Publications by authors named "Koen Van Laere"

301 Publications

Clinical implications of fever at diagnosis in polymyalgia rheumatica: an age- and sex-matched case control study of 120 patients. Reply to Milchert et al. and Manzo et al.

Clin Exp Rheumatol 2021 Nov 3. Epub 2021 Nov 3.

Department of General Internal Medicine, and Department of Microbiology, Immunology, and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disorders, University Hospitals Leuven, Belgium.

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November 2021

Twelve-Week Yoga vs. Aerobic Cycling Initiation in Sedentary Healthy Subjects: A Behavioral and Multiparametric Interventional PET/MR Study.

Front Psychiatry 2021 18;12:739356. Epub 2021 Oct 18.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Interventional yoga studies with an active control group remain scarce and are important to clarify the underlying neurobiology. We conducted an interventional study in healthy controls using simultaneous positron emission tomography/magnetic resonance (PET/MR) imaging and psychometric scales. Thirty healthy, female volunteers (28.4 ± 8.4 years) participated and were randomly assigned to a 12-week yoga or indoor cycling intervention. Before and after the intervention, [F]FDG and [C]UCB-J PET was performed on a simultaneous GE Signa PET/MR with volumetric imaging. Psychometric scales were evaluated on affect, mindfulness, stress, worrying, self-compassion, and interoceptive awareness. Yoga subjects scored higher on interoceptive awareness compared to baseline ( < 0.001). Cognitive ( = 0.009) and overall cognitive functioning ( = 0.01) improved after the yoga intervention compared to the cycling group. We did not observe significant differences in glucose metabolism, synaptic density, or gray matter (GM) volume. The indoor cycling group did not show changes in psychometric variables, but significant increases in relative glucose metabolism were observed in the parahippocampal/fusiform gyrus and cerebellum ( < 0.001). In conclusion, 12 weeks of yoga practice has significant effects on interoceptive awareness and perceived cognitive function in starters. Longer interventions and/or higher frequency of yoga practice may be needed to detect cerebral metabolic and/or morphologic effects on the macroscopic level.
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http://dx.doi.org/10.3389/fpsyt.2021.739356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558251PMC
October 2021

Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease: A PET Study.

Neurology 2021 Oct 18. Epub 2021 Oct 18.

Department of Neurosciences, KU Leuven, Belgium.

Background And Objectives: Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington's disease (HD), but evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD METHODS: In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and gender-matched healthy controls underwent clinical assessment of motor and non-motor manifestations and time-of-flight PET with C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker SV2A. We also performed F-FDG PET in all subjects, as regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated based on individual 3D T1 MRI. Standardized uptake value ratio (SUVR)-1 images were calculated for C-UCB-J with the centrum semiovale as reference region. F-FDG PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and C-UCB-J PET data were calculated.

Results: 18 HD mutation carriers (51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, temporal and frontal cortex, whereas reduced F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, C-UCB-J and F-FDG PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment.

Discussion: Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. C-UCB-J PET is more sensitive than F-FDG PET for detection of extrastriatal changes in early HD.

Classification Of Evidence: This study provides class III evidence that C-UCB-J PET accurately identifies HD from normal controls.
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http://dx.doi.org/10.1212/WNL.0000000000012969DOI Listing
October 2021

Renal Infarction Imaged With [18F]Prostate-Specific Membrane Antigen-1007 PET/CT.

Clin Nucl Med 2021 Oct 12. Epub 2021 Oct 12.

From the Departments of Nuclear Medicine Nephrology and Renal Transplantation, University Hospitals Leuven Department of Microbiology and Immunology, KU Leuven Department of Radiology, University Hospitals Leuven Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Abstract: A 61-year-old post-renal transplant man developed pain in the region of the allograft 4 days after transplantation. Contrast-enhanced CT scan revealed multiple small perfusion defects in the renal graft cortex. Multifocal renal cortical infarction was suspected. A [99mTc]Tc-DMSA SPECT/CT showed several small regions with decreased uptake. In addition, an [18F]PSMA-1007 PET/CT confirmed these uptake defects and revealed additional defects. The renal cortical infarctions presumably originated from intraoperative emboli emerging from the arterial anastomosis. Treatment with acetylsalicylic acid 100 mg led to favorable evolution of the renal function biochemically. Follow-up DMSA scintigraphy 3 months later showed resolution of the renal cortical defects.
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http://dx.doi.org/10.1097/RLU.0000000000003924DOI Listing
October 2021

Changes in synaptic density in the subacute phase after ischemic stroke: A C-UCB-J PET/MR study.

J Cereb Blood Flow Metab 2021 Sep 22:271678X211047759. Epub 2021 Sep 22.

Department of Neurosciences, KU Leuven, Leuven, Belgium.

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratio = 0.67 ± 0.28, p = 0.00023). Moreover, C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = -0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = -0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.
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http://dx.doi.org/10.1177/0271678X211047759DOI Listing
September 2021

Changes in the language system as amyloid-β accumulates.

Brain 2021 Sep 17. Epub 2021 Sep 17.

Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.

