Microstructural and Metabolic Changes in Normal Aging Human Brain Studied with Combined Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

PURPOSE: This study aimed to detect age-related brain metabolic and microstructural changes in healthy human brains by the use of whole-brain proton magnetic resonance spectroscopic imaging (1H­MRSI) and quantitative MR imaging (qMRI). METHODS: In this study, 60 healthy participants with evenly distributed ages (between 21 and 69 years) and sex underwent MRI examinations at 3T including whole-brain 1H­MRSI. The concentrations of the metabolites N­acetylaspartate (NAA), choline-containing compounds (Cho), total creatine and phosphocreatine (tCr), glutamine and glutamate (Glx), and myo-inositol (mI), as well as the brain relaxation times T2, T2' and T1 were measured in 12 regions of interest (ROI) in each hemisphere. Correlations between measured parameters and age were estimated with linear regression analysis and Pearson's correlation test. RESULTS: Significant age-related changes of brain regional metabolite concentrations and tissue relaxation times were found: NAA decreased in eight of twelve ROIs, Cho increased in three ROIs, tCr in four ROIs, and mI in three ROIs. Glx displayed a significant decrease in one ROI and an increase in another ROI. T1 increased in four ROIs and T2 in one ROI, while T2' decreased in two ROIs. A negative correlation of tCr concentrations with T2' relaxation time was found in one ROI as well as the positive correlations of age-related T1 relaxation time with concentrations of tCr, mI, Glx and Cho in another ROI. CONCLUSION: Normal aging in human brain is associated with coexistent brain regional metabolic alterations and microstructural changes, which may be related to age-related decline in cognitive, affective and psychomotor domains of life in the older population.

In vivo magnetic resonance spectrometry imaging demonstrates comparable adaptation of brain energy metabolism to metabolic stress induced by 72 h of fasting in depressed patients and healthy volunteers.

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N = 24) and in healthy individuals (CTRL, N = 22) by application of an established fasting protocol in which calorie intake was omitted for 72 h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.

Imaging Patterns of Rhino-Orbital-Cerebral Mucormycosis in Immunocompromised Patients : When to Suspect Complicated Mucormycosis.

PURPOSE: The aim of this study was to describe radiological imaging findings of a complicated sinusitis, which should raise the suspicion of rhino-orbital-cerebral mucormycosis as being the underlying cause. METHODS: In this retrospective analysis, we describe the cases and imaging findings of 8 patients with proven mucormycosis. These patients presented mostly with new facial or orbital swelling and were referred for imaging to our institution. Magnetic resonance imaging and computed tomography images were classified as abnormal or normal with respect to orbital, paranasal and cerebral signal results. Special emphasis was placed on the distribution of the signal abnormalities regarding involvement of the skull base and the cavernous sinus. RESULTS: Out of a pool of 43 patients with colonization or proven Mucorales infection at different sites of the body, we identified 8 patients with infiltration of the midface and skull base. Unexpectedly seven out of the eight patients with abnormal findings of the paranasal sinuses and the adjacent tissues showed no bony sinus wall destruction. Of the eight patients seven showed inflammatory changes involving the infratemporal fossa and facial/periorbital tissues, three of the eight patients suffered from fungal invasion of the cavernous sinus and the carotid artery and one of the eight patients had a local infection of the hard palate only. CONCLUSION: Imaging findings of inflammatory tissue infiltration adjacent to the paranasal sinuses with possible extension into the pterygopalatine fossa, infratemporal fossa and orbit or the cavernous sinus should raise the suspicion of a mucormycosis, especially in immunocompromised patients.

The developing temporal bone: computed tomography measurements and assessment of suture closure from birth to 18 years of age.

