Wolfgang Block

1H metabolite relaxation times at 3.0 tesla: Measurements of T1 and T2 values in normal brain and determination of regional differences in transverse relaxation

To measure 1H relaxation times of cerebral metabolites at 3 T and to investigate regional variations within the brain.

Proton MR spectroscopy of the hippocampus at 3 T in patients with unipolar major depressive disorder: correlates and predictors of treatment response.

Various lines of research suggest that neurotrophic processes in the hippocampus are key mechanisms in major depressive disorder and are of relevance for response to antidepressive treatment. We performed proton magnetic resonance spectroscopy (1H-MRS) of the hippocampus at 3 T in 18 unmedicated subjects with unipolar major depressive episodes and in 10 age- and gender-matched healthy volunteers. Thirteen patients underwent a second examination after 8 wk treatment with either citalopram (n=7) or nortriptyline (n=6). Of these patients, 11 MRS datasets could be used for the assessment of treatment correlates. In the cross-sectional comparison, we observed a significant reduction of the metabolic ratios Glx/Cr (Glx=glutamine, glutamate and gamma-aminobutyric acid) and glutamine (Gln)/Cr in the patient group. The Gln/Glx ratio also showed a trend towards significant reduction. The individual effect of treatment correlated with an increase in the absolute concentrations of N-acetylaspartate (NAA) and of choline compounds (Cho). Low baseline NAA and Cho levels predicted positive treatment effects. There was no difference in any clinical or metabolic measure, either at baseline or at follow-up between the two treatment groups (citalopram, nortriptyline). Our data provide first evidence for a reduction of Gln in the hippocampus of subjects with major depression. Furthermore, we provide first evidence in patients with major depression for neurorestorative effects in the hippocampus by pharmacological treatment expressed by a correlation of NAA and Cho increases with treatment response. This accounts in particular for those patients with low NAA and Cho baseline levels.

DNA sequence variants of the FKBP5 gene are associated with unipolar depression

FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume.

In-vivo proton MR-spectroscopy of the human brain: Assessment of N-acetylaspartate (NAA) reduction as a marker for neurodegeneration

Summary. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method to investigate changes in brain metabolite composition in different cerebral diseases.We performed proton spectroscopy in patients with dementia of the Alzheimers type (AD) and in patients with motor neuron disease (MND) with the aim to detect the specific metabolic pattern for these neurodegenerative disorders.In the MND group we found a significant reduction of NAA/tCr metabolite ratios in the motor cortex, which correlates with the disease severity and the clinical lateralization of neurological symptoms and further decreases in the time course of the disease. In AD patients a reduction of NAA/tCr was observed in the medial temporal lobe.Since NAA is exclusively expressed in neurons as shown by immunohistochemical studies, reduced NAA levels suggest neuronal loss or dysfunction in the observed regions.The observed regional metabolic alterations reflect the neuronal basis of the characteristic neurological symptoms in AD (dementia) and MND (muscular palsy) and mirrors the disease progress over time.

Proton magnetic resonance spectroscopy in subjects at risk for schizophrenia

We used proton magnetic resonance spectroscopy (1H MRS) to examine biochemical characteristics of the brain tissue in subjects at risk for schizophrenia. Nineteen participants fulfilling research criteria for an early (n=10) or a late (n=9) at-risk syndrome, 21 patients with full disease according to DSM IV and 31 healthy control subjects were included in the study. Single-voxel 1H MRS was performed in the left frontal lobe, the anterior cingulate gyrus and the left superior temporal lobe. Subjects were followed longitudinally to detect conversion to schizophrenia. We observed a significant reduction of the metabolic ratios NAA/Cr and NAA/Cho in the left frontal lobe and of NAA/Cr in the anterior cingulate gyrus in both at-risk groups and in the schizophrenic patients compared with healthy controls. Those at-risk subjects, who converted to schizophrenia within the observation period, had a higher Cho/Cr and a lower NAA/Cho ratio in the anterior cingulate gyrus compared with non-converters. NAA/Cr did not differ between converters and non-converters. Six at-risk subjects were taking antidepressants, two were taking antipsychotics. There was no difference in any metabolic ratio in any region between at-risk subjects with and without medication. We conclude that the reduction of the neuronal marker NAA in the left prefrontal lobe and the anterior cingulate gyrus may represent a vulnerability indicator for schizophrenia in at-risk subjects, while elevated Cho in the anterior cingulate gyrus may be a predictor for conversion from the prodromal state to the full disease.

