Faculty Bibliography

Background: Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS), while its underlying mechanisms are still not clear. There is some evidence from MR-spectroscopy that neuronal damage measured by the decline of the amino acid N-acetyl-aspartate (NAA) is associated with increased fatigue in MS. However, other groups found that fatigue in MS can be caused by white matter lesions related disruption of cortico-subcortical pathways. The aim of the present study was to determine whether MR-markers of subcortical white matter disruption like T2w and T1w lesion burden or a measure of the diffuse global neuronal damage (NAA) correlate more closely with fatigue. Materials and Methods: Eighty - two MS patients (57 female) of mean age 49.4 (23-69) years, with CIS (1) RRMS (64) and SPMS (17) with an average disease duration of 17.7 (3-50) years and mean EDSS of 2.9 (0-6.5), were enrolled. There normalized whole brain NAA (WBNAA) amount was obtained with non localized proton MR spectroscopy. T2w and T1w lesion load were obtained from respective MR images by a semi-automated procedure. Fatigue was measured with the FSMC scale. In a multiple linear regression model, correlations between FSMC sum score and T2w lesion load, WBNAA and disease duration were analyzed. Additionally, t-tests between fatigued and non-fatigued patients for T2w and T1w lesion load, WBNAA, disease duration and EDSS were performed. Results: A significant positive correlation between fatigue measured by the FSMC sum score and T2w lesion load (p = 0.029), but not with WBNAA (p = 0.68) or disease duration (p = 0.07) was found. The t-test for T2w (p = 0.0095) and T1w (p = 0.0165) lesion load and EDSS (p= 0.0147) revealed significant differences between MS-patients with and without fatigue. No differences were found for WBNAA in the two groups. Discussion: In our cohort conventional MR-markers, namely T1w and T2w lesion load, and the EDSS correlated more closely with MS fatigue, as objective mesures of neuroaxonal loss. In our global approach diffuse neuronal damage as measured by WBNAA was not a contributor to MS fatigue. This may point to the importance of subcortical disconnection of functional networks as a mechanism contributing to fatigue in MS

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

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

The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and (1)H-MR spectroscopy. Due to the shorter transverse relaxation time (T(2)) at the higher magnetic fields these studies favor, the echo times used in (1)H-MR spectroscopy subject the metabolites to unknown T(2) weighting, decreasing the accuracy of quantification which is key for inter- and intra-animal comparisons. To establish the 'baseline' (healthy animal) T(2) values, we mapped them for the three main metabolites' T(2)s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three-dimensional multivoxel (1)H-MR spectroscopy at (0.6 x 0.6 x 0.5 cm)(3) = 180 microL spatial resolution over a 4.2 x 3.0 x 2.0 = 25 cm(3) ( approximately 30%) of the macaque brain in a two-point protocol that optimizes T(2) precision per unit time. The estimated T(2)s in several gray and white matter regions are all within 10% of those reported in the human brain (mean +/- standard error of the mean): N-acetylaspartate = 316 +/- 7, creatine = 177 +/- 3, and choline = 264 +/- 9 ms, with no statistically significant gray versus white matter differences

While the inherent low sensitivity of in vivo MR spectroscopy motivated a trend towards higher magnetic fields, B(0), it has since become apparent that this increase does not seem to translate into the anticipated improvement in spectral resolution. This is attributed to the decrease of the transverse relaxation time, T(2)*, in vivo due to macro- and mesoscopic tissue susceptibility. Using spectral contrast-to-noise ratio (SCNR) arguments, we show that if in biological systems the linewidth (on the frequency scale) increases linearly with the field, the spectral resolution (in parts per million) improves approximately as the fifth-root of B(0) for chemically shifted lines and decreases as about B(0)(4/5) (in hertz) for a structure of J-coupled multiplets. It is also shown that for any given B(0) there is a unique voxel size that is optimal in spectral resolution, linking the spectral and spatial resolutions. Since in practical applications the spatial resolution may be dictated by the target anatomy, nomograms to determine the B(0) required to achieve the desired spectral resolution at that voxel size are presented. More generally, the scaling of the nomograms to determine the achievable spectral and spatial resolutions at any given field is described

