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Andreas H Jacobs

Publications and source records attributed to Andreas H Jacobs.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor gamma agonist treatment.

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.

Administration, Oral↗
PubMed2006

Functional brain imaging in combined motor and sleep disorders.

The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope and magnetic resonance techniques, are powerful tools to investigate possible pathomechanisms of combined sleep and motor dysregulation. In patients with Restless legs syndrome (RLS), only a subtle striatal dopamine deficit was found in PET and SPECT despite a good treatment effect of dopaminergic drugs. Functional MRI suggested a central generator of periodic limb movements during sleep (PLMs) in RLS. In contrast, a marked striatal dopamine depletion was demonstrated in patients with REM sleep behaviour disorder (RBD) as the base for the clinical and nosological overlap of RBD with parkinsonian disorders. PET and SPECT also suggested that sleep abnormalities in Parkinson's disease (PD), such as REM sleep diminution or increased PLMs, are indirect manifestations of the primary striatal dopamine deficiency.

Brain↗
PubMed2006

Early ischemic edema on cerebral computed tomography: its relation to diffusion changes and hypoperfusion within 6 h after human ischemic stroke. A comparison of CT, MRI and PET.

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 (<6 h) hypoattenuation. 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.

Adult↗
PubMed2006

Use of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomas.

PURPOSE: 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 [(11)C]methionine (MET). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2006

Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice.

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 with N-(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.

Alzheimer Disease↗
PubMed2006

Pathophysiological changes of the gastrointestinal tract in ischemic stroke.

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 COCHRANE 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.

Deglutition Disorders↗
PubMed2005

Herpes simplex virus 1 amplicon vector-mediated siRNA targeting epidermal growth factor receptor inhibits growth of human glioma cells in vivo.

In primary glioblastomas and other tumor types, the epidermal growth factor receptor (EGFR) is frequently observed with alterations, such as amplification, structural rearrangements, or overexpression of the gene, suggesting an important role in glial tumorigenesis and progression. In this study, we investigated whether posttranscriptional gene silencing by vector-mediated RNAi to inhibit EGFR expression can reduce the growth of cultured human gli36 glioma cells. To "knock down" EGFR expression, we have created HSV-1-based amplicons that contain the RNA polymerase III-dependent H1 promoter to express double-stranded hairpin RNA directed against EGFR at two different locations (pHSVsiEGFR I and pHSVsiEGFR II). We demonstrate that both pHSVsiEGFR I and pHSVsiEGFR II mediated knock-down of transiently transfected full-length EGFR or endogenous EGFR in a dose-dependent manner. The knock-down of EGFR resulted in the growth inhibition of human glioblastoma (gli36-luc) cells both in culture and in athymic mice in vivo. Cell cycle analysis and annexin V staining revealed that siRNA-mediated suppression of EGFR induced apoptosis. Overall HSV-1 amplicons can mediate efficient and specific posttranscriptional gene silencing.

ErbB Receptors↗
PubMed2005

Migratory neural stem cells for improved thymidine kinase-based gene therapy of malignant gliomas.

Gene therapy of glioma based on viral delivery of herpes simplex virus type I thymidine kinase (HSV-TK) has failed in the clinic because of low transduction efficacy. To circumvent this problem, this study evaluated highly migratory HSV-TK-transduced neural stem cells (NSC) for their ability to kill untransduced glioma cells by a gap junction-mediated bystander effect. The admixture of HSV-TK-transduced NSC to U87MG and LN-18 human malignant glioma cell lines at ratios of 1:10 or 1:1 eliminated more than 50% or 90% of glioma cells in the presence of ganciclovir (25 microM). Glioma cell cytotoxicity required cell-cell contact. Similarly, tumor cell cytotoxicity was observed in two of three primary glioblastoma cell cultures, and the presence of this bystander effect correlated with the expression of connexin 43 in the untransduced glioma target cells. In conclusion, we delineate a role for migratory HSV-transfected NSC to eliminate glioma cells purely by means of the bystander effect.

Bystander Effect↗
PubMed2005

Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity.

BACKGROUND: The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD). OBJECTIVE: To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET). DESIGN: Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD). SETTING: University hospital. PATIENTS: A consecutive sample of patients with PD (N = 31; age at symptom onset, 53.6 +/- 11.3 years) with a wide range of symptom duration and severity at the time of study entry. INTERVENTIONS: Investigation by serial fluorodopa F 18 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function. MAIN OUTCOME MEASURES: Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values. RESULTS: In patients with PD, the decline rate of putaminal [(18)F]fluorodopa K(i) correlated inversely with disease duration before study inclusion (r = -0.46, P = .01) and positively with baseline K(i) values (r = 0.44, P = .01), indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6 +/- 3.2 years was calculated with symptom onset at a putaminal K(i) threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [(18)F]fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects. CONCLUSION: These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.

