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#Post#: 5020--------------------------------------------------
(Lancet) MS research in 2025: Earlier diagnosis and halting prog
ression
By: agate Date: December 11, 2025, 2:22 pm
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[font=source sans pro]
From The Lancet (January 2026)--"Multiple sclerosis research in
2025: Earlier diagnosis and halting progression" by Sean J.
Pittock:[/font]
[quote][font=source sans pro]
In 2025, substantial breakthroughs were made with respect to
earlier diagnosis, improved mechanistic understanding, and new
hope for delaying progression of multiple sclerosis. Over
successive refinements, the McDonald criteria have enabled
earlier diagnosis of multiple sclerosis, with the 2017 update
allowing diagnosis at the initial clinical event.[/font] The
newly revised 2024 criteria allow for identification of
asymptomatic disease with biological and radiological
biomarkers. Because optic neuritis is the initial clinical event
in about 25% of people with multiple sclerosis, inclusion of the
optic nerve as a fifth anatomical location for demonstrating
dissemination in space, incorporation of optical coherence
tomography, visual evoked potentials, and orbital MRI as
supportive paraclinical tests are welcome additions to the
diagnostic criteria.
The central vein sign, if present on MRI findings, can now
substitute for the presence of dissemination in time in specific
situations. Diagnosis is possible even without dissemination in
space or dissemination in time if supported by specific MRI
biomarkers (eg, central vein sign or paramagnetic rim lesions)
or CSF findings. The inclusion of the kappa free light chain
index as an alternative to oligoclonal bands simplifies CSF
analysis, reducing reliance on isoelectric focusing and
subjective band interpretation.
Although the goal is earlier diagnosis and more timely
intervention, these newer criteria increase reliance on MRI
pattern recognition, in particular the newly introduced
high-specificity imaging biomarkers central vein sign and
paramagnetic rim lesions require specialised neuroimaging
expertise. In some cases, diagnosis can now be made with MRI
findings solely, without symptoms, CSF analysis, or evidence of
dissemination in time. Early diagnosis allows initiation of
disease modifying agents (eg, B cell depleting therapy) at a
very early stage in disease progression, potentially
transforming multiple sclerosis into a non-disabling chronic
disease.
In parallel, the 2024 MAGNIMS–CMSC–NAIMS consensus outlines the
importance of standardised imaging of the brain, optic nerves,
and spinal cord, and recommends fat-suppressed orbital sequences
and susceptibility-based techniques to detect central vein sign
and paramagnetic rim lesions. The authors highlight that high T2
lesion load, brainstem or spinal cord lesions, paramagnetic rim
lesions, and brain atrophy predict increased likelihood of
long-term disability. From a practice perspective, a
particularly important recommendation concerning spinal cord
imaging is to perform “axial slices at least through the
cervical region with moderately T2-weighted spin-echo or T2
gradient echo”. A 2025 population-based analysis showed that
half of spinal cord lesions are missed when axial imaging is not
performed.
Given that misdiagnosis generally stems from MRI
misinterpretation, the 2024 criteria must be applied judiciously
and in conjunction with neurologist judgment, in order to avoid
overdiagnosis. To reduce misdiagnosis, the authors of the newly
revised 2024 criteria emphasised the importance of considering
lesion morphology and location to avoid mislabeling non-specific
white matter lesions and recognising mimics.
The phase 3 HERCULES trial of the Bruton's tyrosine kinase
inhibitor tolebrutinib provided evidence that progression can be
slowed in non-relapsing secondary progressive multiple
sclerosis. Among more than 1100 participants, tolebrutinib
reduced the risk of confirmed disability progression at 6 months
by 31% compared with placebo, with concordant benefits in
walking speed and MRI lesion burden. For a population that has
long awaited therapeutic success, these findings provide hope
for patients with progressive multiple sclerosis.
However, reasons for caution include the continuous progression
observed in 25% of patients treated with tolebrutinib and the
complication of elevated liver enzymes in 4% of patients.
However, tolebrutinib in relapsing multiple sclerosis trials
(GEMINI 1 and 2) did not outperform teriflunomide in reducing
relapses or MRI activity. This divergence is mechanistically
intriguing. The modest anti-inflammatory effect of tolebrutinib
in relapsing disease, contrasted with its effect on disability
accrual in non-relapsing progressive disease, suggests that
Bruton's tyrosine kinase inhibition might modulate
microglial-driven, smouldering inflammation rather than acute,
lymphocyte-mediated activity. Whether Bruton's tyrosine kinase
inhibition signals a new class of progression-directed
therapies, or merely opens a transient therapeutic window,
remains to be determined.
Two immunopathological studies highlight the importance of novel
mechanistic insights into identification of potential
therapeutic targets to halt progression. In the first study,
using post-mortem tissue from the Netherlands Brain Bank, a
distinct lesion type characterised by a broad rim of macrophages
and microglia at least 1 mm wide—termed the broad rim
lesion—exhibited an immunological and transcriptomic signature
that was associated with rapid disease progression. The authors
observed strong translocator protein (TSPO) 18-kDA
immunoreactivity, considered a marker of myeloid activation, in
the rim region. Since TSPO is a validated PET imaging target,
they conducted an independent TSPO PET study in 114 patients
with multiple sclerosis to search for radiological broad rim
lesions. They found radiological broad rim lesions in about 34%
of patients. These broad rimmed lesions were strongly associated
with disease progression, higher lesion load, and diffuse white
matter injury on MRI. The absence of broad rim lesions in a
third of rapid progressors could be explained by pathogenic
heterogeneity and suggests alternative, neurodegenerative or
diffuse inflammatory mechanisms. Different pathological
mechanisms will probably require personalised diagnostics and
therapeutics in the future.
In the second study, a high-resolution spatial transcriptomic
atlas of chronic active lesions revealed how the immune system
and cellular metabolism interact to sustain CNS inflammation.
Within the rims of chronic active lesions, the authors
identified CD8⁺ tissue-resident T-cell niches intertwined
with IFNγ-responsive, lipid-laden microglia. These foamy
microglia, impaired in cholesterol efflux, accumulate toxic
myelin-derived lipids that perpetuate their inflammatory state.
Disabling microglial cholesterol transporters in animal models
amplified demyelination and T-cell recruitment, whereas
pharmacological stimulation of lipid efflux reversed
inflammation and improved pathological findings and clinical
severity scores in a mouse model of disease. Correcting this
microglial cholesterol efflux defect might provide an
alternative path to treating people who have progressive
multiple sclerosis.
In summary, 2025 has seen the multiple sclerosis scientific
community continuing to redefine the condition as a unified,
biologically continuous, and increasingly modifiable
disease.[/quote]
Author's affiliation: Department of Neurology, Mayo Clinic,
Rochester, MN
[font=source sans pro][Reference notes and "Competing Interests"
omitted.][/font]
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