Alzheimer s & Dementia,
Год журнала:
2019,
Номер
15(6), С. 764 - 775
Опубликована: Май 18, 2019
Abstract
Introduction
Blood‐based
biomarkers
of
pathophysiological
brain
amyloid
β
(Aβ)
accumulation,
particularly
for
preclinical
target
and
large‐scale
interventions,
are
warranted
to
effectively
enrich
Alzheimer's
disease
clinical
trials
management.
Methods
We
investigated
whether
plasma
concentrations
the
Aβ
1–40
/Aβ
1–42
ratio,
assessed
using
single‐molecule
array
(Simoa)
immunoassay,
may
predict
positron
emission
tomography
status
in
a
longitudinal
monocentric
cohort
(N
=
276)
older
individuals
with
subjective
memory
complaints.
performed
hypothesis‐driven
investigation
followed
by
no‐a‐priori
hypothesis
study
machine
learning.
Results
The
receiver
operating
characteristic
curve
learning
showed
balanced
accuracy
76.5%
81%,
respectively,
ratio.
is
not
affected
apolipoprotein
E
(
APOE
)
ε4
allele,
sex,
or
age.
Discussion
Our
results
encourage
an
independent
validation
confirm
indication
that
via
Simoa,
improve
future
standard
care
trial
design.
Molecular Psychiatry,
Год журнала:
2021,
Номер
26(10), С. 5481 - 5503
Опубликована: Авг. 30, 2021
Abstract
Breakthroughs
in
molecular
medicine
have
positioned
the
amyloid-β
(Aβ)
pathway
at
center
of
Alzheimer’s
disease
(AD)
pathophysiology.
While
detailed
mechanisms
and
spatial-temporal
dynamics
leading
to
synaptic
failure,
neurodegeneration,
clinical
onset
are
still
under
intense
investigation,
established
biochemical
alterations
Aβ
cycle
remain
core
biological
hallmark
AD
promising
targets
for
development
disease-modifying
therapies.
Here,
we
systematically
review
update
vast
state-of-the-art
literature
science
with
evidence
from
basic
research
studies
human
genetic
multi-modal
biomarker
investigations,
which
supports
a
crucial
role
dyshomeostasis
pathophysiological
dynamics.
We
discuss
highlighting
differentiated
interaction
distinct
species
other
AD-related
mechanisms,
such
as
tau-mediated,
neuroimmune
inflammatory
changes,
well
neurochemical
imbalance.
Through
lens
latest
multimodal
vivo
biomarkers
AD,
this
cross-disciplinary
examines
compelling
hypothesis-
data-driven
rationale
Aβ-targeting
therapeutic
strategies
early
treatment
AD.
Alzheimer s & Dementia Translational Research & Clinical Interventions,
Год журнала:
2019,
Номер
5(1), С. 272 - 293
Опубликована: Янв. 1, 2019
Abstract
Introduction
Alzheimer's
disease
(AD)
has
few
available
treatments,
and
there
is
a
high
rate
of
failure
in
AD
drug
development
programs.
Study
the
pipeline
can
provide
insight
into
evolution
how
best
to
optimize
practices.
Methods
We
reviewed
clinicaltrials.gov
identified
all
pharmacologic
trials
agents
currently
being
developed
for
treatment
AD.
Results
There
are
132
clinical
Twenty‐eight
42
phase
3
trials;
74
83
2
30
31
1
trials.
an
increase
number
each
compared
with
that
2018
pipeline.
Nineteen
target
cognitive
enhancement,
14
intended
treat
neuropsychiatric
behavioral
symptoms.
96
modification
these,
38
(40%)
have
amyloid
as
primary
or
one
several
effects.
Eighteen
antiamyloid
small
molecules,
20
monoclonal
antibodies
biological
therapies.
Seven
molecules
ten
biologics
tau
combination
(18%).
Amyloid
most
common
specific
Novel
biomarkers
(e.g.,
neurofilament
light),
new
outcomes
Composite
Score
[ADCOMS]),
enrollment
earlier
populations,
innovative
trial
designs
Bayesian
adaptive
designs)
features
recent
Discussion
Drug
continues
robustly
at
phases
despite
setbacks
programs
past.
Continuing
unmet
needs
require
commitment
growing
accelerating
Alzheimer s Research & Therapy,
Год журнала:
2021,
Номер
13(1)
Опубликована: Апрель 17, 2021
Lecanemab
(BAN2401),
an
IgG1
monoclonal
antibody,
preferentially
targets
soluble
aggregated
amyloid
beta
(Aβ),
with
activity
across
oligomers,
protofibrils,
and
insoluble
fibrils.
