Alzheimer s & Dementia,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 13, 2024
Abstract
INTRODUCTION
Progressive
supranuclear
palsy
(PSP)
is
a
devastating
4R
tauopathy
affecting
motor
functions
and
often
misdiagnosed/underdiagnosed
due
to
lack
of
specific
biomarkers.
Synaptic
loss
an
eminent
feature
tauopathies
including
PSP.
Novel
synaptic
positron
emission
tomography
tracer
UCB‐J
holds
great
potential
for
early
diagnosis;
however,
there
substantial
knowledge
gap
in
terms
the
mechanism
extent
nature
METHODS
Here,
we
report
in‐depth
post
mortem
validation
mechanistic
study
PSP
control
brains
using
radioligand/autoradiography
binding
studies,
alongside
biochemical
correlation
analyses
markers.
RESULTS
AND
DISCUSSION
3
H‐UCB‐J
targeted
vesicle
protein
2A
with
high
specificity
demonstrated
distinct
interrelation
markers
patients’
brain
regions.
The
severely
affected
globus
pallidus
revealed
deficits
glutamate/GABAergic
terminals.
Cortical
subcortical
tau
load
differentially
impacted
marker
profiles
across
patients,
warranting
further
investigation.
Highlights
progressive
conserved
single
nM
site
different
depicted
prominent
at
synaptosome
levels
terminals
as
compared
control.
distinctly
influenced
profile
patients
highlighted
that
presynaptic
“ubiquitous”
individually
might
not
be
able
represent
complete
state
deficits/loss
brains.
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
20(4), С. 2589 - 2605
Опубликована: Фев. 16, 2024
Abstract
INTRODUCTION
Synaptic
loss
is
an
early
prominent
feature
of
Alzheimer's
disease
(AD).
The
recently
developed
novel
synaptic
vesicle
2A
protein
(SV2A)
PET‐tracer
UCB‐J
has
shown
great
promise
in
tracking
AD.
However,
there
have
been
discrepancies
between
the
findings
and
a
lack
mechanistic
insight.
METHODS
Here
we
report
first
extensive
pre‐clinical
validation
studies
for
control
(CN;
n
=
11)
AD
(
brains
using
multidimensional
approach
post‐mortem
brain
imaging
techniques,
radioligand
binding,
biochemical
studies.
RESULTS
AND
DISCUSSION
We
demonstrate
that
could
target
SV2A
with
high
specificity
depict
at
synaptosome
levels
regions
compared
to
CNs.
showed
highest
hippocampus
followed
descending
order
by
frontal
cortex,
temporal
parietal
cerebellum.
3
H‐UCB‐J
large
brain‐section
autoradiography
cellular/subcellular
fractions
binding
indicated
potential
off‐target
interaction
phosphorylated
tau
(p‐tau)
species
brains,
which
subsequent
clinical
implications
Highlights
positron
emission
tomography
(PET)–tracer
(AD)
brains.
control.
Potential
studies,
warranting
further
investigations.
Molecular Neurodegeneration,
Год журнала:
2025,
Номер
20(1)
Опубликована: Март 14, 2025
Abstract
Alzheimer’s
disease
(AD)
is
neuropathologically
characterized
by
the
extracellular
deposition
of
amyloid-β
peptide
(Aβ)
and
intraneuronal
accumulation
abnormal
phosphorylated
tau
(τ)-protein
(p-τ).
Most
frequently,
these
hallmark
lesions
are
accompanied
other
co-pathologies
in
brain
that
may
contribute
to
cognitive
impairment,
such
as
vascular
lesions,
transactive-response
DNA-binding
protein
43
(TDP-43),
and/or
α-synuclein
(αSyn)
aggregates.
To
estimate
extent
AD
patients,
several
biomarkers
have
been
developed.
Specific
tracers
target
visualize
Aβ
plaques,
p-τ
αSyn
pathology
or
inflammation
positron
emission
tomography.
In
addition
imaging
biomarkers,
cerebrospinal
fluid,
blood-based
biomarker
assays
reflecting
AD-specific
non-specific
processes
either
already
clinical
use
development.
this
review,
we
will
introduce
pathological
brain,
related
discuss
what
respective
determined
at
post-mortem
histopathological
analysis.
It
became
evident
initial
stages
plaque
not
detected
with
currently
available
biomarkers.
Interestingly,
precedes
deposition,
especially
beginning
when
unable
detect
it.
Later,
takes
lead
accelerates
pathology,
fitting
well
known
evolution
measures
over
time.
Some
still
lack
clinically
established
today,
TDP-43
cortical
microinfarcts.
summary,
specific
for
AD-related
pathologies
allow
accurate
diagnosis
based
on
pathobiological
parameters.
Although
current
excellent
pathologies,
they
fail
which
analysis
required.
