An Investigation of Inflammatory and Metabolic Blood-Based Biomarkers of Cognitive Decline
Citation:
WOLFE, HANNAH, An Investigation of Inflammatory and Metabolic Blood-Based Biomarkers of Cognitive Decline, Trinity College Dublin.School of Medicine.PHYSIOLOGY, 2018Download Item:
Abstract:
Alzheimer’s disease (AD)
and other dementias a
re the
main cause of cognitive
impairment
in older adults. AD is fast becoming a global epidemic, yet the
development of a disease
-
modifying therapy remains elusive. The identification of
earlier preclinical stages of disease offers the best possibility of
slowing down
disease progression, and the use of blood
-
based biomarkers for this purpose is
crucial.
However,
studies so far have shown
poor reproducibility
and few studies
have exami
ned asymptomatic individuals before significant cognitive deficits arise
.
Inflammation is a key feature of
AD pathogenesis, and recently a close link between
inflammation and metabolism has been demonstrated.
The aim
of this study was
to
investigate inflammatory and metabolic blood
-
based biomarkers that could be
indicative of
cognitive decline.
This was accomplished through examining
markers in
monocytes incubat
ed with plasma from cohorts with
cognitiv
e dysfunction, and
by
assess
ing
markers
in
pro
-
inflammatory stimulated
monocyte
-
derived macrophages
(MDMs) and peripheral blood
mononuclear cells (PBMCs)
from a group of healthy
older adults
described as having a subtle cognitive deficit
based on their
performance on a story recall test relative to their estimated IQ
(IQ
-
discrepant)
.
The age
-
related inflammatory phenotype of C57/BL
6 mice was initially assessed and
CXCL1 mRNA was identified in plasma
-
treated monocytes as a potential peripheral
marker of
neuroinflammation
. Expression of IL
-
8, the human homolog of CXCL1, was
revealed to be
upregulated in monocytes incubated with plasma
from IQ
-
discrepant
participants and mild cognitive impairment and AD patients compared with their
respective controls. In addition, monocytes
treated with plasma from AD patients
exhibited an increase in glycolysis. The data suggest that IL
-
8 mRNA
,
and pe
rhaps
glycolysis
,
in plasma
-
treated monocytes could be useful as a potential biomarker
assay for cognitive dysfunction.
MDMs
from IQ
-
discrepant, compared with IQ
-
consistent, participants displayed an
exacerbated
increase in
TNFα
mRNA and
protein expression of TLR2 and CD206
following stimulation with amyloid
-
beta (Aβ)
, as well as a
n exaggerated response to
Aβ +
lipopolysaccharide (LPS) as demonstrated by the increase in TNFα mRNA and
secretion and shift towards glycolysis.
Th
e effect of Aβ
+LPS
stimulation
was
also
greater i
n
PBMCs
from IQ
-
discrepant participants
, as shown by an increase in TNFα,
IL
-
6 and IL
-
8 production, increased glycolysis and
upregulation of
PFKFB3
mRNA
, an
enzyme which drives glycolysis
.
The data
suggest t
hat cells from IQ
-
discrepant
participants have a heightened response to
pro
-
inflammatory stimulation.
Overall, the findings from this study show that IL
-
8 mRNA in plasma
-
treated
monocytes and inflammatory and metabolic markers in MDMs and PBMCs from
subje
cts with an IQ
-
discrepant memory may be useful indicators of cognitive decline
Sponsor
Grant Number
Irish Research Council (IRC)
Author's Homepage:
http://people.tcd.ie/wolfehDescription:
APPROVED
Author: WOLFE, HANNAH
Sponsor:
Irish Research Council (IRC)Advisor:
Lynch, MarinaPublisher:
Trinity College Dublin. School of Medicine. Discipline of PhysiologyType of material:
ThesisAvailability:
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