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Contents |
People
Faculty
- Ravinder Reddy, PhD
- Ari Borthakur, PhD
- George Dodge, PhD
- H. Ralph Schumacher, MD
- J. Bruce Kneeland, MD
- Jess Lonner, MD
Research Staff
Residents & Fellows
- Darmesh Tailor, MD, PhD
Graduate Students
Collaborators
- Navin Bansal, Ph.D.
- Mitchell Schnall, M.D., Ph.D.
- Jerry Glickson, Ph.D.
- Hee Kwon Song, Ph.D.
- Alan H. Stolpen, M.D., Ph.D.
- Jayram Udupa, Ph.D.
- Rahim Rizi, Ph.D.
- Felix Wehrli, Ph.D.
- Virginia M. Y. Lee, Ph.D.
- John Trojanowski, M.D., Ph.D.
- Harish Poptani, Ph.D.
Former Members
- Jen Beers, M.A.
- Frank Casey
- Rahul Dandora, M.S.
- Uma Duvvuri, M.D. Ph.D.
- Alex Gougoutas, M.D.
- Jon Kaufman, Ph.D.
- Sagar Kudchodkar
- Erik Shapiro, Ph.D.
- Andrew Wheaton, Ph.D.
Research
Our research interests are in developing novel magnetic resonance (MR) pulse sequences and strategies for non-invasive measurement of physiological and functional parameters in pathologies such as arthritis, tumors and Alzheimer's disease. Below is a description of some of these investigations.
T1ρ Imaging
T1ρ (the spin-lattice relaxation in the rotating frame) weighted MR imaging can be used to probe/quantify slow molecular motions at high B0 fields with high signal to noise ratio. T1ρ relaxation times in biological tissues invariably have a higher dynamic range compared to T2 relaxation times and are not susceptible to B1 and B0 inhomogeneities. T1ρ MRI is performed by applying a radiofrequency (RF) pulse to “lock” the magnetization in the transverse plane. T1ρ or “spin-lock” MRI shows reduced susceptibility-induced image artifacts and provides robust measurements of relaxation and exchange times. Recent work in our laboratory demonstrated that the T1ρ weighted imaging method has wide array of applications for investigating pathologies such as cancer, arthritis, Alzheimer’s disease and also in indirect detection of oxygen metabolism. Others have shown applications in imaging tumors, breast cancer and ischemic stroke; however, these studies were performed at low magnetic fields (< 0.2T). Despite numerous applications in clinical research, T1ρ MRI pulse sequences are currently restricted to acquiring only a single slice due the difficulty in making the spin-lock pulse slice-selective. Another issue is that T1ρ sequences employ relatively long RF pulses: therefore methods to minimize RF power deposition have to be considered during imaging. Further, to utilize T1ρ MRI in quantifying biochemical and structural changes in biological tissue, the effect of residual dipolar interaction and chemical exchange during spin-locking have to be analyzed.
With this in mind, in endeavoring to realize the full potential of the T1ρ imaging method, we strive to develop (i) multi-slice and 3D T1ρ imaging pulse sequences, (ii) methods for calculating and measuring RF power deposition and/or temperature change during imaging, (iii) new imaging strategies for reducing RF power deposition, and (iv) pulse sequences and appropriate models for computing residual dipolar interaction and exchange times in biological tissues. The developed technology is validated by studies performed on different tissue types in a variety of pathologies.
The following are examples of where this research has taken us and provides some background to some of our current investigations.
MR Imaging in Osteoarthritis
We are developing novel MR-based methods (T1ρ, Sodium MRI and 13C Spectroscopy) to diagnose Arthritis in its early stages. Our lab is developing a technique that will demonstrate the ability of T1ρ MRI to reliably detect foci of minimal osteoarthritis. We are also working to quantify glucosamine metabolism in articular cartilage explants with T1ρ and sodium (23Na) MRI and measure, in vivo, glycosaminoglycans, a biochemical indicator of cartilage integrity, in human joints.
Osteoarthritis (OA) affects more than half of the population above the age of 65 and has a significant negative impact on the quality of life of elderly individuals. In the US, the economic costs resulting from OA have been estimated to be more than 1% of the gross domestic product.
Recent research has led to the development of drugs in experimental animals that have proven capable of protecting macromolecules in cartilage from breakdown, effectively halting the progression of OA. Because of the long natural history of OA (10-20 years), validating the efficacy of these drugs in humans will require a technique that can directly assess their effect on the macromolecular matrix. Conventional medical imaging techniques to date have not proven capable of making this assessment. Plain films offer only a crude and relatively inaccurate estimate of the loss of cartilage thickness that is obtained by measuring the distance between apposed cortical surfaces. In contrast to plain films, magnetic resonance imaging (MRI) using conventional techniques permits the direct visualization of articular cartilage, and has proven accurate for the detection of macroscopic cartilage defects. However, MRI has not proven accurate for the detection of the earliest biochemical changes of OA.
MRI has been applied to the diagnosis of osteoarthritic changes by a large number of investigators. Since the results of previous studies using conventional T1- and T2-weighting and magnetization transfer (MT) weighted MRI have not been conclusive in detecting the earliest stages of degeneration, it is important to develop newer MR techniques that are highly sensitive to early changes of OA in articular cartilage. Recently, sodium MRI and Gd-DTPA2- enhanced proton MRI have been shown to be useful in measuring PG content of cartilage. However, although sodium MRI is highly sensitive to PG, it inherently has a low signal to noise ratio and requires special hardware and relatively high fields. Gd-DTPA-2 enhanced MRI requires an exogenous contrast agent and long waiting period prior to imaging. MRI studies dealing with measurement of diffusion, water content, cartilage thickness and volume and their advantages and drawbacks are elegantly described in recent review articles.