Language dysfunction is common in Alzheimer's disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer's disease. Here we examined in 35 cognitively intact older adults (age range 52-78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a five to six year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex: In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuoperceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxelwise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in fMRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer's disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awab335DOI Listing
September 2021

Rigid motion tracking using moments of inertia in TOF-PET brain studies.

Phys Med Biol 2021 Sep 13;66(18). Epub 2021 Sep 13.

Department of Nuclear Medicine, Vrije Universiteit Brussel, B-1090, Brussels, Belgium.

A data-driven method is proposed for rigid motion estimation directly from time-of-flight (TOF)-positron emission tomography (PET) emission data. Rigid motion parameters (translations and rotations) are estimated from the first and second moments of the emission data masked in a spherical volume. The accuracy of the method is analyzed on 3D analytical simulations of the PET-SORTEO brain phantom, and subsequently tested onF-FDG as well asC-PIB brain datasets acquired on a TOF-PET/CT scanner. The estimated inertia-based motion is later compared to rigid motion parameters obtained by directly registering the short frame backprojections. We find that the method provides sub mm/degree accuracies for the estimated rigid motion parameters for counts corresponding to typical 0.5 s, 1 s, and 2 sF-FDG brain scans, with the current TOF resolutions clinically available. The method provides robust motion estimation for different types of patient motion, most notably for a continuous patient motion case where conventional frame-based approaches which rely on little to no intra-frame motion of short time intervals could fail. The method relies on the detection of stable eigenvectors for accurate motion estimation, and a monitoring of this condition can reveal time-frames where the motion estimation is less accurate, such as in dynamic PET studies.
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http://dx.doi.org/10.1088/1361-6560/ac2268DOI Listing
September 2021

Neuroinflammation and Its Association with Cognition, Neuronal Markers and Peripheral Inflammation after Chemotherapy for Breast Cancer.

Cancers (Basel) 2021 Aug 20;13(16). Epub 2021 Aug 20.

Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.

To uncover mechanisms underlying chemotherapy-induced cognitive impairment in breast cancer, we studied new biomarkers of neuroinflammation and neuronal survival. This cohort study included 74 women (47 ± 10 years) from 22 October 2017 until 20 August 2020. Nineteen chemotherapy-treated and 18 chemotherapy-naïve patients with breast cancer were assessed one month after the completion of surgery and/or chemotherapy, and 37 healthy controls were included. Assessments included neuropsychological testing, questionnaires, blood sampling for 17 inflammatory and two neuronal survival markers (neurofilament light-chain (NfL), and brain-derived neurotrophic factor (BDNF) and PET-MR neuroimaging. To investigate neuroinflammation, translocator protein (TSPO) [F]DPA714-PET-MR was acquired for 15 participants per group, and evaluated by volume of distribution normalized to the cerebellum. Chemotherapy-treated patients showed higher TSPO expression, indicative for neuroinflammation, in the occipital and parietal lobe when compared to healthy controls or chemotherapy-naïve patients. After partial-volume correction, differences with healthy controls persisted ( < 0.05). Additionally, compared to healthy- or chemotherapy-naïve controls, cognitive impairment (17-22%) and altered levels in blood markers ( ≥ 3.7,  ≤ 0.031) were found in chemotherapy-treated patients. NfL, an axonal damage marker, was particularly sensitive in differentiating groups ( = 105, = 4.2 × 10 ), with levels 20-fold higher in chemotherapy-treated patients. Lastly, in chemotherapy-treated patients alone, higher local TSPO expression was associated with worse cognitive performance, higher blood levels of BDNF/NfL, and decreased fiber cross-section in the corpus callosum ( < 0.05). These findings suggest that increased neuroinflammation is associated with chemotherapy-related cognitive impairment in breast cancer. Additionally, NfL could be a useful biomarker to assess neurotoxic effects of anticancer chemotherapies.
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http://dx.doi.org/10.3390/cancers13164198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391457PMC
August 2021

Tau Pathology Associated With Parkinsonism and Mutation of Mitochondrial DNA Helicase Gene .

Neurol Genet 2021 Oct 13;7(5):e620. Epub 2021 Aug 13.

Department of Neurology (W.V.), University Hospitals Leuven; Department of Neurosciences, Laboratory for Parkinson Research (W.V., D.I.), KU Leuven; Leuven Brain Institute (W.V., D.I., A.R., D.R.T.), KU Leuven; Division of Nuclear Medicine (K.V.L.), University Hospitals Leuven; Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging (K.V.L.), KU Leuven; Department of Pathology (L.J., G.D.H., D.R.T.), University Hospitals Leuven; and Department of Imaging and Pathology, Laboratory for Neuropathology (A.R., D.R.T.), KU Leuven, Belgium.

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http://dx.doi.org/10.1212/NXG.0000000000000620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369512PMC
October 2021

Regional glucose metabolic decreases with ageing are associated with microstructural white matter changes: a simultaneous PET/MR study.

