Decreased cerebral α4ß2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography.

PURPOSE: Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer's disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4ß2* nicotinic acetylcholine receptor (α4ß2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD. METHODS: Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP(ND)) of 2-[(18)F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis. RESULTS: Both patients with AD and MCI showed a significant reduction in 2-[(18)F]FA-85380 BP(ND) in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[(18)F]FA-85380 BP(ND) correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[(18)F]FA-85380 BP(ND). CONCLUSION: 2-[(18)F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4ß2* nAChRs which seems to be an early event in AD. In addition, 2-[(18)F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.

Kinetic analyses of [123I]IBZM SPECT for quantification of striatal dopamine D2 receptor binding: a critical evaluation of the single-scan approach.

BACKGROUND: Dopamine-D2 receptor imaging with single-photon emission computed tomography (SPECT) and [(123)I]IBZM is of great interest for basic and applied neurosciences. However, the use of kinetic analyses for quantification of dynamic [(123)I]IBZM SPECT and the validity of the commonly employed single-scan pseudo-equilibrium analysis (PsEA) have not been appropriately investigated. The present study addresses these shortcomings. METHODS: Ten movement disorder patients underwent dynamic SPECT (142 min) after single-bolus [(123)I]IBZM injection. Kinetic analyses comprise: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2) and non-invasive graphical analysis (NIGA). Simplified single-scan analyses were performed at peak time of specific binding (peak-equilibrium analysis, PEA) and during pseudo-equilibrium (PsEA). RESULTS: SRTM and MRTM are compromised by the high noise level of dynamic SPECT. SRTM2 and MRTM2 yielded reliable binding potential estimates that agreed excellently (mean difference=-0.1+/-1.0%, R(2)>0.99). Concordance between SRTM/MRTM and SRTM2/MRTM2 was high in cases in which SRTM/MRTM provided reliable results (SRTM2 or MRTM2 vs. SRTM: 3.7+/-5.0%, R(2)=0.88). NIGA was affected by a negative bias (-9.1+/-6.3%, R(2)=0.75; MRTM2 as reference) or high variability (-1.2+/-7.4%, R(2)=0.71) for analyses without and with inclusion of the k(2)'-term, respectively. PsEA showed a positive bias and low correlation in comparison with SRTM2/MRTM2 (7.6+/-10.8%, R(2)=0.59), which was considerably improved for PEA (-2.7+/-7.6%, R(2)=0.72). MRTM2 provided parametric images with minimal bias suited for voxel-wise statistical analyses. CONCLUSIONS: MRTM2 and SRTM2 can be reliably applied to dynamic [(123)I]IBZM SPECT. PEA is a suitable method for clinical routine, while our results discourage the use of PsEA (current clinical standard).

Effect of progenitor cells on myocardial perfusion and metabolism in patients after recanalization of a chronically occluded coronary artery.

UNLABELLED: Even after recanalization of a chronic total coronary occlusion, functional recovery is incomplete and parts of the myocardium remain hypoperfused. In this randomized, placebo-controlled, and double-blinded study, we investigated relative changes in myocardial perfusion and glucose metabolism induced by intracoronary administration of blood-derived circulating progenitor cells (CPCs), compared with the natural course in a control group after recanalization of total coronary occlusion. METHODS: After recanalization of total coronary occlusion, 26 patients were randomly assigned to the CPC treatment or placebo group. Regional myocardial perfusion and glucose metabolism were assessed by 99mTc-tetrofosmin SPECT and 18F-FDG PET at baseline (after recanalization of total coronary occlusion) and 3 mo after the administration of 69 +/- 14 x 10(6) CPCs or cell-free serum, respectively. Segments were classified as "normal," "perfusion-metabolism mismatch" (dysfunctional segments with a 99mTc-tetrofosmin-18F-FDG mismatch), or "scar." RESULTS: In contrast to the placebo group, CPC administration resulted in a significant decrease in the number of segments with a perfusion-metabolism mismatch, from 3.0 +/- 0.5 to 1.7 +/- 0.6 segments (P < 0.05 vs. baseline). Of the normal segments at baseline, 2.7% in the CPC group and 30% in the placebo group revealed a perfusion-metabolism mismatch at follow-up after 3 mo (P < 0.05 vs. placebo). CONCLUSION: Intracoronary administration of CPCs significantly reduces the amount of myocardium with a perfusion-metabolism mismatch and prevents areas with normal perfusion and metabolism after recanalization of total coronary occlusion from becoming dysfunctional during the next 3 mo. These results show that PET and SPECT can be used to monitor the effect of progenitor cells on myocardial integrity. More important, they provide evidence supporting expansion of the use of progenitor cell treatment to chronic coronary artery disease.

Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study.

