Jonas Jögi

Heart failure diagnostics based on ventilation/perfusion single photon emission computed tomography pattern and quantitative perfusion gradients.

OBJECTIVE Left heart failure (LHF) is a common and frequently overlooked condition owing to insufficient diagnostic methods. This can potentially delay onset of treatment. Our clinical experience with ventilation/perfusion single photon emission computed tomography (V/P SPECT) indicates that perfusion shows an antigravitational distribution pattern in LHF. The aim of the study was to test the hypothesis that LHF diagnosis can be made on the basis of V/P SPECT, and to develop and perform a first evaluation of objective parameters for LHF diagnostics in terms of perfusion gradients. METHODS This retrospective study included 247 consecutive patients with clinical suspicion of pulmonary embolism (PE), who were examined with V/P SPECT. Perfusion gradients were developed and quantified in dorso-ventral and cranio-caudal directions. Quantitative results were compared with visual interpretation of patients with normal and heart failure patterns. Patients with LHF pattern were retrospectively followed up by review of medical records to confirm or discard heart failure diagnosis at the time of V/P SPECT examination. RESULTS LHF pattern on V/P SPECT was identified in 36 patients (15%), normal ventilation/perfusion pattern was found in 67 patients (27%), and PE in 62 patients (25%). The follow-up confirmed heart failure diagnosis in 32 of the 36 cases with LHF pattern, leading to a positive predictive value of 88% for LHF diagnosis based on V/P SPECT. Dorso-ventral perfusion gradients discriminated normal from LHF patients. CONCLUSION In patients with suspected PE, LHF is common. Appropriate V/P SPECT pattern recognition, supported by objectively determined dorso-ventral perfusion gradients, allows the diagnosis of LHF. A positive perfusion gradient in the dorso-ventral direction should lead to consideration of heart failure as a possible explanation for the symptoms in these patients.The objectives of this study were to evaluate the diagnostic accuracy of fluorodeoxyglucose (FDG)-PET and FDG-PET/computed tomography (CT) in the detection of primary tumors in patients presenting with carcinoma of unknown primary (CUP) unidentified by conventional workup, and to compare the statistical difference between the FDG-PET and FDG-PET/CT. Twenty-eight studies (involving a total of 910 patients) published between 1990 and 2007 were reviewed. These studies evaluated the role of FDG-PET and FDG-PET/CT in the detection of unknown primary tumors after physical examination and conventional workup failed to detect a primary tumor. Systematic methods were used to identify, select, and evaluate the methodological quality of the studies as well as to summarize the overall findings of sensitivity, specificity, and detection capacity of the primary tumor. The overall sensitivity and specificity of FDG-PET in detecting unknown primary tumors were 0.78 [95% confidence interval (CI): 0.72–0.84)] and 0.79 (95% CI: 0.74–0.83), respectively. Furthermore, FDG-PET detected 28.54% of tumors that were not apparent after CUP failed to be detected by conventional workup. Data were collected on the locations of primary tumors detected by FDG-PET in 17 studies and detected by FDG-PET/CT in seven studies. Tumors from the base of the tongue accounted for 20.7% (six of 29) of all false-positive FDG-PET scans, corresponding to a false-positive rate of 28.6% (six of 29), much higher than tumors from the others. FDG-PET exhibited a lower sensitivity with respect to the tumors at the base of the tongue and tonsils, which was 68.2 and 76.7%, respectively. In the eight studies with 430 patients diagnosed with CUP by FDG-PET/CT, 31.4% (n=135) of primary tumors were detected. The pooled sensitivity and specificity were 0.81 (95% CI: 0.74–0.87) and 0.83 (95% CI: 0.78–0.87), respectively. FDG-PET and FDG-PET/CT can detect primary tumors that went undetected by physical examination and conventional workup. FDG-PET exhibited lower sensitivity with respect to the tumors at the base of the tongue and the tonsils.

Characterization of the processing and granular targeting of human proteinase 3 after transfection to the rat RBL or the murine 32D leukemic cell lines.

