MRI imaging

INTRODUCTION:
MRI is one of the most important imaging modalities as it offers many advantages over traditional X-ray radiography. The biggest giveaway of MRI is that it is non-invasive – it does not use radiation in order to produce images and produces images with excellent spatial resolution. MRI can also produce images of soft tissues which is not possible by X-ray radiography.
MRI uses a strong magnetic field with a radiofrequency pulse to detect the protons largely in water and fat. This is the reason MRI produces images with such incredible anatomic detail. The radiofrequency distorts the spins of the protons whose relaxation times after the pulse is applied are measured to produce images.
The human body is predominantly made of water and fat. When a magnetic field is applied, the spins (the quantum mechanical equivalent of angular momentum) of protons in the water and fat get aligned in the direction of the magnetic field, B0. If a radiofrequency pulse is applied at this point, the magnetization vectors of the protons get distorted, straining against the pull of the magnetic field. When the pulse is turned off, the spins of the protons decay with time – a process called relaxation, releasing energy, and the time constants of these decays are measured which are processed by a data processor.
While MRI produces images with great spatial resolution and detail, along with a deep tissue penetration owed to the number of protons in the human body, a key challenge associated with MRI is the low inherent contrast. If two tissues have similar relaxation times, which is most of the times, they will appear similar in standard MR images. This can be a problem, for example differentiating between healthy and diseased tissue.
Therefore, in clinical practice, to enhance contrast and to highlight specific anatomies and to measure certain dynamic processes, the endogenous relaxation time contrast can be further enhanced by modifying the pulse sequence. In addition to that, exogenous contrast agents can be administered to further enhance the contrast.
Contrast agents typically affect the net magnetization of the water protons in the body tissues and influence the image contrast. They catalytically shorten the longitudinal and transverse relaxation times of nearby water protons, which ultimately improves the MR signal and allows for the better differentiation between healthy and diseased tissues. Furthermore, they also increase the specificity of the image.
Many methods of enhancing contrast have been proposed. The most common method of producing contrast is by shortening the longitudinal and/or transverse relaxation times which would affect the signal intensity. Contrast agents that shorten both transverse and longitudinal relaxation times to approximately the same degree are called T1 shortening agents. T1 shortening agents give rise to increased signal intensity and therefore are called positive contrast agents and T2 agents are called negative contrast agents as they decrease the signal intensity.
The most common T1 shortening agents are Gadolinium containing acyclic chelate complexes. Their efficiency is determined by their ability to shorten the relaxation times of neighboring protons and is expressed through relaxivity (r1 measured usually in mM-1s-1) which depends on many factors including magnetic field and various structural, electronic and dynamic properties of the agents like the number of coordinated water molecules, rate of exchange between coordinated and bulk water molecules, kex, the distance between Gd iii ion and coordinated water protons among others.
The observed relaxivity of clinically approved contrast agents (approximately 4 to 5 mM-1s-1) is much lower than the theoretical optimum value of relaxivity per coordinated water molecule (approximately 40 mM-1s-1), at a clinically relevant field strength of 1.5 T. This is one of the drawbacks of administering Gd based contrast agents in clinical applications. These metal agents also suffer from the drawback that once administered, the changes in the tissue parameters persist until the agent has left the tissue or the body.
Overcoming these limitations, a new class of MRI contrast agents that function based on the transfer of magnetization among protons through Chemical exchange Saturation Transfer (CEST) have been reported. These contrast agents can provide a significant change in the magnitude of the water proton signal which results in a significant gain relative to the specific agent concentration. In contrast to Gd based agents, when used, the CEST contrast agents rarely perturb the system unless the specific saturation of the exchanging site is performed. CEST techniques generate contrast based on the rate of proton chemical exchange between a metabolite and water.
CEST THEORY:
In the CEST approach, a slowly exchanging group possessing a chemical shift different from water is selectively saturated and the saturation is transferred to bulk water via chemical exchange. The most attractive feature of CEST is that it allows for the contrast to be switched “on” and “off” via a radiofrequency presaturation pulse. The high sensitivity of CEST to the molecular environment around the contrast agent also allows for CEST to be used to image important physiological parameters like pH and metabolic activity (metabolite levels).
