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  • 1.
    Altomare, Daniele
    et al.
    Univ Geneva, Lab Neuroimaging Aging LANVIE, Geneva, Switzerland;Memory Clin, Univ Hosp Geneva, Geneva, Switzerland.
    Ferrari, Clarissa
    IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Serv Stat, Via Pilastroni 4, I-25125 Brescia, Italy.
    Caroli, Anna
    Ist Ric Farmacol Mario Negri IRCCS, Med Imaging Unit, Bergamo, Italy.
    Galluzzi, Samantha
    IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, LANE, Brescia, Italy.
    Prestia, Annapaola
    IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, LANE, Brescia, Italy.
    van der Flier, Wiesje M.
    Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Alzheimer Ctr Amsterdam,Dept Neurol, Amsterdam, Netherlands;Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Dept Epidemiol & Biostat, Amsterdam, Netherlands.
    Ossenkoppele, Rik
    Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Alzheimer Ctr Amsterdam,Dept Neurol, Amsterdam, Netherlands;Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam, Netherlands;Lund Univ, Dept Clin Sci, Clin Memory Res Unit, Malmo, Sweden.
    Van Berckel, Bart
    Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Alzheimer Ctr Amsterdam,Dept Neurol, Amsterdam, Netherlands;Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam, Netherlands.
    Barkhof, Frederik
    Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam, Netherlands;UCL, Inst Neurol, London, England;UCL, Inst Healthcare Engn, London, England.
    Teunissen, Charlotte E.
    Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Dept Clin Chem,Neurochem Lab, Amsterdam, Netherlands.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carter, Stephen F.
    Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden;Univ Manchester, Wolfson Mol Imaging Ctr, Manchester, Lancs, England.
    Scholl, Michael
    Lund Univ, Dept Clin Sci, Clin Memory Res Unit, Malmo, Sweden;Univ Gothenburg, Dept Psychiat & Neurochem, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden;UCL, Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, Queen Sq, London, England.
    Choo, Il Han
    Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden;Chosun Univ, Sch Med, Dept Neuropsychiat, Gwangju, South Korea.
    Grimmer, Timo
    Tech Univ Munich, Dept Psychiat & Psychotherapy, Klinikum Rechts Isar, Munich, Germany.
    Redolfi, Alberto
    IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, LANE, Brescia, Italy.
    Nordberg, Agneta
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden;Karolinska Univ Hosp, Aging Theme, Stockholm, Sweden.
    Scheltens, Philip
    Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Neurosci, Alzheimer Ctr Amsterdam,Dept Neurol, Amsterdam, Netherlands.
    Drzezga, Alexander
    Univ Cologne, Dept Nucl Med, Cologne, Germany.
    Frisoni, Giovanni B.
    Univ Geneva, Lab Neuroimaging Aging LANVIE, Geneva, Switzerland;IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, LANE, Brescia, Italy;Memory Clin, Univ Hosp Geneva, Geneva, Switzerland.
    Prognostic value of Alzheimer's biomarkers in mild cognitive impairment: the effect of age at onset2019In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 266, no 10, p. 2535-2545Article in journal (Refereed)
    Abstract [en]

    Objective The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer's biomarkers in a large sample of patients with mild cognitive impairment (MCI). Methods We measured A beta 42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers. Results In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease. Discussion FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.

  • 2.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital. Uppsala Univ, Uppsala, Sweden..
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Striatal Phosphodiesterase 10A and Medial Prefrontal Cortical Thickness in Patients with Schizophrenia: A PET and MRI Study2017In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 81, no 10, p. S386-S387Article in journal (Other academic)
  • 3.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, no 3, article id e1050Article in journal (Refereed)
    Abstract [en]

    The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [(11)C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [(11)C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [(11)C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [(11)C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

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  • 4.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Larsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Striatal Phosphodiesterase 10A and Thinning of the medial Prefrontal Cortex in Schizophrenia - a PET and MRI study2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S48-S49Article in journal (Refereed)
  • 5. Caroli, A.
    et al.
    Prestia, A.
    Galluzzi, S.
    Ferrari, C.
    van der Flier, W. M.
    Ossenkoppele, R.
    Van Berckel, B.
    Barkhof, F.
    Teunissen, C. E.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Carter, S. F.
    Scholl, M.
    Choo, I. H.
    Grimmer, T.
    Nordberg, A.
    Scheltens, P.
    Drzezga, A.
    Frisoni, G. B.
    Mild cognitive impairment with suspected non AD pathology (SNAP): prediction of progression to dementia2014In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 261, no S1, p. S14-S14, article id OS1103Article in journal (Other academic)
  • 6. Caroli, A.
    et al.
    Prestia, A.
    Galluzzi, S.
    Ferrari, C.
    van der Flier, W. M.
    Ossenkoppele, R.
    Van Berckel, B.
    Barkhof, F.
    Teunissen, C. E.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Carter, S. F.
    Scholl, M.
    Choo, I. H.
    Grimmer, T.
    Nordberg, A.
    Scheltens, P.
    Drzezga, A.
    Frisoni, G. B.
    Mild cognitive impairment with suspected non AD pathology (SNAP): prediction of progression to dementia2014In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 21, p. 19-19Article in journal (Other academic)
  • 7. Caroli, Anna
    et al.
    Prestia, Annapaola
    Galluzzi, Samantha
    Ferrari, Clarissa
    van der Flier, Wiesje M.
    Ossenkoppele, Rik
    Van Berckel, Bart
    Barkhof, Frederik
    Teunissen, Charlotte
    Wall, Anders E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Carter, Stephen F.
    Schoell, Michael
    Choo, Il Han
    Grimmer, Timo
    Redolfi, Alberto
    Nordberg, Agneta
    Scheltens, Philip
    Drzezga, Alexander
    Frisoni, Giovanni B.
    Mild cognitive impairment with suspected nonamyloid pathology (SNAP) Prediction of progression2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 5, p. 508-515Article in journal (Refereed)
    Abstract [en]

    Objectives:The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).Methods:We measured markers of amyloid pathology (CSF -amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [F-18]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.Results:The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE epsilon 4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).Conclusions:Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

