Atkinson, D

Battiston, M

Demetriou, E

Evans, V

Golay, X

Kim, M

Kujawa, A

Okuchi, S

Schneider, T

Wheeler-Kingshott, C

UCL Discovery

Translating pH-sensitive PROgressive saturation for Quantifying Exchange usingSaturation Times (PRO-QUEST) MRI to a 3T Clinical ScannerMina Kim , Marco Battiston , Eleni Demetriou , Aaron Kujawa , Torben Schneider , Vincent Evans , Sachi Okuchi , DavidAtkinson , Claudia Wheeler-Kingshott , and Xavier GolayDepartment of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom,Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, London,United Kingdom, Philips Healthcare, Surrey, United Kingdom, UCL Centre for Medical Imaging, University College London, London, UnitedKingdom, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy, Brain MRI 3T Research Centre, IRCCS MondinoFoundation, Pavia, ItalySynopsisIn this work, a recently developed method called PRO-QUEST (PROgressive saturation for Quantifying Exchange using Saturation Times) istranslated to a 3T clinical scanner for assessing pH-sensitive indices in phantoms and a healthy volunteer. Our results demonstrate thatquantification of pH sensitive indices using PRO-QUEST is feasible at 3T within clinically acceptable acquisition times. Our initial findingssuggest that PRO-QUEST has the potential to provide a new biomarker to study neurological disorders associated with brain tissueacidosis.IntroductionUnderstanding pH regulation in the brain is important both in healthy and pathophysiological conditions because tissue acidity may be a keycharacteristic associated with neurological disorders such as schizophrenia, bipolar disorder, panic attack and ischemia . Recently, the feasibility ofmapping pH sensitive exchange rates was demonstrated in phantoms and in vivo ischemic rat brains using a novel pulse sequence called PRO-QUEST (PROgressive saturation for Quantifying Exchange using Saturation Times) . We aimed to translate PRO-QUEST to a 3T clinical scanner andestimate pH-sensitive indices for phantoms with various pH values and a healthy volunteer.MethodsThe PRO-QUEST sequence was implemented on a 3T Philips Ingenia MRI scanner (Philips Healthcare, Best, the Netherlands) and tested onphantoms consisting of 100mM glutamate in a standard solution of 1x phosphate-buffered saline (PBS) with several pH (6.08, 6.64 and 7.19) and apure PBS sample (pH 7.14). Phantoms and a healthy volunteer were scanned using a 32 channel head coil. First, a Look-Locker (LL) sequence(Figure 1a) was implemented with 20ms delay times (in lieu of off-resonance saturation pulses displayed in Figure 1b) prior to a multishot turbo fieldecho planar imaging (TFEPI) readout (EPI factor=7) and n acquisitions (n=128 for phantom; n=143 for volunteer) with the following imagingparameters: imaging pulse=sinc-gaussian, duration=0.67 ms, flip angle=8°\15°, TE=3.8 ms, time between readout pulses=42 ms, acquiredresolution=1.88x2.14x5 mm  (phantom) and 1.96x2.04x5mm  (volunteer), TR=6s. For the PRO-QUEST scans (Figure 1b), an off-resonance saturationpulse centred at 3.0ppm (glutamate phantom) or 3.5ppm (volunteer) was applied prior to the TFEPI readouts with identical imaging parameters as theLL sequence. Parameters for the off-resonance saturation pulses used in the PRO-QUEST sequence are as follows: off-resonance saturationpulse=sinc-gaussian, bandwidth=300Hz, duration=20 ms, flip angle=400° (equivalent of 1.3μT). For the healthy volunteer scan, single sliceacquisitions were obtained with a scan time of 2 min 6 s (3 averages) per sequence. Imaging parameters are summarised in Table 1. Additionally,standard multi-echo turbo spin echo (TSE) sequence (TSE factor=20) consisting of 10 echoes with TE=20-200ms with 20ms of inter-echo spacingwas used to quantify T  (to be used as a input parameter in equation 2) in the same geometry as PRO-QUEST.Data processing was performed using custom-written scripts in MATLAB (The Mathworks, Natick, MA, USA). The derived Block-McConnell modelswere fitted to magnitude data using maximum likelihood estimation. The following equation was fitted to LL data to estimate the equilibriummagnetization M , T  and B :M (nτ)={1-[(cosθ) e ]}M (τ)/{1-[(cosθ)e ]}+M (1-e )[(cosθ) e  -----[1]where M (τ) = M  (1-e ); t  is the time between the initial saturation pulse and the first readout pulse; τ is the time between readout pulses withsmall flip angle θ; R  = 1/T ; n is number of acquisitions.Next, the obtained M ,T , B  values were used as input parameters for estimating the exchange-dependent relaxation, R  by fitting the PRO-QUESTdata:M (nτ)={1-[(cosθ) e ]}M (τ)/{1-[(cosθ)e ]}+M (1-e )[(cosθ) e ] -----[2]where M (τ) = M  (1-e )(cosθ)e  + M (1-e ; M  = (R cos φ)/R ; R  = R cos φ+(R + R )sin φ; φ is the angle between theeffective field and the z-axis. Further definition of the equations and parameters are described in literature .Results and DiscussionSimilar to the pre-clinical cases , progressive saturation recovery curves with off-resonance saturation pulses show clear separation among sampleswith various pH values in glutamate and PBS (Figure 2b) while the ones without off-resonance saturation pulses are nearly indistinguishable (Figure2a). The estimated R  significantly