Eur J Nucl Med Mol Imaging 2021 Aug 16. Epub 2021 Aug 16.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Purpose: Human ageing is associated with a regional reduction in cerebral neuronal activity as assessed by numerous studies on brain glucose metabolism and perfusion, grey matter (GM) density and white matter (WM) integrity. As glucose metabolism may impact energetics to maintain myelin integrity, but changes in functional connectivity may also alter regional metabolism, we conducted a cross-sectional simultaneous FDG PET/MR study in a large cohort of healthy volunteers with a wide age range, to directly assess the underlying associations between reduced glucose metabolism, GM atrophy and decreased WM integrity in a single ageing cohort.

Methods: In 94 healthy subjects between 19.9 and 82.5 years (mean 50.1 ± 17.1; 47 M/47F, MMSE ≥ 28), simultaneous FDG-PET, structural MR and diffusion tensor imaging (DTI) were performed. Voxel-wise associations between age and grey matter (GM) density, RBV partial-volume corrected (PVC) glucose metabolism, white matter (WM) fractional anisotropy (FA) and mean diffusivity (MD), and age were assessed. Clusters representing changes in glucose metabolism correlating significantly with ageing were used as seed regions for tractography. Both linear and quadratic ageing models were investigated.

Results: An expected age-related reduction in GM density was observed bilaterally in the frontal, lateral and medial temporal cortex, striatum and cerebellum. After PVC, relative FDG uptake was negatively correlated with age in the inferior and midfrontal, cingulate and parietal cortex and subcortical regions, bilaterally. FA decreased with age throughout the entire brain WM. Four white matter tracts were identified connecting brain regions with declining glucose metabolism with age. Within these, relative FDG uptake in both origin and target clusters correlated positively with FA (0.32 ≤ r ≤ 0.71) and negatively with MD (- 0.75 ≤ r ≤  - 0.41).

Conclusion: After appropriate PVC, we demonstrated that regional cerebral glucose metabolic declines with age and that these changes are related to microstructural changes in the interconnecting WM tracts. The temporal course and potential causality between ageing effects on glucose metabolism and WM integrity should be further investigated in longitudinal cohort PET/MR studies.
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http://dx.doi.org/10.1007/s00259-021-05518-6DOI Listing
August 2021

Interhemispheric metabolic asymmetries in patients with anti-NMDA receptor encephalitis.

Acta Neurol Belg 2021 Oct 10;121(5):1385-1387. Epub 2021 Aug 10.

Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1007/s13760-021-01771-6DOI Listing
October 2021

Prospective comparison of simultaneous [Ga]Ga-PSMA-11 PET/MR versus PET/CT in patients with biochemically recurrent prostate cancer.

Eur Radiol 2021 Aug 10. Epub 2021 Aug 10.

Nuclear Medicine, UZ Leuven, Herestraat, 49 3000, Leuven, Belgium.

Objectives: PSMA-PET has become the PET technique of choice to localise the site of biochemically recurrent prostate cancer (PCa). With hybrid PET/MRI, the advantages of MRI are added to molecular characteristic of PET. The aim of this study was to investigate the incremental value of PET/MR versus PET/CT in patients with biochemically recurrent PCa by head-to-head comparison.

Methods: Thirty-four patients with biochemically recurrent PCa were prospectively included. They underwent [Ga]Ga-PSMA-11 PET/CT, followed by simultaneous PET/MR. All PET (PET, PET), CT and MR images were evaluated for number of lesions and location. The number of lesions at specific sites was compared using Wilcoxon-sign-rank test. For PET, the maximum and mean standardised uptake values (SUVs) were calculated for each lesion compared using a two-sided paired t test.

Results: PET and PET scans were positive in 19 and 20 patients, detecting 73 and 79 lesions respectively. All lesions detected on PET were also detected on PET. CT and MRI only were positive in 14 and 17 patients, detecting 38 and 50 lesions, respectively, which was significantly lower than PET and PET respectively. Combined interpretation showed more lesions on PET/MR than on PET/CT (88 vs 81). No significant difference in detection of presence of local recurrence nor distant metastases was found. SUV and SUV values were significantly higher on PET than on PET in local recurrence and lymph node metastases.

Conclusions: [Ga]Ga-PSMA-11 PET/MR was able to detect biochemically recurrent PCa at least as accurately as PET/CT for local recurrence, lymph node metastasis and distant metastasis.

Key Points: • PSMA PET/MRI detects the location of biochemical recurrence at least as accurately as PET/CT. • Substitution of PET/CT by PET/MRI adds sensitivity in PSMA lesion detection also in the setting of distant recurrence due to both the MR and TOF PET components.
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http://dx.doi.org/10.1007/s00330-021-08140-0DOI Listing
August 2021

Minimally invasive quantification of cerebral P2X7R occupancy using dynamic [F]JNJ-64413739 PET and MRA-driven image derived input function.

