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  • 1
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    Bilastine vs. hydroxyzine: occupation of brain histamine H 1 ‐receptors evaluated by positron emission tomography in healthy volunteers
    Wiley ; 2014
    In:  British Journal of Clinical Pharmacology Vol. 78, No. 5 ( 2014-11), p. 970-980
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 78, No. 5 ( 2014-11), p. 970-980
    Kurzfassung: A close correlation exists between positron emission tomography ( PET )‐determined histamine H 1 ‐receptor occupancy ( H 1 RO ) and the incidence of sedation. Antihistamines with H 1 RO 〈 20% are classified as non‐sedating. The objective was to compare the H 1 RO of bilastine, a second generation antihistamine, with that of hydroxyzine. Methods This randomized, double‐blind, crossover study used PET imaging with [ 11 C ]‐doxepin to evaluate H 1 RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H 1 RO s were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs ), were also evaluated. Results The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P   〈  0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H 1 RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P   〈  0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between‐treatment differences were observed for sedation and psychomotor performance. Twenty‐six non‐serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. Conclusions A single oral dose of bilastine 20 mg had minimal H 1 RO , was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment‐related sedative AEs , thus satisfying relevant subjective, objective and PET criteria as a non‐sedating antihistamine.
    Materialart: Online-Ressource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    URL: Article
    DOI: 10.1111/bcp.2014.78.issue-5
    DOI: 10.1111/bcp.12421
    RVK:
    XA 33650
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2014
    ZDB Id: 1498142-7
    SSG: 15,3
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  • 2
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    Colour vision impairment is associated with disease severity in multiple sclerosis
    SAGE Publications ; 2014
    In:  Multiple Sclerosis Journal Vol. 20, No. 9 ( 2014-08), p. 1207-1216
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 20, No. 9 ( 2014-08), p. 1207-1216
    Kurzfassung: Colour vision assessment correlates with damage of the visual pathway and might be informative of overall brain damage in multiple sclerosis (MS). Objective: The objective of this paper is to investigate the association between impaired colour vision and disease severity. Methods: We performed neurological and ophthalmic examinations, as well as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) analyses, on 108 MS patients, both at baseline and after a follow-up of one year. Colour vision was evaluated by Hardy, Rand and Rittler plates. Dyschromatopsia was defined if colour vision was impaired in either eye, except for participants with optic neuritis (ON), for whom only the unaffected eye was considered. We used general linear models adjusted for sex, age, disease duration and MS treatment for comparing presence of dyschromatopsia and disease severity. Results: Impaired colour vision in non-ON eyes was detected in 21 out of 108 patients at baseline. At baseline, patients with dyschromatopsia had lower Multiple Sclerosis Functional Composite (MSFC) scores and Brief Repeatable Battery-Neuropsychology executive function scores than those participants with normal colour vision. In addition, these patients had thinner retinal nerve fiber layer (RNFL), and smaller macular volume, normalized brain volume and normalized gray matter volume (NGMV) at baseline. Moreover, participants with incident dyschromatopsia after one-year follow-up had a greater disability measured by the Expanded Disability Status Scale and MSFC-20 and a greater decrease in NGMV than participants with normal colour vision. Conclusions: Colour vision impairment is associated with greater MS severity.
