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  • 1.
    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)
  • 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. 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, ISSN 2158-3188, 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.

  • 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 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)
  • 4. 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)
  • 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: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 21, p. 19-19Article in journal (Other academic)
  • 6. 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.

  • 7. 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.

  • 8. 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.

  • 9. 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.

  • 10. 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.

  • 11.
    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, 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.

  • 12. 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.

  • 13.
    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.

  • 14. 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.

  • 15.
    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, ISSN 1932-6203, 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.

  • 16.
    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, ISSN 0065-6755, 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.

  • 17. 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.

  • 18. 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.

  • 19. 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.

  • 20.
    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.

  • 21.
    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.

  • 22.
    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)
  • 23.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    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.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of 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.
    Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PETManuscript (preprint) (Other academic)
  • 24.
    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.

  • 25. 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.

  • 26. 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.

  • 27. 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.

  • 28.
    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, 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.

  • 29. 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.

  • 30. 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.

  • 31. 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, 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.

  • 32.
    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)
  • 33.
    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)
  • 34.
    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)
  • 35. 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.

  • 36.
    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.

  • 37.
    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.

  • 38. 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. 

  • 39.
    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, 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.

  • 40.
    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.

  • 41. 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.

  • 42.
    Rodriguez-Vieitez, Elena
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden..
    Carter, Stephen F.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden.;Univ Manchester, Inst Brain Behav & Mental Hlth, Wolfson Mol Imaging Ctr, Manchester, Lancs, England..
    Chiotis, Konstantinos
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden..
    Saint-Aubert, Laure
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden..
    Leuzy, Antoine
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden..
    Scholl, Michael
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden..
    Almkvist, Ove
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 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.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, SE-14157 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Comparison of Early-Phase C-11-Deuterium-L-Deprenyl and C-11-Pittsburgh Compound B PET for Assessing Brain Perfusion in Alzheimer Disease2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 7, p. 1071-1077Article in journal (Refereed)
    Abstract [en]

    The PET tracer C-11-deuterium-L-deprenyl (C-11-DED) has been used to visualize activated astrocytes in vivo in patients with Alzheimer disease (AD). In this multitracer PET study, early-phase C-11-DED and C-11-Pittsburgh compound B (C-11-PiB) (eDED and ePiB, respectively) were compared as surrogate markers of brain perfusion, and the extent to which C-11-DED binding is influenced by brain perfusion was investigated. METHODS: C-11-DED, C-11-PiB, and F-18-FDG dynamic PET scans were obtained in age-matched groups comprising AD patients (n = 8), patients with mild cognitive impairment (n = 17), and healthy controls (n = 16). A modified reference Patlak model was used to quantify C-11-DED binding. A simplified reference tissue model was applied to both C-11-DED and C-11-PiB to measure brain perfusion relative to the cerebellar gray matter (R-1) and binding potentials. C-11-PiB retention and F-18-FDG uptake were also quantified as target-to-pons SUV ratios in 12 regions of interest (ROIs). RESULTS: The strongest within-subject correlations with the corresponding R-1 values (R-1,R-DED and R-1,R-PiB, respectively) and with F-18-FDG uptake were obtained when the eDED and ePiB PET data were measured 1-4 min after injection. The optimum eDED/ePiB intervals also showed strong, significant ROI-based intersubject Pearson correlations with R-1,R-DED/R-1,R-PiB and with F-18-FDG uptake, whereas C-11-DED binding was largely independent of brain perfusion, as measured by eDED. Corresponding voxelwise correlations confirmed the ROI-based results. Temporoparietal eDED or ePiB brain perfusion measurements were highly discriminative between patient and control groups, with discriminative ability statistically comparable to that of temporoparietal F-18-FDG glucose metabolism. Hypometabolism extended over wider regions than hypoperfusion in patient groups compared with controls. CONCLUSION: The 1- to 4-min early-frame intervals of C-11-DED or C-11-PiB are suitable surrogate measures for brain perfusion. C-11-DED binding is independent of brain perfusion, and thus C-11-DED PET can provide information on both functional (brain perfusion) and pathologic (astrocytosis) aspects from a single PET scan. In comparison with glucose metabolism, early-phase C-11-DED and C-11-PiB perfusion appear to provide complementary rather than redundant information.

