Magnetic resonance imaging of myelin using ultrashort Echo time (UTE) pulse sequences: Phantom, specimen, volunteer and multiple sclerosis patient studies

Abstract

Clinical magnetic resonance imaging of multiple sclerosis (MS) has focused on indirect imaging of myelin in white matter by detecting signal from protons in the water associated with myelin. Here we show that protons in myelin can be directly imaged using ultrashort echo time (UTE) free induction decay (FID) and imaging sequences on a clinical 3T MR scanner. An adiabatic inversion recovery UTE (IR-UTE) sequence was used to detect signal from myelin and simultaneously suppress signal from water protons. Validation studies were performed on myelin lipid and myelin basic protein (MBP) phantoms in the forms of lyophilized powders as well as suspensions in D2O and H2O. IR-UTE sequences were then used to image MS brain specimens, healthy volunteers, and patients. The T2* of myelin was measured using a UTE FID sequence, as well as UTE and IR-UTE sequences at different TEs. T2* values of ~110-330μs were measured with UTE FID, as well as with UTE and IR-UTE sequences for myelin powders, myelin-D2O and myelin-H2O phantoms, consistent with selective imaging of myelin protons with IR-UTE sequences. Our studies showed myelin selective imaging of white matter in the brains in vitro and in vivo. Complete or partial signal loss was observed in specimens in areas of the brain with histopathologic evidence of myelin loss, and in the brain of patients with MS.

Keywords: MRI; Myelin; Myelin basic protein; Myelin lipid; UTE.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1

Pulse sequence for 2D UTE imaging using half pulse excitation and radial ramp sampling with a minimal nominal TE of 8 μs (A). An adiabatic IR preparation pulse together with dual echo acquisition was used to create short T2 contrast (B). The adiabatic IR pulse provides robust inversion of the longitudinal magnetizations of gray matter (GM) and the long T2 components in white matter (WML). Myelin has ultrashort T2* and experience significant transverse relaxation during the long adiabatic inversion process, and is not inverted but saturated. UTE acquisition starts when the inverted longitudinal magnetization of WML reaches the null point, leaving signals from myelin and residual GM to be detected by the FID acquisition. The 2nd echo contains signal from GM, with near zero signal from myelin due to its ultrashort T2*. Subtraction of the 2nd echo from the FID provides selective imaging of myelin. However, myelin contrast highly depends on TI (C): when TI is too short, WML has negative magnetization leading to myelin signal cancellation; when TI is too long, WML has positive magnetization leading to myelin signal overestimation. The correct TI can be calculated based on measured T1 of WML and TR.

Figure 2

UTE FID of bovine myelin extract powder with a short rectangular hard pulse excitation (duration = 32 μs) and a half pulse excitation (duration = 472 μs), and UTE FID of bovine myelin extract paste (powder suspended in D2O) with a short hard pulse excitation (C) and half pulse excitation (D). The powder shows single-component signal decay with a T2* of 114±1 μs when excited with the short rectangular pulse (A), or a T2* of 143±1 μs when excited with the half pulse (B). The paste shows bi-component signal decay with a short T2* of 307±3 μs and a longer T2* of 2595 ± 147 μs, as well as a short T2* fraction of 91.9% and longer T2* fraction of 8.1% when excited with the hard pulse (C), and a short T2* of 334±4 μs and a longer T2* of 3022±89 μs, as well as a short T2* fraction of 88.4% and longer T2* fraction of 11.6% when excited with the half pulse (D).

Figure 3

UTE imaging of bovine myelin lipid powder with TEs of 8 μs (A), 0.2 (B), 0.4 (C), 0.6 (D), 0.8 (E) and 1.2 ms (F). The powder shows excellent single-component signal decay with a T2* of 159±4 μs (G). Bovine MBP also shows a high signal with a short T2* of 131±5 μs (H). IR-UTE (TR/TI = 300/110 ms) imaging shows a short T2* of 238±6 μs for the bovine myelin lipid-D2O paste (I), 201±7 μs for the bovine myelin lipid-H2O paste (J), 285±14 μs for the synthetic myelin lipid-D2O paste (K), and 318±12 μs for the synthetic myelin lipid-H2O paste (L).

Figure 4

IR-UTE imaging of the brain from a 64 year old female donor (TR/TI = 1500/410 ms) with confirmed MS with TEs of 8 μs (A), 2.2 ms (B) and subtraction image (C). Single-component fitting (D) shows a T2* of 216±30 μs for an ROI drawn in the NAWM shown in (C). IR-UTE imaging of a 60 year old male volunteer (TR/TI = 1500/412 ms) with TEs of 8 μs (E), 2.2 ms (F) and subtraction image (G). Single-component fitting (H) shows a T2* of 358±36 μs for an ROI drawn in the NAWM shown in (G).

Figure 5

Clinical PD-FSE (A), T2-FSE (B) and FLAIR (C) imaging as well as IR-UTE (TR/TI = 1500/410 ms) (D) imaging of a brain specimen from a 28 year old female donor with confirmed MS. MS lesions are hyperintense (thin arrows, A, B) on the PD-FSE and T2-FSE images, and hypointense (thin arrows, C) on the FLAIR image, and show signal loss on the IR-UTE image (thin arrows, D). Complete myelin loss is obvious in regions indicated by the thin arrows. Partial loss of signal is seen in the IR-UTE image (thick arrow, D) where the PD-FSE, T2-FSE and FLAIR images appear normal (thick arrows, A–C).

Figure 6

A selected slice from IR-UTE imaging of a cadaveric MS brain specimen shows loss of signal within the circled area (A); Histology of frontal subcortical WM from the subacute demyelinating lesion shown in the circle displays marked disruption of the normal histology with numerous reactive astrocytes (H&E) (B); GFAP IHC of the same region demonstrates the reactive, markedly hypertrophic astrocytosis (C); CD-68 staining demonstrates small numbers of perivascular macrophages in the same region as (B) and (C). Rare microglial cells are present in the acellular astroglial scar of the large, chronic demyelinated lesion in the occipital lobe (D, Inset); Another slice from IR-UTE imaging of the same MS brain specimen (E). This shows similar extensive myelin loss (F); A large chronic demylinated lesion in the occipital lobe of the same patient (circle, E) demonstrates the typical paucicellular astroglial scar with H&E staining (F); GFAP immunoreactivity shows the dense astrogial processes that have replaced normal structures in this demyelinated lesion (G); Vimentin immunoreactivity in the microvasculature of the both of the sampled brain regions demonstrates preservation of an epitope that is sensitive to fixation/processing (H). Higher magnification shows the delicate capillary labeling (H, Inset).

Figure 7

Dual echo IR-UTE imaging of a 34 year old healthy volunteer (TR/TI = 1500/420 ms) with a TE of 8 μs (A) and 2.2 ms (B). The subtraction image (C) shows intact myelin in white matter of normal brain. Also shown are images of a 29 year old male MS patient using clinical MP-RAGE (D), FLAIR (E) and IR-UTE (TR/TI = 1500/420 ms) (F) sequences, as well as images of a 43 year old female MS patient using clinical MP-RAGE (G), FLAIR (H) and IR-UTE (TR/TI = 1500/418 ms) (I) sequences. “Black hole” lesions (arrows) visible on MP-RAGE and T2-FLAIR images are clearly visible on IR-UTE images. Several lesions clearly visible on IR- UTE images are invisible or less visible on MP-RAGE and T2-FLAIR images (circles). UTE lesions were confirmed after examining neighboring slices to eliminate the possibility of misdiagnosis due to partial volume effects between GM and WM.