Multiple Sclerosis Research Repository

Category: Uncategorized

“Changes in disability in people with multiple sclerosis: a 10-year prospective study” by David Conradsson et al
1. “Changes in disability in people with multiple sclerosis: a 10-year prospective study” by David Conradsson et al
-The large proportion of our sample receiving immunomodulatory treatment at baseline needs to be taken into account when interpreting the study results. The increase in EDSS scores in our study was similar to previous -1year follow-ups, monitoring cohorts, where a low proportion received immunomodulatory treatment. The similarities in disease progression between our cohort and previous cohort studies might indicate that changes in severity of MS, as measured with EDSS, occur regardless of immunomodulatory treatment.
January 21, 2025
“MRI as an outcome of in multiple sclerosis clinical trials” by M Daumer et al
1. “MRI as an outcome of in multiple sclerosis clinical trials” by M Daumer et al
-in RRMS, TLL (total lesion load) made no independent contribution to predicting change in disability from baseline to trials’s end

-inclusion of gadolinium enhancing lesions into multivariate models did not independently contribute to the predictive value for on-trial relapses

-in SPMS, a small effect of TLL was found for disability change (n=355) but in multivariate analysis this account for less than 5% of the variance in end-of-trial disability

-MRI measures widely used in trials of RRMS and progressive MS add little if anything independently to the clinically relevant relapse and disability outcomes. These results emphasize the importance of validation potential surrogate markers against clinical measures and highlight the need for better MRI markers of disease activity and progression
January 21, 2025
“Clinical trials in multiple sclerosis: milestones” by Yinan Zhang et al
1. “Clinical trials in multiple sclerosis: milestones” by Yinan Zhang et al
-”MRI lesions found on a single or annual basis have not consistently been shown to correlate with individual clinical outcomes in trials”
January 21, 2025
“Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data” by Arman Eshaghi et al
1. “Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data” by Arman Eshaghi et al
-we define MS subtypes as cortex-led, NAWM-led and lesion-led

-people w the lesion led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate

-people w the lesion-led MS subtype show positive treatment response in selected clinical trials

-our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to definite groups of patients in interventional trials

-grouping individuals on the basis of as similar appearance on a single time point MRI is not sufficient as patients belonging in the same subgroup would show different abnormalities as their disease evolves and would appear different

-the ability to distentable temporal and phenotypic heterogeneity

-Here, we aimed to redefine subtypes of MS based on a data driven assessment of the

pathological changes visible on MRI scans, rather than the evolution of clinical symptoms, with a view to targeting therapies to subpopulations who share pathogenic mechanisms

-the lesion-led subtype had the highest EDSS, long disease duration, highest lesion load

at baseline, highest lesion accrual over time, and the smallest cortical and deep grey

matter volumes at baseline (all p less than 0.001); additionally, the lesion-led subtype

sowed the highest SuStaIn stage at baseline and the highest annual increase in SuStaIn

stage in both the training and validation datasets

-the most frequent subtype in both the training and validation datasets was the

cortex-led subtype followed by the NAWM subtype in the training dataset and the

lesion-led subtype in the validation dataset

-there were no differences in age and sex between the MS subtypes

-lesion-led had the most active disease and highest relapse rate

-no significant associations between the standard clinical phenotypes or baseline EDSS

with the time to 24-week CDP suggesting that MRI-based subtypes were more strongly

associated with the risk of disability progression than the standard clinical phenotypes

-no differences in the rate of EDSS worsening were observed between treated patients

and those on placebo/active comparator, who belonged to both the NAWM led and

cortex-led subtype

-we found that a patient’s baseline subtype and stage was associated with the individual

risk of disease progression

-our primary hypothesis was that a model based on MRI rather than solely on clinical

data helps to improve a biological understanding of MS disease progression

-there were differences in the risk of disability progression, disease activity and treatment

response across subtypes which suggested that they reflected different pathobiological mechanisms relevant to the manifestations of the disease

-notably, the lesion-led subtype was the only subtype that showed a significant treatment response in both RRMS and progressive (PP and SP) MS trials

-when looking at the trajectory of MRI changes definition the cortex-led subtype, this group showed early cortical atrophy in the occipital and parietal regions, subsequent development of atrophy in the other grey matter regions and accumulation of T2 lesions and late NAWM abnormalities. This suggests that the pathological underpinning of the cortex-led subtype is more insidious and may relate to neurodegeneration in the cortex and compartmentalised, chronic inflammation in the white matter, wish is not reflected by the visible lesions. The concurrent development of cortical atrophy and accumulation fo lesions points to retrograde neurodegeneration of tracts transected in white matter lesions.

