S. Holm

Out-patient rehabilitation improves activities of daily living, quality of life and exercise tolerance in chronic obstructive pulmonary disease

The purpose of this study was to investigate the effects on activities of daily living, quality of life, and exercise tolerance of a comprehensive out-patient rehabilitation programme for patients with moderate-to-severe chronic obstructive pulmonary disease. In this randomized and controlled trial, the main outcome measures were Activities of Daily Living (ADL) score, York Quality of Life Questionnaire (YQLQ) score, Chronic Respiratory Disease Questionnaire (CRDQ) score, 6 min walking distance (6MWD), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC). The rehabilitation programme included physical training, occupational therapy, education, and smoking cessation therapy, and lasted for 12 weeks. The patients were evaluated at entry, halfway through, and at the end of the programme. Follow-up was at 24 weeks. Forty seven patients were recruited, and 16 in each group completed the trial. There were significant differences in the improvements in ADL and CRDQ between the control and the treatment groups at 12 and 24 weeks, and at 24 weeks, respectively. At 6, 12 and 24 weeks, improvements in the 6MWD were 21.6 versus 79.8, 36.1 versus 113.1 and 21.4 versus 96.2 for control and treatment groups, respectively (p<0.004). A correlation matrix showed only ADL and 6MWD to be significantly correlated; the matrix was also used to validate the translated questionnaires. The programme required 124 staff-hours in total. An inexpensive, comprehensive out-patient rehabilitation programme can produce long-term improvement in activities of daily living, quality of life, and exercise tolerance in patients with moderate-to-severe chronic obstructive pulmonary disease.

Regional differences in the CBF and BOLD responses to hypercapnia: a combined PET and fMRI study.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

PET/CT with intravenous contrast can be used for PET attenuation correction in cancer patients

PurposeIf the CT scan of a combined PET/CT study is performed as a full diagnostic quality CT scan including intravenous (IV) contrast agent, the quality of the joint PET/CT procedure is improved and a separate diagnostic CT scan can be avoided. CT with IV contrast can be used for PET attenuation correction, but this may result in a bias in the attenuation factors. The clinical significance of this bias has not been established. Our aim was to perform a prospective clinical study where each patient had CT performed with and without IV contrast agent to establish whether PET/CT with IV contrast can be used for PET attenuation without reducing the clinical value of the PET scan.MethodsA uniform phantom study was used to document that the PET acquisition itself is not significantly influenced by the presence of IV contrast medium. Then, 19 patients referred to PET/CT with IV contrast underwent CT scans without, and then with contrast agent, followed by an 18F-fluorodeoxyglucose whole-body PET scan. The CT examinations were performed with identical parameters on a GE Discovery LS scanner. The PET data were reconstructed with attenuation correction based on the two CT data sets. A global comparison of standard uptake value (SUV) was performed, and SUVs in tumour, in non-tumour tissue and in the subclavian vein were calculated. Clinical evaluation of the number and location of lesions on all PET/CT scans was performed twice, blinded and in a different random order, by two independent nuclear medicine specialists.ResultsIn all patients, the measured global SUV of PET images based on CT with IV contrast agent was higher than the global activity using non-contrast correction. The overall increase in the mean SUV (for two different conversion tables tested) was 4.5±2.3% and 1.6±0.5%, respectively. In 11/19 patients, focal uptake was identified corresponding to malignant tumours. Eight out of 11 tumours showed an increased SUVmax (2.9±3.1%) on the PET images reconstructed using IV contrast. The clinical evaluation performed by the two specialists comparing contrast and non-contrast CT attenuated PET images showed weighted kappa values of 0.92 (doctor A) and 0.82 (doctor B). No contrast-introduced artefacts were found.ConclusionThis study demonstrates that CT scans with IV contrast agent can be used for attenuation correction of the PET data in combined modality PET/CT scanning, without changing the clinical diagnostic interpretation.

Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS

Objective: To study the association between the cortical cerebral metabolic rate of glucose (CMRglc), MRI T2-weighted total lesion area (TLA), cognitive dysfunction, and neurologic disability in MS. Background: MRI lesion load is widely used in the clinical evaluation of the MS patient but little is known about the associated changes in cortical activation. Methods: Twenty-three patients with clinically definite MS underwent measurements of CMRglc, TLA, motor evoked potentials (MEPs), and cognitive and neurologic disability. CMRglc was calculated using PET and 18-F-deoxyglucose and compared with nine normal control subjects. Results: Reductions in CMRglc (p < 0.01) were found in the cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (Spearman rank correlation coefficient [SRCC] = −0.66, p = 0.001), and rCMRglc correlated with regional lesion load in all cerebral lobes (p ≤ 0.05). Global cortical CMRglc and cognitive disability also correlated (SRCC = 0.58, p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance as well as TLA. There was no correlation between CMRglc and neurologic disability (Expanded Disability Status Scale) or MEP. Conclusion: Global and regional cortical CMRglc is reduced significantly in MS patients compared with normal control subjects. Furthermore, the CMRglc reductions correlate with TLA as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on cortical cerebral neural function.

Frontolimbic Serotonin 2A Receptor Binding in Healthy Subjects Is Associated with Personality Risk Factors for Affective Disorder

BACKGROUND Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain regions of relevance for affective disorders. METHODS Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [(18)F]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding. The correlation between the neuroticism score and frontolimbic serotonin 2A receptor binding was evaluated by multiple linear regression analysis with adjustment for age and gender. RESULTS Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [r(79) = .24, p = .028]. Post hoc analysis of the contributions from the six constituent traits of neuroticism showed that the correlation was primarily driven by two of them: vulnerability and anxiety. Indeed, vulnerability, defined as a persons difficulties in coping with stress, displayed the strongest positive correlation, which remained significant after correction for multiple comparisons (r = .35, p = .009). CONCLUSIONS In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point to a neurobiological link between personality risk factors for affective disorder and the serotonergic transmitter system and identify the serotonin 2A receptor as a biomarker for vulnerability to affective disorder.

Reduced 5-HT2A receptor binding in patients with mild cognitive impairment

Previous studies of patients with Alzheimers disease (AD) have described reduced brain serotonin 2A (5-HT(2A)) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms. We assessed cerebral 5-HT(2A) receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT(2A) receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [(18)F]altanserin PET in a bolus-infusion approach. A significant global reduction of 20-30% in 5-HT(2A) binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT(2A) binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude that widespread reductions in 5-HT(2A) receptor binding were found in amnestic MCI, pointing at the presence of serotonergic dysfunction in prodromal AD. This may provide some of the pathophysiological background for the neuropsychiatric symptoms found in early AD.

A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS

Objective: To study the time-related changes in cerebral metabolic rate of glucose (CMRglc) in MS patients and to correlate these with changes in MRI lesion load and disability. Background: Measurements of MRI lesion load and neurologic disability are used widely to monitor disease progression in longitudinal studies of MS patients, but little is known about the associated changes in cerebral neural function. Methods: The authors studied 10 patients with clinically definite MS who underwent serial measurements of CMRglc, MRI T2-weighted total lesion area (TLA), and clinical evaluation of disability (Expanded Disability Status Scale [EDSS]) over a period of approximately 2 years (three examinations). CMRglc was calculated using PET and 18-fluorodeoxyglucose (FDG). Results: The global cortical CMRglc decreased with time (p < 0.001) and the most pronounced reductions of CMRglc were detected in frontal and parietal cortical areas. There was a statistically significant increase of disability (p < 0.01) and TLA (p < 0.05) measurements during the study, but changes in CMRglc were not correlated to changes in TLA and EDSS. Conclusions: Global cortical cerebral metabolism in MS is decreased significantly during a 2-year observation period, suggesting a deterioration of cortical activity with disease progression. The time-related changes of cortical CMRglc are statistically stronger than changes in TLA measurements and neurologic disability, and might be a useful secondary measure of treatment efficacy.

