uu.seUppsala universitets publikationer
Ändra sökning
Länk till posten
Permanent länk

Direktlänk
BETA
Långström, Bengt
Alternativa namn
Publikationer (10 of 153) Visa alla publikationer
Zou, R., Kuang, G., Ågren, H., Nordberg, A., Långström, B. & Tu, Y. (2019). Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid β Fibril. ACS Chemical Neuroscience, 10(3), 1783-1790
Öppna denna publikation i ny flik eller fönster >>Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid β Fibril
Visa övriga...
2019 (Engelska)Ingår i: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, nr 3, s. 1783-1790Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The amyloid β (Aβ) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of Aβ fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the Aβ fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the Aβ1-42 fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site 2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to Aβ fibril and emphasize the importance to adopt a full dynamical picture when studying tracer fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the Aβ fibril.

Nyckelord
Amyloid beta fibril, binding sites, imaging agents, free energy profiles, molecular dynamics simulation, umbrella sampling
Nationell ämneskategori
Neurovetenskaper Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-381836 (URN)10.1021/acschemneuro.8b00662 (DOI)000462259900081 ()30698013 (PubMedID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF), RB13-0192Swedish National Infrastructure for Computing (SNIC), snic2017-1-425
Tillgänglig från: 2019-04-16 Skapad: 2019-04-16 Senast uppdaterad: 2019-04-16Bibliografiskt granskad
Motilla Hoppe, J., Frick, A., Åhs, F., Linnman, C., Appel, L., Jonasson, M., . . . Furmark, T. (2018). Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits. Translational Psychiatry, 8(1), 168
Öppna denna publikation i ny flik eller fönster >>Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits
Visa övriga...
2018 (Engelska)Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, nr 1, s. 168-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

Nationell ämneskategori
Pedagogik
Identifikatorer
urn:nbn:se:uu:diva-358759 (URN)10.1038/s41398-018-0163-1 (DOI)000443079700001 ()
Tillgänglig från: 2018-08-31 Skapad: 2018-08-31 Senast uppdaterad: 2018-12-10Bibliografiskt granskad
Ni, R., Gillberg, P.-G., Bogdanovic, N., Viitanen, M., Myllykangas, L., Nennesmo, I., . . . Nordberg, A. (2017). Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease. Alzheimer's & Dementia, 13(4), 419-430
Öppna denna publikation i ny flik eller fönster >>Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease
Visa övriga...
2017 (Engelska)Ingår i: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 13, nr 4, s. 419-430Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Introduction: Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-beta aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods: Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe, PS1 M146V, and PS1 E Delta 9 mutations, 13 sporadic AD, and 14 control cases. Results: H-3-PIB, H-3-florbetaben, H-3-AZD2184, and BTA-1 shared a high-and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The H-3-AZD2184 and H-3-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on H-3-AZD84 binding followed by H-3-florbetaben and minimal on H-3-PIB. Discussion: This study implies amyloid tracers of different structures detect different sites on amyloid-beta fibrils or conformations.

Nyckelord
Alzheimer's disease, Amyloid-beta, Autosomal dominant Alzheimer's disease, Positron emission tomography, Resveratrol, Pittsburgh compound B, AZD2184, Florbetaben
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-321327 (URN)10.1016/j.jalz.2016.08.006 (DOI)000398565000006 ()27693181 (PubMedID)
Forskningsfinansiär
VetenskapsrådetStiftelsen för strategisk forskning (SSF)HjärnfondenStiftelsen Gamla Tjänarinnor
Tillgänglig från: 2017-05-31 Skapad: 2017-05-31 Senast uppdaterad: 2017-05-31Bibliografiskt granskad
Kuang, G., Zhou, Y., Zou, R., Halldin, C., Nordberg, A., Långström, B., . . . Tu, Y. (2017). Characterization of the binding mode of the PET tracer [F-18] ASEM to a chimera structure of the alpha 7 nicotinic acetylcholine receptor. RSC Advances, 7(32), 19787-19793
Öppna denna publikation i ny flik eller fönster >>Characterization of the binding mode of the PET tracer [F-18] ASEM to a chimera structure of the alpha 7 nicotinic acetylcholine receptor
Visa övriga...
2017 (Engelska)Ingår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, nr 32, s. 19787-19793Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging alpha 7-nAChR with positron emission tomography (PET). [F-18]ASEM is a novel and potent alpha 7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [F-18] ASEM and alpha 7-nAChR is still unclear. In this paper, the binding profile of [F-18] ASEM to a chimera structure of alpha 7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [F-18] ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b, d] thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and p-p stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [F-18] ASEM. Six binding modes in terms of the side chain dihedral angles chi(1) and chi(2) of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable pi-pi stacking interaction with [F-18] ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.

