Faculty Bibliography

Since mild traumatic brain injury (mTBI) often leads to neurological symptoms even without clinical MRI findings, our goal was to test whether diffuse axonal injury is quantifiable with multivoxel proton MR spectroscopic imaging ((1)H-MRSI). T1- and T2-weighted MRI images and three-dimensional (1)H-MRSI (480 voxels over 360 cm(3), about 30 % of the brain) were acquired at 3 T from 26 mTBI patients (mean Glasgow Coma Scale score 14.7, 18-56 years old, 3-55 days after injury) and 13 healthy matched contemporaries as controls. The N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) concentrations and gray-matter/white-matter (GM/WM) and cerebrospinal fluid fractions were obtained in each voxel. Global GM and WM absolute metabolic concentrations were estimated using linear regression, and patients were compared with controls using two-way analysis of variance. In patients, mean NAA, Cr, Cho and mI concentrations in GM (8.4 +/- 0.7, 6.9 +/- 0.6, 1.3 +/- 0.2, 5.5 +/- 0.6 mM) and Cr, Cho and mI in WM (4.8 +/- 0.5, 1.4 +/- 0.2, 4.6 +/- 0.7 mM) were not different from the values in controls. The NAA concentrations in WM, however, were significantly lower in patients than in controls (7.2 +/- 0.8 vs. 7.7 +/- 0.6 mM, p = 0.0125). The Cho and Cr levels in WM of patients were positively correlated with time since mTBI. This (1)H-MRSI approach allowed us to ascertain that early mTBI sequelae are (1) diffuse (not merely local), (2) neuronal (not glial), and (3) in the global WM (not GM). These findings support the hypothesis that, similar to more severe head trauma, mTBI also results in diffuse axonal injury, but that dysfunction rather than cell death dominates shortly after injury.

Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's (1) H MR spectroscopy ((1) H-MRS) signal, reducing sensitivity to changes. While single-voxel (1) H-MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1-mm(3) resolution MRI into GM, WM and CSF masks that were co-registered with the MRSI grid to yield their partial volumes in approximately every 1 cm(3) spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i- metabolite's GM and WM concentrations C(i) (GM) , C(i) (WM) . With the voxels' GM and WM volumes as independent coefficients, the over-determined system of equations was solved for the global averaged C(i) (GM) and C(i) (WM) . Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N-acetylaspartate, creatine, choline and myo-inositol C(i) (GM) concentrations of 8.5 +/- 0.7, 6.9 +/- 0.6, 1.2 +/- 0.2, 5.3 +/- 0.6mM, respectively, and C(i) (WM) concentrations of 7.7 +/- 0.6, 4.9 +/- 0.5, 1.4 +/- 0.1 and 4.4 +/- 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5-10% (more for ratios), which can often double the sample size required to establish statistical significance

OBJECTIVES: To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-l-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials. METHODS: Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 +/- 5 years old (mean +/- SD), had a disease duration of 47 +/- 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ((1)H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-l-aspartate (1)H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V(B), from MRI segmentation. RESULTS: The baseline WBNAA of the patients (10.5 +/- 1.7 mM) was significantly lower than that of the controls (12.3 +/- 1.3 mM; p < 0.002) and declined significantly (5%/year, p < 0.002) vs that for the controls who did not show a decline (0.4%/year, p > 0.7). Likewise, V(B) values of the patients also declined significantly (0.5%/year, p < 0.0001), whereas those of the controls did not (0.2%/year, p = 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V(B) or WBNAA. CONCLUSIONS: WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies.

The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) ( approximately 30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 +/- 0.8, 5.9 +/- 0.6, 1.4 +/- 0.1, and 4.5 +/- 0.5 mM (mean +/- standard-deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

Non-human primates are often used as preclinical model systems for (mostly diffuse or multi-focal) neurological disorders and their experimental treatment. Due to cost considerations, such studies frequently utilize non-destructive imaging modalities, MRI and proton MR spectroscopy ((1) H MRS). Cost may explain why the inter- and intra-animal reproducibility of the (1) H MRS observed brain metabolites, are not reported. To this end, we performed test-retest three-dimensional brain (1) H MRS in five healthy rhesus macaques at 3 T. Spectra were acquired from 224 isotropic (0.5 cm)(3) = 125 muL voxels, over 28 cm(3) ( approximately 35%) of the brain, then individually phased, frequency aligned and summed into a spectrum representative of the entire volume of interest. This dramatically increases the metabolites' signal-to-noise ratios, while maintaining the (narrow) voxel linewidth. The results show that the average N-acetylaspartate, creatine, choline, and myo-inositol concentrations in the macaque brain are: 7.7 +/- 0.5, 7.0 +/- 0.5, 1.2 +/- 0.1 and 4.0 +/- 0.6 mM/g wet weight (mean +/- standard deviation). Their inter-animal coefficients of variation (CV) are 4%, 4%, 6%, and 15%; and the longitudinal (intra-animal) CVs are lower still: 4%, 5%, 5%, and 4%, much better than the 22%, 33%, 36%, and 45% intra-voxel CVs, demonstrating the advantage of the approach and its utility for preclinical studies of diffuse neurological diseases in rhesus macaques. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

