Positron emission tomography imaging in gliomas: applications in clinical diagnosis, for assessment of prognosis and of treatment effects, and for detection of recurrences.

Neuroimaging plays a significant role in the diagnosis of intracranial tumours, especially brain gliomas, and must consist of an assessment of location and extent of the tumour and of its biological activity. Therefore, morphological imaging modalities and functional, metabolic or molecular imaging modalities should be combined for primary diagnosis and for following the course and evaluating therapeutic effects. Magnetic resonance imaging (MRI) is the gold standard for providing detailed morphological information and can supply some additional insights into metabolism (MR spectroscopy) and perfusion (perfusion-weighted imaging) but still has limitations in identifying tumour grade, invasive growth into neighbouring tissue and treatment-induced changes, as well as recurrences. These insights can be obtained by various positron emission tomography (PET) modalities, including imaging of glucose metabolism, amino acid uptake and nucleoside uptake. Diagnostic accuracy can benefit from coregistration of PET results and MRI, combining high-resolution morphological images with biological information. These procedures are optimized by the newly developed combination of PET and MRI modalities, permitting the simultaneous assessment of morphological, functional, metabolic and molecular information on the human brain.

Post-stroke cognitive decline: an update and perspectives for clinical research.

The close relationship between stroke and dementia is an important health issue. Ischaemic stroke can facilitate the onset of vascular dementia as well as aggravate pre-existing cognitive decline. The onset of cognitive decline may become manifest immediately following the onset of ischaemic stroke, but often there is a delay in the development of cognitive decline after a stroke. This delay can be seen as a therapeutic time window allowing interventions to be applied to preserve cognition following stroke. Both neurodegenerative and vascular mechanisms are activated and probably result in overlapping processes within the neurovascular unit. This review focuses on the incidence and prevalence of cognitive decline following stroke, predisposing stroke aetiologies, pre-stroke decline, imaging factors and biomarkers. Outcomes are discussed in relation to timing of assessment and neuropsychological tests used for evaluation of cognitive decline in ischaemic stroke patients. Including such tests in routine evaluations of stroke patients after some weeks or months is recommended. Finally, an outlook on ongoing and planned intervention trials is added and some recommendations for future research are proposed.

Polarization control of metal-enhanced fluorescence in hybrid assemblies of photosynthetic complexes and gold nanorods.

Fluorescence imaging of hybrid nanostructures composed of a bacterial light-harvesting complex LH2 and Au nanorods with controlled coupling strength is employed to study the spectral dependence of the plasmon-induced fluorescence enhancement. Perfect matching of the plasmon resonances in the nanorods with the absorption bands of the LH2 complexes facilitates a direct comparison of the enhancement factors for longitudinal and transverse plasmon frequencies of the nanorods. We find that the fluorescence enhancement due to excitation of longitudinal resonance can be up to five-fold stronger than for the transverse one. We attribute this result, which is important for designing plasmonic functional systems, to a very different distribution of the enhancement of the electric field due to the excitation of the two characteristic plasmon modes in nanorods.

Concentration and excitation effects on the exciton dynamics of poly(3-hexylthiophene)/PbS quantum dot blend films.

The dynamics of photoexcitations in hybrid blends of poly(3-hexylthiophene) (P3HT) conjugated polymer donor and oleic-acid capped lead sulfide (PbS) quantum dot (QD) acceptors of different concentrations-for light harvesting applications-were investigated using time-resolved transmission and photoluminescence spectroscopies. Following excitation at 400 nm and probing in the 500-1000 nm region, we find that geminate excitation recombination in the blend of P3HT/PbS QDs dominates the transient decays at sub-ns times while intermaterial interactions such as charge transfer processes appear at longer times in the 1-50 ns regime. For the hybrid blend films with lower QD concentrations (<67% wt), polymer exciton recombination dominates the overall transient absorption signal. For higher QD contents, QD state relaxation effects become visible. Excitation density studies reveal the presence of linear exciton relaxation effects in the P3HT region while carrier decay for films with high PbS QD concentration is influenced by QD Auger recombination. Time-resolved luminescence shows that electron transfer from the P3HT/PbS QDs appears relatively inefficient in comparison to the geminate recombination, while hole transfer competes favorably to intrinsic QD recombination.

