Benjamin Bender

Metabolic Mapping of Gliomas Using Hybrid MR-PET Imaging Feasibility of the Method and Spatial Distribution of Metabolic Changes

Background and PurposeThe most powerful adjunct to histopathology for the grading of gliomas seems to be the metabolic imaging using positron emission tomography and magnetic resonance spectroscopy (MRS). The purposes of this study were to examine the feasibility of simultaneous acquisition of both techniques for purposes of tumor grading in a newly launched hybrid magnetic resonance positron emission tomography (MR-PET) and to examine the spatial distributions of metabolic changes in gliomas. Materials and MethodsTwenty-eight consecutive patients with gliomas underwent simultaneous methionine (Met) MR-PET imaging for detection of the most malignant tumor part before surgical sampling. After coregistration and fusion of MR-PET and MRS data, tumor to normal brain (T/N) Met uptake ratios and the corresponding metabolites peaks (choline [Cho], creatine [Cr], and N-acetylaspartate [NAA]) in MRS were recorded. The patients were divided into 4 types on the basis of the relation between the Met uptake area and the increased metabolite ratios: type I, the increased Met uptake area had at least 50% overlap or was completely within the area of increased Cho/NAA ratio; type II, the increased Met uptake site had less than 50% overlap of increased Cho/NAA ratio site; type III, the increased Met uptake region had no spatial relationship with the “hot” lesions in the MRS maps; and type IV, there was no pathologically increased Met uptake. The surgical sampling was performed in the tumor part with the highest Met uptake and, in the absence of increased Met accumulation, in the site with the highest Cho/NAA ratio. All surgical samples were referred to the neuropathology division for histological grading. ResultsA total of 16 low-grade gliomas (World Health Organization grade II) and 12 high-grade gliomas (World Health Organization grade III) were included. Three lesions (10%) of type I were identified. Four lesions (14%) were classified as type II and 6 lesions (21%) were classified as type 3, where the increased Met uptake region had no spatial relationship with the hot lesions in the MRS maps. In 15 of the 28 patients (54%), there was no increased Met accumulation (type 4 lesions). Maps of Cho/NAA and Cr/NAA showed a close spatial relationship in most of the patients. Median T/N Met uptake ratio in the pooled surgically sampled tumor sites was 1.6 (range, 1–3), and median Cho/NAA and Cho/Cr ratios were 2.1 (range, 0.9–5.8) and 1.5 (range, 0.5–8.3), respectively. Spearman rank correlations of the metabolic markers in the low-grade gliomas showed significant correlations between Met uptake and Cr/NAA ratio (&rgr; = 0.59; P = 0.015) as well as between Cho/NAA and Cr/NAA ratios (&rgr; = 0.79; P = 0.0002). The normalized tumor creatine was significantly higher in anaplastic tumors compared with the low-grade gliomas (P = 0.001). A tendency for a significant positive correlation was found between normalized tumor creatine and Met uptake in the anaplastic tumors. ConclusionsMetabolic mapping before histological sampling is feasible using simultaneous MR-PET imaging. High T/N Met uptake ratio reflecting high expression of amino-acid membrane transporters, which is indicative of proliferating tumor cell populations, does not always spatially correlate with neuronal cell loss and cell membrane proliferation (Cho/NAA) seen in MRS. Increased Cr/NAA is associated with increased methionine uptake in low-grade gliomas, whereas normalized creatine in tumor tends to correlate with methionine accumulation, which indicates a possible coupling of these metabolic indices in anaplastic tumors. Thus, spatial distribution differences in gliomas should be taken into account when planning surgical sampling.

De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Objective: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. Methods: In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. Results: HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. Conclusions: Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors.

Diffusion restriction of the optic nerve in patients with acute visual deficit

Diffusion magnetic resonance imaging (MRI) is commonly used in acute stroke, but not considered diagnostic in ischemic optic neuropathy. This study evaluates the presence of diffusion restriction in patients with acute visual loss by analyzing diffusion‐weighted images (DWI).

Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot–Marie–Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.

