1. Comparison of cortical perfusion between relapse-remitting multiple sclerosis patients and healthy controls measured using Arterial Spin Labelling MRI
Ruth A. Oliver1,2, Linda Ly1,2, Heidi Beadnall, Chenyu Wang1,2, Todd Hardy2,
Michael H. Barnett1,2
1. Sydney Neuroimaging Analysis Centre, Australia 2. Brain and Mind Centre, University of Sydney, Australia
Introduction
Results
Arterial spin labelling (ASL) uses magnetically labelled blood water as an endogenous contrast agent to acquire quantitative cerebral blood flow (CBF) measurements, but few studies exist in multiple sclerosis (MS).
It is hypothesised the low grey matter (GM) perfusion in MS could reflect decreased metabolism secondary to neuronal loss or dysfunction, with a predilection for progressive forms of MS.
Increased white matter (WM) perfusion may indicate increased metabolic activity due to inflammation, although ASL has limited utility in measuring WM perfusion due to the longer blood transit time coupled with lower perfusion rates in WM1.
Cortical perfusion is impaired even in early MS and is detectable prior to the development of cortical volume loss2, which suggests ASL measurements may be a biomarker of reversible neuronal dysfunction prior to substantive tissue loss.
GM and WM CBF group results
Controls: Mean GM CBF = 68.1 ml/100g/min Mean WM CBF = 35.3 ml/100g/min
Patients: Mean GM CBF = 74.5 ml/100g/min Mean WM CBF = 34.2 ml/100g/min
Difference between the groups was significant, p = 0.03.
The work is part of a longitudinal study of cortical function and structure in 30 patients with relapse remitting MS commencing disease modifying therapy with dimethyl fumurate (Tecfidera).
GM and WM CBF maps
Healthy control
Methods
Perfusion weighted ASL and proton density data of six relapse-remitting MS patients (5F, 1M, aged 24-56Y, mean = 43.5Y) and six healthy controls (5F, 1M, aged 26-40Y, mean = 32.5Y) was acquired using pCASL labelling with 8 arm 3D stack-of-spirals read-out, total inflow time = 1525 ms, bolus length = 1525 ms, matrix = 128 x 128 x 32, image resolution = 1.88x 1.88 x 5.0 mm3.
T1-weighted IR-SPRG for tissue partial volumes estimation: TE/TR = 2.8/7.1 ms, TI = 450 ms, FA = 12°, matrix = 512 x512 x 248, resolution 0.47 x 0.47 x 0.7 mm3.
T2-weighted FLAIR for lesion characterisation: TE/TR = 162/800 ms, TI = 2181 ms, matrix = 512 x 512 x 480, resolution = 0.47 x 0.47 x 0.6 mm3.
MR acquisition
Original CBF map
GM CBF map
Image processing
All images were inhomogeneity corrected using the Freesurfer bias field correction tool.
For the patients, MS lesions were manually segmented on the FLAIR images by a trained neuroimaging analyst using Jim3 software. The lesion masks were registered to T1 space, before being used to ‘inpaint’ the T1 lesions using FSL lesion_filling.
In order to account for the partial volume effect (PVE), GM, WM and CSF tissue concentrations were created from the T1 images using FSL SIENAX, after inpainting in the cases of patients.
To correct for the contribution to PVE from blurring due to the imaging point spread function (PSF), the 1D PSF in the partition direction was estimated using the Extended Phase Graph algorithm4, for both the perfusion weighted and proton density images. Both sets of images were deblurred using a Richardson-Lucy deconvolution algorithm5.
The images were then separated into GM, WM and CSF contributions to total signal using a linear regression algorithm with a 3D kernel6.
These were combined using the appropriate sequence parameters with a GE specific modification to the general kinetic model7 to produce maps of pure GM and WM CBF:
WM CBF map
Patient
Original CBF map
GM CBF map
Sp is the number of averages, ε is the combined efficiency of labelling and background suppression (= 0. 63), λGM and λWM are the tissue specific partition coefficients ( = 0.98 and 0.82, respectively), τ is the labelling duration, w is the post-labelling delay
Original CBF map
GM CBF map
WM CBF map
WM CBF map
Processing pipeline
The above images show example slices from the middle of the imaging region of total CBF, GM CBF and WM CBF for a patient and healthy control.
For the patient, the greater GM CBF both in the original CBF map, and in the GM CBF map, is clearly visible.
It was found that the GM CBF was consistently higher across all cortical regions for the patient cohort. whereas the group mean WM CBF was lower than the control group.
Conclusion
Our results are discordant with previous studies that indicate reduced perfusion in relapse remitting MS, potentially reflecting dynamic changes in GM perfusion and metabolism in early disease.
Diffusely increased cortical and deep GM perfusion could indicate compensatory metabolic change, or a primary pathogenic event, in relapse remitting MS. Exploration of this hypothesis will follow in a larger, longitudinal cohort.
References
(1) Rashid JNNP 2004 (2) Debernard JNNP 2014 (3) ) (4) Hennig J et al, J Mag Res (5) Richardson WH, J Op Soc Am (1) (6) Oliver RA Thesis 2015 (7) Buxton RB et al MRM :
Acknowledgements: We acknowledge partial funding from Biogen for this study and would like to offer our thanks to Dr. Fernando Zelaya for his assistance with the GE ASL sequence.