Biomedical subjects

W D Heiss

Publications and source records attributed to W D Heiss.

At least 37 records · Page 2Linked to original sources

PubMed2002

Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET.

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimer's disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.

Aged↗

PubMed2002

Stroke--acute interventions.

The reduction of blood flow to parts of the brain is the cause of ischemic stroke leading to functional deficits and, if prolonged, to irreversible neurological and morphological defects. The fast reperfusion, therefore is the most important therapeutic strategy and was proven to be effective in clinical trials. Steps to intervene with secondary biochemical, molecular, or inflammatory disturbances were not successful so far. Since direct therapeutic interventions are limited, the general management of the stroke victim is of utmost importance--and was shown to be most successful in dedicated stroke units. Acute therapeutic interventions in ischemic stroke can only be successful as long as tissue in the area of the ischemic compromise is still viable. The area of irreversible damage can be identified and distinguished from the penumbral zone, i.e., tissue with impaired function but preserved morphology by functional imaging modalities, like positron emission tomography (PET) or perfusion-(PW) and diffusion-weighted (DW) magnetic resonance imaging (MRI). In such studies it was demonstrated that a large portion of the final infarct is irreversibly affected in the first few hours in many patients. A considerable tissue volume is viable but critically hypoperfused; a smaller portion of the final infarct is sufficiently perfused and in this area secondary and delayed biochemical and molecular mechanisms contribute to the damage. Based on this concept the improvement of perfusion within the time window of opportunity must be the primary goal in treatment of ischemic stroke, and neuroprotective and other strategies can only play a supportive and additive role. That this is the case can be seen from the results of many controlled therapeutic trials, in which up to now only thrombolytic therapy with a 3 h time window for systemic and a 6 h time window for intraarterial application proved its efficacy, whereas all trials with neuroprotective, anti-inflammatory or anti-apoptotic strategies failed. Since the direct treatment strategies are limited the acute management of stroke victims is of utmost importance: This can be achieved optimally in dedicated stroke units in which the outcome was significantly improved over the regular care. It is still to be investigated if invasive strategies--e.g., craniectomy and hypothermia--or the combination of reperfusion and neuroprotective therapy can improve the outcome after ischemic stroke.

Ancrod↗

PubMed2002

Prognostic relevance of quantitative topographical EEG in patients with poststroke aphasia.

In this prospective study we analyzed the prognostic value of topographical quantitative EEG (qEEG) in poststroke aphasia. Twenty-three right-handed patients (ages 56 +/- 12 years) with different types of aphasia were studied. Quantitative EEG under resting conditions and an aphasia test battery were applied twice, 2 and 8 weeks after a stroke. EEG power fast Fourier transform was performed for delta (2-3.5 Hz), theta (4-7.5 Hz), alpha (8-13 Hz), and beta (13.5-20 Hz) frequency bands. EEG abnormalities within and outside speech relevant areas are related to restitution of poststroke aphasia. In the ischemic regions they indicate local disturbances; outside they reflect failures in neuronal networks involved in the generation and propagation of the alpha rhythm.

Adult↗

PubMed2002

Molecular imaging of gliomas.

Gliomas are the most common types of brain tumors. Although sophisticated regimens of conventional therapies are being carried out to treat patients with gliomas, the disease invariably leads to death over months or years. Before new and potentially more effective treatment strategies, such as gene- and cell-based therapies, can be effectively implemented in the clinical application, certain prerequisites have to be established. First of all, the exact localization, extent, and metabolic activity of the glioma must be determined to identify the biologically active target tissue for a biological treatment regimen; this is usually performed by imaging the expression of up-regulated endogenous genes coding for glucose or amino acid transporters and cellular hexokinase and thymidine kinase genes, respectively. Second, neuronal function and functional changes within the surrounding brain tissue have to be assessed in order to save this tissue from therapy-induced damage. Third, pathognomonic genetic changes leading to disease have to be explored on the molecular level to serve as specific targets for patient-tailored therapies. Last, a concerted noninvasive analysis of both endogenous and exogenous gene expression in animal models as well as the clinical setting is desirable to effectively translate new treatment strategies from experimental into clinical application. All of these issues can be addressed by multi-modal radionuclide and magnetic resonance imaging techniques and fall into the exciting and fast growing field of molecular and functional imaging. Noninvasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging may reveal the assessment of the "location," "magnitude," and "duration" of therapeutic gene expression and its relation to the therapeutic effect. Detailed reviews on molecular imaging have been published from the perspective of radionuclide imaging (Gambhir et al., 2000; Blasberg and Tjuvajev, 2002) as well as magnetic resonance and optical imaging (Weissleder, 2002). The present review focuses on molecular imaging of gliomas with special reference on the status and perspectives of imaging of endogenous and exogenously introduced gene expression in order to develop improved diagnostics and more effective treatment strategies of gliomas and, in that, to eventually improve the grim prognosis of this devastating disease.

