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Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson’s disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

Microglia-induced neuroinflammation after stroke contributes to the exacerbation of post-ischemic damage but also supports neurorestorative events. Longitudinal molecular imaging of microglia-targeted therapies will support the assessment of target engagement, therapy efficacy, and deciphering the mode of action. We investigated the effects of chronic colony stimulating factor-1 receptor (CSF-1R) inhibitor-mediated microglia depletion on translocator protein (TSPO)-dependent neuroinflammation and cerebrovascular parameters using positron emission tomography (PET)/magnetic resonance (MR) imaging. Methods:N = 40 C57BL/6 mice underwent a 30 minutes transient middle cerebral artery occlusion (tMCAo) and were randomly assigned to either control group or treated with CSF-1R inhibitor (PLX5622; Plexxikon Inc.). N = 8 mice/group were used for 18F-DPA-714 (TSPO) PET imaging at days 7, 14, 21, and 30 post ischemia and behavioural tests prior to and after surgery. An extra group of n = 8 mice/group underwent MR imaging including T2-weighted (infarct), perfusion- (cerebral blood flow) and diffusion-weighted (water diffusion, cellular density) at days 1, 3, 7, 14, 21 and 30. Ex vivo analysis (immunoreactivity, gene expression) were performed to characterize the inflammatory environment. Results: We demonstrated that long-term CSF-1R inhibition transiently decreases the TSPO-PET signal within the infarct. Residual TSPO activity was partly due to potentially resistant Iba-1+ cell populations with low CSF-1R and transmembrane 119 (TMEM119) expression. The decrease in selected pro- and anti-inflammatory marker expression suggested an apparent global dampening of the neuroinflammatory response. Furthermore, the temporal changes of the MRI parameters highlighted treatment-induced effects on reperfusion and tissue homeostasis, associated with impaired motor functions at late stages. Conclusion: Longitudinal TSPO-PET/MR imaging allows the assessment of target engagement and optimization of drug efficiency. PLX5622 has promising immunomodulatory effects and the optimal therapeutic time window for its application needs to be defined.

Zusammenfassung Anamnese Es erfolgt die Aufnahme einer 82-jährigen Patientin zur weiteren Abklärung zunehmender kognitiver Defizite und Gangunsicherheit. Diagnostik und Befunde In der durchgeführten Computertomografie des Kopfes zeigten sich die Zeichen einer fortgeschrittenen subkortikalen arteriosklerotischen Enzephalopathie (SAE). Laborchemisch fiel ein erhöhter Hämoglobinwert von 19,9 g/dl auf. Bei zusätzlicher Mutation in der JAK-2-Analyse wurde die Diagnose einer Polycythämia vera (Pv) gestellt. Nach Aderlass-Therapie zeigte sich eine Verbesserung der Kognition. Diskussion Die progredienten kognitiven Defizite sind bei vorbestehender SAE im Zusammenhang mit der neu diagnostizierten Pv zu sehen. Nach entsprechender Therapie der Pv ist auch langfristig eine Besserung der Kognition zu beobachten, sodass in diesem Fallbericht die Wichtigkeit einer Abklärung sekundärer, potenziell behandelbarer Ursachen von kognitiven Defiziten hervorgehoben wird.

Purpose Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. Methods In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. Results In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. Conclusions [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease.

Vor Diagnosestellung einer malignen Erkrankung konnen neurologische Krankheitsbilder auftreten, die durch eine fehlgeleitete Immunreaktion gegen intrazellulare Antigene oder neuronale Oberflachenantigene ausgelost werden. Zu den haufigsten paraneoplastischen Erkrankungen gehort die subakute Kleinhirndegeneration. Die haufigsten beschriebenen paraneoplastischen Antikorper sind Anti Hu, CRMP5/CV2, Amphiphysin, Ma/Ta bei kleinzelligen Lungenkarzinomen, Mammakarzinomen und Lymphomen. Wir berichten uber einen 67jahrigen Patienten mit einer cerebellaren Symptomatik und ungewollter Gewichtsabnahme von 10 kg, bei dem im Verlauf der diagnostischen Aufarbeitung ein nichtkleinzelliges Bronchialkarzinom gefunden wurde. Serologisch gelang der Nachweis von erhohten Anti-Tr3-Antikorpern, welche typischerweise bei der subakuten Kleinhirndegeneration assoziiert mit einem Morbus Hodgkin, seltener bei Non-Hodgkin Lymphomen gefunden werden. Unter tumoradaptierter Therapie und intravenoser Immunglobulingabe verbesserten sich die neurologischen Kleinhirnsymptome. Im klinischen Verlauf wird sich zeigen, ob die Anti-Tr3 Antikorper tatsachlich im Rahmen des nicht kleinzelligen Bronchialkarzinoms aufgetreten sind oder der Patient noch ein Lymphom entwickeln wird.

The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson's (PD) or Alzheimer's diseases (AD). Here we present the characterisation of the S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue. Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages). Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls. Conclusion: This work shows that 18F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.

As a result of the aging population dementia is a growing challenge, especially in healthcare. Nevertheless, cognitive disorders are often not systematically evaluated, especially during hospital stays for other reasons; however, cognitive impairment is associated with a number of geriatric syndromes, including falls, delirium, dysphagia and lack of adherence to treatment plans. This article considers the current state of diagnosis and treatment of dementia. Non-pharmacological therapeutic approaches as well as current and future pharmacological treatment options are discussed. The drugs of choice for the symptomatic treatment of cognitive deficits in Alzheimer's disease and Parkinson-associated dementia are cholinesterase inhibitors and memantine; there is no specific pharmacological treatment for other types of dementia. Prevention and treatment of cardiovascular risk factors can potentially retard the progression of possibly all forms of dementia.

