In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: Randomized, placebo-controlled, double-blind clinical trial

Frontiers in Aging Neuroscience

Volumn 8, Issue MAY, 2016, Pages

  Gejl, Michael ^a,b   Gjedde, Albert ^b,c   Egefjord, Lærke ^a,b   Møller, Arne ^b   Hansen, Søren B ^b   Vang, Kim ^b   Rodell, Anders ^b   Brændgaard, Hans ^b   Gottrup, Hanne ^b   Schacht, Anna ^b   Møller, Niels ^b   Brock, Birgitte ^a,b   Rungby, Jørgen ^a,d  

^a AARHUS UNIVERSITY   (Denmark)

^b AARHUS UNIVERSITY HOSPITAL   (Denmark)

^c UNIVERSITY OF COPENHAGEN   (Denmark)

^d GENTOFTE UNIVERSITY HOSPITAL   (Denmark)

Author keywords

Alzheimer's disease; Amyloid; Cerebral glucose metabolism; Glucagon like peptide 1; Liraglutide

Indexed keywords

AMYLOID BETA PROTEIN; BRAIN PROTEIN; GLUCAGON LIKE PEPTIDE 1 DERIVATIVE; LIRAGLUTIDE; PLACEBO;

ADULT; ADVERSE DRUG REACTION; AGED; ALZHEIMER DISEASE; ARTICLE; BODY MASS; BRAIN METABOLISM; CEREBELLUM; CLINICAL ARTICLE; COGNITIVE DEFECT; CONTROLLED STUDY; DISORDERS OF CARBOHYDRATE METABOLISM; DOUBLE BLIND PROCEDURE; DRUG DOSE INCREASE; DRUG WITHDRAWAL; FEMALE; GLUCOSE BRAIN LEVEL; GLUCOSE METABOLISM; HUMAN; MALE; MENTAL TEST; NAUSEA; OCCIPITAL LOBE; PARIETAL LOBE; PRECUNEUS; PROTEIN DETERMINATION; RANDOMIZED CONTROLLED TRIAL; SCORING SYSTEM; SYSTOLIC BLOOD PRESSURE; TEMPORAL LOBE; TREATMENT DURATION; TREATMENT RESPONSE; WECHSLER MEMORY SCALE; WEIGHT REDUCTION;

EID: 84974559551     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2016.00108     Document Type: Article

References (48)