Animals↗

PubMed2002

Molecular and functional imaging technology for the development of efficient treatment strategies for gliomas.

Gliomas are the most common types of brain tumors, which invariably lead to death over months or years. Before new and potentially more effective treatment strategies, such as gene therapy, can be effectively introduced into clinical application the following goals must be reached: (1) the determination of localization, extent and metabolic activity of the glioma; (2) the assessment of functional changes within the surrounding brain tissue; (3) the identification of genetic changes on the molecular level leading to disease; and in addition (4) a detailed non-invasive analysis of both endogenous and exogenous gene expression in animal models and in the clinical setting. Non-invasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging techniques may reveal the assessment of the location, magnitude and duration of therapeutic gene expression and its relation to the therapeutic effect. Here, we review the main principles of PET imaging and its key roles in neurooncology research.

Brain Neoplasms↗

PubMed2002

Low interferon gamma producers are better treatment responders: a two-year follow-up of interferon beta-treated multiple sclerosis patients.

As response to interferon beta (IFNB) treatment, a 50% reduction of the mean relapse rate compared to pretreatment values has been reported. However, individual responses vary considerably, ranging from no reduction in exacerbation frequency to complete suppression of relapses for at least two years. At the moment, valid predictors for IFNB response are lacking. Here we present a prospective evaluation of 33 patients with primary relapsing multiple sclerosis who were followed for two years of IFNB treatment A low interferon gamma (IFG) production before treatment predicted a two-year term without exacerbations in 68.8% of cases correctly, whereas a high pretreatment IFG production implied the risk of at least one relapse in the first two years in 70.6%. These preliminary results encourage further evaluation of IFG as predictor of an IFNB treatment response.

Adjuvants, Immunologic↗

PubMed2001

Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas.

In clinical gene-therapy trials for recurrent glioblastomas, transduction of the herpes simplex virus type-1 thymidine kinase (HSV-1-tk) gene with subsequent prodrug activation by ganciclovir was found to be safe, but clinical response was poor. We used positron-emission tomography (PET) with I-124-labelled 2'-fluoro-2'-deoxy-1b-D-arabino-furanosyl-5-iodo-uracil ([124I]-FIAU)-a specific marker substrate for gene expression of HSV-1-tk-to identify the location, magnitude, and extent of vector-mediated HSV-1-tk gene expression in a phase I/II clinical trial of gene therapy for recurrent glioblastoma in five patients. The extent of HSV-1-tk gene expression seemed to predict the therapeutic response. The expression of an exogenous gene introduced by gene therapy into patients with gliomas can be monitored non-invasively by PET.

Aged↗

PubMed2001

Experimental observation of the topological structure of exceptional points.

We report on a microwave cavity experiment where exceptional points (EPs), which are square root singularities of the eigenvalues as function of a complex interaction parameter, are encircled in the laboratory. The real and imaginary parts of an eigenvalue are given by the frequency and width of a resonance and the eigenvectors by the field distributions. Repulsion of eigenvalues--always associated with EPs--implies frequency anticrossing (crossing) whenever width crossing (anticrossing) is present. The eigenvalues and eigenvectors are interchanged while encircling an EP, but one of the eigenvectors undergoes a sign change which can be discerned in the field patterns.

Journal Article↗

PubMed2001

Plasticity of language networks in patients with brain tumors: a positron emission tomography activation study.

