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Mark Lubberink

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YNICL Journal 2026 Journal Article

A data-driven SSM/PCA analysis approach for differential diagnosis of parkinsonism using 11C-PE2I PET

  • Linus Falk
  • Carl Brunius
  • Tea Crnic Bojkovic
  • Lieuwe Appel
  • Charles Widström
  • Dag Nyholm
  • Torsten Danfors
  • My Jonasson

Single-reference SSM/PCA can be unstable in clinical datasets with uncertain labels. Ensemble-SSM/PCA improves robustness through repeated reference sampling. High balanced accuracy achieved on an independent hold-out test set. Our results highlight the potential of an ensemble-based SSM/PCA method to assist differential diagnosis of parkinsonism. Future work will focus on including additional atypical parkinsonian disorders.

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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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YNICL Journal 2020 Journal Article

Image reconstruction methods affect software-aided assessment of pathologies of [18F]flutemetamol and [18F]FDG brain-PET examinations in patients with neurodegenerative diseases

  • Elin Lindström
  • Jenny Oddstig
  • Torsten Danfors
  • Jonas Jögi
  • Oskar Hansson
  • Mark Lubberink

PURPOSE: To assess how some of the new developments in brain positron emission tomography (PET) image reconstruction affect quantitative measures and software-aided assessment of pathology in patients with neurodegenerative diseases. METHODS: F]FDG PET scans. Reconstructed images were obtained by ordered-subsets expectation maximization (OSEM; 3 iterations (i), 16/34 subsets (s), 3/5-mm filter, ±time-of-flight (TOF), ±point-spread function (PSF)) and block-sequential regularized expectation maximization (BSREM; TOF, PSF, β-value 75-300). Standardized uptake value ratios (SUVR) and z-scores were calculated (CortexID Suite, GE Healthcare) using cerebellar gray matter, pons, whole cerebellum and whole brain as reference regions. RESULTS: F]FDG, respectively, increased absolute differences between reconstructions methods compared to normalizing to cerebellar gray matter and whole cerebellum when applying TOF, PSF and BSREM. CONCLUSIONS: Software-aided assessment of patient pathologies should be used with caution when employing other image reconstruction methods than those used for acquisition of the normal database.

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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 2015 Journal Article

Parametric imaging and quantitative analysis of the PET amyloid ligand [ 18 F]flutemetamol

  • Kerstin Heurling
  • Chris Buckley
  • Koen Van Laere
  • Rik Vandenberghe
  • Mark Lubberink

Objectives The amyloid imaging PET tracer [18F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of β-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling. Methods The cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time–activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels. Results The highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2′ (R2 =0. 98), or using a cohort mean k2′ (R2 =0. 97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70–90min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R2 =0. 97, RPM R2 =0. 96 and SUVR R2 =0. 95) Poorest agreement was seen with MRTM without pre-filtering (R2 =0. 68). Conclusions Parametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake.

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YNIMG Journal 2013 Journal Article

Validation of parametric methods for [11C]PE2I positron emission tomography

  • My Jonasson
  • Lieuwe Appel
  • Jonas Engman
  • Andreas Frick
  • Dag Nyholm
  • Håkan Askmark
  • Torsten Danfors
  • Jens Sörensen

Objectives The radioligand [11C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [11C]PE2I. The purpose of this study was to evaluate different methods for producing [11C]PE2I parametric images, showing binding potential (BPND) and relative delivery (R1) at the voxel level, using clinical data as well as simulations. Methods Investigations were made in twelve subjects either with social anxiety disorder (n=6) or parkinsonian syndrome (n=6), each receiving an 80min dynamic PET scan. All subjects underwent a T1-weighted MRI scan which was co-registered to the PET images and used for definition of regions of interest using a probabilistic template (PVElab). Two basis function implementations (receptor parametric mapping: RPM, RPM2) of the simplified reference tissue model (SRTM) and three multilinear reference tissue models (MRTMo, MRTM and MRTM2) were used for computation of parametric BPND and R1 images. In addition, reference Logan and standard uptake value ratio (SUVr) were investigated. Evaluations of BPND and R1 images were performed using linear regression to compare the parametric methods to region-based analyses with SRTM and cerebellar gray matter as reference region. Accuracy and precision of each method were assessed by simulations. Results Correlation and slope of linear regression between parametric and region-based BPND and R1 values in both striatum and extra-striatal regions were optimal for RPM (R2 =0. 99 for both BPND and R1; slopes 0. 99 and 0. 98 for BPND and R1, respectively, in striatum). In addition, accuracy and precision were best for RPM and RPM2. Conclusion The basis function methods provided more robust estimations of the parameters compared to the other models and performed best in simulations. RPM, a basis function implementation of SRTM, is the preferred method for voxel level analysis of [11C]PE2I PET studies.

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