Simple Summary Patients with brain metastasis are at a severe stage of cancer, and brain surgery can prevent neurological morbidity. However, the success of brain surgery might require a patient’s physical integrity prior to the operation. In the present study, we asked whether a preoperative physical decline affects survival in patients with brain metastasis from lung cancer. In order to measure the physical condition, we used a commonly-known index—the so-called frailty index—and additionally measured the thickness of a particular masticatory muscle as muscle loss correlates to physical decline. We found that a decreased muscle thickness was accompanied by worsened survival for patients < 65 years and an increased frailty index correlated to worsened survival for patients ≥ 65 years. These results encourage to use of the frailty index and muscle thickness as easily available parameters in order to more sufficiently estimate individual treatment success in patients with metastatic lung cancer. Abstract Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors’ institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as ‘frail’ (mFI ≥ 0.27) and ‘least and moderately frail’ (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the

Simple Summary Meningiomas are most commonly benign intracranial tumors, and surgical resection represents the treatment modality of choice. However, especially for patients of higher age and with increasing comorbidities, brain surgery might be accompanied by the need for postoperative prolonged intensive care, which might impair intended operative benefit. In the present study, we therefore analyzed prolonged mechanical ventilation (PMV) as an indicator variable for such intensive care treatment with regard to potential effects on mortality after meningioma resection in patients aged 70 years and older. We found that patients with postoperative PMV exhibited a profoundly increased probability to die within 1 year after surgery. Based on these findings, we identified risk factors for postoperative PMV occurrence and developed an easy-to-use score which allows us to estimate the risk of PMV occurrence preliminary to the surgical resection. We believe that this score might help to more sufficiently guide patients in the course of risk–benefit assessment and preoperative counseling. Abstract Indication for surgical treatment in patients with intracranial meningioma must include both clinical aspects and an individual risk–benefit stratification, especially in geriatric patients. Prolonged mechanical ventilation (PMV) has not been investigated for its potential effects in patients with meningioma. We therefore analyzed the impact of PMV on mortality in geriatric patients who had undergone meningioma resection. Between 2009 and 2019, 261 patients aged ≥ 70 years were surgically treated for intracranial meningioma at our institution. PMV was defined as postoperative invasive ventilation of >7 days. Postoperative PMV was present in 17 of 261 geriatric meningioma patients (7%). Twenty-five geriatric patients (10%) died within 1 year after surgery. A scoring system (“ACKT”) based on the variables of age, preoperative C-reactive protein (CRP) value, Karnofsky performance scale and tumor size supports prediction of postoperative PMV (sensitivity 73%, specificity 84%). PMV is significantly associated with increased mortality after surgical treatment of meningiomas in geriatric patients. Furthermore, we suggest a novel score (“ACKT”) to preoperatively estimate the risk of PMV occurrence, which might help to guide future risk–benefit assessment and patient counseling in the geriatric meningioma population.

Object Increasing age is a known negative prognostic factor for glioblastoma. However, a multifactorial approach is necessary to achieve optimal neuro-oncological treatment. It remains unclear to what extent frailty, comorbidity burden, and obesity might exert influence on survival in geriatric glioblastoma patients. We have therefore reviewed our institutional database to assess the prognostic value of these factors in elderly glioblastoma patients. Methods Between 2012 and 2018, patients aged ≥ 65 years with newly diagnosed glioblastoma were included in this retrospective analysis. Patients frailty was analyzed using the modified frailty index (mFI), while patients comorbidity burden was assessed according to the Charlson comorbidity index (CCI). Body mass index (BMI) was used as categorized variable. Results A total of 110 geriatric patients with newly diagnosed glioblastoma were identified. Geriatric patients categorized as least-frail achieved a median overall survival (mOS) of 17 months, whereas most frail patients achieved a mOS of 8 months (p = 0.003). Patients with a CCI > 2 had a lower mOS of 6 months compared to patients with a lower comorbidity burden (12 months; p = 0.03). Multivariate analysis identified “subtotal resection” (p = 0.02), “unmethylated MGMT promoter status” (p = 0.03), “BMI 2 0.31). Conclusions The present study concludes that both increased frailty and comorbidity burden are significantly associated with poor OS in geriatric patients with glioblastoma. Further, the present series suggests an obesity paradox in geriatric glioblastoma patients.

Zusammenfassung Anamnese und klinischer Befund Wir berichten von einem 86-jährigen Patienten, der aufgrund einer zunehmenden Schwäche des rechten Beines aufgenommen wurde. Untersuchungen und Diagnose Laborchemisch zeigten sich erhöhte Blutspiegel von Kreatinkinase und Kreatinin und im EMG konnte zusätzlich eine pseudomonotone Entladung im Sinne einer neuromuskulären Schädigung nachgewiesen werden. Da anamnestisch eine Erhöhung der Statindosis auf 80 mg täglich vor ca. 6 Monaten zu eruieren war, wurde die Diagnose einer Simvastatin-induzierten Myopathie mit Rhabdomyolyse gestellt. Therapie und Verlauf Nach Absetzen der Statin-Therapie und unter Flüssigkeitssubstitution zeigten sich sowohl die Laborwerte als auch die klinische Symptomatik deutlich rückläufig. Folgerung Bei unklarer neurologischer Symptomatik unter Statin-Therapie sollte an eine Statin-induzierte Myopathie gedacht und ggf. die Therapie beendet werden.

The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. Cancer Res; 77(8); 1831–41. ©2017 AACR.

