Reliability of brain atrophy measurements in multiple sclerosis using MRI: an assessment of six freely available software packages for cross-sectional analyses.

PURPOSE: Volume measurement using MRI is important to assess brain atrophy in multiple sclerosis (MS). However, differences between scanners, acquisition protocols, and analysis software introduce unwanted variability of volumes. To quantify theses effects, we compared within-scanner repeatability and between-scanner reproducibility of three different MR scanners for six brain segmentation methods. METHODS: Twenty-one people with MS underwent scanning and rescanning on three 3 T MR scanners (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) to obtain 3D T1-weighted images. FreeSurfer, FSL, SAMSEG, FastSurfer, CAT-12, and SynthSeg were used to quantify brain, white matter and (deep) gray matter volumes both from lesion-filled and non-lesion-filled 3D T1-weighted images. We used intra-class correlation coefficient (ICC) to quantify agreement; repeated-measures ANOVA to analyze systematic differences; and variance component analysis to quantify the standard error of measurement (SEM) and smallest detectable change (SDC). RESULTS: For all six software, both between-scanner agreement (ICCs ranging 0.4-1) and within-scanner agreement (ICC range: 0.6-1) were typically good, and good to excellent (ICC > 0.7) for large structures. No clear differences were found between filled and non-filled images. However, gray and white matter volumes did differ systematically between scanners for all software (p < 0.05). Variance component analysis yielded within-scanner SDC ranging from 1.02% (SAMSEG, whole-brain) to 14.55% (FreeSurfer, CSF); and between-scanner SDC ranging from 4.83% (SynthSeg, thalamus) to 29.25% (CAT12, thalamus). CONCLUSION: Volume measurements of brain, GM and WM showed high repeatability, and high reproducibility despite substantial differences between scanners. Smallest detectable change was high, especially between different scanners, which hampers the clinical implementation of atrophy measurements.

Fast T2 mapping using multi-echo spin-echo MRI: A linear order approach.

PURPOSE: Multi-echo spin-echo sequence is commonly used for T2 mapping. The estimated values using conventional exponential fit, however, are hampered by stimulated and indirect echoes leading to overestimation of T2 . Here, we present fast analysis of multi-echo spin-echo (FAMESE) as a novel approach to decrease the complexity of the search space, which leads to accelerated measurement of T2 . METHODS: We developed FAMESE based on mathematical analysis of the Bloch equations in which the search space dimension decreased to only one. Then, we tested it in both phantom and human brain. Bland-Altman plot was used to assess the agreement between the estimated T2 values from FAMESE and the ones estimated from single-echo spin-echo sequence. The reliability of FAMESE was assessed by intraclass correlation coefficients. In addition, we investigated the noise stability of the method in synthetic and experimental data. RESULTS: In both phantom and healthy participants, FAMESE provided accelerated and SNR-resistant T2 maps. The FAMESE had a very good agreement with the single-echo spin echo for the whole range of T2 values. The intraclass correlation coefficient values for FAMESE were excellent (ie, 0.9998 and 0.9860 < intraclass correlation coefficient < 0.9942 for the phantom and humans, respectively). CONCLUSION: Our developed method FAMESE could be considered as a candidate for rapid T2 mapping with a clinically feasible scan time.

Impact of opium dependency on clinical and neuropsychological indices of multiple sclerosis patients.

The aim of this study was to determine the effect of opium on clinical and neuropsychological parameters in multiple sclerosis (MS) patients with substance dependency. A cross-sectional study was conducted on MS patients in Rafsanjan, Iran. Forty opium-addict MS patients (10 males and 30 females) aged between 18 and 50 years were compared with 40 MS patients with no addiction. Word-Pair Learning, Mini-Mental State Examination (MMSE), Wisconsin Card-Sorting Test (WCST), Depression, Anxiety, Expanded Disability Status Scale (EDSS), Fatigue, and the Multiple Sclerosis Functional Composite (MSFC) were measured and compared in the two groups. The comparison of two groups showed a significant increase trait anxiety (P < 0.001), fatigue (P = 0.009) and significant decrease in the executive function (P = 0.003), MMSE (P = 0.003), and working memory (P < 0.001) in addicted MS. It indicates the better efficiency of processing in the non-addicted MS patients. The MSFC z-score also was significantly higher in the non-addicted group (P < 0.001). The opium addiction has a negative impact on the clinical and neuropsychological outcome in MS patients.