  • 8. Carter, Stephen F.
    et al.
    Scholl, Michael
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Nordberg, Agneta
    Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by (11)C-Deuterium-L-Deprenyl: A Multitracer PET Paradigm Combining (11)C-Pittsburgh Compound B and (18)F-FDG2012In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    Astrocytes colocalize with fibrillar amyloid-beta (A beta) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar A beta. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using (11)C-deuterium-L-deprenyl ((11)C-DED) to measure monoamine oxidase B located in astrocytes. Along with (11)C-DED PET, (11)C-Pittsburgh compound B ((11)C-PIB; fibrillar A beta deposition), (18)F-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients. Methods: (11)C-DED PET was performed in MCI patients (n = 8; mean age 6 SD, 62.6 +/- 7.5 y; mean Mini Mental State Examination, 27.5 +/- 2.1), AD patients (n = 7; mean age, 65.1 +/- 6.3 y; mean Mini Mental State Examination, 24.4 +/- 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 +/- 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the (11)C-DED data. (11)C-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional (18)F-FDG uptake and (11)C-PIB retention were calculated for each patient, with cerebellar gray matter as a reference. Results: ANOVA analysis of the regional (11)C-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high (11)C-PIB retention. Increased (11)C-DED binding in most cortical and subcortical regions was observed in MCI (11)C-PIB+ patients relative to controls, MCI (11)C-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers. Conclusion: Increased (11)C-DED binding throughout the brain of the MCI (11)C-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.

  • 9. Chiotis, K
    et al.
    Saint-Aubert, L
    Rodriguez-Vieitez, E
    Leuzy, A
    Almkvist, O
    Savitcheva, I
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nordberg, A
    Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 7, p. 1666-1673Article in journal (Refereed)
    Abstract [en]

    The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [(18)F]THK5317 (tau deposition) and [(18)F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [(11)C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [(18)F]THK5317 retention over time, in contrast to significant decreases in [(18)F]FDG uptake in temporoparietal areas. The pattern of changes in [(18)F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [(18)F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [(18)F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [(11)C]PIB scan, high [(18)F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [(18)F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.Molecular Psychiatry advance online publication, 16 May 2017; doi:10.1038/mp.2017.108.

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  • 10. Chiotis, Konstantinos
    et al.
    Saint-Aubert, Laure
    Savitcheva, Irina
    Jelic, Vesna
    Andersen, Pia
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Nordberg, Agneta
    Imaging in-vivo tau pathology in Alzheimer's disease with THK5317 PET in a multimodal paradigm2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 9, p. 1686-1699Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [(18)F]THK5317 (also known as (S)-[(18)F]THK5117) retention in different stages of Alzheimer's disease; and study any associations with markers of hypometabolism and amyloid-beta deposition.

    METHODS: Thirty-three individuals were enrolled, including nine patients with Alzheimer's disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer's disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [(18)F]THK5317, [(11)C] Pittsburgh compound B ([(11)C]PIB), and [(18)F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [(11)C]PIB-positive (n = 11) and MCI [(11)C]PIB-negative (n = 2) groups.

    RESULTS: Test-retest variability for [(18)F]THK5317-PET was very low (1.17-3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [(11)C]PIB-positive) and dementia-stage Alzheimer's disease had significantly higher [(18)F]THK5317 retention than healthy controls (p = 0.002 and p = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [(18)F]THK5317 retention and [(18)F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [(18)F]THK5317 and [(11)C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [(11)C]PIB but high [(18)F]THK5317 retentions with a different regional distribution from that in Alzheimer's disease patients.

    CONCLUSIONS: The tau-specific PET tracer [(18)F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.

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  • 11.
    Chiotis, Konstantinos
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Nordberg Translat Mol Imaging Lab, Div Clin Geriatr,Ctr Alzheimer Res, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Neurol, Stockholm, Sweden..
    Savitcheva, Irina
    Karolinska Univ Hosp, Med Radiat Phys & Nucl Med, Stockholm, Sweden..
    Poulakis, Konstantinos
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Westman Neuroimaging Grp,Div Clin Geriatr, Stockholm, Sweden..
    Saint-Aubert, Laure
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Nordberg Translat Mol Imaging Lab, Div Clin Geriatr,Ctr Alzheimer Res, Stockholm, Sweden.;Univ Toulouse, Toulouse NeuroImaging Ctr, INSERM, UPS, Toulouse, France..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Nordberg Translat Mol Imaging Lab, Div Clin Geriatr,Ctr Alzheimer Res, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Aging, Stockholm, Sweden..
    [F-18]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer's disease2021In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 26, no 10, p. 5875-5887Article in journal (Refereed)
    Abstract [en]

    Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer's disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [F-18]THK5317, [C-11]PIB and [F-18]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [F-18]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84-1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (beta estimate -33.67 to -31.02,p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58-0.77) and their levels were not associated with the rate of cognitive decline (beta estimate -4.64 to 15.78,p > 0.05). Baseline [F-18]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [F-18]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.

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  • 12. Choo, Il Han
    et al.
    Ni, Ruiqing
    Scholl, Michael
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Almkvist, Ove
    Nordberg, Agneta
    Combination of F-18-FDG PET and Cerebrospinal Fluid Biomarkers as a Better Predictor of the Progression to Alzheimer's Disease in Mild Cognitive Impairment Patients2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, no 4, p. 929-939Article in journal (Refereed)
    Abstract [en]

    The biomarker-based new diagnostic criteria have been proposed for Alzheimer's disease (AD) spectrum. However, any biomarker alone has not been known to have satisfactory AD predictability. We explored the best combination model with baseline demography, neuropsychology, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) biomarkers, and apolipoprotein E (APOE) genotype evaluation to predict progression to AD in mild cognitive impairment (MCI) patients. Alongitudinal clinical follow-up (mean, 44 months; range, 1.6-161.7 months) of MCI patients was done. Among 83 MCI patients, 26 progressed to AD (MCI-AD) and 51 did not deteriorate (MCI-Stable). We applied that univariate and multivariate logistic regression analyses, and multistep model selection for AD predictors including biomarkers. In univariate logistic analysis, we selected age, Rey Auditory Verbal Retention Test, parietal glucose metabolic rate, CSF total tau, and presence or not of at least one APOE epsilon 4 allele as predictors. Through multivariate stepwise logistic analysis and model selection, we found the combination of parietal glucose metabolic rate and total tau representing the best model for AD prediction. In conclusion, our findings highlight that the combination of regional glucose metabolic assessment by PET and CSF biomarkers evaluation can significantly improve AD predictive diagnostic accuracy of each respective method.

  • 13. Darreh-Shori, T.
    et al.
    Kadir, A.
    Almkvist, O.
    Grut, M.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Blomquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, B.
    Långström, B.
    Nordberg, A.
    Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 2, p. 168-184Article in journal (Refereed)
    Abstract [en]

    The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months Galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by C-11-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

  • 14.
    Degerman Gunnarsson, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindau, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Santillo, A F
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Engler, H
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Re-evaluation of clinical dementia diagnoses with pittsburgh compound B positron emission tomography2013In: Dementia and Geriatric Cognitive Disorders Extra, E-ISSN 1664-5464, Vol. 3, no 1, p. 472-481Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimer's disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET).

