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Gunnar Antoni

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6 papers
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6

YNICL Journal 2021 Journal Article

Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients – A PET/MR study

  • Niklas Marklund
  • Fredrik Vedung
  • Mark Lubberink
  • Yelverton Tegner
  • Jakob Johansson
  • Kaj Blennow
  • Henrik Zetterberg
  • Markus Fahlström

Traumatic brain injury (TBI) and repeated sports-related concussions (rSRCs) are associated with an increased risk for neurodegeneration. Autopsy findings of selected cohorts of long-term TBI survivors and rSRC athletes reveal increased tau aggregation and a persistent neuroinflammation. To assess in vivo tau aggregation and neuroinflammation in young adult TBI and rSRC cohorts, we evaluated 9 healthy controls (mean age 26 ± 5 years; 4 males, 5 females), 12 symptomatic athletes (26 ± 7 years; 6 males, 6 females) attaining ≥3 previous SRCs, and 6 moderate-to severe TBI patients (27 ± 7 years; 4 males, 2 females) in a combined positron emission tomography (PET)/magnetic resonance (MR) scanner ≥6 months post-injury. Dual PET tracers, [18F]THK5317 for tau aggregation and [11C]PK11195 for neuroinflammation/microglial activation, were investigated on the same day. The Repeated Battery Assessment of Neurological Status (RBANS) scores, used for cognitive evaluation, were lower in both the rSRC and TBI groups (p < 0. 05). Neurofilament-light (NF-L) levels were increased in plasma and cerebrospinal fluid (CSF; p < 0. 05), and serum tau levels lower, in TBI although not in rSRC. In rSRC athletes, PET imaging showed increased neuroinflammation in the hippocampus and tau aggregation in the corpus callosum. In TBI patients, tau aggregation was observed in thalami, temporal white matter and midbrain; widespread neuroinflammation was found e. g. in temporal white matter, hippocampus and corpus callosum. In mixed-sex cohorts of young adult athletes with persistent post-concussion symptoms and in TBI patients, increased tau aggregation and neuroinflammation are observed at ≥6 months post-injury using PET. Studies with extended clinical follow-up, biomarker examinations and renewed PET imaging are needed to evaluate whether these findings progress to a neurodegenerative disorder or if spontaneous resolution is possible.

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YNIMG Journal 2019 Journal Article

High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain

  • Xiaotian T. Fang
  • Greta Hultqvist
  • Silvio R. Meier
  • Gunnar Antoni
  • Dag Sehlin
  • Stina Syvänen

PET imaging of amyloid-beta (Aβ) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti-Aβ treatments. Available PET radioligands visualizing Aβ bind to insoluble fibrils, i. e. Aβ plaques. Levels of prefibrillar Aβ forms, e. g. soluble oligomers and protofibrils, correlate better than plaques with disease severity and these soluble species are the neurotoxic form of Aβ leading to neurodegeneration. The goal was to create an antibody-based radioligand, recognizing not only fibrillary Aβ, but also smaller and still soluble aggregates. We designed and expressed a small recombinant bispecific antibody construct, di-scFv 3D6-8D3, targeting the Aβ N-terminus and the transferrin receptor (TfR). Natively expressed at the blood-brain barrier (BBB), TfR could thus be used as a brain-blood shuttle. Di-scFv 3D6-8D3 bound to Aβ1-40 with high affinity and to TfR with moderate affinity. Di-scFv [124I]3D6-8D3 was injected in two transgenic mouse models overexpressing human Aβ and wild-type control mice and PET scanned at 14, 24 or 72 h after injection. Di-scFv [124I]3D6-8D3 was retained in brain of transgenic animals while it was cleared from wild-type lacking Aβ. This difference was observed from 24 h onwards, and at 72 h, 18 months old transgenic animals, with high load of Aβ pathology, displayed SUVR of 2. 2–3. 5 in brain while wild-type showed ratios close to unity. A subset of the mice were also scanned with [11C]PIB. Again wt mice displayed ratios of unity while transgenes showed slightly, non-significantly, elevated SUVR of 1. 2, indicating improved sensitivity with novel di-scFv [124I]3D6-8D3 compared with [11C]PIB. Brain concentrations of di-scFv [124I]3D6-8D3 correlated with soluble Aβ (p < 0. 0001) but not with total Aβ, i. e. plaque load (p = 0. 34). We have successfully created a small bispecific antibody-based radioligand capable of crossing the BBB, subsequently binding to and visualizing intrabrain Aβ in vivo. The radioligand displayed better sensitivity compared with [11C]PIB, and brain concentrations correlated with soluble neurotoxic Aβ aggregates.

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YNICL Journal 2019 Journal Article

Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET

  • My Jonasson
  • Anders Wall
  • Konstantinos Chiotis
  • Antoine Leuzy
  • Jonas Eriksson
  • Gunnar Antoni
  • Agneta Nordberg
  • Mark Lubberink

[18F]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [18F]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R1) parametric images. Nine AD patients and nine controls underwent 90 min [18F]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 ± 4 min for AD patients and in putamen at 20 ± 0 min in controls. Over all regions and subjects, SUVR20–40-1 correlated best with DVR-1, R2 = 0. 97. High correlation was found between values generated using MRI- and SVCA-based reference (R2 = 0. 93 for SUVR20–40-1; R2 = 0. 94 for R1). SUVR20–40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R1 with 40 min scan duration.

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YNIMG Journal 2017 Journal Article

Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations

  • Sofia Gustafsson
  • Jonas Eriksson
  • Stina Syvänen
  • Olof Eriksson
  • Margareta Hammarlund-Udenaes
  • Gunnar Antoni

Methods to investigate blood-brain barrier transport and pharmacologically active drug concentrations in the human brain are limited and data translation between species is challenging. Hence, there is a need to further develop the read-out of techniques like positron emission tomography (PET) for studying neuropharmacokinetics. PET has a high translational applicability from rodents to man and measures total drug concentrations in vivo. The aim of the present study was to investigate the possibility of translating total drug concentrations, acquired through PET, to unbound concentrations, resembling those measured in the interstitial fluid by microdialysis sampling. Simultaneous PET scanning and brain microdialysis sampling were performed in rats throughout a 60min infusion of [N-methyl-11C]oxycodone in combination with a therapeutic dose of oxycodone and during a 60min follow up period after the end of infusion. The oxycodone concentrations acquired with PET were converted into unbound concentrations by compensating for brain tissue binding and brain intracellular distribution, using the unbound volume of distribution in brain (Vu, brain), and were compared to microdialysis measurements of unbound concentrations. A good congruence between the methods was observed throughout the infusion. However, an accumulating divergence in the acquired PET and microdialysis data was apparent and became more pronounced during the elimination phase, most likely due to the passage of radioactive metabolites into the brain. In conclusion, the study showed that PET can be used to translate non-invasively measured total drug concentrations into unbound concentrations as long as the contribution of radiolabelled metabolites is minor or can be compensated for.

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