MRI April 2015Mayo Cliff JackBret Borowski Matt BernsteinArvin Forghanian-

Arani Jeff GunterDave Jones Kejal KantarciRob Reid Denise Reyes Matt SenjemKaely ThostensonPrashanthi Vemuri Chad Ward

Funded MRI InvestigatorsCharlie DeCarli – UCD

Nick Fox – UCL

Mike Weiner/Duygu Tosun – SFVA

Paul Thompson – USC

Danielle Harvey – biostats

MR Company collaboratorsDan Rettmann – GE Mayo

Pete Kollasch – Siemens, Mayo

Yansong Zhao - Philips, BU

ADNI 3 protocol – all sequences in all subjects 3D T1 volume

3D FLAIR T2* GRE ASL –3D, pCASL, background suppression TF-fMRI – 2 tiered, use capability of advanced

systems Advanced - 10 minute, multi band, sub second TR Basic – 10 minute, 3 sec TR

dMRI - 2 tiered, use capability of advanced systems Advanced - 2 b-shells with 48/64 encoding

directions Basic – single shell b=1000

Coronal high res T2 – hippocampal subfields

ADNI 3 MRI protocol rationale 3D T1, FLAIR, T2*GRE

3D T1 (MPRAGE, IR-FSPGR) most precise longitudinal measure (biomarker or

clinical/psych) – core for multi modality comparisons

Associations with tau PET (and other measures) FLAIR

Disease detection – safety standard, clinical reads Associations of CVD with tau PET (and other

measures) Possible improved results with 3D

T2* GRE MCB detection, all clinical trials

ADNI 3 MRI protocol rationale ASL, dMRI, TF-fMRI

Promising associations, but not strong enough to recommend including in trials using ADNI 2 methods

Significant developments since ADNI 2 given in other fields, improved methods =

better diagnostic performance multi modality comparisons in deeply

phenotyped subjects Opportunity to see if advanced methods cross

the diagnostic “value” threshold in ADNI environment

ADNI 3 MRI protocol rationale ASL, dMRI, TF-fMRI

field continues to seek methods which can be used in Phase 2 which provide an early signal of treatment response

measures of brain function may detect neuronal response to therapeutic reduction in toxic molecular species (e.g. soluble Ab or tau)

2016 advanced is 2022 routine – do not want methods to be outmoded by end of ADNI 3 grant cycle

Grantsmanship – novelty

Approach to “experimental sequences ” from ADNI 2 – leveraging the best in class

from other efforts dMRI and TF-MRI – human

connectome project (HCP) ASL – ISMRM expert work group Phantom – NIST/ISMRM QMRI

committee

dMRI approach advanced, HCP-like – 2 shells, b=1000

& 2000 Better ROI-based MD, FA measures Enable adding ROI-based kurtosis measures Enable tractography Enable cortical hub to hub connectivity analyses

Basic – single shell, b=1000 Compatibility – equivalent of basic

dMRI in every subject at no time penalty extract b1000 shell from advanced acquisitions

Rooted in multi center real world trial environment

ADNI 3 dMRI b shell sampling illustrated

2.0 mm isotropic for both

advanced basic

#(b = 0) 18 6

#(b = 1000) 48 48

#(b = 2000) 64 0

Arrangement

Advanced (Multiband, Multishell)skyra

BasicGE 750

EPI Distortion

Correcting EPI Distortion By Acquiring b = 0 volumes with

both P->A and A->P Phase Encoding Directions

TF-fMRI approach

advanced, HCP-like – 10 min, sub second TR, MB More precise measure of time series (temporal

resolution) Less noisy node to node, ICA, graph theory

measures Directly measure physiological parameters Time varying connectivity metrics

Basic – 10 minute, ~3 sec TR Compatibly advanced and basic

down sample advanced time series to 1 volume/~3 sec

MB Acquisition TR=482ms 20 minutes test data from healthy

volunteer Spatial resolution 3x3x3mm MB=8 which has 4x multiplexing and 2x

in plane acceleration Downsampled by cubic spline

interpolation at multiples of 3.0 sec interpolant includes information from

about same “receiver on” time as a fully sampled data – SNR’s of fully sampled TR=3 data ~ downsampled

Downsampling MB fMRI

pseudo-continuous labeling with background suppression

segmented three-dimensional readout without vascular crushing gradients

and calculation and presentation of both label/control difference images and CBF maps

GE product now; Siemens d13; Philips 3D GraSE  now testing

3D pCASL CBF map, volunteer, GE

• 8 Channel Head Coil• Acquisition Orientation: Axial• FOV: 22 cm• TR/TE: 11000/147.0 ms• TI: 2250 ms• Resolution: 3.6*0.86*1.14 (ST*FE*PE)• Scan time: 4:25 (mins:sec)

GE Standard 2D FLAIR

GE V25 3D FLAIR + T2 Prep + PROMO

• 24 Channel Head Coil• Acquisition Orientation: Sagittal• FOV: 25.6 cm• TR/TE: 7600/115.0 ms• TI: 1968 ms• Resolution: 1.4*1*1.14 (ST*FE*PE)• Scan time: 5:14 (mins:sec)

