Brian D. Ross

Magnetic resonance spectroscopy diagnosis of neurological diseases

Introduction MRS basic physics of MR the clinical significance of metabolites an introduction to clinical cases clinical cases degenerative disease - Alzheimer disease, dementia, Huntingtons disease, Parkinsons disease systemic diseases - liver disease, diabetes mellitus osmolar abnormalities trauma - SIADH, hyper-osmolar state, diffuse axonal injury, hypoxic injury global hypoxia -vascular diseases, stroke, infarcts and non vascular focal hypoxia focal lesions - ectopic grey matter, HIV related lesions, tumours and tuberculoma multiple sclerosis and other inflammatory disease paediatrics - abnormal development, Reyes syndrome, inborn errors of metabolism xenobiotics - ethanol, propylene, glycol, mannitol MRS patterns and referral guidelines.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

3-D FLASH imaging using a single surface coil and a new adiabatic pulse, BIR-4.

A new adiabatic pulse, which can induce uniform and arbitrary flip angles despite the presence of transmitter coil magnetic field (B1) inhomogeneities, is employed for 3-D fast imaging using a single surface coil for pulse transmission and signal detection. Computer calculations and phantom, rat, and human surface coil imaging experiments demonstrate the utility of this adiabatic pulse for T1-weighted imaging with a transmitter coil which generates a highly inhomogeneous B1 field profile.

Efficacy of proton magnetic resonance spectroscopy in neurological diagnosis and neurotherapeutic decision making

SummaryAnatomic and functional neuroimaging with magnetic resonance imaging (MRI) includes the technology more widely known as magnetic resonance spectroscopy (MRS). Now a routine automated “add-on” to all clinical magnetic resonance scanners, MRS, which assays regional neurochemical health and disease, is therefore the most accessible diagnostic tool for clinical management of neurometabolic disorders. Furthermore, the noninvasive nature of this technique makes it an ideal tool for therapeutic monitoring of disease and neurotherapeutic decision making. Among the more than 100 brain disorders that fall within this broad category, MRS contributes decisively to clinical decision making in a smaller but growing number. In this review, we will cover how MRS provides therapeutic impact in brain tumors, metabolic disorders such as adrenoleukodystrophy and Canavan’s disease, Alzheimer’s disease, hypoxia, secondary to trauma or ischemia, human immunodeficiency virus dementia and lesions, as well as systemic disease such as hepatic and renal failure. Together, these eight indications for MRS apply to a majority of all cases seen. This review, which examines the role of MRS in enhancing routine neurological practice and treatment concludes: 1) there is added value from MRS where MRI is positive; 2) there is unique decision-making information in MRS when MRI is negative; and 3) MRS usefully informs decision making in neurotherapeutics. Additional efficacy studies could extend the range of this capability.

PASADENA Hyperpolarization of Succinic Acid for MRI and NMR Spectroscopy

We use the PASADENA (parahydrogen and synthesis allow dramatically enhanced nuclear alignment) method to achieve 13C polarization of approximately 20% in seconds in 1-13C-succinic-d2 acid. The high-field 13C multiplets are observed as a function of pH, and the line broadening of C1 is pronounced in the region of the pK values. The 2JCH, 3JCH, and 3JHH couplings needed for spin order transfer vary with pH and are best resolved at low pH leading to our use of pH approximately 3 for both the molecular addition of parahydrogen to 1-13C-fumaric acid-d2 and the subsequent transfer of spin order from the nascent protons to C1 of the succinic acid product. The methods described here may generalize to hyperpolarization of other carboxylic acids. The C1 spin-lattice relaxation time at neutral pH and 4.7 T is measured as 27 s in H2O and 56 s in D2O. Together with known rates of succinate uptake in kidneys, this allows an estimate of the prospects for the molecular spectroscopy of metabolism.

Direct determination of the N‐acetyl‐l‐aspartate synthesis rate in the human brain by 13C MRS and [1‐13C]glucose infusion

A non‐invasive 13C magnetic resonance spectroscopy (MRS) technique is described for the determination of the N‐acetyl‐l‐aspartate (NAA) synthesis rate, VNAA, in the human brain in vivo. In controls, the mean VNAA was 9.2 ± 3.9 nmol/min/g. In Canavan disease, where [NAA] is increased (p < 0.001) and [aspartate] is deceased (p < 0.001), VNAA was significantly reduced to 3.6 ± 0.1 nmol/min/g (p < 0.001). These rates are in close agreement with the activity of the biosynthetic enzyme measured in vitro in animals, and with the rate of urinary excretion of NAA in human subjects with Canavan disease. The present result is consistent with the regulation of NAA synthesis by the activity of a single enzyme, l‐aspartate‐N‐acetyltransferase, in vivo, and with its control in Canavan disease by limited substrate supply and/or product inhibition. The 13C MRS technique provides the means for further determination of abnormal rates of neuronal NAA synthesis among neurological disorders in which low cerebral [NAA] has been identified.

