Robert Bartha

Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimers disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T(1)-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimers Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an epsilon 4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.

Resting state default-mode network connectivity in early depression using a seed region-of-interest analysis : Decreased connectivity with caudate nucleus

Aim:  Reports on resting brain activity in healthy controls have described a default‐mode network (DMN) and important differences in DMN connectivity have emerged for several psychiatric conditions. No study to date, however, has investigated resting‐state DMN in relatively early depression before years of medication treatment. The objective of the present study was, therefore, to investigate the DMN in patients seeking help from specialized mental health services for the first time for symptoms of depression.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Comparison of the quantification precision of human short echo time 1H spectroscopy at 1.5 and 4.0 Tesla

Precise quantification of human in vivo short echo time 1H spectra remains problematic at clinical field strengths due to broad peak linewidths and low signal‐to‐noise ratio (SNR). In this study, multiple STEAM spectra (TE = 20 ms, volume = 8 cm3) were acquired in a single individual at 1.5 T and 4 T to compare quantification precision. Test–retest STEAM spectra (volume = 1.5 cm3) were also acquired from the anterior cingulate and thalamus of 10 individuals at 4.0 T. Metabolite levels were quantified using automated software that incorporated field strength‐specific prior knowledge. With the distinct methods of data acquisition, processing, and fitting used in this study, peak height SNR increased ∼80% while peak linewidth increased by ∼50% in the 8 cm3 volumes at 4.0 T compared to 1.5 T, resulting in an average increase in quantification precision of 39%. Metabolite levels from test–retest data (1.5 cm3 voxels at 4.0 T) were quantified with similar inter‐ and intraindividual variability. Magn Reson Med 44:185–192, 2000. Published 2000 Wiley‐Liss, Inc.

Reduced hippocampal glutamate in Alzheimer disease.

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using (1)H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE=46 ms) (1)H spectra were acquired at 4T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukeys test (p<0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.

Four‐pool modeling of proton exchange processes in biological systems in the presence of MRI–paramagnetic chemical exchange saturation transfer (PARACEST) agents

Signal loss due to magnetization transfer (MT) from the macromolecular protons of biological tissues is an important consideration for the in vivo detection of paramagnetic chemical exchange saturation transfer (PARACEST) agents. In this study, a four‐pool model is presented that is based on the modified Bloch equations and incorporates terms for the proton exchange processes that occur in biological systems in the presence of MRI‐PARACEST contrast agents. The effect of the exchangeable proton chemical shift and PARACEST agent concentration are modeled in the presence of macromolecule‐derived MT. Experimental validation of the model was performed at 9.4 Tesla using Eu3+‐DOTAM‐glycine (Gly)‐phenylalanine (Phe) in both aqueous solution and samples containing 10% bovine serum albumin (BSA). The model was then used to measure the agent‐bound‐water chemical shift and the transverse relaxation time of macromolecular protons of a sample of Vero (nonhuman primate) cells labeled with Eu3+‐DOTAM‐Gly‐Phe and a phantom containing mouse brain tissue and 7 mM Eu3+‐DOTAM‐Gly‐Phe. In the brain tissue phantom, a chemical shift map with standard deviation (SD) < 0.7 ppm and a T2 map with SD < 0.6 μs were obtained. The results demonstrate the feasibility of in vivo temperature measurement based on the bound‐water chemical shift of Eu3+‐DOTAM‐Gly‐Phe in combination with this four‐pool model despite the inherent MT effect. Magn Reson Med 60:1197–1206, 2008.

In vivo 1H2O T †2 measurement in the human occipital lobe at 4T and 7T by Carr‐Purcell MRI: Detection of microscopic susceptibility contrast

A high‐resolution spin‐echo imaging method is presented (called CP‐LASER) which exploits the spin refocusing capability of an adiabatic Carr‐Purcell (CP) pulse sequence to measure apparent 1H2O transverse relaxation (T  †2 ) and generate contrast based on microscopic tissue susceptibility. High‐resolution CP‐LASER images of the human occipital lobe were acquired at four different echo times from six subjects at 4T and eight subjects at 7T to investigate the effect of magnetic field strength (B0) and the CP interpulse time (τcp) on T  †2 . Susceptibility contrast was identified and T  †2 was quantified for long τcp (>10 ms) and short τcp (7 ms at 4T and 6 ms at 7T) in gray matter, white matter, and cerebral spinal fluid. The 1H2O relaxation rate constants (1/T  †2 ) of gray and white matter each increased approximately linearly with field strength and T  †2 was inversely related to τcp. The average T  †2 value of gray matter was 19% and 9% smaller than that of white matter at 4T and 7T, respectively. These results are consistent with higher levels of compartmentalized ferritin and increased blood volume in gray matter compared to white matter in this region of the brain. Magn Reson Med 47:742–750, 2002.

