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Novel Imaging Methods for Early Drug Development

Laurent, Didier and Rooks, Daniel and Roubenoff, Ronenn (2011) Novel Imaging Methods for Early Drug Development. Journal of Nutrition, Health and Aging, 15 (10). pp. 834-846.

Abstract

Sarcopenia, a growing public health problem, is defined as a muscle wasting condition that gradually develops during aging and results in a loss of strength, mobility and functionality. While by 50 years of age, the rate of muscle loss reaches 1-2%/year, the decrease in muscle strength may even be greater, up to 3% over 60 years [1]. Although the exact cause of sarcopenia is unknown, muscle disuse, loss of alpha motor neurons in the spinal cord, and lower hormone levels (e.g., IGF-1, testosterone, and growth hormone) are believed to be the three main factors involved in this progressive syndrome. Proposed therapeutic approaches aim at preserving and eventually restoring muscle mass and function as quickly as possible.
To better understand the underlying mechanism of age-related muscle wasting and develop well adapted treatments, comprehensive clinical trials are needed and must rely on efficient tools that also minimize the overall burden on the frail elderly subjects often participating in these studies. However, the field of biomarkers to assess muscle wasting is still in a rudimentary stage. Main efforts are directed towards biomarkers showing efficacy in early clinical trials, but are yet correlated with restoration of function. In this respect, non-invasive imaging may offer sensitive markers of change in muscle anatomy and physiology by quantifying alterations in muscle mass, tissue metabolism and contractile potential which in turn would provide novel readouts for proof-of-concept/mechanism studies.
Magnetic resonance imaging (MRI) is uniquely suited for volumetric measurement of the skeletal muscle with a high level of accuracy anywhere in the body. The fact that MRI allows for comprehensive assessment of pathological conditions of the skeletal muscle that cause changes in muscle signal intensity (e.g., inflammation, fibrosis, fat infiltration etc) is a key advantage. Thus, MRI can also be used to select the appropriate site of biopsy. Presence of unsafe ferromagnetic metal implants, uncontrollable claustrophobia or the inability to fit into the machine (e.g. obesity, etc.) are the only contraindications for a subject to be scanned. In an effort to guarantee image quality, the subject should lie on a bed for 30 minutes prior to scanning to allow body water to re-equilibrate throughout the body and be comfortable on the table. Then, MRI scans can be acquired on any clinical systems (1.5 or 3 Tesla) using the inherent body coil, with the body part to be imaged (usually the lower/upper limb) being relaxed, parallel to the MRI table and free from compression.
A proton-density weighted MRI sequence encoding fat and water signals for a phase-sensitive three-point Dixon-type analysis is usually considered as an optimal approach. Images can be acquired throughout the limb in a relative short time without loss in image quality. Appropriate methods, preferentially based on interpolation and deformation of a parametric specific object may then be used for image analysis to reach a given level of precision. Muscle mass in kg, but also the subcutaneous (SC) fat and intermuscular adipose tissue (IMAT) mass visible in each MRI section are ultimately determined by multiplying volumes by respective density values. This overall approach allows detection of changes in muscle and fat mass in a specific body region as small as 2%. It also makes possible studies of rather short duration (~2 months follow up) with only 8-10 patients/group. By comparison, whole-body DXA scans are about half as sensitive in detecting similar changes. In any cases, use of a standardized scan acquisition protocol and appropriate analysis software are essential to achieve consistent results. Likewise, because of variability in interpretation of the scans, it is important to utilize centralized scan analysis by an experienced staff.
The age-related decrease in muscle mass and strength appears to be mainly caused by atrophy of the type IIa muscle fibers [2]. Not surprisingly then, specific muscles that are naturally rich in this fiber type, such as the vastus lateralis in the thigh, are most affected by age-related atrophy [3]. The determination of individual muscle volumes may help to better characterize specific therapeutic effects, while increasing statistical power of the clinical trial. However, the main difficulty resides in the the correct delineation of muscle boundaries, especially in areas where the muscle-muscle interface is blurred. Semi-automated software solutions [e.g., 4] now exist to exactly address this challenge while allowing for a fast turnaround on the image reading. However, most of these tools still require thorough validation (against for instance data obtained from manual segmentation) before extending their use.
Given the multi-faceted nature of sarcopenia, other imaging applications may be considered beyond pure volumetric analyses. For instances, chronic subclinical inflammation observed in aged skeletal muscle has been linked to functional limitations in older persons, by negatively influencing skeletal muscle through lower protein synthesis rate [5], direct catabolic effects or indirect mechanisms [6]. As a specialized MR technique, diffusion-weighted imaging (DWI) provides molecular information regarding fluid motion in tissues. Recently, this technique was applied to inflamed muscles from myositis patients and showed clear differences in water diffusion properties compared to unaffected patient muscles [7]. Interestingly, using the same approach also allows differentiating edematous muscles from fat infiltrated muscles which have reduced water diffusion compared to control muscles. Finally, this technique may also inform on longitudinal changes in the fibrous muscle structure occurring during disease progression [7].
The loss of muscle strength as a consequence of aging is particularly obvious during isokinetic testing, but is more subtle under eccentric testing conditions. Although the mechanism is still unclear, the development of muscle stiffness in older adults seems partly related to the preservation of high velocity strength. During sarcopenia, there is a replacement of muscle fibres with fat and an increase in fibrosis, which contributes to tissue stiffening. Magnetic Resonance Elastography (MRE) is a non-invasive phase-contrast MRI technique that can directly measure propagating shear waves in tissue in response to a harmonic mechanical excitation. Recent data have shown that muscle stiffness can be estimated from the measured wave [8]. The assessment relies on a wave image formed from the pixel vibratory displacement. Such displacement is due to the spin-phase shifts in the received MR signal in response to the mechanical shear vibration imposed on the MRI gradient. Like any other MR application mentioned before, stiffness measurements using this technique can easily be combined to volumetric assessments in a single MRI scanning session. Thus far, no MRE data are available on patients with sarcopenia and it remains to be shown that such approach offers enough sensitivity to observe longitudinal changes. The same applies to muscle stiffness measurements using alternative imaging techniques such as the ultrasonography-derived Young’s (or elastic) modulus approach [9]. The interest here lies in the fact that the stand-alone ultrasound device, which both induces and detects propagating shear waves in the muscle, can be used at the bedside while preserving comfort of the patient.
At a more intimate level, the decline in muscle cell contractility is another hallmark of sarcopenia. Newly developed technology using minimally invasive optical microendoscopy showed that high-speed data acquisition enables observation of sarcomere contractile dynamics with millisecond-scale resolution [10]. Data are typically acquired from a single fiber (or no more that 4 or 5 at a time) and clinical applications using a portable device are apparently considered for the foreseeable future. However, given that most muscles are of a mixed fiber type composition, it will be critical to verify how reflective of the whole muscle function such contractility measurements are before rolling out this technology for a widespread use.
Finally, as pointed out earlier, alteration of muscle protein turnover could represent an early and sensitive marker of sarcopenia. Measurement of the nitrogen balance is the most commonly used method to assess protein homeostasis. However, it is also often recognized as not sensitive enough to determine the continuous exchange of amino acids between tissues, which depends on the metabolic status of the organism. The marginal-to-low protein intake compromises muscle size and function, despite a near zero nitrogen equilibrium. This is why the determination of the muscle protein fractional synthetic rate by continuous infusion of two labeled amino-acids (13C-Phe and 2H-Tyr) has lately become the new gold-standard even though it is an invasive, time-consuming and tedious approach. PET imaging using a specific radiolabeled amino acid may help circumvent these issues while providing information on individual muscle protein turnover. Of all the PET tracers tested so far, [11C]MeAIB (methylaminoisobutyrate), an amino acid analogue already in the clinic, showed the most promise as a marker of muscle protein synthesis [11]. The main caveat is that the tracer, while being trapped in the cells, is not incorporated into muscle proteins. A preclinical validation experiment should help to verify how well the uptake rate of this tracer is a good measure of the protein synthesis rate.
To conclude, it is essential that new muscle imaging readouts be available soon as more precise markers of the therapeutic effects typically investigated in clinical trials. Such markers will also help to support trial duration. In order to meet this important need, issues around biological relevance, sensitivity, specificity, variability, safety (i.e., radiation exposure from PET tracers), implementation across multiple sites (i.e., harmonization) and cost will have to be resolved. It is very likely however that these imaging readouts will help fill the gap between the few clinical endpoints available (i.e., patient quality of life and physical function) and pathway-specific markers. Ultimately, the correlation of early changes in muscle size and function with long-term clinical endpoints should offer a unique application of imaging in Phase I and II trials in patients with musculoskeletal impairment.