Bioluminescence imaging in transgenic mice expressing firefly luciferase in Doublecortin+ (Dcx) neuroblasts might serve as a powerful tool to study the role of neurogenesis in models of brain injury and neurodegeneration using non-invasive, longitudinal in vivo imaging. Therefore, we aimed to use BLI in B6(Cg)-Tyrc-2J/J Dcx-Luc (Doublecortin-Luciferase, Dcx-Luc) mice to investigate its suitability to assess neurogenesis in a unilateral injection model of Parkinson's disease. We further aimed to assess the blood brain barrier leakage associated with the intranigral 6-OHDA injection to evaluate its impact on substrate delivery and bioluminescence signal intensity. Two weeks after lesion, we observed an increase in bioluminescence signal in the ipsilateral hippocampal region in both, 6-OHDA and vehicle injected Dcx-Luc mice. At the same time, no corresponding increase in Dcx+ neuroblast numbers could be observed in the dentate gyrus of C57Bl6 mice. Blood brain barrier leakage was observed in the hippocampal region and in the degenerating substantia nigra of C57Bl6 mice in vivo using T1 weighted Magnetic Resonance Imaging with Gadovist® and ex vivo using Evans Blue Fluorescence Reflectance Imaging and mouse Immunoglobulin G staining. Our data suggests a BLI signal dependency on blood brain barrier permeability, underlining a major pitfall of substrate/tracer dependent imaging in invasive disease models.

Objectives To compare the CARG (Cancer and Aging Research Group) and CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score regarding the predictive performance for severe toxicity in older patients with cancer. Methods We recruited patients ≥70 years and applied the CARG and CRASH score before the start of systemic cancer treatment. The CARG predicts severe overall toxicity; the CRASH additionally predicts hematologic and nonhematologic toxicity. We captured ≥ grade 3 toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) from medical records. Predictive performance was assessed using logistic regression and the area under the receiver operating characteristic curve (ROC-AUC). Results The study cohort comprised 120 patients (50% female, mean age 77.2 years, 57% solid tumors). The median of the CARG (range 0–23) and the combined CRASH (range 0–12) were 9 and 8, respectively. 81% of patients experienced toxicity; 67% showed hematologic toxicity. The predictive performance of the CARG and the combined CRASH was similar for overall toxicity (CARG: Odds ratio per unit increase (OR) 1.266, P = .015; ROC-AUC 0.681, P = .010; combined CRASH: OR 1.337, P = .029; ROC-AUC 0.650, P = .032). For hematologic toxicity, the hematologic CRASH was a significant predictor and showed numerically a higher ROC-AUC than the CARG which was not statistically different (CARG: OR 1.048, P = .462; ROC-AUC 0.564, P = .271; hematologic CRASH: OR 1.602, P = .007; ROC-AUC 0.665, P = .005). Conclusion Both scores exhibited similar predictive performance for toxicity in older patients with cancer.

BACKGROUND: Glioblastoma (GBM) is the most devastating brain tumor. Despite the use of multimodal treatments, most patients relapse, often due to the highly invasive nature of gliomas. However, the detection of glioma infiltration remains challenging. The aim of this study was to assess advanced PET and MRI techniques for visualizing biological activity and infiltration of the tumor. METHODS: Using multimodality imaging, we investigated [(18)F]DPA-714, a radiotracer targeting the 18 kDa translocator protein (TSPO), [(18)F]FET PET, non-Gaussian diffusion MRI (apparent diffusion coefficient, kurtosis), and the S-index, a composite diffusion metric, to detect tumor infiltration in a human invasive glioma model. In vivo imaging findings were confirmed by autoradiography and immunofluorescence. RESULTS: Increased tumor-to-contralateral [(18)F]DPA-714 uptake ratios (1.49 ± 0.11) were found starting 7 weeks after glioma cell implantation. TSPO-PET allowed visualization of glioma infiltration into the contralateral hemisphere 2 weeks earlier compared with the clinically relevant biomarker for biological glioma activity [(18)F]FET. Diffusion-weighted imaging (DWI), in particular kurtosis, was more sensitive than standard T2-weighted MRI to detect differences between the glioma-bearing and the contralateral hemisphere at 5 weeks. Immunofluorescence data reflect in vivo findings. Interestingly, labeling for tumoral and stromal TSPO indicates a predominant expression of TSPO by tumor cells. CONCLUSION: These results suggest that advanced PET and MRI methods, such as [(18)F]DPA-714 and DWI, may be superior to standard imaging methods to visualize glioma growth and infiltration at an early stage.

The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, we identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [18F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies.

Background: Activation and dysregulation of innate, adaptive and resident immune cells in response to damage determine the pathophysiology of demyelinating disorders. Among the plethora of involved cells, microglia/macrophages and astrocytes play an important role in the pathogenesis of demyelinating disorders. The in-depth investigation of the spatio-temporal profile of these cell types in vivo may inform about the exact disease state and localization as well as may allow to monitor therapeutic modulation of the components of the neuroinflammatory response during the course of multiple sclerosis (MS). In this study, we aimed to non-invasively decipher the degree and temporal profile of neuroinflammation (TSPO - [F-18]DPA-714 PET) in relation to selected magnetic resonance imaging (MRI) parameters (T-2 maps) in the cuprizone (CPZ)-induced model of demyelination. Methods: C57Bl6 (n=30) mice were fed with a standard chow mixed with 0.2% (w/w) CPZ for 4 (n=10; demyelination) and 6 weeks (n=10; spontaneous remyelination). The degree of neuroinflammation at de- and remyelination was assessed by [F-18]DPA-714 PET, multi-echo T-2 MRI, autoradiography and immunohistochemistry. Results: CPZ-induced brain alterations were confirmed by increase of T-2 relaxation times in both white and grey matter after 3 and 5 weeks of CPZ. Peak [F-18]DPA-714 was found in the corpus callosum (CC, white matter), the hippocampus (HC, grey matter) and thalamus (grey matter) after 4 weeks of CPZ treatment and declined after 6 weeks of CPZ. Ex vivo autoradiography and dedicated immunofluorescence showed demyelination/remyelination with corresponding increased/decreased TSPO levels in the CC and hippocampus, confirming the spatial distribution of [F-18]DPA-714 in vivo. The expression of TSPO microglia and astrocytes is time-dependent in this model. Microglia predominantly express TSPO at demyelination, while the majority of astrocytes express TSPO during remyelination. The combination of PET- and MRI-based imaging biomarkers demonstrated the regional and temporal development of the CPZ model-associated neuroinflammatory response in grey and white matter regions. Conclusions: The combination of [F-18]DPA-714 PET and T-2 mapping may allow to further elucidate the regional and temporal profile of inflammatory signals depending on the myelination status, although the underlying inflammatory microenvironment changes. A combination of the described imaging biomarkers may facilitate the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in MS.

Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography (μPET) using [F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of critical parameters of poststroke inflammation. This allows further evaluation of novel treatment paradigms targeting the postischemic inflammation.

Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa 3.1 activity. Mechanistically, elevated KCa 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca(2+) influx. KCa 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients.

Sarcopenia and frailty are common geriatric syndromes and are associated with adverse health outcome and impaired health-related quality of life. Co-occurrences of these two syndromes with age-related neurological diseases are potentially high but not well investigated. Moreover, it is not well understood how these syndromes interact with neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke. This article introduces the currently most accepted concepts of sarcopenia and frailty, discusses the potential relevance of the syndromes for geriatric patients and presents examples of studies that investigated potential interactions between these geriatric and neurological syndromes and conditions. First results indicate that (i) the co-occurrence of these geriatric syndromes and age-related neurological diseases is high, (ii) sarcopenia and frailty can influence the clinical state of neurological diseases to a relevant extent and (iii) at least some common causes and pathophysiological processes confer the geriatric and neurological conditions. In conclusion, profound knowledge about the interaction of sarcopenia, frailty and age-associated neurological conditions is currently not available. Such knowledge would have an enormous potential for improved therapy of these neurological conditions.

Background FDG-PET detects hypometabolism in premanifest and symptomatic Huntington's disease (HD). A cross-sectional study suggested that whole-brain FDG-PET is capable to detect a phenotype in transgenic (tg) HD rats. Recently, a longitudinal follow-up study showed no FDG-PET changes in tgHD rats. Both studies applied small sample sizes and analysis was limited to whole-brain or striatum. Objective We therefore performed a follow-up study in a larger cohort of tgHD and wild-type (wt) rats encompassing several pre-defined regions of interest (ROIs) and hypothesis free voxel-by-voxel SPM analysis to clarify whether FDG-PET can detect a phenotype in tgHD rats and to determine onset …and effect sizes of changes over time. Methods N = 19 tgHD- and n = 20 wt-rats, mixed gender, were included. Repeated small animal FDG-μPET and MRI were performed at 5,10,15, and 20 months of age. ROIs encompassing entire brain, cortex, striatum, thalamus, subventricular-zone, and cerebellum were placed manually on the MRI and transferred to the co-registered μPET. Mean and maximal FDG-PET activities within ROIs were calculated and normalized to cerebellar FDG uptake. Activity and spatially normalized FDG-μPET were compared between groups on a hypothesis-free voxel-by-voxel basis using SPM. Results FDG uptake showed changes over time in both tgHD- and wt-rats, however, there was no consistent difference between tgHD- and wt-rats in both the manual ROI and SPM analysis. Conclusions In this transgenic rat model of HD FDG-μPET imaging does not detect significant alterations at the ages investigated. Further investigations are warranted employing other age groups and alternative imaging biomarkers for neuronal degeneration, respectively.

Background: Detection of inflamed atherosclerotic plaques is of crucial importance. The carotid artery cuff-model in ApoE � /� mice results in shear-stress induced atherosclerosis with inflamed plaques upstream (US) and ‘stable’ plaques downstream (DS) of the cuff. We evaluated the potential of F-18-FDG PET/CT to differentiate these plaque phenotypes. Methods: A predefined cuff was implanted round the left (n ¼ 23) or right (n ¼ 12) common carotid artery (CCA) of 35 ApoE � /� mice on a cholesterol-rich diet. Small animal F-18-FDG PET/CT was performed after 4, 6 and 8 weeks. F-18-FDG uptake was quantified US and DS of the cuff and on the contralateral CCA. Subsequently, regional F-18-FDG uptake was normalized by the contralateral CCA uptake to obtain plaque-to-background (P/B)-ratios. Thereafter, CCA were explanted and investigated by immuno histology. Results: P/B-ratio in the US-plaques increased from 1.22 � 0.23 at 4 weeks over 1.23 � 0.32 at 6 weeks to 1.37 � 0.56 (p ¼ ns) at 8 weeks after cuff implantation (left and right side of cuff implantation considered together). Uptake in the DS-plaques remained stable (1.14 � 0.23, 1.10 � 0.26 and 1.11 � 0.25; p ¼ ns). Uptake in the US-plaques was significantly higher than in the DS-plaques (all p < 0.05). P/B-ratios correlated with plaque size, degree of stenosis and macrophage density in the plaques. Moreover, there was a correlation between plaque size and macrophage density in the plaque. Conclusions: F-18-FDG-PET/CT distinguishes atherosclerotic plaques with an inflamed from those with a ‘stable’ phenotype in a mouse model of shear-stress induced atherosclerosis in vivo.

