Raffaele Giubbini

Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study

BACKGROUND Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimers disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand (123)I-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included. METHODS We did a phase III study in which we used a (123)I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0.80) and specificity (0.85) targets and prespecified lower thresholds (sensitivity 0.65, specificity 0.73) using one-sided binomial tests with a significance level of alpha=0.025. FINDINGS Abnormal scans had a mean sensitivity of 77.7% for detecting clinical probable DLB, with specificity of 90.4% for excluding non-DLB dementia, which was predominantly due to Alzheimers disease. A mean value of 85.7% was achieved for overall diagnostic accuracy, 82.4% for positive predictive value, and 87.5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohens kappa=0.87). The procedure was well tolerated with few adverse events. INTERPRETATION A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimers disease.

Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy

OBJECTIVES The study evaluated the effects of short- and long-term administration of carvedilol in patients with idiopathic dilated cardiomyopathy. BACKGROUND Carvedilol is a beta-adrenergic blocking agent with vasodilator activity that might be well tolerated in patients with heart failure. METHODS Forty patients with idiopathic dilated cardiomyopathy treated with digoxin, furosemide and angiotensin-converting enzyme inhibitors were randomized in a double-blind manner to receive either placebo or carvedilol. Right heart hemodynamic variables were evaluated up to 8 h after short-term drug administration and, on the next day, during cardiopulmonary exercise testing before and 3 h after drug ingestion. Placebo or carvedilol was added to standard therapy, starting with a dose of 6.25 mg twice a day with weekly increments up to the maximum of 25 mg twice a day. Patients were reevaluated after 4 months by cardiopulmonary exercise testing and measurement of right heart hemodynamic variables 12 h after last drug ingestion and 3 h after drug readministration. Left ventricular ejection fraction and volume, measured by equilibrium radionuclide ventriculography, quality of life and submaximal exercise duration were assessed before and after long-term therapy. RESULTS Compared with placebo, carvedilol produced a short-term reduction in heart rate and pulmonary artery and pulmonary wedge pressures and, after long-term administration, increased both rest and peak exercise cardiac, stroke volume and stroke work indexes, with a further reduction in right atrial, pulmonary artery and pulmonary wedge pressures. Long-term carvedilol administration also improved rest left ventricular ejection fraction (from 20 +/- 7% to 30 +/- 12%, p < 0.001), submaximal exercise capacity, quality of life and New York Heart Association functional class. No baseline variable was predictive of the response to therapy. CONCLUSIONS Short-term carvedilol administration reduces heart rate and mean pulmonary artery and pulmonary wedge pressures, whereas it improves both long-term rest and exercise left ventricular systolic function, reduces heart failure symptoms and improves submaximal exercise tolerance in patients with idiopathic cardiomyopathy.

Differential Effects of β-Blockers in Patients With Heart Failure: A Prospective, Randomized, Double-Blind Comparison of the Long-Term Effects of Metoprolol Versus Carvedilol

BACKGROUND Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. METHODS AND RESULTS We randomized 150 patients with heart failure (left ventricular ejection fraction </=0.35) to double-blind treatment with either metoprolol or carvedilol. When compared with metoprolol (124+/-55 mg/d), patients treated with carvedilol (49+/-18 mg/d) showed larger increases in left ventricular ejection fraction at rest (+10.9+/-11.0 versus +7.2+/-7.7 U, P=0.038) and in left ventricular stroke volume and stroke work during exercise (both P<0. 05) after 13 to 15 months of treatment. In addition, carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and during exercise, than metoprolol (all P<0.05). In contrast, the metoprolol group showed greater increases in maximal exercise capacity than the carvedilol group (P=0.035), but the 2 drugs improved symptoms, submaximal exercise tolerance, and quality of life to a similar degree. After a mean of 23+/-11 months of follow-up, 21 patients in the metoprolol group and 17 patients in the carvedilol group died or underwent urgent transplantation. CONCLUSIONS The present study demonstrates that during long-term therapy, carvedilol improves cardiac performance to a greater extent than metoprolol when administered to patients with heart failure in the doses shown to be effective in clinical trials. These differences were likely related to a greater antiadrenergic activity of carvedilol.

Differential Effects of β-Blockers in Patients With Heart Failure

Background—Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. Methods and Results—We randomized 150 patients with heart failure (left ventricular ejection fraction ≤0.35) to double-blind treatment with either metoprolol or carvedilol. When compared with metoprolol (124±55 mg/d), patients treated with carvedilol (49±18 mg/d) showed larger increases in left ventricular ejection fraction at rest (+10.9±11.0 versus +7.2±7.7 U, P=0.038) and in left ventricular stroke volume and stroke work during exercise (both P<0.05) after 13 to 15 months of treatment. In addition, carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and during exercise, than metoprolol (all P<0.05). In contrast, the metoprolol gr...

