Extracellular Vesicle Biomarkers Track Cognitive Changes Following Intranasal Insulin in Alzheimer's Disease.
Alzheimer’s disease
biomarkers
brain insulin resistance
exosomes
extracellular vesicles
intranasal insulin
Journal
Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863
Informations de publication
Date de publication:
2019
2019
Historique:
pubmed:
9
4
2019
medline:
12
9
2020
entrez:
9
4
2019
Statut:
ppublish
Résumé
Insulin resistance is implicated in Alzheimer's disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance. We sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD. We isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or 40 IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog). There were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ɛ4 non-carriers. Neuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin.
Sections du résumé
BACKGROUND
Insulin resistance is implicated in Alzheimer's disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance.
OBJECTIVE
We sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD.
METHODS
We isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or 40 IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog).
RESULTS
There were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ɛ4 non-carriers.
CONCLUSION
Neuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin.
Identifiants
pubmed: 30958348
pii: JAD180578
doi: 10.3233/JAD-180578
pmc: PMC6668911
mid: NIHMS1037984
doi:
Substances chimiques
Biomarkers
0
Insulin
0
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
489-498Subventions
Organisme : Intramural NIH HHS
ID : Z99 AG999999
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG049638
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001420
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG027415
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AG000975-10
Pays : United States
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