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Factsheet by Poul F. Høilund-Carlsen

Group name: TRANSIC (Translational Neuroscience Imaging Center)
Group leader: Poul F. Høilund-Carlsen, MD, DMSc, Professor
Alternating leader: Albert Gjedde, MD, DMSc, Professor

Group members: 12 Professors (AG, BF, TO, ZI, FRP, TM, HBN, HM, TK, BWK, KB, PFHC) covering in one place: Pharmacy, Physiology, Molecular Medicine, Neurology, Neurosurgery, Psychiatry, Pathology, Nuclear Medicine, Molecular Imaging, PET/CT and PET/MRI, Medical Physics, Clinical Physiolgy and Nuclear Medicine,
3 Assoc. Profs. (KL, MSV, PB) covering Molecular Medicine, PET/CT and MRI, Biomed Lab (animal experiments),
1 PhD student + expected 9,
1 PostDoc + expected 3,
2 Cell biologists,
3 Hospital Physicists,
3 Radiochemists,
1 Biostatistician,
6 Undergraduate students,
1 Small animal technician,
2-4 Medical doctors

Department & University/Hospital/Other: Translational research center under establishment, hosted by the Dept. of Nuclear Medicine, OUH.

Close collaboration with 6 OUH departments: Neurology (Dementia Clinic included), Neurosurgery, Oncology, Occupational Medicine, Psychiatry, Pathology.

Existing or planned collaborations with another 6 OUH departments: Anaesthesia, Endocrinology, Cardiology, Clinical Genetics, Clinical Microbiology, Infectious diseases.

Existing collaboration with 16 other OUH departments on applied molecular imaging science, some of which are poised to become partners.

Collaboration with SDU departments:
Nucleic Acid Center, Single Particle Physics and Engineering, Biomed. Lab, several Molecular Medicine departments and other departments under the Dept. of Clinical Research, SDU.
Planned collaboration on mulitcenter studies with sister departments in Vejle and Esbjerg and with selected foreign Nuclear Medicine Departments.
Funding sources: Part of project 1 is financed by internal and external grants; project 2 is partly funded by internal grants; part of project 3 is funded by the Psychiatry Fund of RSD; a small part of T3DMAD is funded by the Danish Alzheimer Foundation.

Description of research:
Clinical brain research, and in particular applied molecular imaging science, is under expansion at OUH and in RSD. A unifying approach to brain disorders manifested by deficient brain energy metabolism and glucose consumption is the claim that both information processing and energy metabolism are concentrated in the proximity of the synaptic densities of dendritic spines of neurons where presynaptic terminals, monoaminergic varicosities and astroglial processes congregate. The resulting interactions can be imaged and monitored in vivo.

This is emphasized by the decision to (i) establish cyclotron #2 in Odense to secure isotope supply and production of special radioactive isotopes, incl. Auger-emitters for therapy, and (2) install a new generation PET/MRI scanner (GEHC Signa, the world’s best right now), which, due to new technology has double sensitivity with correspondingly lower radiation, allowing repeat patient studies and examination of children. This phase of establishment explains that some elements exist while others are being planned. Almost all necessary equipment and methodologies are present, translational and international research collaboration is there. Shortcomings exist primarily in terms of space, infrastructure, certain key persons, and funding.

1. Auger-emitter therapy. A main research area of the Dept. of Nuclear Medicine is targeted radionuclide therapy of cancers, not so much with 90Y or 177Lu, which are more common, but not curative, but with Auger-electron emitters, which have significant advantages, and has given promising preclincal results (Project GLITZ) in animal models of glioblastomas (ref. HC3). This line of research has many partners and continues also in prostate, lung, and breast cancer.

2. QUAD = Quantification of diaschisis with FDG-PET/CT. Ongoing PhD project by Eivind Segtnan. Has so far resulted in 3 peer-review publications (cf. HC2) and over 15 abstracts of which 11 were published internationally. Several papers and abstracts in the pipeline. Commercially available and locally established processing algorithms are being tested.

3. ASDPET = Neurobiology of autism spectrum disorders revealed by in vivo PET. Accepted PhD project by DVM, MD Lotte Bo Petersen. Cerebral glucose and fat metabolism in ASD patients and matched controls assessed by PET/MRI. Scheduled to start when the PET/MR scanner is up and running.