To understand how CEST works, which is vital in order to formulate and compare the contrast agents, we need to understand how protons interact under a magnetic field. When a nucleus having a net magnetic spin is placed in a magnetic field, the spins distribute among themselves and orient themselves along the magnetic field (low energy – ) and/or against the magnetic field (high energy -) according to the Boltzmann’s equation:
“Nβ” /”Nα” “=” “exp” ⁡(“-∆E” ⁄”kT” )
Figure: The vector on the z-axis on the left representing the Boltzmann spin distribution in magnetic field. When presaturation pulse is applied, the number of fields oriented against the magnetic field increases.
At this point, after bulk saturation, the sample may be thought of as a spin vector aligned with the magnetic field. When a radiofrequency pulse of appropriate frequency is applied, the spins would be promoted from lower energy to higher energy. The magnitude of the bulk magnetization, as a result would be reduced considerably because fewer and fewer spins are aligned along with the magnetic field. When enough energy is applied, the sample gets saturated with equal number of spins in the low and high energy states with zero net magnetization. The signal intensity in MRI is directly proportional to the net magnetization.
Therefore, CEST considers the effects of presaturation in a system undergoing chemical exchange which are observed the exchange process must occur between two magnetically distinct environments with very slow water exchange rate (on the NMR scale). The chemical shift difference between the solvent and the solute has to be greater than the exchange rate. This is given by:
∆ω≥kex
Where ∆ω is the frequency difference and kex is the exchange rate.
For two pools A and B meeting the above condition, the presaturation of pool B has an effect on Pool A as well. The presaturation pulse decreases the bulk magnetization in Pool B where with time, chemical exchange perturbs the Boltzmann equilibrium attained by pool A. This exchange process could be modelled as two two independent equilibria with equal forward and reverse rate constants.
The first equilibrium lies between the low energy () states of Pool A and B. This equilibrium would shift to accommodate more spins in the low energy state of pool B from those in pool A. The second equilibrium occurs between the two high energy states which would shift such that it accommodates more high energy spins in pool A at the expense of those in pool B. Therefore, on the whole, the number of high energy spins in pool A increases as a result of the decrease of high energy spins in pool B – which results in saturation transfer, therefore increasing the contrast. That is, the distribution of spins in pool A moves closer to saturation. Therefore, when the radiofrequency pulse is applied, the signal intensity of pool B is completely absent while the intensity of pool A decreases considerably.
Moreover, if the rate of longitudinal relaxation of pool B is higher than the forward rate constant of the exchange from pool B to pool A, relaxation would not occur as the system would relax back to the Boltzmann distribution before any exchange can happen which would result in a normal NMR spectrum. In the same way, if the relaxation of pool A is too fast, the system would fall back to the Boltzmann’s distribution before the effects could be observed. For this reason, in addition to suitable exchange kinetics, chemical exchange saturation transfer would only be observed when the relaxation times are long enough compared to the exchange rates. This brings us to conclude that the exchange is in competition with the relxation.
Seeing how the signal intensity of one resonance can be altered by applying a presaturation pulse to a second resonance in exchange with the former, Ward et al., proposed exogeneous agents that operate by chemical exchange saturation transfer to generate images with improved contrast. That being the case, a number of sugars, metabolites and other small diamagnetic molecules possessing exchangeable protons were examined to assess their capabilities. This technique has now become the standard method of assessing the capabilities of CEST contrast agents.The spectrum shown below describes what type of diamagnetic substance can change the signal of bulk water and hence is suitable as a contrast agent in MRI. The main disadvantage of using this specific system of diamagnetic substances is also illustrated in this spectrum. The concentration of agent required to generate a considerable change in the solvent water signal is very high. This is quite desirable for clinical use so a more efficacious system by which exogeneous CEST agents could be administered to generate image contrast in MRI is required.
Figure: CEST spectra of 125 mM (blue), 62.5 mM (red), and 31.25 mM (green) solutions of barbituric acid recorded at 300 MHz, pH 7.0 and 37 uC.
One of the limitations of CEST agents is the small signal that is produced from direct presaturation of bulk water that occurs coincidentally during presaturation of exchangeable protons.
