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Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy

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Abstract

Rationale

Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer’s disease (AD).

Objectives

To evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment.

Materials and methods

Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site.

Results

In FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)1A and 5-HT2A receptors were significantly reduced from control values. Of the ten parameters only 5-HT1A receptors showed significant group × site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M1, N-methyl-d-aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD.

Conclusions

Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT1A receptor antagonist may be indicated.

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References

  • Bowen DM, Francis PT, Pangalos MN, Stephens PH, Procter AW, Chessell IP (1992) ‘Traditional’ pharmacotherapy may succeed in Alzheimer’s disease. Trends Neurosci 15:84–85

    Article  PubMed  CAS  Google Scholar 

  • Brun A (1993) Frontal lobe degeneration of non-Alzheimer type revisited. Dementia 4:126–131

    Article  PubMed  CAS  Google Scholar 

  • Burette A, Khatri L, Wyszynski M, Sheng M, Ziff EB, Weinberg RJ (2001) Differential cellular and subcellular localization of ampa receptor-binding protein and glutamate receptor-interacting protein. J Neurosci 21:495–503

    PubMed  CAS  Google Scholar 

  • Chen CP, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, Jobst KA, Francis PT (1996) Presynaptic serotonergic markers in community-acquired cases of Alzheimer’s disease: correlations with depression and neuroleptic medication. J Neurochem 66:1592–1598

    Article  PubMed  CAS  Google Scholar 

  • Chessell IP, Pearson RC, Heath PR, Bowen DM, Francis PT (1997) Selective loss of cholinergic receptors following unilateral intracortical injection of volkensin. Exp Neurol 147:183–191

    Article  PubMed  CAS  Google Scholar 

  • Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ (2004) Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomized controlled trial. Psychopharmacology (Berl) 172:400–408

    Article  CAS  Google Scholar 

  • Dodt HU, Frick A, Kampe K, Zieglgansberger W (1998) NMDA and AMPA receptors on neocortical neurones are differentially distributed. Eur J Neurosci 10:3351–3357

    Article  PubMed  CAS  Google Scholar 

  • Eder M, Becker K, Rammes G, Schierloh G, Azad SC, Zieglgansberger W, Dodt HU (2003) Distribution and properties of functional postsynaptic kainate receptors on neocortical layer V pyramidal neurones. J Neurosci 23:6660–6670

    PubMed  CAS  Google Scholar 

  • Ferrer I (1999) Neurones and their dendrites in frontotemporal dementia. Dement Geriatr Cogn Disord 10(Suppl 1):55–60

    Article  PubMed  Google Scholar 

  • Francis PT, Pangalos MN, Pearson RC, Middlemiss DN, Stratmann GC, Bowen DM (1992) 5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin. J Pharmacol Exp Ther 261:1273–1281

    PubMed  CAS  Google Scholar 

  • Francis PT, Sims NR, Procter AW, Bowen DM (1993a) Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer’s disease: investigative and therapeutic perspectives. J Neurochem 60:1589–1604

    Article  PubMed  CAS  Google Scholar 

  • Francis PT, Holmes C, Webster MT, Stratman GC, Procter AW, Bowen DM (1993b) Preliminary neurochemical fundings in non-Alzheimer dementia due to lobar atrophy. Dementia 4:172–177

    Article  PubMed  CAS  Google Scholar 

  • Hauw J, Duychaerts C, Partridge M (1986) Neuropathological aspects of brain aging and SDAT. In: Courtois Y, Faucheux B, Forette B, Knook D, Treton J (eds) Modern trends in aging research. John Libby Eurotext, London-Paris, pp 435–442

    Google Scholar 

  • Hilbush BS, Morrison JH, Young WG, Sutcliffe JG, Bloom FE (2005) New prospects and strategies for drug target discovery in neurodegenerative disorders. NeuroRx 2:627–637

    Article  PubMed  Google Scholar 

  • Huey ED, Putnam KT, Grafman J (2006) A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology 66:17–22

    Article  PubMed  CAS  Google Scholar 

  • Kepe V, Barrio JR, Huang SC, Ercoli L, Siddarth P, Shoghi-Jadid K, Cole GM, Satyamurthy N, Cummings JL, Small GW, Phelps ME (2006) Serotonin 1A receptors in the living brain of Alzheimer’s disease patients. Proc Natl Acad Sci USA 103:702–707