4. Neuro-WAD = Neurobiological effects of work-related adjustment disorder. Applied for PhD Project by MSc Saga S. Madsen that starts as soon as the PET/MR scanner is ready. Addresses a major societal burden aiming to provide objective evidence for cerebral pathology in patients exposed to occupational stress. We hypothesize that PET by FDG, [11C]raclo¬pride and/or [11C]FLB 457 can detect and quantify pathology in specific brain areas and connections in patients with work related adjustment disorder.

5. SYNAPDIN = Brain synaptic density and network activity in neuropsychiatric and neurodegenerative disorders. Major prospective project by prof. Gjedde. The goal is to determine how brain regions with high functional connectivity density (FCD) determined by fMRI, such as the default mode network (DMN), become vulnerable in aging, dementia, and psychiatric conditions including autism spectrum disorder, Alzheimer’s disease and schizophre¬nia (ASD-AD-S). This is done by measuring glutamatergic and GABAergic (i.e., total) signaling and asso¬ciated energetics using calibrated fMRI to confirm that high FCD regions have highly correlated neuronal activity. A novel PET method uses a radio¬li¬gand (11C-UCB-J) of synaptic vesicle glycoprotein 2A (SV2A) to measure synaptic density. We first validate these methods in animal models of ASD-AD-S against traditional electrophysio¬lo¬gical recordings and immunohi¬sto¬chemistry, and then we apply the validated method to human studies in healthy controls and patients with ASD-AD-S disorders. To de¬ter¬mine the factors that make high FCD regions such as DMN vulnerable to disease, we put together a multi-disciplinary team of experts in MRS, fMRI, PET, metabolism, and electrophysiology, and collaborators who are experts in ASD-AD-S and use R-fMRI to study these disorders.

6. T3DMAD = Defective aerobic glycolysis: the link between diabetes and Alzhei¬mers disease? It has been proposed that impairments in brain insulin/insulin-like growth factor (IGF) signaling is associated with increased accumulation of Aβ, hyperphosphorylated tau, reactive oxygen/nitrogen species, and pro-inflammatory and pro-apoptotic molecules. Both restoration of insulin responsiveness and use of insulin therapy can improve cognitive perfor¬man¬ce. The role of altered glucose metabolism in diabetes type 2 and hyperglycemia has been further documented by Gejl et al. (cf. AG 3,10). The authors demonstrated that glucagon-like peptide-1 (GLP1) decreases intracerebral glucose content during hyperglycemia and diabetes type 2. We hypothesize that insulin resistance manifests itself as reduction in regional cerebral glucose metabolism, aerobic glycolysis, lactate, and cerebral blood flow in patients with diabetes 2, with increased risk of developing AD. To test this hypothesis, including the hypothetical association with brain levels of lactate in the healthy population and in AD patients with and without diabetes, we will use PET to compare the changes of brain energy metabolism and perfusion with the load of ß-amyloid peptide in the brain of elderly healthy volunteers and patients with AD with and without diabetes, and we will use MR spectroscopy to measure lactate levels. We have designed the studies specifically to reveal the role of defective glucose-energy metabolism and aerobic glycolysis in the link between AD and diabetes type 2

7. ADMAC = Alzheimer’s and molecular carotid artery calcification. The above project will be conducted in consert with and in the same cohort of patients as a prospective longitudinal study (by prof. Høilund-Carlsen et al.) on molecular arterial (cardiac, aortic, carotid) calcification in patients referred to the Dept. of Endocrinology, OUH, on suspicion of DM1 or DM2. These paients are screened on entrance by all available and feasible methods meaning that all relevant additional data will be made available to both subprojects. The hypothesis of the current project is that molecular arterial calcification can be detected with PET/CT using sodium flouride (NaF) as tracer in diabetic patients, years or decades before otherwise possible (cf. HC1). If correct, this finding will potentially open for early and likely more effective prevention measures and/or therapy of diabetics, most of whom will die prematurely due to events secondary to arterial arteriosclerosis (acute myocardial infarction, apoplexia, renal failure).

Other: Additional projects applying PET tecnique are under consideration, e.g., projects focusing on Consciousness/Unconscoiusness; Normal pressure hydrochephalus; Transcranial pulsed electromagnetic fields in Parkinson’s disease; Schizophrenia; Integrative medicine for treatment of Alzheimer’s disease; Global and regional cerebral metabolism following electro-convulsive therapy (formerly known as electroshock therapy); Chemobrain (brain metabolism during and following chemotherapy); and the following acute conditions: Acute psychosis; Acute stroke; Acute injury (trauma, car accident, sports).