-the majority of patients belonged to the cortex-led subtype in both the training and validation datasets; this subtype responded to a lesser extent to treatments

-this observations suggests that the neurodegenerative component of MS is clinically relevant and remains difficult to target with treatments

-it is also important to note that SuStaIn disentangles not only the sequence but also the severity of abnormality at each stage

-the parietal cortex showed the greatest early atrophy of all cortical regions, regardless of subtype

-we postulate that this reflects a shorter prodromal period in the lesion-led compared to other subtypes

-another possibility is that longer disease durations in the lesion-led subtypes reflect patients converting from another subtype

-the MRI-based subtypes and stages were more strongly associated with EDSS worsening than the baseline EDSS or clinical phenotypes

-the MRI-based subtypes can be used alongside clinical phenotypes to add value in prognosticating patient outcomes

-we found that the MRI-based subtypes predicted CDP whilst single MRI variables (lesion load and whole brain volume) did not, suggesting that a comprehensive model is necessary to achieve the difficult task to predict disability progression

-we were not able to use the most sensitive MRI measures; this was particularly the case for NAWM

-the spinal cord is affected from early stages and its atrophy is independently associated with disability
January 21, 2025
“Toward Precision Phenotyping of Multiple Sclerosis” by David Pitt, MD et al
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
January 21, 2025
“New Insights into Multiple Sclerosis Clinical Course from the Topographical Model and Functional Reserve”: Stephen C Krieger and James Sumowski
1. “New Insights into Multiple Sclerosis Clinical Course from the Topographical Model and Functional Reserve”: Stephen C Krieger and James Sumowski
-MS-related cognitive dysfunction: this insidious but pervasive symptom has not been fully incorporated into longstanding approaches to disability assessment or conceptualizations of MS phenotypes

-presence or absence of sidious worsening of neurological function in the absence of relapses referred to as disease progression

-progression characterized by neurodegeneration

-the long-term impact of relapses on the clinical course and the accumulation of disability continues to be a matter of debate

-an increased frequency and severity of relapses early in disease course MAY also confer an unfavorable prognosis and rapid development of disability

-older studies of long-term outcomes in MS had identified a very limited impact of early relapses to the development of disability once the progressive phase of MS has become apparent

-acute lesions seen on MRI…serve as a surrogate marker for inflammatory disease activity

-those diagnosed at an older age are at a higher risk of manifesting a PPMS course or developing SPMS after a short interval from diagnosis

-compensatory mechanisms may not be as roust in the older-onset MS population

-it (the topographical model of MS) remains agnostic (as do the other conceptual depictions of a clinical course of disease) to pathophysiologic and cellular mechanisms of the disease

-the spinal cord and optic nerves-the simplest, most linear structure commonly affected by MS-have the least redundancy and capacity for organizational plasticity and rewiring whereas the cerebral hemispheres possess the greatest such structural and functional resilience

-new MRI lesions are a…surrogate marker for relapse

-topographical model of MS; posits that there is a distinct relationship between lesion topography and the loss of functional reserve that drives the clinical course of MS

-the recapitulation hypothesis: progression clinically recapitulates a patient’s prior relapse symptoms and unmasks previously clinically silent lesions, incrementally manifesting above the clinical threshold a patient’s underlying disease topography

-topographical model of MS; is in some respects a relapse-centric model

-the concept that the loss of reserve may yield progressive worsening through loss of compensation for lesion burden helps to explain why high lesion burden early in the course of disease-even if the lesions are initially asymptomatic-is a poor prognostic factor for disability accrued many years later; once compensatory reserve declines, those sub-clinical lesions are no longer sub-threshold