MR Phantom: ADNI Experience

scanners are much more stable now vs 2005 –hence less need to correct for scan to scan geometry fluctuation

use phantom to track scanners through upgrade and maintenance cycles – qualification and re qualification

Phantoms are helpful for establishing comparability of new models of scanners as the come along

ADNI Phantom Designed by ADNI MRI core along with

Rich Mallozzi (GE), Josh Levy(Phantom Labs) in 2004/2005

produced at Phantom Labs in upstate NY – Josh Levy

Priced in the range of $6k per unit Freely available analysis package

distributed via ADNI website – Jeff Gunter (Mayo)

Commercial analysis available from ImageOwl (a Phantom Labs partner)

NIST-ISMRM System Phantom

ISMRM Standards and Quantitative MR committee has developed a quantitative MRI phantom design

Provides similar geometric fidelity measurements to ADNI phantom (that component strongly influenced by ADNI phantom experience)

WITH resolution and slice thickness assessments inspired by ACR-NEMA phantom

AND NIST validated T1, T2, PD arrays

NIST-ISMRM System Phantom

ADNI phantom

NIST-ISMRM System Phantom

“Open Source” philosophy – anybody welcome to manufacture them Currently only vendor has done it more expensive than ADNI phantom –

target price is lower if production can be increased

Analysis software is currently immature (work in progress) – will be open source

NIST-ISMRM System Phantom Specs

• Diameter: 201 mm• Contrast cells, 20 mm ID spheres:• 14 spheres T1 spread (20ms-2s)• 14 spheres T2 spread (8ms–800ms)• 14 spheres proton density• True dimensional/positional accuracy of 0.1 mm on all key elements• Resolution insert with hole/slot arrays (hole dimensions from 1 mm

down to 0.4 mm with 1.2 mm spacing)• Wedges for slice profiling (Two 80 mm x 8mm wedges at a 10° angle)• Physical and MR key to precisely determine phantom alignment• Physical and MR readable serial numbers• NIST verified T1, T2, and dimensional properties• Public domain 3D model, parameter spread sheet

Plan for phantoms in ADNI 3 Use: to qualify and requalify scanners

But ADNI phantoms in field for 10yrs Keep existing ADNI phantoms that are in

the field until they age out of use and need repair/replacement

Previous pharma studies have some ADNI phantoms in storage at Mayo which could be folded into the ADNI fleet as replacements needed

When that supply is exhausted, roll in NIST/ISMRM phantom to replace ADNI phantoms?

Comparison testing this summer

MR measures - Maintain current set of funded MR investigators with roles adapted

to ADNI 3 Structural MRI measures BSI – UCL (Fox) Freesurfer – SFVA (Tosun ) TBM – USC (Thompson) TBM-Syn – Mayo (‘Jack’)

Cerebrovascuar disease – UC Davis (DeCarli) AIRA H (CMB) – Mayo (‘Jack’) ASL – SFVA (Tosun) TF-fMRI – Mayo (‘Jack’) dMRI - USC (Thompson) Hipp subfields – SFVA (Mueller)

Site query

ADNI 3 is predicated on modern scanning methods

Have not been given access to most modern scanner at some sites

Letter to site PIs from Mike – enlisting help in gaining access

will not do dMRI, ASL, TF-fMRI on scanners that can not meet spec for basic protocol

Summary: High res subfield volumetry vs. standard hippocampal volumetry

• Requires special high resolution sequence (8.1 min acquisition time wo acceleration). BUT, acceleration by factor 2 is possible Loss of S/N likely to be compensated by reduced susceptibility to motion.

• Has potential to reduce the sample sizes needed to detect effects of early AD (amyloid positivity, differentiation between EMCI and normal) by a factor 2 to 3 compared to traditional hippocampal volumetry.

• Fully automated algorithms allowing for subfield segmentation of the entire hippocampus available, dedicated longitudinal processing available or being developed. Most algorithms also include parcellation of extrahippocampal mesial temporal structures, e.g. entorhinal cortex, BA36.

Group, (AD, EMCI, LMCI, normal), Normal vs EMCI, detection of hippocampal volume loss in EMCI compared to Amyloid in Normal: subfield volume loss due to amyloid positivity, all analyses corrected for age, ICV

SNAP

Annals Neurol 2012 Objectives Operationalize the NIA-AA criteria How do cognitively normal subjects

(n=450) in MCSA distribute in the NIA-AA scheme?

Proportions of cog normal preclinical A stage Annals, 2012

43%

3%12%

16%

A-N+; suspected non-AD pathophysiology (SNAP) – 23%

suspected pathological basis of SNAP:

heterogeneous Annals 2012 Non-AD pathology

cerebro-vascular disease, Lewy body disease, grain disease, TDP43, hippocampal sclerosis

Medial temporal tauopathy wo amyloidosis - Braak 1997, 2011; Delacourte 2002; Duyckaerts 1997; Price and Morris 1999; Crary 2014 (PART)

Aging