Accordingly,
neuropathological
studies
remain
essential
understand
development
early
stages.
Moreover,
there
an
urgent
need
co-pathologies,
limbic
predominant,
age-related
encephalopathy-related
modify
interacting
p-τ.
Novel
approaches
vesicle-based
cryptic
RNA/peptides
help
better
future.
EBioMedicine,
Год журнала:
2025,
Номер
112, С. 105557 - 105557
Опубликована: Янв. 31, 2025
Synapse
preservation
is
key
for
healthy
cognitive
ageing,
and
synapse
loss
represents
a
critical
anatomical
basis
of
dysfunction
in
Alzheimer's
disease
(AD),
predicting
dementia
onset,
severity,
progression.
viewed
as
primary
pathologic
event,
preceding
neuronal
brain
atrophy
AD.
Synapses
may,
therefore,
represent
one
the
earliest
clinically
most
meaningful
targets
neuropathologic
processes
driving
AD
dementia.
The
highly
selective
particularly
vulnerable
synapses
while
leaving
others,
termed
resilient,
largely
unaffected.
Yet,
anatomic
molecular
hallmarks
resilient
populations
their
association
with
changes
(e.g.
amyloid-β
plaques
tau
tangles)
memory
remain
poorly
understood.
Characterising
selectively
may
be
to
understanding
mechanisms
versus
enable
development
robust
biomarkers
disease-modifying
therapies
Alzheimer s & Dementia,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 28, 2024
Abstract
INTRODUCTION
The
longitudinal
progression
of
synaptic
loss
in
Alzheimer's
disease
(AD)
and
how
it
is
affected
by
tau
pathology
remains
poorly
understood.
METHODS
Thirty
patients
with
amnestic
mild
cognitive
impairment
(aMCI)
26
healthy
controls
underwent
evaluations
tau,
vesicle
protein
2A
(SV2A),
amyloid
positron
emission
tomography.
Twenty‐one
aMCI
2‐year
follow‐up
(FU)
investigations.
RESULTS
Tau
levels
increased
longitudinally
Braak
regions
III
through
VI
but
not
I
II.
SV2A
decreased
all
aMCI.
Baseline
was
negatively
associated
early
at
FU
across
regions.
change
were
decline.
DISCUSSION
accumulation
reaches
a
plateau
already
the
stage
AD.
In
regions,
association
between
baseline
might
reflect
dysfunction
caused
pathology.
Highlights
reached
patients.
show
widespread
decrease
(SV2A)
over
2
years.
predictive
for
loss.
tau–SV2A
relation
showed
individual
variability
negative
cognition.
Neuroscience Letters,
Год журнала:
2025,
Номер
849, С. 138135 - 138135
Опубликована: Фев. 1, 2025
Neuronal
and
synapse
losses
are
seen
under
the
progression
of
Alzheimer's
disease
(AD).
Accordingly,
binding
to
synaptic
vesicle
glycoprotein
2A
(SV2A)
using
selective
radioligand
[3H]UCB-J
was
found
be
reduced
in
frontal
cortex
from
patients
with
AD.
We
report
here
that
reduction
SV2A
is
highly
significant
only
not
carrying
ApoE
ɛ4
allele.
By
contrast,
those
individuals
one
or
two
alleles
had
levels
different
controls.
Because
ApoE4
an
important
genetic
risk
strongly
linked
late-onset
AD,
this
study
raises
interesting
new
unexpected
association
SV2A,
loss,
function.
Journal of Nuclear Medicine,
Год журнала:
2025,
Номер
unknown, С. jnumed.124.269005 - jnumed.124.269005
Опубликована: Март 6, 2025
Synaptic
density
imaging
with
PET
is
a
relatively
new
approach
to
monitoring
synaptic
injury
in
neurodegenerative
diseases.
However,
there
are
remaining
technical
and
clinical
questions,
including
questions
on
reference
region
selection
how
specific
phenotypic
presentations
symptoms
of
Alzheimer
disease
(AD)
reflected
alterations
density.
Methods:
Using
vesicle
glycoprotein
2A
(SV2A)
ligand
radiolabeled
the
18F
isotope
([18F]SynVesT-1),
we
performed
sensitivity
analyses
determine
optimal
tissue
modeling
derive
whole-brain
ratio
images.
these
images
from
sample
young
adults,
older
patients
varied
AD,
then
contrasted
regional
SV2A
vivo
AD
biomarkers.
Results:
Reference
optimization
concluded
that
cerebellar
gray
matter
best
for
deriving
images,
found
strong
inverse
association
between
[18F]SynVesT-1
uptake
amyloid
β
tau
deposition.
Finally,
individuals
lower
temporal
volume
but
higher
show
preserved
performance
mini-mental
state
examination.
Conclusion:
shows
close
pathology,
may
be
possible
marker
resilience
neurodegeneration.