PET in coma and in vegetative state.

Advances in resuscitation and critical care management have resulted in the survival of many patients despite severe brain damage. These patients may remain in coma or in vegetative state. The probability of recovery of conscious function is dependent on the extent of structural brain damage, which is difficult to assess by clinical, laboratory or functional tests. Positron emission tomography (PET) of 18F-fluordeoxyglucose (FDG) can be used to investigate metabolic and functional impairment of the brain. In acute vegetative state (AVS, duration <1 month), overall glucose utilization was significantly reduced in comparison with age-matched controls. In a few cases with locked-in syndrome, cortical metabolism was in the normal range. 11C-Flumazenil (FMZ) measures the density of benzodiazepine receptors (BZRs) and thereby furnishes an estimate of neuronal integrity. PET with this tracer demonstrated a considerable reduction in BZRs in cortical areas, but indicated that the cerebellum was spared from neuronal loss. The comparison of FDG- and FMZ-PET findings in AVS demonstrates that alterations of cerebral glucose consumption do not represent mere functional inactivation, but also irreversible structural damage. In some cases with minimally conscious state, auditory stimuli with emotional valence induced more brain activation (investigated by H215O-PET) than meaningless noise; such studies can be used to detect residual cortical function. To improve prognostication of chances for recovery, a combination of functional activation studies and assessment of the extent of neuronal damage might be the optimal procedure and should be tested in larger cohorts of patients with comatose states of different severity.

Single fibers of cat optic nerve: "thresholds" to light.

Absolute thresholds of 39 single fibers of the optic nerves of 20 cats were determined by inspection of post-stimulus time histograms, each com puted from the responses to 60 to 100 identical flashes of white light. The values found-from 1.1 x 10(-7) to 6.8 x 10(-6) candella per square meter (nits)-agree well with psychophysi cal thresholds found in previous in vestigations.

Strychnine- and pentylenetetrazol-induced changes of excitability in aplysia neurons.

In Aplysia neurons isolated from their synaptic input strychnine induces doublet discharges associated in voltage clamp with a decrease in the threshold for the inward current and a reduction and delayed onset of the outward current. Pentylenetetrazol causes oscillations and bursting behavior in normally silent cells together with an increased inactivation of the delayed outward current and induced or enhanced anomalous rectification.

High resolution positron emission tomography demonstrates basal ganglia dysfunction in early Parkinson's disease.

High resolution positron emission tomography (PET) with the newly developed HRRT scanner (Siemens/CTI) permits the reliable quantification of 18-Fluorodeoxyglucose (FDG) uptake as a marker of neuronal activity in small subcortical nuclei which are involved in the pathophysiology of Parkinson's disease (PD). We investigated the normalized cerebral metabolic rates of glucose (nCMRGlc) with HRRT PET in basal ganglia (BG) nuclei of 10 early-stage PD patients and in 9 healthy volunteers. PET data were co-registered to magnetic resonance images and analyzed in a three-dimensional volume-of-interest (VOI) approach. After normalization for global brain activity, PD patients showed a significantly higher nCMRGlc than controls bilaterally in the BG output nuclei (pallidum, substantia nigra) and unilateral in the caudate and putamen. The metabolic activity of the nucleus accumbens, the subthalamic nucleus, the corpus amygdaloideum and the red nucleus was normal. These first HRRT PET data in living parkinsonian humans extend previous brain imaging findings of abnormal network activity in the BG and confirm output nuclei and striatal overactivation also in early stage PD patients.

Performance of FDG PET for detection of Alzheimer's disease in two independent multicentre samples (NEST-DD and ADNI).