    METHODS:

    Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.

    RESULTS:

    The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up.

    CONCLUSIONS:

    The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.

  • 15. Degerman Gunnarsson, Malin
    et al.
    Lindau, Maria
    Santillo, Alexander
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Engler, Henry
    Lannfelt, Lars
    Basun, Hans
    Kilander, Lena
    Re-evaluation of clinical dementia diagnoses with PET-PIBManuscript (preprint) (Other academic)
    Abstract [en]

    Objectives: There is an overlap regarding Pittsburgh Compound-B (PIB) retention in patients clinically diagnosed as Alzheimer’s disease (AD) and non-AD dementia.  The aim of the present study was to investigate whether there are any differences between PIB+ and PIB PIB- patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with 18 Fluoro-2-deoxy-d-glucose (FDG) PET.

    Methods: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with  PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.

    Results:  The PIB+ patients (7/18) had slower psychomotor speed and more impaired visual episodic memory than the PIB- patients, otherwise performance did not differ between groups. The initial clinical diagnoses were changed in one third of the patients (6/18) during follow-up.  

    Conclusions: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need of amyloid biomarkers and readiness to re-evaluate the initial diagnosis.

  • 16.
    Degerman Gunnarsson, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindau, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Blennow, K
    Darreh-Shori, T
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Nordberg, A
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, H
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study2010In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 29, no 3, p. 204-212Article in journal (Refereed)
    Abstract [en]

    Background:

    The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring β-amyloid (Aβ) load. Associations between PET PIB and cerebrospinal fluid (CSF) Aβ1–42 and apolipoprotein E ε4 (APOE ε4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer’s disease (AD) are less investigated.

    Method:

    PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD.

    Results:

    PIB retention was constant over 1 year, inversely related to low CSF Aβ1–42 (p = 0.01) and correlated positively to the numbers of the APOE ε4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = –0.59, p = 0.07), and plasma cystatin C (r = –0.56, p = 0.09).

    Conclusion:

    PIB retention is strongly related to CSF Aβ1–42, and to the numbers of the APOE ε4 allele.

  • 17. Eriksdotter-Jönhagen, Maria
    et al.
    Linderoth, Bengt
    Lind, Goran
    Aladellie, Layth
    Almkvist, Ove
    Andreasen, Niels
    Blennow, Kaj
    Bogdanovic, Nenad
    Jelic, Vesna
    Kadir, Ahmadul
    Nordberg, Agneta
    Sundström, Erik
    Wahlund, Lars-Olof
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wiberg, Maria
    Winblad, Bengt
    Seiger, Ake
    Almqvist, Per
    Wahlberg, Lars
    Encapsulated Cell Biodelivery of Nerve Growth Factor to the Basal Forebrain in Patients with Alzheimer's Disease2012In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 33, no 1, p. 18-28Article in journal (Refereed)
    Abstract [en]

    Background/Aims:

    Degeneration of cholinergic neurons in the basal forebrain correlates with cognitive decline in patients with Alzheimer's disease (AD). Targeted delivery of exogenous nerve growth factor (NGF) has emerged as a potential AD therapy due to its regenerative effects on the basal forebrain cholinergic neurons in AD animal models. Here we report the results of a first-in-man study of encapsulated cell (EC) biodelivery of NGF to the basal forebrain of AD patients with the primary objective to explore safety and tolerability.

    Methods:

    This was an open-label, 12-month study in 6 AD patients. Patients were implanted stereotactically with EC-NGF biodelivery devices targeting the basal forebrain. Patients were monitored with respect to safety, tolerability, disease progression and implant functionality.

    Results:

    All patients were implanted successfully with bilateral single or double implants without complications or signs of toxicity. No adverse events were related to NGF or the device. All patients completed the study, including removal of implants at 12 months. Positive findings in cognition, EEG and nicotinic receptor binding in 2 of 6 patients were detected.

    Conclusions:

    This study demonstrates that surgical implantation and removal of EC-NGF biodelivery to the basal forebrain in AD patients is safe, well tolerated and feasible.

  • 18.
    Eriksson, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olsson, Ulf
    Unit of Applied Statistics and Mathematics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    [11C]5HTP-PET in Premenstrual Dysphoria2016Data set
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  • 19.
    Eriksson, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olsson, Ulf
    Unit of Applied Statistics and Mathematics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    [15O]-H2O-PET in Premenstrual Dysphoria2018Data set
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  • 20.
    Eriksson, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Olsson, Ulf
    Swedish Univ Agr Sci, Unit Appl Stat & Math, Uppsala, Sweden..
    Marteinsdottir, Ina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Holstad, Maria
    Univ Uppsala Hosp, Dept Neurosci, Psychiat Unit, Uppsala, Sweden..
    Ågren, Hans
    Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Hartvig, Per
    Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark..
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 9, article id e0159538Article in journal (Refereed)
    Abstract [en]

    Study Objective To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. Background Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. Methods Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". Results There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (pre-menstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (r(s) = -0.635; 0.027). The control group showed no such correlation. Conclusion Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies.

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  • 21.
    Eyjolfsdottir, Helga
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, S-17176 Stockholm, Sweden..
    Eriksdotter, Maria
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, S-17176 Stockholm, Sweden..
    Linderoth, Bengt
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Neurosurg, Bldg R3 02, S-17176 Stockholm, Sweden..
    Lind, Goran
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Neurosurg, Bldg R3 02, S-17176 Stockholm, Sweden..
    Juliusson, Bengt
    NsGene Inc, 225 Chapman St, Providence, RI 02905 USA..
    Kusk, Philip
    NsGene Inc, 225 Chapman St, Providence, RI 02905 USA..
    Almkvist, Ove
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Andreasen, Niels
    Karolinska Univ Hosp, Dept Geriatr, S-17176 Stockholm, Sweden..
    Blennow, Kaj
    Univ Gothenburg, Dept Clin Neurosci, Clin Neurochem Lab, S-41345 Gothenburg, Sweden..
    Ferreira, Daniel
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Univ Hosp, Dept Lab Med, Sect Pathol, S-17176 Stockholm, Sweden..
    Karami, Azadeh
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Darreh-Shori, Taher
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Kadir, Ahmadul
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, S-17176 Stockholm, Sweden..
    Sundström, Erik
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Stiftelsen Stockholms Sjukhem, Mariebergsgatan 22, S-11235 Stockholm, Sweden..
    Wahlund, Lars-Olof
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, S-17176 Stockholm, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wiberg, Maria
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Med Imaging & Technol, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Radiol, S-17176 Stockholm, Sweden..
    Winblad, Bengt
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, S-17176 Stockholm, Sweden..
    Seiger, Ake
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Stiftelsen Stockholms Sjukhem, Mariebergsgatan 22, S-11235 Stockholm, Sweden..
    Wahlberg, Lars
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;NsGene Inc, 225 Chapman St, Providence, RI 02905 USA..
    Almqvist, Per
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Neurosurg, Bldg R3 02, S-17176 Stockholm, Sweden..
    Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device2016In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 8, article id 30Article in journal (Refereed)
    Abstract [en]

    Background: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion. Methods: Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day. Results: All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable. Conclusions: The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD.

