Faculty Bibliography

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

Purpose: To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophrenia are metabolically different from those in healthy control subjects. Materials and Methods: This institutional review board-approved study was HIPAA compliant, and all participants provided written informed consent. Twenty-two patients with schizophrenia (13 male, nine female; 39.4 years +/- 10.6 [standard deviation]) and 11 age- and sex-matched control subjects (seven male, four female; 35.5 years +/- 10.7) underwent magnetic resonance (MR) imaging and three-dimensional 3-T voxel proton MR spectroscopy to measure absolute rostral and caudal ACC N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) concentrations. Exact Mann-Whitney test was used to compare patient data with control data, paired-sample Wilcoxon signed rank test was used to compare subregions within groups, and receiver operating characteristic curve analysis was used to assess sensitivity and specificity in diagnosis of schizophrenia. Results: There were no significant metabolic differences between patients and control subjects or between ACC subregions in control subjects. In patients, rostral ACC NAA and Cr concentrations were significantly lower than those in caudal ACC (6.2 mM +/- 1.3 vs 7.1 mM +/- 1.3, P < .01; 5.7 mmol/L +/- 1.4 vs 6.3 mmol/L +/- 1.6, P < .01; respectively); however, this did not hold true for Cho concentrations (1.7 mmol/L +/- 0.5 vs 1.8 mmol/L +/- 0.5). For individual differences between caudal and rostral measurements, only NAA in patients was different from that in control subjects (0.9 mmol/L +/- 1.3 vs -0.1 mmol/L +/- 0.5, P < .01), enabling prediction of schizophrenia with 68% sensitivity and 91% specificity, for a difference of more than 0.4. Conclusion: Significant differences between caudal and rostral NAA concentration are found in ACC of patients with schizophrenia but not in ACC of healthy control subjects, indicating that neuronal density or integrity differences between ACC subregions may be characteristic of the disease. (c) RSNA, 2011

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

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.

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

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

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

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