Małgorzata Marjańska

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.

Proton Echo-Planar Spectroscopic Imaging of J-Coupled Resonances in Human Brain at 3 and 4 Tesla

In this multicenter study, 2D spatial mapping of J‐coupled resonances at 3T and 4T was performed using short‐TE (15 ms) proton echo‐planar spectroscopic imaging (PEPSI). Water‐suppressed (WS) data were acquired in 8.5 min with 1‐cm3 spatial resolution from a supraventricular axial slice. Optimized outer volume suppression (OVS) enabled mapping in close proximity to peripheral scalp regions. Constrained spectral fitting in reference to a non‐WS (NWS) scan was performed with LCModel using correction for relaxation attenuation and partial‐volume effects. The concentrations of total choline (tCho), creatine + phosphocreatine (Cr+PCr), glutamate (Glu), glutamate + glutamine (Glu+Gln), myo‐inositol (Ins), NAA, NAA+NAAG, and two macromolecular resonances at 0.9 and 2.0 ppm were mapped with mean Cramer‐Rao lower bounds (CRLBs) between 6% and 18% and ∼150‐cm3 sensitive volumes. Aspartate, GABA, glutamine (Gln), glutathione (GSH), phosphoethanolamine (PE), and macromolecules (MMs) at 1.2 ppm were also mapped, although with larger mean CRLBs between 30% and 44%. The CRLBs at 4T were 19% lower on average as compared to 3T, consistent with a higher signal‐to‐noise ratio (SNR) and increased spectral resolution. Metabolite concentrations were in the ranges reported in previous studies. Glu concentration was significantly higher in gray matter (GM) compared to white matter (WM), as anticipated. The short acquisition time makes this methodology suitable for clinical studies. Magn Reson Med, 2007.

Regional neurochemical profiles in the human brain measured by ¹H MRS at 7 T using local B₁ shimming.

Increased sensitivity and chemical shift dispersion at ultra‐high magnetic fields enable the precise quantification of an extended range of brain metabolites from 1H MRS. However, all previous neurochemical profiling studies using single‐voxel MRS at 7 T have been limited to data acquired from the occipital lobe with half‐volume coils. The challenges of 1H MRS of the human brain at 7 T include short T2 and complex B1 distribution that imposes limitations on the maximum achievable B1 strength. In this study, the feasibility of acquiring and quantifying short‐echo (TE = 8 ms), single‐voxel 1H MR spectra from multiple brain regions was demonstrated by utilizing a 16‐channel transceiver array coil with 16 independent transmit channels, allowing local transmit B1 (B1+) shimming. Spectra were acquired from volumes of interest of 1–8 mL in brain regions that are of interest for various neurological disorders: frontal white matter, posterior cingulate, putamen, substantia nigra, pons and cerebellar vermis. Local B1+ shimming substantially increased the transmit efficiency, especially in the peripheral and ventral brain regions. By optimizing a STEAM sequence for utilization with a 16‐channel coil, artifact‐free spectra were acquired with a small chemical shift displacement error (<5% /ppm/direction) from all regions. The high signal‐to‐noise ratio enabled the quantification of neurochemical profiles consisting of at least nine metabolites, including γ‐aminobutyric acid, glutamate and glutathione, in all brain regions. Significant differences in neurochemical profiles were observed between brain regions. For example, γ‐aminobutyric acid levels were highest in the substantia nigra, total creatine was highest in the cerebellar vermis and total choline was highest in the pons, consistent with the known biochemistry of these regions. These findings demonstrate that single‐voxel 1H MRS at ultra‐high field can reliably detect region‐specific neurochemical patterns in the human brain, and has the potential to objectively detect alterations in neurochemical profiles associated with neurological diseases. Copyright

Localized 1H NMR spectroscopy in different regions of human brain in vivo at 7 T: T2 relaxation times and concentrations of cerebral metabolites