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  • 22. Farid, Karim
    et al.
    Carter, Stephen F
    Rodriguez-Vieitez, Elena
    Almkvist, Ove
    Andersen, Pia
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Blennow, Kaj
    Portelius, Erik
    Zetterberg, Henrik
    Nordberg, Agneta
    Case Report of Complex Amyotrophic Lateral Sclerosis with Cognitive Impairment and Cortical Amyloid Deposition2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 47, no 3, p. 661-667Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS), a fatal disease of unknown origin, affects motor neurons in the primary motor cortex, brainstem, and spinal cord. Cognitive impairment may occur before the motor symptoms. We present a patient who was initially diagnosed with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) but who developed ALS-like symptoms during follow-up and died shortly thereafter. A 60-year-old subject with cognitive impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) analysis, structural imaging (computed tomography and magnetic resonance imaging) and functional imaging [11C]-Pittsburgh compound B (PIB) positron emission tomography (PET), [18F]-fluorodeoxyglucose (FDG) PET, and [11C]-deuterium-L-deprenyl (DED) PET. Neuropsychological testing showed episodic memory impairment. CSF P-tau and T-tau levels were elevated. CSF amyloid-β (Aβ)42 levels were initially normal but became pathological during follow-up. MCI was diagnosed. [18F]-FDG PET showed hypometabolism in the left temporal and prefrontal cortices and [11C]-PIB PET demonstrated amyloid plaque deposition in the prefrontal, posterior cingulate, and parietal cortices. [11C]-DED PET showed high brain accumulation consistent with astrocytosis. The memory impairment progressed and AD was diagnosed. Motor impairments developed subsequently and, following additional neurological evaluation, ALS was diagnosed. The disease progressed rapidly and the patient died with pronounced motor symptoms three years after the initial cognitive assessment. Since relatives refused autopsy, postmortem analysis was not possible.

  • 23. Forsberg, A
    et al.
    Almkvist, O
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wall, Anders
    Uppsala Imanet AB, GE Healthcare, Uppsala, Sweden.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, A
    High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters2010In: Current Alzheimer Research, ISSN 1567-2050, Vol. 7, no 1, p. 56-66Article in journal (Refereed)
    Abstract [en]

    Background:

    New in vivo amyloid PET imaging tracers, such as 11C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimers disease (AD). In this study we investigated how 11C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers.

    Method:

    Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer 11C-PIB, 18F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-ß (Aβ1-42), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs).

    Results:

    Pooled data from AD and MCI patients showed strong correlations between 11C-PIB retention, levels of CSF biomarkers (especially Aß1-42), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between 11C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between 11C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions.

    Conclusions:

    A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. 11C-PIB PET and CSF Aß1-42 allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

  • 24. Forsberg, Anton
    et al.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Almkvist, Ove
    Blomquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hagman, Goran
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ringheim, Anna
    Langström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    PET imaging of amyloid deposition in patients with mild cognitive impairment2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 10, p. 1456-1465Article in journal (Refereed)
    Abstract [en]

    mild cognitive impairment, converters, amyloid, PET, PIB, FDG, CSF biomarkers/k It is of great clinical value to identify Subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 +/- 7.8 (S.D.) years) Underwent PET Studies with C-11-PIB, and F-18-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, its well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively. were Used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later Lit clinical follow-up converted to AD (8.1 +/- 6.0 (S.D.) months) showed significant higher PI B retention compared to non-converting MCI patients and HC, respcctively (ps < , 0.01). The PIB retention in MCI converters was comparable to AD patients (p > , 0.01). Correlations were observed in the MCI patients between PI B retention and CSF A beta(1-42). total Tau and episodic memory, respectively.

  • 25.
    Iaccarino, Leonardo
    et al.
    Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Neurosci, In Vivo Human Mol & Struct Neuroimaging Unit, Milan, Italy..
    Chiotis, Konstantinos
    Karolinska Inst, Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, Stockholm, Sweden..
    Alongi, Pierpaolo
    IRCCS San Raffaele Hosp, Nucl Med Unit, Milan, Italy.;San Raffaele G Giglio Inst, Nucl Med Unit, Dept Radiol Sci, Cefalu, Italy..
    Almkvist, Ove
    Karolinska Inst, Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, Stockholm, Sweden.;Stockholm Univ, Dept Psychol, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Cerami, Chiara
    IRCCS San Raffaele Sci Inst, Div Neurosci, In Vivo Human Mol & Struct Neuroimaging Unit, Milan, Italy.;IRCCS San Raffaele Hosp, Neurol Rehabil Unit, Dept Clin Neurosci, Milan, Italy..
    Bettinardi, Valentino
    IRCCS San Raffaele Hosp, Nucl Med Unit, Milan, Italy..
    Gianolli, Luigi
    IRCCS San Raffaele Hosp, Nucl Med Unit, Milan, Italy..
    Nordbereg, Agneta
    Karolinska Inst, Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Perani, Daniela
    Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Neurosci, In Vivo Human Mol & Struct Neuroimaging Unit, Milan, Italy.;IRCCS San Raffaele Hosp, Nucl Med Unit, Milan, Italy..
    A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 59, no 2, p. 603-614Article in journal (Refereed)
    Abstract [en]

    Assessments of brain glucose metabolism (F-18-FDG-PET) and cerebral amyloid burden (C-11-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of F-18-FDGPET and C-11-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for F-18-FDG-PET and of standardized uptake value ratio semiquantification for C-11-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57 +/- 7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, F-18-FDG-PET and C-11-PiB-PET. F-18-FDG-PET, compared to C-11-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both F-18-FDG-PET and C-11-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

  • 26.
    Johansson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blomquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Scott, Berit
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Evidence for astrocytosis in ALS demonstrated by 11C(L)-deprenyl-D2 PET2007In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 255, no 1-2, p. 17-22Article in journal (Refereed)
    Abstract [en]

    Objective: To use deuterium-substituted [11C](l)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). Background: In human brain, the enzyme MAO-B is primarily located in astrocytes. l-deprenyl binds to MAO-B and autoradiography with 3H-l-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](l)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. Methods: Deuterium-substituted [11C](l)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. Results: Increased uptake rate of [11C](l)-deprenyl was demonstrated in ALS in pons and white matter. Conclusion: This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](l)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](l)-deprenyl binding tracks disease progression and reflects astrocytosis.

