Faculty Bibliography

Background: Several studies have attempted to investigate the underlying mechanisms of cognitive deficits by different MRI techniques. In this respect, atrophy has been recognized to be one of the best correlates for cognitive changes whilst other MRI measures are less closely related. Since whole brain N-acetyl-aspartate (WBNAA) is used to quantify diffuse neuronal cell injury and has been described to precede brain atrophy in MS one intriguing question is whether WBNAA levels are associated with cognitive abnormalities. Objective: To study the relation between WBNAA, T1w and T2w lesion volume (LV) and cognitive core functions in MS. Methods: 82 MS-patients from our outpatient clinic (mean age 48.9 yrs; 56 female/26 male; CIS = 1; RRMS = 64; SPMS = 17) were prospectively studied. Besides application of different MRI measures (T1w and T2w LV, non-localized proton MR spectroscopy), participants were examined with a set of neuropsychological tests (MUSIC, SDMT). Spearman's rank correlation (one-sided) was used to analyze the associative strength between cognitive and MRI measures. Results: Significant correlations were found between WBNAA, short-term memory (STM) (p = 0.04) and executive functions (p = 0.04). In contrast, T1w and T2w LV did not show relations to these cognitive domains but were significantly correlated with SDMT (p < 0.001), speed (p<= 0.001), mental flexibility (p<= 0.034) and long-term memory (LTM) (p<= 0.041). There was no correlation between WBNAA and T1w and T2w LV, respectively. Discussion: This is one of the first studies on the relation between white matter lesion load, diffuse neuronal damage and cognitive parameters in MS. Interestingly, WBNAA correlated with measures of STM and executive functions but not with those of processing speed, mental flexibility and LTM. In contrast the three latter domains were exclusively related to T1w and T2w LVs. It is conceivable, that different neuropsychological domains are more strongly related to features of predominant neuronal vs. white matter damage. Thus, since WBNAA represents a non-regional parameter of neuronal destruction it can be concluded from the cognitive results that brain tissue alteration most probably occurs within frontal and prefrontal areas leading to functional disconnection. This study might also explain why results of MR correlative studies with cognitive performance need a careful consideration but also offer new means to understand the integration of pathology and clinical phenotypes

BACKGROUND: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group. METHODS: Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3-dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected. RESULTS: Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively. CONCLUSIONS: These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow

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

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

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

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

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

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

Fast, high-resolution, longitudinal relaxation time (T1) mapping is invaluable in clinical and research applications. It has been shown that two spoiled gradient recalled echo (SPGR) images acquired in steady state with variable flip angles is an attractive alternative to the multi-image sets previously acquired with inversion or saturation recovery. The known sensitivity of the two-point method to transmit radiofrequency field (B1) inhomogeneity exacerbated at 3 T and above, however, mandates its combination with an additional, time-consuming and possibly specific-absorption-rate-intensive B1 measurement, preventing direct migration of the method to these fields. To address this, we introduce a method designed to be free of systematic errors caused by B1 inhomogeneity in which the value of T1 is extracted from three SPGR images acquired with echo planar imaging (EPI) readout. The precision of the T1 maps produced is found to be comparable to the two-point method, while the accuracy is greatly improved in the same time and spatial resolution. A welcome byproduct of the method is a map of B1 that can be used to correct other acquisitions in the same session. Tables of the optimal acquisition protocols are provided for several total imaging times