International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(16), P. 8923 - 8923
Published: Aug. 16, 2024
Ocrelizumab
(OCR)
is
a
humanized
anti-CD20
monoclonal
antibody
approved
for
both
Relapsing
and
Primary
Progressive
forms
of
Multiple
Sclerosis
(MS)
treatment.
OCR
postulated
to
act
via
rapid
B
cell
depletion;
however,
by
analogy
with
other
agents,
additional
effects
can
be
envisaged,
such
as
on
Protein
Kinase
C
(PKC).
Hence,
this
work
aims
explore
novel
potential
mechanisms
action
in
peripheral
blood
mononuclear
cells
from
MS
patients
before
after
12
months
We
first
assessed,
up-stream,
PKCβII
subsequently
explored
two
down-stream
pathways:
hypoxia-inducible
factor
1
alpha
(HIF-1α)/vascular
endothelial
growth
(VEGF),
human
antigen
R
(HuR)/manganese-dependent
superoxide
dismutase
(MnSOD)
heat
shock
proteins
70
(HSP70).
At
baseline,
higher
levels
PKCβII,
HIF-1α,
VEGF
were
found
compared
healthy
controls
(HC);
interestingly,
the
overexpression
inflammatory
cascade
was
counteracted
Conversely,
at
content
HuR,
MnSOD,
HSP70
significantly
lower
HC,
while
administration
induced
up-regulation
these
neuroprotective
pathways.
These
results
enable
us
disclose
dual
positive
OCR:
anti-inflammatory
neuroprotective.
Therefore,
addition
depletion,
effect
molecular
cascades
contribute
counteracting
disease
progression.
Current Opinion in Neurology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 30, 2025
Purpose
of
review
Monitoring
disease
activity
and
treatment
response
in
multiple
sclerosis
(MS)
currently
relies
on
the
integration
qualitative
clinical
radiological
data
that
is
limited
predictive
value.
An
array
quantitative
digital
fluid
biomarkers,
many
cusp
broad
translation,
expected
to
herald
a
new
era
data-driven
therapeutic
strategy,
particularly
with
respect
sequencing
disease-modifying
therapies
(DMTs).
Available
highly-effective
DMTs,
which
largely
abolish
acute
inflammatory
early,
relapsing
MS,
have
impact
progressive
MS
biology.
However,
robust
biomarkers
progression
independent
relapse
(PIRA)
emerged
as
major
unmet
need,
fuelled
by
imminent
availability
treatments
target
pathomechanisms
such
chronic
active
or
smouldering
brain
inflammation.
Recent
findings
The
criteria
for
diagnosis
incorporate
both
imaging
cerebrospinal
(CSF)
disease,
lacks
single
diagnostic
‘test’.
recent
validation
objective
CSF
k-FLC
index,
promises
improve
accuracy,
patients
atypical
minor
changes.
Precision
monitoring
therapy
being
transformed
advent
clinically
integrated,
tools;
wearables
patient
reported
outcomes,
including
cognitive
batteries
delivered
personal
devices;
an
ultra-sensitive,
readily-obtained
serum
indicate
severity
tissue
injury
MS.
promise
strategy
further
explored
multimodal
digital/fluid
twin
biomarker
studies
artificial
intelligence
algorithms.
Summary
Here,
we
key
near-term
will
guide
individualised
people
targeting
no
evidence
(NEDA)
early
established
disease.
In
medium
term,
composite
integrated
outcomes
underpinned
transformative
effect
management
Current Opinion in Neurology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 4, 2025
Purpose
of
review
Neuropathological
studies
in
human
brain
tissue
are
indispensable
for
our
understanding
disease
mechanisms
multiple
sclerosis
(MS).
They
inform
concepts
lesion
evolution,
regeneration
and
progression,
ideally
reveal
new
therapeutic
targets.
Here
we
recent
neuropathological
that
have
advanced
knowledge
MS
pathogenesis.