correlates with pH in glutamate samples (Figure 2c). In the healthy volunteer, the PRO-QUEST image of signalevolution at the final phase of the amide proton resonance shows clear contrast between white and grey matters (WM/GM) (figure 3b) as contrary tothe LL image (without off-resonance saturation pulses) (figure 3a). The origin of contrast between WM and GM needs further investigation. As forprerequisite parameters in estimation of PRO-QUEST indices, calculated T  values from the LL scan in a healthy volunteer are remarkably consistentwith literature values (table 2) . The pH sensitive R  shows differences between WM and GM.1 2 1 1 3 4 14 2,5,6 1123 45 61-343 3240 1 1zdn-1 -(n-1)τR1 zd-τR1 0-t Rd 1 n-1 -(n-1)τR1zd 0-τR1 d1 10 1 1 exzsatn -n(τR -t (R -R ) )1 sat 1 1ρ  zsat-(τR -t (R -R ))1 sat 1 1ρ 0-t Rd 1 n -n(-τR -t (R -R ))1 sat 1 1ρzsat ss-(R t )1ρ sat -(τ - t )Rsat 1 0-(τ-t )Rsat 1 ss 121ρ 1ρ 122 ex244ex15-7exDue to intrinsic limitations of the specific absorption rate and duty cycle (50%) at clinical field strength, the efficiency of the off-resonance saturationscheme is somewhat compromised. Nonetheless, clinical translation of this technique is very feasible given its easy implementation on standardclinical platforms and the use of existing LL-type of readouts, therefore not requiring pulse programming. Further work is required to achieve full braincoverage within clinically relevant acquisition time.ConclusionOur results demonstrate that quantification of pH sensitive indices using PRO-QUEST is feasible at 3T within clinical acquisition time. Our initialfindings suggest that it would be worthwhile to apply PRO-QUEST for studies on patients with neurological impairment associated with acidosis tobetter understand its distinct imaging features relative to conventional techniques.AcknowledgementsThis work was supported by funding from the European Union’s Horizon 2020 research and innovation programme under the Grant Agreement No667510.References1. Acids in the brain: a factor in panic? Esquivel G, Schruers KR, Maddock RJ, Colasanti A, Griez EJ. J Psychopharmacol. 2010;24(5):639-47.2. Brain lactate and pH in schizophrenia and bipolar disorder: a systematic review of findings from magnetic resonance studies. Dogan AE,Yuksel C, Du F, Chouinard VA, Öngür D. Neuropsychopharmacology. 2018;43(8):1681-1690.3. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Zhou J, Payen JF, Wilson DA, TraystmanRJ, van Zijl PC. Nat Med. 2003;9(8):1085-90.4. PRO-QUEST: a rapid assessment method based on progressive saturation for quantifying exchange rates using saturation times in CEST.Demetriou E, Tachrount M, Zaiss M, Shmueli K, Golay X. Magn Reson Med. 2018;80(4):1638-1654.5. NMR relaxation times in the human brain at 3.0 Tesla. Wansapura JP, Holland SK, Dunn RS, Ball WS Jr. J Magn Reson Imaging. 1999;9:531–538.6. Interregional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents. Gelman N, EwingJR, Gorell JM, Spickler EM, Solomon EG. Magn Reson Med. 2001;45:71–79.7. Routine clinical brain MRI sequences for use at 3.0 Tesla. Lu H, Nagae-Poetscher LM, Golay X, Lin D, Pomper M, van Zijl PC. J Magn ResonImaging. 2005;22(1):13-22.FiguresFigure1. A simplified diagram of the pulse sequence. First, an initial saturation pulse is employed to achieve effective nulling of the longitudinal watermagnetisation. Then, (a) delays (LL scan) or (b) off-resonance saturation pulses (PRO-QUEST scan) are applied and interleaved with the acquisition ofsegmented exchange-weighted images. Progressive saturation gives rise to an observable signal reduction in M  throughout relaxation.Figure 2. Saturation recovery curves of (a) LL scan (with delay) and (b) PRO-QUEST scan (with off-resonance saturation pulses) in PBS and glutamatez(Glu) samples (100mM) at pH=6.08, 6.64 and 7.19. (c) Correlation between R  and pH in glutamate samples (100mM).Figure 3. Axial brain images of steady-state saturation recovery curves (at the final phase) using (a) LL scan (with delay) and (b) PRO-QUEST scan(with off-resonance saturation pulses) in a healthy volunteer. (c) T  map for which raw data were obtained from two LL sequences with small flipangles of 8° and 15°, was computed by maximum likelihood estimation.Table 1. Imaging parameters utilised in this study. Note that offset frequency is applied to only PRO-QUEST (PQ) scan among 3 scans: 1  LL scan [8°readout pulse x number of acquisitions], 2  LL scan [15° readout pulse x number of acquisitions] and PQ scan [(off-resonance pulse + LL with 8°readout pulse) x number of acquisitions].Table 2. T  relaxation times of the present study as compared to literature and R  values from the present study. ROIs are displayed in Figure 3c.FWM = frontal white matter; OWM = occipital white matter; FGM = frontal grey matter; OGM = occipital grey matter.ex1stnd1 ex

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Translating pH-sensitive PROgressive saturation for Quantifying Exchange using Saturation Times (PRO-QUEST) MRI to a 3T Clinical Scanner

Translating pH-sensitive PROgressive saturation for Quantifying Exchange using Saturation Times (PRO-QUEST) MRI to a 3T Clinical Scanner

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