Ort, förlag, år, upplaga, sidor
Royal Society of Chemistry, 2017
Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:uu:diva-322119 (URN)10.1039/c7ra00496f (DOI)000399242100041 ()
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF), RB13-0192Stockholms läns landsting, K1764-2013Swedish National Infrastructure for Computing (SNIC), m.2015-1-396
Tillgänglig från: 2017-05-16 Skapad: 2017-05-16 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
Stepanov, V., Svedberg, M., Jia, Z., Krasikova, R., Lemoine, L., Okamura, N., . . . Halldin, C. (2017). Development of [C-11]/[H-3-1]THK-5351-A potential novel carbon-11 tau imaging PET radioligand. Nuclear Medicine and Biology, 46, 50-53
Öppna denna publikation i ny flik eller fönster >>Development of [C-11]/[H-3-1]THK-5351-A potential novel carbon-11 tau imaging PET radioligand
Visa övriga...
2017 (Engelska)Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 46, s. 50-53Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Introduction: Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of A beta aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [F-18]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [C-11]THK-5351. In parallel, THK-5351 was also labeled with tritium ([H-3]THK-5351) for use in in vitro autoradiography (ARG). Methods: The carbon -11 labeling was performed starting with di-protected enantiomeric pure precursor-tertbutyl 5-(6-( (2S)-3-fluoro-2-(tetrahydro-2H-Pyran-2-yloxy)proPoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [C-11]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand,[C-11]THK-5351 (S)-1-fluoro-3-(2-(6-([C-11]methylamino)pyridin-3-yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [H-3]THK-5351 were undertaken using similar approach, resulting in [H-3]THK-5351 with RCP >99.8% and specific radioactivity of 13 GB q/mu mol. Results: [C-11]THK-5351 was produced in good yield (1900 +/- 355 MBq), specific radioactivity (SRA) (361 +/- 119 GBq/mu rnol at EOS + 20 min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [H-3]TM-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [H-3]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [H-3] THK-5351 binding. (C) 2016 Elsevier Inc. All rights reserved.

Nyckelord
Tau imaging, Pet, Carbon-11, Proteinopathy, Autoradiography, Tritium
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
urn:nbn:se:uu:diva-317939 (URN)10.1016/j.nucmedbio.2016.12.004 (DOI)000393730700008 ()28013122 (PubMedID)
Tillgänglig från: 2017-04-03 Skapad: 2017-04-03 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
Kumar, R., Kumar, A., Långström, B. & Darreh-Shori, T. (2017). Discovery of novel choline acetyltransferase inhibitors using structure-based virtual screening. Scientific Reports, 7, Article ID 16287.
Öppna denna publikation i ny flik eller fönster >>Discovery of novel choline acetyltransferase inhibitors using structure-based virtual screening
2017 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 16287Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Alzheimer disease and related dementias are major challenges, demanding urgent needs for earliest possible diagnosis to optimize the success rate in finding effective therapeutic interventions. Mounting solid scientific premises point at the core acetylcholine-biosynthesizing cholinergic enzyme, ChAT as a legitimate in vivo target for developing positron emission tomography biomarker for early diagnosis and/or monitoring therapeutic responses in the neurodegenerative dementias. Up-to-date, no PET tracer ligands for ChAT are available. Here we report for the first time a novel hierarchical virtual screening approach on a commercial library of similar to 300,000 compounds, followed by in vitro screening of the hits by a new High-Throughput ChAT assay. We report detailed pharmacodynamic data for three identified selective novel ChAT ligands with IC50 and K-i values ranging from similar to 7 to 26 mu M. In addition, several novel selective inhibitors of the acetylcholine-degrading enzymes, AChE and BuChE were identified, with one of the compounds showing an IC50-value of similar to 6 mu M for AChE. In conclusion, this report provides an excellent starting platform for designing and optimizing potent and selective ChAT ligands, with high potential as PET-imaging probe for early diagnosis of AD, and related dementias, such as Down's syndrome and Lewy body disorders.

Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-361076 (URN)10.1038/s41598-017-16033-w (DOI)000416135000086 ()
Forskningsfinansiär
Vetenskapsrådet, 2016-01806Karolinska Institutets Forskningsstiftelse, 2016fobi50673Stiftelsen Olle Engkvist ByggmästareÅke Wibergs StiftelseGunvor och Josef Anérs stiftelseMagnus Bergvalls StiftelseStiftelsen Lars Hiertas MinneDemensförbundetGun och Bertil Stohnes StiftelseTore Nilsons Stiftelse för medicinsk forskningStiftelsen Gamla TjänarinnorHjärnfonden
Tillgänglig från: 2018-09-20 Skapad: 2018-09-20 Senast uppdaterad: 2018-09-20Bibliografiskt granskad
Balamurugan, K., Murugan, N. A., Långström, B., Nordberg, A. & Agren, H. (2017). Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers: Insight from Molecular Modeling Studies. ACS Chemical Neuroscience, 8(12), 2655-2666
Öppna denna publikation i ny flik eller fönster >>Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers: Insight from Molecular Modeling Studies
Visa övriga...
2017 (Engelska)Ingår i: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 8, nr 12, s. 2655-2666Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the fi region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid fi fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the "C Pittsburgh Compound B (C-11-PIB). However, for in vitro conditions, significant binding of H-3-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid beta fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties.

