Considerations for measuring the fractional anisotropy of metabolites with diffusion tensor spectroscopy.

Diffusion tensor spectroscopy of metabolites in brain is challenging because of their lower diffusivity (i.e. less signal attenuation for a given b value) and much poorer signal-to-noise ratio relative to water. Although diffusion tensor acquisition protocols have been studied in detail for water, they have not been evaluated systematically for the measurement of the fractional anisotropy of metabolites such as N-acetylaspartate, creatine and choline in the white and gray matter of human brain. Diffusion tensor spectroscopy was performed in vivo with variable maximal b values (1815 or 5018 s/mm(2)). Experiments were also performed on simulated spectra and isotropic alcohol phantoms of various diffusivities, ranging from approximately 0.54 × 10(-3) to 0.13 × 10(-3) mm(2)/s, to assess the sensitivity of diffusion tensor spectroscopic parameters to low diffusivity, noise and b value. The low maximum b value of 1815 s/mm(2) yielded elevated fractional anisotropy (0.53-0.60) of N-acetylaspartate in cortical gray matter relative to the more isotropic value (0.25-0.30) obtained with a higher b value of 5018 s/mm(2); in contrast, the fractional anisotropy of white matter was consistently anisotropic with the different maximal b values (i.e. 0.43-0.54 for b = 1815 s/mm(2) and 0.47-0.51 for b = 5018 s/mm(2)). Simulations, phantoms and in vivo data indicate that greater signal attenuation, to a degree, is desirable for the accurate quantification of diffusion-weighted spectra for slowly diffusing metabolites.

Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism.

OBJECTIVES: To determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients. DESIGN: Forty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinson's Disease Rating Scale, separated into dopamine responsive and dopamine non-responsive signs) and neuropsychological testing (memory: California Verbal Learning Test (CVLT)) and a composite of index of executive function (EF): Stroop Interference, Trail Making Test Part B, and digit ordering. All underwent volumetric MRI scans analyzed using voxel-based morphometry (VBM). Group comparisons, and the correlations between MRI gray and white matter volume and motor and cognitive measures were controlled for age, sex and intracranial volume. Cerebellar volume was independently measured using a validated extraction method. RESULTS: Patients and controls were matched for demographics and global cognitive measures. VBM indicated significant gray matter (GM) atrophy in the cerebellum in PD and was confirmed independently. Poor memory was associated with GM atrophy in the left (uncus, middle temporal and fusiform gyri) and right temporal lobes and left putamen. Dopamine non-responsive motor signs and EF were associated with caudate atrophy. EF was also associated with GM atrophy in the middle temporal gyri, the left precuneus and cerebellum. CONCLUSIONS: Cortical and striatal atrophy were associated with dopamine non-responsive motor signs and cognitive impairment and provide a morphologic correlate for progression of PD. Cerebellar atrophy was found in older PD patients.

Acute dextro-amphetamine administration does not alter brain myo-inositol levels in humans and animals: MRS investigations at 3 and 18.8 T.

The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75 min after receiving a 25 mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0 Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1 h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8 T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations.

Anisotropic diffusion of metabolites in peripheral nerve using diffusion weighted magnetic resonance spectroscopy at ultra-high field.

Although the diffusivity and anisotropy of water has been investigated thoroughly in ordered axonal systems (i.e., nervous tissue), there have been very few studies on the directional dependence of diffusion of metabolites. In this study, the mean apparent diffusion coefficient (Trace/3 ADC) and fractional anisotropy (FA) values of the intracellular metabolites N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), choline (Cho), taurine (Tau), and glutamate and glutamine (Glx) were measured parallel and perpendicular to the length of excised frog sciatic nerve using a water suppressed, diffusion-weighted, spin-echo pulse sequence at 18.8T. The degree of anisotropy (FA) of NAA (0.41+/-0.09) was determined to be less than tCr (0.59+/-0.07) and Cho (0.61+/-0.11), which is consistent with previously reported human studies of white matter. In contrast, Glx diffusion was found to be almost isotropic with an FA value of 0.20+/-0.06. The differences of FA between the metabolites is most likely due to their differing micro-environments and could be beneficial as an indicator of compartment specific changes with disease, information not readily available with water diffusion.

