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  • 1.
    Boersma, Greta J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Johansson, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lau Börjesson, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Katsogiannos, Petros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Skrtic, S.
    AstraZeneca, R&D, Gothenburg, Sweden.;AstraZeneca, Dept Med, Gothenburg, Sweden..
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Glucose uptake in skeletal muscle, brain and visceral adipose tissue assessed with PET/MR strongly predicts whole body glucose uptake during hyperinsulinaemia2017Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, s. S80-S80Artikkel i tidsskrift (Annet vitenskapelig)
  • 2.
    Boersma, Greta J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Johansson, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden.
    Skrtic, Stanko
    Lau, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Katsogiannos, Petros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Panagiotou, Grigorios
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical, Mölndal, Sweden.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical, Mölndal, Sweden.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study2018Inngår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 50, nr 8, s. 627-639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

  • 3.
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Characterization of [18F]flutemetamol binding properties: A β-amyloid PET imaging ligand2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The criteria for diagnosing Alzheimer’s disease (AD) have recently been revised to include the use of biomarkers for the in vivo presence of β-amyloid, one of the neuropathological hallmarks of AD. Examples of such biomarkers are positron emission tomography (PET) β-amyloid specific ligands, including [18F]flutemetamol. The aim of this thesis was to characterize the binding properties of [18F]flutemetamol from a tracer kinetic perspective as well as by validating binding measures through comparison with tissue pathology assessments. The applicability of previously developed kinetic models of tracer binding for voxel-based analysis was examined and compared to arterial input compartment modelling, the “gold standard” for PET quantification. Several voxel-based methods were found to exhibit high correlations with compartment modelling, including the semi-quantitative standardized uptake value ratio (SUVR). The kinetic components of [18F]flutemetamol uptake were also investigated without model assumptions using the data driven method spectral analysis, with binding to β-amyloid shown to relate to a slow kinetic component. The same component was also found to predominate in the uptake of white matter, known to be free of β-amyloid accumulation. White matter uptake was however possible to separate from β-amyloid binding based on the relative contribution of the slow component to the total volume of distribution. Uptake of [18F]flutemetamol as quantified using SUVR or assessed visually was found to correlate well with tissue pathology assessments. Classifying the brains of 68 deceased subjects who had undergone [18F]flutemetamol PET scanning ante mortem, based on the spatial distribution of β-amyloid according to pre-defined phases, revealed that abnormal uptake patterns of [18F]flutemetamol were only certain to be found in the last phase of β-amyloid accumulation. In the same cohort however, [18F]flutemetamol was also shown to accurately distinguish between subjects with AD and non-AD dementia. While this supports the use of [18F]flutemetamol in clinical settings for ruling out AD, the association of abnormal [18F]flutemetamol uptake to late phases of β-amyloid accumulation may limit the detection of early accumulation and pre-clinical stages of AD. It remains to be investigated whether application of voxel-based methods and slow component filtering may increase sensitivity, particularly in the context of clinical trials.

    Delarbeid
    1. Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.
    Åpne denne publikasjonen i ny fane eller vindu >>Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.
    Vise andre…
    2015 (engelsk)Inngår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 121, s. 184-192Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: The amyloid imaging PET tracer [(18)F]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' (R(2)=0.98), or using a cohort mean k2' (R(2)=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 R(2)=0.97, RPM R(2)=0.96 and SUVR R(2)=0.95) Poorest agreement was seen with MRTM without pre-filtering (R(2)=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.