    Article  PubMed  CAS  Google Scholar 

  • Kia HK, Miquel MC, Brisorgueil MJ, Daval G, Riad M, El Mestikawy S, Hamon M, Verge D (1996) Immunocytochemical localization of serotonin1A receptors in the rat central nervous system. J Comp Neurol 365:289–305

    Article  PubMed  CAS  Google Scholar 

  • Kingsbury AE, Foster OJ, Nisbet AP, Cairns N, Bray L, Eve DJ, Lees AJ, Marsden CD (1995) Tissue pH as an indicator of mRNA preservation in human post-mortem brain. Brain Res Mol Brain Res 28:311–318

    Article  PubMed  CAS  Google Scholar 

  • Knopman DS (1993) Overview of dementia lacking distinctive histology: pathological designation of a progressive dementia. Dementia 4:132–136

    Article  PubMed  CAS  Google Scholar 

  • Lai MK, Lai OF, Keene J, Esiri MM, Francis PT, Hope T, Chen CP (2001) Psychosis of Alzheimer’s disease is associated with elevated muscarinic M2 binding in the cortex. Neurology 57:805–811

    PubMed  CAS  Google Scholar 

  • Lai MK, Tsang SW, Francis PT, Esiri MM, Keene J, Hope T, Chen CP (2003) Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behaviour in Alzheimer disease. Brain Res 974:82–87

    Article  PubMed  CAS  Google Scholar 

  • Lai MK, Tsang SW, Alder JT, Kene J, Hope T, Esiri MM, Francis PT, Chen CP (2005) Loss of 5-HT2A receptors in the post mortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology (Berl) 179:671–677

    Article  CAS  Google Scholar 

  • Lanius RA, Shaw C (1992) Characterization and regulation of a high affinity [3H]CNQX labelled AMPA receptor in rat neocortex. Brain Res Mol Brain Res 15:256–262

    Article  PubMed  CAS  Google Scholar 

  • Mann DM, South PW, Snowden JS, Neary D (1993) Dementia of frontal lobe type: neuropathology and immunohistochemistry. J Neurol Neurosurg Psychiatry 56:605–614

    PubMed  CAS  Google Scholar 

  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    PubMed  CAS  Google Scholar 

  • Middlemiss DN, Palmer AM, Edel N, Bowen DM (1986) Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin in normal and Alzheimer brain. J Neurochem 46:993–996

    Article  PubMed  CAS  Google Scholar 

  • Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  • Neary D, Snowden J, Mann D (2005) Frontotemporal dementia. Lancet Neurol 4:771–780

    Article  PubMed  Google Scholar 

  • Palmer AM, Stratmann GC, Procter AW, Bowen DM (1988) Possible basis of behavioural changes in Alzheimer’s disease. Ann Neurol 23:616–620

    Article  PubMed  CAS  Google Scholar 

  • Pangalos MN, Schechter LE, Hurko O (2007) Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 6:521–532

    Article  PubMed  CAS  Google Scholar 

  • Patneau DK, Wright PW, Winters C, Mayer ML, Gallo V (1994) Glial cells of the oligodendrocyte lineage express both kainate- and AMPA-preferring subtypes of glutamate receptor. Neuron 12:357–371

    Article  PubMed  CAS  Google Scholar 

  • Pearce BR, Bowen DM (1984) [3H]Kainic acid binding and choline acetyltransferase activity in Alzheimer’s dementia. Brain Res 310:376–378

    Article  PubMed  CAS  Google Scholar 

  • Procter AW, Lowe SL, Palmer AM, Francis PT, Esiri MM, Stratmann GC, Najlerahim A, Patel AJ, Hunt A, Bowen DM (1988) Topographical distribution of neurochemical changes in Alzheimer’s disease. J Neurol Sci 84:125–140

    Article  PubMed  CAS  Google Scholar 

  • Procter AW, Stratmann GC, Francis PT, Lowe SL, Bertolucci PH, Bowen DM (1991) Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor–ionophore complex in human brain. J Neurochem 56:299–310