Adult↗
PubMed2005

Value of gradient-echo magnetic resonance imaging in the diagnosis of familial cerebral cavernous malformation.

BACKGROUND: Cerebral cavernous malformations (CCMs) are congenital vascular anomalies that can cause seizures, intracranial hemorrhages, focal neurological deficits, and migrainelike headaches. Magnetic resonance (MR) imaging has substantially facilitated diagnosis of CCM. It is now widely accepted that familial clustering with an autosomal dominant inheritance pattern should be suspected in cases of multiple lesions. OBJECTIVE: To determine by MR imaging the penetrance of cavernous malformations in a 3-generation family that included 5 members with typical clinical signs and diagnostic findings. METHODS: All family members underwent routine MR T1-weighted and T2-weighted spin-echo sequences in addition to MR T2-weighted gradient-echo sequences. RESULTS: Four family members had been symptomatic with either brainstem bleeding, headaches, or focal neurological signs. The gradient-echo sequences yielded a dramatically higher sensitivity with regard to lesion number and distribution. As in previous reports of familial CCM, an increase in lesion number with increasing age, changes in lesion characteristics, de novo occurrence in serial MR imaging over time, and the phenomenon of anticipation could be confirmed in this family. CONCLUSION: Magnetic resonance gradient-echo sequences should be considered the method of choice for diagnosis of familial CCM.

Adult↗
PubMed2005

Human gene therapy and imaging in neurological diseases.

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.

Gene Expression Profiling↗
PubMed2005

Crossed cerebellar diaschisis in acute human stroke: a PET study of serial changes and response to supratentorial reperfusion.

Crossed cerebellar diaschisis (CCD) is well described in the chronic phase of stroke, but few data describe acute CCD and its serial changes after reperfusion. Using positron emission tomography (PET), we studied acute CCD with respect to supratentorial perfusion and outcome measures. In 19 acute stroke patients receiving intravenous thrombolysis (<3 h), 15O-water PET assessed CCD and supratentorial hypoperfusion volume before thrombolysis, 3, 24 h and 14 days later. Infarct volume at day 14 and NIHSS score at 3 months were assessed. Supratentorial hypoperfusion decreased from 25 cm3 (median) before thrombolysis to 0.1 cm3 at day 14. Baseline CCD was 13.4% and decreased continuously to 6.1% after 14 days. The NIHSS score decreased from 11 to 4 pts after 3 months. Infarct volume was 1.1 cm3. Crossed cerebellar diaschisis correlated to the hypoperfusion volume within the first 24 h after stroke, but not later. Hypoperfusion correlated to outcome measures at the early stage only. In contrast, CCD correlated to outcome values at all four measurements. Reperfusion with recovery of CCD was seen in patients with small infarcts and good clinical outcome and vice versa. Our data suggest that (i) CCD occurs as early as 3 h after stroke and might be reversible; (ii) acute CCD is closely related to the volume of supratentorial hypoperfusion. At later time points, however, CCD is disconnected from supratentorial perfusion but strongly associated to outcome measures; (iii) CCD is not susceptible to non-nutritional reperfusion and adds valuable information to interpret supratentorial reperfusion patterns.

Acute Disease↗
PubMed2005

Imaging in neurooncology.

Imaging in patients with brain tumors aims toward the determination of the localization, extend, type, and malignancy of the tumor. Imaging is being used for primary diagnosis, planning of treatment including placement of stereotaxic biopsy, resection, radiation, guided application of experimental therapeutics, and delineation of tumor from functionally important neuronal tissue. After treatment, imaging is being used to quantify the treatment response and the extent of residual tumor. At follow-up, imaging helps to determine tumor progression and to differentiate recurrent tumor growth from treatment-induced tissue changes, such as radiation necrosis. A variety of complementary imaging methods are currently being used to obtain all the information necessary to achieve the above mentioned goals. Computed tomography and magnetic resonance imaging (MRI) reveal mostly anatomical information on the tumor, whereas magnetic resonance spectroscopy and positron emission tomography (PET) give important information on the metabolic state and molecular events within the tumor. Functional MRI and functional PET, in combination with electrophysiological methods like transcranial magnetic stimulation, are being used to delineate functionally important neuronal tissue, which has to be preserved from treatment-induced damage, as well as to gather information on tumor-induced brain plasticity. In addition, optical imaging devices have been implemented in the past few years for the development of new therapeutics, especially in experimental glioma models. In summary, imaging in patients with brain tumors plays a central role in the management of the disease and in the development of improved imaging-guided therapies.

