Ivan I. Kirov

Characterizing ‘mild’ in traumatic brain injury with proton MR spectroscopy in the thalamus: Initial findings

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.

MR spectroscopy indicates diffuse multiple sclerosis activity during remission

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 (1H-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 cm3 volume of interest (VOI) with 3D multivoxel 1H-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.

Age dependence of regional proton metabolites T2 relaxation times in the human brain at 3 T

Although recent studies indicate that use of a single global transverse relaxation time, T2, per metabolite is sufficient for better than ±10% quantification precision at intermediate and short echo‐time spectroscopy in young adults, the age‐dependence of this finding is unknown. Consequently, the age effect on regional brain choline (Cho), creatine (Cr), and N‐acetylaspartate (NAA) T2s was examined in four age groups using 3D (four slices, 80 voxels 1 cm3 each) proton MR spectroscopy in an optimized two‐point protocol. Metabolite T2s were estimated in each voxel and in 10 gray and white matter (GM, WM) structures in 20 healthy subjects: four adolescents (13 ± 1 years old), eight young adults (26 ± 1); two middle‐aged (51 ± 6), and six elderly (74 ± 3). The results reveal that T2s in GM (average ± standard error of the mean) of adolescents (NAA: 301 ± 30, Cr: 162 ± 7, Cho: 263 ± 7 ms), young adults (NAA: 269 ± 7, Cr: 156 ± 7, Cho: 226 ± 9 ms), and elderly (NAA: 259 ± 13, Cr: 154 ± 8, Cho: 229 ± 14 ms), were 30%, 16%, and 10% shorter than in WM, yielding mean global T2s of NAA: 343, Cr: 172, and Cho: 248 ms. The elderly NAA, Cr, and Cho T2s were 12%, 6%, and 10% shorter than the adolescents, a change of under 1 ms/year assuming a linear decline with age. Formulae for T2 age‐correction for higher quantification precision are provided. Magn Reson Med 60:790–795, 2008.

Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury

Objective: To obtain quantitative neurometabolite measurements, specifically myoinositol (mI) and glutamate plus glutamine (Glx), markers of glial and neuronal excitation, in deep gray matter structures after mild traumatic brain injury (mTBI) using proton magnetic resonance spectroscopy (1H-MRS) and to compare these measurements against normal healthy control subjects. Methods: This study approved by the institutional review board is Health Insurance Portability and Accountability Act compliant. T1-weighted MRI and multi-voxel 1H-MRS imaging were acquired at 3 tesla from 26 patients with mTBI an average of 22 days postinjury and from 13 age-matched healthy controls. Two-way analysis of variance was used to compare patients and controls for mean N-acetylaspartate, choline, creatine (Cr), Glx, and mI levels as well as the respective ratios to Cr within the caudate, globus pallidus, putamen, and thalamus. Results: Quantitative putaminal mI was higher in patients with mTBI compared with controls (p = 0.02). Quantitative neurometabolite ratios of putaminal mI and Glx relative to Cr, mI/Cr, and Glx/Cr were also higher among patients with mTBI compared with controls (p = 0.01 and 0.02, respectively). No other differences in neurometabolite levels or ratios were observed in any other brain region evaluated. Conclusion: Increased putaminal mI, mI/Cr, and Glx/Cr in patients after mTBI compared with control subjects supports the notion of a complex glial and excitatory response to injury without concomitant neuronal loss, evidenced by preserved N-acetylaspartate levels in this region.

Two-year serial whole-brain N-acetyl-l-aspartate in patients with relapsing-remitting multiple sclerosis

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 (1H-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 1H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, VB, 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, VB 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 VB 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.

Longitudinal Whole-Brain N-Acetylaspartate Concentration in Healthy Adults

This article addresses the issue of neuronal changes over time. N-acetylaspartate is surrogate marker of neuronal viability and integrity as seen on hydrogen MR spectroscopy. Here, the authors utilized their own method of measuring whole-brain NAA in a small cohort of healthy adults with each receiving 4 scans (baseline and annual) during a 3-year period. The data were converted to absolute millimole concentrations of this metabolite. They found that whole-brain NAA was 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. 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, QNAA, was obtained with nonlocalizing proton MR spectroscopy from 9 subjects (7 women, 2 men; 31.2 ± 5.6 years old). QNAA was converted into absolute millimole amount by using phantom-replacement. The WBNAA concentration was derived by dividing QNAA with the brain parenchyma volume, VB, 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 VB 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.

N-acetyl-aspartate levels correlate with intra-axonal compartment parameters from diffusion MRI

Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De||), extra-axonal radial diffusivity (De┴), axonal water fraction (AWF), and tortuosity (α) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy ((1)H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, α, and fractional anisotropy; negative correlations between NAA and De,┴ and the overall radial diffusivity (D┴). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De|| and Cho, and a positive trend between De|| and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De|| with mI and Cho, both predominantly present extra-axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra-axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De┴, AWF, and α).

Brain Metabolite Proton T2 Mapping at 3.0 T in Relapsing-Remitting Multiple Sclerosis

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.

Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8-depleted rhesus macaques: proton MRS imaging at 3 T

To test the hypotheses that global decreased neuro‐axonal integrity reflected by decreased N‐acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo‐inositol (mI), present in a CD8‐depleted rhesus macaque model of HIV‐associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre‐ and 4–6 weeks post‐simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm3 spatial resolution over ~35% of the brain) using linear regression. Pre‐ to post‐infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p < 0.003); global mI increased 11%: 5.7 ± 0.4 to 6.5 ± 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response. Copyright

Retrospective correction for T1-weighting bias in T2 values obtained with various spectroscopic spin-echo acquisition schemes

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.