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Age-related changes in human skeletal muscle microstructure and architecture assessed by DT-MRI and their association with muscle strength

Donnie Cameron^1,2, David A. Reiter³, Fatemeh Adelnia⁴, Ceereena Ubaida-Mohien⁵, Christopher M. Bergeron⁶, Seongjin Choi⁷, Kenneth W. Fishbein⁶, Richard G. Spencer⁶, and Luigi Ferrucci⁵
¹Norwich Medical School, University of East Anglia, Norwich, United Kingdom, ²Department of Radiology, Leiden University Medical Center, Leiden, Netherlands, ³Emory University School of Medicine, Atlanta, GA, United States, ⁴Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, United States, ⁵Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States, ⁶Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States, ⁷Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States

Synopsis

Here we apply diffusion-tensor-(DT)-MRI to study muscle microstructural and architectural changes with healthy ageing in 94 participants (median age=56, range=22-89yrs). Fractional anisotropy (FA) and mean diffusivity (MD), were calculated for 12 thigh muscles, as were pennation angle, fascicle length, fibre curvature, and physiological cross-sectional area (PCSA) for the rectus femoris and biceps femoris longus. Knee extension/flexion torques were also measured. FA and MD were significantly associated with age (β=0.34 and −0.34, p<0.05), as were architecture parameters. Pennation angle and PCSA were positively associated with strength. This may prove useful for studying muscle response to interventions designed to delay sarcopenia.

INTRODUCTION

Diffusion-tensor (DT)-MRI is proving increasingly useful for studying human skeletal muscle architecture. Parameters such as fractional anisotropy (FA) and mean diffusivity (MD) are sensitive to histological features such as the decrease in muscle fibre size that occurs in sarcopenia—the loss of muscle mass and function with ageing. Only a few pre-clinical and human studies have investigated changes in DT-MRI metrics with age;^1-8 however, these studies were conducted in relatively small samples with somewhat narrow age ranges, or show data for only one sex. A more comprehensive application in a larger cohort of male and female participants could elucidate age-related effects in DT-MRI and tractography metrics.

In this work we use DT-MRI to probe thigh muscle microstructure and architecture in a large healthy-ageing cohort, with the aim of characterising age-related skeletal muscle microstructural and architectural differences using DT-MRI and comparing these to functional measures such as muscle strength.

METHODS

A total of 94 participants (median age=56, range=22-89yrs) were recruited as part of the GESTALT longitudinal study of ageing. Imaging experiments were conducted on a 3T scanner (Achieva, Philips Healthcare, NL) with a 32-channel cardiac coil for signal reception.

Two-point 2D Dixon was applied in the left thigh as an anatomical reference. DT-MRI was applied with the following parameters: spin echo single-shot EPI, TR/TE=3,500/33ms; FOV=256×225mm; 30 slices, thickness=6mm; in-plane resolution=2.56×2.61mm; 8 averages; SENSE factor=2; spectral adiabatic inversion recovery and slice-select gradient reversal fat suppression; and 15 gradient directions, with b=0 and 450s/mm². After DT-MRI, B₀ maps were collected to correct for susceptibility-related distortions. Noise scans, without RF or gradients, were collected calculate signal-to-noise ratios (SNRs).

Our processing pipeline is summarised in Figure 1. Briefly, DT-MRI data were denoised via an overcomplete local principal component analysis filter,⁹ and distortion and eddy-current corrected in FSL (FMRIB, University of Oxford, UK). SNR was estimated using a region-of-interest (ROI) drawn over the muscle area of the thickest part of the thigh.¹⁰ Muscle ROIs were drawn on Dixon water images in the: rectus femoris (RF); vastus intermedius, medialis, and lateralis; sartorius; gracilis; adductor magnus; adductor longus; semimembranosus; semitendinosus; and biceps femoris short and long (BFL) heads. To transform ROIs into DT-MRI image space, Dixon images were aligned to DT-MRI data using elastix (v5.0.0), and transformations were applied per ROI.

Diffusion-tensor calculation and fibre tractography were performed in DSI Studio (Fang-Cheng Yeh, Carnegie Mellon University, USA), with muscle ROIs serving as seed regions for fibre tracking, and regions of high tract density or fat fraction>35%, serving as terminative regions. Muscle fascicle lengths, fibre pennation angles, and curvatures were estimated in the RF and the BFL as the length of a polynomial curve fitted to each fibre tract, the angle between the origin-insertion of a fascicle and the muscle’s long axis, and via the Frenet-Serret formula, respectively. Physiological cross-sectional area (PCSA) was determined by dividing muscle volumes by mean fascicle length.

