Ulrich Pilatus

Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions

Diagnosis of primary and secondary brain tumours and other focal intracranial mass lesions based on imaging procedures alone is still a challenging problem. Proton magnetic resonance spectroscopy (1H-MRS) gives completely different information related to cell membrane proliferation, neuronal damage, energy metabolism and necrotic transformation of brain or tumour tissues. Our purpose was to evaluate the clinical utility of 1H-MRS added to MRI for the differentiation of intracranial neoplastic and non-neoplastic mass lesions. 176 mostly histologically verified lesions were studied with a constant clinically available single volume 1H-MRS protocol following routine MRI. 12 spectra (6.8%) were not of satisfactory diagnostic quality; 164 spectroscopic data sets were therefore available for definitive evaluation. Our study shows that spectroscopy added to MRI helps in tissue characterization of intracranial mass lesions, thereby leading to an improved diagnosis of focal brain disease. Non-neoplastic lesions such as cerebral infarctions and brain abscesses are marked by decreases in choline (Cho), creatine (Cr) and N-acetyl-aspartate (NAA), while tumours generally have elevated Cho and decreased levels of Cr and NAA. Gliomas exhibit significantly increased Cho and lipid formation with higher WHO tumour grading. Metastases have elevated Cho similar to anaplastic astrocytomas, but can be differentiated from high-grade gliomas by their higher lipid levels. Extra-axial tumours, i.e. meningiomas and neurinomas, are characterized by a nearly complete absence of the neuronal marker NAA. The additive information of 1H-MRS led to a 15.4%-higher number of correct diagnoses, to 6.2% fewer incorrect and 16% fewer equivocal diagnoses than with structural MRI data alone.

Short-term effects of coenzyme Q10 in progressive supranuclear palsy: A randomized, placebo-controlled trial

Mitochondrial complex I appears to be dysfunctional in progressive supranuclear palsy (PSP). Coenzyme Q10 (CoQ10) is a physiological cofactor of complex I. Therefore, we evaluated the short‐term effects of CoQ10 in PSP. We performed a double‐blind, randomized, placebo‐controlled, phase II trial, including 21 clinically probable PSP patients (stage ≤ III) to receive a liquid nanodispersion of CoQ10 (5 mg/kg/day) or matching placebo. Over a 6‐week period, we determined the change in CoQ10 serum concentration, cerebral energy metabolites (by 31P‐ and 1H‐magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Åsberg Depression Scale). CoQ10 was safe and well tolerated. In patients receiving CoQ10 compared to placebo, the concentration of low‐energy phosphates (adenosine‐diphosphate, unphosphorylated creatine) decreased. Consequently, the ratio of high‐energy phosphates to low‐energy phosphates (adenosine‐triphosphate to adenosine‐diphosphate, phospho‐creatine to unphosphorylated creatine) increased. These changes were significant in the occipital lobe and showed a consistent trend in the basal ganglia. Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ10 treatment compared to placebo. Since CoQ10 appears to improve cerebral energy metabolism in PSP, long‐term treatment might have a disease‐modifying, neuroprotective effect.

Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson's disease

Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinsons disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinsons disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinsons disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinsons disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinsons disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinsons disease which occurs early in the course of the disease.

Functional MRI using sensitivity-encoded echo planar imaging (SENSE-EPI)

Parallel imaging methods become increasingly available on clinical MR scanners. To investigate the potential of sensitivity-encoded single-shot EPI (SENSE-EPI) for functional MRI, five imaging protocols at different SENSE reduction factors (R) and matrix sizes were compared with respect to their noise characteristics and their sensitivity toward functional activation in a motor task examination. At constant echo times, SENSE-EPI was either used to shorten the single volume acquisition times (TR(min)) at matrix size 128 x 100 (22 slices) from 3.9 s (no SENSE) to 2.0 s at R = 3, or to increase the matrix size to 192 x 153 (22 slices), resulting in TR(min) = 5.3 s for R = 2 or TR(min) = 3.4 s for R = 3. At the lower resolution, the bisection of echo train length (R = 2) substantially reduced distortions and blurring, while signal-to-noise and statistical power (measured by cluster size and maximum t value per unit time) were hardly reduced. At R = 3 the additional gain in speed and distortion reduction was quite small, while signal-to-noise and statistical power dropped significantly. With enhanced spatial resolution the time course signal-to-noise was better than expected from theory for purely thermal noise because of a reduced contribution of physiological noise, and statistical power almost reached that of the regular, low-resolution single-shot EPI, with a slight drop off toward R = 3. Thus, SENSE-EPI allows to substantially increase speed and spatial resolution in fMRI. At SENSE reduction factors up to R = 2, the potential drawbacks regarding signal-to-noise and statistical power are almost negligible.

