Accurate,rapid and reliable,fully automated MRI brainstem segmentation for application in multiple sclerosis and neurodegenerative diseases

Neurodegenerative disorders, such as Alzheimer's disease (AD) and progressive forms of multiple sclerosis (MS), can affect the brainstem and are associated with atrophy that can be visualized by MRI. Anatomically accurate, large‐scale assessments of brainstem atrophy are challenging due to lack of automated, accurate segmentation methods. We present a novel method for brainstem volumetry using a fully‐automated segmentation approach based on multi‐dimensional gated recurrent units (MD‐GRU), a deep learning based semantic segmentation approach employing a convolutional adaptation of gated recurrent units. The neural network was trained on 67 3D‐high resolution T1‐weighted MRI scans from MS patients and healthy controls (HC) and refined using segmentations of 20 independent MS patients' scans. Reproducibility was assessed in MR test–retest experiments in 33 HC. Accuracy and robustness were examined by Dice scores comparing MD‐GRU to FreeSurfer and manual brainstem segmentations in independent MS and AD datasets. The mean %‐change/SD between test–retest brainstem volumes were 0.45%/0.005 (MD‐GRU), 0.95%/0.009 (FreeSurfer), 0.86%/0.007 (manually edited segmentations). Comparing MD‐GRU to manually edited segmentations the mean Dice scores/SD were: 0.97/0.005 (brainstem), 0.95/0.013 (mesencephalon), 0.98/0.006 (pons), 0.95/0.015 (medulla oblongata). Compared to the manual gold standard, MD‐GRU brainstem segmentations were more accurate than FreeSurfer segmentations (p < .001). In the multi‐centric acquired AD data, the mean Dice score/SD for the MD‐GRU‐manual segmentation comparison was 0.97/0.006. The fully automated brainstem segmentation method MD‐GRU provides accurate, highly reproducible, and robust segmentations in HC and patients with MS and AD in 200 s/scan on an Nvidia GeForce GTX 1080 GPU and shows potential for application in large and longitudinal datasets.     

Monoclonal antibodies and recombinant immunoglobulins for the treatment of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory and degenerative disease leading to demyelination and axonal damage in the CNS. Autoimmunity plays a central role in MS pathogenesis. Per definition, monoclonal antibodies are recombinant biological compounds with a well defined target, thus carrying the promise of targeting pathogenic cells or molecules with high specificity, avoiding undesired off-target effects. Natalizumab was the first monoclonal antibody to be approved for the treatment of MS. Several other monoclonal antibodies are in development and have demonstrated promising efficacy in phase II studies. They can be categorized according to their mode of action into compounds targeting (i) leukocyte migration into the CNS (natalizumab); (ii) cytolytic antibodies (rituximab, ocrelizumab, ofatumumab, alemtuzumab); or (iii) antibodies and recombinant proteins targeting cytokines and chemokines and their receptors (daclizumab, ustekinumab, atacicept, tabalumab [Ly-2127399], secukinumab [AIN457]). In this review, we discuss the specific molecular targets, clinical efficacy and safety of these compounds and discuss criteria to anticipate the position of monoclonal antibodies in the diversifying armamentarium of MS therapy in the coming years.     

Altered functional adaptation to attention and working memory tasks with increasing complexity in relapsing-remitting multiple sclerosis patients

As attention, processing speed, and working memory seem to be fundamental for a broad range of cognitive performance, the present study on patients with mild forms of relapsing-remitting multiple sclerosis (RR-MS) focused on these domains. To explore subtle neuropsychological changes in either the clinical or fMRI domain, we applied a multistep experimental design with increasing task complexity to investigate global brain activity, functional adaptation, and behavioral responses to typical cognitive processes related to attention and working memory. Fifteen patients with RR-MS (mean age 38 years, 22-49 years, 9 females, mean disease duration 5.9 years (SD = 3.6 years), mean Expanded Disability Status Scale score, 2.3 (SD = 1.3) but without reported cognitive impairment), and 15 age-matched healthy controls (HC; mean age, 34 years, 23-50 years, 6 women) participated. After a comprehensive neuropsychological assessment, participants performed different fMRI experiments testing attention and working memory. In the neuropsychological assessment, patients showed only subtle reduction in learning and memory abilities. In the fMRI experiments, both groups activated the brain areas typically involved in attention and working memory. HC showed a linear in- or decrease in activation paralleling the changing task complexity. Patients showed stronger activation change at the level of the simple tasks and a subsequent saturation effect of (de-)activation at the highest task load. These group/task interaction differences were found in the right parahippocampal cortex and in the middle and medial frontal regions. Our results indicate that, in MS, functional adaptation patterns can be found which precede clinical evidence of apparent cognitive decline.     