AIM: We investigated the performance of FDG PET using an automated procedure for discrimination between Alzheimer's disease (AD) and controls, and studied the influence of demographic and technical factors. METHODS: FDG PET data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [102 controls (76.0 +/- 4.9 years) and 89 AD patients (75.7 +/- 7.6 years, MMSE 23.5 +/- 2.1) and the Network for Standardisation of Dementia Diagnosis (NEST-DD) [36 controls (62.2 +/- 5.0 years) and 237 AD patients (70.8 +/- 8.3 years, MMSE 20.9 +/- 4.4). The procedure created t-maps of abnormal voxels. The sum of t-values in predefined areas that are typically affected by AD (AD t-sum) provided a measure of scan abnormality associated with a preset threshold for discrimination between patients and controls. RESULTS: AD patients had much higher AD t-sum scores compared to controls (p < 0.01), which were significantly related to dementia severity (ADNI: r = -0.62, p < 0.01; NEST-DD: r = -0.59, p < 0.01). Early-onset AD patients had significantly higher AD t-sum scores than late-onset AD patients (p < 0.01). Differences between databases were mainly due to different age distributions. The predefined AD t-sum threshold yielded a sensitivity and specificity of 83 and 78% in ADNI and 78 and 94% in NEST-DD, respectively. CONCLUSION: The automated FDG PET analysis procedure provided good discrimination power, and was most accurate for early-onset AD.

CSF total and phosphorylated tau protein, regional glucose metabolism and dementia severity in Alzheimer's disease.

BACKGROUND AND PURPOSE: We investigated associations between severity of cognitive impairment, cerebrospinal fluid (CSF) concentrations of total-tau (t-tau) protein and tau phosphorylated at threonin 181 (p-tau(181)) and regional glucose metabolism measured with 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) in patients with probable Alzheimer's disease (AD). METHODS: In 38 patients (mean age 66.5 +/- 8.0 years) with AD, Mini-Mental State Examination (MMSE) scores were evaluated and CSF levels of t-tau and p-tau(181) measured. All patients underwent an 18F-FDG-PET scan. Image analysis including correlation analysis and principal component analysis (PCA) were performed using SPM5 and VINCI. RESULTS: Dementia severity (MMSE 21.2 +/- 4.9) correlated well with metabolic impairment especially in left hemisphere association areas that are typically affected in patients with AD (e.g. inferior parietal lobule, r = 0.512; medial temporal gyrus, r = 0.478; inferior temporal gyrus, r = 0.488; precuneus, r = 0.468; PCA: r = 0.639, F = 7.751; all P < 0.001). There were no associations between t-tau and p-tau(181) with dementia severity and only weak correlations between t-tau and cerebral glucose metabolism (superior parietal gyrus, r = -0.325, P < 0.05; precentral gyrus r = -0.418, P < 0.01; amygdala r = -0.362, P < 0.05). No correlations were found between p-tau(181) and regional hypometabolism in FDG-PET. CONCLUSION: MMSE and CSF t-tau represent different aspects of disease severity. Whilst MMSE is closely related to impaired cerebral glucose metabolism, CSF t-tau is less closely related and appears to be less well suited for assessment of disease progression.

In vivo evaluation of the uptake of [(123)I]FIAU, [(123)I]IVFRU and [(123)I]IVFAU by normal mouse brain: potential for noninvasive assessment of HSV-1 thymidine kinase gene expression in gliomas.

Radioiodinated 5-iodo-1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)uracil (F *IAU) is most commonly used for noninvasive assessment of herpes simplex virus type 1 thymidine kinase (HSV-1-tk) gene expression. However, it does not permeate the intact blood-brain barrier (BBB) because of its moderate lipophilicity. In this work, three iodo-nucleosides, FIAU, IVFRU, and IVFAU, were radiolabeled with iodine-123 and tested for permeation of the BBB in mice and for potential measurement of HSV-1-tk gene expression in gliomas. The results demonstrate that brain uptake and retention of these nucleosides is not directly related to their lipophilicity. The low brain uptake of IVFAU, in conjunction with its higher and constant brain/blood ratio, may reflect greater stability against hydrolysis of the N-glycosidic bond. In vivo PET evaluations of [(124)I]IVFRU and [(124)I]IVFAU in tumor-bearing mice are warranted.

Imaging of acetylcholine esterase activity in brainstem nuclei involved in regulation of sleep and wakefulness.