    Emneord
    PET; Amyloid imaging; [F-18]flutemetamol; Parametric imaging
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261034 (URN)10.1016/j.neuroimage.2015.07.037 (DOI)000363122000017 ()26209803 (PubMedID)
    Tilgjengelig fra: 2015-08-28 Laget: 2015-08-28 Sist oppdatert: 2017-12-04bibliografisk kontrollert
    2. Separation of β-amyloid binding and white matter uptake of [18F]flutemetamol using spectral analysis
    Åpne denne publikasjonen i ny fane eller vindu >>Separation of β-amyloid binding and white matter uptake of [18F]flutemetamol using spectral analysis
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Annet vitenskapelig) In press
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-262077 (URN)
    Tilgjengelig fra: 2015-09-08 Laget: 2015-09-08 Sist oppdatert: 2015-11-10
    3. An exploratory efficacy study of the amyloid imaging agent [F-18]flutemetamol in Japanese Subjects
    Åpne denne publikasjonen i ny fane eller vindu >>An exploratory efficacy study of the amyloid imaging agent [F-18]flutemetamol in Japanese Subjects
    Vise andre…
    2015 (engelsk)Inngår i: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 29, nr 5, s. 391-399Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The aim of the study presented was to investigate the brain uptake properties of the amyloid PET agent [F-18]flutemetamol in Japanese healthy controls and clinically probable Alzheimer's disease (AD) patients, and to make a comparison with the results of a previously performed study on Caucasian subjects. [F-18]flutemetamol was recently approved by the American Food and Drug Administration and the European Medicines Agency for visualization of amyloid in vivo. Since the first clinical study of [F-18]flutemetamol-an F-18 derivative of the PET tracer 11C-Pittsburgh Compound B targeting beta-amyloid--took place, several clinical studies have been performed, but few focusing on a Japanese population. In the Step A, three elderly healthy volunteers and three AD subjects underwent dynamic PET scanning 0-30 and 60-150 min after injection of 185 MBq [F-18]flutemetamol. The brain volume of distribution (V-T) was quantified using Logan's linear graphical analysis and as standardized uptake value ratios (SUVR) with a cerebellar reference. The optimal acquisition window was determined from brain time activity curves for Step B. In the Step B, 5 AD and 5 elderly healthy volunteers were scanned from 80 to 140 min after intravenous injection of [F-18]flutemetamol. The data from the two parts were pooled for estimation of overall efficacy. [F-18]Flutemetamol injection was shown to be safe-no serious adverse events were reported during this study. A simplified SUVR estimate of the uptake of [F-18]flutemetamol using a time window of 85-115 min post injection successfully discriminated AD cases from healthy volunteers. AD subjects showed an elevated tracer uptake in prefrontal cortex, the lateral temporal cortex and precuneus amongst other regions. No significant [F-18]flutemetamol PET differences could be seen between the Japanese AD cases in this study and those from an earlier Caucasian study, or between control subjects in Japanese and Caucasian studies. This study supports the use of [F-18]flutemetamol PET in Japanese population as a marker of the presence of fibrillar beta-amyloid. The lack of differences between the Japanese cohort and those from a previous Caucasian cohort supports the extrapolation of results from other Caucasian [F-18]flutemetamol PET studies to the Japanese population.

    Emneord
    [F-18] flutemetamol, Alzheimer's disease, Amyloid beta, Japanese population, Positron emission tomography
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-258778 (URN)10.1007/s12149-015-0957-7 (DOI)000356938000001 ()25874747 (PubMedID)
    Tilgjengelig fra: 2015-07-20 Laget: 2015-07-20 Sist oppdatert: 2017-12-04bibliografisk kontrollert
    4. Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.
    Åpne denne publikasjonen i ny fane eller vindu >>Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.
    Vise andre…
    2013 (engelsk)Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 20, nr 7, s. 1043-52Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical biopsy.

    METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain.

    RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-β levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003).

    CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-β in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-β pathology, both in patients with possible NPH and among the wider population.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261037 (URN)10.1111/ene.12102 (DOI)23398333 (PubMedID)
    Tilgjengelig fra: 2015-08-28 Laget: 2015-08-28 Sist oppdatert: 2017-12-04
    5. Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
    Åpne denne publikasjonen i ny fane eller vindu >>Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
    Vise andre…
    2014 (engelsk)Inngår i: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 2, s. 46-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    INTRODUCTION: PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.

    RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.

    CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261036 (URN)10.1186/2051-5960-2-46 (DOI)24755237 (PubMedID)
    Tilgjengelig fra: 2015-08-28 Laget: 2015-08-28 Sist oppdatert: 2017-05-10
    6. [(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology.
    Åpne denne publikasjonen i ny fane eller vindu >>[(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology.
    Vise andre…
    2015 (engelsk)Inngår i: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, nr 8, s. 975-85Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Amyloid positron emission tomography (PET) has become an important tool to identify amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [(18)F]flutemetamol in relation to Aβ pathology at autopsy.

    METHODS: [(18)F]flutemetamol PET was carried out in a cohort of 68 patients included in a [(18)F]flutemetamol amyloid PET imaging end-of-life study (GE067-007). At autopsy, AD pathology was determined and Aβ plaque pathology was classified into phases of its regional distribution (0-5).

    RESULTS: [(18)F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aβ pathology (Aβ phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non-AD dementia cases with initial Aβ phases 1 and 2, whereas 33.3% of the phase 3 cases were positive.