Sci Rep 2021 08 9;11(1):16172. Epub 2021 Aug 9.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University Hospital and KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

[F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (V) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF). Regional postdose V values were compared with corresponding V estimates using a arterial input function (AIF), in terms of absolute values, test-retest reliability and receptor occupancy. Compared to an invasive AIF approach, postdose V values and corresponding receptor occupancies showed only limited bias (Bland-Altman analysis: 0.06 ± 0.27 and 3.1% ± 6.4%) while demonstrating a high correlation (Spearman ρ = 0.78 and ρ = 0.98 respectively). In terms of test-retest reliability, regional intraclass correlation coefficients were 0.98 ± 0.02 for V compared to 0.97 ± 0.01 for V These results confirmed that a postdose IDIF, guided by MR angiography and using baseline blood and metabolite data, can be considered for accurate [F]JNJ-64413739 PET quantification in a repeated PET study design, thus avoiding multiple invasive arterial sampling and increasing dosing flexibility.
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http://dx.doi.org/10.1038/s41598-021-95715-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352986PMC
August 2021

Clinical implications of fever at diagnosis in polymyalgia rheumatica: an age- and sex-matched case control study of 120 patients.

Clin Exp Rheumatol 2021 Jul 24. Epub 2021 Jul 24.

Department of General Internal Medicine, University Hospitals Leuven, and Department of Microbiology, Immunology, and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disorders, KU Leuven, Belgium.

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July 2021

Lower regional gray matter volume in the absence of higher cortical amyloid burden in late-life depression.

Sci Rep 2021 08 5;11(1):15981. Epub 2021 Aug 5.

Neuropsychiatry, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.

Late-life depression (LLD) is associated with a risk of developing Alzheimer's disease (AD). However, the role of AD-pathophysiology in LLD, and its association with clinical symptoms and cognitive function are elusive. In this study, one hundred subjects underwent amyloid positron emission tomography (PET) imaging with [F]-flutemetamol and structural MRI: 48 severely depressed elderly subjects (age 74.1 ± 7.5 years, 33 female) and 52 age-/gender-matched healthy controls (72.4 ± 6.4 years, 37 female). The Geriatric Depression Scale (GDS) and Rey Auditory Verbal Learning Test (RAVLT) were used to assess the severity of depressive symptoms and episodic memory function respectively. Amyloid deposition was quantified using the standardized uptake value ratio. Whole-brain voxel-wise comparisons of amyloid deposition and gray matter volume (GMV) between LLD and controls were performed. Multivariate analysis of covariance was conducted to investigate the association of regional differences in amyloid deposition and GMV with clinical factors, including GDS and RAVLT. As a result, there were no significant group differences in amyloid deposition. In contrast, LLD showed significant lower GMV in the left temporal and parietal region. GMV reduction in the left temporal region was associated with episodic memory dysfunction, but not with depression severity. Regional GMV reduction was not associated with amyloid deposition. LLD is associated with lower GMV in regions that overlap with AD-pathophysiology, and which are associated with episodic memory function. The lack of corresponding associations with amyloid suggests that lower GMV driven by non-amyloid pathology may play a central role in the neurobiology of LLD presenting as a psychiatric disorder.Trial registration: European Union Drug Regulating Authorities Clinical Trials identifier: EudraCT 2009-018064-95.
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http://dx.doi.org/10.1038/s41598-021-95206-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342521PMC
August 2021

Influence of medication and PTH levels on detection of parathyroid adenomas with dual isotope parathyroid scintigraphy.

Am J Nucl Med Mol Imaging 2021 15;11(3):207-217. Epub 2021 Jun 15.

Division of Nuclear Medicine, University Hospitals Leuven Leuven, Belgium.

Localization of parathyroid adenomas is a crucial step to facilitate minimally invasive parathyroidectomy. In this study, we investigated sensitivity and positivity rate of SPECT-based dual isotope parathyroid scintigraphy in detecting parathyroid adenomas, and the effect of medication and parathyroid hormone (PTH)-level on detection of adenomas. Two hundred and thirty-seven patients with primary hyperparathyroidism undergoing dual isotope parathyroid scintigraphy with SPECT-CT in our centre between January 1 2013 and December 31 2017 were included in this retrospective study. Sensitivity and positivity rate for accurate location of parathyroid adenomas, based on histopathological findings after surgery and follow-up PTH and calcium, were calculated. The impact of pre-operative medication (thyroxin, calcium-antagonists, antacids, vitamin D, bisphosphonates and calcium) and PTH-levels between positive and negative scans was evaluated by using univariate and multivariate analysis, and a ROC analysis respectively. Overall patient-based sensitivity of scintigraphy for finding parathyroid adenomas was 72% for scintigraphy, with a positivity rate of 60%. No significant effect of investigated medication on positivity rate was found. PTH-level was significantly higher in patients with positive scintigraphy (median 96.3 ng/L vs 75.2 ng/L, P < 0.01). Optimum cut-off for detection of adenomas for PTH was 79.4 ng/L with a sensitivity of 67% and a specificity of 63%. In this retrospective cohort, sensitivity and positivity rate of dual-isotope SPECT-CT for parathyroid adenomas were in line with previous studies. No statistically significant influence of medication on positivity of scintigraphy was found, suggesting these medication types should not be stopped prior to scintigraphy. PTH level was no useful parameter to predict positivity of scintigraphic imaging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255219PMC
June 2021

Effects of chronic voluntary alcohol consumption on PDE10A availability: a longitudinal behavioral and [F]JNJ42259152 PET study in rats.