Angiogenesis is a key event in the progression of glioblastomas (GBM). Our goal was to measure different anatomical and physiological parameters of GBM vessels using steady-state contrast-enhanced magnetic resonance imaging (SSCE-MRI), together with the assessment of biochemical parameters on GBM proliferation and angiogenesis using [(11)C]methyl-L-methionine (MET) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and positron emission tomography (PET). We focused on how these anatomical and biochemical read-outs correlate with one another and with immunohistochemistry.SSCE-MRI together with (11)C-MET and (18)F-FLT PET were performed 3 weeks after intracranial implantation of human GBM spheroids in nude rats (n = 8). Total cerebral blood volume (tCBV), blood volume present in microvessels (μCBV), vessel density and size were calculated. Rats were treated with bevacizumab (n = 4) or vehicle (n = 4) for 3 weeks. Imaging was repeated at week 6, and thereafter immunohistochemistry was performed.Three weeks after implantation, MRI showed an increase of vessel density and μCBV in the tumour compared to the contralateral brain. At week 6, non-treated rats showed a pronounced increase of (11)C-MET and (18)F-FLT tumour uptake. Between weeks 3 and 6, tCBV and vessel size increased, whereas vessel density and μCBV decreased. In rats treated with bevacizumab μCBV values were significantly smaller at week 6 than in non-treated rats, whereas the mean vessel size was higher. Accumulation of both radiotracers was lower for the treated versus the non-treated group. Most importantly, non-invasive measurement of tumour vessel characteristics and tumour proliferation correlated to immunohistochemistry findings.Our study demonstrates that SSCE-MRI enables non-invasive assessment of the anatomy and physiology of the vasculature of experimental gliomas. Combined SSCE-MRI and (11)C-MET/(18)F-FLT PET for monitoring biochemical markers of angiogenesis and proliferation in addition to vessel anatomy could be useful to improve our understanding of therapy response of gliomas.

3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096–105. ©2016 AACR.

Contains fulltext : 173132.pdf (Publisher’s version ) (Open Access) Occlusion of the middle cerebral artery (MCAo) is among the most common causes of ischemic stroke in humans. Cerebral ischemia leads to brain lesions existing of an irreversibly injured core and an ischemic boundary zone, the penumbra, containing damaged but potentially salvageable tissue. Using a transient occlusion (30 min) of the middle cerebral artery (tMCAo) mouse model in this cross-institutional study we investigated the neurorestorative efficacy of a dietary approach (Fortasyn) comprising docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium as therapeutic approach to counteract neuroinflammation and impairments of cerebral (structural+functional) connectivity, cerebral blood flow (CBF), and motor function. Male adult C57BL/6j mice were subjected to right tMCAo using the intraluminal filament model. Following tMCAo, animals were either maintained on Control diet or switched to the multicomponent Fortasyn diet. At several time points after tMCAo, behavioral tests, and MRI and PET scanning were conducted to identify the impact of the multicomponent diet on the elicited neuroinflammatory response, loss of cerebral connectivity, and the resulting impairment of motor function after experimental stroke. Mice on the multicomponent diet showed decreased neuroinflammation, improved functional and structural connectivity, beneficial effect on CBF, and also improved motor function after tMCAo. Our present data show that this specific dietary intervention may have beneficial effects on structural and functional recovery and therefore therapeutic potential after ischemic stroke.

Molecular imaging with the PET tracer 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) allows assessment of the proliferative state of organs in vivo. Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [18F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [18F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089–95. ©2016 AACR.

The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo. Methods: Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using 18F-FDG, 11C-methyl-l-methionine (11C-MET), and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and by MRI at 3–6 wk after implantation. For image validation, parameters were coregistered with immunohistochemical analysis. Results: Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of 11C-MET and 18F-FLT and relatively low uptake of 18F-FDG. 11C-MET was an early indicator of vessel remodeling and tumor proliferation. 18F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate 11C-MET and 18F-FLT and impaired the 18F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast. Conclusion: For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and 11C-MET was more sensitive than 18F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood–brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative 18F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided antiangiogenic and antiproliferative therapies.

Ausschlaggebend fur die individuelle Therapieentscheidung und die Abschatzung der Prognose bei Patienten mit vermutetem Lungenkarzinom ist die korrekte Klassifizierung der Erkrankung. Hierfur liegt die momentan gultige 7. Version der TNM-Klassifikation vor, die auf einer Analyse einer grosen Zahl von Patientendatensatzen beruht und somit eine valide prognostische Gruppierung der Patienten mit Lungenkarzinom erlaubt. Sowohl fur die initiale Diagnostik als auch fur das Staging gibt es eine Vielzahl an invasiven und nicht invasiven Untersuchungsmethoden. Eine evidenzbasierte Grundlage fur das diagnostische Vorgehen und die anschliesende Therapie bietet die aktuell gultige nationale S3-Leitlinie fur die Pravention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms. Basierend auf dieser Leitlinie sollen in dieser Ubersicht die etablierten diagnostischen Verfahren bewertet werden.

Systemic cancer is the second most common cause of death in developed countries and metastatic brain tumour the most common tumour of the central nervous system (CNS). As the incidence of brain metastases appears to be rising, more accurate non-invasive imaging modalities for diagnosis, prognosis, prediction and follow-up of treatment are requisites for efficient patient management. Positron emission tomography (PET) imaging has the ability to evaluate different aspects of tumour microenvironment on the molecular and cellular level and impact the workup of patients with brain metastasis. This article reviews the current application of PET imaging in patients with metastatic brain disease.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Anamnese und Aufnahmebefund: Ein 74-jahriger Patient wurde nach operativer Sanierung einer LWK-3-Fraktur bei inkomplettem Cauda-Equina-Syndrom zur weiteren Mobilisation aus der neurochirurgischen Abteilung ubernommen. Bei Aufnahme war der Patient allseits orientiert. Im korperlichen Untersuchungsbefund fand sich eine leichtgradige, proximal betonte, schlaffe Parese des rechten Beines. Ziel war eine fruhrehabilitative geriatrische Therapie zur Erlangung der Selbstandigkeit. Untersuchungsbefunde: Laborchemisch zeigte sich eine normochrome, normozytare Anamie (Hb 10,4 mg/dl) und erhohte Infektparameter (CRP 2 mg/dl), die am ehesten im Rahmen des postoperativen Verlaufes interpretiert wurden. Therapie und Verlauf: Unter einem multimodalen Therapiekonzept mit aktivierender Pflege, Krankengymnastik und Ergotherapie wurde eine Mobilisation am Rollator erreicht. Im Verlauf kam es zu Diarrhoen mit Nachweis von Clostridien in der Stuhlkultur. Am 6. Tag einer Therapie mit Metronidazol kam es zu einer hypertensiven Entgleisung, gefolgt von den Zeichen einer vorwiegend sensorischen, gemischten Aphasie. Im MRT fand sich kein Hinweis auf eine frische zerebrale Ischamie. Die kardiovaskulare Diagnostik zeigte keine richtungsweisenden Befunde. Die Symptome persistierten auch nach Blutdrucknormalisierung. Erst nach Umstellung von Metronidazol auf Vancomycin besserte sich die Symptomatik rasch bis zur Restitutio ad integrum. Folgerung: Bei neu auftretendem neurologischem Defizit unter Metronidazol sollte an eine Metronidazol-induzierte Enzephalopathie gedacht werden.