Positron emission tomography with 11C-N-methyl-4-piperidyl-acetate (MP4A) was applied in eight healthy volunteers and two patients with mild Alzheimer's disease (AD) to assess acetylcholine esterase (AChE) activity in magnetic resonance imaging-identified brainstem nuclei. Uptake ratios in lateral dorsal tegmental and pedunculopontine nuclei relative to cerebellum yielded reproducible values for the AChE activity in controls and reduced values in AD, more marked in a patient with complaints of disturbed sleep. Cortical AChE activity was related to the extent of cognitive impairment which was more severe in the AD patient without sleep disturbance. This preliminary observational study demonstrates the feasibility to image and assess AChE activity in small nuclei of the brain stem. This approach may be helpful to investigate the interaction of various nuclei in the complex network regulating sleep and wakefulness in representative patient groups with documented sleep disturbance.

A proposed regional hierarchy in recovery of post-stroke aphasia.

Activation studies in patients with aphasia due to stroke or tumours in the dominant hemisphere have revealed effects of disinhibition in ipsilateral perilesional and in contralateral homotopic cortical regions, referred to as collateral and transcallosal disinhibition. These findings were supported by studies with selective disturbance of cortical areas by repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers and in patients with focal brain lesions. Both, collateral as well as transcallosal disinhibition might be relevant for the compensation of lesions within a functional network. From these data a hierarchical organization of recovery of aphasia after stroke and of compensation of language defects due to brain tumours can be deduced, by which the reactivation of undamaged network areas of the ipsilateral hemisphere usually lead to better outcome than the involvement of homotopic contra-lateral regions. rTMS can be used to identify areas relevant for speech production and might play a role in treatment strategies targeted at modulating the activity of contralateral homotopic areas of the functional network which might interfere with language recovery.

Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients.

BACKGROUND AND PURPOSE: In a prospective, double-blind, placebo-controlled study, it was investigated whether piracetam improves language recovery in poststroke aphasia assessed by neuropsychological tests and activation PET measurement of cerebral blood flow. METHODS: Twenty-four stroke patients with aphasia were randomly allocated to 2 groups: 12 patients received 2400 mg piracetam twice daily, 12 placebo. Before and at the end of the 6-week treatment period in which both groups received intensive speech therapy, the patients were examined neuropsychologically and studied with H(2)(15)O PET at rest and during activation with a word-repetition task. Blood flow was analyzed in 14 language-activated brain regions defined on reconstructed surface views from MRI coregistered to the PET images. RESULTS: Before treatment, both groups were comparable with respect to performance in language tasks and to type and severity of aphasia. In the piracetam group, increase of activation effect was significantly higher (P:<0.05) in the left transverse temporal gyrus, left triangular part of inferior frontal gyrus, and left posterior superior temporal gyrus after the treatment period compared with the initial measures. The placebo group showed an increase of activation effect only in the left vocalization area. In the test battery, the piracetam group improved in 6 language functions, the placebo group only in 3 subtests. CONCLUSIONS: Piracetam as an adjuvant to speech therapy improves recovery of various language functions, and this effect is accompanied by a significant increase of task-related flow activation in eloquent areas of the left hemisphere.

Calcium ion transients in peri-infarct depolarizations may deteriorate ion homeostasis and expand infarction in focal cerebral ischemia in cats.