Cell tracking using (19)F magnetic resonance imaging: technical aspects and challenges towards clinical applications.

(19)F MRI is emerging as a new imaging technique for cell tracking. It is particularly attractive because of its potential for direct and precise cell quantification. The most important challenge towards in vivo applications is the sensitivity of the technique, i.e. the detection limit in a reasonable imaging time. Optimal sensitivity can be achieved with dedicated (19)F compounds together with specifically adapted hardware and acquisition methods. In this paper we introduce the (19)F MRI technique focusing on these key sensitivity issues and review the state-of-the-art of (19)F MRI and developments towards its clinical use. We calculate (19)F detection limits reported in preclinical cell and clinical (19)F drug studies in terms of tissue concentration in a 1 cm(3) voxel, as an alternate way to compare detection limits. We estimate that a tissue concentration of a few millimoles per litre (mM) of (19)F is required for a human study at a resolution of 1 cm(3).

Recent progress in migraine pathophysiology: role of cortical spreading depression and magnetic resonance imaging.

Migraine is characterised by debilitating pain, which affects the quality of life in affected patients in both the western and the eastern worlds. The purpose of this article is to give a detailed outline of the pathophysiology of migraine pain, which is one of the most confounding pathologies among pain disorders in clinical conditions. We critically evaluate the scientific basis of various theories concerning migraine pathophysiology, and draw insights from brain imaging approaches that have unraveled the prevalence of cortical spreading depression (CSD) in migraine. The findings supporting the role of CSD as a physiological substrate in clinical pain are discussed. We also give an exhaustive overview of brain imaging approaches that have been employed to solve the genesis of migraine pain, and its possible links to the brainstem, the neocortex, genetic endophenotypes, and pathogenetic factors (such as dopaminergic hypersensitivity). Furthermore, a roadmap is proposed to provide a better understanding of pain pathophysiology in migraine, to enable the development of strategies using leads from brain imaging studies for the identification of early biomarkers, efficient prognosis, and treatment planning, which eventually may help in alleviating some of the devastating impact of pain morbidity in patients afflicted with migraine.

The effects of a custom foot orthosis on dynamic plantar pressure in patients with chronic plantar fasciitis: A randomized controlled trial.

BACKGROUND: Plantar fasciitis is one of the most common causes of heel pain. The plantar fascia supports the longitudinal arch and absorbs ground reaction forces during the static and dynamic phase(s) of weight-bearing. The purpose of this randomized controlled trial study was to determine the effects of CAD/CAM foot orthoses that were designed based on the dynamic plantar pressure in patients with plantar fasciitis. METHODS: This study was performed on 34 patients with plantar fasciitis. Outcomes were compared based on plantar fascia thickness; peak pressure, mean pressure, and maximum force; and pain, activity of daily living, quality of life, and sports activity that were evaluated by ultrasound, plantar pressure platform, and the Foot and Ankle Outcome Score, respectively. The patients were randomly assigned into two groups: the experimental group (CAD/CAM orthoses and night splint) and the control group (night splint only). All data were recorded again after 4 weeks. RESULTS: Pain ( P = 0.002) and plantar fascia thickness ( P = 0.001) decreased significantly after 1 month of intervention. Activity of daily living ( P = 0.044) and quality of life ( P = 0.001) showed a significant increase. There was a trend in increasing peak pressure in all masking regions in both groups. The maximum force remarkably reduced in the experimental group in all regions. CONCLUSIONS: The results demonstrated that CAD/CAM foot orthoses designed based on dynamic plantar pressure with night splint can reduce the plantar fascia thickness and pain associated with plantar fasciitis and increase the activity of daily living, quality of life, and sports activity.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Pyrolytic carbon coating for cytocompatibility of titanium oxide nanoparticles: a promising candidate for medical applications.