Eur J Nucl Med Mol Imaging 2021 Jun 17. Epub 2021 Jun 17.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Purpose: Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in dopamine-receptive striatal medium spiny neurons, which are involved in psychiatric disorders such as alcohol use disorders (AUD). Although preclinical studies suggest a correlation of PDE10A mRNA expression in neuronal and behavioral responses to alcohol intake, little is known about the effects of alcohol exposure on in vivo PDE10A activity in relation to apparent risk factors for AUD such as decision-making and anxiety.

Methods: We performed a longitudinal [F]JNJ42259152 microPET study to evaluate PDE10A changes over a 9-week intermittent access to alcohol model, including 6 weeks of alcohol exposure, 2 weeks of abstinence followed by 1 week relapse. Parametric PDE10A-binding potential (BP) images were generated using a Logan reference tissue model with cerebellum as reference region and were analyzed using both a volume-of-interest and voxel-based approach. Moreover, individual decision-making and anxiety levels were assessed with the rat Iowa Gambling Task and open-field test over the IAE model.

Results: We observed an increased alcohol preference especially in those animals that exhibited poor initial decision-making. The first 2 weeks of alcohol exposure resulted in an increased striatal PDE10A binding (> 10%). Comparing PDE10A-binding potential after 2 versus 4 weeks of exposure showed a significant decreased PDE10A in the caudate-putamen and nucleus accumbens (p < 0.05). This striatal PDE10A decrease was related to alcohol consumption and preference. Normalization of striatal PDE10A to initial levels was observed after 1 week of relapse, apart from the globus pallidus.

Conclusion: This study shows that chronic voluntary alcohol consumption induces a reversible increased PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. Thus, PDE10A-mediated signaling plays an important role in modulating the reinforcing effects of alcohol, and the data suggest that PDE10A inhibition may have beneficial behavioral effects on alcohol intake.
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http://dx.doi.org/10.1007/s00259-021-05448-3DOI Listing
June 2021

Distinguishing Primary Lateral Sclerosis from Parkinsonian Syndromes with the Help of Advanced Imaging.

J Nucl Med 2021 Sep 20;62(9):1318-1319. Epub 2021 May 20.

Neuromuscular Reference Centre, Department of Neurology, University Hospitals Leuven, Leuven, Belgium;

We describe a unique case of a patient presenting with unilateral mild paresis, slowing of the upper limb, and parkinsonism, who underwent a full imaging work-up including MRI, I-FP-CIT PET, F-FE-PE2I PET, and F-FDG PET. This case demonstrates that imaging may aid substantially in the diagnostic work-up of complex neurologic disorders.
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http://dx.doi.org/10.2967/jnumed.121.261942DOI Listing
September 2021

Parameters predicting [F]PSMA-1007 scan positivity and type and number of detected lesions in patients with biochemical recurrence of prostate cancer.

EJNMMI Res 2021 Apr 30;11(1):41. Epub 2021 Apr 30.

Department of Nuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Detection of the site of recurrence using PSMA-PET/CT is important to guide treatment in patients with biochemical recurrence of prostate cancer (PCa). The aim of this study was to evaluate the positivity rate of [F]PSMA-1007-PET/CT in patients with biochemically recurrent PCa and identify parameters that predict scan positivity as well as the type and number of detected lesions. This monocentric retrospective study included 137 PCa patients with biochemical recurrence who underwent one or more [F]PSMA-1007-PET/CT scans between August 2018 and June 2019. PET-positive malignant lesions were classified as local recurrence, lymph node (LN), bone or soft tissue lesions. The association between biochemical/paraclinical parameters, as PSA value, PSA doubling time, PSA velocity, Gleason score (GS) and androgen deprivation therapy (ADT), and scan positivity as well as type and number of detected lesions was evaluated using logistic regression analysis (binary outcomes) and Poisson models (count-type outcomes).

Results: We included 175 [F]PSMA-1007-PET/CT scans after radical prostatectomy (78%), external beam radiation therapy (8.8%), ADT (7.3%), brachytherapy (5.1%) and high intensity focused ultrasound (0.7%) as primary treatment (median PSA value 1.6 ng/ml). Positivity rate was 80%. PSA value and PSA velocity were significant predictors of scan positivity as well as of the presence of bone and soft tissue lesions and number of bone, LN and soft tissue lesions, both in uni- and/or multivariable analysis. Multivariable analysis also showed prior ADT as predictor of bone and soft tissue lesions, GS as predictor of the number of bone lesions and ongoing ADT as predictor of the number of LN lesions.

Conclusion: [F]PSMA-1007-PET/CT showed a high positivity rate in patients with biochemically recurrent PCa. PSA value and PSA velocity were significant predictors of scan positivity as well as of the presence and number of bone and soft tissue lesions and the number of LN lesions. Our findings can guide clinicians in optimal patient selection for [F]PSMA-1007-PET/CT and support further research leading to the development of a prediction nomogram.
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http://dx.doi.org/10.1186/s13550-021-00783-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087750PMC
April 2021

Human biodistribution and dosimetry of [C]-UCB-J, a PET radiotracer for imaging synaptic density.

