Simulations of symptomatic treatments for Alzheimer's disease: Computational analysis of pathology and mechanisms of drug action

Alzheimer's Research and Therapy

Volumn 4, Issue 6, 2012, Pages

  Roberts, Patrick D ^a,b   Spiros, Athan ^b   Geerts, Hugo ^b  

^a Oregon Health and Science University Department of Biomedical Engineering   (United States)

^b In Silico BioSciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APOLIPOPROTEIN E; CATECHOLAMINE; DONEPEZIL; GALANTAMINE; INTEPIRDINE; RIVASTIGMINE;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COGNITION; COMPUTER MODEL; COMPUTER SIMULATION; CONTROLLED STUDY; DISEASE ASSESSMENT; DRUG MECHANISM; FEMALE; GENOTYPE; MALE; MILD COGNITIVE IMPAIRMENT; MOUSE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; WORKING MEMORY;

EID: 84869878419     PISSN: None     EISSN: 17589193     Source Type: Journal    
DOI: 10.1186/alzrt153     Document Type: Article

References (98)

1. Agoram B, Demin O: Integration not isolation: arguing the case for quantitative and systems pharmacology in drug discovery and development. Drug Discov Today 2011, 16:1031-1036.
2. Gauthier S, Emre M, Farlow M, Bullock R, Grossberg G, Potkin S: Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors. Curr Med Res Opin 2003, 19:707-714.
3. Conn P, Jones C, Lindsley C: Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci 2009, 30:148-155.
4. Buckingham S, Jones A, Brown L, Sattelle D: Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. Pharmacol Rev 2009, 61:39-61.
5. Maillet M, Robert S, Lezoualc'h F: New insights into serotonin 5-HT4 receptors: a novel therapeutic target for Alzheimer's disease? Curr Alzheimer Res 2004, 1:79-85.
6. Maher-Edwards G, Zvartau-Hind M, Hunter A, Gold M, Hopton G, Jacobs G, Davy M, Williams P: Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Curr Alzheimer Res 2010, 7:374-385.
7. Maher-Edwards G, Dixon R, Hunter J, Gold M, Hopton G, Jacobs G, Williams P: SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry 2011, 26:536-544.
8. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius H: Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003, 348:1333-1341.
9. Tegner J, Compte A, Auffray C, An G, Cedersund G, Clermont G, Gutkin B, Oltvai Z, Stephan K, Thomas R, Villoslada P: Computational disease modeling - fact or fiction? BMC Syst Biol 2009, 3:56.
10. Spiros A, Carr R, Geerts H: Not all partial dopamine D(2) receptor agonists are the same in treating schizophrenia. Exploring the effects of bifeprunox and aripiprazole using a computer model of a primate striatal dopaminergic synapse. Neuropsychiatr Dis Treat 2010, 6:589-603.
11. Durstewitz D, Seamans J, Sejnowski T: Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 2000, 83:1733-1750.
12. Spiros A, Geerts H: A quantitative way to estimate clinical off-target effects for human membrane brain targets in CNS Research and Development. Exp Pharmacology 2012, 4:53-61.
13. Montague P, McClure S, Baldwin P, Phillips P, Budygin E, Stuber G, Kilpatrick M, Wightman R: Dynamic gain control of dopamine delivery in freely moving animals. J Neurosci 2004, 24:1754-1759.
14. Geerts H: The virtual synapse what is its contribution to understanding cholinergic neural transmission? Therapie 2004, 59:21-23.
15. Zhang W, Basile A, Gomeza J, Volpicelli L, Levey A, Wess J: Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. J Neurosci 2002, 22:1709-1717.
16. Slutsky I, Wess J, Gomeza J, Dudel J, Parnas I, Parnas H: Use of knockout mice reveals involvement of M2-muscarinic receptors in control of the kinetics of acetylcholine release. J Neurophysiol 2003, 89:1954-1967.
17. Aosaki T, Tsubokawa H, Ishida A, Watanabe K, Graybiel A, Kimura M: Responses of tonically active neurons in the primate's striatum undergo systematic changes during behavioral sensorimotor conditioning. J Neurosci 1994, 14:3969-3984.
18. Szalisznyo K, Muller L: Dopamine induced switch in the subthreshold dynamics of the striatal cholinergic interneurons: a numerical study. J Theor Biol 2009, 256:547-560.