  • 27.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Uppsala, Sweden..
    Wall, Anders
    Univ Uppsala Hosp, Uppsala, Sweden..
    Chiotis, K.
    Karolinska Inst, Stockholm, Sweden..
    Heurling, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Saint-Aubert, L.
    Karolinska Inst, Stockholm, Sweden..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Univ Uppsala Hosp, Uppsala, Sweden..
    Nordberg, A.
    Karolinska Inst, Stockholm, Sweden..
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Uppsala, Sweden..
    Supervised Cluster Analysis for Automatic Extraction of Reference Region in Dynamic [F-18]THK5317 PET2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S25-S25Article in journal (Refereed)
  • 28.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Chiotis, Konstantinos
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Leuzy, Antoine
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nordberg, Agneta
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET2019In: NeuroImage: Clinical, E-ISSN 2213-1582, Vol. 22, article id 101681Article in journal (Refereed)
    Abstract [en]

    [F-18]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 [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]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 R-1 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, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). 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 R-1 with 40 min scan duration.

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  • 29.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Med Phys, Uppsala, Sweden.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Chiotis, Konstantinos
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
    Saint-Aubert, Laure
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
    Wilking, Helena
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Sprycha, Margareta
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Borg, Beatrice
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Thibblin, Alf
    Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.; Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, Stockholm, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Med Phys, Uppsala, Sweden.
    Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology.2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 4, p. 574-581Article in journal (Refereed)
    Abstract [en]

    Because a correlation between tau pathology and the clinical symptoms of Alzheimer's disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-(18)F-THK5117.

    METHODS: 9 subjects (5 with AD, 4 with mild cognitive impairment) received a 90 min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. VOI-based analysis was performed using plasma-input models; single-tissue and two-tissue (2TCM) compartment models and plasma-input Logan, and reference tissue models; simplified reference tissue model (SRTM), reference Logan and standardised uptake value ratio (SUVr). Cerebellum grey matter was used as reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan and SUVr. Regionally averaged voxel values were compared to VOI-based values from the optimal reference tissue model and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40 and 60 min data were analysed.

    RESULTS: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2=0.99, slope=0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2=1.00, slope≈1.00) while SUVr70-90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2=0.99, slope=1.03). SUVr70-90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in grey matter. Simulations showed poorer accuracy and precision for SUVr70-90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min.

    CONCLUSION: SRTM BPND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-(18)F-THK5117 DVR-1 parametric images with the greatest accuracy and precision, and with a much lower white matter signal than seen with SUVr-1 images.

  • 30. Kadir, A.
    et al.
    Darreh-Shori, T.
    Almkvist, O.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Grut, M.
    Strandberg, B.
    Ringheim, A.
    Eriksson, B.
    Blomquist, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, B.
    Nordberg, A.
    PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 8, p. 1204-1217Article in journal (Refereed)
    Abstract [en]

    The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients' cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and 6 patients the placebo, and this was followed by 9 months' galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity (C-11-PMP) and C-11-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30-40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical C-11-nicotine binding was observed during the study. C-11-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and C-11-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and C-11-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.

  • 31. Kadir, Ahmadul
    et al.
    Almkvist, Ove
    Forsberg, Anton
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 1, p. 198.e1-198.e14Article in journal (Refereed)
    Abstract [en]

    In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer’s disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [11C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole (11C-PIB) and 18F-fluorodeoxyglucose (18F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.

  • 32. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Nordberg, Agneta
    Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale  

    Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer’s disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD.

    Objective  

    To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment.

    Materials and methods  

    Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of 15O–water and (S)(–)11C–nicotine was used to assess 11C–nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically.

    Results  

    The 11C–nicotine binding sites were significantly increased 12–19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical 11C–nicotine binding. The 11C–nicotine binding positively correlated with attentional task at the 12-month follow-up.

    Conclusion  

    Changes in the 11C–nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 33.
    Karami, Azadeh
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Eyjolfsdottir, Helga
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Vijayaraghavan, Swetha
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Lind, Goran
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden..
    Almqvist, Per
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden..
    Kadir, Ahmadul
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Linderoth, Bengt
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden..
    Andreasen, Niels
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Blennow, Kaj
    Univ Gothenburg, Clin Neurochem Lab, Dept Clin Neurosci, Gothenburg, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Ferreira, Daniel
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Wiberg, Maria Kristoffersen
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden..
    Wahlund, Lars-Olof
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Seiger, Ake
    Stockholms Sjukhem, Stockholm, Sweden..
    Nordberg, Agenta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Wahlberg, Lars
    NsGene Inc, Providence, RI USA..
    Darreh-Taher, Taher
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Eriksdotter, Maria
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Geriatr, Stockholm, Sweden..
    Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease2015In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 11, p. 1316-1328Article in journal (Refereed)
    Abstract [en]

    Introduction: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. Results: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-beta, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. Discussion: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.

  • 34. Kehler, Jan
    et al.
    Kilburn, John Paul
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Christensen, Soren Rahn
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Thibblin, Alf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Bundgaard, Christoffer
    Brennum, Lise Tottrup
    Steiniger-Brach, Bjoern
    Christoffersen, Claus Tornby
    Timmermann, Stine
    Kreilgaard, Mads
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Bang-Andersen, Benny
    Nielsen, Jacob
    Discovery and Development of C-11-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 9, p. 1513-1518Article in journal (Refereed)
    Abstract [en]

    Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-C-11-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (C-11-Lu AE92686) and its tritiated analog H-3-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and C-11-labeled compounds were synthesized. 3H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and C-11-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: C-11-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3H-Lu AE92686. The binding of C-11-Lu AE92686 and 3H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of C-11-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible-that is, BP(ND)s were 6.5 +/- 0.3 (n = 3) and 7.5 +/- 1.0 (n = 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that C-11-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.

