Chris C. Hanstock

Decreased Prefrontal Myo-Inositol in Major Depressive Disorder

BACKGROUNDnPostmortem 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.nnnMETHODSnThirteen 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.nnnRESULTSnPatients with MDD showed significantly lower myo-inositol/creatine ratios (.94+/-.23) than control subjects (1.32+/-.37) [F(1,23)=6.9; p=.016].nnnCONCLUSIONSnThese 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.

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

OBJECTIVESnTo determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients.nnnDESIGNnForty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinsons 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.nnnRESULTSnPatients 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.nnnCONCLUSIONSnCortical 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.

Posterior cingulate metabolic changes occur in Parkinson's disease patients without dementia

The basis for cognitive deficits in Parkinsons disease (PD) is unknown. Hippocampal atrophy has been shown in Alzheimers disease (AD) and PD. N-Acetyl aspartate (NAA)/creatine (Cr) ratio in the posterior cingulate gyrus (PCG) is decreased in AD, but unknown in PD. Volumetric magnetic resonance (MR) imaging (at 1.5 T) determined corrected HC volume and MR spectroscopy (MRS) PCG metabolites in 12 non-demented mild to moderately affected PD patients (six male, six female) and ten controls (five male, five female). Age (PD=60.6 years, control=62.2; P=0.62), education (PD=14.1 years, controls=13.8; P=0.89) and global cognition (Mini-Mental State Exam score: PD=28.7, controls=29.6; P=0.14) did not differ. Only recall (CVLT-II, P=0.046) and NAA/Cr (PD=1.53, controls=1.78; P=0.03) were decreased in PD. Memory correlated with NAA/Cr (r=0.65, P=0.02) in PD. In conclusion, cingulate metabolic changes occur in PD.

Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder.

BACKGROUNDnWomen who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs).nnnMETHODSnTwelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase.nnnRESULTSnA phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found.nnnCONCLUSIONSnThe optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

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 1H‐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. Magn Reson Med, 2006.

Combined structural and neurochemical evaluation of the corticospinal tract in amyotrophic lateral sclerosis.

Our objective was to characterize the structural and metabolic changes of the corticospinal tract (CST) in ALS patients using combined diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI). Fourteen patients (male:female, 6:8; mean age, 54 years) and 14 controls (male:female, 8:6; mean age, 53 years) underwent imaging. Four regions of the CST were evaluated: precentral gyrus, corona radiata, posterior limb of the internal capsule, and cerebral peduncle. DTI and MRSI indices tested included fractional anisotropy (FA), apparent diffusion coefficient (ADC), and the ratio of N-acetylaspartate to choline (NAA/Cho) and creatine (NAA/Cr). In the precentral gyrus, NAA/Cho was reduced 18% (p<0.001), NAA/Cr was reduced 9% (p=0.01), and FA was reduced 3% (p=0.02). NAA/Cho and NAA/Cr were reduced in the corona radiata (p<0.001). Reduced NAA/Cho in the precentral gyrus correlated with shorter symptom duration (r=0.66, p=0.02) and faster disease progression (r=−0.65, p=0.008). Increased spasticity correlated with higher ADC in the precentral gyrus (R=0.52, p=0.005). In conclusion, both MRSI and DTI provided in vivo evidence of intracranial degeneration of the CST in ALS that was most prominent rostrally in the precentral gyrus.

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 × 10−3 mm2/s) appears to be less than that of tCr (0.17 ± 0.04 × 10−3 mm2/s) and Cho (0.18 ± 0.05 × 10−3 mm2/s) in human brain. Magn Reson Med 53:1025–1032, 2005.

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia

Age‐related ventricular enlargement is accelerated in Alzheimers disease, but its relationship to cognitive decline in Parkinsons disease is less clear, even though dementia is common in Parkinsons disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinsons disease patients developing cognitive decline. Older nondemented patients with Parkinsons disease (33) and age‐ and sex‐matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1‐weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinsons disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini‐Mental Status Examination in the Parkinsons disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinsons disease with dementia, with similar change over time in both Parkinsons disease and Parkinsons disease with dementia. White matter volumes were not significantly different between Parkinsons disease and Parkinsons disease with dementia; however, the decrease over time might be greater in Parkinsons disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinsons disease, possibly reflecting both cortical gray and white matter loss.

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 5018u2009s/mm2). Experiments were also performed on simulated spectra and isotropic alcohol phantoms of various diffusivities, ranging from approximately 0.54u2009×u200910−3 to 0.13u2009×u200910−3 mm2/s, to assess the sensitivity of diffusion tensor spectroscopic parameters to low diffusivity, noise and b value. The low maximum b value of 1815u2009s/mm2 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 5018u2009s/mm2; in contrast, the fractional anisotropy of white matter was consistently anisotropic with the different maximal b values (i.e. 0.43–0.54 for bu2009=u20091815u2009s/mm2 and 0.47–0.51 for bu2009=u20095018u2009s/mm2). 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. Copyright

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.