Faculty Bibliography

Although the concentration of N-acetylaspartate (NAA) is often used as a neuronal integrity marker, its normal temporal variations are not well documented. To assess them over the 1-2 year periods of typical clinical trials, the whole-brain NAA concentration was measured longitudinally, over 4 years, in a cohort of healthy young adults. No significant change (adjusted for both sex and age) was measured either interpersonally or intrapersonally over the entire duration of the study

OBJECTIVE: Although most mild traumatic brain injury (mTBI) patients suffer any of several post-concussion symptoms suggestive of thalamic involvement, they rarely present with any MRI-visible pathology. The aim here, therefore, is to characterize their thalamic metabolite levels with proton MR spectroscopy (1H-MRS) compared with healthy controls. METHODS: T1-weighted MRI and multi-voxel 1H-MRS were acquired at 3 Tesla from 20 mTBI (Glasgow Coma Scale score of 15-13) patients, 19-59 years old, 0-7 years post-injury; and from 17 age and gender matched healthy controls. Mixed model regression was used to compare patients and controls with respect to the mean absolute N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) levels within each thalamus. RESULTS: The mTBI-induced thalamic metabolite concentration changes were under +/- 13.0% for NAA, +/- 13.5% for Cr and +/- 18.8% for Cho relative to their corresponding concentrations in the controls: NAA: 10.08 +/- 0.30 (mean +/- standard error), Cr: 5.62 +/- 0.18 and Cho: 2.08 +/- 0.09 mM. These limits represent the minimal detectable differences between the two cohorts. CONCLUSION: The change in metabolic levels in the thalamus of patients who sustained clinically defined mTBI could be an instrumental characteristic of 'mildness'. 1H-MRS could, therefore, serve as an objective laboratory indicator for differentiating 'mild' from more severe categories of head-trauma, regardless of the presence or lack of current clinical symptoms

Proton MR spectroscopic imaging (MRSI) at higher magnetic fields (B(0)) suffers metabolite localization errors from different chemical-shift displacements (CSDs) if spatially-selective excitation is used. This phenomenon is exacerbated by the decreasing radiofrequency (RF) field strength, B(1), at higher B(0)s, precluding its suppression with stronger gradients. To address this, two new methods are proposed: 1) segmenting the volume-of-interest (VOI) into several slabs, allowing proportionally stronger slice-select gradients; and 2) sequentially cascading rather than superposing the components of the Hadamard selective pulses used for reasons of better point-spread function (PSF) to localize the few slices within each slab. This can reduce the peak B(1) to that of a single slice. Combining these approaches permits us to increase the selective gradient four- to eightfold per given B(1), to 12 or 18mT/m for 4- or 2-cm VOIs. This 'brute force' approach reduces the CSD to under 0.05 cm/ppm at 7T, or less than half that at 3T

The transverse relaxation times, T(2), of N-acetylaspartate (NAA), total choline (Cho), and creatine (Cr) obtained at 3T in several human brain regions of eight healthy volunteers are reported. They were obtained simultaneously in 320 voxels with three-dimensional (3D) proton MR spectroscopy ((1)H-MRS) at 1 cm(3) spatial resolution. A two-point protocol, optimized for the least error per given time by adjusting both the echo delay (TE(i)) and number of averages, N(i), at each point, was used. Eight healthy subjects (four males and four females, age = 26 +/- 2 years) underwent the hour-long procedure of four 15-min, 3D acquisitions (TE(1) = 35 ms, N(1) = 1; and TE(2) = 285 ms, N(2) = 3). The results reveal that across all subjects the NAA and Cr T(2)s in gray matter (GM) structures (226 +/- 17 and 137 +/- 12 ms, respectively) were 13-17% shorter than the corresponding T(2)s in white matter (WM; 264 +/- 10 and 155 +/- 7 ms, respectively). The T(2)s of Cho did not differ between GM and WM (207 +/- 17 and 202 +/- 8, respectively). For the purpose of metabolic quantification, these values justify to within +/-10% the previous use of one T(2) per metabolite for 1) the entire brain and 2) all subjects. These T(2) values (which to our knowledge were obtained for the first time at this field, spatial resolution, coverage, and precision) are essential for reliable absolute metabolic quantification.