  • 35.
    Latini, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Vedung, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Stensson, Staffan
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Tegner, Yelverton
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Affidea CDRC Centre de Diagnostic Radiologique de Carouge SA, Clos de la Fonderie.
    Johansson, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Skåne University Hospital; Lund University.
    Refined Analysis of Chronic White Matter Changes after Traumatic Brain Injury and Repeated Sports-Related Concussions: Of Use in Targeted Rehabilitative Approaches?2022In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, no 2, article id 358Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC (p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC (p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

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  • 36. Leuzy, Antoine
    et al.
    Carter, Stephen F.
    Chiotis, Konstantinos
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Nordberg, Agneta
    Concordance and Diagnostic Accuracy of [C-11]PIB PET and Cerebrospinal Fluid Biomarkers in a Sample of Patients with Mild Cognitive Impairment and Alzheimer's Disease2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 45, no 4, p. 1077-1088Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-beta(1-42) (A beta(1-42)), total-tau (t-tau), and phosphorylated tau (p- tau(181p)), as well as with positron emission tomography (PET) using [C-11]Pittsburgh compound-B ([C-11]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [C-11]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD. Objective: To determine concordance and classification accuracy of CSF biomarkers and [C-11]PIB PET in a cohort of patients with MCI and AD. Methods: 68 patients (MCI, n = 33; AD, n = 35) underwent [C-11]PIB PET and CSF sampling. Cutoffs of >1.41 ([C-11]PIB), <450 pg/mL-and a more lenient cutoff of 550 pg/mL-(A beta(1-42)), <6.5 (A beta(1-42)/p-tau181p), and 1.14 (A beta(1- 42)/t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI). Results: Concordance between [C-11]PIB and A beta(1-42) was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using A beta(1-42) < 550 pg/mL, or A beta(1-42) to tau ratios. Logistic regression showed that classification accuracy of [11C] PIB, between sMCI and pMCI, was superior to A beta(1-42) (73% versus 58%), A beta(1-42)/t-tau (63%), and A beta(1-42)/p-tau181p (65%). Conclusion: In the present study, [C-11]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of A beta(1-42) or A beta(1-42)/tau. Discordance between PET and CSF markers for A beta(1-42) suggests they cannot be used interchangeably, as is currently the case.

  • 37. Leuzy, Antoine
    et al.
    Rodriguez-Vieitez, Elena
    Saint-Aubert, Laure
    Chiotis, Konstantinos
    Almkvist, Ove
    Savitcheva, Irina
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nordberg, Agneta
    Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease.2018In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 14, no 5, p. 652-663Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single positron emission tomography study can provide both functional and molecular information.

    METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change.

    RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317.

    DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.

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  • 38.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Chiotis, K.
    Karolinska Inst, Translat Alzheimer Neurobiol, Stockholm, Sweden..
    Saint-Aubert, L.
    Karolinska Inst, Translat Alzheimer Neurobiol, Stockholm, Sweden..
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Okamura, N.
    Tohoku Univ, Sch Med, Pharmacol, Sendai, Miyagi, Japan..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Nordberg, A.
    Karolinska Inst, Translat Alzheimer Neurobiol, Stockholm, Sweden..
    Tracer kinetic analysis of [18f](s)-thk5117 as a pet tracer for tau pathology2016In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 36, no Suppl. 1, p. 16-17, article id 63Article in journal (Other academic)
  • 39.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Chiotis, Konstantinos
    Saint-Aubert, Laure
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Okamura, Nobuyuki
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Nordberg, Agneta
    Tracer kinetic analysis of (S)-[F-18]THK5117 as a PET tracer for tau pathology2015Conference paper (Other academic)
  • 40.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Bruce, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Johansen, P.
    Kehler, J.
    Bang-Andersen, B.
    Bundgaard, C.
    Christensen, S. Rahn
    Kilburn, J. P.
    Kreilgard, M.
    Thibblin, Alf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Steiniger-Brach, B.
    Nielsen, J.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tracer kinetic analysis of C-11-LuAE92686, a novel PET ligand for imaging of phosphodiesterase 10A2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S210-S210, article id OP228Article in journal (Other academic)
  • 41.
    Marklund, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden..
    Vedung, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Medical Physics, Uppsala University Hospital, Uppsala, Sweden..
    Tegner, Yelverton
    Department of Health Sciences, Luleå University of Technology, Sweden..
    Johansson, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Blennow, Kaj
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry , Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden..
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry , Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; UK Dementia Research Institute at UCL, London, United Kingdom.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom..
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. CIMC Ctr Imagerie Med Cornavin, Pl Cornavin 18, CH-1201 Geneva, Switzerland..
    Stenson, Staffan
    Uppsala Univ Hosp, Rehabil Med PET Ctr, Dept Neurosci, Uppsala, Sweden..
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients – A PET/MR study2021In: NeuroImage: Clinical, E-ISSN 2213-1582, Vol. 30, article id 102665Article in journal (Refereed)
    Abstract [en]

    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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  • 42. McParland, Brian J.
    et al.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    The clinical safety, biodistribution and internal radiation dosimetry of [F-18]fluciclovine in healthy adult volunteers2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no 8, p. 1256-1264Article in journal (Refereed)
    Abstract [en]

    We report on the biodistribution and internal radiation dosimetry in humans of [F-18]fluciclovine, a synthetic L-leucine analogue being investigated as a potential diagnostic biomarker for neoplasia. Whole-body positron emission tomography (PET) scans of 6 healthy volunteers were acquired at up to 16 time points up to about 5 h after a bolus administration of [F-18]fluciclovine (153.8 +/- 2.2 MBq). Venous blood samples were taken up to about 4 h post-injection from which F-18 activity concentrations in whole blood and plasma were measured. Urine was collected as voided up to 4 h post-injection, from which the excreted F-18 activity was measured. Absolute values of the F-18 activity contained in up to 11 source regions (brain, salivary glands, lung, heart, pancreas, spleen, liver, red bone marrow, kidneys, uterus and urinary bladder contents) were determined directly from quantitative analysis of the images. For each source region, the F-18 activity decay-corrected and normalised to that injected, as a function of time, was fit by an analytical function which was subsequently integrated to yield the cumulated activity normalised to the injected activity. These normalised cumulated activities were then used as input to the Organ Level INternal Dose Assessment/EXponential Modelling (OLINDA/EXM) package to calculate the internal radiation dosimetry of each subject following the Medical Internal Radiation Dose (MIRD) schema. An effective dose was then estimated for each subject. [F-18]Fluciclovine was clinically well tolerated in this study. Very little F-18 was excreted with only a mean value of 3.3 % present in the urine at about 4 h post-injection; no activity within the intestinal contents was noted. The highest mean initial uptakes were measured in the liver (13.8 %), red bone marrow (11.1 %) and lung (7.1 %). The highest mean radiation absorbed doses per unit administered activity were received by the pancreas (102.2 mu Gy/MBq), the cardiac wall (51.7 mu Gy/MBq) and the uterine wall (44.6 mu Gy/MBq). The mean effective dose per unit administered activity was 22.1 mu Sv/MBq. The internal radiation dosimetry of [F-18]fluciclovine appears acceptable for PET imaging.

