Thomas Lindqvist

Automated determination of brain parenchymal fraction in multiple sclerosis.

BACKGROUND AND PURPOSE: Brain atrophy is a manifestation of tissue damage in MS. Reduction in brain parenchymal fraction is an accepted marker of brain atrophy. In this study, the approach of synthetic tissue mapping was applied, in which brain parenchymal fraction was automatically calculated based on absolute quantification of the tissue relaxation rates R1 and R2 and the proton attenuation. MATERIALS AND METHODS: The BPF values of 99 patients with MS and 35 control subjects were determined by using SyMap and tested in relationship to clinical variables. A subset of 5 patients with MS and 5 control subjects were also analyzed with a manual segmentation technique as a reference. Reproducibility of SyMap was assessed in a separate group of 6 healthy subjects, each scanned 6 consecutive times. RESULTS: Patients with MS had significantly lower BPF (0.852 ± 0.0041, mean ± SE) compared with control subjects (0.890 ± 0.0040). Significant linear relationships between BPF and age, disease duration, and Expanded Disability Status Scale scores were observed (P < .001). A strong correlation existed between SyMap and the reference method (r = 0.96; P < .001) with no significant difference in mean BPF. Coefficient of variation of repeated SyMap BPF measurements was 0.45%. Scan time was <6 minutes, and postprocessing time was <2 minutes. CONCLUSIONS: SyMap is a valid and reproducible method for determining BPF in MS within a clinically acceptable scan time and postprocessing time. Results are highly congruent with those described using other methods and show high agreement with the manual reference method.

Evaluation of Automatic Measurement of the Intracranial Volume Based on Quantitative MR Imaging

BACKGROUND AND PURPOSE: Brain size is commonly described in relation to ICV, whereby accurate assessment of this quantity is fundamental. Recently, an optimized MR sequence (QRAPMASTER) was developed for simultaneous quantification of T1, T2, and proton density. ICV can be measured automatically within minutes from QRAPMASTER outputs and a dedicated software, SyMRI. Automatic estimations of ICV were evaluated against the manual segmentation. MATERIALS AND METHODS: In 19 healthy subjects, manual segmentation of ICV was performed by 2 neuroradiologists (Obs1, Obs2) by using QBrain software and conventional T2-weighted images. The automatic segmentation from the QRAPMASTER output was performed by using SyMRI. Manual corrections of the automatic segmentation were performed (corrected-automatic) by Obs1 and Obs2, who were blinded from each other. Finally, the repeatability of the automatic method was evaluated in 6 additional healthy subjects, each having 6 repeated QRAPMASTER scans. The time required to measure ICV was recorded. RESULTS: No significant difference was found between reference and automatic (and corrected-automatic) ICV (P > .25). The mean difference between the reference and automatic measurement was −4.84 ± 19.57 mL (or 0.31 ± 1.35%). Mean differences between the reference and the corrected-automatic measurements were −0.47 ± 17.95 mL (−0.01 ± 1.24%) and −1.26 ± 17.68 mL (−0.06 ± 1.22%) for Obs1 and Obs2, respectively. The repeatability errors of the automatic and the corrected-automatic method were <1%. The automatic method required 1 minute 11 seconds (SD = 12 seconds) of processing. Adding manual corrections required another 1 minute 32 seconds (SD = 38 seconds). CONCLUSIONS: Automatic and corrected-automatic quantification of ICV showed good agreement with the reference method. SyMRI software provided a fast and reproducible measure of ICV.

Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction

Background Neurofilament light (NFL) and Glial Fibrillary Acidic Protein (GFAP) are integral parts of the axonal and astrocytal cytoskeletons respectively and are released into the cerebrospinal fluid (CSF) in cases of cellular damage. In order to interpret the levels of these biomarkers in disease states, knowledge on normal levels in the healthy is required. Another biomarker for neurodegeneration is brain atrophy, commonly measured as brain parenchymal fraction (BPF) using magnetic resonance imaging (MRI). Potential correlations between levels of NFL, GFAP and BPF in healthy individuals have not been investigated. Objectives To present levels of NFL and GFAP in healthy individuals stratified for age, and investigate the correlation between them as well as their correlation with BPF. Methods The CSF was analysed in 53 healthy volunteers aged 21 to 70 (1 sample missing for GFAP analysis) and 48 of the volunteers underwent determination of BPF using MRI. Results Mean (±SD) NFL was 355 ng/L (±214), mean GFAP was 421 ng/L (±129) and mean BPF was 0.867 (±0.035). All three biomarkers correlated with age. NFL also correlated with both GFAP and BPF. When controlled for age, only the correlation between NFL and GFAP retained statistical significance. Conclusions This study presents data on age-stratified levels of NFL and GFAP in the CSF of healthy individuals. There is a correlation between levels of NFL and GFAP and both increase with age. A correlation between NFL and BPF was also found, but did not retain statistical significance if controlled for age.

Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally.

Objective: We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment. Methods: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 × 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2–3 months. Results: The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3–6 month period. Conclusions: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments. Classification of evidence: This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab

Objective: To describe the effects of switching treatment from ongoing first-line injectable therapies to rituximab on inflammatory activity measured by MRI and levels of CSF neurofilament light chain (CSF-NFL) in a cohort of patients with clinically stable relapsing-remitting multiple sclerosis (RRMS). Method: Seventy-five patients with clinically stable RRMS treated with the first-line injectables interferon-β (IFN-β) and glatiramer acetate (GA) at 3 Swedish centers were switched to rituximab in this open-label phase II multicenter study. After a run-in period of 3 months, 2 IV doses of 1,000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months. Results: The mean cumulated number of gadolinium-enhancing lesions per patient at months 3 and 6 after treatment shift to rituximab was reduced compared to the run-in period (0.028 vs 0.36, p = 0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per patient was reduced (0.01 vs 0.28, p = 0.004) and mean CSF-NFL levels were reduced by 21% (p = 0.01). Conclusions: For patients with RRMS, a treatment switch from IFN or GA to rituximab is associated with reduced inflammatory activity measured by MRI and CSF-NFL. Classification of evidence: This study provides Class IV evidence that rituximab has an equal or superior effect in reducing inflammatory activity in RRMS measured by MRI and CSF-NFL compared to first-line injectables during the first year after treatment shift.

Brain parenchymal fraction in an age-stratified healthy population : determined by MRI using manual segmentation and three automated segmentation methods

BACKGROUND AND PURPOSE Brain atrophy is a prominent feature in many neurodegenerative diseases, such as multiple sclerosis, but age-related decrease of brain volume occurs regardless of pathological neurodegeneration. Changes in brain volume can be described by use of the brain parenchymal fraction (BPF), most often defined as the ratio of total brain parenchyma to total intracranial space. The BPF is of interest both in research and in clinical practice. To be able to properly interpret this variable, the normal range of BPF must be known. The objective of this study is to present normal values for BPF, stratified by age, and compare manual BPF measurement to three automated methods. MATERIALS AND METHODS The BPFs of 106 healthy individuals aged 21 to 85 years were determined by the automated segmentation methods SyMap, VBM8 and SPM12. In a subgroup of 54 randomly selected individuals, the BPF was also determined by manual segmentation. RESULTS The median (IQR) BPFs of the whole study population were 0.857 (0.064), 0.819 (0.028) and 0.784 (0.073) determined by SyMap, VBM8 and SPM12, respectively. The BPF decreased with increasing age. The correlation coefficients between manual segmentation and SyMap, VBM8 and SPM12 were 0.93 (P<0.001), 0.77 (P<0.001) and 0.56 (P<0.001), respectively. CONCLUSIONS There was a clear relationship between increasing age and decreasing BPF. Knowledge of the range of normal BPF in relation to age group will help in the interpretation of BPF data. The automated segmentation methods displayed varying degrees of similarity to the manual reference, with SyMap being the most similar.