TheoriginaltheoryofferedbyBraak&Braak(1991)?thatneurofibrillarytanglepathologyproceedsalongwell- definedpredilectionsitesbeginninginthemedialtemporalcortex?hasbeenmodifiedbythesameauthorto suggest that the pathologic process instead commences in the lower brainstem (Braak et al 2011). The first visiblepathologicchangesarenowthoughttooccurinthelocuscoeruleus(LC)andthenspreadviaitsaxonal projections to transentorhinal/entorhinal cortex (TEC). We propose to study LC change using a novel computational morphology method, combined with novel methods of measuring white matter microstructural tractography and functional connectivity to TEC. These new methods are designed to overcome major shortcomingsincurrentneuro-MRIanalysismethodsthatlimittheabilitytodetectsubtlestructuralandfunctional changesassociatedwithearlyAD.Suchalterationsacrosstheaging-MCI-ADcontinuum,aswellasinthose cognitivelynormalindividualswithriskfactorsforAD(e.g.,CSFADbiomarkers;?apolipoproteinEe?4carriers), would provide significant advances in our understanding of the pathogenesis of AD across clinical transition pointsandperhapsduringthis?silent?period(i.e.,priortotheoccurrenceoftraditionalADbiomarkerpositivities). UsingournewlydevelopeddiagnosticandMRImetrics,weproposetoquantifyvariationsinLCmorphologyand itsprojectionstoTEC(whichwetermtheLC-TECsystem).
Aim 1. Examine locus coeruleus morphology, contrast, and associated cortical thickness. Morphological variationswillbecharacterizedbysphericalwavedecomposition(SWD)ofhigh-resolutionanatomicalMRIdata supplementedbyrecentcontrastratio(Takahashietal.2015)analysesofT1FastSpinEchoMRIscans.
Aim2. ExaminestructuralconnectivityoftheLC-TECsystem.Neuralconnectivitywillbecharacterizedbyour noveldiffusiontensorimaging(DTI)tractographymethod(geometric-opticbasedentropyspectrumpathways, GO-ESPDTI)toquantifyafferentandefferentpathwaysbetweentheLCandTEC,andefferentprojectionsfrom theLCtocerebellumandcortex.
Aim3. ExaminefunctionalconnectivityoftheLC-TECsystem.Restingstatefunctionalmodesandconnectivity willbederivedfromournovelentropyfielddecomposition(EFD)analysisofrsFMRIdataguidedbytheprediction thatADtauopathyinitsearliestphasesisnotdeterminedbylargelossesofneuronsbutbyenormousnumbers of nerve cells that survive with limited functionality (Braak & Del Tredici 2015);? alterations in functional connectivityoftheLC-TECsystemwillserveasasurrogatemarkerofthislimitedfunctionality. Demonstrations of improvement in diagnostic and imaging precision in Preclinical AD will have an important impactonprospectivedesignoffuturestudiesand,ifsuccessful,producenewbiomarkerassessmentmodalities andfundamentalshiftsinourtherapeutictargetsforAD.
Weareenteringaneweraofresearchandclinicalactivitythatwillincreasinglyfocusontheroleofbiomarkers inAlzheimer?sdisease(AD)detection,diagnosis,andclinicaloutcome.Braaketal.(2011)havemodifiedtheir longstandingtheoryofADpathogenesistosuggestthatthefirstvisiblepathologicchangesoccurinthelocus coeruleus(LC)andthenspreadviaitsaxonalprojectionstotransentorhinal/entorhinalcortex(TEC),andwe proposetoemployanovelmorphologicalanalysismethodtostudywhetherLCchanges,combinedwithnovel methods of measuring white matter microstructural tractography and functional connectivity to TEC, are demonstrableintheearlieststagesofAD.Suchalterationsacrosstheaging-MCI-ADcontinuum,aswellasin those cognitively normal individuals with risk factors for AD (e.g., CSF AD biomarkers;? apolipoprotein E e?4 carriers), would provide significant advances in our understanding of the pathogenesis of AD across clinical transitionpointsandperhapsduringthis?silent?period(i.e.,priortotheoccurrenceoftraditionalADbiomarker positivities).
| Berry, David B; Regner, Benjamin; Galinsky, Vitaly et al. (2018) Relationships between tissue microstructure and the diffusion tensor in simulated skeletal muscle. Magn Reson Med 80:317-329 |