  • 43.
    Rodriguez-Vieitez, Elena
    et al.
    Karolinska Inst, Dept NVS, Stockholm, Sweden..
    Leuzy, Antoine
    Karolinska Inst, Dept NVS, Stockholm, Sweden..
    Chiotis, Konstantinos
    Karolinska Inst, Dept NVS, Stockholm, Sweden..
    Saint-Aubert, Laure
    Karolinska Inst, Dept NVS, Stockholm, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nordberg, Agneta
    Karolinska Inst, Dept NVS, Stockholm, Sweden.;Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, Stockholm, Sweden..
    Comparability of [F-18]THK5317 and [C-11]PIB blood flow proxy images with [F-18]FDG positron emission tomography in Alzheimer's disease2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, no 2, p. 740-749Article in journal (Refereed)
    Abstract [en]

    For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R-1) has been shown to serve as a marker of brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal Alzheimer's disease and nine Alzheimer's disease dementia patients underwent [F-18]THK5317, carbon-11 Pittsburgh Compound-B ([C-11]PIB), and 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) positron emission tomography to assess the possible use of early-phase [F-18]THK5317 and R-1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal vs Alzheimer's disease dementia) of [F-18]THK5317 (early-phase SUVr and R-1) was compared with that of [C-11]PIB (early-phase SUVr and R-1) and [F-18]FDG. Strong positive correlations were found between [F-18]THK5317 (early-phase, R-1) and [F-18]FDG, particularly in frontal and temporoparietal regions. Differences in correlations between early-phase and R-1 ([F-18]THK5317 and [C-11]PIB) and [F-18]FDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. Our findings suggest that early-phase [F-18]THK5317 and R-1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single positron emission tomography study with [F-18]THK5317 may provide information about both tau pathology and brain perfusion in Alzheimer's disease, with potential clinical applications.

  • 44.
    Rodriguez-Vieitez, Elena
    et al.
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden..
    Saint-Aubert, Laure
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden..
    Carter, Stephen F.
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden.;Univ Manchester, Wolfson Mol Imaging Ctr, Manchester M20 3LJ, Lancs, England..
    Almkvist, Ove
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden.;Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, S-14186 Stockholm, Sweden..
    Farid, Karim
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden..
    Scholl, Michael
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden.;Univ Gothenburg, MedTech West, S-41345 Gothenburg, Sweden.;Univ Gothenburg, Dept Clin Neurosci & Rehabil, S-41345 Gothenburg, Sweden..
    Chiotis, Konstantinos
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden..
    Thordardottir, Steinunn
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, S-14186 Stockholm, Sweden.;Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden..
    Graff, Caroline
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, S-14186 Stockholm, Sweden.;Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Långstrom, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Nordberg, Agneta
    Karolinska Inst, Div Translat Alzheimer Neurobiol, Ctr Alzheimer Res, Dept NVS, S-14157 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, S-14186 Stockholm, Sweden..
    Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease2016In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 139, no 3, p. 922-936Article in journal (Refereed)
    Abstract [en]

    The relationships between pathophysiological processes in Alzheimer's disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer's disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.See Schott and Fox (doi: 10.1093/brain/awv405) for a scientific commentary on this article. The relationships between pathophysiological processes in Alzheimer's disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer's disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-beta, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer C-11-deuterium-L-deprenyl), fibrillar amyloid-beta plaque deposition (C-11-Pittsburgh compound B), and glucose metabolism (F-18-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 +/- 10.3 years old) and non-carriers (n = 16; 51.1 +/- 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 +/- 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 +/- 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into C-11-Pittsburgh compound B-positive (n = 13; 62.0 +/- 6.4; seven male) and C-11-Pittsburgh compound B-negative (n = 4; 61.8 +/- 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 +/- 0.6 years. By using linear mixed-effects models, fibrillar amyloid-beta plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-beta plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-beta plaque deposition. Patients with sporadic mild cognitive impairment who were C-11-Pittsburgh compound B-positive at baseline showed increasing amyloid-beta plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-beta plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.