In vivo molecular profiling of human glioma using diffusion kurtosis imaging

The purpose of this study is to assess the diagnostic performance of diffusion kurtosis imaging (DKI) for in vivo molecular profiling of human glioma. Normalized mean kurtosis (MKn) and mean diffusivity (MDn) metrics from DKI were assessed in 50 patients with histopathologically confirmed glioma. The results were compared in regard to the WHO-based histological findings and molecular characteristics leading to integrated diagnosis (Haarlem Consensus): isocitrate-dehydrogenase (IDH1/2) mutation status, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression, chromosome 1p/19q loss of heterozygosity (LOH), and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. MKn was significantly lower in tumors with IDH1/2 mutation (0.43 ± 0.09) and ATRX loss of expression (0.41 ± 0.11) than in those with IDH1/2 wild type (0.57 ± 0.09, p < 0.001) and ATRX maintained expression (0.51 ± 0.10, p = 0.004), respectively. Regarding the integrated molecular diagnosis, MKn was significantly higher in primary glioblastoma (0.57 ± 0.10) than in astrocytoma (0.39 ± 0.11, p < 0.001) and oligodendroglioma (0.47 ± 0.05, p = 0.003). MK may be used to provide insight into the human glioma molecular profile regarding IDH1/2 mutation status and ATRX expression. Considering the diagnostic and prognostic significance of these molecular markers, MK appears to be a promising in vivo biomarker for glioma. The diagnostic performance of MK seems to fit more with the integrated molecular approach than the conventional histological findings of the current WHO 2007 classification.

Differentiation between idiopathic and atypical parkinsonian syndromes using three-dimensional magnetic resonance spectroscopic imaging

Objectives Degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta is the primary cause of idiopathic Parkinsons disease (iPD). In early stages of disease in particular, presentation of symptoms is non-specific leading to difficulties in differentiating between iPD and atypical parkinsonian syndromes (aPS). The aim of this study was to evaluate the feasibility of three-dimensional magnetic resonance spectroscopic imaging (MRSI) of the SN region for differentiation between iPD and aPS. Methods 20 patients with iPD, 10 with aPS and 22 controls were examined on a 3 T MR scanner using three-dimensional MRSI with a voxel size of 0.252 ml and an echo time of 30 ms. Excitation volume was positioned in such a way that in each hemisphere 1 voxel defines the rostral and 1 voxel the caudal SN region. Using a fully automatic spectra evaluation, the metabolite ratios of N-acetyl aspartate/creatine (NAA/Cr) were calculated. Results In all cases spectra with good quality were obtained. Differences in rostral to caudal NAA/Cr ratios were significant between controls and iPD patients, as well as between iPD and aPS patients (p<0.001 for both). For controls, rostral NAA/Cr was greater than caudal, whereas in iPD patients this ratio was reversed. aPS patients showed similar ratios as controls. Conclusions Typical reversed rostral to caudal NAA/Cr ratios in iPD patients suggests that they could be linked to specific pathology of neuronal loss in the SN pars compacta. Therefore, the results suggest that MRSI may support the differential diagnosis of patients with clinically unclassifiable parkinsonian syndromes who do not yet fulfil the established clinical criteria.

Intraoperative visualization of residual tumor: the role of perfusion-weighted imaging in a high-field intraoperative magnetic resonance scanner.

BACKGROUND: High-field, intraoperative magnetic resonance imaging (iMRI) achieves free tumor margins in glioma surgery by involving anatomic neuronavigation and sophisticated functional imaging. OBJECTIVE: To evaluate the role of perfusion-weighted iMRI as an aid to detect residual tumor and to guide its resection. METHODS: Twenty-two patients undergoing intraoperative scanning (in a dual-room 1.5-T magnet setting) during the resection of high-grade gliomas were examined with perfusion-weighted iMRI. The generated relative cerebral blood volume (rCBV) maps were scrutinized for any hot spots indicative of tumor remnants, and region-of-interest analysis was performed. Differences among the rCBV region-of-interest estimates in residual tumor, free tumor margins, and normal white matter were analyzed. Histopathology of the tissue specimens and the neurosurgeon’s intraoperative macroscopic estimations were considered the reference standards. RESULTS: In all cases, diagnostic rCBV perfusion maps were generated. Interpretation of perfusion maps demonstrated that gross total resection of gliomas was achieved in 4 of 22 cases (18%), which was macroscopically and histopathologically verified, whereas in 18 of 22 cases (82%), the perfusion-weighted iMRI revealed hot spots indicating subtotal tumor removal. The latter proved to be true in all but 1 case. The receiver-operating characteristic curves of the qualitative visual and quantitative analyses showed excellent sensitivity and specificity rates. Statistical analysis demonstrated statistically significant differences for the mean rCBV and maximum rCBV between residual disease and tumor-free margins (P = .002 for both). CONCLUSION: Perfusion-weighted iMRI may be implemented easily into imaging protocols and may assist the surgeon in detecting residual tumor volume. ABBREVIATIONS: CBV, cerebral blood volume CI, confidence interval iMRI, intraoperative magnetic resonance imaging rCBV, relative cerebral blood volume ROC, receiver-operating characteristic WHO, World Health Organization

