Longitudinal assessment of neurocognitive function in people with relapsing multiple sclerosis initiating alemtuzumab in routine clinical practice: LEM-COG study results.

BACKGROUND: Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS. METHODS: This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression. RESULTS: Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest. CONCLUSION: The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.

Rapid myelin water imaging for the assessment of cervical spinal cord myelin damage.

BACKGROUND: Rapid myelin water imaging (MWI) using a combined gradient and spin echo (GRASE) sequence can produce myelin specific metrics for the human brain. Spinal cord MWI could be similarly useful, but technical challenges have hindered routine application. GRASE rapid MWI was recently successfully implemented for imaging of healthy cervical spinal cord and may complement other advanced imaging methods, such as diffusion tensor imaging (DTI) and quantitative T1 (qT1). OBJECTIVE: To demonstrate the feasibility of cervical cord GRASE rapid MWI in multiple sclerosis (MS), primary lateral sclerosis (PLS) and neuromyelitis optica spectrum disorder (NMO), with comparison to DTI and qT1 metrics. METHODS: GRASE MWI, DTI and qT1 data were acquired in 2 PLS, 1 relapsing-remitting MS (RRMS), 1 primary-progressive MS (PPMS) and 2 NMO subjects, as well as 6 age (±3 yrs) and sex matched healthy controls (HC). Internal cord structure guided template registrations, used for region of interest (ROI) analysis. Z score maps were calculated for the difference between disease subject and mean HC metric values. RESULTS: PLS subjects had low myelin water fraction (MWF) in the lateral funiculi compared to HC. RRMS subject MWF was heterogeneous within the cord. The PPMS subject showed no trends in ROI results but had a region of low MWF Z score corresponding to a focal lesion. The NMO subject with a longitudinally extensive transverse myelitis lesion had low values for whole cord mean MWF of 12.8% compared to 24.3% (standard deviation 2.2%) for HC. The NMO subject without lesions also had low MWF compared to HC. DTI and qT1 metrics showed similar trends, corroborating the MWF results and providing complementary information. CONCLUSION: GRASE is sufficiently sensitive to detect decreased myelin within MS spinal cord plaques, NMO lesions, and PLS diffuse spinal cord injury. Decreased MWF in PLS is consistent with demyelination secondary to motor neuron degeneration. GRASE MWI is a feasible method for rapid assessment of myelin content in the cervical spinal cord and provides complementary information to that of DTI and qT1 measures.