In vivo demonstration of microstructural brain pathology in progressive supranuclear palsy: A DTI study using TBSS

We investigated DTI changes, potentially indicating alterations of microstructure and brain tissue integrity in 13 patients with probable progressive supranuclear palsy (PSP, Richardson syndrome) at stage III or less and 10 age‐matched controls using a whole brain analysis of diffusion tensor imaging (DTI) data. DTI images were analyzed using tract‐based spatial statistics, a hypothesis‐free technique. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were determined. In patients with PSP, significant increases in FA (P < 0.0001), an unspecific measure of microstructural tissue integrity, were found in the cerebellum and in the superior cerebellar peduncle bilaterally, in the fornix, the body of the corpus callosum and the olfactory region, when compared with age‐matched healthy controls. Further, regional reductions in AD (P < 0.0001), an indicator of altered axonal integrity, were observed in the pons, the right substantia nigra and the cerebellar white matter bilaterally. Significant increases in RD (P < 0.0001), a potential measure of altered myelin integrity, occurred bilaterally in the superior cerebellar peduncle, the cerebellar white matter, the vermis of the cerebellum, the fornix, the body of the corpus callosum, and the olfactory region. RD values in the superior cerebellar peduncle discriminated patients with PSP and controls with high sensitivity (0.92) and specificity (1.0). The findings are supported by neuropathological studies. Our data suggest the usefulness of this clinically available new technique as a possible tool for differential diagnosis.

Diagnostic value of proton magnetic resonance spectroscopy in the noninvasive grading of solid gliomas: comparison of maximum and mean choline values.

OBJECTIVEMagnetic resonance spectroscopy is widely used in addition to magnetic resonance imaging in the characterization of brain tumors. Compounds containing choline (Cho) have an important role in the evaluation of tumor malignancy. For this purpose, various ratios of Cho and other metabolites, such as creatine (Cr), have been assessed. The aim of this study was to compare normalized mean and maximum levels of Cho as single parameters in the noninvasive grading of gliomas. METHODSProton spectroscopic imaging data of 63 patients with suspected World Health Organization (WHO) grade II or III gliomas were acquired at 3 T. Cho concentrations of the tumor were analyzed by a frequency domain fit and normalized to the corresponding contralateral healthy brain tissue. Metabolite images were used to determine the maximum and mean Cho as well as Cr concentrations of the tumor. Furthermore, contrast enhancement of the tumor was analyzed on standard magnetic resonance imaging. All patients subsequently underwent tumor resection or stereotactic biopsy to confirm diagnosis of glioma. Statistical analysis using the Kruskal-Wallis test, Mann-Whitney U test, and receiver operating characteristic curve analysis was performed with BiAS software (Epsilon Verlag GmbH, Frankfurt, Germany). RESULTSHistopathological examinations revealed WHO grades II (n = 27), III (n = 26), and IV (n = 10). There was a statistically significant difference in both normalized maximum and mean Cho between WHO grade II and non-necrotic WHO grade III/IV gliomas (mean, 1.45 ± 0.28 versus 2.16 ± 0.36, P < 0.05; maximum, 1.64 ± 0.32 versus 3.32 ± 0.55, P < 0.0001). Receiver operating characteristic analyses rendered a 2.02 cutoff value for maximum Cho with a sensitivity and specificity of 86.1% and 77.8%, respectively. For mean Cho, we found a cutoff value of 1.52 (sensitivity, 77.8%; specificity, 63.0%). The diagnostic accuracy of maximum Cho was superior to that of mean Cho and also the ratio of Cho/Cr (82.5% versus 71.4% and 72.1%, respectively), but all 3 parameters were superior to contrast enhancement of the tumor (61.9%). CONCLUSIONBoth maximum and mean Cho differ between low- and high-grade gliomas. Compared with contrast enhancement, mean Cho, and Cho/Cr, maximum Cho of the tumor provides the highest accuracy in discriminating between low- and high-grade tumors, indicating usefulness of this single parameter in the process of therapeutic decision making.