BACKGROUND AND PURPOSE: Although NAA is often used as a marker of neural integrity and health in different neurologic disorders, the temporal behavior of WBNAA is not well characterized. Our goal therefore was to establish its normal variations in a cohort of healthy adults over typical clinical trial periods. MATERIALS AND METHODS: Baseline amount of brain NAA, Q(NAA), was obtained with nonlocalizing proton MR spectroscopy from 9 subjects (7 women, 2 men; 31.2 +/- 5.6 years old). Q(NAA) was converted into absolute millimole amount by using phantom-replacement. The WBNAA concentration was derived by dividing Q(NAA) with the brain parenchyma volume, V(B), segmented from MR imaging. Temporal variations were determined with 4 annual scans of each participant. RESULTS: The distribution of WBNAA levels was not different among time points with respect to the mean, 12.1 +/- 1.5 mmol/L (P > .6), nor was its intrasubject change (coefficient of variation = 8.6%) significant between any 2 scans (P > .5). There was a small (0.2 mL) but significant (P = .05) annual V(B) decline. CONCLUSIONS: WBNAA is stable over a 3-year period in healthy adults. It qualifies therefore as a biomarker for global neuronal loss and dysfunction in diffuse neurologic disorders that may be well worth considering as a secondary outcome measure candidate for clinical trials

Purpose: To test the hypothesis that T2 signals in lesions and normal-appearing tissue are sufficiently similar that signal variations represent true variations in metabolite concentration. Materials and Methods: The T2 distributions of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) at 3.0 T were mapped in the brain of 10 relapsing-remitting (RR) MS patients of 0.3-12 years disease duration with multivoxel (four sections of 80 1-cm(3) voxels) point-resolved proton spectroscopy imaging in a two-point protocol. Institutional review board approval and written informed consent were obtained; the study was Health Insurance Portability and Accountability-compliant. Mixed-model analysis of variance was performed to compare brain regions and lesion types for each metabolite; a Wilcoxon test was performed to compare observed T2 values with age-based predictions. Results: The T2 histograms from 320 voxels in each patient were similar in peak position for mean values (+/- standard error) for NAA (250 msec +/- 9), Cr (166 msec +/- 3), and Cho (221 msec +/- 6); shape was characterized by full width at half maximum values of 174 msec +/- 11, 98 msec +/- 3, and 143 msec +/- 5, respectively. Regional T2 values in white matter (WM; 298 msec +/- 6, 162 msec +/- 1, and 222 msec +/- 4 for NAA, Cr, and Cho, respectively) were all significantly longer than in gray matter (GM; 221 msec +/- 7, 143 msec +/- 4, and 205 msec +/- 8, respectively) but not different from isointense (313 msec +/- 24, 188 msec +/- 12, and 238 msec +/- 17, respectively) or hypointense (296 msec +/- 27, 163 msec +/- 12, and 199 msec +/- 12, respectively) lesions, except for the Cho value for hypointense lesion, which was significantly lower. When compared with corresponding values in healthy contemporaries, these T2 values were shorter by 18%, 8%, and 14% in GM and by 21%, 12%, and 13% in WM for NAA, Cr, and Cho, respectively. Conclusion: For the purpose of metabolic quantification at 3.0 T and echo times of less than 100 msec, an average T2 value per metabolite should suffice for any brain region and lesion regardless of disease duration, age, or disability in any RR MS patient and their controls. (c) RSNA, 2010

Localized tissue transverse relaxation time (T(2)) is obtained by fitting a decaying exponential to the signals from several spin-echo experiments at different echo times (TE). Unfortunately, time constraints in magnetic resonance spectroscopy (MRS) often mandate in vivo acquisition schemes at short repetition times (TR), that is, comparable with the longitudinal relaxation constant (T(1)). This leads to different T(1)-weighting of the signals at each TE. Unaccounted for, this varying weighting causes systematic underestimation of the T(2)'s, sometimes by as mush as 30%. In this article, we (i) analyze the phenomenon for common MRS spin-echo T(2) acquisition schemes; (ii) propose a general post hoc T(1)-bias correction for any (TR, TE) combination; (iii) show that approximate knowledge of T(1) is sufficient, since a 20% uncertainty in T(1) leads to under 3% bias in T(2); and consequently, (iv) efficient, precision-optimized short TR spin-echo T(2) measurement protocols can be designed and used without risk of accuracy loss. Tables of correction for single-refocusing (conventional) spin-echo and double refocusing, such as, PRESS acquisitions, are provided

OBJECTIVE: To test the hypothesis that diffuse abnormalities precede axonal damage and atrophy in the MRI normal-appearing tissue of relapsing-remitting (RR) multiple sclerosis (MS) patients, and that these processes continue during clinical remission. METHODS: Twenty-one recently diagnosed mildly disabled (mean disease duration 2.3 years, mean Expanded Disability Status Scale score of 1.4) RR MS patients and 15 healthy matched controls were scanned with MRI and proton MR spectroscopic imaging ((1)H-MRSI) at 3 T. Metabolite concentrations: N-acetylaspartate (NAA) for neuronal integrity; choline (Cho) for membrane turnover rate; creatine (Cr) and myo-inositol (mI) for glial status were obtained in a 360 cm(3) volume of interest (VOI) with 3D multivoxel (1)H-MRSI. They were converted into absolute amounts using phantom replacement and normalised into absolute concentrations by dividing by the VOI tissue volume fraction obtained from MRI segmentation. RESULTS: The patients' mean VOI tissue volume fraction, 0.92 and NAA concentration, 9.6 mM, were not different from controls' 0.94 and 9.6 mM. In contrast, the patients' mean Cr, Cho and mI levels 7.7, 1.9 and 4.1 mM were 9%, 14% and 20%, higher than the controls' 7.1, 1.6 and 3.4 mM (p = 0.0097, 0.003 and 0.0023). CONCLUSIONS: The absence of early tissue atrophy and apparent axonal dysfunction (NAA loss) in these RR MS patients suggests that both are preceded by diffuse glial proliferation (astrogliosis), as well as possible inflammation, demyelination and remyelination reflected by elevated mI, Cho and Cr, even during clinical remission and despite immunomodulatory treatment