Nyckelord
Alzheimer's disease, PET tracers, autosomal dominant Alzheimer's disease, molecular dynamics simulation, docking, MM/GBSA, familial mutations
Nationell ämneskategori
Medicinsk bioteknologi
Identifikatorer
urn:nbn:se:uu:diva-340324 (URN)10.1021/acschemneuro.7b00215 (DOI)000418786100014 ()28898051 (PubMedID)
Tillgänglig från: 2018-02-08 Skapad: 2018-02-08 Senast uppdaterad: 2018-02-08Bibliografiskt granskad
Rahman, O., Långström, B. & Halldin, C. (2016). Alkyl Iodides and [C-11]CO in Nickel-Mediated Cross-Coupling Reactions: Successful Use of Alkyl Electrophiles containing a beta Hydrogen Atom in Metal-Mediated [C-11]Carbonylation. CHEMISTRYSELECT, 1(10), 2498-2501
Öppna denna publikation i ny flik eller fönster >>Alkyl Iodides and [C-11]CO in Nickel-Mediated Cross-Coupling Reactions: Successful Use of Alkyl Electrophiles containing a beta Hydrogen Atom in Metal-Mediated [C-11]Carbonylation
2016 (Engelska)Ingår i: CHEMISTRYSELECT, ISSN 2365-6549, Vol. 1, nr 10, s. 2498-2501Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Transition metal-mediated cross-coupling reactions of non-activated alkyl electrophiles suffer from competing b-hydride elimination and therefore have limited applications in synthetic organic chemistry. Hereby the first successful use of nickel-mediated carbonylative cross-coupling of non-activated alkyl iodides using [C-11] carbon monoxide is presented. The reaction conditions were optimised for the synthesis of N-(pyridine-2-yl) cyclohexane([C-11] carbonyl)-carboxamide. The nickel(0) complex, Ni(COD) 2, in the presence of bathophenanthroline in the non-polar protic solvent tert-butanol at 100 degrees C offered the highest trapping efficiency (TE) and radiochemical yield (RCY) of 89% and 72%, respectively. The applicability of the method was further explored in the syntheses of five additional ([C-11] carbonyl) amides (6a to 6e in Figure 2) and the TE and RCY in the latter cases were 70-90% and 33-57%, respectively. The presented method has a potential for the development of C-11-labelled PET tracers with a carbonyl group connected to an alkyl chain containing beta hydrogen.

Nyckelord
[C-11]carbonylation, PET, alkyl iodides, nickel-mediated, cross-coupling
Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:uu:diva-319900 (URN)10.1002/slct.201600643 (DOI)000395417800063 ()
Tillgänglig från: 2017-04-10 Skapad: 2017-04-10 Senast uppdaterad: 2017-04-10Bibliografiskt granskad
Rodriguez-Vieitez, E., Carter, S. F., Chiotis, K., Saint-Aubert, L., Leuzy, A., Scholl, M., . . . Nordberg, A. (2016). Comparison of Early-Phase C-11-Deuterium-L-Deprenyl and C-11-Pittsburgh Compound B PET for Assessing Brain Perfusion in Alzheimer Disease. Journal of Nuclear Medicine, 57(7), 1071-1077
Öppna denna publikation i ny flik eller fönster >>Comparison of Early-Phase C-11-Deuterium-L-Deprenyl and C-11-Pittsburgh Compound B PET for Assessing Brain Perfusion in Alzheimer Disease
Visa övriga...
2016 (Engelska)Ingår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, nr 7, s. 1071-1077Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
amyloid, astrocytosis, brain perfusion, early-phase PET
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
urn:nbn:se:uu:diva-300056 (URN)10.2967/jnumed.115.168732 (DOI)000378979200016 ()26912447 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 05817Stiftelsen för strategisk forskning (SSF)Knut och Alice Wallenbergs StiftelseKarolinska Institutets ForskningsstiftelseHjärnfondenDemensförbundetEU, FP7, Sjunde ramprogrammetStiftelsen Gamla TjänarinnorWenner-Gren Stiftelserna
Tillgänglig från: 2016-08-02 Skapad: 2016-08-02 Senast uppdaterad: 2017-11-28Bibliografiskt granskad
Rodriguez-Vieitez, E., Saint-Aubert, L., Carter, S. F., Almkvist, O., Farid, K., Scholl, M., . . . Nordberg, A. (2016). Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease. Brain, 139(3), 922-936
Öppna denna publikation i ny flik eller fönster >>Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease
Visa övriga...
2016 (Engelska)Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 139, nr 3, s. 922-936Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
astrocytosis, autosomal dominant Alzheimer's disease, C-11-deuterium-L-deprenyl, F-18-fluorodeoxyglucose, C-11-Pittsburgh compound B
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-282820 (URN)10.1093/brain/awv404 (DOI)000371694600031 ()26813969 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 05817Stiftelsen för strategisk forskning (SSF)Knut och Alice Wallenbergs StiftelseStockholms läns landstingHjärnfondenDemensförbundetEU, Europeiska forskningsrådetStiftelsen Gamla TjänarinnorWenner-Gren Stiftelserna
Tillgänglig från: 2016-04-07 Skapad: 2016-04-07 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
Organisationer

Sök vidare i DiVA

Visa alla publikationer