Jan A. den Hollander

Abnormal Myocardial Phosphorus-31 Nuclear Magnetic Resonance Spectroscopy in Women with Chest Pain but Normal Coronary Angiograms

BACKGROUND After hospitalization for chest pain, women are more likely than men to have normal coronary-artery angiograms. In such women, myocardial ischemia in the absence of clinically significant coronary-artery obstruction has long been suspected. Most methods for the detection of the metabolic effects of myocardial ischemia are highly invasive. Phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy is a noninvasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischemia. METHODS We enrolled 35 women who were hospitalized for chest pain but who had no angiographically significant coronary-artery obstructions and 12 age- and weight-matched control women with no evidence of heart disease. Myocardial high-energy phosphates were measured with 31P-NMR spectroscopy at 1.5 tesla before, during, and after isometric handgrip exercise at a level that was 30 percent of the maximal voluntary grip strength. We measured the change in the ratio of phosphocreatine to ATP during exercise. RESULTS Seven (20 percent) of the 35 women with chest pain and no angiographically significant stenosis had decreases in the phosphocreatine:ATP ratio during exercise that were more than 2 SD below the mean value in the control subjects without chest pain. There were no significant differences between the two groups with respect to hemodynamic variables at rest and during exercise, risk factors for ischemic heart disease, findings on magnetic resonance imaging and radionuclide perfusion studies of the heart, or changes in brachial flow during the infusion of acetylcholine. CONCLUSIONS Our results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain consistent with the occurrence of myocardial ischemia but no angiographically significant coronary stenoses. The most likely cause is microvascular coronary artery disease.

Neurometabolites in schizophrenia and bipolar disorder — A systematic review and meta-analysis

This meta-analysis evaluates alterations of neurometabolites in schizophrenia and bipolar disorder. PubMed was searched to find controlled studies evaluating N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr) assessed with ((1))H-MRS (proton magnetic resonance spectroscopy) in patients with schizophrenia and bipolar disorder up to September 2010. Random effects meta-analyses were conducted to estimate pooled standardized mean differences. The statistic was used to quantify inconsistencies. Subgroup analyses were conducted to explore potential explanations for inconsistencies. The systematic review included 146 studies with 5643 participants. NAA levels were affected in schizophrenia and bipolar disorder. Decreased levels in the basal ganglia and frontal lobe were the most consistent findings in schizophrenia; decreased levels in the basal ganglia were the most consistent findings in bipolar disorder. Cho and Cr levels were not altered in either disorder. Findings for Cr were most consistent in the thalamus, frontal lobe and dorsolateral prefrontal cortex in schizophrenia and the basal ganglia and frontal lobe in bipolar disorder. Findings for Cho were most consistent in the thalamus, frontal lobe and anterior cingulate cortex in schizophrenia and basal ganglia in bipolar disorder. Large, carefully designed studies are needed to better estimate the extent of alterations in neurometabolites.

Assessments of Function and Biochemistry of the Anterior Cingulate Cortex in Schizophrenia

BACKGROUND Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. METHODS We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. RESULTS In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. CONCLUSIONS Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.

Regional Decoupling of N -acetyl-aspartate and Glutamate in Schizophrenia

Proton magnetic resonance spectroscopy (1H-MRS) allows the non-invasive measurement of several metabolites, including N-acetyl-aspartate (NAA), an amino acid exclusively synthesized in the mitochondria of neurons, and glutamate, an amino acid involved in excitatory neurotransmission and metabolism. In view of recent postmortem studies in schizophrenia (SZ) revealing mitochondrial abnormalities as well as perturbed expression of the enzymes regulating the glutamate–glutamine cycle, we hypothesized that a disruption in the homeostasis of NAA and glutamate in SZ is present. Fifty subjects with SZ and 48 matched healthy controls (HC) were enrolled in this 1H-MRS study. Voxels were placed in the anterior cingulate cortex (ACC) and hippocampus; NAA/Cr and glutamate + glutamine (Glx)/Cr ratios were obtained. We did not find any significant differences between the groups in metabolite levels in both the ACC and hippocampus. In the hippocampus we found that NAA/Cr and Glx/Cr ratios were significantly correlated in HC (r=0.40, p<0.01 (corrected p=0.048)) but not in SZ (r=−0.06; p=0.71), a difference that was statistically significant (z=2.22, p=0.02). Although no differences in neurometabolites between SZ and HC were apparent, correlations between NAA/Cr and Glx/Cr in healthy subjects in the hippocampus were found, and this correlation was lost in subjects with SZ. To our knowledge, this is the first study to suggest decoupling of these metabolites, a pathophysiological change that may be unique to SZ. However, these results warrant replication and further exploration before definite conclusions can be drawn.