  • 45.
    Scholl, Michael
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.;Univ Gothenburg, MedTech West, S-41345 Gothenburg, Sweden.;Univ Gothenburg, Dept Clin Neurosci & Rehabil, S-41345 Gothenburg, Sweden..
    Carter, Stephen F.
    Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.;Univ Manchester, Wolfson Mol Imaging Ctr, Manchester M20 3LJ, Lancs, England..
    Westman, Eric
    Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Clin Geriatr, S-14157 Huddinge, Sweden..
    Rodriguez-Vieitez, Elena
    Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden..
    Almkvist, Ove
    Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.;Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, S-14186 Stockholm, Sweden.;Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden..
    Thordardottir, Steinunn
    Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, S-14186 Stockholm, Sweden.;Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Neurogeriatr, S-14157 Huddinge, Sweden..
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Graff, Caroline
    Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, S-14186 Stockholm, Sweden.;Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Neurogeriatr, S-14157 Huddinge, Sweden..
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Nordberg, Agneta
    Karolinska Inst, Ctr Alzheimer Res, Dept NVS, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.;Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, S-14186 Stockholm, Sweden..
    Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 16404Article in journal (Refereed)
    Abstract [en]

    Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround beta-amyloid (A beta) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar A beta, astrocytosis and cerebral glucose metabolism with the radiotracers C-11-Pittsburgh compound-B (PIB), C-11-deuterium-L-deprenyl (DED) and F-18-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar A beta or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.

  • 46. Schöll, Michael
    et al.
    Almkvist, Ove
    Axelman, Karin
    Stefanova, Elka
    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.
    Westman, Eric
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Graff, Caroline
    Nordberg, Agneta
    Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 8, p. 1388-1399Article in journal (Refereed)
    Abstract [en]

    Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an (11)C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.

  • 47. Schöll, Michael
    et al.
    Almkvist, Ove
    Bogdanovic, Nenad
    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.
    Viitanen, Matti
    Nordberg, Agneta
    Time Course of Glucose Metabolism in Relation to Cognitive Performance and Postmortem Neuropathology in Met146Val PSEN1 Mutation Carriers2011In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 24, no 3, p. 495-506Article in journal (Refereed)
    Abstract [en]

    Studies in carriers of mutations that cause early-onset familial Alzheimer's disease (eoFAD) are of significant interest. We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1 (PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with 18F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also observed when compared with a group of 23 healthy controls and a group 27 sporadic Alzheimer's disease (sAD) patients. This decline correlated with cognitive deterioration over time as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by 18F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology.

  • 48. Schöll, Michael
    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.
    Thordardottir, Steinunn
    Ferreira, Daniel
    Bogdanovic, Nenad
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Almkvist, Ove
    Graff, Caroline
    Nordberg, Agneta
    Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 3, p. 229-236Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD).

    Methods: We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with C-11-labeled Pittsburgh compound B (PiB) and F-18-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs).

    Results: Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of A beta(1-42), total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs.

    Conclusions: The lack of fibrillar beta-amyloid (A beta) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of A beta(1-42) in CSF, that other forms of A beta such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease.

  • 49.
    Somer, E. J.
    et al.
    GE Healthcare, Life Sci, Imaging R&D, Amersham, England..
    Owenius, Rikard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. GE Healthcare, Life Sci, Imaging R&D, Uppsala, Sweden..
    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.
    Thibblin, Alf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    The clinical safety, biodistribution and internal radiation dosimetry of [F-18]AH113804 in healthy adult volunteers2016In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 6, article id 87Article in journal (Refereed)
    Abstract [en]

    Background: Quantitative biodistribution, venous blood and excretion data have been obtained following the intravenous bolus injection of AH113804 (F-18) Injection in six healthy volunteers (HVs), four males and two females, up to approximately 5 h post-injection. For each subject, key organs and tissues were delineated and analytical fits were made to the image data as functions of time to yield the normalised cumulated activities. These were input to an internal radiation dosimetry calculation based upon the Medical Internal Radiation Dose (MIRD) schema for the Cristy-Eckerman adult male or female phantom. The absorbed doses per unit administered activity to the 24 MIRD-specified target organs were evaluated for an assumed 3.5-h urinary bladder voiding interval using the Organ Level INternal Dose Assessment/Exponential Modelling (OLINDA/EXM) code. The sex-specific absorbed doses were then averaged, and the effective dose per unit administered activity was calculated. Results: Excluding the remaining tissue category, the three source regions with the highest mean initial F-18 activity uptake were the liver (18.3%), lung (5.1%) and kidney (4.5%) and the highest mean normalised cumulated activities were the urinary bladder contents and voided urine (1.057 MBq h/MBq), liver (0.129 MBq h/MBq) and kidneys (0.065 MBq h/MBq). The three organs/tissues with the highest mean sex-averaged absorbed doses per unit administered activity were the urinary bladder wall (0.351 mGy/MBq), kidneys (0.052 mGy/MBq) and uterus (0. 031 mGy/MBq). Conclusions: AH113804 (F-18) Injection was safe and well tolerated. Although the effective dose, 0.0298 mSv/MBq, is slightly greater than for other common F-18 PET imaging radiopharmaceuticals, the biodistribution and radiation dosimetry profile remain favourable for clinical PET imaging.