A sensitive PARACEST contrast agent for temperature MRI: Eu3+-DOTAM-glycine (Gly)-phenylalanine (Phe)

Tissue temperature is a fundamental physiological parameter that can provide insight into pathological processes. The purpose of this study was to develop and characterize a novel paramagnetic chemical exchange saturation transfer (CEST) agent suitable for in vivo temperature mapping at 9.4T. The CEST properties of the europium (Eu3+) complex of the DOTAM‐Glycine (Gly)‐Phenylalanine (Phe) ligand were studied in vitro at 9.4T as a function of temperature, pH, and agent concentration. The transfer of magnetization (CEST effect) from the bound water to bulk water pools was ∼75% greater for Eu3+‐DOTAM‐Gly‐Phe compared to Eu3+‐DOTAM‐Gly at physiologic temperature (38°C) and pH (7.0 pH units) when using power level sufficiently low for in vivo imaging. Unlike Eu3+‐DOTAM‐Gly, whose CEST effect decreased with increasing temperature in the physiologic range, the CEST effect of Eu3+‐DOTAM‐Gly‐Phe was optimal at body temperature. A strong linear dependence of the chemical shift of the bound water pool on temperature was observed (0.3 ppm/°C), which was insensitive to pH and agent concentration. Temperature maps with SDs < 1°C were acquired at 9.4T in phantoms containing: 1) phantom A, an aqueous solution of 10 mM Eu3+‐DOTAM‐Gly‐Phe; 2) phantom B, 5% bovine serum albumin (BSA) with 15 mM Eu3+‐DOTAM‐Gly‐Phe; and 3) phantom C, mouse brain tissue with 4 mM Eu3+‐DOTAM‐Gly‐Phe. The temperature sensitivity combined with the high CEST effect observed at low concentration using low saturation power (B1) suggests this compound may be a good choice for in vivo temperature mapping at 9.4T. Magn Reson Med 59:374–381, 2008.

A short echo proton magnetic resonance spectroscopy study of the left mesial-temporal lobe in first-onset schizophrenic patients

BACKGROUND Past 1H magnetic resonance spectroscopy (MRS) studies of the temporal lobe in schizophrenic patients have shown decreased levels of N-acetylaspartate (NAA) suggesting reduced neuronal density in this region. However, the measured volumes have been large and included contributions from mostly white matter. METHODS Short echo 1H MRS was used to measure levels of NAA and other metabolites (i.e., glutamate and glutamine) from a 6 cm3 volume in the left mesial-temporal lobe of 11 first-episode schizophrenic patients and 11 healthy control subjects of comparable age, gender, handedness, education, and parental education levels. Spectra were quantified without operator interaction using automated software developed in our laboratory. Metabolite levels were normalized to the internal water concentration of each volume studied. Images were also obtained to determine temporal lobe gray and white matter volumes. RESULTS No significant differences were found between levels of NAA or other metabolites, or gray and white matter volumes, in first-episode schizophrenic patients and comparison subjects. CONCLUSIONS Since the volume studied was small compared to previous studies and contained mostly gray matter, this result suggests consequential NAA decreases may be restricted to regions of white matter.

Quantitative proton short‐echo‐time LASER spectroscopy of normal human white matter and hippocampus at 4 Tesla incorporating macromolecule subtraction

Accurate quantification of in vivo short‐echo‐time (TE) 1H spectra must account for contributions from both mobile metabolites and less mobile macromolecules, which can fluctuate in disease. The purpose of this study was to develop an approach for the acquisition and processing of macromolecule information to optimize metabolite quantification accuracy and precision. Human parietal white matter (8‐cm3 voxel) and posterior hippocampus (1.7‐cm3 voxel) metabolite levels were quantified, following manomolecule subtraction, from short‐echo‐time spectra (TE = 46 ms) acquired at 4.0 Tesla with localization by adiabatic selective refocusing (LASER). Nineteen metabolites were fit using a time domain Levenberg‐Marquardt minimization that incorporated prior knowledge of metabolite lineshapes. The macromolecule contribution to the spectrum was reduced by 87% (P < 0.05) when the acquisition of single averages of the full spectrum and macromolecule spectrum were interleaved to reduce subtraction errors due to motion. Subtracting the Hankel Lanczos singular value decomposition (HLSVD) fit of the macromolecule spectrum, which contained no random noise, did not alter quantified metabolite levels but did not increase metabolite quantification precision. Several metabolites had higher concentrations in the posterior hippocampus compared to parietal white matter, which emphasizes the need to carefully control for partial volume contamination in hippocampal spectroscopy studies. Magn Reson Med 49:918–927, 2003.