We investigated plasticity of language networks exposed to slowly evolving brain damage. Single subject 0-15-water language activation positron emission tomography studies were analyzed in 61 right-handed patients with brain tumors of the left hemisphere, and 12 normal controls. In controls, activations were found in left Brodmann's Area (BA)44 and BA45, superior posterior temporal gyrus bilaterally, and right cerebellum. Patients additionally activated left BA46, BA47, anterior insula, and left cerebellum. Superior temporal activation was less frequent, and activations in areas other than posterior temporal gyrus were found bilaterally. Frontolateral activations within the nondominant hemisphere were only seen in patients (63%) with frontal or posterior temporal lesions. Laterality indices of frontolateral cortex showed reversed language dominance in 18% of patients. Laterality indices of the cerebellum were negatively correlated with language performance. Two compensatory mechanisms in patients with slowly evolving brain lesions are described: An intrahemispheric mechanism with recruitment of left frontolateral regions other than classic language areas; and an interhemispheric compensatory mechanism with frontolateral activation in the nondominant hemisphere. The latter one was only found in patients with frontal or posterior temporal lesions, thus supporting the hypothesis that right frontolateral activations are a disinhibition phenomenon.

Adult↗

PubMed2001

PET measurement of cerebral acetylcholine esterase activity without blood sampling.

Measurement of cerebral acetylcholine esterase (AChE) activity is of clinical interest for the differential diagnosis of memory disorders and dementia. We developed and tested a non-invasive method for quantitation of regional cortical AChE activity with carbon-11-labelled N-methyl-4-piperidyl acetate (11C-MP4A) that does not require arterial blood sampling. AChE activity was measured in terms of the rate constant for hydrolysis of 11C-MP4A (k3). The physiological model is based on the very high AChE activity in the basal ganglia, which are used as a reference structure. Non-invasive k3 was compared with k3 determined with a standard technique by fitting kinetic tissue and metabolite-corrected plasma data in nine subjects with and without dementia. Across all regional values, a very high correlation of 0.92 was found, with a tendency towards moderate underestimation of k3 by 5%-14% with the non-invasive technique as compared to the invasive technique. In addition to its advantages with respect to practicability, the new non-invasive technique overcomes problems of the invasive technique that are related to interindividual variation of delay times between cerebral and peripheral tracer arrival and measurement of very small amounts of non-hydrolysed tracer in plasma samples.

Acetates↗

PubMed2001

Increased pineal Fdopa uptake is related to severity of Parkinson's disease--a PET study.

We investigated regional L-3,4-dihydroxy-6-[18F]fluoro-phenyl-alanine (Fdopa) uptake within the pineal gland using co-registration of Fdopa PET and MRI images. Data from 12 early Parkinson's disease (PD) and 9 advanced PD patients were compared with those from 13 age-matched healthy controls. We found a significant increase of Fdopa influx constants (Ki) and relative Fdopa tracer activity in the pineal gland of PD patients. Additionally, significant correlations were found between Ki and the Hoehn and Yahr (H&Y) scores, and between the relative Fdopa activity and the parameters disease duration, H&Y disease score and Unified Parkinson's Disease Rating Scale (UPDRS). Our studies in patients with PD indicate a participation of extrastriatal dopaminergic structures within the scope of pathophysiological processes in PD. The result may be explained as a compensatory upregulation of monoaminergic transmitter systems outside the basal ganglia. Increased Fdopa uptake in the pineal gland may reflect pineal dysfunction in PD patients.

Adult↗

PubMed2001

Elevation of extracellular glutamate in the final, ischemic stage of progressive epidural mass lesion in cats.

Epidural mass lesions may cause ischemia due to progressive intracranial hypertension. In order to investigate the impact of intracranial pressure on accumulation of neuroactive substances, we gradually raised intracranial pressure in five halothane anesthetized cats by inflation of an epidural balloon. We evaluated in the parietal cortex contralateral to the site of balloon inflation, alterations of extracellular glutamate and purine catabolites and of the lactate/pyruvate ratio in relation to changes of intracranial, cerebral perfusion and mean arterial blood pressure. In a complementary experiment, regional cerebral blood flow was assessed by sequential positron emission tomography. In this simplified mass lesion model, extracellular glutamate increased in all cats at a late, critical stage after tentorial herniation, when intracranial pressure had increased to more than 90 mm Hg, cerebral perfusion pressure had decreased below 40-50 mm Hg. Positron emission tomography assessments revealed that the ischemic threshold for glutamate accumulation was in the range of 15-20 mL/100 g/min. Purine catabolites and the lactate/pyruvate ratio increased somewhat earlier than glutamate, but also after reaching the critical, terminal stage. We conclude that in this model of progressive epidural compression, glutamate-mediated excitotoxic processes at sites remote from the initial focal lesion depend on processes such as delayed ischemia in combination with tentorial herniation and systemic hypotension. These processes seem to be initiated by a decrease of cerebral perfusion pressure below a threshold of 40-50 mm Hg.

