Alzheimer?s disease (AD) afflicts millions of Americans, but no effective treatments exist. Although abnormal proteins (amyloid and tau) accumulate and accompany neurodegeneration inAD, recent studies suggest that inflammation led by the brain?s immune cells (microglia) is an important factor. However, inflammationischallengingtomeasureinlivingpatients.Ironisakeycomponentofinflammationandmaybe toxicinAD.BecauseitcanbemeasuredbyMRI,ironmaybeapracticalsurrogatemeasureforinflammation. CouplingMRIwithpathologyslideshasshownthatironispresentwithinmicrogliainAD,inparticularinapart of the brain important for memory, the hippocampus. This project proposes that iron-containing microglia accumulate early in the disease process. The end result of this inflammation could be tau accumulation and neuronaldeath.Ifiron-containingmicrogliacanbedetectedbyMRIearlyinthediseaseprocess,beforememory hasbecometooimpaired,thiscouldrevolutionizeADdiagnosisandtreatment. Theprojectgoalsareasfollows.(1)Determinewhethertheaccumulationofiron-containingmicrogliais concomitantwithwidespreadamyloiddepositionandantecedenttotaupropagation.Thisprojectwillexamine the post-mortem hippocampus of patients with and without AD pathology. By combining MRI with a careful examination of pathology slides, this project will prove that MRI is measuring iron-containing microglia across thestagesofAD.Wewillalsoseehowtheiron,microglia,amyloid,andtauoverlapwithoneanotherinhuman brain specimens. (2) Determine whether iron is higher in the hippocampus in AD compared to no AD using advanced microscopy. This project will employ X-ray microscopy and electron microscopy to measure exactly howmuchironisinthehippocampus,andtodefinethepreciselocationwhereitisincreasedinAD.(3)Determine whetheriron-containingmicrogliaarepresentalongwithamyloidandtauinlivingADpatients,presentwithalong amyloid in patients with mild or no AD symptoms, and absent in patients with no amyloid. This proposal will recruitpatientswithAD,patientswithmildcognitiveimpairment,andhealthycontrolparticipantsfromStanford?s Alzheimer?s Disease Research Center. We will balance for gender and age across groups, perform a full neuropsychologicalevaluation,andobtainAPOEstatus.Participantswillundergothreestudies:a7TGREMRI, anamyloidPET-MRscan,andatauPET-MRscan.Thisprojectwillshowhowiron-containingmicroglia,amyloid, andtauoverlapwithoneanotherinlivinghumans. Thecontributionofthisprojectwillbetoshowthat7TGREMRmeasuresiron-containingmicroglia.This measurement can serve as an effective biomarker for inflammation in early AD. This project will enable many excitingopportunitiestotestnewtherapiesbeforetheonsetofmemorydecline.
Theproposedresearchisrelevanttopublichealthbecausethediscoveryofabiomarkerforinflammationin ADisexpectedtoenablethedevelopmentofnewtherapeuticstotargetinflammationandstop neurodegeneration.ThisresearchisrelevanttotheNIH?smissionofidentifyingnewapproachestoprovide novelinsightintoAD,assistinthediagnosisofAD,andpredictoutcome.
