Faculty Bibliography

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

BACKGROUND AND PURPOSE: Neuro-axonal damage is a well known sequelae of MS pathogeneses. Consequently, our aim was to test whether the approximately 20% of patients with MS exhibiting a clinically benign disease course also have minimal neural dysfunction as reflected by the global concentration of their MR imaging marker NAA. MATERIALS AND METHODS: Q(NAA) was obtained with nonlocalizing whole-head (1)H-MR spectroscopy in 43 patients with benign RRMS (30 women, 13 men; mean age, 44.7 +/- 7.3 years of age) with 21.0 +/- 4.4 years (range, 15-35 years) of disease duration from the first symptom and an EDSS score of 1.9 (range, 0-3). Q(NAA) was by divided by the brain volume (from MR imaging segmentation) to normalize it into WBNAA. All participants gave institutional review board-approved written informed consent, and the study was HIPAA compliant. RESULTS: The patients' lesion load was 12.2 +/- 7.7 cm(3). Their 8.3 +/- 1.8 mmol/L WBNAA was 35% lower than that in controls (P < .001). Individual average loss rates (absolute loss compared with controls divided by disease duration) clustered around 0.22 +/- 0.09 mmol/L/year (1.7%/year, assuming monotonic decline). This rate could be extrapolated from that already reported for patients with RRMS of much shorter disease duration. WBNAA did not correlate with lesion load or EDSS. CONCLUSIONS: Normal WBNAA is not characteristic of benign MS and is not an early predictor of its course. These patients, therefore, probably benefit from successful compensation and sparing of eloquent regions. Because they may ultimately have a rapid decline once their brain plasticity is exhausted, they may benefit from treatment options offered to more affected patients

BACKGROUND: The aim of this study was to evaluate the effect of dehydroepiandrosterone (DHEA) supplementation on in vitro fertilization (IVF) data and outcomes among poor-responder patients. METHODS: A randomized, prospective, controlled study was conducted. All patients received the long-protocol IVF. Those in the study group received 75 mg of DHEA once a day before starting the next IVF cycle and during treatment. RESULTS: Thirty-three women with significantly diminished ovarian reserves were enrolled, 17 in the DHEA group and 16 in the control group. The 33 patients underwent 51 IVF cycles. The DHEA group demonstrated a non-significant improvement in estradiol levels on day of hCG (P = 0.09) and improved embryo quality during treatment (P = 0.04) between first and second cycles. Patients in the DHEA group also had a significantly higher live birth rate compared with controls (23.1% versus 4.0%; P = 0.05), respectively. Six of seven deliveries were among patients with secondary infertility (P = 0.006). CONCLUSION: Dehydroepiandrosterone supplementation can have a beneficial effect on ovarian reserves for poor-responder patients on IVF treatment. Clinicaltrials.gov: NCT01145144.

The accuracy of metabolic quantification in MR spectroscopy is limited by the unknown radiofrequency field and T(1). To address both issues in proton ((1)H) MR spectroscopy, we obtained radiofrequency field-corrected T(1) maps of N-acetylaspartate, choline, and creatine in five healthy rhesus macaques at 3 T. For efficient use of the 4 hour experiment, we used a new three-point protocol that optimizes the precision of T(1) in three-dimensional (1)H-MR spectroscopy localization for extensive, approximately 30%, brain coverage at 0.6 x 0.6 x 0.5 cm(3) = 180-microL spatial resolution. The resulting mean T(1)s in 700 voxels were N-acetylaspartate = 1232 +/- 44, creatine = 1238 +/- 23 and choline = 1107 +/- 56 ms (mean +/- standard error of the mean). Their histograms from all 140 voxels in each animal were similar in position and shape, characterized by standard errors of the mean of the full width at half maximum divided by their means of better than 8%. Regional gray matter N-acetylaspartate, choline, and creatine T(1)s (1333 +/- 43, 1265 +/- 52, and 1131 +/- 28 ms) were 5-10% longer than white matter: 1188 +/- 34, 1201 +/- 24, and 1082 +/- 50 ms (statistically significant for the N-acetylaspartate only), all within 10% of the corresponding published values in the human brain

Purpose: To establish an imaging approach to visualize the 100-mum-thick hippocampal neuron-generating dentate granule cell layer (DGCL) consistently within a clinically feasible magnetic resonance (MR) imaging duration and to assess its sensitivity by quantifying the likelihood that it will be detected in healthy young adults. Materials and Methods: The study was HIPAA compliant and institutional review board approved. All subjects provided written informed consent. Ten healthy volunteers (five male subjects, five female subjects; mean age, 26 years +/- 6 [standard deviation]) were imaged at 7.0 T by using a 24-element head coil array with three-dimensional T1-weighted MR imaging for anatomic reference, followed by T2*-weighted gradient-echo (echo time, 25 msec; repetition time, 944 msec) imaging at 232-mum in-plane resolution (0.05-mm(3) pixels) in coronal and sagittal slabs (17 sections at 1 mm thick) over the hippocampus in 14 minutes. The entire study took 45 minutes. Results: The DGCL was consistently visible in all 10 enrolled subjects. All larger subfields were visible in excellent detail and contrast in every subject. Conclusion: The spatial resolution and tissue contrast at high field strength (7.0 T) MR imaging can be used to consistently reveal hippocampal morphology down to 100-mum subfields within a clinically acceptable imaging duration. This imaging technique might be used to detect cellular disarray and degenerative changes in this sensitive circuit earlier than at 1.5 T or even 3.0 T. (c) RSNA, 2010

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

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

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