Spatial modulation (tagging) of the longitudinal magnetization allows diffusive displacements to be measured over times approximately as long as T 1 and over correspondingly long distances. Magnetization tagging is used here with hyperpolarized 3 He gas in canine lungs with unilateral elastase-induced emphysema. A new scheme for analyzing images subsequent to tagging determines the spatially-resolved fractional modulation and its decay rate, using a sliding window. The free diffusivity D o of 3 He, dilute in air or N 2 , is exceptionally large at 0.88 cm 2 /s. Thus, the root mean square (RMS) free displacement of a typical 3 He atom during several milliseconds is larger than the diameter of the acinar airways, with the result that the apparent diffusivity measured over such times is restricted by collisions with airway walls and is near 0.2 cm 2 /s in healthy lung (1-4). Airway expansion and destruction of airway and alveolar walls in emphysema (5) result in reduced restriction of diffusion (D Ϸ 0.55 cm 2 /s in a group of severely diseased subjects) (3). Nearly all of the work to date has measured D msec , taken from the decay of transverse magnetization measured at two b-values (that is, with and without a pulsed, diffusion-sensitizing field gradient) (3,4,6 -8). The experiment is sensitive to displacements during the gradient waveform that is typically several milliseconds in duration, corresponding to displacements of a few hundred microns. This time is limited by the short T* 2 of 3 He in lung (about 20 ms in 1.5 T) (9,10). The small length scale associated with this method limits the motion to individual acinar airways where 95% of the gas resides; the time is not sufficient for many of the atoms to move from one airway to the next. Multi-b-value measurements of the decay of transverse magnetization over times of milliseconds have been understood in terms of anisotropic diffusion, with different values longitudinal and transverse to the airways (D L and D T ) (1). Diffusion values so measured are sensitive indicators of the changes in localized lung morphology that accompany emphysema.However, by probing gas diffusion over longer times, one can examine the structure of the airway network over longer length scales. In the canonical description of lung (11), there are 24 levels of branching airways, where the trachea is Z ϭ 0 and the alveolar sacs are Z ϭ 23. The acinar units are the primary regions of gas exchange and comprise the highest-numbered eight airway levels. The mean linear size of an acinar unit is about 7 mm, with individual acinar airways having lengths of approximately 1 mm (11). Because the average acinar-airway length is small, and the acini contain the vast majority of gas in the lung, diffusion between arbitrary points that are centimeter(s) apart requires that atoms must travel from one acinus to another, connecting via a common conducting airway node. From the alveolar sacs, for example, this is a path through eight or more airway levels. The diffusion coefficient measured over such long ...

Despite a long history of development, diagnostic tools for in vivo regional assessment of lungs in patients with pulmonary emphysema are not yet readily available. Recently, a new imaging technique, in vivo lung morphometry, was introduced by our group. This technique is based on MRI measurements of diffusion of hyperpolarized 3 He gas in lung air spaces and provides quantitative in vivo tomographic information on lung microstructure at the level of the acinar airways. Compared with standard diffusivity measurements that strongly depend on pulse sequence parameters (mainly diffusion time), our approach evaluates a "hard number," the average acinar airway radius. For healthy dogs, we find here a mean acinar airway radius of ~0.3 mm compared with 0.36 mm in healthy humans. The purpose of the present study is the application of this technique for quantification of emphysema progression in dogs with experimentally induced disease. The diffusivity measurements and resulting acinar airway geometrical characteristics were correlated with the local lung density and local lung-specific air volume calculated from quantitative computed tomography data obtained on the same dogs. The results establish an important association between the two modalities. The observed sensitivity of our method to emphysema progression suggests that this technique has potential for the diagnosis of emphysema and tracking of disease progression or improvement via a pharmaceutical intervention. Keywords hyperpolarized gases; magnetic resonance imaging; diffusionPulmonary emphysema, which is defined as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of their walls, without fibrosis" (23), is a major medical problem worldwide. There are several conventional methods of diagnosing and evaluating emphysema: pulmonary function tests, chest radiography, and computed tomography (CT). These methods in general provide a gross assessment of the degree of emphysema and are used for qualitative, clinical applications. Pulmonary function tests are reportedly insensitive to early, mild changes of emphysema (24); the same is true for conventional chest radiography (25). CT is more sensitive