Metabolic imaging of mild traumatic brain injury

Traumatic brain injury results in a metabolic cascade of changes that occur at the molecular level, invisible to conventional imaging methods such as computed tomography or magnetic resonance imaging. Non-invasive metabolic imaging tools such as single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance spectroscopy (MRS) are the ideal methods for providing insight to these changes by measuring regional cerebral blood flow, glucose metabolism, and brain metabolite concentrations, respectively, after mild traumatic brain injury (mTBI). The purpose of this review is to provide an overview of the different methodologies and provide an up-to-date summary of recent findings with SPECT, PET, and MRS technologies, specifically after mTBI, as defined by standardized criteria. Given that the different physiological and pathological responses are heterogeneous, efforts will be made to separate studies at different time points after injury (acute, subacute, and chronic stages) as well as to the different types of mTBI such sports-related head injury where repetitive head injuries are much more common and may present a unique signature.

Real-Time Molecular Imaging of Tricarboxylic Acid Cycle Metabolism in Vivo by Hyperpolarized 1- 13 C Diethyl Succinate

The Krebs tricarboxylic acid cycle (TCA) is central to metabolic energy production and is known to be altered in many disease states. Real-time molecular imaging of the TCA cycle in vivo will be important in understanding the metabolic basis of several diseases. Positron emission tomography (PET) with FDG-glucose (2-[(18)F]fluoro-2-deoxy-d-glucose) is already being used as a metabolic imaging agent in clinics. However, FDG-glucose does not reveal anything past glucose uptake and phosphorylation. We have developed a new metabolic imaging agent, hyperpolarized diethyl succinate-1-(13)C-2,3-d(2) , that allows for real-time in vivo imaging and spectroscopy of the TCA cycle. Diethyl succinate can be hyperpolarized via parahydrogen-induced polarization (PHIP) in an aqueous solution with signal enhancement of 5000 compared to Boltzmann polarization. (13)C magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) were achieved in vivo seconds after injection of 10-20 μmol of hyperpolarized diethyl succinate into normal mice. The downstream metabolites of hyperpolarized diethyl succinate were identified in vivo as malate, succinate, fumarate, and aspartate. The metabolism of diethyl succinate was altered after exposing the animal to 3-nitropropionate, a known irreversible inhibitor of succinate dehydrogenase. On the basis of our results, hyperpolarized diethyl succinate allows for real-time in vivo MRI and MRS with a high signal-to-noise ratio and with visualization of multiple steps of the TCA cycle. Hyperpolarization of diethyl succinate and its in vivo applications may reveal an entirely new regime wherein the local status of TCA cycle metabolism is interrogated on the time scale of seconds to minutes with unprecedented chemical specificity and MR sensitivity.

Developmental changes in choline‐ and ethanolamine‐containing compounds measured with proton‐decoupled 31P MRS in in vivo human brain

Cerebral phosphorylated metabolites, possibly involved in membrane and myelin sheath metabolism, were measured and quantified using proton‐decoupled 31P ({1H}‐31P) MRS in 32 children and 28 adults. Age‐dependent changes were determined for phosphorylethanolamine (PE), phosphorylcholine (PC), glycerophosphorylethanolamine (GPE), glycerophosphorylcholine (GPC), and phosphocreatine (PCr) concentrations. In the neonate, PE dominates the spectrum and decreases with age along with PC, whereas GPE, GPC, and PCr increase in concentration with postnatal age. PE (1.23 ± 0.13 mM) and GPE (0.57 ± 0.08 mM) co‐resonate with choline in 1H MRS. Together with PC (0.57 ± 0.12 mM) and GPC (0.94 ± 0.13 mM) these four metabolites accounted for all of the visible 1H MRS choline in normal adult brain. Children with diseases that affect myelination were found to have abnormal {1H}‐31P MRS. The new quantitative assay may provide novel insights in determining and monitoring normal and abnormal brain maturation noninvasively. Magn Reson Med 42:643–654, 1999.

Neurospectroscopy: The Past, Present and Future

Neurospectroscopy with respect to its past, present and future has been reported. It is helpful to understand the biochemical relevance of each of the major resonances in the brain spectra. Lactate is seen in the spectrum as a doublet at 1.33 ppm. Healthy tissues do not have sufficient lactate to be detectable by MRS. Neurospectroscopy provides information on brain constituents. Pattern recognition blends pattern recognition techniques and multivariate statistical analysis with solid, comprehensive software engineering practices. Neurospectroscopy offers a window into the chemistry of the human brain, reporting on normal mechanisms as well as the changes that occur with degeneration, disease, pain, cancer, and infection. Alzheimers disease can now be identified much earlier than before offering earlier management before the disease progresses. The long-term effect of shaken baby syndrome and traumatic brain injury can be gauged by neurospectroscopy.