Decreased frontal lobe ratio of N-acetyl aspartate to choline in familial schizophrenia : a proton magnetic resonance spectroscopy study

Neuropathological and neuroimaging studies suggest neuronal dysfunction in schizophrenia. N-acetyl aspartate (NAA) is a useful marker of neuronal dysfunction that can be measured with magnetic resonance spectroscopy (MRS). In the present study NAA, choline (Cho), phospho-creatine ((P)Cr), inositol containing compounds and glutamine/glutamate (Glx) were assessed in the left frontal lobe and basal ganglia of subjects with familial schizophrenia, family members with mixed psychiatric diagnoses, unaffected family members, and community controls. Concentrations of metabolites were analyzed and expressed as ratios. NAA/Cho, NAA/(P)Cr and Glx containing compounds showed a negative correlation with age in the frontal lobe. After covarying for age, subjects with schizophrenia had a significant reduction in the left frontal lobe NAA/Cho ratio compared with unaffected family members (P=0.018) as well as with community non-familial (P=0.037) controls. These MRS observations support the hypothesis of a disease-related neuronal deficit in the frontal lobe of schizophrenic patients, and relatively normal basal ganglia.

Interrelated neuropsychological and anatomical evidence of hippocampal pathology in the at-risk mental state.

BACKGROUND Verbal learning and memory deficits are frequent among patients with schizophrenia and correlate with reduced magnetic resonance imaging (MRI) volumes of the hippocampus in these patients. A crucial question is the extent to which interrelated structural-functional deficits of the hippocampus reflect a vulnerability to schizophrenia, as opposed to the disorder per se. METHOD We combined brain structural measures and the Rey Auditory Verbal Learning Test (RAVLT) to assess hippocampal structure and function in 36 never-medicated individuals suspected to be in early (EPS) or late prodromal states (LPS) of schizophrenia relative to 30 healthy controls. RESULTS Group comparisons revealed bilaterally reduced MRI hippocampal volumes in both EPS and LPS subjects. In LPS subjects but not in EPS subjects, these reductions were correlated with poorer performance in RAVLT delayed recall. CONCLUSIONS Our findings suggest progressive and interrelated structural-functional pathology of the hippocampus, as prodromal symptoms and behaviours accumulate, and the level of risk for psychosis increases. Given the inverse correlation of learning and memory deficits with social and vocational functioning in established schizophrenia, our findings substantiate the rationale for developing preventive treatment strategies that maintain cognitive capacities in the at-risk mental state.

Unipolar depression and hippocampal volume: Impact of DNA sequence variants of the glucocorticoid receptor gene†

Glucocorticoid receptor (GR) plays a major role in regulation of the hypothalamic–pituitary–adrenocortical (HPA) system; HPA dysregulation represents the most consistent biological pattern of depression. Multiple functional polymorphisms are known for the GR gene, which might influence the development of unipolar depression. Previous studies reported associations to some variants in this gene but not consistently so. We investigated seven genetic polymorphisms in the GR gene (NR3C1) located in the putative promoter, exon 2 and intron 2 region. Study populations were 322 German inpatients with recurrent unipolar depression, and 298 German controls recruited from the general population. The relationships between intermediate phenotypes (hippocampal and amygdala volumes) and NR3C1 DNA sequence variants were additionally explored in a subpopulation of patients. We found association between the diagnosis of depression and DNA sequence variants in intron 2 as well as in the 5′ region of the NR3C1 gene but not for the previously studied exon 2 and putative promoter variants (global test after control of multiple testing, P = 0.02). In patients, diagnosis‐related alleles were also associated to hippocampal volume reduction and amygdala volume variation. Unipolar depression is associated with DNA variants of the NR3C1 gene in our population. Neurobiological underpinnings of depression as volumetric reductions of the hippocampus may also be mediated by variants in this gene.