Transplantation of blood-derived circulating progenitor cells (CPC) has been shown to improve myocardial regeneration after myocardial infarction. It remains unclear whether CPC transplantation exerts beneficial effects also in patients with chronic myocardial ischemia. We initiated a randomized, double-blind, placebo-controlled study evaluating the impact of intracoronary infusion of CPCs on coronary vasomotion and left ventricular (LV) function in patients after recanalization of chronic coronary total occlusion (CTO). After recanalization of CTO, 26 patients (age, 63+/-2 years; LV ejection fraction, 53+/-2%) were randomly assigned to the treatment (intracoronary transplantation of CPCs) or control group. Coronary flow reserve in response to adenosine (2.4 mg/min) was measured in the target vessel at the beginning of the study and after 3 months. LV function and infarct size were assessed by MRI and metabolism by 18F deoxyglucose positron emission tomography. CPC application resulted in an increase in coronary flow reserve by 43% from 2.3+/-0.3 to 3.3+/-0.5 (P<0.05 versus beginning and control). At 3 months, the number of hibernating segments in the target region (from 2.9+/-0.6 to 2.0+/-0.6 segments, P<0.05 versus beginning and control) had declined in the treatment group, whereas no significant changes were observed in the control group. MRI revealed a reduction in infarct size by 16% and an increase in LV ejection fraction by 14% in the treatment group (from 51.7+/-3.7 to 58.9+/-3.2%; P<0.05 versus beginning and control) because of an augmented wall motion in the target region. Hence, intracoronary transplantation of CPCs after recanalization of CTO results in an improvement of macro- and microvascular function and contributes to the recruitment of hibernating myocardium.

Measurement of the alpha4beta2* nicotinic acetylcholine receptor ligand 2-[(18)F]Fluoro-A-85380 and its metabolites in human blood during PET investigation: a methodological study.

2-[(18)F]fluoro-A-85380 (2-[(18)F]FA) is a new radioligand for noninvasive imaging of alpha4beta2* nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET) in human brain. In most cases, quantification of 2-[(18)F]FA receptor binding involves measurement of free nonmetabolized radioligand concentration in blood. This requires an efficient and reliable method to separate radioactive metabolites from the parent compound. In the present study, three analytical methods, thin layer chromatography (TLC), high-performance liquid chromatography (HPLC) and solid phase extraction (SPE) have been tested. Reversed-phase TLC of deproteinized aqueous samples of plasma provides good estimates of 2-[(18)F]FA and its metabolites. However, because of the decreased radioactivity in plasma samples, this method can be used in humans over the first 2 h after radioligand injection only. Reliable quantification of the parent radioligand and its main metabolites was obtained using reversed-phase HPLC, followed by counting of eluted fractions in a well gamma counter. Three main and five minor metabolites of 2-[(18)F]FA were detected in human blood using this method. On average, the unchanged 2-[(18)F]FA fraction in plasma of healthy volunteers measured at 14, 60, 120, 240 and 420 min after radioligand injection was 87.3+/-2.2%, 74.4+/-3%, 68.8+/-5%, 62.3+/-8% and 61.0+/-8%, respectively. In patients with neurodegenerative disorders, the values corresponding to the three last time points were significantly lower. The fraction of nonmetabolized 2-[(18)F]FA in plasma determined using SPE did not differ significantly from that obtained by HPLC (+gamma counting) (n=73, r=.95). Since SPE is less time-consuming than HPLC and provides comparable results, we conclude that SPE appears to be the most suitable method for measurement of 2-[(18)F]FA parent fraction during PET investigations.

Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial.

BACKGROUND: Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. We therefore conducted a randomized study to compare the effects of exercise training versus standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical end point (death of cardiac cause, stroke, CABG, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in hospitalization). METHODS AND RESULTS: A total of 101 male patients aged < or =70 years were recruited after routine coronary angiography and randomized to 12 months of exercise training (20 minutes of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in US dollars) needed to improve the Canadian Cardiovascular Society class by 1 class. Exercise training was associated with a higher event-free survival (88% versus 70% in the PCI group, P=0.023) and increased maximal oxygen uptake (+16%, from 22.7+/-0.7 to 26.2+/-0.8 mL O2/kg, P<0.001 versus baseline, P<0.001 versus PCI group after 12 months). To gain 1 Canadian Cardiovascular Society class, 6956 dollars was spent in the PCI group versus 3429 dollars in the training group (P<0.001). CONCLUSIONS: Compared with PCI, a 12-month program of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably owing to reduced rehospitalizations and repeat revascularizations.

Reduced alpha4beta2*-nicotinic acetylcholine receptor binding and its relationship to mild cognitive and depressive symptoms in Parkinson disease.

CONTEXT: Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs). OBJECTIVE: To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD. DESIGN: Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography. SETTING: Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany. PARTICIPANTS: Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers. MAIN OUTCOME MEASURES: Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed. RESULTS: In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum. CONCLUSIONS: There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.

Acetylcholine receptors in dementia and mild cognitive impairment.

