Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

Abstract

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized (3)He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii-parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials.

Fig. 1.

Schematic structure of an acinar airway with 8 alveoli distributed along the annular ring (8-alveolar model). Each airway (duct or sac) can be considered geometrically as a cylindrical object consisting of an alveolar sleeve with alveoli opening toward the internal cylindrical air passage. The diagram defines inner (r) and outer (R) airway radii (as in Fig. 1 in Ref. 16) and effective alveolar diameter (L). We assume that the alveolar size L along the airway is the same as in cross section: L = 2R sin(π/8). h, Alveolar sleeve depth.

Fig. 2.

Examples of the parameter maps obtained from normal lung (N2) and lungs with different stages of emphysema [mild (M1) and severe (S1)]. The long dimension of the lung in each of the axial images is ∼20 cm. ADC, apparent diffusion coefficient (cm²/s); Lm, mean linear intercept (mm), R, acinar airway radius (mm); h, alveolar depth (mm); N_a, alveolar density (mm⁻³); S/V, surface-to-volume ratio (cm⁻¹).

Fig. 3.

Summary of data obtained for 6 lung specimens. A: ADC and ³He gas diffusion coefficients along (D_L0) and perpendicular to (D_T0) airway direction. B: R and h. C: S/V. D: N_a. Green markers, 2 control healthy lungs; orange markers, 2 lungs with mild emphysema; red markers, 2 lungs with severe emphysema. Each data point is a median calculated across all imaging voxels for a given lung specimen. Horizontal axis is the mean Lm obtained from direct histological measurements on the same lungs.

Fig. 4.

Mean linear intercept obtained by means of lung morphometry with hyperpolarized ³He diffusion MRI (Lm ³He) vs. direct measurement (Lm direct). Left: Lm (median calculated across the corresponding lung specimen). Right: Lm variability (each column is 1 SD of the Lm distribution across the corresponding lung specimen).

Fig. 5.

Plots representing data obtained by Monte-Carlo simulations of the longitudinal diffusion coefficient D_L0 (A), longitudinal kurtosis βL (B), and transverse diffusion coefficient D_T0 (C) as functions of h/R for R = 280, 300, 320, 350, 375, and 400 μm (shown by numbers next to the curve in C; in A and B symbols corresponding to different R values collapse in a single line and are indistinguishable). D: D_T0 at h = 0 (r = R) as a function of R/L₂. Solid lines are calculated according to Eqs. A4 and A5. Data are presented in the form that clearly demonstrates the scaling relationships.