Oded Gonen

Total brain N-acetylaspartate A new measure of disease load in MS

Objective: To quantitate the extent of neuronal cell loss in MS via the whole brain’s N-acetylaspartate (NAA) concentration (WBNAA). Methods: Because NAA is assumed to be present only in neuronal cell bodies and their axons, we measured WBNAA as a marker for viable neurons in 12 patients (9 women and 3 men, 26 to 53 years of age) suffering from relapsing-remitting (RR) MS for at least 5 years and compared them with 13 age- and sex-matched normal controls. Total brain NAA was determined with proton MR spectroscopy, and WBNAA was obtained by dividing it by the total brain volume, calculated from high resolution MRI. Results: The WBNAA of the RR MS patients was lower than their matched controls (p < 0.005). This difference was greater among older than younger subjects. The linear prediction equations of WBNAA with age indicate a faster, ×10, decline in the patients, ∼0.8% per year of age (p = 0.022). Conclusion: The age-dependent decrease of whole brain N-acetylaspartate (WBNAA) in the patients suggests that progressive neuronal cell loss is a cardinal feature of this disease. WBNAA offers a quick, highly reproducible measure of disease progression and may be an important marker of treatment efficacy in MS as well as other neurodegenerative diseases.

Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: A randomized prospective study

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.

Whole-Brain N-Acetylaspartate as a Surrogate Marker of Neuronal Damage in Diffuse Neurologic Disorders

SUMMARY: Proton MR spectroscopy (1H-MR spectroscopy) is a quantitative MR imaging technique often used to complement the sensitivity of conventional MR imaging with specific metabolic information. A key metabolite is the amino acid derivative N-acetylaspartate (NAA), which is almost exclusive to neurons and their processes and is, therefore, an accepted marker of their health and attenuation. Unfortunately, most 1H-MR spectroscopy studies only account for small 1- to 200-cm volumes of interest (VOI), representing less than 20% of the total brain volume. These VOIs have at least 5 additional restrictions: 1) To avoid contamination from subcutaneous and bone marrow lipids, they must be placed away from the skull, thereby missing most of the cortex. 2) They must be image-guided onto MR imaging–visible pathology, subjecting them to the implicit assumption that metabolic changes occur only there. 3) They encounter misregistration errors in serial studies. 4) The time needed to accumulate sufficient signal-intensity quality is often restrictive, and 5) they incur (unknown) T1- and T2-weighting. All these issues are avoided (at the cost of specific localization) by measuring the nonlocalized average NAA concentration over the entire brain. Indeed, whole-brain NAA quantification has been applied to several diffuse neurodegenerative diseases (where specific localization is less important than the total load of the pathology), and the results are presented in this review.

Three-dimensional proton spectroscopy of deep gray matter nuclei in relapsing-remitting MS.

The metabolic changes in the deep gray matter (GM) nuclei, thalamus, and basal ganglia of patients with relapsing–remitting multiple sclerosis were investigated with quantitative, multivoxel, three-dimensional proton MR spectroscopy. This technique facilitated the study of several bilateral structures in a single session at sub–cubic centimeter spatial resolution. Compared with 9 matched control subjects, the deep GM nuclei of 11 patients showed 7% lower N-acetylaspartate and 14% higher choline levels (p = 0.02 for both).

Robust fully automated shimming of the human brain for high‐field 1H spectroscopic imaging

Although a variety of methods have been proposed to provide automated adjustment of shim homogeneity, these methods typically fail or require large numbers of iterations in vivo when applied to regions with poor homogeneity, such as the temporal lobe. These limitations are largely due to 1) the limited accuracy of single evolution time measurements when full B0 mapping studies are used, and 2) inaccuracies arising from projection‐based methods when the projections pass through regions where the inhomogeneity exceeds the order of the fitted parameters. To overcome these limitations we developed a novel B0 mapping method using multiple evolution times with a novel unwrapping scheme in combination with a user‐defined ROI selection tool. We used these methods at 4T on 10 control subjects to obtain high‐resolution spectroscopic images of glutamate from the bilateral hippocampi. Magn Reson Med, 2006.

Human brain‐structure resolved T2 relaxation times of proton metabolites at 3 tesla

The transverse relaxation times, T2, of N‐acetylaspartate (NAA), total choline (Cho), and creatine (Cr) obtained at 3T in several human brain regions of eight healthy volunteers are reported. They were obtained simultaneously in 320 voxels with three‐dimensional (3D) proton MR spectroscopy (1H‐MRS) at 1 cm3 spatial resolution. A two‐point protocol, optimized for the least error per given time by adjusting both the echo delay (TEi) and number of averages, Ni, at each point, was used. Eight healthy subjects (four males and four females, age = 26 ± 2 years) underwent the hour‐long procedure of four 15‐min, 3D acquisitions (TE1 = 35 ms, N1 = 1; and TE2 = 285 ms, N2 = 3). The results reveal that across all subjects the NAA and Cr T2s in gray matter (GM) structures (226 ± 17 and 137 ± 12 ms, respectively) were 13–17% shorter than the corresponding T2s in white matter (WM; 264 ± 10 and 155 ± 7 ms, respectively). The T2s of Cho did not differ between GM and WM (207 ± 17 and 202 ± 8, respectively). For the purpose of metabolic quantification, these values justify to within ±10% the previous use of one T2 per metabolite for 1) the entire brain and 2) all subjects. These T2 values (which to our knowledge were obtained for the first time at this field, spatial resolution, coverage, and precision) are essential for reliable absolute metabolic quantification. Magn Reson Med 57:983–989, 2007.

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.

Optimizing the efficiency of high-field multivoxel spectroscopic imaging by multiplexing in space and time

A new strategy to yield information from the maximum number of voxels, each at the optimum signal‐to‐noise ratio (SNR) per unit time, in MR spectroscopic imaging (MRSI) is introduced. In the past, maximum acquisition duty‐cycle was obtained by multiplexing in time several single slices each repetition time (TR), while optimal SNR was achieved by encoding the entire volume of interest (VOI) each TR. We show that optimal SNR and acquisition efficiency can both be achieved simultaneously by multiplexing in space and time several slabs of several slices, each. Since coverage of common VOIs in 3D proton MRSI in the human brain typically requires eight or more slices, at 3 T or higher magnetic fields, two or more slabs can fit into the optimum TR (∼1.6 s). Since typically four or less slices would then fit into each slab, Hadamard encoding is favored in that direction for slice profile reasons. It is demonstrated that per fixed examination length, the new method gives, at 3 T, twice as many voxels, each of the same SNR and size, compared with current 3D chemical shift imaging techniques. It is shown that this gain will increase for more extensive spatial coverage or higher fields. Magn Reson Med, 2006.

Neuronal cell injury precedes brain atrophy in multiple sclerosis.

arrive in the Journal office in hopes that comparable books might be published soon. Likewise, to compare older editions of some texts to more recently published volumes may not be appropriate. We welcome suggestions. The more serious issue raised by Dr. Kaufman is that of conflict of interest. We share Dr. Kaufman’s concern that reviewers be objective. When reviewers are invited to review a paper for Neurology, they are asked to declare conflicts of interest before the review is assigned.3,4 We are implementing a process to declare conflicts of interest for book reviewers as well. Because reviewers are experts in their fields, they may have conflicts of interest. However, declared conflicts do not preclude a fair review; the Editors are more concerned about undeclared conflicts, but this is beyond our control.5 We will begin including disclosure statements on future Book Review pages, but our continued trust in the professionalism, ethics, and objectivity of our colleagues remains fundamental to the review process.6 Garrett H. Riggs, PhD, MD, Book Review Editor, Rochester, NY