PURPOSE: To describe the normal CT appearance of the developing temporal bone in children from birth to 18 years of age. METHODS: Two hundred and six temporal bone CTs of children from 0.14 to 18.95 years were retrospectively selected and reviewed. Temporal bones were measured in a standardized slice orientation using the length of the basal turn of the cochlea, the length and width of the petrous bone, the coronal extent, trailing edge and anterior-posterior dimension of the temporal bone and the angle between petrous bone's length and the midsagittal line in the axial plane showing the basal turn of the cochlea in its greatest extent. Two sutures, two synchondroses and three fissures of the temporal bone were evaluated and graded. RESULTS: Chosen measurements and calculations demonstrate an increase of values from 0 to 18 years with the greatest increase occurring during the first 2 years of life. The angle between the basal turn of the cochlea and the midsagittal line shows a large variability. Logarithmic trend lines illustrate larger measurements of males as compared to females. The ratio of the basal turn of the cochlea and the length of the petrous bone is about 1:4.1 (f/m) during the first year of life and about 1:6.1 (f)/1:6.8 (m) from 17 years onwards. Results of suture closure are described using box-and-whisker plots. CONCLUSIONS: The developing temporal bone grows the most during the first 2 years of life. Knowledge of changing proportions and suture closure is essential for evaluation of temporal bone CT of children.

Characterisation of Lesions after Stereotactic Radiosurgery for Brain Metastases: Impact of Delayed Contrast Magnetic Resonance Imaging.

AIMS: To investigate if brain metastases and radiation injuries after stereotactic radiosurgery (SRS) have different signal intensity (SI) time courses up to 55 min after contrast agent application and if delayed contrast magnetic resonance imaging (MRI) contributes to improve diagnostic accuracy. MATERIALS AND METHODS: Thirty-four consecutive patients treated with SRS for cerebral metastases were prospectively enrolled in the study. T1-weighted images were acquired on a 3-Tesla MR unit at three time points, at 2 (TP1), 15 (TP2) and 55 (TP3) min after administering contrast agent. A simultaneous, matched-pairs approach was used for region of interest analysis of the entire contrast-enhancing lesion (SI-e), the centre (SI-c), the border of the lesion (SI-b) and the adjacent non-contrast-enhancing tissue (SI-p). SIs of brain metastases and radiation injuries after SRS were compared using a two-level, linear, mixed-effects regression model. RESULTS: In total, 41 lesions were analysed: 16 metastases and 25 radiation injuries. The SI time course of SI-e, SI-c and SI-b proved to be significantly different for both entities (P < 0.001) from TP2 to TP3. The SI of 39/41 lesions increased from TP1 to TP2 for the three parameters. Radiation injuries showed a further signal increase at least for SI-c from TP2 to TP3, whereas for all the three parameters SI decreased in all metastases. CONCLUSION: Brain metastases and radiation injuries after SRS have a characteristic and statistically significantly different SI time course on sequential gadolinium enhancement MRI when late MR studies are included.

[Angiographic procedures for determination of cessation of cerebral circulation]. / Angiographische Verfahren zur Feststellung des zerebralen Zirkulationsstillstandes.

In several European countries catheter angiography is permitted as a confirmatory procedure for the determination of irreversible loss of brain function (brain death). In Germany catheter angiography requires the possibility of a therapeutic implication as a prerequisite. In the updated German guidelines computed tomography angiography (CTA) has been accredited as a new confirmatory procedure if a standardized protocol and predefined assessment parameters are adhered to. The CTA can be performed within a few minutes, even in situations with unstable intensive care patients. Magnetic resonance (MR) angiography has not yet been adequately validated and is not permitted in Germany as a confirmatory procedure for the determination of irreversible loss of brain function.

