Hyungseok Jang1, Annette von Drygalski1, Xing Lu1, Yajun Ma1, Srila Gopal1, Jiang Du1, and Eric Chang1,2
1University of California, San Diego, San Diego, CA, United States, 2VA San Diego Healthcare System, San Diego, CA, United States
Synopsis
Hemophilia is a
genetic bleeding disorder afflicting about 20,000 people in the US and over 400,000
people in the world. Severe hemophilia is characterized by frequent joint
bleeding, resulting in debilitating arthropathy because of toxic iron
depositions (e.g., hemosiderin) in synovium and cartilage. Development of a
sensitive, non-invasive biomarker is of high importance to determine efficacy
of costly treatment plans. In this study, we investigate the feasibility of ultrashort
echo time-based QSM (UTE-QSM) to identify hemosiderin deposition and to provide
a sensitive biomarker for joint disease in hemophilia.
Introduction
Hemophilia is a genetic bleeding disorder that
occurs in 1 out of every 5000 male births, afflicting about 20,000 people in the
US alone and over 400,000 people throughout the world. Severe hemophilia is characterized
by frequent joint bleeding, resulting in debilitating arthropathy because of
toxic iron depositions in synovium and cartilage (hemosiderin). Frequent
manifestations of iron-induced arthropathy are painful inflammatory synovial
hypertrophy and osteochondral degeneration1. Subclinical joint
bleeding can occur; therefore, development of a sensitive, non-invasive biomarker
is of high importance to optimize efficacy of costly treatment plans and to
monitor progression of disease. In magnetic resonance imaging (MRI), quantitative
susceptibility mapping (QSM) is a promising technique that allows quantification
of iron accumulation. However, it is challenging to measure susceptibility of highly
concentrated iron with conventional MR imaging techniques due to the short T2* decay.
In this study, we investigate the feasibility of ultrashort echo time-based QSM
(UTE-QSM) to identify hemosiderin deposition and to provide a sensitive
biomarker for joint disease in hemophilia.Methods
In this study, 3D UTE-Cones sequence was used to
acquire multiple images at different TEs including UTE2 as shown in Figure 1. The multiple
MR images acquired at the different TEs were input to IDEAL3 to estimate a total field
map in the presence of fat signal. Then, projection onto dipole field (PDF)
algorithm was applied to acquire a local field map4. The resultant local field
map was input to the morphology-enabled dipole inversion (MEDI) QSM algorithm5 to estimate the final
susceptibility map.
To evaluate the
feasibility of the proposed UTE-QSM in hemophilia, three patients with hemophilic
arthropathy were recruited in accordance with the IRB. Two patients underwent
knee imaging (Patient #1: 28-year-old male, Patient #2: 33-year-old male), while
one patient underwent ankle imaging (Patient #3: 37-year-old male) using a 3T
clinical MR system (GE-MR750). Patient #1 subsequently underwent total knee
arthroplasty after the MR imaging. The tissue harvested from the surgery was
immersed in saline and imaged at 3T (GE-MR750) for an additional ex vivo
UTE-QSM experiment with higher spatial resolution.
In the in vivo
knee and ankle experiments, the following imaging parameters were used: GE 8-channel
transmit/receive knee coil; flip angle (FA)=15o; field of view (FOV)=160x160x140mm3;
axial scan; matrix=160x160x100; readout bandwidth (BW)=±125kHz; TR=10ms; TE=0, 0.2,
0.4, 2.8, 3.6, and 4.4ms acquired with three dual echo scans; and total scan time=18
min. For the ex vivo experiment, the imaging parameters were matched with the
knee experiment except for: homemade 30cc birdcage coil; FOV=120x120x60 mm3;
matrix=240x240x120; TE=0, 0.1, 0.2, 0.3, and 0.4ms; and total scan time=57min
14sec. MEDI QSM was performed with the following parameters: radius of kernel=5,
Lagrange multiplier (λ)=30000 for the in vivo and 10000 for the ex vivo
experiment. QSM for the ex vivo experiment was performed without application of
IDEAL.Results
Figure 2-a and -b show magnitude and phase images
at the acquired six different TEs from Patient #1, where rapid signal decay is
observed in a posterior joint recess (red arrows) due to the accumulated
hemosiderin. Figure 2-c shows a total field map estimated using IDEAL, a local
field estimated using PDF algorithm, and the resultant susceptibility map
estimated using MEDI. The estimated susceptibility map shows high
susceptibility in the region where the rapid signal decay is observed (yellow
arrow). Figure 3 shows the results from Patient #1, reformatted to sagittal
plane. Strong signal dropoff is observed at the later TEs in the region
indicated by green arrows. In the resultant susceptibility map (Figure 3-b), increased
susceptibility is detected in the knee joint (yellow arrows). The estimated
susceptibility in the ROI is 3.6±1.9 ppm. Figure 4 shows the results from the
ex vivo experiment with the tissue harvested from the knee replacement surgery of
Patient #1. The estimated susceptibility in the ROI is 4.1±2.8 ppm, which shows
a similar estimate to that of the in vivo experiment. Figure 5 shows the QSM
result from the other two patients (Patients #2 and #3). As shown, increased
susceptibility is detected in several regions. In the ROI, the estimated
susceptibility is 2.4±1.6 ppm and 1.7±0.8 ppm for Patients #2 and #3,
respectively.Discussion
We have
quantified and demonstrated increased intra-articular susceptibility in
patients with hemophilic arthropathy, which is consistent with known hemosiderin
accumulation. The hemophilic arthropathy was less progressed in Patient #2 and
#3 than in Patient #1, and the susceptibility values were detected to be lower in
the joints, implying feasibility of UTE-QSM as a quantitative diagnostic tool
for arthropathy in hemophilia. However, further validation and optimization is
required. In future works, this will be systematically verified by performing biochemical
and histological analysis on the harvested tissues from hemophilic patients as
a ground truth. Moreover, we will recruit a larger number of hemophilic patients
to evaluate the sensitivity and specificity of the proposed biomarker based on
UTE-QSM compared with other conventional imaging techniques. Combined with
calibration using phantoms6, the proposed method will provide a measurement
of hemosiderin concentration in hemophilia.Conclusion
We showed the feasibility of UTE-QSM in detecting
hemosiderin accumulation in joints of hemophilic patients, which could provide
a sensitive biomarker for toxic iron accumulation in joints to improve
management of hemophilic arthropathy.Acknowledgements
The authors
acknowledge grant support from NIH (R01AR075825, 2R01AR062581, 1R01 AR068987),
Veterans Affairs (Merit Awards 1I01RX002604), and GE Healthcare. References
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