Abstract

Wearefacingagrowingcrisisofagreaternumberofseniorslivingwithadeclineincognitivefunctionasa commonconsequenceofaging.Onceanimpairmenthasreachedalevelofclinicalsignificance,treatment optionsarelimited.Weproposetoexamineage-relateddifferencesintraitandstateautonomiccontrolofheart rateandtheirrelationtocognitiveperformancehumansandrats.Whilecognitivechangesmaybemaskedby compensatoryefforts,autonomicmeasuresmaybemorerevealingoftheunderlyingage-relatedchangesinthe neuralsubstratesandneurochemistryofaginganditsclinicalcourse.Wewillexaminetheseautonomic regulationofheartrate,itsrelationtoandmodulationbycognitiveperformance,asaperipheralproxyofearly centralalterationofthecholinergicbasalforebrain(BF),aprogenitorofsystem-wideneuroanatomicaland neurochemicalchangesrelatedtoaging.Tounderstandtheunderlyingneuralmechanisticbasesofthese autonomicindices,wewillapplyacross-speciesapproach,includinghumanfunctionalneuroimagingaswellas nonhumanneurochemicalexaminations.
SpecificAim1 willexaminewhetherage-relateddifferencesin cognitivecontrolareassociatedwithalteredautonomicregulationoftheheart.Approach:Wewillemploy across-sectionalexaminationofinhibitorycognitivecontroltasks,whichwehaveshowntodependonthe cholinergicBFinrats,inadiversesampleofmaleandfemaleyoung,middle-aged,andolderadults,examining howcognitiveperformancerelatestoautonomicparasympatheticinfluencesontheheart,reflectedinvagally- mediatedheartratevariability(phasic,beat-to-beatheartratevariability).
SpecificAim2 willexaminethe specificroleoftheBF,anditsafferentnetworks,inconnectingage-relateddifferencesincognitive controlandautonomicregulationoftheheart.Approach:Wewillemploymulti-echofMRItoacquirehigh SNRsignalfromBFnucleiandautonomicphasicparasympatheticinfluencesonheart,andtheirrelationto neurocognitiveaging,whilecharacterizingandcontrollingforage-relateddifferencesincerebralbloodflowwith arterialspinlabelling.
SpecificAim3 willtestthehypothesizedparallelcausalcontributionsofBF cholinergicneuronstocentralcognitiveregulationandperipheralautonomicregulationoftheheart. Approach:Usingcholinergicimmunotoxiclesions,aratmodelofcognitiveagingwillassessthecausalroleof theBFtocognitivecontrolandparasympatheticautonomicregulationofheartrate(vmHRV)inmaleandfemale young,middle-aged,andolderrats.Revealingperipheralautonomicaspectsofage-relateddifferencesinbrain integrityandcognitivestatuswouldadvanceourunderstandingofnormativeandpotentiallypathological neurochemicalchangesinaging.Itwillfurtheradvancetheuseofanoninvasive,low-costperipheralbiomarker foridentifyingthosewhomayprogresstomildneurocognitivedisorder(mNCD).Suchareadilyadministered screenforearlymNCDcouldbetteraffordearlydetection,monitoring,andpotentialinterventionbeforethe onsetofmNCDandpotentialconversiontoAlzheimer?sDisease.

Public Health Relevance

Theproposedstudieswilluseparasympatheticinfluencesonheartratetoassess,inhumans andrats,neurocognitiveaging.Wewillfurtherexaminewhetherthebasalforebrainsupportsa commonregulatorycapacityonbothcognitiveandautonomiccontrol,andthusunderliestheir commonaging-relateddecline.Theproposedresearchmayfurtheradvancetheuseofa noninvasive,low-costdigitalbiomarkerofneurocognitiveagingandservetoidentifythosewho mayprogresstomildneurocognitivedisorderandultimatelyconverttoAlzheimer?sDisease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG066430-02
Application #
10161696
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
2020-05-15
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
Cornell University
Department
Other Health Professions
Type
Sch of Home Econ/Human Ecology
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850