Detection of Normal Aging Effects on Human Brain Metabolite Concentrations and Microstructure with Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

BACKGROUND AND PURPOSE: Knowledge of age-related physiological changes in the human brain is a prerequisite to identify neurodegenerative diseases. Therefore, in this study whole-brain (1)H-MRS was used in combination with quantitative MR imaging to study the effects of normal aging on healthy human brain metabolites and microstructure. MATERIALS AND METHODS: Sixty healthy volunteers, 21-70 years of age, were studied. Brain maps of the metabolites NAA, creatine and phosphocreatine, and Cho and the tissue irreversible and reversible transverse relaxation times T2 and T2' were derived from the datasets. The relative metabolite concentrations and the values of relaxation times were measured with ROIs placed within the frontal and parietal WM, centrum semiovale, splenium of the corpus callosum, hand motor area, occipital GM, putamen, thalamus, pons ventral/dorsal, and cerebellar white matter and posterior lobe. Linear regression analysis and Pearson correlation tests were used to analyze the data. RESULTS: Aging resulted in decreased NAA concentrations in the occipital GM, putamen, splenium of the corpus callosum, and pons ventral and decreased creatine and phosphocreatine concentrations in the pons dorsal and putamen. Cho concentrations did not change significantly in selected brain regions. T2 increased in the cerebellar white matter and decreased in the splenium of the corpus callosum with aging, while the T2' decreased in the occipital GM, hand motor area, and putamen, and increased in the splenium of the corpus callosum. Correlations were found between NAA concentrations and T2' in the occipital GM and putamen and between creatine and phosphocreatine concentrations and T2' in the putamen. CONCLUSIONS: The effects of normal aging on brain metabolites and microstructure are region-dependent. Correlations between both processes are evident in the gray matter. The obtained data could be used as references for future studies on patients.

Imaging of Irreversible Loss of Brain Function.

UNLABELLED: The updated guidelines for the determination of irreversible loss of brain function include a substantial innovation, i. e., the use of CT angiography as a supplementary technical examination. Adherence to a standardized protocol is the prerequisite for the application of CT angiography. The guidelines for standardized execution of perfusion scintigraphy are unchanged and still valid. Requirements regarding the quality of examining physicians are specified. KEY POINTS: • The guidelines for determining irreversible loss of brain function were updated.• The approval of CT angiography as a supplementary examination method is a major innovation.• CT angiography is to be performed to determine the cessation of cerebral blood circulation according to a standard protocol.• The guidelines for the standardized implementation of perfusion scintigraphy continue to be valid.• Quality requirements regarding examining physicians were specified.

Pharmacological MRI (phMRI) of the Human Central Nervous System.

Pharmacological magnetic resonance imaging (phMRI) of the central nervous system (CNS) addresses the increasing demands in the biopharma industry for new methods that can accurately predict, as early as possible, whether novel CNS agents will be effective and safe. Imaging of physiological and molecular-level function can provide a more direct measure of a drug mechanism of action, enabling more predictive measures of drug activity. The availability of phMRI of the nervous system within the professional infrastructure of the Clinical Research Center (CRC) Hannover as proof of concept center ensures that advances in basic science progress swiftly into benefits for patients. Advanced standardized MRI techniques including quantitative MRI, kurtosis determination, functional MRI, and spectroscopic imaging of the entire brain are necessary for phMRI. As a result, MR scanners will evolve into high-precision measuring instruments for assessment of desirable and undesirable effects of drugs as the basic precondition for individually tailored therapy. The CRC's Imaging Unit with high-end large-scale equipment will allow the following unique opportunities: for example, identification of MR-based biomarkers to assess the effect of drugs (surrogate parameters), establishment of normal levels and reference ranges for MRI-based biomarkers, evaluation of the most relevant MRI sequences for drug monitoring in outpatient care. Another very important prerequisite for phMRI is the MHH Core Facility as the scientific and operational study unit of the CRC partner Hannover Medical School. This unit is responsible for the study coordination, conduction, complete study logistics, administration, and application of the quality assurance system based on required industry standards.

[Not Available]. / Einsatz der CT-Angiographie zur Feststellung des zerebralen Zirkulationsstillstandes.