PURPOSE: To clarify whether changes in the cholinergic transmission occur early in the course of Alzheimer's disease (AD), we carried out positron emission tomography (PET) with the radioligand 2-[(18)F]F-A-85380, which is supposed to be specific for alpha4beta2 nicotinic acetylcholine receptors (nAChRs). METHOD: We included patients with moderate to severe AD and patients with amnestic mild cognitive impairment (MCI), presumed to present preclinical AD. RESULTS: Both patients with AD and MCI showed significant reductions in alpha4beta2 nAChRs in brain regions typically affected by AD pathology. These findings indicate that a reduction in alpha4beta2 nAChRs occurs during early symptomatic stages of AD. The alpha4beta2 nAChR availability in these regions correlated with the severity of cognitive impairment, indicating a stage sensitivity of the alpha4beta2 nAChR status. CONCLUSION: Together, our results provide evidence for the potential of 2-[(18)]F-A-85380 nAChR PET in the diagnosis of patients at risk for AD. Because of the extraordinary long acquisition time with 2-[(18)F]F-A-85380, we developed the new alpha4beta2 nAChR-specific radioligands (+)- and (-)-[(18)F]norchloro-fluoro-homoepibatidine (NCFHEB) and evaluated them preclinically. (-)-[(18)F]NCFHEB shows twofold higher brain uptake and significantly shorter acquisition times. Therefore, (-)-[(18)F]NCFHEB should be a suitable radioligand for larger clinical investigations.

In vivo measurement of nicotinic acetylcholine receptors with [18F]norchloro-fluoro-homoepibatidine.

Functional changes of nicotinic acetylcholine receptors (nAChR) are important during age-related neuronal degeneration. Recent studies demonstrate the applicability of the nAChR ligand 2-[(18)F]F-A-85380 for neuroimaging of patients with dementias. However, its binding kinetics demands a 7-h acquisition time limiting its practicality for clinical PET studies. Thus, the authors developed [(18)F]norchloro-fluoro-homoepibatidine ([(18)F]NCFHEB) for nAChR imaging. The kinetics of the two enantiomers of [(18)F]NCFHEB were compared with 2-[(18)F]F-A85380 in porcine brain to evaluate their potential for human neuroimaging. Twenty-four juvenile female pigs were studied with PET using [(18)F]NCFHEB. Nine animals received an additional i.v. injection (1 mg/kg) of the nAChR agonist A81418 before radiotracer administration followed by infusion (2 mg/kg/7h) thereafter. Several compartment models were applied for quantification. (-)- and (+)-[(18)F]NCFHEB showed a twofold to threefold higher brain uptake than 2-[(18)F]F-A-85380. All three radiotracers displayed spatially heterogeneous binding kinetics in regions with high, moderate, or low specific binding. The equilibrium of specific binding of (-)-[(18)F]NCFHEB was reached earlier than that of (+)-[(18)F]NCFHEB or 2-[(18)F]F-A85380. Continuous administration of the nAChR agonist A81418 inhibited the specific binding of (-)- and (+)-[(18)F]NCFHEB but not of 2-[(18)F]F-A85380. The peripheral metabolism of (+)-[(18)F]NCFHEB proceeded somewhat slower than that of the other radiotracers. Both enantiomers of [(18)F]NCFHEB are appropriate radiotracers for neuroimaging of nAChR in pigs. Their binding profile in vivo appears to be more selective than that of 2-[(18)F]F-A85380. (-)-[(18)F]NCFHEB offers a faster equilibrium of specific binding than 2-[(18)F]F-A85380.

Changes in myocardial perfusion due to physical exercise in patients with stable coronary artery disease.

PURPOSE: Percutaneous transluminal coronary angioplasty (PTCA) is one of the main therapy options for patients with coronary artery disease (CAD), resulting in an improvement in myocardial perfusion and exercise capacity. Nevertheless, studies have also demonstrated a positive effect of regular exercise training on myocardial perfusion and maximum exercise capacity. The aim of this study was to evaluate changes in myocardial stress perfusion after 1 year of exercise training in comparison with the effects of PTCA in patients with CAD. METHODS: In 66 male patients with angiographically confirmed significant coronary artery stenosis in one target vessel, myocardial perfusion scintigraphy was performed at baseline and 12 months after randomisation into either a physical exercise group or a PTCA group. Circumferential count rate profiles in 16 wall segments were classified according to their relative count rate and localisation within or outside the area supplied by the stenosed vessel. RESULTS: Ischaemic segments showed a significant improvement in myocardial count rate within the target area after 12 months in both the PTCA and the training group (PTCA group: from 76.8+/-4.9% to 86.6+/-10.9%, p=0.03; training group: from 74.0+/-7.3% to 83.7+/-10.8%, p<0.01). Outside the target area only the training group showed a significant improvement (from 77.7+/-4.4% to 91.7+/-4.8%, p<0.01). CONCLUSION: Our data indicate a significant improvement in stress myocardial perfusion in the training group after 12 months. The ischaemia is reduced not only in the target region of the leading stenosis but also in other ischaemic myocardial areas. In contrast, after PTCA stress perfusion improves only in the initially ischaemic parts of the target area.