References

1. Doherty TJ. Invited review: aging and sarcopenia. J Appl Physiol 2003; 95:1717-27
2. Morley et al. Sarcopenia. J Lab Clin Med 2001; 137:231-243
3. Nikolic M et al. Age-related skeletal muscle atrophy in humans: an immunohistochemical and morphopetric study. Coll Antropol 2001; 25(2):545-553
4. HajGhanbari et al, MRI-based 3D shape analysis of thigh muscles. Acad Radiol 2011; 18:155-166
5. Toth MJ et al. Age-related differences in skeletal muscle protein synthesis: relation to markers of immune activation. An J Physiol Endocrinol Metab 2005; 288(5):E883-891
6. Roubenoff R. Catabolism of aging: is it an inflammatory process? Curr Opin Clin Nutr Metab Care 2003; 6(3):295-299.
7. Qi J et al. Diffusion-weighted imaging of inflammatory myopathies: polymyositis and dermatomyositis. J Magn Reson Imaging 2008; 27:212-217
8. Bensamoun et al. Detrmination of thigh muscle stiffness using magnetic resonance elastography. J Magn Reson Imaging 2006; 23:242-247
9. Shinohara et al. Real-time visualization of muscle stiffness distribution with ultrasound shear wave imaging during muscle contraction. Muscle & Nerve 2010; 42:438-441
10. Llewellyn et al. Minimally invasive high-speed imaging of sarcomere contractile dynamics in mice and humans. Nature 2008; 454(7205):784-788
11. Asola et al. Amnio acid uptake in the skeletal muscle measured using [11C]methylaminoisobutyrate (MEAIB) and PET. Eur J Nucl Med <ol Imaging 2002; 29(11):1485-1491

Item Type: Article
Keywords: Sarcopenia, Imaging, Biomarkers, Muscle
Date Deposited: 28 Apr 2018 00:45
Last Modified: 28 Apr 2018 00:45
URI: https://oak.novartis.com/id/eprint/4957

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