W81XWH TITLE: PRINCIPAL INVESTIGATOR: Charles Bernick, MD, MPH

Transcription

1 AWARD NUMBER: XXXXXX W81XWH TITLE: Recgnitin f Chrnic Traumatic Encephalpathy thrugh FDDNP PET Imaging PRINCIPAL INVESTIGATOR: Charles Bernick, MD, MPH CONTRACTING ORGANIZATION: Cleveland Clinic Fundatin 9500 Euclid Ave Cleveland, Ohi REPORT DATE: 2/1/2017 XXXXXX Octber 2016 OF Annual Reprt FOR: U Army Med Research and Materiel Cmmand Frt Detrick, Maryland DISTRIBUTION STATEMENT: Apprved fr Public Distributin Unlimited

2 The pinins and/r findings cntained in this reprt are thse f authr(s) shuld nt be cnstrued as an fficial Department f the Army psitin, plicy r decisin s by ther dcumentatin.

3 REPORT DOCUMENTATION PAGE Public reporling burden fr this cllectin f infrmatin is estimated t average 1 hur per respnse. needed, and and reviewing this cllectin f infrmatin. Send cmments this burden t Department Services, Directrate fr Operatins and Reprts shuld be aware that shall be subject t any penally fr failing t cmply PLEASE DO NOT RETURN 1. REPORT DATE 3. DATES COVERED 2/1/ /30/15-12/31/2016 xxxxxxxx 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Early f Chrnic Traumatic W81XWH Sep Sep2016 XXXXXXX Octber 2016 xxxxxxxxxxx XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXX Early Recgnitin f Chrnic Traumatic Encephalpathy Thrugh FDDNP PET Imaging 5b. G GRANT c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Charles Bernick, MD, MPH 5d. PROJECT NUMBER PT e. TASK NUMBER Sf. WORK UNIT NUMBER burden number 8. PERFORMING ORGANIZATION REPORT NUMBER Cleveland, Ohi 9. SPONSORING I MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) and Materiel Cmmand SPONSOR/MONITOR'S REPORT NUMBER(S) 12. DISTRIBUTION I AVAILABILITY STATEMENT Apprved fr Public Distributin Unlimited 14. ABSTRACT 1. The PET bimarker, F-FDDNP (2-( {6 [(2-[F-18] lamin] -2 ) malnnitrile) [FDDNP] has shwn viv detectin f tau in additin t sheet-cntaining brain neuraggregates. Tau prtein in a characteristic distributin is felt t be the cardinal feature f Chrnic Traumatic This ect will examine whether FDDNP PET imaging crrelates with, can predict, decline in ive functin in thse expsed t cumulative head trauma. 15. SUBJECT TERMS Traumatic Brain ury Psitrn Emissin.<..IUlU'::!.!. "'. 16. SECURITY CLASSIFICATlON OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT b. ABSTRACT c. THIS PAGE 8 19b. TELEPHONE NUMBER (include area cde) Unclassified Unclassified Unclassified Unclassified Pa 9 e 3 Standard Frm 298 (Rev. 8-98) Prescribed by ANSI SId.

4 Table f Cntents 1. Intrductin Keywrds...III li... IIII Accmplishments...5 Impact ChangeslPrblems Prducts e... II.,... " It...., ill... II "" 1t.8 Participants/Other Cllabratrs Quad Chart II.,". III... It... It II It...., II It It... II... '*,.....,

5 1. Intrductin: injuries and ther head sustained in battle have assciated with the develpment chrnic traumatic encephalpathy (CTE). Pathlgical have indicated that a characteristic feature f CTE is accumulatin f tau prtein in the brain. Until very recently, there has been n reliable way f measuring tau depsitin in the brain during life. One PET bimarker, F-FDDNP (2-(1-{6-[(2-[F-18]flurethyl(methyl)amin]-2-naphthyl} ethylidene) malnnitrile) [FDDNP] shwn sensitivity fr in viv detectin f tau in additin t B-sheet-cntaining brain amylid neuraggregates. This prject will examine whether FDDNP PET with, and/r can predict, decline in functin in expsed t 2. Keywrds: Traumatic Brain Chrnic Traumatic Encephalpathy, PET imaging, Tau 3. Accmplishments: Upn receiving apprval frm Human Prtectin Office, enrllment f participants began in March, We have cmpleted 45 PET FDDNP with 6 additinal subjects scheduled within the next 4 weeks. Recruitment prgress is reflected in the fllwing Unim Cntrl 3 8 8/ /12 Active, Impaired /12 Retired, Unimpa / Retired, Impaired /12 /68 is t fllwed yearly fr 3 years as f the Prfessinal Fighters Brain Health Study. Of the 26 participants due fr fllw up in 23 participants cmpleted fllw (88%retentin). Of Page 5

6 thse wh are verdue fr year ne fllw up, 2 have been unable t return due t wrk (we will cntinue attempting t schedule their fllw up) and 1 is lst t fllw up due t mving permanently t Australia). Once 50% f the chrt was enrlled, we undertk several analytical appraches t the acquired data that has resulted in three abstract presentatins. Traditinally, PET FDDNP images were analyzed using manually drawn regin f interests (ROI). Because this is nt likely t be a clinically practical methd f interpreting the images, the FDDNP data were prcessed using the autmated MIAKAT (Imanva) kinetic analysis sftware. Parametric images f distributin vlume rati (DVR) were generated with the cerebellum as the reference regin. Reginal DVR measurements were btained using the built-in brain template with gray mask applied. The results indicate a relatinship between increased expsure t head trauma (measured by number f fights) and increased FDDNP uptake in the amygdala and ther tempral lbe structures 135. ~re Fighter O Bx O MMA C 'be) III Num",r ~f Pr Fignn In additin, there was an assciatin between increased uptake in the parahippcampal crtex and wrse perfrmance n several cgnitive measures: Table 3: Uptake and Verbal Prcessi Psychm Reactin cgnitive tests Memry ng Speed tr Speed Time amygdala, ns ns ns Ns hippcampus ns ns ns Ns parahippcampal gyrus ns -.437* brainstem ns ns ns Ns tempral ns ns ns Ns We have als cnducted analyses f the FDDNP images using manual ROI techniques. While many Page 6

