Author Of 1 Presentation
FC03.05 - Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO
In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.
To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.
At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.
In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.
In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.
Author Of 1 Presentation
P0553 - Bundle-specific microstructural alterations in normal appearing white matter of cognitively preserved MS patients using advanced diffusion MRI (ID 1718)
Although diffusion tensor imaging (DTI) has been widely used to investigate the microstructure of white matter (WM) in patients with multiple sclerosis (MS), it has several limitations; thus different approaches to model diffusion magnetic resonance imaging (dMRI) data are needed.
To investigate alterations in the normal appearing WM (NAWM) of cognitively preserved relapsing remitting MS (RRMS) patients using different modelling of dMRI data.
We included 39 patients (23 females; mean age: 34±6.7 years; median EDSS: 2, range 0-4; mean disease duration: 7±4.6 years) and 39 age- and gender-matched healthy controls (HC). All subjects underwent cognitive (corsi block, n-back, PASAT) and clinical assessment (EDSS) as well as MRI using a 3 Tesla scanner (Siemens Prisma). We assessed 14 diffusion measures applying DTI, freewater volume fraction (FW) corrected tissue DTI (tDTI) and High Angular Resolution Diffusion Imaging (HARDI). Streamline-based particle filtering tractography was used to extract 33 major WM bundles with a multi-atlas/multi-parameter version of RecoBundle. For every bundle, the average of each diffusion measure was computed for the NAWM section. Groups were compared using t-tests and corrected for multiplicity (FDR, q=0.05).
Patients and controls did not differ in cognitive performance. For each measure, the number of bundles showing a group difference and the effect size are reported: DTI (AD: 3 bundles, effect size r:0.3-0.47; RD: 16, r:0.29-0.44; MD: 16, r:0.29-0.48; FA: 11, r:-0.28- -0.5, MODE: 1,r:-0.29), tDTI (FW: 16, r:0.28-0.56; ADt: 2, r:0.34-0.44; RDt: 15, r:0.28-0.43; MDt: 14, r:0.29-0.41; FAt: 11, r:-0.29- -0.5) and HARDI (apparent fiber density (AFD): 9, r:-0.31- -0.41; generalized fractional anisotropy (GFA): 10, r:-0.29- -0.5; anisotropic power (AP): 10, r:-0.28- -0.51; number of fiber orientations (NuFO): 2, r:0.28-0.29). Differences were most prominent in the right arcuate fasciculus, right inferior fronto-occipital fasciculus, bilateral inferior longitudinal fasciculus, right optic radiation and right superior longitudinal fasciculus.
All approaches used to model dMRI data showed structural alterations of several major WM bundles associated with cognitive functions despite patients’ normal cognitive performance. Hence, diffusion MRI could be used to assess disease progression in early stages of the disease when compensatory mechanisms can still support normal cognitive performance.