Biology subjects

George, N.

Publications and source records attributed to George, N..

4 recordsLinked to original sources

bioRxiv2018

First in-human PET study of 3 novel tau radiopharmaceuticals: RO6958948

Background[11C]RO-963, [11C]RO-643 and [18F]RO-948 (previously referred as [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data (1,2). Here we describe the first human evaluation of these novel radiotracers.\n\nMethodsAmyloid PET positive Alzheimers disease (AD) patients and young healthy subjects (YC) each received two different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO-963, [11C]RO-643 or [18F]RO-948. Arterial blood sampling was performed in 11 healthy controls (HC) and 11 AD. Regions were defined on MRI, and PET data were quantified by plasma reference graphical analysis (for VT) and target cerebellum ratio (SUVR60-90). SUVR images were also analyzed voxelwise. Five older healthy subjects (OC) each received two scans with [18F]RO-948 for evaluation of test-retest variability. Four AD subjects received a repeat [18F]RO-948 scan over about 1 year. Six additional HC (3M: 3F; 41-67y) each received one whole body dosimetry scan with [18F]RO-948.\n\nResultsIn YC, peak SUV values were observed in the temporal lobe with values of approximately 3.0 for [11C]RO-963, 1.5 for [11C]RO-643 and 3.5 for [18F]RO-948. Over all brain regions and subjects, the trend was that [18F]RO-948 had the highest peak SUV value, followed by [11C]RO-963, and then [11C]RO-643. Regional analysis of SUVR and VT for [11C]RO-643 and [18F]RO-948 clearly discriminated AD and HC groups. Compartmental modeling confirmed that [11C]RO-643 had lower brain entry than both [18F]RO-963 and [18F]RO-948, and [18F]RO-948 showed a better contrast between (predicted) areas of high vs low tau accumulation. Thus, our subsequent analysis focused on [18F]RO-948. Both voxelwise and region-based analysis of [18F]RO-948 binding in HC vs AD revealed multiple areas where AD and HC significantly differed. Of 22 high-binding regions, 13 showed significant group difference (following ANOVA, F=45, p<10-5). Voxelwise analysis also revealed a set of symmetrical clusters where AD>HC (threshold of p<0.001, cluster size k>50).\n\nConclusions[18F]RO-948 demonstrates superior characteristics to [11C]RO-643 and [18F]RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of RO-948 compare favorably with existing other tau PET tracers.

neuroscience↗

bioRxiv2018

PET Brain imaging of α7-nAChR with ASEM Reproducibility, occupancy, receptor density, and changes in schizophrenia

The 7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The a7-nAChR primarily is located in cerebral cortex and sub-cortical regions, compared to the 4{beta}2 nAChR subtype that has a more subcortical distribution. The highly cortical distribution suggests a role of a7-nAChR in cognition. We expanded the first-in-human PET imaging of 7-nAChR with [18F]ASEM from five to 21 healthy non-smoking volunteers and added preliminary evidence of binding in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [18F]ASEM binding in normal volunteers, 2) demonstration of specificity of [18F]ASEM binding by competition with DMXB-A, an 7-nAChR partial agonist previously tested in clinical trials of patients with schizophrenia, 3) estimation of [18F]ASEM binding potentials and 7-nAChR density in vivo in humans, and 4) 7-nAChR binding in patients with schizophrenia compared to healthy volunteers.\n\nTest-retest PET confirmed reproducibility (>90%) (variability [≤] 7%) of [18F]ASEM volume of distribution (VO_SCPLOWTC_SCPLOW) estimates in healthy volunteers. Repeated sessions of PET in five healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of 7-nAChR by DMXB-A at 17-49% for plasma concentrations at 60-200 nM DMXB-A. In agreement with evidence post-mortem, 7-nAChR density (Bmax) averaged 0.67-0.82 nM and inhibitor affinity constant (KO_SCPLOWIC_SCPLOW) averaged 170-385 nM. Median VO_SCPLOWTC_SCPLOW in a feasibility study of six patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus. Mann-Whitney test identified cingulate cortex and hippocampus as regions with significantly lower median VO_SCPLOWTC_SCPLOW in patients than in healthy volunteers when a single outlier patient was excluded from analysis (P = 0.02, corrected for multiple comparisons).

neuroscience↗

bioRxiv2017

White matter correlates of hemi-face dominance in emotional expression

The neural underpinnings of human emotional expression are thought to be unevenly distributed among the two brain hemispheres. However, little is known on the anatomy supporting this claim, particularly in the cerebral white matter. Here, we explored the relationship between hemi-face dominance in emotional expression and cerebral white matter asymmetries in 33 healthy participants. Measures of emotional expression were derived from pictures of the participants faces in a happy smiling and a sad frowning conditions. Chimeric faces were constructed by mirroring right and left hemi-faces, as done in previous studies, resulting in a left mirrored and right mirrored chimeric face per picture. To gain measures of hemi-face dominance per participant, a jury of 20 additional participants rated which chimeric face shows higher intensity of emotional expressivity, by marking a 155mm line between the two versions. Measures of the asymmetry of the uncinate, the cingulum and the three branches of superior longitudinal fasciculi were derived from diffusion weighted imaging tractography dissections. Group effect analyses indicated that the degree of asymmetry in emotional expression was not as prominent as reported in the literature and showed a large inter-individual variability. The degree of asymmetry in emotional expression was, however, significantly associated with the asymmetries in connective properties of the fronto-temporal and fronto-parietal tracts, specifically the uncinate fasciculus and the first branch of the superior longitudinal fasciculus. Therefore, this result raises novel hypotheses on the relationship of specific white matter tracts and emotional expression, especially their role in mood disorders. Ethical statementO_LINone of the authors have a conflict of interest C_LIO_LIData collection from human participants was approved by the Comite de Protection des Personnes "CPP Ile de France V" C_LIO_LIAll participants provided written informed consent C_LIO_LIFunding from ERC (grant agreement No. 818521) and "Agence Nationale de la Recherche" [grants numbers ANR-13-JSV4-0001-01 an ANR-10-IAIHU-06] C_LI

neuroscience↗

bioRxiv2017

ADAM17 Is The Main Sheddase For The Generation Of Human Triggering Receptor Expressed In Myeloid Cells (hTREM2) Ectodomain And Cleaves TREM2 After Histidine 157

Triggering receptor expressed in myeloid cells (TREM2) is a member of the immunoglobulin superfamily and is expressed in macrophages, dendritic cells, microglia, and osteoclasts. TREM2 plays a role in phagocytosis, regulates release of cytokine, contributes to microglia maintenance, and its ectodomain is shed from the cell surface. Using both pharmacological and genetic approaches we report here that the main protease contributing to the release of TREM2 ectodomain is ADAM17, (a disintegrin and metalloproteinase domain containing protein, also called TACE, TNF converting enzyme) while ADAM10 plays a minor role. Using mutational analysis, we demonstrate that the main cleavage site of the sheddases is located within the stalk region of TREM2 proximal to the plasma membrane. Complementary biochemical experiments reveal that cleavage occurs between histidine 157 and serine 158. Shedding is not altered for the R47H-mutated TREM2 protein that confers an increased risk for the development of Alzheimers disease. O-glycosylation is detected within the stalk region, but distant to the cleavage site. These findings reveal a link between shedding of TREM2 and its regulation during inflammatory conditions or chronic neurodegenerative disease like AD in which activity or expression of sheddases might be altered.

cell biology↗