Quantitative MRI Mapping of Muscular Architecture in Elderly Lymphedema Patients

Thesis Abstract

This study addresses the neglected gap in understanding how age-related muscular architecture reorganizes in the presence of chronic lymphedema, using quantitative MRI as an objective biomarker to enhance assessment, prognosis, and rehabilitation planning in elderly populations. The aim is to characterize, quantify, and model skeletal muscle architectural changes in elderly lymphedema patients and to relate these changes to functional outcomes and edema severity. Specific objectives are (1) to quantify muscle cross-sectional area, volume, pennation angle, fascicle length, and intramuscular fat infiltration in the lower limbs using high-resolution 3D Dixon and diffusion-weighted MRI; (2) to examine regional variation in architectural parameters within the gastrocnemius, soleus, and tibialis anterior muscles; (3) to evaluate associations between MRI-derived architectural metrics and clinical measures of edema severity, limb girth, and gait performance; (4) to develop a multivariate predictive model linking muscular architecture to functional impairment; and (5) to test the applicability of a biopsychosocial framework (integrating physical and disability-related factors) to interpret imaging findings. The methodology adopts a cross-sectional analytical design with a nested longitudinal component to assess repeatability over six months in a subsample. The population comprises individuals aged 65 years and older diagnosed with unilateral or bilateral chronic lower-extremity lymphedema attending vascular and edema clinics in a metropolitan tertiary hospital. A total sample of 120 participants will be recruited, with 60 lymphedema patients and 60 age- and sex-matched controls without edema, matched for diabetes status and BMI. MRI data will be acquired on a 3T scanner using a standardized protocol 3D T1-weighted, multi-echo Dixon fat-water separation for fat fraction quantification, diffusion tensor imaging for muscle microarchitecture, and diffusion kurtosis imaging to capture non-Gaussian diffusion in muscle fibers. Conventional clinical assessments will include limb circumference measurements, bioimpedance spectroscopy for edema staging, and timed up-and-go and 6-minute walk tests for functional capacity. Data collection instruments include the MRI sequences described, calibrated with phantom measurements for quality assurance, and validated clinical assessment tools for edema severity and function. Validity and reliability will be established through intra- and inter-rater reliability analyses for manual segmentation of muscles and automated post-processing pipelines, with ICC thresholds above 0.80 deemed acceptable. Data analysis will proceed in three stages first, descriptive statistics and normality checks; second, multivariate mixed-effects models to examine differences in architectural parameters between patients and controls, adjusting for age, sex, BMI, and activity level; and third, regression analyses to explore associations between MRI metrics (e.g., muscle volume, pennation, fat fraction, fractional anisotropy, mean diffusivity) and clinical outcomes, with model selection guided by Akaike information criterion. A structural equation modeling approach will test a hypothesized pathway from edema severity to muscular architectural disruption and subsequent functional limitation, incorporating potential mediators such as physical activity and comorbidity burden. The study will also perform subgroup analyses by edema stage and by limb involvement. The expected findings include reduced muscle volume and pennation angles, increased intermuscular fat infiltration, altered diffusion metrics indicating microstructural muscle degradation, and region-specific architectural disruption, particularly in the calf muscles. These MRI-derived features are anticipated to correlate moderately with edema metrics and functional tests, supporting a link between tissue-level changes and functional impairment. The study aims to contribute to knowledge by establishing normative MRI-based benchmarks for elderly skeletal muscle architecture in lymphedema, identifying imaging biomarkers that predict functional decline, and informing targeted rehabilitation strategies such as strength and mobility training tailored to identified architectural deficits. The main conclusion is that quantitative MRI provides a sensitive and specific non-invasive tool to characterize age-associated muscular remodeling in lymphedema and to predict functional outcomes, enabling more precise monitoring and individualized therapy. Recommendations include integrating quantitative MRI assessments into routine clinical evaluation of elderly lymphedema patients, developing exercise interventions aimed at preserving pennation and reducing fat infiltration, and conducting longitudinal trials to determine causality and the impact of rehabilitative programs on muscle architecture over time.