Animals↗
PubMed2005

18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors.

UNLABELLED: Because of the high glucose metabolism in normal brain tissue 18F-FDG is not the ideal tracer for the detection of gliomas. Methyl-11C-l-methionine (11C-MET) is better suited for imaging the extent of gliomas, because it is transported specifically into tumors but only insignificantly into normal brain. 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been introduced as a proliferation marker in a variety of neoplasias and has promising potential for the detection of brain tumors, because its uptake in normal brain is low. Additionally, the longer half-life might permit differentiation between transport and intracellular phosphorylation. METHODS: PET of 18F-FLT and 11C-MET was performed on 23 patients (age range, 20-70 y) with histologically verified gliomas of different grades. On all patients, conventional MRI was performed, and 16 patients additionally underwent contrast-enhanced imaging. Images were coregistered, and the volumes of abnormality were defined for PET and MRI. Uptake ratios and standardized uptake values (SUVs) of various tumors and regions were assessed by region-of-interest analysis. Kinetic modeling was performed on 14 patients for regional time-activity curves of 18F-FLT from tumorous and normal brain tissue. RESULTS: Sensitivity for the detection of tumors was lower for 18F-FLT than for 11C-MET (78.3% vs. 91.3%), especially for low-grade astrocytomas. Tumor volumes detected by 18F-FLT and 11C-MET were larger than tumor regions displaying gadolinium enhancement (P<0.01). Uptake ratios of 18F-FLT were higher than uptake ratios of 11C-MET (P<0.01). Uptake ratios of 18F-FLT were higher in glioblastomas than in astrocytomas (P<0.01). Absolute radiotracer uptake of 18F-FLT was low and significantly lower than that of 11C-MET (SUV, 1.3+/-0.7 vs. 3.1+/-1.0; P<0.01). Some tumor regions were detected only by either 18F-FLT (7 patients) or 11C-MET (13 patients). Kinetic modeling revealed that 18F-FLT uptake in tumor tissue seems to be predominantly due to elevated transport and net influx. However, a moderate correlation was found between uptake ratio and phosphorylation rate k3 (r=0.65 and P=0.01 for grade II-IV gliomas; r=0.76 and P<0.01 for grade III-IV tumors). CONCLUSION: 18F-FLT is a promising tracer for the detection and characterization of primary central nervous system tumors and might help to differentiate between low- and high-grade gliomas. 18F-FLT uptake is mainly due to increased transport, but irreversible incorporation by phosphorylation might also contribute. In some tumors and tumor areas, 18F-FLT uptake is not related to 11C-MET uptake. In view of the high sensitivity and specificity of 11C-MET PET for imaging of gliomas, it cannot be excluded that 18F-FLT PET was false positive in these areas. However, the discrepancies observed for the various imaging modalities (18F-FLT and 11C-MET PET as well as gadolinium-enhanced MRI) yield complementary information on the activity and the extent of gliomas and might improve early evaluation of treatment effects, especially in patients with high-grade gliomas. Further studies are needed, including coregistered histology and kinetic analysis in patients undergoing chemotherapy.

Adult↗
PubMed2004

Delineation of brain tumor extent with [11C]L-methionine positron emission tomography: local comparison with stereotactic histopathology.