EJNMMI Phys 2021 Apr 23;8(1):37. Epub 2021 Apr 23.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Rationale: [C]-UCB-J is an emerging tool for the noninvasive measurement of synaptic vesicle density in vivo. Here, we report human biodistribution and dosimetry estimates derived from sequential whole-body PET using two versions of the OLINDA dosimetry program.

Methods: Sequential whole-body PET scans were performed in 3 healthy subjects for 2 h after injection of 254 ± 77 MBq [C]-UCB-J. Volumes of interest were drawn over relevant source organs to generate time-activity curves and calculate time-integrated activity coefficients, with effective dose coefficients calculated using OLINDA 2.1 and compared to values derived from OLINDA 1.1 and those recently reported in the literature.

Results: [C]-UCB-J administration was safe and showed mixed renal and hepatobiliary clearance, with largest organ absorbed dose coefficients for the urinary bladder wall and small intestine (21.7 and 23.5 μGy/MBq, respectively). The average (±SD) effective dose coefficient was 5.4 ± 0.7 and 5.1 ± 0.8 μSv/MBq for OLINDA versions 1.1 and 2.1 respectively. Doses were lower than previously reported in the literature using either software version.

Conclusions: A single IV administration of 370 MBq [C]-UCB-J corresponds to an effective dose of less than 2.0 mSv, enabling multiple PET examinations to be carried out in the same subject.

Trial Registration: EudraCT number: 2016-001190-32. Registered 16 March 2016, no URL available for phase 1 trials.
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http://dx.doi.org/10.1186/s40658-021-00384-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065069PMC
April 2021

Baseline cognition is the best predictor of 4-year cognitive change in cognitively intact older adults.

Alzheimers Res Ther 2021 04 7;13(1):75. Epub 2021 Apr 7.

Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.

Background: We examined in cognitively intact older adults the relative weight of cognitive, genetic, structural and amyloid brain imaging variables for predicting cognitive change over a 4-year time course.

Methods: One hundred-eighty community-recruited cognitively intact older adults (mean age 68 years, range 52-80 years, 81 women) belonging to the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK) longitudinal observational cohort underwent a baseline evaluation consisting of detailed cognitive assessment, structural MRI and F-flutemetamol PET. At inclusion, subjects were stratified based on Apolipoprotein E (APOE) ε4 and Brain-Derived Neurotrophic Factor (BDNF) val66met polymorphism according to a factorial design. At inclusion, 15% were amyloid-PET positive (Centiloid >23.4). All subjects underwent 2-yearly follow-up of cognitive performance for a 4-year time period. Baseline cognitive scores were analysed using factor analysis. The slope of cognitive change over time was modelled using latent growth curve analysis. Using correlation analysis, hierarchical regression and mediation analysis, we examined the effect of demographic (age, sex, education) and genetic variables, baseline cognition, MRI volumetric (both voxelwise and region-based) as well as amyloid imaging measures on the longitudinal slope of cognitive change.

Results: A base model of age and sex explained 18.5% of variance in episodic memory decline. This increased to 41.6% by adding baseline episodic memory scores. Adding amyloid load or volumetric measures explained only a negligible additional amount of variance (increase to 42.2%). A mediation analysis indicated that the effect of age on episodic memory scores was partly direct and partly mediated via hippocampal volume. Amyloid load did not play a significant role as mediator between age, hippocampal volume and episodic memory decline.

Conclusion: In cognitively intact older adults, the strongest baseline predictor of subsequent episodic memory decline was the baseline episodic memory score. When this score was included, only very limited explanatory power was added by brain volume or amyloid load measures. The data warn against classifications that are purely biomarker-based and highlight the value of baseline cognitive performance levels in predictive models.
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http://dx.doi.org/10.1186/s13195-021-00798-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028179PMC
April 2021

The Role of Amyloid PET in Diagnosing Possible Transmissible Cerebral Amyloid Angiopathy in Young Adults with a History of Neurosurgery: A Case Series.

Cerebrovasc Dis 2021 19;50(3):356-360. Epub 2021 Mar 19.

Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven, Belgium.

Background: Cerebral amyloid angiopathy (CAA) is a common cause of cerebrovascular disease in the elderly. There is accumulating evidence suggestive of transmissibility of β-amyloid resulting in amyloid pathology at younger age. According to the Boston criteria, defining CAA in patients <55 years requires histological evidence which may hamper diagnosis. We explored the role of amyloid PET in the diagnosis of possible transmissible CAA in young adults.

Cases: We report 4 young adults (<55 years) presenting with clinical and neuroimaging features suggestive of CAA but without genetic evidence of hereditary CAA explaining the young onset. A common factor in all cases was a medical history of neurosurgery during childhood. All patients underwent amyloid PET to support the diagnosis of an amyloid-related pathology and the result was positive in all 4.