Decreased prefrontal Myo-inositol in major depressive disorder.

BACKGROUND: Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. METHODS: Thirteen nonmedicated moderate-severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time=168 msec; mixing time=28 msec; repetition time=3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. RESULTS: Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94+/-.23) than control subjects (1.32+/-.37) [F(1,23)=6.9; p=.016]. CONCLUSIONS: These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD.

Spectral editing of weakly coupled spins using variable flip angles in PRESS constant echo time difference spectroscopy: application to GABA.

A general in vivo magnetic resonance spectroscopy editing technique is presented to detect weakly coupled spin systems through subtraction, while preserving singlets through addition, and is applied to the specific brain metabolite gamma-aminobutyric acid (GABA) at 4.7 T. The new method uses double spin echo localization (PRESS) and is based on a constant echo time difference spectroscopy approach employing subtraction of two asymmetric echo timings, which is normally only applicable to strongly coupled spin systems. By utilizing flip angle reduction of one of the two refocusing pulses in the PRESS sequence, we demonstrate that this difference method may be extended to weakly coupled systems, thereby providing a very simple yet effective editing process. The difference method is first illustrated analytically using a simple two spin weakly coupled spin system. The technique was then demonstrated for the 3.01 ppm resonance of GABA, which is obscured by the strong singlet peak of creatine in vivo. Full numerical simulations, as well as phantom and in vivo experiments were performed. The difference method used two asymmetric PRESS timings with a constant total echo time of 131 ms and a reduced 120 degrees final pulse, providing 25% GABA yield upon subtraction compared to two short echo standard PRESS experiments. Phantom and in vivo results from human brain demonstrate efficacy of this method in agreement with numerical simulations.

Diffusion tensor spectroscopy (DTS) of human brain.

The diffusion tensor of N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), and choline (Cho) was measured at 3T using a diffusion weighted STEAM (1)H-MRS sequence in the healthy human brain in 6 distinct regions (4 white matter and 2 cortical gray matter). The Trace/3 apparent diffusion coefficient (ADC) of each metabolite was significantly greater in white matter than gray matter. The Trace/3 ADC values of tCr and Cho were found to be significantly greater than NAA in white matter, whereas all 3 metabolites had similar Trace/3 ADC in cortical gray matter. Fractional anisotropy (FA) values for all 3 metabolites were consistent with water FA values in the 4 white matter regions; however, metabolite FA values were found to be higher than expected in the cortical gray matter. The principal diffusion direction derived for NAA was in good agreement with expected anatomic tract directions in the white matter.

Trace apparent diffusion coefficients of metabolites in human brain using diffusion weighted magnetic resonance spectroscopy.

The rotationally invariant trace/3 apparent diffusion coefficients (ADC) of N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), and choline (Cho) were determined using a diffusion-weighted stimulated echo acquisition mode sequence at 3 T in three separate human brain regions, namely the subcortical white matter, occipital gray matter, and frontal gray matter. The measurement of the mean diffusivity eliminates the dependence of the measured ADC on the direction of the diffusion gradient relative to the tissue microstructure (i.e., anisotropy). Macroscopic brain motions induce phase errors that were compensated for by phasing (zero and first order) on the single average spectrum (zero order on the NAA peak) prior to summing the individual spectra. This method yielded reproducible trace/3 ADC values in the expected range without the use of cardiac gating. The mean diffusivity of NAA (0.14 +/- 0.03 x 10(-3) mm(2)/s) appears to be less than that of tCr (0.17 +/- 0.04 x 10(-3) mm(2)/s) and Cho (0.18 +/- 0.05 x 10(-3) mm(2)/s) in human brain.