PURPOSE: Methyl-[11C]L-methionine ([11C]MET) positron emission tomography (PET) in brain tumors reflects amino acid transport and has been shown to be more sensitive than magnetic resonance imaging in stereotactic biopsy planning. It remains unclear whether the increased [11C]MET uptake is limited to solid tumor tissue or even detects infiltrating tumor parts. EXPERIMENTAL DESIGN: In 30 patients, a primary or recurrent brain tumor was suspected on magnetic resonance imaging. Patients were investigated with [11C]MET-PET before stereotactic biopsy. The biopsy trajectories were plotted into the [11C]MET-PET images with a newly designed C-based software program. The exact local [11C]MET uptake was determined within rectangular regions of interest of 4 mm in width and length aligned with the biopsy specimen. Individual histologic specimens were rated for the presence of solid tumor tissue, infiltration area, and nontumorous tissue changes. RESULTS: Receiver operating characteristics analysis demonstrated a sensitivity of 87% and specificity of 89% for the detection of tumor tissue at a threshold of 1.3-fold [11C]MET uptake relative to normal brain tissue. At this threshold, only 13 of 100 tumor positive specimen were false negative mainly in grade 2 astrocytoma. In grade 2 astrocytoma, mean [11C]MET uptake in the infiltration area was significantly higher than in solid tumor tissue (P < 0.003). CONCLUSIONS: [11C]MET-PET detects solid parts of brain tumors, as well as the infiltration area at high sensitivity and specificity. High [11C]MET uptake in infiltrating tumor of astrocytoma WHO grade 2 reflects high activity in this tumor compartment. Molecular imaging, with [11C]MET, will guide improved management of patients with brain tumors.

Adult↗
PubMed2004

Probability of cortical infarction predicted by flumazenil binding and diffusion-weighted imaging signal intensity: a comparative positron emission tomography/magnetic resonance imaging study in early ischemic stroke.

BACKGROUND AND PURPOSE: The differentiation of reversible from irreversible ischemic damage is essential for identifying patients with acute ischemic deficits who may benefit from therapeutic interventions. Diffusion-weighted imaging (DWI) has become the method of choice to detect ischemic lesions. Positron emission tomography (PET) of the central benzodiazepine receptor ligand 11C flumazenil (FMZ) has been shown to be a reliable marker of neuronal integrity. These 2 imaging parameters were compared with respect to the probability to predict cortical infarction in early ischemic stroke. METHODS: In 12 patients with acute stroke, results from DWI (median, 6.5 hours after symptom onset) and FMZ-PET (interval, 85 minutes between DWI and PET) were compared with infarct extension 24 to 48 hours after onset of stroke on T2-weighted magnetic resonance imaging (T2-MRI). Probability curves predictive of eventual infarction were computed using respective DWI, FMZ, and apparent diffusion coefficient (ADC) values for voxels of interest (VOI) later classified as representing infarcted or noninfarcted tissue. RESULTS: Ninety-five percent limits predictive of cortical infarction were determined for relative FMZ binding (< or =3.2), DWI signal intensity (> or =1.18), and ADC values (< or =0.83). Cortical regions with values beyond these 95% limits did not necessarily overlap with nor were fully congruous with final cortical infarct volumes. The respective median volumes for these regions were FMZ median 10.9, range 0 to 99.7 cm3; DWI median 15.2, range 0 to 116.0 cm3; ADC median 12.4, range 0 to 112.7 cm3; and final infarct median 14.9, range 0 to 114.7 cm(3). Overall, 83.5% of the final infarct, on average, was predicted by decreased FMZ binding, 84.7% by increased DWI signal intensity, and 70.9% by a decreased ADC value. The portions of the final infarct not predicted in the early investigation (false-negatives) were 4.8 cm3 (median) for FMZ, 3.7 cm3 for DWI, and 6.0 cm3 for ADC. The false-positive volumes not included in the final infarct were 0 cm3 (median) for FMZ, 5.1 cm3 for DWI, and 3.6 cm3 for ADC. CONCLUSIONS: These results indicate that FMZ-PET and DWI are comparable in the prediction of probability of ischemic cortical infarction, but FMZ-PET carries a lower probability of false-positive prediction. The final infarcts include tissue not identified by these imaging modalities; at the time of the study, these tissue compartments are viable and could benefit from treatment. The discrepancy in predictive probability could be related to the fundamental difference of the measured variables: benzodiazepine receptor activity is a reliable marker of neuronal integrity in the cortex, and movement of water molecules in the extracellular space might be a more variable indicator of tissue damage.

Adult↗
PubMed2004

Role for neuronal insulin resistance in neurodegenerative diseases.

Impairment of insulin signaling in the brain has been linked to neurodegenerative diseases. To test the hypothesis that neuronal insulin resistance contributes to defects in neuronal function, we have performed a detailed analysis of brain/neuron-specific insulin receptor knockout (NIRKO) mice. We find that NIRKO mice exhibit a complete loss of insulin-mediated activation of phosphatidylinositol 3-kinase and inhibition of neuronal apoptosis. In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3 beta, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases. Nevertheless, these animals exhibit no alteration in neuronal proliferation/survival, memory, or basal brain glucose metabolism. Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3 beta activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease.

Animals↗