PURPOSE: To quantify proton magnetic resonance (MR) spectroscopy-detectable metabolite concentrations along anteroposterior axis of hippocampus in healthy young and elderly subjects. MATERIALS AND METHODS: Young (three women, three men; age range, 25-35 years) and elderly (four women, two men; age range, 68-72 years) groups underwent MR imaging and proton MR spectroscopic imaging at 3 T in this HIPAA-compliant prospective study and gave institutional review board-approved written consent. Volume of interest was centered on and tilted parallel to hippocampal anteroposterior plane. Absolute N-acetylaspartate (NAA), choline, and creatine levels were obtained in each voxel, with phantom replacement. RESULTS: Mean NAA, creatine, and choline concentrations in the young group were higher in posterior hippocampus (12.9 mmol/L +/- 2.0 [standard deviation], 7.8 mmol/L +/- 1.2, 2.3 mmol/L +/- 0.4, respectively) than anterior hippocampus (8.0 mmol/L +/- 1.1, 6.0 mmol/L +/- 1.4, 1.5 mmol/L +/- 0.2; P = .005, .02, and .0002, respectively). In the elderly group, mean concentrations were higher in posterior hippocampus (8.6 mmol/L +/- 0.9, 5.6 mmol/L +/- 0.6, 1.5 mmol/L +/- 0.2, respectively) than anterior hippocampus (7.2 mmol/L +/- 1.0, 2.4 mmol/L +/- 0.3, 1.0 mmol/L +/- 0.2; P = .006, .0001, .04, respectively). Mean concentrations were significantly higher in the young group (13.2 mmol/L +/- 1.0, 7.4 mmol/L +/- 0.8, 2.1 mmol/L +/- 0.3, respectively) than in the elderly group (9.0 mmol/L +/- 1.0, 5.8 mmol/L +/- 0.8, 1.8 mmol/L +/- 0.3; P = .0001, .01, .05, respectively). Posteroanterior metabolic gradients differed: NAA decreased faster in the young group (-1.0 mmol/L x cm(-1)) than the elderly group (-0.7 mmol/L x cm(-1)); creatine and choline concentrations decreased faster in the elderly group (-0.8 and -0.058 mmol/L x cm(-1), respectively) than the young group (-0.16 and -0.008 mmol/L x cm(-1), respectively). No left-right metabolic differences were found. CONCLUSION: Significant metabolic heterogeneity was observed between groups and along anteroposterior axis of healthy hippocampus in both groups. Age matching and consistent voxel placement are important for correct comparisons of both absolute metabolic levels and metabolite ratios in longitudinal intra- and intersubject cross-sectional studies

Although recent studies indicate that use of a single global transverse relaxation time, T(2), 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) T(2)s was examined in four age groups using 3D (four slices, 80 voxels 1 cm(3) each) proton MR spectroscopy in an optimized two-point protocol. Metabolite T(2)s 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 T(2)s 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 T(2)s of NAA: 343, Cr: 172, and Cho: 248 ms. The elderly NAA, Cr, and Cho T(2)s were 12%, 6%, and 10% shorter than the adolescents, a change of under 1 ms/year assuming a linear decline with age. Formulae for T(2) age-correction for higher quantification precision are provided

Although Fourier gradient phase-encoding and Hadamard radio-frequency encoding are two established spatial MR localization techniques, the absence of voxel-shift and interpolation postprocessing algorithms for the latter has always placed it at a discouraging disadvantage. This article presents a method for voxel-shift and interpolation of Hadamard-encoded data and demonstrates both theoretically and experimentally the similarities of the respective operations between the two localization methods

OBJECTIVE: The aim of this study was to assess quantitatively structural changes in myelin content occurring during demyelination and remyelination by magnetization transfer imaging (MTI). MATERIALS AND METHODS: In a reversible model of demyelination with no axonal loss, mice intoxicated by cuprizone were studied by MTI in vivo at 9.4 T. MRI data were compared to histopathological examinations. RESULTS: Data revealed that the magnetization transfer ratio (MTR) decreased significantly during demyelination and increased during remyelination with strong correlation to the myelin content (r=0.79, P=0.01). CONCLUSIONS: This study demonstrated that MTR is a sensitive and reproducible quantitative marker to assess myelin loss and repair. This may lead to in vivo monitoring of therapeutic strategies promoting remyelination

BACKGROUND AND PURPOSE: Despite the prominent peak of N-acetylaspartate (NAA) in proton MR spectroscopy ((1)H-MR spectroscopy) of the adult brain and its almost exclusive presence in neuronal cells, the total amount of NAA, regarded as their marker, is difficult to obtain due to signal contamination from the skull lipids. This article compares the performance of 2 methods that overcome this difficulty to yield the whole-brain NAA signal, important for the assessment of the total disease load in diffuse neurologic disorders. MATERIALS AND METHODS: The heads of 12 healthy volunteers, 3 women and 9 men, 31.0 +/- 7.1 years of age, were scanned at 3T by using 2 nonlocalizing (1)H-MR spectroscopy sequences: One nulls the NAA (TI = 940 ms) every second acquisition by inversion-recovery to cancel the signals of the lipids (T1 << TI) in an add-subtract scheme. The other nulls the signal of the lipids (TI = 155 ms) directly after each acquisition, requiring half as many averages for the same signal-to-noise ratio. Each sequence was repeated 3 times back-to-back on 3 occasions, and the comparison criteria were intrasubject precision (reproducibility) and total measurement duration. RESULTS: NAA nulling is nearly twice as precise in its intrinsic back-to-back (5.8% versus 8.6%) as well as longitudinal (10.6% versus 19.7%) coefficients of variation compared with lipid nulling, but at the cost of double the acquisition time. CONCLUSION: When speed is a more stringent requirement than precision, the new lipid-nulling sequence is a viable alternative. For precision in cross-sectional or longitudinal global NAA quantification, however, NAA nulling is still the approach of choice despite its x2 ( approximately 5 minutes) time penalty compared with the lipid-nulling approach