BACKGROUND AND PURPOSE: Harmful effects of peri-infarct depolarizations (PIDs) may depend on recurrent Ca(2+) influx. Thus far, few studies have documented the relevance of PIDs in gyrencephalic animals, and the progressive nature of this process has not been investigated over extended periods. We therefore studied in prolonged focal ischemia in cats spatial and temporal profiles of extracellular calcium ([Ca(2+)](o)) shifts in relation to direct current (DC) potential, nitric oxide (NO) concentration and regional cerebral blood flow alterations, and final pathological outcome. METHODS: In halothane-anesthetized cats receiving either vehicle (n=12) or MK-801 treatment (5 mg/kg IV; n=10), the left middle cerebral artery was permanently occluded. Laser-Doppler probes, ion-selective microelectrodes, and NO electrodes measured simultaneously regional cerebral blood flow, DC potential, electrocorticogram, [Ca(2+)](o), and NO concentrations in ectosylvian and suprasylvian gyri of the left cerebral cortex. RESULTS: Persistent depolarization immediately after middle cerebral artery occlusion occurred in 10 ectosylvian and 4 suprasylvian gyri of vehicle-treated animals and in 9 ectosylvian and 3 suprasylvian gyri of MK-801-treated animals. PIDs associated with transient decreases of [Ca(2+)](o) were detected in suprasylvian gyri of only 4 vehicle-treated animals, of which 3 developed recurrent PIDs. Electrocorticogram was suppressed during PIDs, and electrocorticogram recovery worsened in a stepwise manner with consecutive depolarizations. PID duration increased slightly with ongoing ischemia and evolved to persistent depolarization at a final stage. NO transients were not detected during PID, and regional cerebral blood flow transients were not pronounced. Infarction was larger with initial persistent depolarization than with PID and was smallest in MK-801-treated animals. CONCLUSIONS: PID is not a common finding in peri-infarct zones in cats, and it is suppressed by the N:-methyl-D-aspartate antagonist MK-801. However, if repeated PIDs are generated, they result in a stepwise, progressive breakdown of neuronal function and ion homeostasis, probably contributing to the growth of infarction in focal cerebral ischemia. Recurrent Ca(2+) influx is a mechanism that presumably contributes to this process.

Which time-to-peak threshold best identifies penumbral flow? A comparison of perfusion-weighted magnetic resonance imaging and positron emission tomography in acute ischemic stroke.

BACKGROUND AND PURPOSE: In acute ischemic stroke, the hypoperfused but viable tissue is the main therapeutic target. In clinical routine, time-to-peak (TTP) maps are frequently used to estimate the hemodynamic compromise and to calculate the mismatch volume. We evaluated the accuracy of TTP maps to identify penumbral flow by comparison with positron emission tomography (PET). METHODS: Magnetic resonance imaging (MRI) and PET were performed in 11 patients with acute ischemic stroke (median 8 hours after stroke onset, 60 minutes between MRI and PET imaging). The volumes defined by increasing TTP thresholds (relative TTP delay of >2, >4, >6, >8, and >10 seconds) were compared with the volume of hypoperfusion (<20 mL/100 g per min) assessed by 15O-water PET. In a volumetric analysis, each threshold's sensitivity, specificity, and predictive values were calculated. RESULTS: The median hypoperfusion volume was 34.5 cm3. Low TTP thresholds included large parts of the hypoperfused but also large parts of normoperfused tissue (median sensitivity/specificity: 93%/60% for TTP >2) and vice versa (50%/91% for TTP >10). TTP >4 seconds best identifies hypoperfusion (84%/77%). The positive predictive values increased with the size of hypoperfusion. CONCLUSIONS: This first comparison of quantitative PET-CBF with TTP maps in acute ischemic human stroke indicates that the TTP threshold is crucial to reliably identify the tissue at risk; TTP >4 seconds best identifies penumbral flow; and TTP maps overestimate the extent of true hemodynamic compromise depending on the size of ischemia. Only if methodological restrictions are kept in mind, relative TTP maps are suitable to estimate the mismatch volume.

Predictive value of neurochemical monitoring in large middle cerebral artery infarction.

BACKGROUND AND PURPOSE: Space-occupying brain edema is a life-threatening complication in patients with large hemispheric stroke. Early identification of patients at risk is necessary to decide on invasive therapies such as decompressive hemicraniectomy or hypothermia. To assess potential predictors of malignant brain edema by measurement of intracranial pressure (ICP) and microdialysis in patients with large hemispheric stroke and different clinical course. METHODS: In an ongoing prospective clinical study, an ICP and microdialysis probe were placed into the parenchyma of the ipsilateral frontal lobe of 10 patients. Extracellular concentrations of glutamate, lactate, pyruvate, and glycerol were measured continuously. Repeated cranial CT scans were scrutinized for size of infarction and presence of mass effect. RESULTS: The dynamics of the different substances varied in accordance with the clinical course, size of infarction, and local brain edema: Increase in ICP and in glutamate concentration and lactate-pyruvate ratio was followed by massive edema and large infarcts; generally low and stable ICP and substrate concentrations were found in patients without progressive space-occupying infarcts. CONCLUSIONS: In patients with large hemispheric infarction, bedside monitoring with microdialysis is feasible and might be helpful together with ICP recording to follow the development of malignant brain edema.