The purpose of this study was to investigate the potential of 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) to detect early treatment responses in gliomas. Human glioma cells were stably transduced with genes yielding therapeutic activity, sorted for different levels of exogenous gene expression, and implanted subcutaneously into nude mice. Multimodality imaging during prodrug therapy included (a) magnetic resonance imaging, (b) PET with 9-(4-[¹⁸F]fluoro-3-hydroxymethylbutyl)guanine assessing exogenous gene expression, and (c) repeat [¹⁸F]FLT PET assessing antiproliferative therapeutic response. All stably transduced gliomas responded to therapy with significant reduction in tumor volume and [¹⁸F]FLT accumulation within 3 days after initiation of therapy. The change in [¹⁸F]FLT uptake before and after treatment correlated to volumetrically calculated growth rates. Therapeutic efficacy as monitored by [¹⁸F]FLT PET correlated to levels of therapeutic gene expression measured in vivo. Thus, [¹⁸F]FLT PET assesses early antiproliferative effects, making it a promising radiotracer for the development of novel treatments for glioma.

Purpose. Primary brain tumors and metastases are common causes of symptomatic epilepsy. Seizures, neurological and neuropsychological deficits can interfere with driving ability.The present paper aims to systematically review the incidence of epileptic seizures in brain tumor patients and to discuss driving ability in the context of the current German guidelines and expert opinions. Methods. To evaluate the incidence of epileptic seizures which occur at the beginning and in the course of the disease, we performed a systematic literature research in PubMed from 1960 to 2007. Additionally on the basis of this data we performed a survey collecting expert opinions regarding the driving ability of brain tumor patients from members of the German working groups"Arbeitsgemeinschaft fur prachirurgische Epilepsie-diagnostik und operative Epilepsietherapie" (Working Group for Presurgical Epilepsy Diagnostics and Operative Epileptic Therapy) and "Neuroonkologische Arbeitsgemeinschaft" (Neuro-oncological Working Group). Results. The incidence of epileptic seizures depends on the entity, dignity and localization of the tumor. The driving ability of brain tumor patients is not explicitly regulated in Germany. Of the interviewed experts 72% judged the guidelines to be precise enough and 44% did not want to deprive the patients of their driving ability without a first seizure, independent of the individual risk. Discussion. The available studies are methodologically insufficient and show that a further evaluation is necessary to assess the driving ability. Possible restrictions of the driving ability in patients with a high risk of seizures in the course of the disease have to take into account the balance between individual rights and the interests of the general public.

Methyl-L-(11)C-methionine ((11)C-MET) PET has been shown to detect brain tumors with a high sensitivity and specificity. In this study, we investigated the potential of (11)C-MET PET to noninvasively detect tumor progression in patients with gliomas. Moreover, we analyzed the relationship between changes in (11)C-MET uptake on PET and changes in various molecular immunohistochemical markers during progression of gliomas.Twenty-four patients with histologically proven glioma were investigated repeatedly with (11)C-MET PET. (11)C-MET uptake was determined for a circular region of interest. Histologic and molecular analyses for tumor progression were performed after open surgery and stereotactic biopsy, respectively.In patients with malignant progression, the mean increase in (11)C-MET uptake was 54.4% (SD, 45.5%; range, 3.1%-162.2%), whereas in patients without a change in tumor grade, mean (11)C-MET uptake did not significantly change (3.9%; SD, 13.7%; range, -24.4% to 26.3%). The difference in the change in (11)C-MET uptake between the group with malignant progression and the group without malignant progression was highly significant (P0.001). Receiver-operating-curve analysis revealed a sensitivity of 90% and a specificity of 92.3% for the detection of malignant transformation by an increase in (11)C-MET uptake of more than 14.6%. Increased (11)C-MET uptake of more than 14.6% was indicative of malignant progression in all but 3 leave-one-out iterations. A detailed immunohistochemical analysis demonstrated a significant correlation between changes in (11)C-MET uptake and the expression of vascular endothelial growth factor.These data suggest that (11)C-MET-PET represents a noninvasive method to detect malignant progression in patients with gliomas. Moreover, the increase in (11)C-MET uptake during malignant progression is reflected by an increase in angiogenesis-promoting markers as vascular endothelial growth factor.

Purpose Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Methods Based on the analysis of 11 patients with glioma (WHO grade II–IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time–activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood–brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. Results The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p