Global N-acetylaspartate concentration in benign and non-benign multiple sclerosis patients of long disease duration

Background and objective

To examine whether clinically benign multiple sclerosis patients (BMS) show similar losses of their global N-acetylaspartate (NAA) neuronal marker relative to more clinically disabled patients of similar disease duration.

Methods

The whole-brain NAA concentration (WBNAA) was acquired with whole-head non-localizing proton MR spectroscopy. Fractional brain parenchymal volume (fBPV), T₂ and T₁ lesion loads, were obtained from the MRI in: (i) 24 BMS patients: 23.1 ± 7.2 years disease duration, median Expanded Disability Status Scale (EDSS) score of 2.0 (range: 0–3); (ii) 26 non-benign MS patients (non-BMS), 24.5 ± 7.4 years disease duration, median EDSS of 4.0 (range: 3.5–6.5); (iii) 15 healthy controls.

Results

Controls’ 12.4 ± 2.3 mM WBNAA was significantly higher than the BMS's and non-BMS's 10.5 ± 2.4 and 9.9 ± 2.1 mM (both p < 0.02), but the difference between the patients’ groups was not (p > 0.4). Likewise, the controls’ 81.2 ± 4.5% fBPV exceeded the BMS and non-BMS's 77.0 ± 5.8% and 76.3 ± 8.6% (p < 0.03), which were also not different from one another (p > 0.7). BMS patients’ T₁-hypointense lesion load, 2.1 ± 2.2 cm³, was not significantly different than the non-BMS's 4.1 ± 5.4 cm³ (p > 0.08) and T₂-hyperintense loads: 6.0 ± 5.7 cm³ and 8.7 ± 7.8 cm³, were also not different (p > 0.1).

Conclusions

WBNAA differentiates normal controls from MS patients but does not distinguish BMS from more disabled MS patients of similar disease duration. Nevertheless, all MS patients who remain RR for 15+ years suffered WBNAA loss similar to the average RR MS population at fourfold shorter disease duration suggesting relative global neuronal sparing or leveling-off of the neurodegeneration rate.     

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI--and patient--resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.     

Interferon-beta1b in the treatment of secondary progressive MS: impact on quality of life.

BACKGROUND: The recent randomized, controlled trial of interferon-beta1b (IFN-beta1b) in 718 patients with secondary progressive MS (SP-MS) demonstrated a significant effect on the development of disability as evaluated by the physician. Its effect on patient-reported health-related quality of life (HrQoL) is reported herein. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, outpatients with SP-MS scoring between 3.0 and 6.5 on the Expanded Disability Status Scale received either 8 x 10(6) IU of IFN-beta1b or placebo for up to 3 years. A range of outcomes was measured, including HrQoL, which was assessed using the Sickness Impact Profile (SIP), a self-report questionnaire validated for use in MS. Measurements were undertaken at baseline and at 6-monthly intervals thereafter for 36 months. RESULTS: A slight positive effect on the HrQoL of the IFN group in comparison with the placebo group was found, which reached significance in the physical scale of the SIP at 6 and 12 months and at last visit. There was moderate correlation between physician-assessed evaluation of change and patient-reported change. CONCLUSIONS: IFN-beta1b may delay sustained deterioration in patient-reported HrQoL in SP-MS. Methods of interpreting change in HrQoL are currently insufficiently developed to determine how clinically important these changes are for this population.