Nordberg Translational Molecular Imaging Lab
Proteinopathies are common features of neurodegenerative brain disorders and used as an umbrella term for different brain disorders, commonly leading to dementia. The proteinopathies are characterized by the accumulation or change in function of different specific proteins within or outside the neurons in the brain parenchyma, and presenting with different regional distributions in the brain.
Alzheimer’s disease (AD), the leading cause of dementia, is characterized by the deposition of amyloid-β (Aβ) plaques and hyperphosphorylated tau protein tangles. In addition, multiple factors including the activation of astrocytes and microglia and neurovascular processes play interactive roles leading to synaptic dysfunction, brain atrophy and cognitive impairment. Many other neurodegenerative diseases, non-AD tauopathies, are pathologically characterized by the deposition of tau tangles, as well as complex factors involving other protein deposits.
AD has a long presymptomatic period during which neuropathology starts to accumulate decades before clinical onset and these processes can be quantifiable in subjects using brain imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) which can be used as early biomarkers
Our research group has a translational approach using in vitro and in vivo molecular brain imaging techniques, and our aim is to characterize the complex pathophysiological features of neurodegenerative diseases, with a strong focus on AD but also other proteinopathies, in order to develop new early diagnostic markers and new drug targets for early intervention in disease process.
Research group leader
We have extensive collaboration within our own department (NVS), with other departments at KI as well as other research groups at other universities in Sweden including Uppsala, Gothenburg and Stockholm. We also have strong collaboration with several foreign universities including University of Helsinki, University of Turku, University of Manchester, Indiana University School of Medicine, Denver University, Geneva university, Harvard Medical School, La Pitie Salpetriere-Charles Foix hospital, Amsterdam University, McGill University, and Universitat Autónoma de Barcelona.
- Swedish Foundation For Strategic Research (SSF): “New Biomarkers in Early Diagnosis and Treatment of Alzheimer´s disease” . Agneta Nordberg (PI), Eric Westman, Christer Halldin Karolinska Institutet (KI), Hans Ågren Royal Institute of Technology ( KTH), Bengt Långström Uppsala University (UU)
- Swedish Research Council (VR) Dementia Platform, “Proteinopathies in neurodegenerative diseases –new imaging biomarkers and targets for new drugs”, Agneta Nordberg (PI), Christer Halldin , Per Svenningsson KI, Hans Ågren KTH, Bengt Långström UU
- Innovative Medicines Initiative (IMI) AMYPAD, “Amyloid imaging to prevent Alzheimer´s disease”. Project coordinator Frederik Barkhof, University of Amsterdam. PI Stockholm( KI) Agneta Nordberg.
Proteinopathies in neurodegenerative disorders - new imaging biomarkers and drug targets
In vitro imaging studies
New radiolabelled PET tracers will allow further understanding of the relationship between different hallmarks of AD including Aβ plaques, tau deposits and activated astrocytes.
We perform multi-tracer binding assay studies in human postmortem brain tissue both frozen and paraffin fixed.
With the recent developments of first and second generation tau tracers, PET imaging allows us to visualize tau neuropathology and to compare tau pathology in AD and non-AD tauopathies, including corticobasal dementia, progressive supranuclear palsy, frontotemporal dementias as well as down syndrome.
We have several questions we would like to answer such as:
- What are the newly developed tau PET tracers targeting exactly in vitro ?
- Are there differences between sporadic AD, familial forms of AD and non-AD tauopathies ?
- How is the spatial relationship between tau and other pathological features including Aβ plaques, activated astrocytes and synaptic density at diferent Braak stages in sporadic AD brains in comparison to control brains ?
- Can we develop new PET tracers specific for alpha 7 nicotinic receptors in neurons and astrocytes?
In vivo imaging studies
In our group, we perform multi-tracer PET imaging studies in cross-sectional and longitudinal study designs, in AD as well as in non-AD dementias. Patients are recruited from the Memory Clinic, Theme Aging, Karolinska University Hospital, Stockholm. Research participants include individuals from known families with genetic forms (autosomal dominant forms) of AD and other non-AD dementia.