The table below shows the CEST data of some small molecules reported by Balaban et al. Some conclusions could be drawn from the data and are listed as: (a) these agents are inherently pH and temperature sensitive. (b) depending on the frequency saturation, a single compound with multiple exchange sites can have completely different CEST properties. (c) the efficiency of the CEST agent increases linearly with concentration but the line shape of the CEST peak is maintained. (d) the CEST peak shape becomes broader and shifts towards bulk water as the exchange rate of the substance increases.
Tuning the water exchange rates is a key strategy to maximize the efficiencies of the CEST agents. CEST agents require relatively slow rates and the water exchange rates of Lanthanide containing complexes are determined from their dependence of transverse relaxation rates on temperature.
Although paraCEST agents offer higher sensitivity to the chemical exchange rates, the imaging in itself is not as sensitive as the more expensive and advanced imaging modalities such as positron emission tomography (PET) and Single proton emission computed tomography (SPECT). Besides, a change of 5% in the water signal intensity is enough to generate contrast. Imaging using CEST agents typically requires high doses of paraCEST agents – typically 5 g for a 70 kg individual.
Also, the change in the signal intensity must occur within a strict power limit. The power limits are more acute CEST imaging as presaturation pulse must be applied. Therefore, development of CEST agents musyt take place within the power limitations of clinical scanners. Therefore, to improve the efficiency of CEST agents, we must maximise the water exchange rates, reduce the dose and meet the required clinical presaturation power requirements.
In this proposal, we discuss ways to improve the efficiency of the contrast agents through chemical kinetics and optimizing the water exchange rates using exchange theory. More importantly, we compare the efficiency of the contrast agents made of different lanthanide ions.
USING EXCHANGE THEORY TO OPTIMIZE THE WATER EXCHANGE RATES:
Consider the previously mentioned idealized two pool system where some protons on a CEST agent (pool B) exchange with those of pool A. after presaturation of pool B, the proton exchange causes partial saturation of pool A, which results in a lower MR signal and its intensity is determined by several factors such as the properties of CEST agent, water, and the instrument controls etc.
Consequently, the spins distribute themselves according to Boltzmann distribution. The magnitude of magnetization is directly proportional to the concentrations of the molecules in the pool so the magnetizations of each pool are given by:
[H]a = M0a and [H]b = M0b
When exchange occurs, protons move from pool A to pool B following first order kinetics with a rate constant ka (s-1) given by:
ka =1/τa where a is residence lifetime of bulk protons.
Once the system reaches steady state, the rates of change of magnetizations of both the pools become equal such that
Rearrangement of the above equation gives normalized steady state value of Maz called Z-value.
Smaller the Z value, larger would be the CEST effect. The above equation implies that the CEST effect would be larger when: residence lifetime of pool A (a) is short and longitudinal relaxation time of pool A is long.
Using mass balance:kbMob = kaMoa⇒a = b (Mob/Moa)Writing eqn 1 in terms of b , we get
Above equation shows that maximum CEST occurs when:(i)Residence time of proton on the agent, b is short.(ii)Concentration of agent (Mob) is as high as possible.
In addition to the above factors, the extent of saturation of pool B is determined by the field strength of the applied presaturation pulse, B1 as well as other physical characteristics of the nuclear spin system such as relaxation times, exchange rates, chemical shifts etc. The dichotomy is that CEST will nearly always increase with larger applied B1, yet this (power) is the very parameter that we need to minimize for in vivo work.
Therefore there are three parameters that could be modified in order to optimize the saturation:Residence life of the protons on the agent, b,the chemical shift of the exchangeable protons,,relaxation properties of the agent
The optimal value of b is therefore given by
For a relatively small B1 of 50 Hz, an optimal CEST effect will be observed for an agent with a bound water lifetime,b, of 3 ms, a value that is much longer than any paraCEST agent reported to date. For B1 values of 100, 200 or 500 Hz, the optimal bound water lifetimes decrease to 1.5 ms, 735 ms, and 296 ms. respectively. Thus, a greater presaturation power means that an agent going through a faster exchange could be chosen.

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