Nanoparticles for biomedical use must be cytocompatible with the biological environment that they are exposed to. Current research has focused on the surface functionalization of nanoparticles by using proteins, polymers, thiols and other organic compounds. Here we show that inorganic nanoparticles such as titanium oxide can be coated by pyrolytic carbon (PyC) and that the coating has cytocompatible properties. Pyrolization and condensation of methane formed a thin layer of pyrolytic carbon on the titanium oxide core. The formation of the PyC shell retards coalescence and sintering of the ceramic phase. Our MTT assay shows that the PyC-coated particles are cytocompatible at employed doses.

Harmonization of multi-scanner in vivo magnetic resonance spectroscopy: ENIGMA consortium task group considerations.

Magnetic resonance spectroscopy is a powerful, non-invasive, quantitative imaging technique that allows for the measurement of brain metabolites that has demonstrated utility in diagnosing and characterizing a broad range of neurological diseases. Its impact, however, has been limited due to small sample sizes and methodological variability in addition to intrinsic limitations of the method itself such as its sensitivity to motion. The lack of standardization from a data acquisition and data processing perspective makes it difficult to pool multiple studies and/or conduct multisite studies that are necessary for supporting clinically relevant findings. Based on the experience of the ENIGMA MRS work group and a review of the literature, this manuscript provides an overview of the current state of MRS data harmonization. Key factors that need to be taken into consideration when conducting both retrospective and prospective studies are described. These include (1) MRS acquisition issues such as pulse sequence, RF and B0 calibrations, echo time, and SNR; (2) data processing issues such as pre-processing steps, modeling, and quantitation; and (3) biological factors such as voxel location, age, sex, and pathology. Various approaches to MRS data harmonization are then described including meta-analysis, mega-analysis, linear modeling, ComBat and artificial intelligence approaches. The goal is to provide both novice and experienced readers with the necessary knowledge for conducting MRS data harmonization studies.

Magnetic and relaxation properties of multifunctional polymer-based nanostructured bioferrofluids as MRI contrast agents.

A series of maghemite/polymer composite ferrofluids with variable magnetic core size, which show a good efficiency as MRI contrast agents, are presented. These ferrofluids are biocompatible and can be proposed as possible platforms for multifunctional biomedical applications, as they contain anchoring groups for biofunctionalization, can incorporate fluorescent dyes, and have shown low cellular toxicity. The magnetic properties of the ferrofluids have been determined by means of magnetization and ac susceptibility measurements as a function of temperature and frequency. The NMR dispersion profiles show that the low frequency behavior of the longitudinal relaxivity r(1) is well described by the heuristic model of (1)H nuclear relaxation induced by superparamagnetic nanoparticles proposed by Roch and co-workers. The contrast efficiency parameter, i.e., the nuclear transverse relaxivity r(2), for samples with d > 10 nm assumes values comparable with or better than the ones of commercial samples, the best results obtained in particles with the biggest magnetic core, d = 15 nm. The contrast efficiency results are confirmed by in vitro MRI experiments at ν = 8.5 MHz, thus allowing us to propose a set of optimal microstructural parameters for multifunctional ferrofluids to be used in MRI medical diagnosis.

Cortical control of aggression: GABA signalling in the anterior cingulate cortex.

Reduced top-down control by cortical areas is assumed to underlie pathological forms of aggression. While the precise underlying molecular mechanisms are still elusive, it seems that balancing the excitatory and inhibitory tones of cortical brain areas has a role in aggression control. The molecular mechanisms underpinning aggression control were examined in the BALB/cJ mouse model. First, these mice were extensively phenotyped for aggression and anxiety in comparison to BALB/cByJ controls. Microarray data was then used to construct a molecular landscape, based on the mRNAs that were differentially expressed in the brains of BALB/cJ mice. Subsequently, we provided corroborating evidence for the key findings from the landscape through 1H-magnetic resonance imaging and quantitative polymerase chain reactions, specifically in the anterior cingulate cortex (ACC). The molecular landscape predicted that altered GABA signalling may underlie the observed increased aggression and anxiety in BALB/cJ mice. This was supported by a 40% reduction of 1H-MRS GABA levels and a 20-fold increase of the GABA-degrading enzyme Abat in the ventral ACC. As a possible compensation, Kcc2, a potassium-chloride channel involved in GABA-A receptor signalling, was found increased. Moreover, we observed aggressive behaviour that could be linked to altered expression of neuroligin-2, a membrane-bound cell adhesion protein that mediates synaptogenesis of mainly inhibitory synapses. In conclusion, Abat and Kcc2 seem to be involved in modulating aggressive and anxious behaviours observed in BALB/cJ mice through affecting GABA signalling in the ACC.