    CONCLUSIONS: [(18)F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261035 (URN)10.1016/j.jalz.2015.05.018 (DOI)000360912300009 ()26141264 (PubMedID)
    Tilgjengelig fra: 2015-08-28 Laget: 2015-08-28 Sist oppdatert: 2017-12-04bibliografisk kontrollert
  • 4.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Buckley, C.
    GE Healthcare, Life Sci, Amersham, England..
    Van Laere, K.
    KU Leuven Hosp, Nucl Med & Mol Imaging, Leuven, Belgium..
    Vandenberghe, R.
    KU Leuven Hosp, Expt Neurol, Leuven, Belgium..
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Spectral analysis of [18f]flutemetamol grey and white matter kinetics2016Inngår i: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 36, nr Suppl. 1, s. 80-81, artikkel-id 154Artikkel i tidsskrift (Annet vitenskapelig)
  • 5.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Buckley, Chris
    Van Laere, Koen
    Vandenberghe, Rik
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Akademiska sjukhuset.
    Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.2015Inngår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 121, s. 184-192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: The amyloid imaging PET tracer [(18)F]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' (R(2)=0.98), or using a cohort mean k2' (R(2)=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 R(2)=0.97, RPM R(2)=0.96 and SUVR R(2)=0.95) Poorest agreement was seen with MRTM without pre-filtering (R(2)=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.

  • 6.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Buckley, Christopher
    Vandenberghe, Rik
    Laere, Koen Van
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Separation of β-amyloid binding and white matter uptake of (18)F-flutemetamol using spectral analysis.2015Inngår i: American journal of nuclear medicine and molecular imaging, ISSN 2160-8407, Vol. 5, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The kinetic components of the β-amyloid ligand (18)F-flutemetamol binding in grey and white matter were investigated through spectral analysis, and a method developed for creation of parametric images separating grey and white matter uptake. Tracer uptake in grey and white matter and cerebellar cortex was analyzed through spectral analysis in six subjects, with (n=4) or without (n=2) apparent β-amyloid deposition, having undergone dynamic (18)F-flutemetamol scanning with arterial blood sampling. The spectra were divided into three components: slow, intermediate and fast basis function rates. The contribution of each of the components to total volume of distribution (VT) was assessed for different tissue types. The slow component dominated in white matter (average 90%), had a higher contribution to grey matter VT in subjects with β-amyloid deposition (average 44%) than without (average 6%) and was absent in cerebellar cortex, attributing the slow component of (18)F-flutemetamol uptake in grey matter to β-amyloid binding. Parametric images of voxel-based spectral analysis were created for VT, the slow component and images segmented based on the slow component contribution; confirming that grey matter and white matter uptake can be discriminated on voxel-level using a threshold for the contribution from the slow component to VT.

  • 7.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Buckley, Christopher
    GE Healthcare, Amersham, UK.
    Vandenberghe, Rik
    Department of Neurosciences, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
    Van Laere, Koen
    Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Medical Physics, Akademiska sjukhuset.
    Separation of β-amyloid binding and white matter uptake of [18F]flutemetamol using spectral analysisArtikkel i tidsskrift (Annet vitenskapelig)
  • 8.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden.
    Leuzy, Antoine
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Zimmer, Eduardo R
    Nordberg, Agneta
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Quantitative positron emission tomography in brain research2017Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1670, s. 220-234, artikkel-id S0006-8993(17)30270-6Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The application of positron emission tomography (PET) in brain research has increased substantially during the past 20 years, and is still growing. PET provides a unique insight into physiological and pathological processes in vivo. In this article we introduce the fundamentals of PET, and the methods available for acquiring quantitative estimates of the parameters of interest. A short introduction to different areas of application is also given, including basic research of brain function and in neurology, psychiatry, drug receptor occupancy studies, and its application in diagnostics of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Our aim is to inform the unfamiliar reader of the underlying basics and potential applications of PET, hoping to inspire the reader into considering how the technique could be of benefit for his or her own research.