PET and functional testing in temporal lobe epilepsy.

Thirty-seven patients with severe temporal lobe epilepsy were studied interictally with [18F]fluorodeoxyglucose-PET in each of three conditions: resting, during emotional speech, and while performing a visual recognition task. In the resting state, each patient exhibited regional hypometabolism in agreement with his epileptic EEG focus, but that area was typically very large. The zone of maximum dysfunction was significantly better demarcated on activated scans showing an increase in whole-brain metabolism averaging 18%. Concurrently, the midtemporal-focus metabolic contrast was improved by 27%. This effect was more consistently produced by the speech paradigm that also induced significant amygdala recruitment and revealed the individual hemispheric speech dominance. Psychological trait factors played a role only for unspecific global activation.

Ischemic penumbra: evidence from functional imaging in man.

The ischemic penumbra is defined as tissue with flow within the thresholds for maintenance of function and of morphologic integrity. Penumbra tissue has the potential for recovery and therefore is the target for interventional therapy in acute ischemic stroke. The identification of the penumbra necessitates measuring flow reduced less than the functional threshold and differentiating between morphologic integrity and damage. This can be achieved by multitracer positron emission tomography (PET) and perfusion-weighted (PW) and diffusion-weighted magnetic resonance imaging (DW-MRI) in experimental models, in which the recovery of critically perfused tissue or its conversion to infarction was documented in repeat studies. Neuroimaging modalities applied in patients with acute ischemic stroke--multitracer PET, PW- and DW-MRI, single photon emission computed tomography (SPECT), perfusion, and Xe-enhanced computed tomography (CT)-- often cannot reliably identify penumbra tissue: multitracer studies for the assessment of flow and irreversible metabolic damage usually cannot be performed in the clinical setting; CT and MRI do not reliably detect irreversible damage in the first hours after stroke, and even DW-MRI may be misleading in some cases: determinations of perfusion alone yield a poor estimate of the state of the tissue as long as the time course of changes is not known in individual cases. Therefore, the range of flow values in ischemic tissue found later, either within or outside the infarct, was rather broad. New tracers--for example, receptor ligands or hypoxia markers--might improve the identification of penumbra tissue in the future. Despite these methodologic limitations, the validity of the concept of the penumbra was proven in several therapeutic studies in which thrombolytic treatment reversed critical ischemia and decreased the volume of final infarcts. Such neuroimaging findings might serve as surrogate targets in the selection of other therapeutic strategies for large clinical trials.

Functional imaging correlates of recovery after stroke in humans.

The mechanisms that are responsible for the remarkable potential for functional recovery from stroke in humans remain unclear, and functional tomographic neuroimaging techniques increasingly are being used to investigate this issue. Such studies confirmed that recovery of function is related to the volume of penumbra tissue that escapes infarction. For language, reactivation of the primary functional areas in the dominant hemisphere is associated with the best prognosis. Evidence for functional plasticity in the immediate vicinity of infarcts, as demonstrated under experimental conditions with invasive methods, is still limited after stroke in humans, probably because of the limitations of spatial resolution of most currently available methods. Often, functional changes in the large-scale networks that support motor (for example, supplementary and premotor cortex) and language functions (for example, prefrontal cortex) have been found, more extensively after lesions acquired during childhood than at adult age. A frequent finding is an increase in the cerebral blood flow response in corresponding regions of the healthy hemisphere during unilateral motor activation or language activation. It is, however, not yet clear whether that is related to functional recovery, and there are several observations indicating that it is often inefficient. Further systematic follow-up studies and therapeutic intervention trials are needed to clarify these issues.