Ultra-high-field MRS can directly identify molecular markers like IDH1 and IDH2 mutations in gliomas in less than 5 minutes with high sensitivity and specificity. It detected 2-HG in two case studies of patients with gliomas, leading to a diagnosis of IDH2 mutation in one case. Compared to standard 3T MRS, 7T MRS using a double spin echo technique had improved detection of 2-HG. Ultra-high-field MRS provides a non-invasive method for prognostic precision medicine by stratifying and monitoring IDH mutant glioma patients through detection of genetic and metabolic biomarkers.

1. Ultra-High-Field 1H
MRS as a
Prognostic
Precision Medicine
Biomarker
Detection System
for Gliomas
Uzay E Emir
• School of Health Sciences and Weldon
School of Biomedical Engineering,
Purdue University, West Lafayette, IN,
United States
• uemir@purdue.edu

2. Precision Medicine

3. New Molecular
& Genetic
Information
(IDH1 and IDH2
mutations or
1p/19q
codeletion)
Diagnostic Imaging
• Improved diagnostic
accuracy
• Improved
prognostication
• Improved
preoperative planning

4. Standardized brain
tumor MRI protocol
• 3-dimensional (3-D) T1,
• Axial fluid-attenuated inversion
recovery (FLAIR),
• Axial diffusion-weighted imaging
(DWI),
• Axial gadolinium contrast-
enhanced T2,
• 3-D gadolinium contrast-
enhanced T1,
• Performed on a
minimum 1.5 tesla
MR system.
Johnson et al, RadioGraphics 2017
General Case
Specific Case
Ellingson et al Neuro-Oncology 2015
Layered Diagnosis
Molecular Status
IDH1 and IDH2 mutations or
1p/19q codeletion
ISN-Haarlem Brain Tumor Classification
Guidelines Brain Pathology, 2014

5. Diagnostic
Imaging of
Gliomas via
MRI
• Recent literature
suggests that
• 1p/19q codeletion
• IDH
may also be assessable
by MR imaging
These are all less directly
identifications
of IDH mutation or 1p/19q
codeletion
FLAIR for 1p/19q status
Lasocki, AJNR Am J Neuroradiol , 2018
ADC for IDH status,
Villanueva-Meyer, American Journal of
Roentgenology 2018
23NA, sodium, MRI,
Regnery, NeuroImage: Clinical 2020

6. Molecular Status: Direct identification 1
Roles of wt/IDH1/2/3 and some of the potential multiple
effects of IDH mutation
Schofield Lab, Current Opinion in Chemical Biology, 2020
5 - 35
mM
2-HG
Gold
Standard
Dang L Nature. 2009

7. Molecular Status: Direct identification 2 (non-invasive)
Roles of wt/IDH1/2/3 and some of the potential multiple
effects of IDH mutation

8. Molecular Status: Direct identification
via 3 Tesla MRI
Short TE: Pope, J NeuroonNat Medcol, 2012
Editing: Andronesi, Sci Transl Med, 2012
Long TE: Choi, Nat Med, 2012
Improved 2-Hydroxyglutarate Detection at 3T via
Double Spin Echo Adiabatic Localization
SEMI-LASER with a TE of 110 ms
Berrington, Tomography, 2016, Steel Scientific Reports, 2018 and Li, Radiology, 2020
Spatial Distribution of 2-HG

9. Clinical Need
1p/19q codeletion and
IDH status can be
assessable by MR imaging
The need for MRS?
The need for Ultra-High-Field MRS?

10. The need for
Ultra-High-Field
MRS
Sensitivity
Molecular
Status
less than 5
seconds
IDH1 and IDH2
mutations

11. The need for
Ultra-High-Field
MRS
Sensitivity
Molecular Status
Beyond IDH
mutations
less than 5
minutes
1p/19q codeletion and
beyond
2-HG
2-HG
Specificity

12. The need for
Ultra-High-Field
MRS
A Prognostic Precision Medicine
Biomarker Detection System
Precision medicine strategies
• Tailoring therapies,
• Delivering more effective treatments,
whilst avoiding or reducing adverse
outcomes
v Identify
v Stratifying,
v Monitoring IDH1 and IDH2 mutant
glioma patients

13. Improved 2-
Hydroxyglutarate
Detection at 7 Tesla
via Double Spin Echo
Adiabatic Localization
SEMI-LASER with a
TE of 110 ms
Long TE: Emir, Cancer Research 2016
IDH1 (n = 15), IDH2 (n = 5) and IDH (n=7) -ve

14. Lazovic et al.(2012), fig. 3c
TR/TE = 4000/6.9 ms;
number of averages=512; VOI = 3 mL
IDH1 R132H
TR/TE = 5000/110 ms;
number of averages=4; VOI = 8 mL
tCho
tCr
Glu
tNAA
Lac
2-HG

15. CASE 1

16. Final Diagnosis: Oligodendroglioma (WHO
grade 2)
IHC: -ve, DNA Sequencing: IDH2 R172W
2-HG
Lactate
Prediction of UHF MRS IDH2
1st biopsy: not conclusive
Then, total resection
SEMI-LASER TE of 110 ms,
Total Acquisition: 5 minutes

17. Case 2
2-HG Lactate
Prediction of UHF MRS: IDH2
Final Diagnosis: N/A
SEMI-LASER TE of 110 ms,
Total Acquisition: 5 minutes

21. 2-HG detection comparison
3T vs 7T
SEMI-LASER with a TE of 110 ms, Berrington, NMR biomed, 2018

22. Metabolite detection in vivo Error of fitting = Cramer-Rao Lower Bounds (CRLBs)
*p < 0.05

24. Distinguishing the Chemical Signature of Different IDH Mutations in Brain Tumor Patients
at 7 Tesla

28. Case 2
2-HG Lactate
Prediction of UHF MRS: IDH2
Final Diagnosis: N/A
SEMI-LASER TE of 110 ms,
Total Acquisition: 5 minutes

29. 1
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
CYSTATHIONINE
-Co-deletion Co-deletion
IDH2 mutations predominantly occur in
oligodendroglial tumors
IDH2 mutations are commonly associated
with 1p/19q codeletion
Cystathionine may be a marker for
1p/19q codeleted gliomas
Branzoli, Neuro Oncol, 2019

30. Summary
• Improved Sensitivity and Specificity at UHF
• Subtype genetic mutations in Gliomas
• Subcellular compartmentalization of the genetic mutations
• Detecting 2-HG is insufficient to predict the clinical response of IDH mutant
patients (Amatangelo,Blood, 2017), Accurate Measurement associated
metabolites is crucial.
• In vivo UHF 1H MRS data via metabolomics approaches
• not only reveal insights into the underlying metabolic pathways
of tumorigenesis,
• but also monitor the pharmacodynamics and the identification of
new pharmacological targets of anti-cancer treatments.

32. Thank you so much
Oxford University
• Irene Tracey
• Heidi Johansen-Berg
• Olaf Ansorge
• Natalie Voets
• Puneet Plaha
• Christopher Schofield
• Thomas Cadoux-Hudson
• James Mccullagh
• Peter Jezzard
Acibadem University,
Turkey
• Alp Dincer