Key publications (last 10 years):
Selected Gjedde publications:
1. Rodell AB, O'Keefe G, Rowe CC, Villemagne VL, Gjedde A. Cerebral Blood Flow and Aβ-Amyloid Estimates by WARM Analysis of [11C]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging. Front Aging Neurosci 2017;8:321.

2. Aanerud J, Borghammer P, Rodell A, Jónsdottir KY, Gjedde A. Sex differences of human cortical blood flow and energy metabolism. J Cereb Blood Flow Metab 2016:271678X16668536.

3. Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K, Rodell A, Brændgaard H, Gottrup H, Schacht A, Møller N, Brock B, Rungby J. In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci 2016;8:108.

4. Stender J, Mortensen KN, Thibaut A, Darkner S, Laureys S, Gjedde A, Kupers R. The Minimal Energetic Requirement of Sustained Awareness after Brain Injury. Curr Biol 2016;26(11):1494-9.

5. Hyder F, Herman P, Bailey CJ, Møller A, Globinsky R, Fulbright RK, Rothman DL, Gjedde A. Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis. J Cereb Blood Flow Metab 2016;36(5):903-16.

6. Nahimi A, Jakobsen S, Munk OL, Vang K, Phan JA, Rodell A, Gjedde A. Mapping α2 adrenoceptors of the human brain with 11C-yohimbine. J Nucl Med 2015 Mar;56(3):392-8.

7. Phan JA, Landau AM, Wong DF, Jakobsen S, Nahimi A, Doudet DJ, Gjedde A. Quantification of [(11)C]yohimbine binding to α2 adrenoceptors in rat brain in vivo. J Cereb Blood Flow Metab 2015;35(3):501-11.

8. Stender J, Kupers R, Rodell A, Thibaut A, Chatelle C, Bruno MA, Gejl M, Bernard C, Hustinx R, Laureys S, Gjedde A. Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients. J Cereb Blood Flow Metab 2015;35(1):58-65.

9. Iversen P, Mouridsen K, Hansen MB, Jensen SB, Sørensen M, Bak LK, Waagepetersen HS, Schousboe A, Ott P, Vilstrup H, Keiding S, Gjedde A. Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans. Front Neurosci. 2014 Nov 3;8:353.

10. Gejl M, Lerche S, Egefjord L, Brock B, Møller N, Vang K, Rodell AB, Bibby BM, Holst JJ, Rungby J, Gjedde A. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain. Front Neuroenergetics. 2013 Mar 27;5:2. doi: 10.3389/fnene.2013.00002.

11. Gjedde A, Aanerud J, Braendgaard H, Rodell AB. Blood-brain transfer of Pittsburgh compound B in humans. Front Aging Neurosci. 2013;5:70.

12. Gjedde A, Aanerud J, Peterson E, Ashkanian M, Iversen P, Vafaee M, Møller A, Borghammer P. Variable ATP yields and uncoupling of oxygen consumption in human brain. Adv Exp Med Biol. 2011;701:243-8.

13. Gjedde A, Keiding S, Vilstrup H, Iversen P. No oxygen delivery limitation in hepatic encephalopathy. Metab Brain Dis. 2010 Mar;25(1):57-63.

14. Gjedde A, Kumakura Y, Cumming P, Linnet J, Møller A. Inverted-U-shaped correlation between dopamine receptor availability in striatum and sensation seeking. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3870-5.

15. Gjedde A, Geday J. Deep brain stimulation reveals emotional impact processing in ventromedial prefrontal cortex. PLoS One. 2009 Dec 7;4(12):e8120.

Recent Høilund-Carlsen publications:
1. Blomberg BA, de Jong PA, Thomassen A, Lam MG, Vach W, Olsen MH, Mali WP, Narula J, Alavi A, Høilund-Carlsen PF. Thoracic aorta calcification but not inflammation is associated with increased cardiovascular disease risk: results of the CAMONA Study. Eur J Nucl Med Mol Imaging 2017; 44(2): 249-58.

2. Segtnan EA, Grupe P, Jarden JO, Gerke O, Ivanidze J, Christlieb SB, Constantinescu C, Pedersen JE, Houshmand S, Hess S, Zarei M, Gjedde A, Alavi A, Høilund-Carlsen PF. Prognostic implications of total hemispheric glucose metabolism ratio in cerebrocerebellar diaschisis. J Nucl Med 2017; 58(5): 768-773.

3. Thisgaard H, Halle B, Aaberg-Jessen C, Olsen BB, Therkelsen ASN; Dam JH, Langkjær N, Munthe S, Någren K, Høilund-Carlsen PF, Kristensen BW. Highly effective auger-electron therapy in an orthotopic glioblastoma xenograft model using convection-enhanced delivery. Theranostics 2016; 6(12): 2278-91.