Multi-tracer in vivo PET studies measuring different pathological markers including Aβ and tau deposition, astrocytosis, and cerebral glucose metabolism combined with cognitive tests, cerebrospinal fluid (CSF) biomarkers and MRI aim to answer following questions :
- What are the links between different regional pathological mechanisms leading to AD and non-AD dementias?
- Are the familial forms of AD a suitable model to better understand sporadic AD?
- Inflammation is playing a central role in AD. What is the relationship between the different proteinopathies and inflammatory processes?
- How can we develop new PET tracers for in vivo visualizing of important hallmarks of the neurodegenerative diseases?
- How can we bring molecular imaging into clinical practice and show its usefulness in selecting patients to certain therapies?
A translational research approach combining in vitro techniques, identifying specific molecular targets for PET tracers, and in vivo imaging will increase our understanding of different dynamics of pathophysiological events in neurodegenerative disorders, being of importance for the evaluation of outcome of disease-modifying/secondary prevention treatment strategies.
With special thanks to the following donors for the support they provide or earlier provided to our research:
- Swedish Research Council (VR)
- Swedish Foundation for Strategic Research (SSF)
- Swedish Brain Foundation
- Swedish Alzheimer foundation
- The Stockholm County Council and Karolinska Institutet regional agreement of medical training and clinical research (ALF)
- Karolinska institutet Foundations
- The Dementia Foundation
- Foundation for Old Servants
- Gun and Bertil Stohne´s Foundation
- Sigurd and Elsa Goljes Memorial
- Loo and Hans Osterman Foundation
- Tore Nilsson Foundation
- KI Foundation for Geriatric Disease
- KTH-SLL grant
- Axel Linders Foundation
- Åke Wiberg Foundation
- The EU FW7 large-scale integrating project INMIND (http://www.unimuenster.de/INMIND)
- IMI AMYPAD
Tau PET imaging in neurodegenerative tauopathies-still a challenge.
Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, et al
Mol. Psychiatry 2019 08;24(8):1112-1134
Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer's disease.
Leuzy A, Cicognola C, Chiotis K, Saint-Aubert L, Lemoine L, Andreasen N, et al
Eur. J. Nucl. Med. Mol. Imaging 2019 May;46(5):1152-1163
Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain.
Chiotis K, Stenkrona P, Almkvist O, Stepanov V, Ferreira D, Arakawa R, et al
Eur. J. Nucl. Med. Mol. Imaging 2018 07;45(9):1605-1617
Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia.
Chiotis K, Saint-Aubert L, Rodriguez-Vieitez E, Leuzy A, Almkvist O, Savitcheva I, et al
Mol. Psychiatry 2018 07;23(7):1666-1673
Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease.
Ni R, Gillberg PG, Bogdanovic N, Viitanen M, Myllykangas L, Nennesmo I, et al
Alzheimers Dement 2017 Apr;13(4):419-430
Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains.
Lemoine L, Gillberg PG, Svedberg M, Stepanov V, Jia Z, Huang J, et al
Alzheimers Res Ther 2017 Dec;9(1):96
Cortical laminar tau deposits and activated astrocytes in Alzheimer's disease visualised by 3H-THK5117 and 3H-deprenyl autoradiography.
Lemoine L, Saint-Aubert L, Nennesmo I, Gillberg PG, Nordberg A
Sci Rep 2017 04;7():45496
Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.
Rodriguez-Vieitez E, Saint-Aubert L, Carter S, Almkvist O, Farid K, Schöll M, et al
Brain 2016 Mar;139(Pt 3):922-36
Imaging in-vivo tau pathology in Alzheimer's disease with THK5317 PET in a multimodal paradigm.
Chiotis K, Saint-Aubert L, Savitcheva I, Jelic V, Andersen P, Jonasson M, et al
Eur. J. Nucl. Med. Mol. Imaging 2016 Aug;43(9):1686-99