aperture (PA), time of PA, and percentage time of PA were recorded. The correlation between key events in the grasp and transport trajectories were investigated. Performance between conditions and groups were compared. Results: Both groups demonstrated a significant correlation between the start time of aperture and the start time of transport and between the time of PA and PV in both conditions. A significant correlation was found between the time of PA and the PD in both conditions for the healthy group, but in neither condition for the stroke group. Movements by participants with stroke had a significantly longer movement duration, a smaller PV, and an earlier absolute time of PV and PD, and an earlier percentage time of PV and PD. They also had a smaller aperture than healthy participants. Wearing the splint resulted in a significantly higher PV, later absolute and percentage time of PV, PD, and PA, and a smaller PA compared to moving without the splint. The timing of transport variables time to peak velocity and time to peak deceleration, were strongest determinants of movement duration. Conclusion: The modified reach-to-grasp movement performed without the constraint of the splint, demonstrates similar motor control and coordination between the grasp and transport components of reach-to-grasp as in seated reach-to-grasp. This provides a new task that may be used to explore reach-to-grasp in the fMRI environment.

Diurnal stability and long-term repeatability of neurometabolites using single voxel 1H magnetic resonance spectroscopy.

PURPOSE: This study was designed to evaluate the diurnal stability and long-term repeatability and reliability of one-dimensional (1D) hydrogen magnetic resonance spectroscopy (1H-MRS) in vitro and in vivo at 3 T. MATERIAL AND METHOD: A standard brain phantom was used for in vitro study. In vivo diurnal evaluation involved ten healthy subjects, while repeatability study involved six subjects. MRS was acquired from posterior cingulate gyrus (PCG), and processed with LCModel. Diurnal effects were assessed with repeated measures ANOVAs, repeatability was evaluated using coefficient of variation (CV), while reliability was assessed with standard error measurement (SEM) and intra-class correlation coefficient (ICC). RESULTS: Diurnal metabolic changes in vitro were non-significant. The intra/inter-in vitro CVs for the major metabolites; N-acetylaspartate (NAA), creatine (Cr), myo-inositol (mI), glutamate + glutamine (Glx) and total choline (tCho) were 1-3%/2-6%, respectively. Statistically significant in vivo diurnal effects were only seen for glycerophosphocholine (GPC, +10%, F = 10.6, p = 0.001) and Glx (+6%, F = 5.1, p = 0.018). The intra/inter-subject CVs for the major metabolites ranged from 2-5%/ 5-9%, respectively. The major metabolites displayed ICC ranging from 0.5-0.7 and low SEM (0.001-0.078) reflecting high reliability in detecting neurometabolites. The inter-week interval for in vivo measurements had minimal effect on metabolite ratios (F = 1.4, p = 0.09). CONCLUSION: In vitro MRS showed no diurnal effects and minimal variation in metabolite levels. Most PCG metabolites are not altered diurnally. The low in vivo variability of metabolite concentration supports the use of localised MRS on clinical 3 T scanners for reliable neurometabolic profiling of the brain.

Regression and statistical shape model based substitute CT generation for MRI alone external beam radiation therapy from standard clinical MRI sequences.

In MR only radiation therapy planning, generation of the tissue specific HU map directly from the MRI would eliminate the need of CT image acquisition and may improve radiation therapy planning. The aim of this work is to generate and validate substitute CT (sCT) scans generated from standard T2 weighted MR pelvic scans in prostate radiation therapy dose planning. A Siemens Skyra 3T MRI scanner with laser bridge, flat couch and pelvic coil mounts was used to scan 39 patients scheduled for external beam radiation therapy for localized prostate cancer. For sCT generation a whole pelvis MRI (1.6 mm 3D isotropic T2w SPACE sequence) was acquired. Patients received a routine planning CT scan. Co-registered whole pelvis CT and T2w MRI pairs were used as training images. Advanced tissue specific non-linear regression models to predict HU for the fat, muscle, bladder and air were created from co-registered CT-MRI image pairs. On a test case T2w MRI, the bones and bladder were automatically segmented using a novel statistical shape and appearance model, while other soft tissues were separated using an Expectation-Maximization based clustering model. The CT bone in the training database that was most 'similar' to the segmented bone was then transformed with deformable registration to create the sCT component of the test case T2w MRI bone tissue. Predictions for the bone, air and soft tissue from the separate regression models were successively combined to generate a whole pelvis sCT. The change in monitor units between the sCT-based plans relative to the gold standard CT plan for the same IMRT dose plan was found to be [Formula: see text] (mean ± standard deviation) for 39 patients. The 3D Gamma pass rate was [Formula: see text] (2 mm/2%). The novel hybrid model is computationally efficient, generating an sCT in 20 min from standard T2w images for prostate cancer radiation therapy dose planning and DRR generation.