  • 43.
    Mörtberg, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cumming, Paul
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    A PET study of regional cerebral blood flow after experimental cardiopulmonary resuscitation2007In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 75, no 1, p. 98-104Article in journal (Refereed)
    Abstract [en]

    Cerebral blood flow (CBF) during cardiopulmonary resuscitation and after restoration of spontaneous circulation (ROSC) from cardiac arrest has previously been measured with the microspheres and laser Doppler techniques. We used positron emission tomography (PET) with [15O]--water to map the haemodynamic changes after ROSC in nine young pigs. After the baseline PET recording, ventricular fibrillation of 5 min duration was induced, followed by closed-chest cardiopulmonary resuscitation (CPR) in conjunction with IV administration of three bolus doses of adrenaline (epinephrine). After CPR, external defibrillatory shocks were applied to achieve ROSC. CBF was measured at intervals during 4h after ROSC. Relative to the mean global CBF at baseline (32+/-5 ml hg(-1)min(-1)), there was a substantial global increase in CBF at 10 min, especially in the diencephalon. This was followed by an interval of cortical hypoperfusion and a subsequent gradual return to baseline values.

  • 44.
    Nordberg, Agneta
    et al.
    Karolinska Inst, Dept NVS, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14187 Huddinge, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Kadir, Ahmadul
    Karolinska Inst, Dept NVS, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14187 Huddinge, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Andreasen, Niels
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Almkvist, Ove
    Karolinska Inst, Dept NVS, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14187 Huddinge, Sweden.;Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Blennow, Kaj
    Gothenburg Univ, Sect Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Langstrom, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Zetterberg, Henrik
    Gothenburg Univ, Inst Neurosci & Physiol, Clin Neurochem Lab, Gothenburg, Sweden..
    Correlations between Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cerebral Glucose Metabolism after 12 Months of Phenserine Treatment2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 47, no 3, p. 691-704Article in journal (Refereed)
    Abstract [en]

    New therapeutic strategies in Alzheimer's disease (AD) are focused on targeting amyloid-beta (A beta) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-A beta compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for A beta and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF A beta(40) and alpha- and beta-secretase-cleaved soluble amyloid-beta protein precursor (sA beta PP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF A beta(40) and sA beta PP correlated positively with rCMRglc and cognition while CSF A beta(42) levels, the A beta(42/40) ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF A beta(40), sA beta PP alpha, and sA beta PP beta, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects.

  • 45.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Szalisznyo, Krisztina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. PET-Centre, Uppsala University Hospital.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. PET-Centre, Uppsala University Hospital.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Zora, Hatice
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study2020In: European Archives of Psychiatry and Clinical Neuroscience, ISSN 0940-1334, E-ISSN 1433-8491, Vol. 270, no 4, p. 451-459Article in journal (Refereed)
    Abstract [en]

    Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

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  • 46.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, PET Ctr, Uppsala, Sweden..
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala Univ Hosp, PET Ctr, Uppsala, Sweden..
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Inhibitory and excitatory neurotransmitter systems in depressed and healthy: A positron emission tomography and magnetic resonance spectroscopy study2021In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 315, article id 111327Article in journal (Refereed)
    Abstract [en]

    The Gamma-aminobutyric acid (GABA) and glutamate (Glu) neurotransmitter systems are implicated in depression. While previous studies found reduced GABA levels, and a tendency towards reduced Glu, using proton (H-1) magnetic resonance spectroscopy (H-1-MRS), little is known about GABA(A) receptor availability in depression. Here, the aim was to characterize GABA and Glu-levels in dorsal anterior cingulate cortex (dACC), whole-brain GABA(A) availability, and their relationship in patients with depression compared to healthy controls. Forty-two patients and 45 controls underwent H-1-MRS using a MEGA-PRESS sequence to quantify dACC GABA+ and Glu (contrasted against creatine [Cr]). Immediately preceding the H-1-MRS, a subsample of 28 patients and 15 controls underwent positron emission tomography (PET) with [C-11]Flumazenil to assess whole-brain GABA(A) receptor availability. There were no differences in dACC GABA+/Cr or Glu/Cr ratios between patients and controls. The same was true for whole-brain GABA(A) receptor availability. However, there was a significant negative relationship between GABA+/Cr ratio and receptor availability in ACC, in a whole-brain voxel-wise analysis across patients and controls, controlling for group or depressive symptoms. This relatively large study did not support the GABA-deficit hypothesis in depression, but shed light on GABA-system functioning, suggesting a balance between neurotransmitter concentration and receptor availability in dACC.

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  • 47. Prestia, Annapaola
    et al.
    Caroli, Anna
    van der Flier, Wiesje M.
    Ossenkoppele, Rik
    Van Berckel, Bart
    Barkhof, Frederik
    Teunissen, Charlotte E.
    Wall, Anders E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Carter, Stephen F.
    Scholl, Michael
    Choo, Il Han
    Nordberg, Agneta
    Scheltens, Philip
    Frisoni, Giovanni B.
    Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease2013In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 80, no 11, p. 1048-1056Article in journal (Refereed)
    Abstract [en]

    Objectives: The current model of Alzheimer disease (AD) stipulates that brain amyloidosis biomarkers turn abnormal earliest, followed by cortical hypometabolism, and finally brain atrophy ones. The aim of this study is to provide clinical evidence of the model in patients with mild cognitive impairment (MCI). Methods: A total of 73 patients with MCI from 3 European memory clinics were included. Brain amyloidosis was assessed by CSF A beta 42 concentration, cortical metabolism by an index of temporoparietal hypometabolism on FDG-PET, and brain atrophy by automated hippocampal volume. Patients were divided into groups based on biomarker positivity: 1) A beta 422- FDG-PET- Hippo-, 2) A beta 42+ FDG-PET- Hippo-, 3) A beta 42+ FDG-PET + Hippo-, 4) A beta 42+ FDG-PET+ Hippo+, and 5) any other combination not in line with the model. Measures of validity were prevalence of group 5, increasing incidence of progression to dementia with increasing biological severity, and decreasing conversion time. Results: When patients with MCI underwent clinical follow-up, 29 progressed to dementia, while 44 remained stable. A total of 26% of patients were in group 5. Incident dementia was increasing with greater biological severity in groups 1 to 5 from 4% to 27%, 64%, and 100% (p for trend, 0.0001), and occurred increasingly earlier (p for trend = 0.024). Conclusions: The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab) normality. 