At the high field strength of 7 T, in vivo spectra of the human brain with exceptional spectral quality sufficient to quantify 16 metabolites have been obtained previously only in the occipital lobe. However, neurochemical abnormalities associated with many brain disorders are expected to occur in brain structures other than the occipital lobe. The purpose of the present study was to obtain high‐quality spectra from various brain regions at 7 T and to quantify the concentrations of different metabolites. To obtain concentrations of metabolites within four different regions of the brain, such as the occipital lobe, motor cortex, basal ganglia and cerebellum, the T2 relaxation times of the singlets and J‐coupled metabolites in these regions were measured for the first time at 7 T. Our results demonstrate that high‐quality, quantifiable spectra can be obtained in regions other than the occipital lobe at 7 T utilizing a 16‐channel transceiver coil and B1+ shimming. Copyright

Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: A New Tool in Alzheimer's Disease Research

Alzheimers disease (AD) is the most common cause of dementia in the elderly. Cardinal pathologic features of AD are amyloid plaques and neurofibrillary tangles, and most in the field believe that the initiating events ultimately leading to clinical AD center on disordered metabolism of amyloid beta protein. Mouse models of AD have been created by inserting one or more human mutations associated with disordered amyloid metabolism and that cause early onset familial AD into the mouse genome. Human-like amyloid plaque formation increases dramatically with age in these transgenic mice. Amyloid reduction in humans is a major therapeutic objective, and AD transgenic mice allow controlled study of this biology. Recent work has shown that amyloid plaques as small as 35 μm can be detected using in vivo magnetic resonance microimaging (MRMI) at high magnetic field (9.4 T). In addition, age-dependent changes in metabolite concentration analogous to those that have been identified in human AD patients can be detected in these transgenic mice using single-voxel 1H magnetic resonance spectroscopy (1H MRS) at high magnetic field. These MR-based techniques provide a new set of tools to the scientific community engaged in studying the biology of AD in transgenic models of the disease. For example, an obvious application is evaluating therapeutic modification of disease progression. Toward the end of this review, the authors include results from a pilot study demonstrating feasibility of using MRMI to detect therapeutic modification of plaque progression in AD transgenic mice.

Magnetic resonance imaging of Alzheimer's disease.

A modern challenge for neuroimaging techniques is to contribute to the early diagnosis of neurodegenerative diseases, such as Alzheimer’s disease (AD). Early diagnosis includes recognition of pre-demented conditions, such as mild cognitive impairment (MCI) or having a high risk of developing AD. The role of neuroimaging therefore extends beyond its traditional role of excluding other conditions such as neurosurgical lesions. In addition, early diagnosis would allow early treatment using currently available therapies or new therapies in the future. Structural imaging can detect and follow the time course of subtle brain atrophy as a surrogate marker for pathological processes. New MR techniques and image analysis software can detect subtle brain microstructural, perfusion or metabolic changes that provide new tools to study the pathological processes and detect pre-demented conditions. This review focuses on markers of macro- and microstructural, perfusion, diffusion and metabolic MR imaging and spectroscopy in AD.

In vivo 13C spectroscopy in the rat brain using hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate

The low sensitivity of 13C spectroscopy can be enhanced using dynamic nuclear polarization. Detection of hyperpolarized [1-(13)C]pyruvate and its metabolic products has been reported in kidney, liver, and muscle. In this work, the feasibility of measuring 13C signals of hyperpolarized 13C metabolic products in the rat brain in vivo following the injection of hyperpolarized [1-(13)C]pyruvate and [2-(13)C]pyruvate is investigated. Injection of [2-(13)C]pyruvate led to the detection of [2-(13)C]lactate, but no other downstream metabolites such as TCA cycle intermediates were detected. Injection of [1-(13)C]pyruvate enabled the detection of both [1-(13)C]lactate and [13C]bicarbonate. A metabolic model was used to fit the hyperpolarized 13C time courses obtained during infusion of [1-(13)C]pyruvate and to determine the values of VPDH and VLDH.