-the topographical model: depicts the loss of reserve as beginning at the outset of disease, congruent with findings at CIS and RIS supporting the concept that early treatment to prevent disease activity-keeping the disease topography flat-may forestall the development of progressive disability later in the disease course

-topographical model: further congruent with findings that progressive accumulation of disability-be it in a context of SPMS or PPMS-is an age-related phenomenon; in the model, it takes years for reserve to be lost and for the clinical threshold to decline sufficiently for the progressive unmasking of disease topography to begin

-topographical model: does prioritize the loss of reserve-the declining threshold-as the crucial driver of disability in progressive disease

-clinical-radiologic paradox: the observation that some persons are better able to withstand neurological disease without or before suffering disability

-reserve is, in essence, the difference between the actual and expected disability for a given level of disease burden

-DMTs are “modifiable factors to maintain as much reserve as possible”

-greater cognitive leisure is linked with larger hippocampal volume in MS patients

-the goals of care in MS include both preventing new disease topography as well as maximizing reserve and “keeping the tank full” to augment a person’s capacity to keep the disease submerged

-”the goal of DMT for relapsing MS: keeping the topography flat, preventing new lesions from emerging and relapses from crossing the threshold (*but what about PIRA, neurodegeneration, and so many other aspects of MS pathology and activity that drive progression and disability worsening?*)
January 21, 2025
“Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold” by Stephen Kireger, Karin Cook and Carrie M Hersh
1. “Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold” by Stephen Kireger, Karin Cook and Carrie M Hersh
-:Such phenotyping is inherently defined by what can be observed and measured

-MS is characterized by both acute and diffuse inflammation as well as neurodegeneration, all of which begin from the onset…

-While clinical phenotyping was essential to organizing pivotal clinical trials that rendered MS a treatable disease 30 years ago…

-the clinical-radiological paradox by distinguishing above- and below-threshold disease burden

-dynamic transition to clinically-apparent progression

-This view of disease evolution acknowledges a shift from acute macroinflammatory

injury seen with local lesions to widespread chronic inflammation and neurodegeneration

-this perspective disrupts a dichotomized view of distinct disease phases in favor of a

combination of interdependent and dynamic patholobiological axes

-Pitt et al emphasize how apparent clinically homogeneity could obscure such crucial

differences in underlying mechanistic processes; this concept underscores how clinical

phenotype may not track with “ground truth” drivers of disease

-a key current limitation is the lack of primary outcomes that are sensitive enough to

reflect the biological basis of progressive disease via a measurable clinical endpoint

-clinical disease manifestations in an individual patient are likely drive by the extent in

which reserve compensates for CNS damage

-”ground truth” of an individual patient cannot be directly measured; can only be gleaned

by inference

-the use of chameleon concepts such as “smoldering MS” which, while omnipresent in

the discourse, can be subjectively interpreted as encompassing various pathologic

processes and thus mask the specificity needed to target the disease mechanistically

-underling nonlesional mechanisms

-increasing evidence suggests that the thalamus may be implicated in the early degeneration in MS; in a foundational case-controlled study, mean thalamic volumes were found to be significantly lower in RIS patients vs controls

-diffuse neurodegenerative processes

-although emerging MRI techniques reveal how much of the disease pathology we are not yet able to visualize in routine practice, conventional MRi measures as used in practice and clinical trials remain a reliable window into mechanisms associated with acute injury for diagnosis, prognosis, and monitoring of individuals with MS (*FALSE!*)

-the clinical-radiologic paradox that underscores the mismatched heterogeneity between MRI appearance, clinical severity, and uncertain prognosis is explained by the ability or lack thereof of compensatory reserve to keep much of the disease burden “submerged” below the threshold

-the topographical model of MS hypothesizes that progression emerges as an unmasking of prior damage as reserve is lost, incrementally revealed above the declining clinical threshold. This is most pronounced in the eloquent CNS structures, i e the spinal cord and the infratentorial region in the “shallow end” of the CNS, where there is less compensatory reserve