Recently, we demonstrated that the T1r relaxation rate strongly correlates with PG changes in bovine cartilage whereas correlation between the T2 rate and PG change is rather poor. Furthermore, in bovine as well as in ex vivo human cartilage, the T1ρ relaxation time is ~50% higher than T2 which results in higher dynamic range and improved signal to noise ratio (SNR). Another advantage of T1ρ imaging is that it provides a unique contrast between cartilage, fluid and other structures in the joint. The above advantages of T1ρ imaging potentially lead to the computation of early degenerative changes with high accuracy and precision.
Diagnostic Imaging of Brain Injury and Alzheimer’s Disease
Alzheimer's disease is the most common form of dementia in the elderly. Over 25 million people are affected by it and as the aging population increases, this number is expected to double by 2025. Classic symptoms of the disease include memory loss, confusion and biological features such as the formation of NFT and SP and gray matter atrophy in the brain. There are several avenues of treatment; symptomatic treatments, disease-modifying drugs and drugs that delay the onset of the disease. Despite promising research, there are few successes at preventing or reversing the progress of the disease. As a result, the mean survival for AD patients is only 6 years after initial diagnosis. However, as specific drug therapies are developed, there would be an increase in the demand for an early diagnosis of AD particularly in animal models of the disease. Recently several transgenic (tg) models of AD have been developed. One such model over-expresses the human form of the amyloid precursor protein and presenilin-1 (APP/PS1). This APP/PS1 model is characterized by the presence of Ab deposition in selected regions of the brain and is, therefore, commonly used to study disease etiology as well as in the development of novel therapeutic strategies.
Detecting atrophy in the early stages of any degenerative process would help distinguish patterns of atrophy and facilitate differential diagnosis.
Recent work by our group has demonstrated the feasibility of measuring regional blood flow and oxygen metabolism in the rat brain via T1ρ imaging. T1ρ-weighted MRI has shown some promise in generating tissue contrast based on variations in protein content. For example, we have shown that T1ρ MRI can map the distribution of glycosaminoglycans in cartilage. Preliminary studies on a transgenic mouse model of AD in our laboratory have shown that T1ρ weighted MRI is a promising method for detecting early changes due to AD. This work is being verified and expanded, and new models and clinical investigations are being pursued.
T1ρ Sequence Development
T1ρ imaging has been shown to be a highly promising technique for early detection of osteoarthritis, detection of AD plaques in Alzheimer’s disease, monitoring of tumor response to therapy and indirect detection of H217O in biological tissues. However, most of these studies have been restricted to single slices due to the difficulty in making the spin-locking pulse slice selective. Other aspects that hampered the progress in this area are the issue of RF power deposition, and the lack of detailed information on the effect of spin-locking on different interactions in biological tissues.
The development of 3D and multi-slice T1r sequences, as well as strategies for calculating and reducing RF power deposition during the pulse sequence will tremendously impact the applications of T1ρ imaging sequence in studying different pathologies. Further, spin-locking based pulse sequence development for quantifying residual dipolar coupling in biological tissues and quantitation of relative contributions of different relaxation mechanisms to T1ρ will provide a quantitative tool for computing the structural and biochemical integrity of various biological tissues. These developments drive several collaborative projects dealing with studies of different pathologies.
17O MR Techniques
Oxygen consumption provides vital information about neuronal activity. Neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia are associated with hampered enzymatic activity that catalyzes the reactions involved in oxidative metabolism. Oxygen consumption also has the potential for detecting regions of viable tissue following cerebral ischemia. Quantitative mapping of cerebral oxygen consumption contributes to the better understanding of the patho-physiology of several neurological disorders. A current method for such measurements is positron emission tomography (PET), which provides a low-resolution image and involves radioactive isotopes. Furthermore, due to short half-life of 15O2, PET studies require an on site cyclotron. Current direct17O magnetic resonance imaging (MRI) based methods, have limitations such as low sensitivity and requirement of invasive procedure and necessity of ultra-high magnetic fields. These limitations, coupled with the high cost of 17O2 gas, limit the applicability of direct 17O MRI methods to small animal studies. Consequently, there are no non-invasive methods for measuring oxygen consumption in humans in vivo combining safety with high spatial and temporal resolution.
Our interest and effort rests in the development of an integrated approach that combines an efficient 17O2 gas delivery system with improved, noninvasive, MRI strategies for computing the cerebral metabolic rate of oxygen consumption (CMRO2). Specifically, an efficient 17O2 gas delivery system, that reduces the 17O2 gas requirement by an order of magnitude is being designed and optimized for use on large animals and in humans. Efficacy of this system must be tested on an animal model. Improved MRI methods need to be designed to measure arterial input function of metabolically produced water (mpH217O) and validate it by the conventional approach of blood sampling. With integration of the above-mentioned system and MRI techniques an improved indirect 17O MRI strategy for measuring mpH217O to compute CMRO2 in the brain in vivo will be realized. Once the aims are accomplished, an efficient 17O gas delivery system and a noninvasive tool will become available to measure CMRO2 with high spatial resolution, which can be immediately extended to in vivo human studies. This approach will have substantial impact on the both scientific and clinical studies of neurological disorders and in the development and evaluation of novel therapies.