Novel approaches using mesenchymal stem cells for curing peripheral nerve injuries.

Peripheral nerve injury (PNI) is a common life-changing disability of peripheral nervous system with significant socioeconomic consequences. Conventional therapeutic approaches for PNI have several drawbacks such as need to autologous nerve scarifying, surplus surgery, and difficult accessibility to donor nerve; therefore, other therapeutic strategies such as mesenchymal stem cells (MSCs) therapy are getting more interesting. MSCs have been proved to be safe and efficient in numerous degenerative diseases of central and peripheral nervous systems. In this paper, we review novel biotechnological advancements in treating PNI using MSCs.

Various strategies to improve efficacy of stem cell transplantation in multiple sclerosis: Focus on mesenchymal stem cells and neuroprotection.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which predominantly affect young adults and undergo heavy socioeconomic burdens. Conventional therapeutic modalities for MS mostly downregulate aggressive immune responses and are almost insufficient for management of progressive course of the disease. Mesenchymal stem cells (MSCs), due to both immunomodulatory and neuroprotective properties have been known as practical cells for treatment of neurodegenerative diseases like MS. However, clinical translation of MSCs is associated with some limitations such as short-life engraftment duration, little in vivo trans-differentiation and restricted accessibility into damaged sites. Therefore, laboratory manipulation of MSCs can improve efficacy of MSCs transplantation in MS patients. In this review, we discuss several novel approaches, which can potentially enhance MSCs capabilities for treating MS.

Carvacrol ameliorates experimental autoimmune encephalomyelitis through modulating pro- and anti-inflammatory cytokines.

AIM: The inflammatory process is a key step in multiple sclerosis (MS) development. Carvacrol exhibits various anti-inflammatory properties. We aimed to assess the Carvacrol effects on clinical manifestations and production of pro-inflammatory (IFN-γ, IL-6 and IL-17) and anti-inflammatory (TGF-ß, IL-4, and IL-10) cytokines in experimental autoimmune encephalomyelitis (EAE) as MS animal model. MAIN METHODS: EAE mice were treated with 5, 10 mg/kg dose of Carvacrol or vehicle, as the control EAE group, every other day until day-21 post EAE induction. On day22, the leukocyte infiltration within the CNS was estimated using hematoxylin-eosin staining. The cytokine production by splenocytes was determined after in vitro stimulating with myelin oligodendrocyte protein (MOG). KEY FINDINGS: The EAE clinical scores in 5 and 10 mg/kg Carvacrol-treated mice were lower than untreated group (P < 0.001 and P < 0.01, respectively). The amounts of IFN-γ and IL-6 production by splenocytes of 5 and 10 mg/kg Carvacrol-administered mice were lower than control group (P < 0.001, and P < 0.01 for IFN-γ respectively; P ˂ 0.05 for IL-6). Splenocytes of 5 and 10 mg/kg Carvacrol-treated mice produced higher levels of TGF-ß than untreated mice (P < 0.001). in splenocytes of 5 mg/kg Carvacrol-treated group the IL-10 production was higher while IL-17 secretion was lower than control group (both with P < 0.01). SIGNIFICANCE: Carvacrol exhibits modulatory effects on expression of pro- and anti-inflammatory cytokines. It ameliorates EAE clinical and pathological consequences and therefore its potentials may be considered in treating MS patients.

Novel imaging phantom for accurate and robust measurement of brain atrophy rates using clinical MRI.