1. Ahren, B., Winzell, M. S., Wierup, N., Sundler, F., Burkey, B., and Hughes, T. E. (2007). DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide. Regul. Pept. 143, 97-103. doi: 10.1016/j.regpep.2007.03.008
2. Alexander, G. E., Chen, K., Pietrini, P., Rapoport, S. I., and Reiman, E. M. (2002). Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in alzheimer's disease treatment studies. Am. J. Psychiatry 159, 738-745. doi: 10.1176/appi.ajp.159.5.738
3. Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J. C., Decker, H., et al. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease-associated Abeta oligomers. J. Clin. Invest. 122, 1339-1353. doi: 10.1172/JCI57256
4. Craft, S., Baker, L. D., Montine, T. J., Minoshima, S., Watson, G. S., Claxton, A., et al. (2012). Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. 69, 29-38. doi: 10.1001/archneurol.2011.233
5. Dubois, B., Feldman, H. H., Jacova, C., Hampel, H., Molinuevo, J. L., Blennow, K., et al. (2014). Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 13, 614-629. doi: 10.1016/S1474-4422(14)70090-0
6. During, M. J., Cao, L., Zuzga, D. S., Francis, J. S., Fitzsimons, H. L., Jiao, X., et al. (2003). Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 9, 1173-1179. doi: 10.1038/nm919
7. Egefjord, L., Gejl, M., Moller, A., Braendgaard, H., Gottrup, H., Antropova, O., et al. (2012). Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease-protocol for a controlled, randomized double-blinded trial. Dan. Med. J. 59:A4519.
8. Engler, H., Forsberg, A., Almkvist, O., Blomquist, G., Larsson, E., Savitcheva, I., et al. (2006). Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 129, 2856-2866. doi: 10.1093/brain/awl178
9. Femminella, G. D., and Edison, P. (2014). Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimers Dement 10, S55-S61. doi: 10.1016/j.jalz.2013.12.012
10. Freiherr, J., Hallschmid, M., Frey, W. H., Brunner, Y. F., Chapman, C. D., Holscher, C., et al. (2013). Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs 27, 505-514. doi: 10.1007/s40263-013-0076-8
11. Gejl, M., Egefjord, L., Lerche, S., Vang, K., Bibby, B. M., Holst, J. J., et al. (2012). Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. J. Cereb. Blood Flow Metab. 32, 2146-2152. doi: 10.1038/jcbfm.2012.118
12. Gejl, M., Lerche, S., Egefjord, L., Brock, B., Moller, N., Vang, K., et al. (2013). Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain. Front. Neuroenerget. 5:2. doi: 10.3389/fnene.2013.00002
13. Gejl, M., Rungby, J., Brock, B., and Gjedde, A. (2014). At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose. Basic Clin. Pharmacol. Toxicol. 115, 162-171. doi: 10.1111/bcpt.12240
14. Gjedde, A. (1982). Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: a re-examination. Brain Res. 257, 237-274. doi: 10.1016/0165-0173(82)90018-2
15. Gjedde, A. (1983). Modulation of substrate transport to the brain. Acta Neurol. Scand. 67, 3-25. doi: 10.1111/j.1600-0404.1983.tb04541.x
16. Hansen, H. H., Fabricius, K., Barkholt, P., Niehoff, M. L., Morley, J. E., Jelsing, J., et al. (2015). The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal ca1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer's Disease. J. Alzheimers Dis. 46, 877-888. doi: 10.3233/JAD-143090
17. Hardy, J. A., and Higgins, G. A. (1992). Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184-185. doi: 10.1126/science.1566067
18. Holscher, C. (2014). New drug treatments show neuroprotective effects in Alzheimer's and Parkinson's diseases. Neural Regen. Res. 9, 1870-1873. doi: 10.4103/1673-5374.145342
19. Hunt, A., Schonknecht, P., Henze, M., Seidl, U., Haberkorn, U., and Schroder, J. (2007). Reduced cerebral glucose metabolism in patients at risk for Alzheimer's disease. Psychiatry Res. 155, 147-154. doi: 10.1016/j.pscychresns.2006.12.003
20. Hunter, K., and Holscher, C. (2012). Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 13:33. doi: 10.1186/1471-2202-13-33
21. Jendle, J., Nauck, M. A., Matthews, D. R., Frid, A., Hermansen, K., During, M., et al. (2009). Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab. 11, 1163-1172. doi: 10.1111/j.1463-1326.2009.01158.x
22. Kadir, A., Almkvist, O., Forsberg, A., Wall, A., Engler, H., Langstrom, B., et al. (2012). Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease. Neurobiol. Aging 33, 198-214. doi: 10.1016/j.neurobiolaging.2010.06.015
23. Kelly, P., McClean, P. L., Ackermann, M., Konerding, M. A., Holscher, C., and Mitchell, C. A. (2015). Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with Liraglutide. Microcirculation 22, 133-145. doi: 10.1111/micc.12186
24. Kuwabara, H., Evans, A. C., and Gjedde, A. (1990). Michaelis-Menten constraints improved cerebral glucose metabolism and regional lumped constant measurements with [18F] fluorodeoxyglucose. J. Cereb Blood Flow Metab. 10, 180-189. doi: 10.1038/jcbfm.1990.33