Finally, left-leg strength was evaluated during concentric knee-extension and flexion exercises using an isokinetic dynamometer (Biodex Medical Systems, Inc., USA)

RESULTS

Table 1 shows demographic and strength data for our cohort. All DT-MRI datasets showed SNRs greater than the minimum of 25 recommended for tractography.¹¹

Figure 2 illustrates relationships between conventional DT-MRI measures and age, showing volume-weighted averages of FA and MD for the whole thigh. Both measures were significantly associated with age after adjusting for sex (β=0.34 for FA, β=−0.34 for MD; p<0.05).

Figure 3 shows representative distributions of DT-MRI muscle architecture measures in individuals, and Figure 4 (top panel) shows scatter plots of these versus age, prior to adjustment, for the whole cohort. In the RF, pennation angle, fibre curvature, fascicle length, and PCSA were all significantly associated with age (β =−0.22, 0.26, −0.23, and −0.31, respectively; p<0.05), after adjusting for sex, while in the BFL only curvature and fascicle length were associated with age (β =0.36, and −0.40, respectively; p<0.001). Figure 4 (bottom panel) shows scatter plots of architecture parameters versus knee extension/flexion strength, prior to adjustment. In the RF, pennation angle and PCSA were associated with strength (β =0.31, and 0.47, respectively; p<0.01), adjusting for sex, whereas only PCSA was associated with strength in the BFL (β =0.43; p<0.001).

DISCUSSION

To our knowledge, ours is the first study to relate DT-MRI skeletal muscle architecture measures to ageing and muscle strength. In our large cohort of healthy participants, we found that FA tends to increase while MD decreases with ageing, in the whole muscle volume of the thigh. In terms of muscle architecture measured in the RF and BFL, we show that pennation angle, fascicle length, and PCSA tend to decrease with increasing age, while curvature increases. Lastly, we found that pennation angle and PCSA are positively associated with muscle strength, suggesting these metrics capture muscle tissue characteristics that are important for muscle quality.

In conclusion, we have shown the utility of DT-MRI for exploring muscle architectural changes with ageing in a large cohort. Our approach may be used in the future to better understand progression of age-related changes into sarcopenia, and for monitoring training interventions, where effects on different muscles and muscle regions would be accessible within a single measurement.

Acknowledgements

We are grateful to Palchamy Elango and Marta Zampino for their help with obtaining data, and Fang-Cheng Yeh for his assistance with tractography in DSI Studio.

References

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Figures

Figure 1. Schematic showing the diffusion tensor (DT)-MRI data-processing pipeline for this study. Representative DT-MRI and Dixon data are shown for an 89-year-old male subject. The top row shows denoising and distortion correction, while the bottom row describes region-of-interest (ROI) drawing on Dixon images, registration to the DT-MRI data, and the volumetry. Tractography is performed on the processed DT-MRI data using muscle volumes as seed regions and regions of high fat fraction and tract density as termination regions.

Table 1. Demographic and muscle strength data for the participants included in this study. Data are expressed as mean (standard deviation) if normally distributed or median [interquartile range] if not. Differences between men and women were assessed using Student’s t-tests or Mann-Whitney U tests, respectively.

Figure 2. Tractography results (top), and whole-thigh fractional anisotropy (FA, middle) and mean diffusivity (MD, bottom) versus age. Tractography results are linked to their corresponding FA and MD whole-thigh results by dashed lines and are presented as anterior coronal views of the thigh showing muscle regions-of-interest (ROIs), fibre directionality, and tracts coloured by their average FA or MD. Standardised linear regressions demonstrate associations with age, and regression lines, 95% confidence intervals, and regression statistics are shown.

Figure 3. Density plots showing muscle architecture parameters in the rectus femoris (RF, top) and biceps femoris longus (BFL, bottom) in two subjects (male, age=30 & 78yrs). Coronal tractography images, inset, highlight the muscle structure for each. RF pennation angle and fascicle length are lower in the older participant. BFL fascicle lengths are lower in the older participant, but pennation angle and curvature are higher. Generally, parameters show bi-/multi-modal distributions, perhaps indicating different compartments.

Figure 4. Scatter plots of muscle architecture parameters vs age (top panel) and peak concentric, isokinetic knee extension/flexion torques (bottom panel) from the rectus femoris (RF) and biceps femoris longus (BFL), respectively. These unadjusted linear regressions show significant associations between curvature, fascicle length, and physiological cross-sectional area (PCSA) and age, particularly in the RF. Positive associations are seen between pennation angle and torque and PCSA and torque, in both muscles.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

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DOI: https://doi.org/10.58530/2022/0667