TY - JOUR
T1 - Neuronal insulin signaling and brain structure in nondemented older adults
T2 - the Atherosclerosis Risk in Communities Study
AU - Walker, Keenan A.
AU - Chawla, Sahil
AU - Nogueras-Ortiz, Carlos
AU - Coresh, Josef
AU - Sharrett, A. Richey
AU - Wong, Dean F.
AU - Jack, Clifford R.
AU - Spychalla, Anthony J.
AU - Gottesman, Rebecca F.
AU - Kapogiannis, Dimitrios
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1
Y1 - 2021/1
N2 - We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities–Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.
AB - We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities–Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.
KW - Brain
KW - Exosome
KW - Extracellular vesicle
KW - Insulin
KW - Magnetic resonance imaging
KW - White matter disease
UR - http://www.scopus.com/inward/record.url?scp=85095716816&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095716816&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2020.09.022
DO - 10.1016/j.neurobiolaging.2020.09.022
M3 - Article
C2 - 33160263
AN - SCOPUS:85095716816
SN - 0197-4580
VL - 97
SP - 65
EP - 72
JO - Neurobiology of aging
JF - Neurobiology of aging
ER -