Animals↗

PubMed2001

Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia.

Active treatment of acute ischaemic stroke can only be successful as long as tissue in the area of ischaemic compromise is still viable. Therefore, the identification of the area of irreversible damage, and its distinction from the penumbral zone, may improve the estimation of the potential efficacy of various therapeutic strategies. Ten patients (seven male, three female, aged 52-75 years) with acute ischaemic stroke, in whom MRI delineated an infarct involving the cortex 3 weeks after the attack, were studied by [(11)C]flumazenil (FMZ) PET to assess their neuronal integrity, and regional cerebral blood flow (CBF) was measured by H(2)(15)O PET 2-12 h (median interval 6 h) after onset of symptoms. Cortical volumes of interest (3 mm radius) were placed on co-registered CBF, FMZ and on late MRI scans. Using initial CBF and FMZ binding data from volumes of interest finally located within or outside the cortical infarct, cumulative probability curves were computed to predict eventual infarction or non-infarction. Positive (at least 95% chance of infarct) and negative (at least 95% chance of non-infarct) prediction limits for CBF (4.8 and 14.1 ml/100 g/min, respectively) and for FMZ binding (3.4 and 5.5 times the mean of normal white matter, respectively) were determined to define the penumbral range. Using the lower FMZ binding threshold of 3.4 for irreversible tissue damage and the upper CBF value of 14.1 ml/ 100 g/min for the threshold of critical perfusion at or above which tissue will likely be preserved, various cortical subcompartments were identified: of the final cortical infarct (median size 25.7 cm(3)) a major portion comprising, on average, 55.1% showed FMZ binding critically decreased, thus predicting necrosis. In 20.5% of the final infarct, on average, CBF was in the penumbral range (<14.1 ml/100 g/min) and FMZ binding was above the critical threshold of irreversible damage. Only 12.9% of the final infarct exhibited neuronal integrity and CBF values above the penumbral range. Therefore, most of the final infarct is irreversibly damaged already at the time of the initial evaluation, when studied several hours after stroke onset. A much smaller portion is still viable but suffers from insufficient blood supply: this tissue may be salvaged by effective reperfusion. Only an even smaller compartment is viable and sufficiently perfused, but eventually becomes necrotic, mainly owing to delayed mechanisms, and may benefit from neuroprotective or other measures targeted at secondary damage. Therefore, early reperfusion is crucial in acute ischaemic stroke.

Aged↗

PubMed2001

Adenosine in relation to calcium homeostasis: comparison between gray and white matter ischemia.

In vitro studies suggest that adenosine may attenuate anoxic white matter damage as an intrinsic protective substance. The authors investigated ischemic alterations of purines in relation to tissue depolarization and extracellular calcium and amino acid concentrations in vivo using microdialysis and ion-selective electrodes in cortical gray and subcortical white matter of 10 cats during 120 minutes of global brain ischemia. Immediately on induction of ischemia, regional cerebral blood flow ceased in all cats in both gray and white matter. The direct current potential rapidly decreased, the decline being slower and shallower in white matter. Extracellular calcium levels decreased in gray matter. In contrast, they first increased in white matter and started to decrease below control levels only after approximately 30 minutes. Adenosine levels transiently increased in both tissue compartments; the peak was delayed by 30 minutes in white matter. Thereafter, levels declined faster in gray than in white matter and remained elevated in the latter tissue compartment. Inosine and hypoxanthine elevations were progressive in both regions but smaller in white matter. Levels of gamma-aminobutyric acid, another putatively protective agent, steadily increased, starting immediately in gray matter and delayed by almost 1 hour in white matter. The delayed and prolonged accumulation of adenosine correlates with a slower adenosine triphosphate breakdown in white matter ischemia and may result in protection of white matter by suspending cellular calcium influx.