  • 50.
    Thordardottir, Steinunn
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, S-14157 Huddinge, Sweden;Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden.
    Rodriguez-Vieitez, Elena
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
    Almkvist, Ove
    Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden;Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden.
    Ferreira, Daniel
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, S-14157 Huddinge, Sweden.
    Saint-Aubert, Laure
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden;Univ Toulouse, Toulouse NeuroImaging Ctr, INSERM, UPS, Toulouse, France.
    Kinhult-Stahlbom, Anne
    Karolinska Inst, Ctr Alzheimer Res, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, S-14157 Huddinge, Sweden;Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden.
    Thonberg, Hakan
    Karolinska Inst, Ctr Alzheimer Res, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, S-14157 Huddinge, Sweden;Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden.
    Scholl, Michael
    Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, S-41345 Gothenburg, Sweden;Univ Gothenburg, Dept Psychiat & Neurochem, S-41345 Gothenburg, Sweden;Lund Univ, Clin Memory Res Unit, S-21224 Malmo, Sweden.
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, S-14157 Huddinge, Sweden.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksdotte, Maria
    Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, S-14157 Huddinge, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Sahlgrenska Acad, S-43180 Molndal, Sweden;UCL Inst Neurol, Queen Sq, London WC1N 3BG, England;UCL, UK Dementia Res Inst, London WC1N 3BG, England;Sahlgrens Univ Hosp, Clin Neurochem Lab, S-43180 Molndal, Sweden.
    Blennow, Kaj
    Univ Gothenburg, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Sahlgrenska Acad, S-43180 Molndal, Sweden;Sahlgrens Univ Hosp, Clin Neurochem Lab, S-43180 Molndal, Sweden.
    Nordberg, Agneta
    Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
    Graff, Caroline
    Karolinska Inst, Ctr Alzheimer Res, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, S-14157 Huddinge, Sweden;Karolinska Univ Hosp Huddinge, Theme Aging, S-14186 Stockholm, Sweden.
    Reduced penetrance of the PSEN1 H163Y autosomal dominant Alzheimer mutation: a 22-year follow-up study2018In: Alzheimer's Research & Therapy, ISSN 0065-6755, E-ISSN 1758-9193, Vol. 10, article id 45Article in journal (Refereed)
    Abstract [en]

    Background: The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years.

    Methods: Two brothers (A and B), both carriers of the H163Y mutation, were followed between 1995 and 2017. They underwent repeated clinical evaluations, neuropsychological assessments, and cerebrospinal fluid analyses, as well as brain imaging examinations with structural magnetic resonance, [18F]fluorodeoxyglucose positron emission tomography, and [11C]Pittsburgh compound B positron emission tomography.

    Results: Brother A was followed between 44 and 64 years of age. Cognitive symptoms due to Alzheimer’s disease set in at the age of 54. Gradual worsening of symptoms resulted in admittance to a nursing home owing to dependence on others for all activities of daily living. He showed a curvilinear decline in cognitive function on neuropsychological tests, and changes on magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid supported a clinical diagnosis of Alzheimer’s disease. Brother A died at the age of 64 and fulfilled the criteria for definitive Alzheimer’s disease according to neuropathological examination results. Brother B was followed between the ages of 43 and 65 and showed no cognitive deterioration on repeated neuropsychological test occasions. In addition, no biomarker evidence of Alzheimer’s disease pathology was detected, either on imaging examinations or in cerebrospinal fluid.

    Conclusions: The average (SD) age of symptom onset for PSEN1 H163Y is 51 ± 7 years according to previous studies. However, we present a case of a biomarker-verified reduction in penetrance in a mutation carrier who was still symptom-free at the age of 65. This suggests that other genetic, epigenetic, and/or environmental factors modify the onset age.

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