CT-angiography (CTA) has been accredited as an additional technical method for the detection of the cessation of cerebral blood circulation in the updated German guidelines for the determination of irreversible loss of brain function. A standardized CTA protocol was defined. The evaluation of the CTA has to be done by radiologists with several years of experience in neuroradiology, preferably by radiologists certified as neuroradiologists. The so-called "stasis filling", a slow progressive spread of contrast media into the cerebral arteries despite cessation of cerebral blood circulation, has to be considered.

Whole Brain ¹H-Spectroscopy: A Developing Technique for Advanced Analysis of Cerebral Metabolism.

OBJECTIVE: Accompanying the advance of neuroscientific research and modern therapeutic methods, efforts have been made to develop more practical and effective advanced magnetic resonance (MR) spectroscopic techniques. METHODS: We present a brief overview on (1)H-MRS techniques in neuroradiological diagnosis and several application examples of recently reported whole brain MR spectroscopic imaging technique (wbMRSI). RESULTS: Despite the benefits of using established (1)H-MRS techniques both single voxel MR spectroscopy (SVS) and chemical shift imaging (CSI) techniques suffer from limited spatial coverage. It is always necessary to define prior to the MRS examination which brain structure is physiologically or pathologically involved and thus should be targeted with (1)H-MRS. In contrast, the advanced wbMRSI allows estimating metabolite changes within a much larger brain region and at multiple brain structures simultaneously. CONCLUSIONS: As a developing technique for advanced analysis of cerebral metabolism a wide application of the wbMRSI in both clinical diagnostics and neuroscience could be expected.

Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: self-imposed protein restriction may be harmful.

BACKGROUND: In untreated patients, phenylketonuria (PKU) results in severe encephalopathy with mental retardation. A protein-restricted diet is recommended which can be relaxed in adolescence/adulthood. METHODS: We contacted all 72 adult/adolescent PKU patients who had been treated in our center during early childhood. Some still regularly attended our outpatient clinics, while others were lost for follow-up, giving 51 patients in our study. We asked all patients to complete a dietary protocol as well as a questionnaire on quality of life. Blood and urine were analyzed and body impedance plethysmography and cerebral MRI were performed. RESULTS: 42 % of the patients followed protein restriction supplemented with amino acid mixtures (AAM), others had a vegan diet with (8 %) or without (14 %) AAM; 36 % said they were eating normally and did not need any AAM. However, based on dietary protocols and blood urea levels, protein intake was restricted in this patient group. None of the patients examined had serious nutritional deficits. Phenylalanine levels were higher in patients not taking AAM. MRI of the brain was not different from those following protein restriction and taking AAM. The lesions score and mood correlated best with the cumulative phenylalanine values during the first 10 years of life. CONCLUSION: In summary, 50 % of adult/adolescent patients from our center did not take AAM at the start of our survey although they unknowingly followed self-imposed protein restriction. They had no overt nutritional deficits; however, long-term brain function may be compromised. Our study emphasizes the need for specialized metabolic care in PKU during adulthood.

Objectification and quantification of the cognitive impairment from an existing HIV infection or HIV encephalopathy using magnetic resonance spectroscopy.

Some patients with HIV develop dementia. Using in vivo proton nuclear magnetic resonance ((1)H-NMR) spectroscopy, it is possible to measure the metabolic changes noninvasively. In this study, it is of interest to answer the clinically relevant question of whether magnetic resonance spectroscopy is suitable for the diagnosis of HIV encephalopathy. In total, 14 HIV-positive patients were investigated by means of localized (1)H-NMR spectroscopy in the following locations: (1) the mid-parietal gray matter, (2) the parietal white matter (PWM), and (3) the frontal white matter. All patients had no other brain diseases, apart from the HIV encephalopathy. The clinical extent of HIV encephalopathy of each patient was investigated using the following tests: (1) an electroencephalogram, (2) a neurological examination and psychiatric assessment, and (3) a psychometrical test. The spectroscopic changes in the PWM were more pronounced than those in the cortex, and the myo-inositol/creatine (mI/Cr) signal showed a clear increase in the cortex. Overall, the mI/Cr ratio emerged as the most reliable and earliest parameter to indicate an HIV encephalopathy.