Purpose:To evaluate the safety of hyperpolarized helium 3 ( 3 He) magnetic resonance (MR) imaging. Materials and Methods:Local institutional review board approval and informed consent were obtained. Physiologic monitoring data were obtained before, during, and after hyperpolarized 3 He MR imaging in 100 consecutive subjects (57 men, 43 women; mean age, 52 years Ϯ 14 [standard deviation]). The subjects inhaled 1-3 L of a gas mixture containing 300 -500 mL 3 He and 0 -2700 mL N 2 and held their breath for up to 15 seconds during MR imaging. Heart rate and rhythm and oxygen saturation of hemoglobin as measured by pulse oximetry (SpO 2 ) were monitored continuously throughout each study. The effects of 3 He MR imaging on vital signs and SpO 2 and the relationship between pulmonary function, number of doses, and clinical classification (healthy volunteers, patients with asthma, heavy smokers, patients undergoing lung volume reduction surgery for severe emphysema, and patients with lung cancer) and the lowest observed SpO 2 were assessed. Any subjective symptoms were noted. Results:Except for a small postimaging decrease in mean heart rate (from 78 beats per minute Ϯ 13 to 73 beats per minute Ϯ 11, P Ͻ .001), there was no effect on vital signs. A mean transient decrease in SpO 2 of 4% Ϯ 3 was observed during the first minute after gas inhalation (P Ͻ .001) in 77 subjects who inhaled a dose of 1 L for 10 seconds or less, reaching a nadir of less than 90% at least once in 20 subjects and of less than 85% in four subjects. There was no correlation between the lowest SpO 2 and pulmonary function parameters other than baseline SpO 2 (r ϭ 0.36, P ϭ .001). The lowest mean SpO 2 varied by 1% between the first and second and second and third doses (P Ͻ .001) and was unrelated to clinical classification (P ϭ .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred.

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Familial hypobetalipoproteinemia (FHBL) subjects may develop fatty liver. Liver fat was assessed in 21 FHBL with six different apolipoprotein B (apoB) truncations (apoB-4 to apoB-89) and 14 controls by magnetic resonance spectroscopy (MRS). Liver fat percentages were 16.7 ؎ 11.5 and 3.3 ؎ 2.9 (mean ؎ SD) ( P ‫؍‬ 0.001). Liver fat percentage was positively correlated with body mass index, waist circumference, and areas under the insulin curves of 2 h glucose tolerance tests, suggesting that obesity may affect the severity of liver fat accumulation in both groups. Despite 5-fold differences in liver fat percentage, mean values for obesity and insulin indexes were similar. Thus, for similar degrees of obesity, FHBL subjects have more hepatic fat. VLDL-triglyceride (TG)-fatty acids arise from plasma and nonplasma sources (liver and splanchnic tissues). To assess the relative contributions of each, [ 2 H 2 ]palmitate was infused over 12 h in 13 FHBL subjects and 11 controls. Isotopic enrichment of plasma free palmitate and VLDL-TGpalmitate was determined by mass spectrometry. Nonplasma sources contributed 51 ؎ 15% in FHBL and 37 ؎ 13% in controls ( P ‫؍‬ 0.02). Correlations of liver fat percentage and percent VLDL-TG-palmitate from liver were r ‫؍‬ 0.89 ( P ‫؍‬ 0.0001) for FHBL subjects and r ‫؍‬ 0.69 ( P ‫؍‬ 0.01) for controls. Thus, apoB truncation-producing mutations result in fatty liver and in altered assembly of VLDL-TG. (1) that may be divided into at least four genetic subclasses: a ) mutations of APOB (40 truncation-producing mutations ranging from apoB2 to apoB-89) (2-5); b ) FHBL linked to chomosome 3p21 (6, 7); c ) LDL receptor-deficient familial hypercholesterolemia in which a "cholesterol lowering gene" is linked to chomsome 13p (8, 9); and d ) FHBL linked to none of the above loci (Schonfeld, unpublished observations). Most FHBL subjects are heterozygous and are usually asymptomatic, but an undetermined proportion have nonalcoholic fatty liver (NAFL) (5, 10-18). Since in several previous studies of liver fat the genetic classification of reported subjects was not specified, and in all studies a semi-quantitative measure of liver fat (ultrasound) was used, it is not clear how the specific genetic basis of FHBL affects either the frequency or severity of the fatty liver. We now report on liver fat in our group of subjects with the heterozygous form of FHBL due to APOB defects using a noninvasive quantitative method, magnetic resonance spectroscopy (MRS) (19)(20)(21)(22). Since NAFL in humans is often associated with obesity and/or insulin resistance (23), we also measured indexes of obesity and insulin resistance in our FHBL subjects.VLDL particles are assembled in liver from several apolipoproteins, the most important in humans being apoB-100, and the three major lipid classes: triglycerides (TG), cholesterol, and phospholipids. The TG component of VLDL particles is assembled from glycerol and fatty acids (FA). The FA incorporated into VLDL-TG may be derived from more than one source. Circulat...