Conclusion: Combining the clinical presentation and imaging findings of the 4 cases, we postulate transmissible CAA as the possible diagnosis. Further epidemiological studies are required to gain more insight in the prevalence of this novel entity. Amyloid PET may be a useful, non-invasive tool in these analyses especially since pathological evidence will be lacking in most of these studies.
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http://dx.doi.org/10.1159/000514139DOI Listing
August 2021

Toward a Universal Readout for F-Labeled Amyloid Tracers: The CAPTAINs Study.

J Nucl Med 2021 Jul 12;62(7):999-1005. Epub 2021 Mar 12.

University Hospital Cologne, Multimodal Neuroimaging Group, Department of Nuclear Medicine, Cologne, Germany.

To date, 3 F-labeled PET tracers have been approved for assessing cerebral amyloid plaque pathology in the diagnostic workup of suspected Alzheimer disease (AD). Although scanning protocols are relatively similar across tracers, U.S. Food and Drug Administration- and the European Medicines Agency-approved visual rating protocols differ among the 3 tracers. This proof-of-concept study assessed the comparability of the 3 approved visual rating protocols to classify a scan as amyloid-positive or -negative, when applied by groups of experts and nonexperts to all 3 amyloid tracers. In an international multicenter approach, both expert ( = 4) and nonexpert raters ( = 3) rated scans acquired with F-florbetaben, F-florbetapir and F-flutemetamol. Scans obtained with each tracer were presented for reading according to all 3 approved visual rating protocols. In a randomized order, every single scan was rated by each reader according to all 3 protocols. Raters were blinded for the amyloid tracer used and asked to rate each scan as positive or negative, giving a confidence judgment after each response. Percentage of visual reader agreement, interrater reliability, and agreement of each visual read with binary quantitative measures (fixed SUV ratio threshold for positive or negative scans) were computed. These metrics were analyzed separately for expert and nonexpert groups. No significant differences in using the different approved visual rating protocols were observed across the different metrics of agreement in the group of experts. Nominal differences suggested that the F-florbetaben visual rating protocol achieved the highest interrater reliability and accuracy especially under low confidence conditions. For the group of nonexpert raters, significant differences between the different visual rating protocols were observed with overall moderate-to-fair accuracy and with the highest reliability for the F-florbetapir visual rating protocol. We observed high interrater agreement despite applying different visual rating protocols for all F-labeled amyloid tracers. This implies that the results of the visual interpretation of amyloid imaging can be well standardized and do not depend on the rating protocol in experts. Consequently, the creation of a universal visual assessment protocol for all amyloid imaging tracers appears feasible, which could benefit especially the less-experienced readers.
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http://dx.doi.org/10.2967/jnumed.120.250290DOI Listing
July 2021

Synaptic density in healthy human aging is not influenced by age or sex: a C-UCB-J PET study.

Neuroimage 2021 05 24;232:117877. Epub 2021 Feb 24.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Belgium; Division of Nuclear Medicine, University Hospitals Leuven, Belgium.

Rationale: C-UCB-J binds to synaptic vesicle glycoprotein 2A, a protein ubiquitously expressed in presynaptic nerve terminals, and can therefore serve as in vivo proxy of synaptic density. There are discrepancies in postmortem data on stability of synaptic density with healthy aging. In this study, healthy aging and sex as potential modifiers of C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex.

Methods: 80 healthy volunteers underwent C-UCB-J PET and structural T1 and T2 MR imaging. Grey matter changes with aging were firstly evaluated by voxel-based morphometry (VBM). Parametric C-UCB-J standardized uptake value ratio (SUVR) images were calculated using the centrum semiovale as reference tissue. To correct for atrophy-related partial volume effects, a region-based voxel-wise type partial volume correction (PVC) was applied in FreeSurfer. The correlations of C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging.

Results: Full results were available for 78 participants (19-85y; 33 M/45 F). VBM grey matter concentration changes with aging were most predominant in the perisylvian and frontal regions. After PVC, no significantly decreased C-UCB-J SUVR with aging was found in the voxel-based analysis, whereas the VOI-based analysis showed a slight decrease in the caudate nucleus (-1.7% decrease per decade, p= 0.0025) only. There was no association between sex and C-UCB-J SUVR, nor an interaction between aging and sex for this parameter.

Conclusion: In vivo, PET using C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117877DOI Listing
May 2021

Predictive value of metabolic and perfusion changes outside the seizure onset zone for postoperative outcome in patients with refractory focal epilepsy.

Acta Neurol Belg 2021 Feb 5. Epub 2021 Feb 5.