-unfortunately, spinal cord imaging in MS remains all but absent from clinical trials and of suboptimal quality in clinical practice…these most prognostically-important MS lesions may still be hiding in plain sight, just below the limit of radiographic detection

-better need to detect “subthreshold” deficits

-the concept of “silent progression”-the insidious accrual of disability often thought too subtle to discern-is only silent if we are not listening carefully enough. ANd the “invisible symptoms” of MS are only invisible if we are not looking sufficiently closely

-the coarseness and intensity of our standard measure of MS disability used in clinical practice and clinical trials confers methodological limitations; if an EDSS of 0 is not in fact “normal,” then the entire scale right from the beginning is miscalibrated

-concerns that EDSS scale is not granular enough to capture early changes in function, esp in certain domains

-the neurological exam does not account for maximal function at an individual level and may not be sensitive enough to capture early changes in function

-How much is being missed below the threshold of both clinical and radiologic detection?

-Barcelona group: the authors stated that early MS patients with PIRA should be considered to have progressive MS, whether or not they have inflammatory activity and independent of their disability score or disease duration

-PIRA was the dominant driver of disability after year 1

-DMTs delayed disability accrual by years with the highest potential for delaying disability early in the disease (*No citation for this assertion; what evidence/studies is it based on?*)

-4 distinct phenotypes were defined in 1996 based on descriptions of clinical course, though neither objective biological support nor the ability to link the clinical course with MRI findings was then possible

-revised in 2013, the clinical course phenotypes incorporated the concept that disease activity could co-occur with progression, but maintained the distinction that RRMS phenotype is one without progressive manifestations

-Indeed, if progressive mechanisms start early, and MS is a disease spectrum, then all RRMS trials are SPMS trials if analyzed carefully enough
January 21, 2025
“Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic”: Jerome de Seze et al
1. “Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic”: Jerome de Seze et al
1. Rituximab in RRMS: RIFUND-MS trial: no significant difference was observed between the groups (rituximab and tecfidera) for the EDSS, even though rituximab outperformed tecfidera in terms of reducing relapses/ARR, no new MRI activity, and reduced numbers of T2 and GD+ lesions
2. Ocrevus, Phase II trials (OPERA I and OPERA II): results were inconclusive due to a failure of the statistical hierarchical testing procedure; in the OLE, patients switching from IFN-B-1a to Ocrevus (at 2 years) had a similar ARR at 5 years; the proportion of patients withCDP at five years was lower with Ocrevus compared to patients switching from IFN-B-1a to Ocrevus (16.1% to 21.3%, respectively); brain volume loss was unchanged in patients treated with Ocrevus for 5 years
3. Kesimpta in RMS: ASCLEPIOS I and ASCLEPIOS II: annualized rate of brain volume loss did not differ significantly between patients treated with Kesimpta vs Aubagio, even though Kesimpta outperformed Aubagio in terms of T1 GD+ lesions; in ASCLEPIOS I, patients on Kesimpta had a lower adjusted ARR than those in the Aubagio group (similar results seen in ASCLEPIOS II)
4. Briumvi in RMS:
5. ULTIMATE II trial: 43% of Briumvi group showed NEDA vs 11.4% in Aubagio group; however, no significant difference in the worsening of disability at 12 weeks was found between Briumvi and Aubagio patients in the pooled analysis of the 2 trials (5.2% vs 5.9%); brain volume change was not significant between the 2 groups
January 21, 2025
“Lessons for clinical trials from natalizumab in multiple sclerosis” by Abhiit Chaudhuri
1. “Lessons for clinical trials from natalizumab in multiple sclerosis” by Abhiit Chaudhuri
-FDA gave natalizumab accelerated approval to treat relapsing MS

-approval was given on the basis of short term (1 year) data from 2 multi-centre, randomised double blind placebo controlled phase 3 trials; neither trial was published in a peer reviewed journal and the FDA granted approval before final trial and cumulative safety data were available

-primary end point of each trial was: ARR at 1 year

-FDA conclude that natalizumab was superior to all available treatments for relapsing MS (3 types of interferon beta and glatiramer)

