Patterning Chronic Active Demyelination in Slowly Expanding/Evolving White Matter MS Lesions.

BACKGROUND AND PURPOSE: Slowly expanding/evolving lesions measured by conventional T1-weighted/T2-weighted brain MR imaging may contribute to progressive disability accumulation in MS. We evaluated the longitudinal change in myelin and axonal tissue integrity in white matter slowly expanding/evolving lesions by means of the magnetization transfer ratio and DTI radial diffusivity. MATERIALS AND METHODS: Slowly expanding/evolving lesions were detected within the Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) Phase 2 clinical trial dataset (NCT01864148), comprising patients with relapsing-remitting and secondary-progressive MS (n = 299) with T1-weighted/T2-weighted MR imaging at all trial time points (baseline to week 72). RESULTS: Compared with non-slowly expanding/evolving lesions (areas not classified as slowly expanding/evolving lesion) of baseline nonenhancing T2 lesions, slowly expanding/evolving lesions had a lower normalized magnetization transfer ratio and greater DTI radial diffusivity, both in patients with relapsing-remitting MS (n = 242) and secondary-progressive MS (n = 57, P < .001 for all). Although the changes with time in both the normalized magnetization transfer ratio and DTI radial diffusivity between slowly expanding/evolving lesions and non-slowly expanding/evolving lesions were positively correlated (P < .001), a decrease in the normalized magnetization transfer ratio and a greater increase in DTI radial diffusivity were observed in slowly expanding/evolving lesions versus non-slowly expanding/evolving lesions from baseline to week 72 in relapsing-remitting MS and secondary-progressive MS (P < .001 for all). CONCLUSIONS: Patterns of longitudinal change in the normalized magnetization transfer ratio and DTI radial diffusivity in slowly expanding/evolving lesions were consistent with progressive demyelination and tissue loss, as seen in smoldering white matter MS plaques.

Clinical Development of Aducanumab, an Anti-Aß Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease.

The amyloid hypothesis has been the dominant framework for Alzheimer's disease (AD) research, including the development of anti-AD therapies. However, none of the phase III clinical trials conducted to date that targeted amyloid ß (Aß) production, aggregation, or clearance demonstrated a statistically significant treatment effect in patients with AD. This includes the approach of using monoclonal antibodies that recognize various Aß epitopes and display different binding selectivity. While some monoclonal antibodies have failed in phase III trials, several are still in development. Aducanumab (BIIB037) is a human antibody that selectively targets aggregated forms of Aß, including soluble oligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib trial (N=196 patients dosed), aducanumab was shown to reduce Aß plaques and slow decline in clinical measures in patients with prodromal or mild AD, with acceptable safety and tolerability. The main safety finding was amyloid-related imaging abnormalities (ARIA), a side effect associated with removal of Aß, which was dose-dependent and occurred more often in ApoE ε4 carriers than non-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase III trials of aducanumab in early AD, have been designed based on the outcomes of PRIME and on lessons from past clinical trials in patients with AD. Those study design features include patient selection with confirmed Aß pathology, ensuring sufficient target engagement, and conducting clinical trials in patients at earlier symptomatic stages of AD.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. CASE REPORT AND RESULTS: The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. CONCLUSIONS: New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.