Proteinase 3 (PR3) is a neutrophil serine protease stored in the azurophil granules of the promyelocyte and its successors. The protease has been identified as an autoantigen for anti‐neutrophil cytoplasmic autoantibodies (ANCA) occurring in patients with Wegeners granulomatosis. To characterize the biosynthesis and processing of human PR3 in a transgenic cellular model, cDNA encoding human pre‐proproteinase 3 cloned from U‐937 cells was transfected to the rat basophilic/mast cell line RBL‐1 and the murine myeloblast‐like cell line 32D cl3. The stable expression of transgenic proteinase 3 was characterized by biosynthetic labeling, followed by immunoprecipitation, sodium dodecyl sulfate‐polyacrylamide gel electrophoresis, and fluorography. After pulse labeling for 30 min two proforms of PR3 (32 and 35 kDa), differing in carbohydrate content but with protein cores of identical size, were demonstrated. Chase of the label resulted in a processed 32‐kDa form clearly visible in RBL, but only faintly in 32D cells, probably indicating delayed intracellular transfer in the latter cell line. Partial digestion with N‐glycosidase F showed that both potential N‐glycosylation sites on PR3 were occupied and conversion of the oligosaccharide side chains into complex forms was demonstrated by acquisition of resistance to endoglycosidase H. Translocation of PR3 to granules was shown by subcellular fractionation and immunocytochemistry. Enzymatic activation of PR3 was suggested by affinity to diisopropylfluorophosphate and removal of an amino‐terminal propeptide. Cells transfected with PR3 showed positive immunofluorescence for ANCA‐containing sera from patients with Wegeners granulomatosis. Our results show that human PR3 transfected to RBL or 32D cells is synthesized as a 29‐kDa protein core glycosylated on two distinct sites. Oligosaccharide trimming and proteolytic processing occur and the protein is targeted for granular storage in a form antigenic for ANCA. J. Leukoc. Biol. 61: 113–123; 1997.

Increased basal ganglia binding of 18F‐AV‐1451 in patients with progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work‐up of PSP.

In vivo retention of (18)F-AV-1451 in corticobasal syndrome

Objective: To study the usefulness of 18F-AV-1451 PET in patients with corticobasal syndrome (CBS). Methods: We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, 18F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent 18F-FDG-PET. Results: In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of 18F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using 18F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of 18F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where 18F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism. Conclusions: Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased 18F-fluorodeoxyglucose uptake were more widespread than 18F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS. Classification of evidence: This study provides Class III evidence that 18F-AV-1451 PET distinguishes between CBS and AD or PSP.

18F‐AV‐1451 and CSF T‐tau and P‐tau as biomarkers in Alzheimer's disease

To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18F‐AV‐1451 in Alzheimers disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F‐AV‐1451, and mainly in demented AD patients. 18F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F‐AV‐1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F‐AV‐1451 retention was always increased at this disease stage. We conclude that CSF T‐tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F‐AV‐1451 is a biomarker of “disease stage”, since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.

Modeling strategies for quantification of in vivo 18F-AV1451 binding in patients with tau pathology

Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer disease (AD). In vivo imaging with PET may offer important insights into pathophysiologic mechanisms, diagnosis, and disease progression. We describe different strategies for quantification of 18F-AV-1451 (T807) tau binding, including models with blood sampling and noninvasive alternatives. Methods: Fifteen subjects (4 controls, 6 AD, 3 progressive supranuclear palsy, 2 cortico basal syndrome) underwent 180-min PET with 18F-AV-1451 and arterial blood sampling. Modeling with arterial input functions included 1-, 2-, and 3-tissue-compartment models and the Logan plot. Using the cerebellum as reference region, we applied the simplified reference tissue model 2 and Logan reference plot. Finally, simplified outcome measures were calculated as ratio, with reference to cerebellar concentrations (SUV ratio [SUVR]) and SUVs. Results: Tissue compartment models were not able to describe the kinetics of 18F-AV-1451, with poor fits in 33%–53% of cortical regions and 80% in subcortical areas. In contrast, the Logan plot showed excellent fits and parameter variance (total volume of distribution SE < 5%). Compared with the 180-min arterial-based Logan model, strong agreement was obtained for the Logan reference plot also for a reduced scan time of 100 min (R2 = 0.91) and SUVR 100–120 min (R2 = 0.94), with 80–100 min already representing a reasonable compromise between duration and accuracy (R2 = 0.93). Time–activity curves and kinetic parameters were equal for cortical regions and the cerebellum in control subjects but different in the putamen. Cerebellar total volumes of distribution were higher in controls than patients. For these methods, increased cortical binding was observed for AD patients and to some extent for cortico basal syndrome, but not progressive supranuclear palsy. Conclusion: The Logan plot provided the best estimate of tau binding using arterial input functions. Assuming that the cerebellum is a valid reference region, simplified methods seem to provide robust alternatives for quantification, such as the Logan reference plot with 100-min scan time. Furthermore, SUVRs between target and cerebellar activities obtained from an 80- to 100-min static scan offer promising potential for clinical routine application.