Combined 99mTc-ECD SPECT and neuropsychological studies in MCI for the assessment of conversion to AD

Identifying pre-clinical Alzheimers disease (AD) in subjects with mild cognitive impairment (MCI) is a major issue in clinical diagnosis. Establishing a combination of predictive markers from different fields of research might help in increasing the diagnostic accuracy. Aim of this study was to evaluate the potential role of 99mTc-ECD single photon emission computed tomography (SPECT) and memory scores in predicting conversion to AD in MCI subjects. Thirty-one MCI subjects underwent a clinical and neuropsychological examination, and a regional cerebral blood flow (rCBF) SPECT scan at baseline. Subjects had been followed periodically through 2 years in order to monitor the progression of cognitive symptoms. Canonical variate analysis of principal components was able to separate all subjects who converted to AD from those who remained stable, the former being characterized by a specific hypometabolic pattern, involving the parietal and temporal lobes, precuneus, and posterior cingulate cortex. Canonical correlation analysis of combined baseline memory deficits and rCBF SPECT images identified pre-clinical AD with a sensitivity and specificity of 77.8%. The pattern of hypoperfusion 99mTc-ECD SPECT and the severity of memory deficits predict the risk of progression to probable AD dementia in MCI subjects.

Prognostic value of tomographic rest-redistribution thallium 201 imaging in medically treated patients with coronary artery disease and left ventricular dysfunction☆☆☆

BackgroundPrevious studies show that rest-redistribution thallium imaging is useful in the assessment of myocardial viability. The impact of such studies on patient outcome is not well defined. This study examined the prognostic value of tomographic rest-redistribution 201TI imaging in 81 medically treated patients with coronary artery disease and left ventricular dysfunction.Methods and ResultsRest-redistribution single-photon emission computed tomographic images were obtained and analyzed quantitatively. The segmental thallium uptake (20 segments per patient) was interpreted as normal, reversible defect, mild to moderate fixed defect, or severe fixed defect. The thallium images were abnormal in 80 patients. The left ventricular ejection fraction was 27%±8% in patients with no redistribution and 26%±7% in patients with redistribution (difference not significant). In patients with no ischemia, there were 7±5 severe fixed defects and 5±4 mild to moderate fixed defects per patient. In patients with ischemia there were 7±4 reversible defects, 3±3 mild to moderate fixed defects, and 5±4 severe fixed defects per patient. The number of any abnormal segments was 11±5 in patients with no ischemia and 14±4 in patients with ischemia (p=0.03). During a mean follow-up of 31±24 months, there were 11 cardiac deaths in patients with no ischemia (26%) and 22 in patients with ischemia (58%); the survival rate was worse in patients with than without ischemia (p<0.05). Multivariate Cox survival analysis on important clinical, angiographic, and thallium variables showed that the presence of redistribution was an independent predictor of death (x2=5; p=0.03).ConclusionsPatients with left ventricular dysfunction and redistribution on rest thallium imaging, a marker of hibernating myocardium, have a higher mortality rate with medical therapy than do patients with a comparable degree of left ventricular dysfunction but with fixed defects only. Thus observations similar to those made with positron emission tomography can be made in a much more straightforward, simple, and probably cost-effective manner with single-photon emission computed tomography.

Diagnostic and Clinical Significance of F-18-FDG-PET/CT Thyroid Incidentalomas

CONTEXT Thyroid incidentaloma diagnosed by 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (F-18-FDG-PET/CT) is defined as a thyroid uptake incidentally and newly detected in a patient studied for nonthyroid purpose. In this review, we have comprehensively analyzed the diagnostic and clinical significance of F-18-FDG-PET/CT thyroid incidentalomas revealed during studies performed for an unrelated and nonthyroid purpose. EVIDENCE ACQUISITION A comprehensive literature research of the PubMed/MEDLINE databases was conducted to find relevant published articles about the F-18-FDG-PET or F-18-FDG-PET/CT thyroid incidentalomas. EVIDENCE SYNTHESIS All studies considered in this review have investigated a very large number of patients, achieving overall about 147,505 units. The pooled incidence of thyroid incidentalomas detected by F-18-FDG-PET or PET/CT was 2.46% (95% confidence interval, 1.68-3.39%). The malignancy ratio was 34.6% (95% confidence interval, 29.3-40.2%). CONCLUSION F-18-FDG-PET/CT thyroid incidentaloma is a relevant clinical finding; diffuse uptakes and most focal uptakes are commonly caused by benign diseases, whereas about one third of focal uptakes are malignant; the most frequent malignant histological type responsible for F-18-FDG-PET/CT thyroid incidentaloma is papillary thyroid carcinoma.

Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH--an update.

CONTEXT GH deficiency (GHD) of the adult is a clinical condition characterized by the presence of several traditional and emerging cardiovascular risk factors that can significantly increase cardiovascular morbidity and mortality. It is still an open issue whether GH replacement is able not only to improve cardiovascular risk factors but also to decrease cardiovascular morbidity and mortality. EVIDENCE ACQUISITION The major source of data acquisition included PubMed research strategies. Original articles, systematic reviews and meta-analyses, and included relevant citations were screened. EVIDENCE SYNTHESIS In untreated GHD, cardiovascular risk is increased due to abnormal lipid profile (increased total and low-density lipoprotein cholesterol, increased triglycerides, and reduced high-density lipoprotein cholesterol) and impaired glucose metabolism. Emerging cardiovascular risk factors/markers such as proinflammatory cytokines, C-reactive protein, and adipokines are also increased in GHD patients. Increased cardiovascular morbidity and mortality have also been reported in GHD. GH treatment has been shown to improve both traditional and emerging cardiovascular risk factors and markers. However, evidence on the effects of GH replacement on cardiovascular events and mortality is limited. CONCLUSION The GHD population may be considered at high cardiovascular risk, and GH substitution may be expected to bring an added value to patients with hypopituitarism in terms of cardiovascular protection. However, there is too limited evidence (rarely coming from randomized and controlled studies) to recommend GH treatment based on the cardiovascular status of the patients.

Recovery of myocardial function. The ultimate target of coronary revascularization. Discussion

Recovery of myocardial contraction represents an important target of coronary revascularization and the preoperative recognition of viable akinetic (hibernating) myocardium is a crucial point of the preoperative investigation of patients with chronically depressed left ventricular function. In 14 patients dobutamine infusion during echocardiography was utilized to evoke the contractile reserve retained by viable akinetic segments. Redistribution of thallium(TI)-201 after the rest injection was also used to assess the viability of akinetic areas. The wall motion response to dobutamine infusion predicted immediate postoperative improvement in 85 of 93 segments (sensitivity 91.3%) and identified 25 of the 32 segments which did not exhibit early postoperative improvement (specificity 78.1%). Rest redistribution of TI-201 demonstrated high sensitivity (93.0%) but low specificity (43.7%) for predicting the early recovery of regional wall motion. When late recovery was also considered, the specificity of this method increased to 64.0%. Rest distribution of TI-201 identifies viability which is not necessarily associated with the early recovery of function postoperatively. When the echo-dobutamine test is positive, on the other hand, the recovery of function usually occurs immediately after revascularization and the operative risk is expected to be low even in the presence of severely compromised left ventricular function.

Accuracy and safety of technetium-99m hexakis 2-methoxy-2-isobutyl isonitrile (Sestamibi) myocardial scintigraphy with high dose dipyridamole test in patients with effort angina pectoris: A multicenter study

Clinical and physiologic evidence indicates that maximal coronary vasodilation is not achieved in a large number of patients with use of the standard dose of dipyridamole (0.56 mg/kg body weight over 4 min). The feasibility, safety and accuracy of technetium-99m hexakis 2-methoxy-2-isobutyl isonitrile (Sestamibi) scintigraphy associated with intravenous high dose dipyridamole (0.56 mg/kg over 4 min followed 4 min later by an additional 0.28 mg/kg over 2 min) were evaluated in a multicenter study. Planar myocardial perfusion images were obtained at rest and after dipyridamole in 101 patients with effort chest pain and no prior myocardial infarction. High dose dipyridamole (62 patients) was used when typical chest pain or electrocardiographic (ECG) signs of ischemia, or both, did not occur during or after the standard dose (39 patients). With high dose dipyridamole, 34 patients had pain (18 patients) or ECG signs of ischemia (ST depression greater than or equal to 2 mm) (8 patients), or both (8 patients), whereas the other 28 patients had Sestamibi injection in the absence of symptoms or ECG changes. All patients underwent coronary angiography: 81 had significant coronary artery disease (greater than or equal to 50% reduction of lumen diameter) (affecting one vessel in 38, two vessels in 19 and three vessels in 24 patients) and 20 patients had normal coronary arteries. The overall sensitivity, specificity and predictive accuracy of Sestamibi scintigraphy were 81%, 90% and 83%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)