Only a few Methyl-[11C]-l-methionine (MET) positron emission tomography (PET) studies have focused on children and young adults with brain neoplasm. Due to radiation exposure, long scan acquisition time, and the need for sedation in young children MET-PET studies should be restricted to this group of patients when a decision for further therapy is not possible from routine diagnostic procedures alone, e.g., structural imaging. We investigated the diagnostic accuracy of MET-PET for the differentiation between tumorous and non-tumorous lesions in this group of patients. Forty eight MET-PET scans from 39 patients aged from 2 to 21 years (mean 15 ± 5.0 years) were analyzed. The MET tumor-uptake relative to a corresponding control region was calculated. A receiver operating characteristic (ROC) was performed to determine the MET-uptake value that best distinguishes tumorous from non-tumorous brain lesions. A differentiation between tumorous (n = 39) and non-tumorous brain lesions (n = 9) was possible at a threshold of 1.48 of relative MET-uptake with a sensitivity of 83% and a specificity of 92%, respectively. A differentiation between high grade malignant lesions (mean MET-uptake = 2.00 ± 0.46) and low grade tumors (mean MET-uptake = 1.84 ± 0.31) was not possible. There was a significant difference in MET-uptake between the histologically homogeneous subgroups of astrocytoma WHO grade II and anaplastic astrocytoma WHO grade III (P = 0.02). MET-PET might be a useful tool to differentiate tumorous from non-tumorous lesions in children and young adults when a decision for further therapy is difficult or impossible from routine structural imaging procedures alone. Keywords Brain tumor - Children - PET - Methionine - Molecular imaging

Improvements of radionuclide and magnetic resonance-based imaging modalities over the past decade have enabled clinicians to noninvasively assess the dynamics of disease-specific processes at the molecular level in humans. This article will provide an overview of the recent advances in multimodal molecular neuroimaging in patients with primary brain tumors. To date, a range of complementary imaging parameters have been established in the diagnosis of brain tumors. Magnetic resonance imaging (MRI) provides mostly morphological and functional information such as tumor localization, vascular permeability, cell density, and tumor perfusion. The use of positron emission tomography (PET) enables the assessment of molecular processes, such as glucose consumption, expression of nucleoside and amino acid transporters, as well as alterations of DNA and protein synthesis. Taken together, MRI and PET give complementary information about tumor biology and activity, providing an improved understanding about the kinetics of tumor growth.

Purpose: The aim of this study was to investigate the relationship between the in vivo derived kinetic parameters of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and the proliferation rate measured in vitro by Ki-67 staining in patients with newly diagnosed high-grade gliomas. Experimental Design: Thirteen patients with newly diagnosed high-grade gliomas were investigated with 18F-FLT and methyl-11C- l-methionine (11C-MET) positron emission tomography (PET) and T1-, Gd-T1–, and T2-weighted magnetic resonance imaging on consecutive days. Tracer kinetic parameters of 18F-FLT as well as the standardized uptake value and the tumor-to-background (T/B) ratio of 18F-FLT and 11C-MET were determined. Data of kinetic modeling, standardized uptake value, and T/B values derived from 18F-FLT-PET were compared with T/B values derived from 11C-MET-PET and to the in vitro proliferation marker Ki-67. Results: A significant correlation was observed between the metabolic rate constant Ki and the proliferation index as measured by Ki-67 immunostaining [Ki, r = 0.79 (P = 0.004)]. Also, the phosphorylation rate constant k3 correlated with Ki-67 [k3, r = 0.76 (P = 0.006)], whereas the rate constant for transport through the blood brain barrier K1 showed a weaker correlation with Ki-67 [K1, r = 0.62 (P = 0.044)]. No significant correlation between 11C-MET and 18F-FLT uptake ratios and Ki-67 was observed. Conclusions: This study shows that kinetic analysis of 18F-FLT tracer uptake is essential for the in vivo assessment of tumor proliferation in high-grade gliomas, whereas uptake ratios of 11C-MET and 18F-FLT failed to correlate with the in vitro determined proliferation marker. Thus, kinetic analysis of 18F-FLT might provide an accurate method for the assessment of early response to glioma treatment in the future.

HISTORY AND CLINICAL FINDINGS: A 43-year-old woman was admitted with a 14-day history of general malaise, subfebrile temperature, radicular dysaesthesias in the "riding breeches" area, severe pain in the lumbar region and progressive disorders of bladder and rectal emptying. Physical examination showed a conus-cauda syndrome. Differential diagnosis was between myelitis (inflammatory or infectious), space-occupying intraspinal mass or vascular lesion. INVESTIGATIONS: Cerebrospinal fluid contained 1700/3 cells and there was intrathecal antibody synthesis against varicella zoster virus (VZV) and positive VZV-DNA analysis in the polymerase chain reaction. Magnetic resonance imaging of the lumbar spine revealed an inflamed enlarged conal and epiconal area with small haemorrhagic spots. There was no evidence of an underlying immune-modulated disease. TREATMENT AND COURSE: With the diagnosis of varicella zoster myelitis with cutaneous changes having been established the clinical signs and symptoms regressed almost completely with aciclovir administration (10mg/kg intravenously for 14 days). CONCLUSION: VZV without cutaneous involvement should be considered in the differential diagnosis of the radicular pain syndrome. When clinical signs of beginning myelitis or encephalitis are present, immediate investigations and therapy are necessary.

Introduction Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. Imaging of AD characteristic changes by μPET The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. Summary In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers’ disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases.

Glioblastoma (GBM) is the most common and most malignant tumour of the central nervous system. Despite recent advances in understanding the biology of GBM, the disease still remains in desperate need of effective treatment options resulting in long-term improvements in overall patient survival. Molecularly targeted therapies, anti-angiogenic therapy and immunotherapy are promising avenues under investigation as future therapeutic options. Molecular imaging (MI) is an essential tool in the development of these targeted treatments, both preclinically and clinically. MI facilitates the preclinical study and interrogation of potential therapies. MI further supports non-invasive, longitudinal monitoring of therapy response and allows the study of emergence of treatment resistance via an imaging-guided therapeutic approach.

Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235.Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry.Treatment with BEV resulted in a pronounced decrease in tumour volume (T2-weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [(18)F]FLT uptake studies were used to support the observations. Using ΔR2* and ΔR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [(18)F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts.Assessing MR imaging biomarker parameters together with [(18)F]FET and [(18)F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combination regimen as a novel therapeutic approach in oncology.