  • 48.
    Prestia, Annapaola
    et al.
    IRCCS, Ctr San Giovanni Dio Fatebenefratelli, Lab Epidemiol & Neuroimaging, Brescia, Italy..
    Caroli, Anna
    IRCCS, Mario Negri Inst Pharmacol Res, Dept Biomed Engn, Med Imaging Unit, Bergamo, Italy..
    Wade, Sara K.
    Univ Cambridge, Dept Engn, Cambridge CB2 1PZ, England.;Bocconi Univ, Dept Decis Sci, Milan, Italy..
    van der Flier, Wiesjie M.
    Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands..
    Ossenkoppele, Rik
    Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Radiol & Nucl Med & PET Res, Amsterdam, Netherlands..
    Van Berckel, Bart
    Vrije Univ Amsterdam Med Ctr, Dept Radiol & Nucl Med & PET Res, Amsterdam, Netherlands..
    Barkhof, Frederik
    Vrije Univ Amsterdam Med Ctr, Dept Radiol & Nucl Med & PET Res, Amsterdam, Netherlands..
    Teunissen, Charlotte E.
    Vrije Univ Amsterdam Med Ctr, Dept Clin Chem, Amsterdam, Netherlands..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carter, Stephen F.
    Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden..
    Scholl, Michael
    Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden..
    Choo, Il Han
    Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden.;Chosun Univ, Sch Med, Dept Neuropsychiat, Gwangju, South Korea..
    Nordberg, Agneta
    Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden.;Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, Stockholm, Sweden..
    Scheltens, Philip
    Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands..
    Frisoni, Giovanni B.
    IRCCS, Ctr San Giovanni Dio Fatebenefratelli, Lab Epidemiol & Neuroimaging, Brescia, Italy.;Univ Hosp Geneva, Dept Internal Med, Geneva, Switzerland.;Univ Hosp Geneva, Dept Psychiat, Geneva, Switzerland.;Univ Geneva, Geneva, Switzerland..
    Prediction of AD dementia by biomarkers following the NIA-AA and IWG diagnostic criteria in MCI patients from three European memory clinics2015In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 10, p. 1191-1201Article in journal (Refereed)
    Abstract [en]

    Introduction: Proposed diagnostic criteria (international working group and National Institute on Aging and Alzheimer's Association) for Alzheimer's disease (AD) include markers of amyloidosis (abnormal cerebrospinal fluid [CSF] amyloid beta [A beta]42) and neurodegeneration (hippocampal atrophy, temporo-parietal hypometabolism on [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and abnormal CSF tau). We aim to compare the accuracy of these biomarkers, individually and in combination, in predicting AD among mild cognitive impairment (MCI) patients. Methods: In 73 MCI patients, followed to ascertain AD progression, markers were measured. Sensitivity and specificity, positive (LR+) and negative (LR-) likelihood ratios, and crude and adjusted hazard ratios were computed. Results: Twenty-nine MCI patients progressed and 44 remained stable. Positivity to any marker achieved the lowest LR- (0.0), whereas the combination A beta 42 plus FDG-PET achieved the highest LR+ (6.45). In a survival analysis, positivity to any marker was associated with 100% conversion rate, whereas negativity to all markers was associated with 100% stability. Discussion: The best criteria combined amyloidosis and neurodegeneration biomarkers, whereas the individual biomarker with the best performance was FDG-PET.

  • 49.
    Razifar, Pasha
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Engler, Henry
    Ringheim, Anna
    Estrada, Sergio
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    An automated method for delineating a reference region using masked volumewise principal-component analysis in 11C-PIB PET2009In: Journal of Nuclear Medicine Technology, ISSN 0091-4916, E-ISSN 1535-5675, Vol. 37, no 1, p. 38-44Article in journal (Refereed)
    Abstract [en]

    Kinetic modeling using a reference region is a common method for the analysis of dynamic PET studies. Available methods for outlining regions of interest representing reference regions are usually time-consuming and difficult and tend to be subjective; therefore, MRI is used to help physicians and experts to define regions of interest with higher precision. The current work introduces a fast and automated method to delineate the reference region of images obtained from an N-methyl-(11)C-2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) PET study on Alzheimer disease patients and healthy controls using a newly introduced masked volumewise principal-component analysis.

    METHODS: The analysis was performed on PET studies from 22 Alzheimer disease patients (baseline, follow-up, and test/retest studies) and 4 healthy controls, that is, a total of 26 individual scans. The second principal-component images, which illustrate the kinetic behavior of the tracer in gray matter of the cerebellar cortex, were used as input data for automatic delineation of the reference region. To study the variation associated with the manual and proposed automatic methods, we defined the reference region repeatedly.

    RESULTS: As expected, the automatic method showed no variation whereas the manual method varied significantly on repetition. Furthermore, the automatic method was significantly faster, more robust, and less biased.

    CONCLUSION: The automatic method is helpful in the delineation of the reference region of (11)C-PIB PET studies of the human brain and is much faster and more precise than manual delineation.

  • 50. Reshef, Ayelet
    et al.
    Shirvan, Anat
    Akselrod-Ballin, Ayelet
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Ziv, Ilan
    Small-molecule biomarkers for clinical PET imaging of apoptosis.2010In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 51, no 6, p. 837-40Article in journal (Refereed)
    Abstract [en]

    Apoptosis is a fundamental biologic process. Molecular imaging of apoptosis in vivo may have important implications for clinical practice, assisting in early detection of disease, monitoring of disease course, assessment of treatment efficacy, or development of new therapies. Although a PET probe for clinical imaging of apoptosis would be highly desirable, this is yet an unachieved goal, mainly because of the required challenging integration of various features, including sensitive and selective detection of the apoptotic cells, clinical aspects such as favorable biodistribution and safety profiles, and compatibility with the radiochemistry and imaging routines of clinical PET centers. Several approaches are being developed to address this challenge, all based on novel small-molecule structures targeting various steps of the apoptotic cascade. This novel concept of small-molecule PET probes for apoptosis is the focus of this review.

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