  • 9.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Leuzy, Antoine
    Zimmer, Eduardo R
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Nordberg, Agneta
    Imaging β-amyloid using [(18)F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, nr 2, s. 362-373Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In Alzheimer's disease (AD), the deposition of β-amyloid (Aβ) is hypothesized to result in a series of secondary neurodegenerative processes, leading ultimately to synaptic dysfunction and neuronal loss. Since the advent of the first Aβ-specific positron emission tomography (PET) ligand, (11)C-Pittsburgh compound B ([(11)C]PIB), several (18)F ligands have been developed that circumvent the limitations of [(11)C]PIB tied to its short half-life. To date, three such compounds have been approved for clinical use by the US and European regulatory bodies, including [(18)F]AV-45 ([(18)F]florbetapir; Amyvid™), [(18)F]-BAY94-9172 ([(18)F]florbetaben; Neuraceq™) and [(18)F]3'-F-PIB ([(18)F]flutemetamol; Vizamyl™). The present review aims to summarize and discuss the currently available knowledge on [(18)F]flutemetamol PET. As the (18)F analogue of [(11)C]PIB, [(18)F]flutemetamol may be of use in the differentiation of AD from related neurodegenerative disorders and may help with subject selection and measurement of target engagement in the context of clinical trials testing anti-amyloid therapeutics. We will also discuss its potential use in non-AD amyloidopathies.

  • 10.
    Heurling, Kerstin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Moreno, Anaisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala Univ, Uppsala, Sweden..
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Rosqvist, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Univ Uppsala Hosp, Uppsala, Sweden..
    Eriksson, J. P.
    Univ Uppsala Hosp, Uppsala, Sweden..
    Nordeman, Patrik
    Univ Uppsala Hosp, Uppsala, Sweden..
    Sprycha, M.
    Univ Uppsala Hosp, Uppsala, Sweden..
    Wilking, H.
    Univ Uppsala Hosp, Uppsala, Sweden..
    Edner, A. Gronowski
    Univ Uppsala Hosp, Uppsala, Sweden..
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Univ Uppsala Hosp, Uppsala, Sweden..
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Univ Uppsala Hosp, Uppsala, Sweden..
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Impact of overfeeding with saturated and polyunsaturated fat on hepatic [C-11]palmitate uptake and fat content using PET-MR2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, s. S448-S448Artikkel i tidsskrift (Fagfellevurdert)
  • 11. Ikonomovic, Milos D
    et al.
    Buckley, Chris J
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. GE Healthcare, S-75184 Uppsala, Sweden.
    Sherwin, Paul
    Jones, Paul A
    Zanette, Michelle
    Mathis, Chester A
    Klunk, William E
    Chakrabarty, Aruna
    Ironside, James
    Ismail, Azzam
    Smith, Colin
    Thal, Dietmar R
    Beach, Thomas G
    Farrar, Gill
    Smith, Adrian P L
    Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection2016Inngår i: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 4, artikkel-id 130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [(18)F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [(18)F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [(18)F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of β-amyloid deposits were [(18)F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [(18)F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [(18)F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of β-amyloid pathology detectable with [(18)F]flutemetamol PET imaging.

  • 12.
    Johansson, Emil
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala Örebro-Reg Res Council, Uppsala.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Skrtic, Stanko
    AstraZeneca R&D, Gothenburg; Sahlgrenska Academy at Gothenburg University, Gothenburg.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical, Mölndal.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical, Mölndal.
    Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study.2018Inngår i: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 286, nr 1, s. 271-278Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose

    To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (18F) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value).

    Materials and Methods

    An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated 18F-FDG tissue influx rate (Ki) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and Ki were studied in multiple tissues by using the Pearson correlation.

    Results

    Positive correlations were found between M value and Ki in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P , .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 20.798; P = .006). The MR imaging–based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions.

    Conclusion

    This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated 18F-FDG influx rates, tissue depots, and M value.

  • 13.
    Jonasson, My
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Univ Uppsala Hosp, Uppsala, Sweden..
    Wall, Anders
    Univ Uppsala Hosp, Uppsala, Sweden..
    Chiotis, K.
    Karolinska Inst, Stockholm, Sweden..
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Saint-Aubert, L.
    Karolinska Inst, Stockholm, Sweden..
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Univ Uppsala Hosp, Uppsala, Sweden..
    Nordberg, A.
    Karolinska Inst, Stockholm, Sweden..
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Univ Uppsala Hosp, Uppsala, Sweden..
    Supervised Cluster Analysis for Automatic Extraction of Reference Region in Dynamic [F-18]THK5317 PET2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, s. S25-S25Artikkel i tidsskrift (Fagfellevurdert)
  • 14. Leinonen, V
    et al.
    Rinne, J O
    Virtanen, K A
    Eskola, O
    Rummukainen, J
    Huttunen, J
    von Und Zu Fraunberg, M
    Nerg, O
    Koivisto, A M
    Rinne, J
    Jääskeläinen, J E
    Buckley, C
    Smith, A
    Jones, P A
    Sherwin, P
    Farrar, G
    McLain, R
    Kailajärvi, M
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Grachev, I D
    Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.2013Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 20, nr 7, s. 1043-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical biopsy.

    METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain.

    RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-β levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003).

    CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-β in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-β pathology, both in patients with possible NPH and among the wider population.

  • 15. Leinonen, Ville
    et al.
    Rinne, Juha O
    Wong, Dean F
    Wolk, David A
    Trojanowski, John Q
    Sherwin, Paul F
    Smith, Adrian
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Su, Mandy
    Grachev, Igor D
    Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.2014Inngår i: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 2, s. 46-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.

    RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.

    CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.

  • 16. Leuzy, Antoine
    et al.
    Zimmer, Eduardo Rigon
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Rosa-Neto, Pedro
    Gauthier, Serge
    Use of amyloid PET across the spectrum of Alzheimer's disease: clinical utility and associated ethical issues2014Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, nr 3, s. 143-148Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Recent advances have made possible the in vivo detection of beta-amyloid (Ab) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Ab among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.

  • 17.
    Miki, Takami
    et al.
    Osaka City Univ Hosp, Dept Geriatr, Abeno Ku, 5-7 Asahi Machi 1 Chome, Osaka, Japan.;Izumiotsu Municipal Hosp, Shimojyo Chou 16-1, Izumiotsu, Osaka 5950027, Japan..
    Shimada, Hiroyuki
    Osaka City Univ Hosp, Dept Geriatr, Abeno Ku, 5-7 Asahi Machi 1 Chome, Osaka, Japan..
    Kim, Jae-Seung
    Asan Med Ctr, Dept Nucl Med, 388-1 Pungnap 2 Dong, Seoul, South Korea..
    Yamamoto, Yasuji
    Kobe Univ Hosp, Neuropsychiat Dept, Chuo Ku, 5-2 Kusunoki Cho 7 Chome, Kobe, Hyogo, Japan..
    Sugino, Masakazu
    Aino Hosp, Ctr Geriatr Somatopsychol Care, 11-18 Takada Cho, Ibaraki, Osaka, Japan..
    Kowa, Hisatomo
    Kobe Univ Hosp, Dept Neurol, Chuo Ku, 5-2 Kusunoki Cho 7 Chome, Kobe, Hyogo, Japan..
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. GE Healthcare, Uppsala, Sweden.
    Zanette, Michelle
    GE Healthcare, Marlborough, MA USA..
    Sherwin, Paul F.
    GE Healthcare, Marlborough, MA USA..
    Senda, Michio
    Inst Biomed Res & Innovat Hosp, Positron Med Dept, Chuo Ku, 2 Minatojima Minami Machi 2 Chome, Kobe, Hyogo, Japan..
    Brain uptake and safety of Flutemetamol F 18 injection in Japanese subjects with probable Alzheimer's disease, subjects with amnestic mild cognitive impairment and healthy volunteers2017Inngår i: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 31, nr 3, s. 260-272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective This Phase 2 study assessed the performance of positron emission tomography (PET) brain images made with Flutemetamol F 18 Injection in detecting beta-amyloid neuritic plaques in Japanese subjects. Methods Seventy subjects (25 with probable Alzheimer's disease (pAD), 20 with amnestic mild cognitive impairment (aMCI), and 25 cognitively normal healthy volunteers[HVs]) underwent PET brain imaging after intravenous Flutemetamol F 18 Injection (185 MBq). Images were interpreted as normal or abnormal for neuritic plaque density by each of five non-Japanese and five Japanese readers who were blinded to clinical data. The primary efficacy analysis (based on HV and pAD data) was the agreement of the non-Japanese readers' image interpretations with the clinical diagnosis, resulting in estimates of positive percent agreement (PPA; based on AD subjects; similar to sensitivity) and negative percent agreement (NPA; based on HVs; similar to specificity). Secondary analyses included PPA and NPA for the Japanese readers; inter-reader agreement (IRA); intra-reader reproducibility (IRR); quantitative image interpretations (standardized uptake value ratios [SUVRs]) by diagnostic subgroup; test-retest variability in five pAD subjects; and safety. Results PPA was 92% for all non-Japanese readers and ranged from 88 to 92% for the Japanese readers. NPA ranged from 96 to 100% for both the non-Japanese readers and the Japanese readers. The majority image interpretations (the interpretations made independently by ae<yen>3 of 5 readers) resulted in PPA values of 92 and 92% and NPA values of 100 and 96% for the non-Japanese and Japanese readers, respectively. IRA and IRR were strong. Composite SUVR values (mean of multiple regional values) allowed clear differentiation between pAD subjects and HVs. Test-retest variability ranged from 1.14 to 2.27%, and test-retest agreement of the blinded visual interpretations was 100% for all readers. Flutemetamol F 18 Injection was generally well tolerated. Conclusion The detection of brain neuritic plaques in Japanese subjects using [F-18]Flutemetamol PET images gave results highly consistent with clinical diagnosis, with non-Japanese and Japanese readers giving similar results. Inter-reader agreement and intra-reader reproducibility were high for both sets of readers. Visual delineation of abnormal and normal scans was corroborated by quantitative assessment, with low test-retest variability.