-the 2 reported cases of MS do not answer the important question of whether natalizumab had a therapeutic effect on the pathology of multiple sclerosis distinct from demylelination due to PML

-none of the published trials showed convincing evidence of the efficacy of natalizumab in relapsing MS

-the first placebo controlled study where natalizumb (Antegren, Elan) was infused every 2 months showed no clinical effect

-Natalizumab had no proved effect on the progression of disability in these studies or in the two unpublished trials that formed the basis of its approval

-in the unpublished trials, the claimed benefit of natalizumb was based on radiological measures (number of enhancing lesions in MRI images of brain) and relapse rates, none of which correlate with long term disability in MS

-relapse rates are not continuous but discrete number, and fractional relapse rates are meaningless. Results of the AFFIRM trial indicate that without treatment (and associated risk of side effects) a patient would experience only one extra relapse in 16-18 months. Although the statistics of these trials may seem impressive, there is no half or three quarter relapse in a patient’s life

-annualized relapse rate for interferon beta-1a alone was slightly worse than for placebo in the natalizumab monotherapy trial (0.78% and 0.74%), a result that questions the effectiveness of the drug

-reducing relapse is not necessarily an effective strategy to prevent serious and chronic disability in MS as indicated by recent epidemiological models

-the cost effectiveness of this treatment approach is also uncertain and has not been confirmed for interferon beta-1a, the most commonly prescribed DMD in MS

-surrogate markers based on imaging results used as outcome measures in MS trials do not mirror the clinical course of the disease

-imaging surrogates for neuroaxonal loss have not been validated for predicting future disability

-a successful treatment delay progressive tissue loss irrespective of relapse rates and clinical phenotype

-short term solutions for a chronic disease like MS are not likely to be effective, and PML results from treatment with natalizumab should be taken as a signal to change the way we treat this disease
January 21, 2025
“Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging” by Reza Rahmanzadeh et al

“Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging” by Reza Rahmanzadeh et al

-neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort

-progressive patients differ from RRMS patients because of more extensive axon/myelin damage in the cortex

-myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage

-despite the applied measures demonstrating good sensitivity to pathological changes in MS patients, they lack specificity for both myelin and axonal damage

-MCMDI is an alternative technique to the NODDI model that provides estimates of intra- and extra-neurite compartments in the brain, which has been applied to MS patients

-MP2RAGE and 3D-EPI permit identification of the specific lesion subtypes such as cortical and chronic active lesions

-cortical lesions more common in PMS than RRMS

-vertex-wise analysis showed areas across NAGM in which MWF and NODDI-NDI were lower in PMS compared to RRMS

-MWF and NDI in white matter lesions did not correlate with EDSS when the entire cohort was considered

-in patients with clinical deficits (EDSS greater than 1)-NDI in white matter lesions was associated with EDSS

-MWF and NDI in white matter lesions were related to serum NfL, but this correlation was not significant after adjusting for T2 lesion volume; however, when only patients with EDSS greater than 1 were considered, white matter lesion MWF correlated with serum neurofilaments

-suggesting that axon and myelin damage are synchronized and/or driven by a common pathological event

-in a large majority of lesions-axonal damage outweighed myelin damage; may be due to a primary axonal pathology as previously suggested

-a pivotal finding of this study is the presence of axonal damage independent of demyelination in both focal white matter lesions and NAWM; these findings are also in line with previous spectroscopy studies showing a very early diffuse reduction of N-acetylaspartate in NAWM in RRMS and increase in lipid levels at the site of future MS lesions; pathologically, this may be related to primary oliogodendrocytopathy leading to axonal damage via disruption of oligodendrocyte neuron cross-talk or to direct damage to the neuroaxonal unit

-magnetization transfer ratio-another surrogate measure of both myelin and axonal damage-is mostly related to disability when measured in lesions and not in the normal-appearing tissue

-it may well be that those patients experience a higher functional reserve and more effective mechanisms compensating for structural damages, which is often the case at early disease stages

-MWF and NDI: provide surrogate-not direct-markers of myelin and axon characteristics

January 21, 2025