Evaluating brain damage in multiple sclerosis with simultaneous multi-angular-relaxometry of tissue

OBJECTIVE: Multiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous-Multi-Angular-Relaxometry-of-Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART-derived MPF metric as a potential imaging biomarker of demyelination. METHODS: Twenty healthy control (HC), 11 relapsing-remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART-derived MPF metric was determined in normal-appearing cortical gray matter (NAGM), normal-appearing subcortical white matter (NAWM), and demyelinating lesions. MPF metric was evaluated for correlations with physical and cognitive test scores. Comparisons were made between HC and MS and between MS subtypes. Furthermore, correlations were determined between MPF and neuropathology in the biopsied person. RESULTS: SMART-derived MPF in NAGM and NAWM were lower in MS than HC (p \u3c 0.001). MPF in NAGM, NAWM and lesions differentiated RRMS from PMS (p \u3c 0.01, p \u3c 0.001, p \u3c 0.001, respectively), whereas lesion volumes did not. MPF in NAGM, NAWM and lesions correlated with the Expanded Disability Status Scale (p \u3c 0.01, p \u3c 0.001, p \u3c 0.001, respectively) and nine-hole peg test (p \u3c 0.001, p \u3c 0.001, p \u3c 0.01, respectively). MPF was lower in the histopathologically confirmed inflammatory demyelinating lesion than the contralateral NAWM and increased in the biopsied lesion over time, mirroring improved clinical performance. INTERPRETATION: SMART-derived MPF metric holds potential as a quantitative imaging biomarker of demyelination and remyelination

In vivo evaluation of heme and non-heme iron content and neuronal density in human basal ganglia

Non-heme iron is an important element supporting the structure and functioning of biological tissues. Imbalance in non-heme iron can lead to different neurological disorders. Several MRI approaches have been developed for iron quantification relying either on the relaxation properties of MRI signal or measuring tissue magnetic susceptibility. Specific quantification of the non-heme iron can, however, be constrained by the presence of the heme iron in the deoxygenated blood and contribution of cellular composition. The goal of this paper is to introduce theoretical background and experimental MRI method allowing disentangling contributions of heme and non-heme irons simultaneously with evaluation of tissue neuronal density in the iron-rich basal ganglia. Our approach is based on the quantitative Gradient Recalled Echo (qGRE) MRI technique that allows separation of the total R2* metric characterizing decay of GRE signal into tissue-specific (R2t*) and the baseline blood oxygen level-dependent (BOLD) contributions. A combination with the QSM data (also available from the qGRE signal phase) allowed further separation of the tissue-specific R2t* metric in a cell-specific and non-heme-iron-specific contributions. It is shown that the non-heme iron contribution to R2t* relaxation can be described with the previously developed Gaussian Phase Approximation (GPA) approach. qGRE data were obtained from 22 healthy control participants (ages 26–63 years). Results suggest that the ferritin complexes are aggregated in clusters with an average radius about 100nm comprising approximately 2600 individual ferritin units. It is also demonstrated that the concentrations of heme and non-heme iron tend to increase with age. The strongest age effect was seen in the pallidum region, where the highest age-related non-heme iron accumulation was observed

Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

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 3He 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