Hyaline cartilage tissue consists of
a small cellular fraction and an extracellular matrix, which is mainly composed
of oriented collagen fibers and an abundant ground substance rich in proteoglycan
(PG) content (1). PG are made up of a variety of
glycosaminoglycans (GAG), i.e., long unbranched oligosaccharides that are bound
to a protein (2,3). Via a strong negative charge, GAG
mediate the attractive potential of PG for cations and their capability to bind
water molecules (4). Since loss of proteoglycans is
thought to mark the beginning of osteoarthritis (5,6), the search for, preferably
non-invasive, options to quantify PG content in vivo has emerged into
the focus of research.
Several MRI methods such as sodium
imaging (7,8), delayed gadolinium-enhanced MRI of
cartilage (dGEMRIC, (9)), measurements of the longitudinal
relaxation time in the rotating frame (T1ρ, (10,11)) , and chemical exchange saturation
transfer (CEST, (12)) imaging have since been presented
as techniques with the potential to measure PG content in connective tissues.
These techniques exploit the biochemical properties of GAG, i.e., their fixed
charge density (sodium and dGEMRIC) or chemical exchange of labile protons with
bulk water (T1ρ and gagCEST), respectively. However, a broader use
of these techniques in clinical routine has so far been limited by low
specificity (T1ρ, (13)), low signal-to-noise ratio (SNR)
at clinical field strengths (sodium imaging, (14)), or a complicated measurement
protocol involving the administration of a double-dose of gadolinium based
contrast agent and a significant delay between contrast agent administration
and MR examination (dGEMRIC, (15)).
It was shown that labile –NH (δ=3.2
ppm offset from the water resonance) and –OH (δ=0.9 to 1.9 ppm) protons of GAG
can be used as CEST agents through selective saturation of their resonance
signals (16). This selectivity is also the
fundamental difference between gagCEST and T1ρ relaxation, with the
latter being caused by a sum of non-distinguishable exchange effects.
Recent studies aimed mostly at
general optimization of gagCEST imaging techniques (17-19), but also the feasibility of
gagCEST imaging in human subjects was demonstrated at 3T and 7T for cartilage
imaging (12,16,20-25) and intervertebral discs (26-33). Various methods of validation of
gagCEST were performed for in vivo studies, e.g. correlation with sodium
imaging (25), or correlation with dGEMRIC (21).
Generally, reported gagCEST signal
intensities for intervertebral discs (IVD) range higher compared with those
reported for cartilage at a given field strength. This is suspected to be due
to a slightly higher absolute proteoglycan content as well as the different
biochemical composition of the two tissue types (34). This higher available CEST signal
together with the larger dimensions of an IVD versus articular cartilage have
so far enabled more gagCEST studies of IVDs than cartilage at 3T.
If gagCEST experiments are performed
at a field strength of 3 Tesla, several challenges are expected to arise in
comparison to experiments performed at 7 Tesla based on theoretical considerations:
Due to the shorter T1 relaxation time, the lifetime of saturated protons
would decrease resulting in a faster decay of the CEST signal. The lower
chemical shift dispersion would reduce the possibility to saturate selectively
and increase the amount of unwanted direct water saturation (spillover) during
off-resonant irradiation. The intrinsically lower MR signal of water limits the
spatial resolution, which can be obtained with sufficient SNR in reasonable
scan times. An advantage at lower field can be seen in reduced specific
absorption rate (SAR) values enabling higher saturation powers. The fast exchange of the –OH protons
(12), which is in the order of a few 100
to greater than 1000 Hz, however, enables faster transfer of labeled magnetization
(35), so higher saturation powers can be
applied for shorter intervals, giving rise to effective contrast generation
without strongly exacerbating concomitant spillover effects (36). As all endogenous CEST contrasts
are strongly affected by the magnetization transfer (MT) background and water
T1 relaxation, labeling with strong B1 fields gives rise to MT effects
originating from protons bound to semi-solid molecules, e.g. macromolecules.
The CEST effect has also been exploited to
detect hydroxyl protons of lactate (Lac) or the guanidinium group of creatine (37-39). Both metabolites relate directly
to the energy metabolism of every cell and can thus be very valuable for
studying physiological effects in skeletal muscle. A wide range of applications
for use in musculoskeletal disease, e.g. exercise physiology, has been
suggested. Using the signal amplification effect of CEST in combination with
fast imaging, energy metabolism can be resolved non-invasively with spatial and
temporal resolutions far better than with alternative techniques, such as 31P MRS.
However,
due to the fast exchange of the labile protons of creatine (Cr) and Lac combined
with small off-resonance from water protons (δ=0.4 ppm for Lac and δ=2.0 ppm for Cr), the technical complexity for
isolating characteristic exchange-related effects of these metabolites from
others is high. Additionally, cellular environments, which are of interest to
energy metabolism commonly contain a wide range of solute molecules, which
could potentially act as endogenous CEST agents as well, and give rise to competing
effects that cannot be easily distinguished. The apparent exchange-dependent relaxation (AREX) metric has for
example been introduced to derive a purely exchange-rate-weighted CEST contrast
for Cr at 7T (39). As with gagCEST, Lac and Cr based
CEST contrasts will benefit from ultra-high field strengths.
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