Combined 1H and 31P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis

1H MRSI has evolved as an important tool to study the onset and progression of brain damage in multiple sclerosis. Abnormal increases in total creatine, total choline and myoinositol have been noted in multiple sclerosis. However, the pathobiochemical mechanisms related to these changes are still largely unclear. The combination of 1H MRSI and 1H‐decoupled 31P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined 1H and 31P MRSI data were obtained at 3 T in 22 patients with multiple sclerosis and in 23 healthy controls, and aligned with structural MRI to allow for correction for partial volume effects caused by cerebrospinal fluid and lesion load. A significant increase in total creatine was found in multiple sclerosis, and this was attributed to equal changes in the phosphorylated and unphosphorylated components. The concentrations of the putative glial markers total creatine and myoinositol in lesion‐free 1H MRSI voxels correlated with the global lesion load. We conclude that changes in total creatine are not related to altered energy metabolism, but rather indicate gliosis. Together with the increase in myoinositol, total creatine can be considered as a biomarker for disease severity. A significant total choline increase was mainly a result of choline components not visible by 31P MRS. The origin of this residual choline fraction remains to be investigated. Copyright

Conversion to dementia in mild cognitive impairment is associated with decline of N-actylaspartate and creatine as revealed by magnetic resonance spectroscopy

The purpose of the present study was to longitudinally track changes of metabolite markers detectable by magnetic resonance spectroscopy (MRS) in subjects with mild cognitive impairment (MCI) and to analyze these changes with respect to the rate of cognitive decline and clinical disease progression. Fifteen subjects with MCI and 12 healthy elderly controls were investigated longitudinally (average follow-up period: 3.4 years) using absolute quantification of metabolites within the mid-parietal grey matter and the parietal white matter [N-acetylaspartate (NAA), myo-inositol, choline, creatine, glutamine)] Our main findings include that a longitudinal decline in cognitive function (particularly in memory function) within the MCI group was predicted by a decline in absolute concentrations of the metabolic markers NAA and creatine. This effect was mainly explained by a significant decrease of NAA and creatine in those MCI subjects who converted to Alzheimers dementia (AD) during the follow-up period. No differences were found at baseline between MCI converters and stable subjects, indicating that at least in the present study MRS did provide a predictive discrimination between converters and stable subjects. Our findings support the use of MRS as a tool for objectively monitoring disease progression even during the earliest stages of AD.

Preoperative Proton-MR Spectroscopy of Gliomas – Correlation with Quantitative Nuclear Morphology in Surgical Specimen

A comparison between data from proton-MR spectroscopy (1HMRS) and quantitative histomorphology of tumor cell nuclei in gliomas has not been reported up to now. Therefore, the question must be answered, if there are any significant correlations between histomorphology of gliomas and quantitative data from 1HMRS concerning tissue metabolites.Surgical glioma specimen (glioblastomas, astrocytomas, oligodendrogliomas) from 46 patients with tumor grades II–IV according to WHO have been evaluated by means of a digital image analysis system using Ki-67-immunostained paraffin sections. Nuclear density, Ki-67-proliferation index, nuclear area and shape variables (roundness factor, Fourier-amplitudes) have been determined from 200 randomly selected tumor cell nuclei in each tumor specimen. These data have been correlated with preoperative data from 1HMRS.A positive correlation between Fourier-amplitudes, choline peak and lipide peak was observed, as well as a negative correlation between these variables and the nuclear roundness factor. This result indicates higher choline and lipide peaks with increasing irregularity of nuclear outlines. Proliferation index Ki-67 was positively correlated with the lipide peak, nuclear density showed a positive correlation with the choline peak. Glioblastomas (n = 29) showed an additional positive correlation between mean nuclear size and total creatine. Anaplastic gliomas (n = 12) showed a positive correlation between lactate peak and the standard deviation of the nuclear roundness factor. Further multivariate analyses have shown, that for the present collective of 46 cases, histometric variables have a higher significance than spectroscopic data for the differentiation of the different tumor grades.These results verify a significant correlation between preoperative data from 1HMRS and histomorphology of tumor cell nuclei in gliomas, supporting the biological significance of both histomorphometry and 1HMRS for the evaluation of these tumors.

Proton magnetic resonance spectroscopy in ecstasy (MDMA) users

The popular recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has well-recognized neurotoxic effects upon central serotonergic systems in animal studies. In humans, the use of MDMA has been linked to cognitive problems, particularly to deficits in long-term memory and learning. Recent studies with proton magnetic resonance spectroscopy (1H MRS) have reported relatively low levels of the neuronal marker N-acetylaspartate (NAA) in MDMA users, however, these results have been ambiguous. Moreover, the only available 1H MRS study of the hippocampus reported normal findings in a small sample of five MDMA users. In the present study, we compared 13 polyvalent ecstasy users with 13 matched controls. We found no differences between the NAA/creatine/phosphocreatine (Cr) ratios of users and controls in neocortical regions, and only a tendency towards lower NAA/Cr ratios in the left hippocampus of MDMA users. Thus, compared with cognitive deficits, 1H MRS appears to be a less sensitive marker of potential neurotoxic damage in ecstasy users.