BACKGROUND AND PURPOSE: More than 85% of brain traumas are classified as 'mild'; MR imaging findings are minimal if any and do not correspond to clinical symptoms. Our goal, therefore, was to quantify the global decline of the neuronal marker N-acetylaspartate (NAA), as well as gray (GM) and white matter (WM) atrophy after mild traumatic brain injury (mTBI). MATERIALS AND METHODS: Twenty patients (11 male, 9 female; age range, 19-57 years; median, 35 years) with mTBI (Glasgow Coma Scale score 13-15 with loss of consciousness for at least 30 seconds) and 19 age- and sex-matched control subjects were studied. Seven patients were studied within 9 days of TBI; the other 13 ranged from 1.2 months to 31.5 years (average and median of 4.6 and 1.7 years, respectively) after injury. Whole-brain NAA (WBNAA) concentration was obtained in all subjects with nonlocalizing proton MR spectroscopy. Brain volume and GM and WM fractions were segmented from T1-weighted MR imaging and normalized to the total intracranial volume, suitable for intersubject comparisons. The data were analyzed with least squares regression. RESULTS: Patients with mTBI exhibited, on average, a 12% WBNAA deficit that increased with age, compared with the control subjects (p<.05). Adjusted for age effects, patients also suffered both global atrophy (-1.09%/year; P=.029) and GM atrophy (-0.89%/year; P=.042). Patients with and without visible MR imaging pathology, typically punctate foci of suspected shearing injury, were indistinguishable in both atrophy and WBNAA. CONCLUSION: WBNAA detected neuronal/axonal injury beyond the minimal focal MR-visible lesions in mTBI. Combined with GM atrophy, the findings may provide further, noninvasive insight into the nature and progression of mTBI

BACKGROUND AND PURPOSE: The cross-sectional rate of whole-brain N-acetylaspartate (NAA, a neuronal cell marker) loss in clinically similar relapsing-remitting multiple sclerosis (RRMS) patients has recently been shown to fall into 3 distinct decline rate strata. Our goal was to test the reproducibility of this observation in a new cohort of RRMS patients. MATERIALS AND METHODS: Sixteen serial patients (12 women, 4 men, median age 38 [27-55] years) with clinically definite RRMS for an average of 5 (0.3-18) years' disease duration and a mean Expanded Disability Status Score of 2.0 (0-6) were studied, once each. Their whole-brain NAA (WBNAA) amounts, obtained with proton MR spectroscopy, were divided by brain volumes (segmented from MR imaging) to yield concentrations suitable for cross-sectional comparisons. RESULTS: Three distinct strata of cross-sectional NAA decline rates were found: -0.031, -0.32, and -1.71 mmol/L/y when disease duration was estimated from confirmed diagnosis, or -0.057, -0.20, and -1.38 mmol/L/y when measured from the first clinical symptom. These rates and their corresponding fractions of the study population were indistinguishable from those reported previously in a different group of 49 clinically similar (mean Expanded Disability Status Score also 2.0) RRMS patients. CONCLUSION: Reproducing the previous cohort's cross-sectional WBNAA decline characteristics in this new group of clinically similar RRMS patients indicates that 3 WBNAA loss strata may be a general attribute of MS. Consequently, WBNAA could serve as a surrogate marker for the global load of neuronal and axonal dysfunction and damage in this disease

Quantitative MR metrics (e.g., T1, T2, diffusion coefficients, and magnetization transfer ratios (MTRs etc)) are often derived from two images collected with one acquisition parameter changed between them (the 'two-point' method). Since a low signal-to-noise-ratio (SNR) adversely affects the precision of these metrics, averaging is frequently used, although improvement accrues slowly-in proportion to the square root of imaging time. Fortunately, the relationship between the images' SNRs and the metric's precision can be exploited to our advantage. Using error propagation rules, we show that for a given sequence, specifying the total imaging time uniquely determines the optimal acquisition protocol. Specifically, instead of changing only one acquisition parameter and repeating the imaging pair until all available time is spent, we propose to adjust all of the parameters and the number of averages at each point according to their contribution to the sought metric's precision. The tactic is shown to increase the precision of the well-known two-point T1, T2, and diffusion coefficients estimation by 13-90% for the same sample, sequence, hardware, and duration. It is also shown that under this general framework, precision accrues faster than the square root of time. Tables of optimal parameters are provided for various experimental scenarios