The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPARgamma plays a crucial role in regulation of insulin sensitivity, synthetic agonists are already in clinical use for type II diabetes treatment. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPARgamma agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPARgamma-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPARgamma mutant. Furthermore, proliferation was reduced by pioglitazone, as measured by Ki-67 immunoreactivity, in vitro. Continuous intracerebral infusion of pioglitazone into gliomas induced by intrastriatal injection of C6 cells reduced tumor volumes by 83%. Oral administration of pioglitazone reduced tumor volumes by 76.9%. Subsequent brain tissue analysis revealed induction of apoptotic cell death. Ki-67 expression and BrdU incorporation revealed a reduction of proliferation in vivo. Reduced invasion of C6 cells and lower matrix metalloproteinase 9 levels in vivo indicate pioglitazone-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.

OBJECTIVE: Dysphagia is common after stroke and represents a marker of poor prognosis. After ischemic stroke, dysphagia represents only one part of the clinical spectrum of changes in the gastrointestinal (GI) tract and includes GI hemorrhage, delayed GI emptying, and colorectal dysfunction. State-of-the-art imaging techniques have started to revolutionize to study the cortical and brainstem control of these GI symptoms. It has become increasingly obvious that GI alterations after stroke are complex and its recovery following stroke is even more so. METHODS: In this review, an electronic database research was performed in MEDLINE, EMBASE, and the COCHRAINE database using the terms stroke, dysphagia, GI motility, or cortical reorganization; an extensive manual searching was additionally conducted. RESULTS: Cerebral ischemia may lead to an interruption of the axis between central nervous system and GI system. This altered interrelation between the central nervous system and the GI system may cause, among other things, mainly dysphagia, GI dysmotility, and GI hemorrhage. The consecutive clinical symptoms can often be directly attributed to specific cerebral ischemic lesions involving the brain stem as well as certain cortical and subcortical structures. However, in some cases the pathophysiological mechanisms leading to GI symptoms are incompletely understood. Recent improvement of imaging techniques, especially in functional imaging, has lead to new insights of the central control of the GI tract, suggesting that its cortical and medullar organization is multifocal, and bilateral with handness-independent hemispheric dominance. CONCLUSIONS: Following stroke, patients may have swallowing impairment and other changes of the GI tract that could affect nutritional and hydration status and that lead to aspiration pneumonia. Impaired nutritional status is associated with reduced functional improvement, increased complication rates, and prolonged hospital stays.

Die fatale familiare Insomnie (FFI) ist eine vererbbare Prionenerkrankung, die durch eine Mutation im Codon 178 des Prionproteingens (PRNP) auf Chromosom 20 verursacht wird. Die Erkrankung ist durch gestorten Nachtschlaf und hieraus resultierende Vigilanzstorungen sowie eine Vielzahl weiterer neurologischer Symptome gekennzeichnet. In dieser Arbeit werden anhand einer Kasuistik die typischen klinischen und bildgebenden Befunde diskutiert. Im vorliegenden Fall konnte die Diagnose erst post mortem gesichert werden, nachdem ein immunsuppressiver Behandlungsversuch unter der klinischen Verdachtsdiagnose einer zerebralen Vaskulitis das Fortschreiten der Erkrankung nicht verhindern konnte. Insbesondere wird erlautert, inwiefern moderne Diagnosemethoden wie die Positronenemissionstomographie PET mit [15O]H2O und [18F]FDG sowie die Single-Photon-Emissions-Computertomographie (SPECT) eine sinnvolle Erganzung zu konventionellen bildgebenden Methoden und der genetischen Testung darstellen.

The purpose of this study was to monitor the metabolic effects of temozolomide (TMZ) chemotherapy in malignant gliomas by means of repeated positron emission tomography (PET) with [11C]methionine (MET). Fifteen patients with histologically proven malignant glioma were treated by TMZ chemotherapy. MET-PET studies were performed before and after the third cycle of TMZ chemotherapy in all patients, and in 12 patients also after the sixth cycle. Gadolinium-enhanced MRI studies were performed in 12 patients before the first and after the sixth cycle. Clinical status was assessed by the modified Rankin scale. Long-term outcome was assessed by calculating the time to progression (TTP) in months. Decline in MET uptake during therapy corresponded to a stable clinical status. The median TTP was significantly longer in patients with decline in MET uptake than in those with increasing MET uptake (23 vs 3.5 months; p=0.01, log rank test). There was no significant correlation between change in MET uptake and change in contrast enhancement during treatment for all patients. The present data demonstrate that clinical stability, which is often achieved under TMZ chemotherapy of malignant glioma, corresponds to a decline in or stability of tumour amino acid metabolism. Tumour responses can already be demonstrated with MET-PET after three cycles of chemotherapy, and absence of progression at that time indicates a high probability of further stability during the next three cycles. A reduction in MET uptake during TMZ treatment predicts a favourable clinical outcome. Molecular imaging of amino acid uptake by MET-PET offers a new method of measurement of the biological activity of recurrent glioma.

Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer’s disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration withN-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

Background: Brain tissue hypoattenuation on early computed tomography is frequently included in decision making in acute stroke management. However, its pathophysiological counterpart needs further evaluation. Methods: By comparative imaging with diffusion-weighted imaging and 15O-water positron emission tomography we aimed to interpret early (Results: In 11 patients, the hypoattenuation corresponded to a decreased proton diffusion (median 115.9% relative DWI value) measured by magnetic resonance imaging and to a severe hypoperfusion (below 12 ml/100 g/ min) assessed by positron emission tomography. The volume of parenchymal hypoattenuation correlated to the tissue with disturbed diffusion (Spearman’s rho = 0.73), but largely underestimated the hypoperfusion below 20 ml/100 g/min. Conclusions: Early hypoattenuation reflects the coupling of the severity of ischemia and resulting diffusion changes. It allows an estimate of the infarct core but underestimates the penumbral hypoperfusion.

Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and "phenotyping" of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy's experimental knowledge into clinical applications and the way in which this process is being promoted through the use of novel imaging approaches.