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© 2019 The Author(s). Background: The tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain. Methods: We performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches. Results: On qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology. Conclusions: 18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

©The Author(s) 2018. Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (K i) using 6-[ 18 F]fluoro-l-m-tyrosine ([ 18 F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [ 11 C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [ 11 C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [ 18 F]FMT K i and the baseline (placebo) [ 11 C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [ 18 F]FMT and methylphenidate-induced [ 11 C]raclopride displacement. These findings shed light on the nature of regulation between pre-and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.

© The Authors, some rights reserved. The biological properties of trifluoromethyl compounds have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions. We report the serendipitous discovery of a borane-catalyzed formal C(sp3)-CF3reductive elimination from Au(III) that accesses these compounds by a distinct mechanism proceeding via fluoride abstraction, migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction. The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic protocols, enabling the synthesis of complex organic derivatives without cleavage of the Au-C bond. This feature, combined with the "fluoride-rebound" mechanism, was translated into a protocol for the synthesis of 18F-radiolabeled aliphatic CF3-containing compounds, enabling the preparation of potential tracers for use in positron emission tomography.

© 2017 Elsevier Inc. β-amyloid (Aβ) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [18F]AV-1451 (for tau) and [11C]PiB (for Aβ) positron emission tomography (PET) and 1.5 T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB—AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p

Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[18F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging.Significance statementFew studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.

The paper considers the basic approaches and issues al-Ghazali's teachings about the reason and faith in the context of the ideal knowledge of the “golden period” of the classical Arab-Muslim philosophy. The basic approach to the understanding of al-Ghazali’s system was formulated by Ibn Rushd, who said that in al-Ghazali’s books he did not associate themselves with any of the exercises, being “with Ash'arites Ash’arites, with Sufis Sufi, with philosophers philosopher”. The problem of faith and reason is considered it from the point of view of kalam (“speculative theology”), fiqh (Islamic law) and Sufis. It is noted that a key reason for the understanding of his teachings as a system of metaphysics is the study, in which faith and reason complement each other on the field of knowledge, ie, it is a question of the unity of knowledge, both secular and religious.

Background: Rheumatic heart disease remains a major health cardiac problem in developing countries as the culprit of rheumatic fever. Mitral valve stenosis is the most common complication of valvular heart disease and its consequences of increase in pulmonary hypertension, heart failure, pulmonary vascular disease and if untreated death ensues. The management of this condition varies depending on availability of expertise and resource; however in a facility deprived country with low economic status closed mitral valvotomy remain the standard palliative treatment! The aim of this study was to evaluate the clinical status of patients with mitral stenosis following closed mitral valvotomy treated at Muhimbili National Hospital, Cardiothoracic Unit. Methods: All patients presenting with severe mitral stenosis in absence of calcification in its leaflets and regurgitation were enrolled for the study from May 2008 to November 2009. Excluded were those who failure consents. Results:A total of fourteen patients were included in the study of which 10 (71.4%) were females and 4 (28.6%) were males. They had a mean age of 21.5±8.8 and range from 11 to 41 years. The diagnosis was based on clinical evaluation using NYHA class and 2D-Echocardiography findings. All patients’ demographic data, preoperative and post operative findings were taken and data analysis was done using an SPSS 11.5 program. Categorical data were compared and analyzed using two Tailed- χ2 and values were taken 5% significance level. Conclusion: There was an overall highly significant improvement in clinical stage of the disease, reduction in mean pressure gradient across the mitral valve, reduction in pulmonary hypertension and mean left atrial size. Similarly there was improvement in ventricular function in terms of ejection fraction and increase in mean mitral valve area.