7 areas f uptake were strngly age, there des appear t be a relatinship between FDDNP uptake and bth expsure f fights) and reactin time in tempral lbe. prject has prvided a training pprtunity fr ur pst -dctrate student, Bern wh has wrked n assessing the relatinship FDDNP imaging results and neurpsychlgical measures. Preliminary results nted abve have fr presentatin at three cnferences: Lancet Neurlgy Cnference n Preclinical Neurdegenerative Disease (Lndn, Human Amylid Imaging (Miami, 1/17), Neurpsychlgical Sciety (New 2/17). Over the next reprting perid, emphasis will be placed n cmpleting enrllment (hpefully by cntinuing fllw up f the We will als be explring different rn,l"h,\rlc analysis taking int accunt the prblems that we have identified s far ( see as well as further ptential relatinships between ( PET FDDNP and MRI). 4. At the current stage, the impact frm this is limited. The preliminary data we have presented has what we knw abut PET FDDNP beynd the small series that was with retired 5 Changes/Prblems: The prblem we have encuntered is with rate f recruitment, particularly fr cntrl subjects. that slwed enrllment were: 1) unavailability f the FDDNP tracer ver mnth 2) Replacement f ur MRI scanner during Octber and Nvember we PET scan with the MRI we t enrllment issues nw been reslved. We ur recruitment effrts by n t ther studies at ur center that will be cntrl subjects, as well as cntinuing t ut t ther rganizatins in the cmmunity. Given age seems t have an imprtant relatinship t FDDNP uptake, we have placed particular attentin t enrll cntrl subjects that are matched fr age with ur subjects. In rder t cmplete the 3 year fllw up f accrdingly. we will need t extend the cmpletin date Anther challenge that has arisen as we have preliminary analyses f the is the ptimal way t interpret the scans. Because the distributin f tau in Chrnic Traumatic t be mre examining small ROls may t n:>rrl'"l'\c f FDDNP assessment f uptake in 7

8 that may result in a mre means t detect abnrmal tau depsitin. 6. fllwing cnference presentatins been presented at natinal Sarah J. Banks, Vladimir Kepe, Frank DiFilipp, Jrge Barri, and Charles Bernick. Uptake in Relatin t Prfessinal (lancet Neurlgy Preclinical Disrders, lndn, 10/16) FDDNP Sarah J. Banks, Vladimir Kepe, Frank P. DiFilipp, Bern Lee Jrge Barri, and Charles Bernick Reginal FDDNP Uptake and Expsure t Prfessinal Fighting (Human Amylid Imaging, Miami, 1/17) BernG. Neurcgnitin, and Number f Neurpsychlgy Sciety, New Bxers and MMA Uptake, N prducts resulted frm this study ver the last year. 7. and ther Cllabrating individuals wh have wrked n this prject include: Bernick n change Banks - n change Barri n change Image analyst Cntributin t prject - Prcessing PET FDDI\IP Frank DiFillip Supprt - Cleveland Clinic rle analyst t prject Prcessing f PET FDDNP Supprt - Cleveland Clinic 8

9 8. Quad Chart Early Recgnitin f CTE thrugh PET FDDNP Imaging PT PI: Charles Bernick Org: Cleveland Clinic Award Amunt: $746,068 I Study/Prduct Aim(s) Study: Exam the perfrmance f PET FDDNP in a grup f active and retired prfessinal bxers and nn trauma expsed cntrls. Outcmes: T determine if PET FDDNP imaging may be a ptential bimarker f and diagnstic tl fr CTE Apprach Chrt derived frm the Prfessinal Fighters Brain Health Study Active and retired bxers, bth cgnitively nrmal and cgnitively impaired Subjects underg baseline PET FDDNP imaging and fllwed annually with cgnitive, behaviral, and neurlgical testing Timeline and Cst Activities Baseline PET FDDNP Annual MRI, cgnitive, behaviral assessments Analysis Estimated Budget ($K) p04 1$30 $4E $46 $48 I Active and Retired Bxers "''''''''" - - 3year annual fllw up (cgnitive. behavklral. neurlgical Gals/Milestnes CY13 Gal- Develp SOP and train crdinatr IRS Submissin Finalize lgistics f transfer f FDDNP frm prductin t site CY14 Gals IRS apprval btained HRPO apprval btained Identified eligible subjects CY15 Gal- Enrllment f subjects, 1 st subject enrlled 3/15 CY16 Gal Cntinue enrllment and begin annual fllw up visits, analyses CY 17 Gal Cmplete enrllment and cntinue annual fllw up visits, analyses Cmments/Challengesllssues/Cncerns Delay in cmpletin f service agreemenvirs apprvallhrpo apprval delayed initial enrllment; PET FDDNP imaging began 3/15. MRI scanner replacement slwed 2016 enrllment. Prjected enrllment cmpletin 7/16.. Page 9