19. Shafferman A, Velan B, Ordentlich A, Kronman C, Grosfeld H, Leitner M, Flashner Y, Cohen S, Barak D, Ariel N: Substrate inhibition of acetylcholinesterase: residues affecting signal transduction from the surface to the catalytic center. EMBO J 1992, 11:3561-3568.
20. Anglister L: Acetylcholinesterase from the motor nerve terminal accumulates on the synaptic basal lamina of the myofiber. J Cell Biol 1991, 115:755-764.
21. Kuffler S, Yoshikami D: The number of transmitter molecules in a quantum: an estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J Physiol 1975, 251:465-482.
22. Giniatullin R, Talantova M, Vyskocil F: Desensitization shortens the high-quantal-content endplate current time course in frog muscle with intact cholinesterase. J Physiol 1997, 502:641-648.
23. Garzon M, Pickel V: Subcellular distribution of M2 muscarinic receptors in relation to dopaminergic neurons of the rat ventral tegmental area. J Comp Neurol 2006, 498:821-839.
24. DeFelipe J: Cortical interneurons: from Cajal to 2001. Prog Brain Res 2002, 136:215-238.
25. Williams GV, Goldman-Rakic PS: Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995, 376:572-575.
26. Sidiropoulou K, Lu F, Fowler M, Xiao R, Phillips C, Ozkan E, Zhu M, White F, Cooper D: Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat Neurosci 2009, 12:190-199.
27. Hines M, Carnevale T: The NEURON simulation environment. Neural Comput 1997, 9:1179-1209.
28. Hodgkin AL, Huxley AF: A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (London) 1952, 108:37-77.
29. Traub R, Bibbig A, LeBeau F, Buhl E, Whittington M: Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro. Annu Rev Neurosci 2004, 27:247-278.
30. Destexhe A, Mainen Z, Sejnowski T: Kinetic models of synaptic transmission. Methods Neuronal Model 1998, 1-25.
31. Jahr C, Stevens C: Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics. J Neurosci 1990, 10(9):3178-3182.
32. Levy R, Goldman-Rakic P: Segregation of working memory functions within the dorsolateral prefrontal cortex. Exp Brain Res 2000, 133:23-32.
33. Lacroix L, Dawson L, Hagan J, Heidbreder C: 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex. Synapse 2004, 51:158-164.
34. Hirst W, Abrahamsen B, Blaney F, Calver A, Aloj L, Price G, Medhurst A: Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol Pharmacol 2003, 64:1295-1308.
35. Marcos B, Gil-Bea F, Hirst W, Garcia-Alloza M, Ramirez M: Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci 2006, 24:1299-1306.
36. Minabe Y, Shirayama Y, Hashimoto K, Routledge C, Hagan J, Ashby JCR: Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study. Synapse 2004, 52:20-28.
37. Gartside S, Hajos-Korcsok E, Bagdy E, Harsing JLG, Sharp T, Hajos M: Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons. Neuroscience 2000, 98:295-300.
38. Erkent U, Koytchev R: The use of truncated area under the curves in the bioequivalence evaluation of long half-life drugs. Studies Donepezil Memantine. Arzneimittelforschung 2008, 58:255-258.
39. Ball M: Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol 1977, 37:111-118.
40. Masliah E, Terry R, De Teresa R, Hansen L: Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 1989, 103:234-239.
41. Davies P, Maloney A: Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 1976, 2:1403.
42. Boileau I, Dagher A, Leyton M, Welfeld K, Booij L, Diksic M, Benkelfat C: Conditioned dopamine release in humans: a positron emission tomography [11C]raclopride study with amphetamine. J Neurosci 2007, 27:3998-4003.
43. Ito K, Ahadieh S, Corrigan B, French J, Fullerton T, Tensfeldt T: Disease progression meta-analysis model in Alzheimer's disease. Alzheimers Dement 2010, 6:39-53.
44. Gauthier S, Aisen P, Ferris S, Saumier D, Duong A, Haine D, Garceau D, Suhy J, Oh J, Lau W, Sampalis J: Effect of tramiprosate in patients with mild-to-moderate Alzheimer's disease: exploratory analyses of the MRI sub-group of the Alphase study. J Nutr Health Aging 2009, 13:550-557.
45. Green R, Schneider L, Amato D, Beelen A, Wilcock G, Swabb E, Zavitz K: Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009, 302:2557-2564.
46. Schneider L, Sano M: Current Alzheimer's disease clinical trials: methods and placebo outcomes. Alzheimers Dement 2009, 5:388-397.