Recent
findings
cohort
support
the
notion
different
clinical
phenotypes
share
underlying
pathological
features,
heterogeneity
is
derived
from
a
variable
combination
innate
adaptive
inflammation,
demyelinating
activity,
neuroaxonal
loss.
Importantly,
emerging
technologies
spatial
transcriptome
analysis
enable
an
unprecedented
glimpse
into
cellular
composition
molecular
involved
evolution.
These
promising
will
help
identify
identification
hubs
governing
damage
regeneration.
Summary
helped
to
correlates
disability
progression.
Substantial
progress
revealed
complexity
MS-related
features.
Close
collaboration
between
tissue-based,
molecular,
bioinformatic,
pharmacologic,
imaging
experts
needed
continue
advance
field,
particularly
benefit
people
with
progressive
MS.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 29, 2025
Abstract
Both
CD4
+
and
CD8
T
cells
play
critical
roles
in
the
immunopathogenesis
of
multiple
sclerosis
(MS).
1C6
cell
receptor
transgenic
(TcR-Tg)
mice
on
nonobese
diabetic
(NOD)
background
have
a
MOG
[35-55]-
specific,
MHC
class
II-restricted,
TcR
that
selects
for
both
cells.
Adoptive
transfer
helper
17
(Th17)
can
induce
experimental
autoimmune
encephalomyelitis
(EAE)
with
progressive
disease
course.
In
current
study,
we
assessed
function
pathogenicity
We
found
they
proliferated
produced
inflammatory
cytokines
response
to
[35-55]
peptide
under
cytotoxic
1
(Tc1)
Tc17
differentiation
conditions,
albeit
reduced
expansion
relative
their
Th1
or
Th17
counterparts.
Tc1
were
able
EAE
upon
adoptive
NOD.
Scid
mice.
Intriguingly,
noted
vivo
spleen
CNS
recipients
as
well
lymphocyte-sufficient
animals,
despite
Tc
being
purified
expression
prior
transfer.
Furthermore,
expressed
ThPOK,
master
factor
Finally,
anti-CD4
blockade
abrogated
infiltration
induction
recipient
Our
data
provide
insight
into
interplay
autoimmunity.
Current Opinion in Neurology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 8, 2025
Purpose
of
review
The
purpose
this
article
is
to
provide
an
overview
progression
in
multiple
sclerosis
(MS),
including
definitions,
pathological
mechanisms,
and
evidence
that
progressive
biology
begins
early
the
disease
course.
Recent
findings
Definitions
MS
clinical
course
have
been
refined
acknowledge
presence
both
relapse
throughout
disease.
Progression
independent
activity
represents
a
significant
proportion
disability
worsening
relapsing–remitting
(RRMS)
appears
be
caused
by
complex
interplay
processes,
nonresolving
inflammation,
microglial
activation,
oxidative
stress,
mitochondrial
dysfunction,
energetic
failure,
neuro-axonal
degeneration.
These
processes
appear
begin
earliest
stages
their
contribution
phenotypes
dynamic
over
time.
Promising
results
from
trials
tolebrutinib,
particular,
underline
utility
targeting
innate
adaptive
immune
mechanisms
reduce
accumulation.
Summary
Pathological
underpin
are
detectable
RRMS,
evolve
correlate
with
should
not
defined
dichotomously
–
focus
instead
on
recognizing
components
based
measures
biomarkers
better
individualize
treatment
strategies.
The
objective
of
this
study
was
to
determine,
at
the
time
diagnosis,
a
CSF
and
MRI
profile
intrathecal
compartmentalized
inflammation
predictive
progression
independent
relapse
activity
(PIRA)
in
early
relapsing-remitting
multiple
sclerosis
(RRMS).
This
five-year
prospective
included
80
treatment-naïve
patients
with
RRMS
enrolled
diagnosis.
All
underwent
lumbar
puncture,
regular
neurologic
evaluations
including
an
Expanded
Disability
Status
Scale
(EDSS)
assessment
every
6
months,
annual
3T
brain
MRI.