Brain metabolism differs in Alzheimer's disease and Parkinson's disease dementia

Few comparative studies exist of metabolic brain changes among neurodegenerative illnesses. We compared brain metabolic abnormalities in Alzheimers disease (AD) and in Parkinsons disease with dementia (PDD) as measured by proton magnetic resonance spectroscopy (MRS).

1H NMR Spectroscopic Imaging of Myocardial Triglycerides in Excised Dog Hearts Subjected to 24 Hours of Coronary Occlusion

BACKGROUND Myocardial ischemic insult causes depression of fatty-acid beta-oxidation and increased fatty-acid esterification with triglyceride (TG) accumulation. This accumulation has been demonstrated to occur in the territory with diminished blood flow surrounding an infarct, ie, the region at risk. To evaluate whether the extent of TG accumulation in the canine heart after 24 hours of ischemia could be detected, we applied myocardial 1H nuclear magnetic resonance (NMR) spectroscopic imaging (SI). METHODS AND RESULTS Seven adult mongrel dogs underwent 24 hours of left anterior descending coronary artery occlusion. Postmortem, the hearts were excised and the size and location of the infarct were determined. With a Philips 1.5-T clinical NMR imaging/spectroscopic system, two-dimensional (2D) 1H NMR SI was performed. TG 1H NMR chemical shift images were reconstructed from the frequency domain spectra by numerical integration. A statistically significant (P < .05) increase in TG signal intensity was demonstrated in the region at risk compared with the nonischemic control region. There was an intermediate quantity of TG in the infarct region. Biochemical determination of tissue TG content (milligrams per gram wet weight) in the control, at-risk, and infarct regions confirmed the 1H NMR measurements. Histological evaluation with oil red O staining also demonstrated graded TG accumulation in myocytes. The highest TG levels were found in the at-risk region and the lowest levels in the control region. CONCLUSIONS By use of 2D 1H NMR SI, the present study confirms and extends previous work that demonstrates preferential accumulation of TG in the reversibly injured myocardium after 24 hours of coronary occlusion. This study provides an important step toward the clinical application of TG imaging. When TG imaging is ultimately possible, resultant data would have diagnostic, prognostic, and therapeutic implications.

Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging

BACKGROUND Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. METHODS We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). RESULTS The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. CONCLUSIONS We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.

Brain N-acetylaspartate is reduced in Parkinson disease with dementia.

Persons with Parkinson disease (PD) are at risk of developing dementia. Of the dementias affecting patients with PD, PD with dementia (PDD) is not well understood, although brain imaging studies to date have observed characteristic patterns of brain atrophy. Metabolic differences have been observed in magnetic resonance spectroscopy (MRS) studies comparing patients with PDD to nondemented PD patients, although it is unclear whether PDD patients have abnormally low MRS ratios compared with healthy age-matched adults. In this study, 12 patients with PDD, 12 patients with PD and no dementia, and 12 age-matched healthy older adults underwent MRS of the posterior cingulate gyrus. Patients with PDD showed lower N-acetylaspartate/creatine (NAA/Cr) compared with controls (P=0.004) and compared with nondemented PD patients (P=0.003). No abnormalities were observed in choline/Cr or myo-Inositol/Cr. NAA/Cr was correlated with mental status in patients with PD and in patients with PDD (r=0.56; P=0.029). The findings suggest that reduced NAA/Cr of the posterior cingulate could be used as a marker for dementia in patients with PD. Future studies investigating the utility of brain MRS as a predictor of dementia in PD and comparing brain metabolism in PDD with other dementias seem warranted.

Magnetic Resonance Imaging Volume of the Angular Gyri Predicts Financial Skill Deficits in People with Amnestic Mild Cognitive Impairment

OBJECTIVES: To better understand how brain atrophy in amnestic mild cognitive impairment (MCI) as measured using magnetic resonance imaging (MRI) volumetrics could affect instrumental activities of daily living (IADLs) such as financial abilities.

Chapter 6 Proton Magnetic Resonance Spectroscopy In Dementias And Mild Cognitive Impairment

With the anticipated increase in dementias due to the aging demographic of industrialized nations, biomarkers for neurodegenerative diseases are increasingly important as new therapies are being developed for clinical trials. Proton MR spectroscopy ((1)H MRS) appears poised to be a viable means of tracking brain metabolic changes due to neurodegenerative diseases and potentially as a biomarker for treatment effects in clinical therapeutic trials. This review highlights the body of literature investigating brain metabolic abnormalities in Alzheimers disease, amnestic mild cognitive impairment, frontotemporal dementia, vascular dementia, Lewy body dementia, and Parkinsons disease dementia. In particular, the review addresses the viability of (1)H MRS to discriminate among dementias, to measure disease progression, and to measure the effects of pharmacological treatments. While findings to date are encouraging, more study is needed in longitudinal patterns of brain metabolic changes, correspondence with changes in clinical markers of disease progression, and sensitivity of (1)H MRS measures to treatment effects. Such developments will hopefully benefit the search for effective treatments of dementias in the twenty-first century.