Brain volume loss, or atrophy, has been proven to be an important characteristic of neurological diseases such as Alzheimer's disease and multiple sclerosis. To use atrophy rate as a reliable clinical biomarker and to increase statistical power in clinical treatment trials, measurement variability needs to be minimized. Among other sources, systematic differences between different MR scanners are suspected to contribute to this variability. In this study we developed and performed initial validation tests of an MR-compatible phantom and analysis software for robust and reliable evaluation of the brain volume loss. The phantom contained three inflatable models of brain structures, i.e. cerebral hemisphere, putamen, and caudate nucleus. Software to reliably quantify volumes form the phantom images was also developed. To validate the method, the phantom was imaged using 3D T1-weighted protocols at three clinical 3T MR scanners from different vendors. Calculated volume change from MRI was compared with the known applied volume change using ICC and mean absolute difference. As assessed by the ICC, the agreement between our developed software and the applied volume change for different structures ranged from 0.999-1 for hemisphere, 0.976-0.998 for putamen, and 0.985-0.999 for caudate nucleus. The mean absolute differences between measured and applied volume change were 109-332 µL for hemisphere, 2.9-11.9 µL for putamen, and 2.2-10.1 µL for caudate nucleus. This method offers a reliable and robust measurement of volume change using MR images and could potentially be used to standardize clinical measurement of atrophy rates.

Achillea millefolium is beneficial as an add-on therapy in patients with multiple sclerosis: A randomized placebo-controlled clinical trial.

BACKGROUND: Multiple sclerosis (MS) is a neurological disease for which to date there is no cure and the existing disease-modifying drugs just slow down the disease progression. PURPOSE: In this clinical trial we evaluated the efficacy of Achillea millefolium (A. millefolium) aqueous extract in MS patients. METHODS: A triple-blind randomized placebo-controlled parallel group trial was conducted on 75 MS patients. The patients were randomized into three groups including placebo and two groups receiving A. millefolium with two different doses, i.e. 250  mg/day and 500  mg/day, for 1 year. The primary outcome was the annualized relapse rate. Also, number and volume of lesions were obtained from magnetic resonance imaging (MRI) scans. Furthermore, we performed a comprehensive neurological and cognitive tests as follows: changes in the expanded disability status scale (EDSS), the multiple sclerosis functional composite (MSFC), fatigue severity scale (FSS), Ashworth spasticity assessment, Beck depression test, State-trait anxiety inventory (STAI), mini-mental status examination (MMSE), Wisconsin card sorting test (WCST), tower of London test (TOL), word-pair learning, paced auditory serial addition task (PASAT) and standard laboratory tests. RESULTS: This study showed one year administration of A. millefolium (both doses) decreased the annual relapse rate in MS patients. The mean volume change of lesions significantly decreased in the 500 mg A. millefolium group. The add-on therapy also increased time to first relapse and the MSFC z-score; it decreased the EDSS score and improved performance in word-pair learning, PASAT, and WCST. CONCLUSION: We found beneficial effects of A. millefolium aqueous extract as an add-on therapy in MS patients.

Converging evidence points towards a role of insulin signaling in regulating compulsive behavior.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with childhood onset, and is characterized by intrusive thoughts and fears (obsessions) that lead to repetitive behaviors (compulsions). Previously, we identified insulin signaling being associated with OCD and here, we aim to further investigate this link in vivo. We studied TALLYHO/JngJ (TH) mice, a model of type 2 diabetes mellitus, to (1) assess compulsive and anxious behaviors, (2) determine neuro-metabolite levels by 1 H magnetic resonance spectroscopy (MRS) and brain structural connectivity by diffusion tensor imaging (DTI), and (3) investigate plasma and brain protein levels for molecules previously associated with OCD (insulin, Igf1, Kcnq1, and Bdnf) in these subjects. TH mice showed increased compulsivity-like behavior (reduced spontaneous alternation in the Y-maze) and more anxiety (less time spent in the open arms of the elevated plus maze). In parallel, their brains differed in the white matter microstructure measures fractional anisotropy (FA) and mean diffusivity (MD) in the midline corpus callosum (increased FA and decreased MD), in myelinated fibers of the dorsomedial striatum (decreased FA and MD), and superior cerebellar peduncles (decreased FA and MD). MRS revealed increased glucose levels in the dorsomedial striatum and increased glutathione levels in the anterior cingulate cortex in the TH mice relative to their controls. Igf1 expression was reduced in the cerebellum of TH mice but increased in the plasma. In conclusion, our data indicates a role of (abnormal) insulin signaling in compulsivity-like behavior.

