Multiple Sclerosis Research Repository

1. “Toward Precision Phenotyping of Multiple Sclerosis” by David Pitt, MD et al

-the separation of activity from progression has proven to be clinically relevant because the MS treatments, siponimod and rituximab, are effective in active progressive but not in nonactive progressive patients

-by unlinking activity and progression, the new Lublin classification has taken an important step.  However, it consider only white matter lesion formation (“activity”) and remains agnostic to other key pathologic processes such as cortical demyelination, chronic perilesional WM inflammation, neuroaxonal degeneration and remyelination. As a result, patients are grouped based on similar clinical phenotypes although they might have different underlying disease-driving pathologic processes.  As a logical extension to the current classification, we propose that additional pathology axes are required to more precisely capture the range of phenotypes observed across patients with MS and within individual patients over time.  Thus, we are suggesting a framework that extends beyond the clinical MS classification providing a new conceptual view of MS.  This framework will guide biomarker development and may ultimately improve personalized treatment and drug discovery

-the main pathologic axes of which: 1) acute inflammation; 2) chronic parenchymal and interstitial inflammation; 3) white and grey matter demyelination; 4) axonal degeneration; 5) neuronal loss; and 6) remyelination.  We hypothesize that the clinical heterogeneity in MS is caused by differing activity along these key pathologic axes, both across patients with MS and within individual patients over time

-”axonal damage is abundant in acute MS lesions and becomes less frequent in chronic active and chronic silent lesions” (*I don’t think this is true; I need to fact-check this*)

-”neuronal loss in the neocortex is widespread in MS, ranging between 25% and 40%, although less prominent than in classical neurodegenerative diseases”

–synaptic density in the remaining neurons is substantially decreased, as is neuronal activity measured by fMRI

-neuroaxonal damage is believed to be the major determinant of disability 

-near absence of remyelination in cerebellar lesions

-distinct oligodendrocyte response patterns

-RRMS/SPMS does not differ from PPMS regarding overall Wm lesion load; presence of active, chronic active, and chronic silent WM lesions (albeit with different proportions); extent of axonal damage; and meningeal inflammation

-as in RRMS, the correlation between WM lesion load and clinical disability in PPMS is poor

-these studies suggest that clinical phenotypes do not align well with specific pathomechanisms outside the extremes of the clinical spectrum, early relapsing MS and late-stage progression; that is, in most patients

-most modifiers exert quantitative rather than qualitative 9on-off) effects

-neuropathologic variability predicts high variability of clinical presentations

-the clinical categories do not correspond to unique pathologic processes

-we argue that MS can be described as a combination of multiple, interconnected pathologic processes that present with different degrees of activity at different time points; this approach provides a ground truth about the disease state that clinical observations cannot provide

–By quantifying the extent and type of activity along each pathologic axis, our model would be able to assign specific profiles for individual patients with MS.  While the clinical classification into RRMS and SPMS is intuitive, it may obscure individual level pathologic profiles.  For example, MS progression may be driven by chronic perilesional inflammation, meningeal inflammation, or inflammation independent of degeneration of denuded axons, which the description “progression” is not able to distinguish.  Tis suggests that additional pathologic axes might provide improved resolution of MS phenotypes.  

-3 MS subtypes were identified based on changes in MRI patterns over time.  Patients exhibited early cortical atrophy (cortical-led phenotype), early reduction in the T1/T2 ratio across various NAWM areas (NAWM led phenotype) or early and extensive accrual of T2 lesions followed by severe deep gray matter atrophy.  These 3 subgroups exhibited substantial differences regarding risk of progression, relapse rate, and treatment responses.  This example illustrates that MRi pattern-based MS subtypes, which correlate with different pathologic processes (neuronal damage, WM tissue damage, and inflammation demyelination) predict disease activity, disability progression and treatment response better than conventional clinical phenotypes.  Similarly, the incorporation of different oligodendrocyte response patterns into the classification system and its quantification with biomarkers might be highly informative about potential responses to pre-remyelinating drugs

-NfL levels in CS correlated with brain atrophy, whereas CH13L1 levels correlated with spinal cord atrophy

-elevated CXCL12 and osteopontin levels in the CSF were associated with PPMS and elevated IL-10 with RRMS

-only active progressive, but not nonactive progressive patients respond to MS treatments

-the paradox that clinical categories do not align with specific pathologies

-by determining whether a patient will respond to a specific DMT based on his or hera activity profile

This may include monitoring the newly postulated specific oligodendrocyte response patterns, the presence of neurotoxic and neuroprotective glial subpopulations and determinants of neuroaxonal damage such as mitochondrial dysfunction