Adenosine↗

PubMed2001

Imaging in cerebrovascular disease.

Various functional imaging modalities can be applied in acute ischaemic stroke to identify functionally impaired, but morphologically preserved tissue (i.e. the penumbra), and to distinguish it from irreversibly damaged tissue. Flow thresholds for irreversible tissue destruction resulting in functional impairment, as determined by positron emission tomography, perfusion and diffusion-weighted magnetic resonance imaging, single-photon computed tomography and xenon computed tomography, were comparable and ranged between 5 and 12 ml/100 g per min for the lower and 14 and 22 ml/100 g per min for the upper limit of penumbra. These imaging modalities help to select patients for thrombolytic therapy and provide evidence for the effect of this treatment on critically perfused tissue. They can also serve as surrogate markers in the evaluation of therapeutic efficacy. Further progress in interventional neuroradiology has been achieved with intra-arterial thrombolysis, which has become a treatment option beyond the 3-h therapeutic window in acute ischaemic stroke. Angioplasty and stenting of stenosis of arteries that supply the brain with blood have reached a point in their development at which a randomized trial to compare these treatments with vascular surgery is warranted.

Angiography, Digital Subtraction↗

PubMed2001

Relevance of experimental ischemia in cats for stroke management: a comparative reevaluation.

Repeat studies in animal models of acute focal ischemia can be compared to incidental studies in the course of ischemic stroke in order to shed light on the development of changes causing ischemic infarcts or recovery of critically perfused tissue. Positron emission tomography (PET) studies of regional cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction (OEF), cerebral metabolic rate of glucose and flumazenil (FMZ) binding in the cat middle cerebral artery occlusion (MCAO) model and in patients with acute ischemic hemispheric stroke were reviewed. After permanent MCAO, the development of "misery-perfused" penumbral tissue and its centrifugal conversion into necrosis could be demonstrated, resembling focal pathophysiological changes in patients with ischemic attacks. In the experimental model and in vascular insults in humans, a chance of recovery existed if collateral perfusion developed spontaneously within the first hours. In transient MCAO, reperfusion was only effective in preventing infarction when it was initiated as long as misery perfusion persisted; in these cases tissue was salvaged and large infarcts did not develop. In the other instances when oxygen metabolism broke down, and an increased OEF was no longer seen, reperfusion even at levels above preocclusion had no effect, and large space-occupying infarcts developed. These experimental findings are comparable to the variable outcome after thrombolytic therapy; if reperfusion is achieved within the therapeutic window of tissue viability, large infarcts are prevented and complete or partial recovery can be achieved. In the experimental model of focal ischemia and in human stroke, FMZ can be utilized as a marker of neuronal integrity. If FMZ binding in the cortex is decreased below 4 times the mean value of white matter in the acute stage, permanent infarcts were observed on late CT/MRI; this irreversible damage could not be prevented by thrombolytic therapy. These results demonstrated that PET studies in suitable ischemia models in cats can help to explain various courses and diverging outcomes of acute ischemic stroke. Comparable findings from experimental ischemia and human stroke may affect the selection of appropriate therapeutic strategies.

Animals↗

PubMed2001

Intravenous thrombolysis in proximal middle cerebral artery occlusion.

Subgroup analyses of data from an open-label study of intravenous recombinant tissue plasminogen activator (rt-PA) administered to stroke patients were performed. Clinical outcome and incidence of intracranial hemorrhage were evaluated in 20 patients diagnosed by transcranial Doppler ultrasound as having proximal middle cerebral artery (MCA) occlusion. Additionally early infarct signs and size of final infarction were assessed. A favorable outcome (mRS 0-2) was seen in 30% of all patients. The incidence of symptomatic intracranial hematoma (10%) in patients with proximal MCA occlusion was higher than the overall hemorrhage rate of intravenous rt-PA treatment, but comparable to the data on intra-arterial thrombolysis in this stroke subgroup. All patients except 1 developed ischemic infarction in the MCA territory. Intravenous rt-PA treatment within 3 h may also be effective in patients with proximal MCA occlusion. The risk of intracerebral hematoma does not seem to be greater than in intra-arterial thrombolysis.

Aged↗

PubMed2001

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.

Animals↗