  • 18. Senda, Michio
    et al.
    Yamamoto, Yasuji
    Sasaki, Masahiro
    Yamane, Tomohiko
    Brooks, David J.
    Farrar, Gill
    McParland, Brian
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    An exploratory efficacy study of the amyloid imaging agent [F-18]flutemetamol in Japanese Subjects2015Inngår i: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 29, nr 5, s. 391-399Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of the study presented was to investigate the brain uptake properties of the amyloid PET agent [F-18]flutemetamol in Japanese healthy controls and clinically probable Alzheimer's disease (AD) patients, and to make a comparison with the results of a previously performed study on Caucasian subjects. [F-18]flutemetamol was recently approved by the American Food and Drug Administration and the European Medicines Agency for visualization of amyloid in vivo. Since the first clinical study of [F-18]flutemetamol-an F-18 derivative of the PET tracer 11C-Pittsburgh Compound B targeting beta-amyloid--took place, several clinical studies have been performed, but few focusing on a Japanese population. In the Step A, three elderly healthy volunteers and three AD subjects underwent dynamic PET scanning 0-30 and 60-150 min after injection of 185 MBq [F-18]flutemetamol. The brain volume of distribution (V-T) was quantified using Logan's linear graphical analysis and as standardized uptake value ratios (SUVR) with a cerebellar reference. The optimal acquisition window was determined from brain time activity curves for Step B. In the Step B, 5 AD and 5 elderly healthy volunteers were scanned from 80 to 140 min after intravenous injection of [F-18]flutemetamol. The data from the two parts were pooled for estimation of overall efficacy. [F-18]Flutemetamol injection was shown to be safe-no serious adverse events were reported during this study. A simplified SUVR estimate of the uptake of [F-18]flutemetamol using a time window of 85-115 min post injection successfully discriminated AD cases from healthy volunteers. AD subjects showed an elevated tracer uptake in prefrontal cortex, the lateral temporal cortex and precuneus amongst other regions. No significant [F-18]flutemetamol PET differences could be seen between the Japanese AD cases in this study and those from an earlier Caucasian study, or between control subjects in Japanese and Caucasian studies. This study supports the use of [F-18]flutemetamol PET in Japanese population as a marker of the presence of fibrillar beta-amyloid. The lack of differences between the Japanese cohort and those from a previous Caucasian cohort supports the extrapolation of results from other Caucasian [F-18]flutemetamol PET studies to the Japanese population.

  • 19. Thal, Dietmar Rudolf
    et al.
    Beach, Thomas G
    Zanette, Michelle
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Chakrabarty, Aruna
    Ismail, Azzam
    Smith, Adrian P L
    Buckley, Christopher
    [(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology.2015Inngår i: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, nr 8, s. 975-85Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Amyloid positron emission tomography (PET) has become an important tool to identify amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [(18)F]flutemetamol in relation to Aβ pathology at autopsy.

    METHODS: [(18)F]flutemetamol PET was carried out in a cohort of 68 patients included in a [(18)F]flutemetamol amyloid PET imaging end-of-life study (GE067-007). At autopsy, AD pathology was determined and Aβ plaque pathology was classified into phases of its regional distribution (0-5).

    RESULTS: [(18)F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aβ pathology (Aβ phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non-AD dementia cases with initial Aβ phases 1 and 2, whereas 33.3% of the phase 3 cases were positive.

    CONCLUSIONS: [(18)F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

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