47. Tannenberg R, Scott H, Tannenberg A, Dodd P: Selective loss of synaptic proteins in Alzheimer's disease: evidence for an increased severity with APOE varepsilon4. Neurochem Int 2006, 49:631-639.
48. Cohen R, Podruchny T, Bokde A, Carson R, Herscovitch P, Kiesewetter D, Eckelman W, Sunderland T: Higher in vivo muscarinic-2 receptor distribution volumes in aging subjects with an apolipoprotein E-epsilon4 allele. Synapse 2003, 49:150-156.
49. Box G: George's Column: Do Interactions Matter? J Quality Engineering 1990, 2(3):365-369.
50. Ghosh S, Rao C: Design and Analysis of Experiments. Handbook of Statistics 13 Amsterdam: North-Holland; 1996.
51. John C, Budygin E, Mateo Y, Jones S: Neurochemical characterization of the release and uptake of dopamine in ventral tegmental area and serotonin in substantia nigra of the mouse. J Neurochem 2006, 96:267-282.
52. Ogren SO, Eriksson TM, Elvander-Tottie E, D'Addario C, Ekstrom JC, Svenningsson P, Meister B, Kehr J, Stiedl O: The role of 5-HT(1A) receptors in learning and memory. Behav Brain Res 2008, 195:54-77.
53. Audinot V, Newman-Tancredi A, Cussac D, Millan M: Inverse agonist properties of antipsychotic agents at cloned, human (h) serotonin (5-HT) (1B) and h5-HT(1D) receptors. Neuropsychopharmacology 2001, 25:410-422.
54. Pendyam S, Mohan A, Kalivas P, Nair S: Computational model of extracellular glutamate in the nucleus accumbens incorporates neuroadaptations by chronic cocaine. Neuroscience 2009, 158:1266-1276.
55. Mamo D, Graff A, Mizrahi R, Shammi C, Romeyer F, Kapur S: Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 2007, 164:1411-1417.
56. Rasmussen H, Ebdrup B, Erritzoe D, Aggernaes B, Oranje B, Kalbitzer J, Pinborg L, Baare W, Svarer C, Lublin H, Knudsen G, Glenthoj B: Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine. Psychopharmacology (Berl) 2011, 213:583-592.
57. Trichard C, Paillere-Martinot M, Attar-Levy D, Recassens C, Monnet F, Martinot J: Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry 1998, 155:505-508.
58. Kapur S, Zipursky R, Remington G, Jones C, McKay G, Houle S: PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am J Psychiatry 1997, 154:1525-1529.
59. Kapur S, Cho R, Jones C, McKay G, Zipursky R: Is amoxapine an atypical antipsychotic? Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy. Biol Psychiatry 1999, 45:1217-1220.
60. Howes O, Egerton A, Allan V, McGuire P, Stokes P, Kapur S: Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Curr Pharm Des 2009, 15:2550-2559.
61. Howes O, Montgomery A, Asselin M, Murray R, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire P, Grasby P: Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 2009, 66:13-20.
62. Kaasinen V, Nagren K, Jarvenpaa T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne J: Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease. J Clin Psychopharmacol 2002, 22:615-620.
63. Bohnen N, Kaufer D, Hendrickson R, Ivanco L, Lopresti B, Koeppe R, Meltzer C, Constantine G, Davis J, Mathis C, Dekosky S, Moore R: Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2005, 76:315-319.
64. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Grut M, Strandberg B, Ringheim A, Eriksson B, Blomquist G, Langstrom B, Nordberg A: PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiol Aging 2008, 29:1204-1217.
65. Parker C, Cunningham V, Martarello L, Rabiner E, Searle G, Gee A, Davy M, Johnson C, Ahmed M, Gunn R, Laruelle M: Evaluation of the novel 5-HT6 receptor radioligand,[11C] GSK-215083 in human. Neuroimage 2008, 41: T20-T20.
66. Roses A: Apolipoprotein E in neurology. Curr Opin Neurol 1996, 9:265-270.
67. Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G, Roses A, Haines J, Pericak-Vance M: >Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261:921-923.
68. Aerssens J, Raeymaekers P, Lilienfeld S, Geerts H, Konings F, Parys W: APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease. Dement Geriatr Cogn Disord 2001, 12:69-77.
69. DeKosky S, Ikonomovic M, Styren S, Beckett L, Wisniewski S, Bennett D, Cochran E, Kordower J, Mufson E: Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Annals of neurology 2002, 51(2):145-155.