Incremental value of quantitative CMR including parametric mapping for the diagnosis of acute myocarditis

AIM Cardiac magnetic resonance (CMR) can visualize inflammatory tissue changes in acute myocarditis. Several quantitative image-derived parameters have been described to enhance the diagnostic value of CMR, but no direct comparison of these techniques is available. METHODS AND RESULTS A total of 34 patients with suspected acute myocarditis and 50 control subjects underwent CMR. CMR protocol included quantitative assessment of T1 relaxation times using modified Look-Locker inversion recovery (MOLLI) and shortened MOLLI (ShMOLLI) acquisition schemes, extracellular volume fraction (ECV), T2 relaxation times, and longitudinal strain. Established Lake-Louise criteria (LLC) consisting of T2-weighted signal intensity ratio (T2-ratio), early gadolinium enhancement ratio (EGEr), and late gadolinium enhancement (LGE) were assessed. Receiver operating characteristics analysis was performed to compare diagnostic performance. Areas under the curve of native T1 (MOLLI: 0.95; ShMOLLI: 0.92) and T2 relaxation times (0.92) were higher compared with those of the other CMR parameters (T2-ratio: 0.71, EGEr: 0.71, LGE: 0.87, LLC: 0.90, ECV MOLLI: 0.77, ECV ShMOLLI: 0.80, longitudinal strain: 0.83). Combined with LGE, each native mapping technique outperformed the diagnostic performance of LLC (P < 0.01, respectively). A combination of native parameters (T1, T2, and longitudinal strain) significantly increased the diagnostic performance of CMR compared with LLC without need of contrast media application (0.99 vs. 0.90; P = 0.008). CONCLUSION In patients suspected of having acute myocarditis, diagnostic performance of CMR can be improved by implementation of quantitative CMR parameters. Especially, native mapping techniques have the potential to replace current LLC. CLINICALTRIALS. GOV NUMBER NCT02299856.

N-Acetylaspartylglutamate (NAAG) and N-Acetylaspartate (NAA) in Patients With Schizophrenia

UNLABELLED BACKGROUND : Imbalance of glutamatergic neurotransmission has been proposed as a key mechanism underlying symptoms of schizophrenia. The neuropetide N-acetylaspartylglutamate (NAAG) modulates glutamate release. NAAG provides a component of the proton magnetic resonance spectrum (1H-MRS) in humans. The signal of NAAG, however, largely overlaps with its precursor and degrading product N-acetylaspartate (NAA) that by itself does not act in glutamatergic neurotransmission. METHODS We quantified NAAG and NAA separately from the 1H-MRS signal in 20 patients with schizophrenia and 20 healthy comparison subjects on a 3.0 Tesla MR scanner. The 1H-MRS voxels were positioned in the anterior cingulate cortex (ACC) and in the left frontal lobe. Psychopathological symptoms and cognitive performance were assessed. RESULTS In the ACC, the ratio NAAG/NAA was increased (P = .041) and NAAG was increased at a trend level (P = .066) in patients, while NAA was reduced (P = .030). NAA correlated with attention performance in patients (r = .64, P = .005) in the ACC. There was no group difference of NAAG, NAA, or NAAG/NAA in the frontal lobe but an inverse correlation of NAAG with negatives symptoms (Positive and Negative Symptoms Scale [PANSS] negative, r = -.58, P = .018) and with the total symptom score (PANSS total, r = -.50, P = .049). In addition, there was a positive correlation of frontal lobe NAAG (r = .53, P = .035) and NAAG/NAA (r = .54, P = .030) with episodic memory in patients. CONCLUSIONS In this study, we present the first in vivo evidence for altered NAAG concentration in patients with schizophrenia.