Urgent challenges in quantification and interpretation of brain grey matter atrophy in individual MS patients using MRI.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS.

Agreement of MSmetrix with established methods for measuring cross-sectional and longitudinal brain atrophy.

INTRODUCTION: Despite the recognized importance of atrophy in multiple sclerosis (MS), methods for its quantification have been mostly restricted to the research domain. Recently, a CE labelled and FDA approved MS-specific atrophy quantification method, MSmetrix, has become commercially available. Here we perform a validation of MSmetrix against established methods in simulated and in vivo MRI data. METHODS: Whole-brain and gray matter (GM) volume were measured with the cross-sectional pipeline of MSmetrix and compared to the outcomes of FreeSurfer (cross-sectional pipeline), SIENAX and SPM. For this comparison we investigated 20 simulated brain images, as well as in vivo data from 100 MS patients and 20 matched healthy controls. In fifty of the MS patients a second time point was available. In this subgroup, we additionally analyzed the whole-brain and GM volume change using the longitudinal pipeline of MSmetrix and compared the results with those of FreeSurfer (longitudinal pipeline) and SIENA. RESULTS: In the simulated data, SIENAX displayed the smallest average deviation compared with the reference whole-brain volume (+ 19.56 ± 10.34 mL), followed by MSmetrix (- 38.15 ± 17.77 mL), SPM (- 42.99 ± 17.12 mL) and FreeSurfer (- 78.51 ± 12.68 mL). A similar pattern was seen in vivo. Among the cross-sectional methods, Deming regression analyses revealed proportional errors particularly in MSmetrix and SPM. The mean difference percentage brain volume change (PBVC) was lowest between longitudinal MSmetrix and SIENA (+ 0.16 ± 0.91%). A strong proportional error was present between longitudinal percentage gray matter volume change (PGVC) measures of MSmetrix and FreeSurfer (slope = 2.48). All longitudinal methods were sensitive to the MRI hardware upgrade that occurred during the time of the study. CONCLUSION: MSmetrix, FreeSurfer, FSL and SPM show differences in atrophy measurements, even at the whole-brain level, that are large compared to typical atrophy rates observed in MS. Especially striking are the proportional errors between methods. Cross-sectional MSmetrix behaved similarly to SPM, both in terms of mean volume difference as well as proportional error. Longitudinal MSmetrix behaved most similar to SIENA. Our results indicate that brain volume measurement and normalization from T1-weighted images remains an unsolved problem that requires much more attention.

A data-driven statistical model that estimates measurement uncertainty improves interpretation of ADC reproducibility: a multi-site study of liver metastases.

Apparent Diffusion Coefficient (ADC) is a potential quantitative imaging biomarker for tumour cell density and is widely used to detect early treatment changes in cancer therapy. We propose a strategy to improve confidence in the interpretation of measured changes in ADC using a data-driven model that describes sources of measurement error. Observed ADC is then standardised against this estimation of uncertainty for any given measurement. 20 patients were recruited prospectively and equitably across 4 sites, and scanned twice (test-retest) within 7 days. Repeatability measurements of defined regions (ROIs) of tumour and normal tissue were quantified as percentage change in mean ADC (test vs. re-test) and then standardised against an estimation of uncertainty. Multi-site reproducibility, (quantified as width of the 95% confidence bound between the lower confidence interval and higher confidence interval for all repeatability measurements), was compared before and after standardisation to the model. The 95% confidence interval width used to determine a statistically significant change reduced from 21.1 to 2.7% after standardisation. Small tumour volumes and respiratory motion were found to be important contributors to poor reproducibility. A look up chart has been provided for investigators who would like to estimate uncertainty from statistical error on individual ADC measurements.