70. Danysz W, Parsons C: The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence. Int J Geriatr Psychiatry 2003, 18:S23-32.
71. Rammsayer T: Effects of pharmacologically induced changes in NMDA-receptor activity on long-term memory in humans. Learn Mem 2001, 8:20-25.
72. Peskind E, Potkin S, Pomara N, Ott B, Graham S, Olin J, McDonald S: Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006, 14:704-715.
73. Winblad B, Poritis N: Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999, 14:135-146.
74. 2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J Neurosci 2009, 29:2774-2779.
75. Monyer H, Burnashev N, Laurie D, Sakmann B, Seeburg P: Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994, 12:529-540.
76. Lipton S: The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity uncompetitive antagonism. Curr Alzheimer Res 2005, 2:155-165.
77. Lundqvist M, Rehn M, Djurfeldt M, Lansner A: Attractor dynamics in a modular network model of neocortex. Network 2006, 17:253-276.
78. Ji M, Xiong C, Grundman M: Hypothesis testing of a change point during cognitive decline among Alzheimer's disease patients. J Alzheimers Dis 2003, 5:375-382.
79. Bobinski M, Wegiel J, Tarnawski M, de Leon M, Reisberg B, Miller D, Wisniewski H: Duration of neurofibrillary changes in the hippocampal pyramidal neurons. Brain Res 1998, 799:156-158.
80. Darreh-Shori T, Soininen H: Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimers disease: A review of recent clinical studies. Curr Alzheimer Res 2010, 7:67-73.
81. Weinshenker D: Functional Consequences of Locus Coeruleus Degeneration in Alzheimers Disease. Curr Alzheimer Res 2008, 5(3):342-345.
82. Lanari A, Amenta F, Silvestrelli G, Tomassoni D, Parnetti L: Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease. Mechanisms of ageing and development 2006, 127(2):158-165.
83. Danysz W, Parsons C, Kornhuber J, Schmidt W, Quack G: Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents-preclinical studies. Neurosci Biobehav Rev 1997, 21:455-468.
84. Creeley C, Wozniak D, Labruyere J, Taylor G, Olney J: Low doses of memantine disrupt memory in adult rats. J Neurosci 2006, 26:3923-3932.
85. Povysheva N, Zaitsev A, Rotaru D, Gonzalez-Burgos G, Lewis D, Krimer L: Parvalbumin-positive basket interneurons in monkey and rat prefrontal cortex. J Neurophysiol 2008, 100:2348-2360.
86. Markram H: The blue brain project. Nat Rev Neurosci 2006, 7:153-160.
87. Woloszyn L, Sheinberg D: Neural dynamics in inferior temporal cortex during a visual working memory task. J Neurosci 2009, 29:5494-5507.
88. Isaacson J, Scanziani M: How inhibition shapes cortical activity. Neuron 2011, 72:231-243.
89. Marder E, Taylor A: Multiple models to capture the variability in biological neurons and networks. Nat Neurosci 2011, 14:133-138.
90. Ferris S: General measures of cognition. Int Psychogeriatr 15 Suppl 2003, 1:215-217.
91. Pietrzak R, Maruff P, Snyder P: Methodological improvements in quantifying cognitive change in clinical trials: an example with singledose administration of donepezil. J Nutr Health Aging 2009, 13:268-273.
92. Castel A, Balota D, McCabe D: Memory efficiency and the strategic control of attention at encoding: impairments of value-directed remembering in Alzheimer's disease. Neuropsychology 2009, 23:297-306.
93. Geerts H: Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS Drugs 2009, 23:915-926.
94. DeKosky S, Scheff S, Styren S: Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 1996, 5:417-421.
95. Whitehouse P, Struble R, Hedreen J, Clark A, White C, Parhad I, Price D: Neuroanatomical evidence for a cholinergic deficit in Alzheimer's disease. Psychopharmacol Bull 1983, 19:437-440.
96. Haltia L, Rinne J, Helin S, Parkkola R, Nagren K, Kaasinen V: Effects of intravenous placebo with glucose expectation on human basal ganglia dopaminergic function. Synapse 2008, 62:682-688.
97. Zhang L, Zhou F, Dani J: Cholinergic drugs for Alzheimer's disease enhance in vitro dopamine release. Mol Pharmacol 2004, 66:538-544.
98. Gulledge A, Stuart G: Cholinergic inhibition of neocortical pyramidal neurons. J Neurosci 2005, 25:10308-10320.