[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

OBJECTIVES: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. METHODS: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and ß-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. RESULTS: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and ß-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. CONCLUSIONS: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

Tau deposition patterns are associated with functional connectivity in primary tauopathies.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Stereoselective Access to Azetidine-Based α-Amino Acids and Applications to Small Peptide Synthesis.

Non-natural azetidine-based amino acids (Aze) present interesting features in protein engineering. A simple organometallic route toward unsaturated carboxylic acid precursors is presented. Subsequent metal-catalyzed asymmetric reduction allowed for the synthesis of a new library of 2-azetidinylcarboxylic acids, which were finally employed in the formation of small peptide chains.

The physician-based sentinel surveillance project - a pilot programme for internet-based sentinel surveillance - Poster abstract

OBJECTIVE: To establish and evaluate an internet-based pilot programme for sentinel surveillance of emerging health problems among the private sector physicians in three Caribbean countries. DESIGN AND METHODS: Participating physicians were identified in cooperation with local chapters of the Caribbean College of Family Physicians in Jamaica, Trinidad andTobago and St Lucia. A menu-driven Epi Info programme was used for reporting as well as on-site analysis of individual site data. Hardware was installed,participants were trained and surveillance data entry began in September-October, 1999. Three disease entities were chosen by consensus as the initial targets for surveillance - diarrhoeal disease, fever/rash syndrome, and sexually transmitted diseases. Evaluation criteria for the programme included the achievement of timely data entry and reporting, the establishment of regular feedback, and the regular use of internet-based data transfer for reporting and communication. RESULTS: The practices of twenty-one physicians were chosen as initial pilot sites. All Ministries valued the enhancement of their existing surveillance through the project and cited improved public-private partnership as a positive impact. Reduced cost of communication through use of theinternet was partially offset by the high initial cost of computer hardware, and the relatively high cost of local internet connections. Other limitations included a constrained communication infrastructure, limited baseline computer skills administrative barriers, and cost. CONCLUSION: The strengths of the programme were simplicity; potential for improved data quality; and improved competency in computer skills and surveillance among participating physicians. Proposed changes in the next phase include improvement in the software programme and development of a more extended network and e-mail forum. (Au)

Analysis of medical paediatric admissions to the Port-of-Spain General Hospital

Admissions to the medical paediatric wards of the Port-of-Spain General Hospital from January 1, 1982 to December 31, 1982 were studied. Data on age, sex, final diagnosis, death in hospital or after discharge, and day of death were analysed. The study revealed that the bulk of sickness demanding hospital care consists of a few common diseases. Most of these are partly or wholly preventable. Gastroenteritis (36 percent), upper respiratory infection (18.8 percent), lower respiratory infection (12.3 percent), and accidental poisoning (7 percent) were the leading causes of admission. Malnutrition/gastroenteritis complex and lower respiratory infection were the major causes of death, constituting 51.9 percent of all deaths. Fifty per cent of the deaths occurred in the first twenty-four hours of hospital admission. Solutions to the problems at various levels of health care are outlined (AU)