Cutoff value of choline concentration reliably reveals high-grade brain tumors among other contrast-enhancing brain lesions.

BACKGROUND AND AIM: To evaluate whether there is a cutoff value for a metabolite concentration measured by 1 H MR spectroscopy (MRS), which can be used to differentiate malignant brain tumors (high-grade gliomas, primary CNS lymphomas [PCNSL] and metastases) from other contrast-enhancing lesions like low-grade gliomas and non-neoplastic lesions. MATERIAL AND METHODS: 1 H MRS was performed in 252 consecutive patients with space-occupying brain lesions which were enhanced with application of a contrast agent. Concentrations of N-acetyl-aspartate, total creatine, choline containing metabolites (total choline, tCho), lipids, and lactate were evaluated from the contrast-enhancing part of the lesions and from the normal appearing brain tissue. Linear discriminant analysis was used to find the best predictor for malignant brain tumors. In addition, receiver operating characteristic analysis (ROC) was performed to determine a cutoff value for the best predictor in detecting malignant brain tumors with a specificity of >95%. RESULTS: All brain tumors and 20 out of 47 nonneoplastic lesions were examined histopathologically. The remaining 27 diagnoses were based on MR imaging, clinical findings, and follow-up. The final diagnosis was 134 high-grade gliomas (WHO grade III/IV), 36 metastases, 9 PCNSL, 8 low-grade gliomas (WHO grade I/II), 34 infections, 9 infarctions, 2 hematomas, and 2 vasculitides. 18 patients were excluded due to insufficient spectral quality. The tCho concentration was the best predictor to differentiate malignant brain tumors from enhancing low-grade gliomas or non-neoplastic lesions (F=26.6 [df: 25.833], p<0.0005). The ROC revealed that a cutoff tCho value, based on an increase of ≥40% compared to normal, yielded a specificity of 100% and a sensitivity of 89.4% to correctly diagnose a malignant brain tumor. CONCLUSION: 1 H MRS reliably differentiates malignant brain tumors from other contrast-enhancing brain lesions. At least a 40% increase of tCho compared to normal brain tissue indicates a malignant tumor (WHO grade III/IV gliomas, PCNSL, metastases) with >90% specificity and sensitivity.

Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.

OBJECTIVE: Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease. METHODS: 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms. RESULTS: Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01). CONCLUSION: As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection.

Combined 1H and 31P MR spectroscopic imaging: impaired energy metabolism in severe carotid stenosis and changes upon treatment.

OBJECT: To evaluate if combined (1)H and (31)P MR spectroscopic imaging (MRSI) before and after treatment of severe internal carotid artery (ICA) stenosis detects significant changes in energy metabolism in the basal ganglia of both hemispheres. MATERIALS AND METHODS: A group of 14 patients with high-grade ICA stenosis and 11 healthy control subjects were examined with 2D (1)H MRSI and 3D (31)P MRSI at 3 T before and after treatment of severe ICA stenosis. Spectroscopic data were processed with LCModel and jMRUI software. Changes of the phosphorylated metabolites, pH, N-acetyl-acetate, creatine and choline-containing compounds prior/post intervention were analyzed and patients' data were compared with that of control subjects. RESULTS: Untreated patients had significantly higher Adenosindiphosphate (ADP) in basal ganglia ipsi- and contralateral to the side of ACI stenosis compared to controls. After treatment, ADP of both hemispheres significantly decreased by approximately 20% compared to the pre-treatment values. Further, significant decreases of phosphorylated metabolites prior/post intervention were found for patients compared to controls. CONCLUSION: This spectroscopic study reveals that unilateral high-grade ICA stenosis has an effect on cerebral high-energy metabolism of both hemispheres, which is at least partially reversible after treatment. Therefore the restoration of blood flow in high-grade ICA stenosis recovers the impaired energy balance of the brain.