Noninvasive Detection of Presymptomatic and Progressive Neurodegeneration in a Mouse Model of Spinocerebellar Ataxia Type 1

Recent studies with a conditional mouse model of spinocerebellar ataxia type 1 (SCA1) suggest that neuronal dysfunction is reversible and neurodegeneration preventable with early interventions. Success of such interventions will depend on early detection of neuronal and glial abnormalities before cell loss and availability of objective methods to monitor progressive neurodegeneration. Cerebellar concentrations of N-acetylaspartate (NAA), myo-inositol, and glutamate as measured by magnetic resonance spectroscopy (MRS) correlate with ataxia scores of patients with SCA1, indicating their potential as reliable biomarkers of neurodegeneration. Here we investigated whether neurochemical levels are altered by early, presymptomatic disease and whether they gauge disease progression in a mouse model of SCA1. Cerebellar neurochemical profiles of transgenic mice that overexpress the mutant human ataxin-1 (the SCA1[82Q] line) were measured longitudinally up to 1 year by MRS at 9.4 T and compared to those of transgenic mice that overexpress the normal human ataxin-1 (the SCA1[30Q] line) and wild-type controls. Multiple neurochemicals distinguished the SCA1[82Q] mice from controls with no overlap at all ages. Six neurochemicals were significantly different in SCA1[82Q] mice at 6 weeks, before major pathological and neurological changes. Alterations in NAA, myo-inositol, and glutamate progressively worsened and were significantly correlated (p < 0.0001) with disease progression as assessed by histology (molecular layer thickness and an overall severity score). Therefore, the neurochemicals that correlate with clinical status in patients reflected progressive pathology in the mouse model. These data demonstrate that presymptomatic and progressive neurodegeneration in SCA1 can be noninvasively monitored using MRS.

Detection of an antioxidant profile in the human brain in vivo via double editing with MEGA-PRESS

Vitamin C (ascorbate) and glutathione (GSH) are the two most concentrated non‐enzymatic antioxidants in the human brain. Double editing with (DEW) MEGA‐PRESS at 4T was designed in this study to measure both antioxidants in the same amount of time previously required to measure one. In the occipital lobe of four human subjects, resolved ascorbate (Asc) and GSH resonances were detected repeatedly and simultaneously using DEW MEGA‐PRESS. The Asc and GSH concentrations measured using LCModel analysis of DEW MEGA‐PRESS spectra were 0.8 ± 0.1 and 1.0 ± 0.1 μmol/g (mean ± SD), with average Cramer‐Rao lower bounds (CRLB) of 10% and 7%, respectively. Aside from the effects of J‐modulation at a common echo time (TE), double editing did not compromise sensitivity. To determine the extent to which the oxidized forms of Asc and GSH contribute to DEW MEGA‐PRESS spectra in vivo, chemical shifts and coupling constants for dehydroascorbate (DHA) and oxidized glutathione (GSSG) were measured at physiologic pH and temperature. DHA does not contribute to the 3.73 ppm DEW MEGA‐PRESS Asc resonance. GSSG contributions to the DEW MEGA‐PRESS GSH resonance (3.0 ppm) are negligible under physiologic conditions, and would be evidenced by a distinct GSSG resonance (3.3 ppm) at exceptionally high concentrations. Magn Reson Med, 2006.

Sequence design for magnetic resonance spectroscopic imaging of prostate cancer at 3 T

Magnetic resonance spectroscopic imaging (MRSI) has proven to be a powerful tool for the metabolic characterization of prostate cancer in patients before and following therapy. The metabolites that are of particular interest are citrate and choline because an increased choline‐to‐citrate ratio can be used as a marker for cancer. High‐field systems offer the advantage of improved spectral resolution as well as increased magnetization. Initial attempts at extending MRSI methods to 3 T have been confounded by the J‐modulation of the citrate resonances. A new pulse sequence is presented that controls the J‐modulation of citrate at 3 T such that citrate is upright, with high amplitude, at a practical echo time. The design of short (14 ms) spectral–spatial refocusing pulses and trains of nonselective refocusing pulses are described. Phantom studies and simulations showed that upright citrate with negligible sidebands is observed at an echo time of 85 ms. Studies in a human subject verified that this behavior is reproduced in vivo and demonstrated that the water and lipid suppression of the new pulse sequence are sufficient for application in prostate cancer patients. Magn Reson Med 53:1033–1039, 2005.