In vivo human amyloid imaging.

PET imaging agents such as Pittsburgh compound B (PiB) allow detection of fibrillar ß-amyloid (Aß) in vivo. In addition to quantification of Aß deposition in mild cognitive impairment and Alzheimer's disease, PiB has also increased our understanding of Aß deposition in older adults without cognitive impairment. In vivo Aß deposition has been studied in relation to genotype, structural and functional brain changes, as well as alterations in biomarker levels. To date, several studies have reported changes in Aß burden over time. This, together with investigation of the relationship between Aß deposition and cognition, sets the stage for elucidation of the temporal sequence of the neurobiological events leading to cognitive decline. Furthermore, correlation of Aß levels detected by PiB PET and those obtained from biopsy or postmortem specimens will allow more rigorous quantitative interpretation of PiB PET data in relation to neuropathological evaluation. Since the first human study in 2004, in vivo amyloid imaging has led to advances in our understanding of the role of Aß deposition in human aging and cognitive decline, as well as provided new tools for patient selection and therapeutic monitoring in clinical trials.

Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB.

OBJECTIVE: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia. METHOD: [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. RESULTS: [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. CONCLUSIONS: Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Does performing image registration and subtraction in ictal brain SPECT help localize neocortical seizures?

UNLABELLED: Ictal brain SPECT (IS) findings in neocortical epilepsy (patients without mesiotemporal sclerosis) can be subtle. This study is aimed at assessing how the seizure focus identification was improved by the inclusion of individual IS and interictal brain SPECT (ITS)-MRI image registration as well as performing IS - ITS image subtraction. METHODS: The study involved the posthoc analysis of 64 IS scans using 99mTc-ethyl cysteinate dimer that were obtained in 38 patients without mesiotemporal sclerosis but with or without other abnormalities on MRI. Radiotracer injection occurred during video-electroencephalographic (EEG) monitoring. Patients were injected 2-80 s (median time, 13 s) after clinical or EEG seizure onset. All patients had sufficient follow-up to correlate findings with the SPECT results. All patients had ITS and MRI, including a coronal volume sequence used for registration. Image registration (IS and ITS to MRI) was performed using automated software. After normalization, IS - ITS subtraction was performed. The IS, ITS, and subtraction studies were read by 2 experienced observers who were unaware of the clinical data and who assessed the presence and localization of an identifiable seizure focus before and after image registration and subtraction. Correlation was made with video-EEG (surface and invasive) and clinical and surgical follow-up. RESULTS: Probable or definite foci were identified in 38 (59%) studies in 33 (87%) patients. In 52% of the studies, the image registration aided localization, and in 58% the subtraction images contributed additional information. In 9%, the subtraction images confused the interpretation. In follow-up after surgery, intracranial EEG or video-EEG monitoring (or both) has confirmed close or reasonable localization in 28 (74%) patients. In 6 (16%) patients, SPECT indicated false seizure localization. CONCLUSION: Image registration and image subtraction improve the localization of neocortical seizure foci using IS, but close correlation with the original images is required. False localizations occur in a minority of patients.

Production of hydrogen peroxide by alveolar macrophages from rats exposed to subacute and chronic hypoxia.

We have studied in vitro alveolar macrophages (AMs) obtained by tracheobronchial lavage from rats exposed to subacute (3 hours and 3 days) and chronic (3 weeks) hypoxia (FiO2 = 0.1) and from rats recovering from chronic hypoxia. Hydrogen peroxide production by AMs was measured by luminol-dependent chemiluminescence after AMs adhered to the walls of the measuring cuvette, after stimulation with phorbol-myristate-acetate (PMA), and when N-formyl-methionyl-leucyl-phenylanine (FMLP) was added subsequently to the cells which had been previously stimulated by adherence or PMA. H2O2 production after cell adherence and adherence combined with FMLP stimulation did not differ between the groups. The increase of H2O2 production after adding PMA, and FMLP in addition to PMA was significantly higher in AMs from rats exposed to hypoxia for 3 days than in the controls. Other experimental groups did not differ from their controls. It is concluded that 3 days' hypoxia primes AMs for enhanced production of H2O2 upon stimulation. The mechanism is probably at the level of synthesis of proteins involved in H2O2 production, or the shift to a more reactive phenotype of alveolar macrophages subpopulations.

Production of hydrogen peroxide by alveolar macrophages. Effect of barbiturates.

Production of hydrogen peroxide by rat lung alveolar macrophages represents one of the key events in the inflammatory process. For the interpretation of the in vitro measurements it is important to control all possible interfering influences. The present work documents that the type of anaesthesia might critically influence the observed results. H2O2 production was measured in isolated rat alveolar macrophages by luminol chemiluminescence catalyzed by horseradish peroxidase. Three different mechanisms of H2O2 production were observed after stimulation of cells with a chemotactic peptide (FMLP), phorbol ester (PMA), and during cell adherence. All these activities were influenced independently by the treatment with barbiturates, which both stimulated or inhibited the H2O2 production, depending on the barbiturate concentration. As the effective barbiturate concentrations were found to be within the range used for the anaesthesia of experimental animals, the presented results imply that barbiturates are not suitable for experiments in which the production of reactive oxygen species by phagocytes is measured, and that other anaesthetics should be tested.