    Materialart: Online-Ressource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458513517591
    Sprache: Englisch
    Verlag: SAGE Publications
    Publikationsdatum: 2014
    ZDB Id: 2008225-3
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  • 3
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    Trans‐synaptic axonal degeneration in the visual pathway in multiple sclerosis
    Wiley ; 2014
    In:  Annals of Neurology Vol. 75, No. 1 ( 2014-01), p. 98-107
    Details
    In: Annals of Neurology, Wiley, Vol. 75, No. 1 ( 2014-01), p. 98-107
    Kurzfassung: To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans‐synaptic degeneration in multiple sclerosis (MS). Methods We performed a longitudinal evaluation on a cohort of 100 patients with MS, acquiring retinal optical coherence tomography to measure anterior visual pathway damage (peripapillary retinal nerve fiber layer [RNFL] thickness and macular volume) and 3T brain magnetic resonance imaging (MRI) for posterior visual pathway damage (volumetry and spectroscopy of visual cortex, lesion volume within optic radiations) at inclusion and after 1 year. Freesurfer and SPM8 software was used for MRI analysis. We evaluated the relationships between the damage in the anterior and posterior visual pathway by voxel‐based morphometry (VBM), multiple linear regressions, and general linear models. Results VBM analysis showed that RNFL thinning was specifically associated with atrophy of the visual cortex and with lesions in optic radiations at study inclusion ( p 〈 0.05). Visual cortex volume (β = +0.601, 95% confidence interval [CI] = +0.04 to +1.16), N‐acetyl aspartate in visual cortex (β = +1.075, 95% CI = +0.190 to +1.961), and lesion volume within optic radiations (β = −2.551, 95% CI = −3.910 to −1.192) significantly influenced average RNFL thinning at study inclusion independently of other confounders, especially optic neuritis (ON). The model indicates that a decrease of 1cm 3 in visual cortex volume predicts a reduction of 0.6μm in RNFL thickness. This association was also observed after 1 year of follow‐up. Patients with severe prior ON (adjusted difference = −3.01, 95% CI = −5.08 to −0.95) and mild prior ON (adjusted difference = −1.03, 95% CI = −3.02 to +0.95) had a lower adjusted mean visual cortex volume than patients without ON. Interpretation Our results suggest the presence of trans‐synaptic degeneration as a contributor to chronic axon damage in MS. ANN NEUROL 2014;75:98–107
    Materialart: Online-Ressource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v75.1
    DOI: 10.1002/ana.24030
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2014
    ZDB Id: 2037912-2
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  • 4
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    Test–retest variability and reliability of123I-IBZM SPECT measurement of striatal dopamine D2 receptor availability in healthy volunteers and influence of iterative reconstruction algorithms
    Wiley ; 2008
    In:  Synapse Vol. 62, No. 1 ( 2008-01), p. 62-69
    Details
    In: Synapse, Wiley, Vol. 62, No. 1 ( 2008-01), p. 62-69
    Materialart: Online-Ressource
    ISSN: 0887-4476 , 1098-2396
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/syn.v62:1
    DOI: 10.1002/(ISSN)1098-2396
    DOI: 10.1002/syn.20465
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2008
    ZDB Id: 1474927-0
    SSG: 12
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  • 5
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    Translational characterization of [ 11 C]GSK931145, a PET ligand for the glycine transporter type 1
    Wiley ; 2011
    In:  Synapse Vol. 65, No. 12 ( 2011-12), p. 1319-1332
    Details
    In: Synapse, Wiley, Vol. 65, No. 12 ( 2011-12), p. 1319-1332
    Kurzfassung: The current interest in developing Glycine transporter Type 1 (GlyT‐1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT‐1 PET molecular imaging tool to aid drug development and dose selection. We report on [ 11 C]GSK931145 as a novel GlyT‐1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma‐occupancy relationship of the GlyT‐1 inhibitor GSK1018921. Human PET studies were performed to determine the test–retest reproducibility of [ 11 C]GSK931145 and the plasma‐occupancy relationship of GSK1018921. [ 11 C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction ( f P : 0.8 vs. 8%) and delivery ( K 1 : 0.025 vs. 0.126 ml cm −3 min −1 ) were significantly lower in humans. Test–retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR( V T ): 29–38%), but was improved using a pseudo reference tissue model (VAR(BP ND ): 16–23%). GSK1018921 EC 50 estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively. Synapse, 2011. © 2011 Wiley‐Liss, Inc.
    Materialart: Online-Ressource
    ISSN: 0887-4476 , 1098-2396
    URL: Issue
    URL: Article
    DOI: 10.1002/syn.v65.12
    DOI: 10.1002/syn.20966
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2011
    ZDB Id: 1474927-0
    SSG: 12
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  • 6
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    Early detection of amyloid load using 18F-florbetaben PET
    Springer Science and Business Media LLC ; 2021
    In:  Alzheimer's Research & Therapy Vol. 13, No. 1 ( 2021-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Kurzfassung: A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18 F-florbetaben PET. Quantitative thresholds for the early (SUVR early ) and established (SUVR estab ) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects ( n  = 287 (cognitively normal healthy controls), n  = 166 (subjects with subjective cognitive decline (SCD)), n  = 129 (subjects with MCI), and n  = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
    Materialart: Online-Ressource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-021-00807-6
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2021
    ZDB Id: 2506521-X
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  • 7
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    Amyloid PET imaging: applications beyond Alzheimer’s disease
    Springer Science and Business Media LLC ; 2015
    In:  Clinical and Translational Imaging Vol. 3, No. 1 ( 2015-02), p. 39-55
    Details
    In: Clinical and Translational Imaging, Springer Science and Business Media LLC, Vol. 3, No. 1 ( 2015-02), p. 39-55
    Kurzfassung: As a biomarker of beta-amyloid, positron emission tomography (PET) amyloid imaging offers a unique opportunity to detect the presence of this protein in the human body during life. Besides Alzheimer’s disease (AD), deposits of beta-amyloid in the brain are also present in other neurodegenerative diseases associated to dementia, such as Parkinson’s disease and dementia with Lewy bodies, as well as in other processes affecting brain function, such as cerebral amyloid angiopathy, brain trauma, Down’s syndrome and meningiomas, as shown by post-mortem pathology studies. Furthermore, in systemic amyloidosis other organs besides the brain are affected, and amyloid PET imaging may be suitable for the identification of these extra-cerebral amyloid depositions. Finally, the potential use of amyloid PET tracer accumulation in cerebral white matter (WM) as a marker of myelin is being investigated, leading to some promising results in patients with WM lesions and multiple sclerosis. In this article, a review of the ongoing research pointing to a broader application of amyloid PET imaging in clinical practice beyond AD is provided.