4. Hildebrandt MG, Gerke O, Baun C, Falch K, Hansen JA, Farahani ZA, Petersen H, Larsen LB, Duvnjak S, Buskevica I, Bektas S, Søe K, Jylling AM, Ewertz M, Alavi A, Høilund-Carlsen PF. [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in suspected recurrent breast cancer: a prospective comparative study of dual-time-point FDG-PET/CT, contrast-enhanced ct, and bone scintigraphy. J Clin Oncol 2016;34(16):1889-97.

5. Petersen H, Holdgaard PC, Madsen PH, Knudsen LM, Gad D, Gravergaard AE, Rhode M, Godballe C, Engelmann BE, Bech K, Theilmann-Jørgensen D, Mogensen O, Karstoft J, Johansen J, Christensen JB, Johansen A, Høilund-Carlsen PF; PET/CT Task Force of the Region of Southern Denmark. FDG PET/CT in cancer: comparison of actual use with literature-based recommendations. Eur J Nucl Med Mol Imaging 2016; 43(4): 695-706.

Other outputs:
One patent in Auger-emitter therapy of glioblastomas, one biotech company (GlioPharma) established in RSD.

Key collaborations:
Danish: The main Danish collaborators are mentioned above.
General Electric Healthcare (Bich Lee, Global Manager PET/CT and Lars Kervefelt, Segment Leader Molecular Imaging Nordic):
Long-term cooperation (without sponsor¬ship). Our department is GE Healthcare's largest customer in the Nordic region. Bich Lee wants PFHC as head of advisory board regarding molecular arterial calcification and cancer.

Gothenburg and Lund-Malmö Universities (Prof. Lars Edenbrandt):
Long-term collaboration on intelligent computer technology to support the interpretation of gamma camera and PET studies. Valuable in assessing myocardial perfusion and cancer spread to the bones.

Uppsala University (Prof. Vladimir Tolmachev):
Collaboration on highly promising new PET traces for diagnostics and also radioisotope treatment of prostate and other cancers.

TracerPharma and GlioPharma (CEO John Bo Jacobsen and CFO Jette Breum):
These two Danish companies are mentioned here because of their many international contacts. Our research concerns on brain tumors together with Pathology and Neurosurgery, OUH, have resulted in the creation of a biotech company (GlioPharma) in the RSD.

University of Pennsylvania, Philadelphia, PA, USA (Prof. Abass Alavi):
Since 2011 of great importance to us (and OUH). At the Society of Nuclear Medicine's Annual 2017 Meeting in Denver in June this year, PENN and NMA are the two departments with the highest number of accepeted abstracts. At the forthcoming World Congress in Molecular Imaging in Philadelphia later this year and the forthcoming European Association of Nuclear Medicine Congress in October in Vienna, NMA also expects to be among top 3 in terms of number of abstracts.

Geneva University, Geneva, Switzerland (Prof. Habib Zaidi):
Advanced cooperation on especially technical aspects of clinical PET/CT, PET/MR and preclinical PET/CT/SPECT and PET/MR in animals.

John Hopkins University and Medical Institutions, Baltimore, MD, USA (Prof. Dean F. Wong):
Leader in the study of neurotransmission and the effect of CNS drugs.

Yale University, New Haven, CT, USA (Prof. Fahmeed Hyder):
Initial cooperation in neuroscience focusing on PET/MRI and mapping of brain energy conversion.

Karolinska Instituttet, Stockholm (Prof. Christer Halldin):
Potential collaboration on brain tracers.

Shahid Besheshti University, Tehran, Iran (Prof. Mojtaba Zarei):
Prof. Høilund-Carlsen is an adjunct professor at this university, who is currently setting up a large PET center with the same PET/MRI scanner as in Odense. Students from here are expected to solve several demanding mathematical-physical research tasks for the clinical use of PET/MR.

Tabriz University of Medical Sciences, Tabriz, Iran (Chancellor Somi, Dean Shakouri):
Cooperation on PhD education and aging science (brain, cardiovascular and musculoskeletal diseases).

As mentioned, with few exceptions, almost all types of equipment, know-how, experience and standardized routines in basic, preclinical and clinical examinations involved in the above studies are available in Odense at OUH and SDU. This includes also experience with study designs, database administration, and publication. Exceptions are specific exepertises in MRI, additional space, additional manpower, and additional funding