Prognostic Value of Blood Flow Measurements Using Arterial Spin Labeling in Gliomas

The period of event-free survival (EFS) within the same histopathological glioma grades may have high variability, mainly without a known cause. The purpose of this study was to reveal the prognostic value of quantified tumor blood flow (TBF) values obtained by arterial spin labeling (ASL) for EFS in patients with histopathologically proven astrocytomas independent of WHO (World Health Organization) grade. Twenty-four patients with untreated gliomas underwent tumor perfusion quantification by means of pulsed ASL in 3T. The clinical history of the patients was retrospectively extracted from the local database. Six patients had to be excluded due to insufficent follow-up data for further evaluation or histopathologically verified oligodendroglioma tumor components. Receiver operating characteristic (ROC) curves were used to define an optimal cut-off value of maximum TBF (mTBF) values for subgrouping in low-perfused and high-perfused gliomas. Kaplan-Meier curves and Cox proportional hazard regression model were used to determine the prognostic value of mTBF for EFS. An optimal mTBF cut-off value of 182 ml/100 g/min (sensitivity  = 83%, specificity  = 100%) was determined. Patients with low-perfused gliomas had significantly longer EFS compared to patients with high-perfused gliomas (p = 0.0012) independent of the WHO glioma grade. Quantified mTBF values obtained by ASL offer a new and totally non-invasive marker to prognosticate the EFS, independently on histopathological tumor grading, in patients with gliomas.

Post-processing of structural MRI for individualized diagnostics

Currently, a relevant proportion of all histopathologically proven focal cortical dysplasia (FCD) escape visual detection; this shows the need for additional improvements in analyzing MRI data. A positive MRI is still the strongest prognostic factor for postoperative freedom of seizures. Among several post-processing methods voxel-based morphometry (VBM) of T1- and T2-weighted sequences and T2 relaxometry are routinely applied in pre-surgical diagnostics of cryptogenic epilepsy in epilepsy centers. VBM is superior to conventional visual analysis with 9-15% more identified epileptogenic foci, while T2 relaxometry has its main application in (mesial) temporal lobe epilepsy. Further methods such as surface-based morphometry (SBM) or diffusion tensor imaging are promising but there is a lack of current studies comparing their individual diagnostic value. Post-processing methods represent an important addition to conventional visual analysis but need to be interpreted with expertise and experience so that they should be apprehended as a complementary tool within the context of the multi-modal evaluation of epilepsy patients. This review will give an overview of existing post-processing methods of structural MRI and outline their clinical relevance in detection of epileptogenic structural changes.

Prognostic value of blood flow estimated by arterial spin labeling and dynamic susceptibility contrast-enhanced MR imaging in high-grade gliomas

Several studies evaluated the predictive value of dynamic susceptibility contrast enhanced (DSC) imaging and arterial spin labeling (ASL) with regard to histological grade. Yet still less is known about their significance in terms of patients prognosis. Our purpose was to evaluate the agreement between them and the prognostic value of ASL- and DSC-CBF measurements for time-to-recurrence (TTR). Sixty nine cases of WHO Grade 3–4 gliomas underwent both DSC- and ASL-MRI. Normalized ASL and DSC-based cerebral blood flow (CBF) maps as well as DSC-derived cerebral blood volume maps (CBV) were analyzed. Wilcoxon test and Bland–Altman plot analysis were applied in order to compare DSC-rCBF and ASL-rCBF. Spearman’s rank correlation coefficients were determined for all perfusion parameters. Receiver operating characteristic (ROC) curve and survival curve analyses were performed. The median values of ASL-rCBF, DSC-rCBF, and DSC-rCBV were 5.3, 6.9, and 8.0, respectively. There was neither significant correlation nor difference between ASL-rCBF and DSC-rCBF. Slight proportional bias was demonstrated in the Bland–Altman plot analysis of ASL-rCBF and DSC-rCBF values. Unlikely to DSC-rCBV, DSC- and ASL-based rCBF parameters demonstrated moderate sensitivity and specifitity for tumor recurrence but no statistical significance regarding their prognostic values for TTR in the Kaplan–Meier analysis. There were neither correlation nor interchangeability between the DSC-rCBF and ASL-rCBF estimations, which demonstrated comparable, though not significant prognostic value for the prediction of TTR. rCBV measurements seem to provide the best sensitivity and specificity to predict tumor recurrence and survival time in these patients.