BACKGROUND AND PURPOSE: Radiologic markers in multicenter trials are often confounded by different instrumentation used. Our goal was to estimate the variance of the global concentration of the neuronal cell marker N-acetylaspartate (NAA) among research centers using MR imaging scanners of different models, from different manufacturers, and of different magnetic field strength. MATERIALS AND METHODS: Absolute millimolar amounts of whole-brain NAA (WBNAA) were quantified with nonlocalizing proton MR spectroscopy in the brains of 101 healthy subjects (53 women, 48 men) aged 16-59 years (mean, 34.2 years). Twenty-three were scanned at 1 institute in a 1.5T Siemens Vision; 31 from another institute were studied with a 1.5T Siemens SP63; 36 were scanned at a third institute (24 with a 1.5T Vision, 12 with a 3T Siemens Trio); and 11 were obtained at a fourth institute using a 4T GE Signa 5.x. The NAA amounts were quantified with phantom-replacement and divided by the brain volume, segmented from MR imaging, to yield the concentration, a metric independent of brain size suitable for cross-sectional comparison. RESULTS: The average WBNAA concentration among institutions was 12.2 +/- 1.2 mmol/L. The subjects' WBNAA distributions did not differ significantly (p > .237) among the 4 centers, regardless of scanner manufacturer, model, or field strength and irrespective of whether adjustments were made for age or sex. CONCLUSION: Absolute quantification against a standard makes the WBNAA concentration insensitive to the MR hardware used to acquire it. This important attribute renders it a robust surrogate marker for multicenter neurologic trials

BACKGROUND AND PURPOSE: Glial cancer cells can be found well beyond the MR imaging T2 signal-intensity hyperintensity. To quantify the extent of the diffuse microstructural tissue damage possibly due to the presence of these satellite tumor cells, we investigated the relationships between global metabolic and microstructural abnormalities in the normal-appearing brain regions of patients with newly diagnosed glioma. MATERIAL AND METHODS: Ten patients (6 men, 4 women) with radiologically suspected untreated supratentorial glial tumors and 9 healthy controls (5 men, 4 women) were studied with T1- and T2-weighted MR imaging, diffusion-weighted echo-planar MR imaging, and whole-brain N-acetylaspartate (WBNAA) proton MR spectroscopy. The relationship between the WBNAA concentration, the mean diffusivity (MD), and fractional anisotropy (FA) values in a large contralateral normal-appearing white matter (NAWM) brain region was investigated with the Spearman rank correlation test. RESULTS: WBNAA values were significantly lower (P < .001) in patients (9.7 +/- 1.7 mmol/L) than controls (13.1 +/- 1.1 mmol/L). MD values were higher (P = .0001) in patients (0.95 +/- 0.07 mm(2)s(-1)) than in controls (0.61 +/- 0.04 mm(2)s(-1)). FA values did not differ between patients (0.42 +/- 0.08) and controls (0.43 +/- 0.041). A strong inverse correlation between WBNAA and MD (r = -0.88, P = .0008) was found in the patients but not in controls (r = 0.012, P = .975). CONCLUSION: The correlation between the WBNAA and MD in the contralateral NAWM suggests that the microstructural damage possibly related to the presence of infiltrative tumor cells contributes to WBNAA decline in these patients

A new strategy to yield information from the maximum number of voxels, each at the optimum signal-to-noise ratio (SNR) per unit time, in MR spectroscopic imaging (MRSI) is introduced. In the past, maximum acquisition duty-cycle was obtained by multiplexing in time several single slices each repetition time (TR), while optimal SNR was achieved by encoding the entire volume of interest (VOI) each TR. We show that optimal SNR and acquisition efficiency can both be achieved simultaneously by multiplexing in space and time several slabs of several slices, each. Since coverage of common VOIs in 3D proton MRSI in the human brain typically requires eight or more slices, at 3 T or higher magnetic fields, two or more slabs can fit into the optimum TR (approximately 1.6 s). Since typically four or less slices would then fit into each slab, Hadamard encoding is favored in that direction for slice profile reasons. It is demonstrated that per fixed examination length, the new method gives, at 3 T, twice as many voxels, each of the same SNR and size, compared with current 3D chemical shift imaging techniques. It is shown that this gain will increase for more extensive spatial coverage or higher fields