Test-retest reliability of arterial spin labelling for cerebral blood flow in older adults with small vessel disease

Lauren R Binnie, Mathilde M H Pauls, Philip Benjamin, Mohani-Preet K Dhillon, Shai Betteridge, Brian Clarke, Rita Ghatala, Fearghal A H Hainsworth, Franklyn A Howe, Usman Khan, Christina Kruuse, Jeremy B Madigan, Barry Moynihan, Bhavini Patel, Anthony C Pereira, Egill Rostrup, Anan B Y Shtaya, Catherine A Spilling, Sarah Trippier, Rebecca Williams, Jeremy D Isaacs, Thomas R Barrick, Atticus H Hainsworth, Lauren R Binnie, Mathilde M H Pauls, Philip Benjamin, Mohani-Preet K Dhillon, Shai Betteridge, Brian Clarke, Rita Ghatala, Fearghal A H Hainsworth, Franklyn A Howe, Usman Khan, Christina Kruuse, Jeremy B Madigan, Barry Moynihan, Bhavini Patel, Anthony C Pereira, Egill Rostrup, Anan B Y Shtaya, Catherine A Spilling, Sarah Trippier, Rebecca Williams, Jeremy D Isaacs, Thomas R Barrick, Atticus H Hainsworth

Abstract

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test-retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test-retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test-retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015).

Keywords: Arterial spin labelling; Cerebral blood flow; Small vessel disease; Vascular aging; White matter lesions.

Conflict of interest statement

LRB and MMHP were employed as part of the PASTIS trial, JDI was Principal Investigator, and AHH was Chief Investigator. CK is a PI on clinical trials with Bristol-Myers-Squibb and Bayer and has received funding from Novo Nordisk, Bayer and Bristol-Myers-Squibb, all not relevant to the present trial. JDI has been a PI on clinical trials funded by Roche, Merck and Lupin Pharmaceuticals and has received funds from Biogen and Roche, none relevant to the present trial. AHH has received honoraria from Eli-Lilly and from NIA, he chairs the Vascular Cognitive Disorders PIA within ISTAART, and he leads MRC-Dementias Platform UK Vascular Experimental Medicine group. All other authors report no relevant disclosures.

© 2021. The Author(s).

Figures

Figure 1
Figure 1
Example of white matter hyperintensities (WMH) in an older adult with small vessel disease. A, axial FLAIR scan, showing WMH. B, the same axial slice following semi-automated highlighting of WMH using Jim 7.0 software. Participant #022, female aged 77 y, with total WMH volume of 34,510 mm3 (across all scan slices).
Figure 2
Figure 2
An example of regional anatomical and CBF mapping, with tissue segmentation. A, FLAIR image at full resolution. B, FLAIR image co-registered to the cerebral blood flow map, with voxels re-sized to be comparable with pCASL map. C, cerebral blood flow map, derived from pCASL. The calibration bar shows 0.0 - 80.0 ml/min/100g. D, tissue segmentation map for CBF computation. Each voxel has been defined as either: grey matter (GM), normal appearing white matter (NAWM), white matter hyperintensity (WMH) or cerebrospinal fluid (CSF). E, F: graphs show the probability density functions of cerebral blood flow values in voxels assigned as grey matter (in E) and normal appearing white matter (F). For this participant, median CBF in grey matter was 51.3 mm/min/100g and in NAWM 21.8 ml/min/100g. Participant #023, female, aged 56 y, visit 1.
Figure 3
Figure 3
Test–retest reliability for CBF measurements (ml/min/100g) between visit 1 and visit 2. A) total grey matter, B) deep grey matter nuclei (caudate-putamen, thalamus), C) normal appearing white matter, D) white matter hyperintensities (WMH), E) whole brain. Each data point represents an individual participant, at study visit 1 (X-axis) relative to visit 2 (Y-axis). Dashed lines show the line of identity.
Figure 4
Figure 4
CBF with respect to age and diastolic blood pressure (DBP). CBF (ml/min/100g) for total grey matter (panels A, C) and normal appearing white matter (B, D) are plotted with respect to participant age (A, B) and DBP (C, D). CBF data are derived from the average across visit 1 and visit 2 for each participant (N=54). Solid lines show the least-squares linear best fit to the data.

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