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD

OBJECTIVES Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9μg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9μg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a β2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

Tomographic ventilation/perfusion lung scintigraphy in the monitoring of the effect of treatment in pulmonary embolism: serial follow-up over a 6-month period.

BackgroundPulmonary embolism (PE) is a severe condition with nonspecific symptoms. Diagnosis relies on medical imaging but follow-up is currently based on clinical symptoms and general risk factors. The duration of anticoagulant treatment after an acute episode of PE is still subject to debate and the best method of identifying the risk of recurrence in individual patients is undefined. Tomographic lung scintigraphy [ventilation/perfusion single photon emission computed tomography (V/P SPECT)] has improved the diagnostic accuracy with regard to PE but has not been evaluated for PE follow-up. AimThe aim of this prospective study was to quantitatively follow the natural history of treated PE using V/P SPECT, which could prove helpful in defining an anticoagulant treatment regime for individual patients. MethodsOf 83 consecutive patients with clinically suspected PE examined with V/P SPECT, 23 patients with confirmed PE were followed by serial V/P SPECT examinations over a 6-month period. All patients were also followed clinically. ResultsThe mean relative decrease in PE extent compared with the time of diagnosis was 54±26% at 2 weeks, 79±30% at 3 months, and 82±30% at 6 months. Significant resolution of mismatched perfusion defects occurred between V/P SPECT controls within the first 3 months of anticoagulation (P<0.001) but not thereafter. V/P SPECT identified four patients with chronic PE, even though all patients were free from symptoms at 3-month follow-up. ConclusionFollow-up of PE with V/P SPECT is feasible to evaluate treatment effectiveness in individual patients and to identify patients that develop chronic PE. This study also confirms that resolution of perfusion defects after PE occurs within the first 3 months of treatment. It is therefore recommended that V/P SPECT follow-up should be considered at 3 months after diagnosis.

Posterior accumulation of tau and concordant hypometabolism in an early-onset Alzheimer's disease patient with presenilin-1 mutation

It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimers disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in regions affected by tau aggregates.

Discrimination of ST deviation caused by acute coronary occlusion from normal variants and other abnormal conditions, using computed electrocardiographic imaging based on 12-lead ECG.

BACKGROUND Many graphical methods for displaying ST-segment deviation in the ECG have been tried for enhancing decision-making in patients with suspected acute coronary syndromes. Computed electrocardiographic imaging (CEI), based on a mathematical inverse solution, has been recently applied to transform ST-J point measurements made in conventional 12-lead ECG into a display of epicardial potentials in bulls-eye format. The purpose of this study is to assess utility of CEI in the clinical setting. METHODS In 99 patients with stable coronary disease, 12-lead ECGs were recorded during elective percutaneous coronary intervention (PCI), first before balloon-catheter insertion and then when an intracoronary balloon blocked blood supply to a region of myocardium for more than 4minutes (typically 5minutes). Four groups of patients were additionally studied, namely those with preexcitation, pericarditis, early repolarization syndrome (ERS), and left ventricular hypertrophy (LVH) with strain. Comparisons between performances of published criteria for ST-elevation myocardial infarction (STEMI) and quantitative as well as visual assessment of CEI images were based on sensitivities and specificities. RESULTS Visual assessment of CEI outperformed STEMI criteria. This was especially evident for the capability of detecting LCx occlusion with sensitivities for STEMI criteria=35% and for visual assessment of CEI by 2 physicians=71%, i. e. twice as many patients were correctly identified by CEI. False positive rates for CEI were low in patients with LVH with strain as well as with preexcitation for both methods. For pericarditis and ERS, visual as well as quantitative assessment of CEI performed better than STEMI criteria. CONCLUSION Visual assessment of CEI is a promising method for increasing the accuracy of ECG-based triage to PCI or conservative care.