Division of Nuclear Medicine, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

The value of functional molecular changes outside the seizure onset zone as independent predictive factors of surgical outcome has been scarcely evaluated. The aim of this retrospective study was to evaluate relative metabolic and perfusion changes outside the seizure onset zone as predictors of postoperative outcome in patients with unifocal refractory focal epilepsy. Eighty-six unifocal epilepsy patients who underwent F-FDG PET prior to surgery were included. Ictal and interictal perfusion SPECT was available in 65 patients. Good postoperative outcome was defined as the International League against Epilepsy class 1. Using univariate statistical analysis, the predictive ability of volume-of-interest based relative metabolism/perfusion for outcome classification was quantified by AUC ROC-curve, using composite, unilateral cortical (frontal, orbitofrontal, temporal, parietal, occipital) and central volumes-of-interest. The results were cross-validated, and a false discovery rate (FDR) correction was applied. As a secondary objective, a subgroup analysis was performed on temporal lobe epilepsy patients (N = 64). Increased relative ictal perfusion in the contralateral central volume-of-interest was significantly associated with the good surgical outcome both in the total population (AUC 0.79, p = 0.009) and the temporal lobe epilepsy subgroup (AUC 0.80, p = 0.028). No other significant associations between functional molecular changes and postoperative outcome were found. Increased relative ictal perfusion in the contralateral central region significantly predicted outcome after epilepsy surgery in patients with refractory focal epilepsy. We postulate that these relative perfusion changes could be an expression of better preoperative neuronal network integration and centralization in the contralateral central structures, which is suggested to be associated with better postoperative outcome.
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http://dx.doi.org/10.1007/s13760-020-01569-yDOI Listing
February 2021

The Leuven late life depression (L3D) study: PET-MRI biomarkers of pathological brain ageing in late-life depression: study protocol.

BMC Psychiatry 2021 01 28;21(1):64. Epub 2021 Jan 28.

Geriatric Psychiatry, University Psychiatric Center KU Leuven, B-3000, Leuven, Belgium.

Background: Major depressive disorders rank in the top ten causes of ill health in all but four countries worldwide and are the leading cause of years lived with disability in Europe (WHO). Recent research suggests that neurodegenerative pathology may contribute to the development of late-life depression (LLD) in a sub-group of patients and represent a target for prevention and early diagnosis. In parallel, electroconvulsive therapy (ECT), which is the most effective treatment for severe LLD, has been associated with significant brain structural changes. In both LLD and ECT hippocampal volume change plays a central role; however, the neurobiological mechanism underlying it and its relevance for clinical outcomes remain unresolved.

Methods: This is a monocentric, clinical cohort study with a cross-sectional arm evaluating PET-MR imaging and behavioural measures in 64 patients with LLD compared to 64 healthy controls, and a longitudinal arm evaluating the same imaging and behavioural measures after 10 ECT sessions in 20 patients receiving ECT as part of their normal clinical management. Triple tracer PET-MRI data will be used to measure: hippocampal volume (high resolution MRI), synaptic density using [C]UCB-J, which targets the Synaptic Vesicle Glycoprotein 2A receptor, tau pathology using [F]MK-6240, and cerebral amyloid using [F]-Flutemetamol, which targets beta-amyloid neuritic plaques in the brain. Additional MRI measures and ultrasound will assess cerebral vascular structure and brain connectivity. Formal clinical and neuropsychological assessments will be conducted alongside experience sampling and physiological monitoring to assess mood, stress, cognition and psychomotor function.

Discussion: The main aim of the study is to identify the origin and consequences of hippocampal volume differences in LLD by investigating how biomarkers of pathological ageing contribute to medial temporal lobe pathology. Studying how synaptic density, tau, amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT, will increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations occurring in depression and what effect this has on clinical outcome. It may also lead to improvements in the differential diagnosis of depression and dementia yielding earlier, more optimal, cost-effective clinical management. Finally, it will improve our understanding of the neurobiological mechanism of ECT.

Trial Registration: ClinicalTrials.gov Identifier: NCT03849417 , 21/2/2019.
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http://dx.doi.org/10.1186/s12888-021-03063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845114PMC
January 2021

In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences.

J Cereb Blood Flow Metab 2021 08 14;41(8):1978-1987. Epub 2021 Jan 14.

Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [C]UCB-J were indeed highly significantly correlated ( > 0.47,  < 0.001). However, regional differences in relative [F]FDG and [C]UCB-J uptake were observed, with up to 19% higher [C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.
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http://dx.doi.org/10.1177/0271678X20981502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327121PMC
August 2021

A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate.

Nature 2021 02 1;590(7845):320-325. Epub 2020 Dec 1.

KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Virology and Chemotherapy, Molecular Vaccinology and Vaccine Discovery, KU Leuven, Leuven, Belgium.

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and-concomitantly-protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.
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http://dx.doi.org/10.1038/s41586-020-3035-9DOI Listing
February 2021

Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach.

Brain Commun 2020 2;2(2):fcaa183. Epub 2020 Nov 2.

Epilepsy Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain.

Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10-15% transient GABA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo  = 26; padsevonil  = 24). Their median age was 36 years (range 18-60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14;  = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted  = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.
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http://dx.doi.org/10.1093/braincomms/fcaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677606PMC
November 2020

STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters.

Nat Commun 2020 11 17;11(1):5838. Epub 2020 Nov 17.

Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven Department of Microbiology, Immunology and Transplantation, 3000, Leuven, Belgium.

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.
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http://dx.doi.org/10.1038/s41467-020-19684-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672082PMC
November 2020
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