Cerebral blood flow, oxidative metabolism and cerebrovascular carbon dioxide reactivity in patients with acute bacterial meningitis

Background: The optimal arterial carbon dioxide tension (PaCO2) in patients with acute bacterial meningitis (ABM) is unknown and controversial. The objective of this study was to measure global cerebral blood flow (CBF), cerebrovascular CO2 reactivity (CO2R), and cerebral metabolic rates (CMR) of oxygen (O2), glucose (glu), and lactate (lac), in patients with ABM and compare the results to those obtained in healthy volunteers.

Safety, dosimetry and tumor detection ability of 68Ga-NOTA-AE105 - a novel radioligand for uPAR PET imaging: first-in-humans study.

The overexpression of urokinase-type plasminogen activator receptors (uPARs) represents an established biomarker for aggressiveness in most common malignant diseases, including breast cancer (BC), prostate cancer (PC), and urinary bladder cancer (UBC), and is therefore an important target for new cancer therapeutic and diagnostic strategies. In this study, uPAR PET imaging using a 68Ga-labeled version of the uPAR-targeting peptide (AE105) was investigated in a group of patients with BC, PC, and UBC. The aim of this first-in-human, phase I clinical trial was to investigate the safety and biodistribution in normal tissues and uptake in tumor lesions. Methods: Ten patients (6 PC, 2 BC, and 2 UBC) received a single intravenous dose of 68Ga-NOTA-AE105 (154 ± 59 MBq; range, 48–208 MBq). The biodistribution and radiation dosimetry were assessed by serial whole-body PET/CT scans (10 min, 1 h, and 2 h after injection). Safety assessment included measurements of vital signs with regular intervals during the imaging sessions and laboratory blood screening tests performed before and after injection. In a subgroup of patients, the in vivo stability of 68Ga-NOTA-AE105 was determined in collected blood and urine. PET images were visually analyzed for visible tumor uptake of 68Ga-NOTA-AE105, and SUVs were obtained from tumor lesions by manually drawing volumes of interest in the malignant tissue. Results: No adverse events or clinically detectable pharmacologic effects were found. The radioligand exhibited good in vivo stability and fast clearance from tissue compartments primarily by renal excretion. The effective dose was 0.015 mSv/MBq, leading to a radiation burden of 3 mSv when the clinical target dose of 200 MBq was used. In addition, radioligand accumulation was seen in primary tumor lesions as well as in metastases. Conclusion: This first-in-human, phase I clinical trial demonstrates the safe use and clinical potential of 68Ga-NOTA-AE105 as a new radioligand for uPAR PET imaging in cancer patients.

P2-253: Serotonin receptor binding in mild cognitive impairment studied by PET and [18f]-altanserin

brain (WB), as predictors and correlates of clinical status, and their incremental accuracy over the parieto-temporal and posterior cingulate cortices. Results: At baseline, reductions in Hip, Amy, and WB MRglc were found for NL-MCI, MCI and AD as compared to NL-NL (p .05). The NL-MCI had Hip (17%, p ), WB (14%) and Amy (8%, p ) MRglc reductions that were comparable to those observed in clinical MCI patients (19%, 16% and 11%, respectively). These MRglc measures predicted decline from NL to MCI with accuracies of 81% (Hip), 67% (WB), and 65% (Amy). No differences in baseline cortical MRglc were found between NL-MCI and NL-NL, whereas the MCI group showed reduced temporal cortex MRglc, and the AD group showed the typical parietal, temporal, and posterior cingulate cortex hypometabolism (p .05, corrected). Longitudinally, Hip MRglc highly correlated with clinical progression with greater rates of annual reductions in the following order: AD (3.7%) MCI (2.9%) NLMCI (2.1%) NL-NL(1.2%). Conclusions: Years prior to clinical change, NL subjects destined to decline to MCI show a PET profile intermediate between normal aging and MCI, characterized by early WB and MTL MRglc reductions. These findings show that PET MRglc measures are predictors and correlates of cognitive impairment, and may help identify subjects at risk for future AD.