PIRA
defined
as
having
confirmed
disability
activity.
levels
68
inflammatory
molecules
were
evaluated
combination
white
matter
cortical
lesion
number
(CLn)
volume,
regional
gray
thickness
volume.
During
follow-up,
23
(28.8%)
experienced
PIRA.
At
participants
older
(44.0
±
10.7
vs
37.4
12.4,
p
=
0.017)
more
(median
EDSS
score
[interquartile
range]
3
[range
2-4]
for
1.5
1-2]
no
group,
<
0.001).
Random
forest
selected
LIGHT,
CXCL13,
sTNFR1,
sTNFR2,
CCL7,
MIF,
sIL6Rbeta,
IL35,
CCL2,
IFNβ
markers
best
associated
sTNFR1
(hazard
ratio
[HR]
10.11
[2.61-39.10],
0.001),
sTNFR2
(HR
5.05
[1.63-15.64],
0.005),
LIGHT
1.79
[1.11-2.88],
0.018)
predictors
regression
analysis.
Baseline
thalamus
volume
0.98
[0.97-0.99],
middle
frontal
gyrus
0.05
[0.01-0.72],
0.028),
CLn
1.15
[1.05-1.25],
0.003)
A
specific
TNF
superfamily
markers,
CLn,
atrophy
several
deep
regions,
assessed
is
MS.
Multiple Sclerosis Journal,
Journal Year:
2024,
Volume and Issue:
30(11-12), P. 1402 - 1404
Published: Aug. 28, 2024
Progression
independent
of
relapse
activity
(PIRA)
has
been
recently
proposed
in
multiple
sclerosis
(MS)
as
a
model
identifying
continuous
silent
progression
disability
without
the
manifestation
new
clinical
and
magnetic
resonance
imaging
(MRI)
events
that
contribute
to
MS
worsening.
Despite
evidence
suggesting
manifestations
often
affect
cognitive
functioning
importance
neuropsychological
monitoring
over
time,
attention
is
lacking,
PIRA
concept
does
not
include
measure
function.
In
this
personal
viewpoint,
we
highlight
need
cognition
have
more
comprehensive
understanding
patients
with
MS.
Acta Neuropathologica,
Journal Year:
2024,
Volume and Issue:
148(1)
Published: Aug. 31, 2024
Abstract
The
pathogenic
mechanisms
contributing
to
neurological
disability
in
progressive
multiple
sclerosis
(PMS)
are
poorly
understood.
Cortical
neuronal
loss
independent
of
cerebral
white
matter
(WM)
demyelination
myelocortical
MS
(MCMS)
and
identification
patients
with
widespread
cortical
atrophy
progression
relapse
activity
(PIRA)
support
other
than
WM
demyelination.
three-dimensional
distribution
underlying
pathology
myelinated
T2
lesions
were
investigated
postmortem
MCMS
brains.
Postmortem
brain
slices
from
previously
characterized
(10
cases)
typical
(TMS)
cases
(12
co-registered
situ
hyperintensities
T1
hypointensities.
intensity
thresholds
used
establish
a
classifier
that
differentiates
TMS.
was
validated
36
uncharacterized
brains
applied
baseline
MRIs
255
living
PMS
participants
enrolled
SPRINT-MS.
Myelinated
have
contiguous
periventricular
expands
at
the
occipital
poles
lateral
ventricles
where
surface-in
gradient
axonal
degeneration
observed.
MRI
distinguished
pathologically
confirmed
TMS
an
accuracy
94%.
For
SPRINT-MS
patients,
identified
78%
as
TMS,
10%
MCMS,
12%
paucity
intensities.
In
SPRINT-MS,
expanded
status
scale
measures
similar
cohorts.
A
22%
raises
questions
regarding
primary
role
for
all
has
implications
clinical
management
trial
outcomes
PMS.
Periventricular
fiber
provides
additional
gradients
neurodegeneration
MS.