25. Lacalle-Aurioles, M., Mateos-Perez, J. M., Guzman-De-Villoria, J. A., Olazaran, J., Cruz-Orduna, I., Aleman-Gomez, Y., et al. (2014). Cerebral blood flow is an earlier indicator of perfusion abnormalities than cerebral blood volume in Alzheimer's disease. J. Cereb. Blood Flow Metab. 34, 654-659. doi: 10.1038/jcbfm.2013.241
26. Leinonen, V., Alafuzoff, I., Aalto, S., Suotunen, T., Savolainen, S., Nagren, K., et al. (2008). Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B. Arch. Neurol. 65, 1304-1309. doi: 10.1001/archneur.65.10.noc80013
27. Lerche, S., Brock, B., Rungby, J., Botker, H. E., Moller, N., Rodell, A., et al. (2008). Glucagon-like peptide-1 inhibits blood-brain glucose transfer in humans. Diabetes 57, 325-331. doi: 10.2337/db07-1162
28. McClean, P. L., Gault, V. A., Harriott, P., and Holscher, C. (2010). Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer's disease. Eur. J. Pharmacol. 630, 158-162. doi: 10.1016/j.ejphar.2009.12.023
29. McClean, P. L., and Holscher, C. (2014). Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology 76(Pt A), 57-67. doi: 10.1016/j.neuropharm.2013.08.005
30. McClean, P. L., Jalewa, J., and Holscher, C. (2015). Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav. Brain Res. 293, 96-106. doi: 10.1016/j.bbr.2015.07.024
31. McClean, P. L., Parthsarathy, V., Faivre, E., and Holscher, C. (2011). The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J. Neurosci. 31, 6587-6594. doi: 10.1523/JNEUROSCI.0529-11.2011
32. Mooradian, A. D., Chung, H. C., and Shah, G. N. (1997). GLUT-1 expression in the cerebra of patients with Alzheimer's disease. Neurobiol. Aging 18, 469-474. doi: 10.1016/S0197-4580(97)00111-5
33. Mosconi, L. (2005). Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Eur. J. Nucl. Med. Mol. Imaging 32, 486-510. doi: 10.1007/s00259-005-1762-7
34. Nauck, M. A. (2004). Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Horm. Metab. Res. 36, 852-858. doi: 10.1055/s-2004-826175
35. Nordberg, A., Rinne, J. O., Kadir, A., and Langstrom, B. (2010). The use of PET in Alzheimer disease. Nat. Rev. Neurol. 6, 78-87. doi: 10.1038/nrneurol.2009.217
36. Patlak, C. S., Blasberg, R. G., and Fenstermacher, J. D. (1983). Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J. Cereb. Blood Flow Metab. 3, 1-7. doi: 10.1038/jcbfm.1983.1
37. Perry, T., and Greig, N. H. (2005). Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. Curr. Alzheimer Res. 2, 377-385. doi: 10.2174/1567205054367892
38. Rodell, A., Aanerud, J., Braendgaard, H., and Gjedde, A. (2013). Washout allometric reference method (WARM) for parametric analysis of [(11)C]PIB in human brains. Front. Aging Neurosci. 5:45. doi: 10.3389/fnagi.2013.00045
39. 2 effect. Front. Neuroenerget. 4:8. doi: 10.3389/fnene.2012.00008
40. Scheltens, P., Kamphuis, P. J., Verhey, F. R., Olde Rikkert, M. G., Wurtman, R. J., Wilkinson, D., et al. (2010). Efficacy of a medical food in mild Alzheimer's disease: a randomized, controlled trial. Alzheimers Dement 6, 1-10. doi: 10.1016/j.jalz.2009.10.003
41. Simpson, I. A., Chundu, K. R., Davies-Hill, T., Honer, W. G., and Davies, P. (1994). Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann Neurol 35, 546-551. doi: 10.1002/ana.410350507
42. Small, G. W., Ercoli, L. M., Silverman, D. H., Huang, S. C., Komo, S., Bookheimer, S. Y., et al. (2000). Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 97, 6037-6042. doi: 10.1073/pnas.090106797
43. Smith, G. S., Laxton, A. W., Tang-Wai, D. F., McAndrews, M. P., Diaconescu, A. O., Workman, C. I., et al. (2012). Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. Arch. Neurol. 69, 1141-1148. doi: 10.1001/archneurol.2012.590
44. Solbach, C., Uebele, M., Reischl, G., and Machulla, H. J. (2005). Efficient radiosynthesis of carbon-11 labelled uncharged Thioflavin T derivatives using [11C]methyl triflate for beta-amyloid imaging in Alzheimer's Disease with PET. Appl. Radiat. Isot. 62, 591-595. doi: 10.1016/j.apradiso.2004.09.003
45. Talairach, J., and Tournoux, P. (1988). Co-Planar Stereotaxic Atlas of the Human Brain. New York, NY: Thieme Verlag.
46. Talbot, K., Wang, H. Y., Bakshi, K., Trojanowski, J., and Arnold, S. (2011). The diabetes drug liraglutide ameliorates insulin resistance in the hippocampal formation of Alzheimer's disease (AD) cases. Alzheimer's Dementia 7:e65. doi: 10.1016/j.jalz.2011.09.137
47. Winkler, E. A., Nishida, Y., Sagare, A. P., Rege, S. V., Bell, R. D., Perlmutter, D., et al. (2015). GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18, 521-530. doi: 10.1038/nn.3966
48. Xu, W. L., von Stranss, E., Qiu, C. X., Winblad, B., and Fratiglioni, L. (2009). Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Diabetologia 52, 1031-1039. doi: 10.1007/s00125-009-1323-x