    Materialart: Online-Ressource
    ISSN: 2281-5872 , 2281-7565
    URL: Article
    DOI: 10.1007/s40336-014-0098-3
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2015
    ZDB Id: 2736976-6
    ZDB Id: 2712000-4
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  • 8
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    Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects—a MissionAD tau sub-study
    Springer Science and Business Media LLC ; 2022
    In:  Alzheimer's Research & Therapy Vol. 14, No. 1 ( 2022-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2022-12)
    Kurzfassung: The ability of 18 F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer’s disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using 18 F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition. Methods Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive 18 F-florbetaben PET scan ( n =74, 76 ± 7 years, 38 females) underwent a baseline 18 F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aβ42/Aβ40 ratio, p-tau, t-tau) ( n =22) and several cognitive tests. A 1-year follow-up 18 F-PI-2620 PET scans and cognitive assessments were done in 15 subjects. Results Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in 18 F-florbetaben Centiloids (CL) (7.7% ( 〈 36 CL), 80% ( 〉 83 CL)). 18 F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased 18 F-florbetaben CL in several regions of interest. Elevated 18 F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau ( p =0.0006 and p =0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline ( p =0.006 (mesial temporal); p =0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex ( p =0.04, p =0.047, p =0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline. Conclusions The findings support the hypothesis that 18 F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in 18 F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of 18 F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents. Trial registration Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov ( NCT02956486 ;  NCT03036280 ).
    Materialart: Online-Ressource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-022-01048-x
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2022
    ZDB Id: 2506521-X
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  • 9
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    Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach
    Springer Science and Business Media LLC ; 2021
    In:  Alzheimer's Research & Therapy Vol. 13, No. 1 ( 2021-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Kurzfassung: Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [ 18 F]florbetaben (FBB) and [ 18 F]florbetapir (FBP) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples. Methods We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer’s Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample ( N =62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants ( N =295). Results The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [ 18 F]FBB: CL whole cerebellum  = 157.15 × SUVR FBB  − 151.87; threshold=1.08, 18 CL [ 18 F]FBP: CL whole cerebellum  = 188.22 × SUVR FBP  − 189.16; threshold=1.11, 20 CL [ 18 F]FBB: CL composite  = 244.20 × SUVR FBB  − 170.80 [ 18 F]FBP: CL composite  = 300.66 × SUVR FBP  − 208.84 Conclusions FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.
    Materialart: Online-Ressource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-021-00836-1
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2021
    ZDB Id: 2506521-X
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  • 10
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    Contribution of SPECT Measurements of D 2 and 5-HT 2A Occupancy to the Clinical Development of the Antipsychotic SB-773812
    Society of Nuclear Medicine ; 2011
    In:  Journal of Nuclear Medicine Vol. 52, No. 4 ( 2011-04), p. 526-534
    Details
    In: Journal of Nuclear Medicine, Society of Nuclear Medicine, Vol. 52, No. 4 ( 2011-04), p. 526-534
    Materialart: Online-Ressource
    ISSN: 0161-5505 , 2159-662X
    URL: Article
    DOI: 10.2967/jnumed.110.081885
    RVK:
    XA 55300
    Sprache: Englisch
    Verlag: Society of Nuclear Medicine
    Publikationsdatum: 2011
    ZDB Id: 2040222-3
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