BAN2401-G000-201,
a
randomized
double-blind
clinical
trial,
utilized
Bayesian
design
response-adaptive
randomization
to
assess
3
doses
2
regimens
of
lecanemab
versus
placebo
in
early
Alzheimer's
disease,
mild
cognitive
impairment
due
disease
(AD)
AD
dementia.
Biological Psychiatry,
Год журнала:
2020,
Номер
89(8), С. 745 - 756
Опубликована: Фев. 13, 2020
BACE1
(beta-site
amyloid
precursor
protein
cleaving
enzyme
1)
was
initially
cloned
and
characterized
in
1999.
It
is
required
for
the
generation
of
all
monomeric
forms
amyloid-β
(Aβ),
including
Aβ
Acta Neuropathologica,
Год журнала:
2021,
Номер
141(5), С. 709 - 724
Опубликована: Фев. 14, 2021
Abstract
The
quantification
of
phosphorylated
tau
in
biofluids,
either
cerebrospinal
fluid
(CSF)
or
plasma,
has
shown
great
promise
detecting
Alzheimer’s
disease
(AD)
pathophysiology.
Tau
at
threonine
231
(p-tau231)
is
one
such
biomarker
CSF
but
its
usefulness
as
a
blood
currently
unknown.
Here,
we
developed
an
ultrasensitive
Single
molecule
array
(Simoa)
for
the
plasma
p-tau231
which
was
validated
four
independent
cohorts
(
n
=
588)
different
settings,
including
full
AD
continuum
and
non-AD
neurodegenerative
disorders.
Plasma
able
to
identify
patients
with
differentiate
them
from
amyloid-β
negative
cognitively
unimpaired
(CU)
older
adults
high
accuracy
(AUC
0.92–0.94).
also
distinguished
disorders
0.93),
well
MCI
0.89).
In
neuropathology
cohort,
samples
taken
on
avergae
4.2
years
prior
post-mortem
very
accurately
identified
comparison
0.99),
this
despite
all
being
given
dementia
diagnosis
during
life.
highly
correlated
p-tau231,
pathology
assessed
by
[
18
F]MK-6240
positron
emission
tomography
(PET),
brain
amyloidosis
F]AZD469
PET.
Remarkably,
inflection
point
increasing
function
continuous
PET
standardized
uptake
value
ratio,
be
earlier
than
standard
thresholds
positivity
increase
p-tau181.
Furthermore,
significantly
increased
quartiles
2–4,
whereas
p-tau217
p-tau181
only
3–4
4,
respectively.
Finally,
differentiated
individuals
across
entire
Braak
stage
spectrum,
staging
0
through
I–II,
not
observed
To
conclude,
novel
assay
identifies
clinical
stages
equally
p-tau181,
increases
earlier,
already
subtle
deposition,
threshold
been
attained,
response
early
deposition.
Thus,
promising
emerging
potential
facilitate
trials
vulnerable
populations
below
apparent
entorhinal
Nature Reviews Neurology,
Год журнала:
2020,
Номер
16(7), С. 381 - 400
Опубликована: Июнь 15, 2020
Pain
medication
plays
an
important
role
in
the
treatment
of
acute
and
chronic
pain
conditions,
but
some
drugs,
opioids
particular,
have
been
overprescribed
or
prescribed
without
adequate
safeguards,
leading
to
alarming
rise
medication-related
overdose
deaths.
The
NIH
Helping
End
Addiction
Long-term
(HEAL)
Initiative
is
a
trans-agency
effort
provide
scientific
solutions
stem
opioid
crisis.
One
component
initiative
support
biomarker
discovery
rigorous
validation
collaboration
with
industry
leaders
accelerate
high-quality
clinical
research
into
neurotherapeutics
pain.
use
objective
biomarkers
trial
end
points
throughout
drug
development
process
crucial
help
define
pathophysiological
subsets
pain,
evaluate
target
engagement
new
drugs
predict
analgesic
efficacy
drugs.
In
2018,
NIH-led
Discovery
Validation
Biomarkers
Develop
Non-Addictive
Therapeutics
for
workshop
convened
from
academia,
industry,
government
patient
advocacy
groups
discuss
progress,
challenges,
gaps
ideas
facilitate
outcomes
this
are
outlined
Consensus
Statement.
strategies