    Article  PubMed  CAS  Google Scholar 

  • Procter AW, Francis PT, Stratmann GC, Bowen DM (1992) Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms. Neurochem Res 17:917–922

    Article  PubMed  CAS  Google Scholar 

  • Procter AW, Qume M, Francis PT (1999) Neurochemical features of frontotemporal dementia. Dement Geriatr Cogn Disord 10(Suppl 1):80–84

    Article  PubMed  CAS  Google Scholar 

  • Qume M, Zeman S, Stratmann G, Worth C, Francis PT, Procter AW, Bowen DM (1994) A neurochemical study of non-Alzheimer dementia. Br J Pharmacol 112:487(abstract)

    Google Scholar 

  • Qume M, Misra A, Zeman S, Boddy JL, Cross AJ, Francis PT, Procter AW, Mann DM, Bowen DM (1995a) Non-serotonergic profiles of lobar atrophies. Biochem Soc Trans 23:601S

    PubMed  CAS  Google Scholar 

  • Qume M, Misra A, Zeman S, Muthu J, Cross AJ, Francis PT, Procter AW, Neary D, Bowen DM (1995b) Serotonergic profiles of lobar atrophies. Biochem Soc Trans 23:600S

    PubMed  CAS  Google Scholar 

  • Qume M, Zeman S, Francis PT, Procter AW, Bowen DM (1995c) Changes in cortical 5-HT1A receptor binding in lobar atrophies (Pick’s disease and dementia of the frontal lobe). Br JPharmacol 116:237(abstract)

    Google Scholar 

  • Ross S, Thorberg S-O, Jerning E, Mohell N, Stenfors C, Wallstern C (1999) Robalzotan (NAD-299) a novel selective 5-HT1A receptor antagonist. CNS Drug Reviews 5:213–232

    Article  CAS  Google Scholar 

  • Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F (2004) Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurones of the rat prefrontal cortex. Cereb Cortex 14:1100–1109

    Article  PubMed  Google Scholar 

  • Schechter LE, Smith DL, Rosenzweig-Lipson S, Sukoff SJ, Dawson LA, Marquis K, Jones D, Piesla M, Andree T, Nawoschik S, Harder JA, Womack MD, Buccafusco J, Terry AV, Hoebel B, Rada P, Kelly M, Abou-Gharbia M, Barrett JE, Childers W (2005) Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. J Pharmacol Exp Ther 314:1274–1289

    Article  PubMed  CAS  Google Scholar 

  • Schiapparelli L, Del Rio J, Frechilla D (2005) Serotonin 5-HT receptor blockade enhances Ca(2+)/calmodulin-dependent protein kinase II function and membrane expression of AMPA receptor subunits in the rat hippocampus: implications for memory formation. J Neurochem 94:884–895

    Article  PubMed  CAS  Google Scholar 

  • Shi J, Shaw CL, Du Plessis D, Richardson AM, Bailey KL, Julien C, Stopford C, Thompson J, Varma A, Craufurd D, Tian J, Pickering-Brown S, Neary D, Snowden JS, Mann DM (2005) Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol 110:501–512

    Article  PubMed  Google Scholar 

  • Sjogren M, Minthon L, Passant U, Blennow K, Wallin A (1998) Decreased monoamine metabolites in frontotemporal dementia and Alzheimer’s disease. Neurobiol Aging 19:379–384

    Article  PubMed  CAS  Google Scholar 

  • Sparks DL, Markesbery WR (1991) Altered serotonergic and cholinergic synaptic markers in Pick’s disease. Arch Neurol 48:796–799

    PubMed  CAS  Google Scholar 

  • The Lund and Manchester Groups (1994) Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57:416–418

    Article  Google Scholar 

  • Vignes M, Clarke VR, Parry MJ, Bleakman D, Lodge D, Ornstein PL, Collingridge GL (1998) The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus. Neuropharmacology 37:1269–1277

    Article  PubMed  CAS  Google Scholar 

  • Vogt BA, Plager MD, Crino PB, Bird ED (1990) Laminar distributions of muscarinic acetylcholine, serotonin, GABA and opioid receptors in human posterior cingulate cortex. Neuroscience 36:165–174

    Article  PubMed  CAS  Google Scholar 

  • Winfield DA, Gatter KC, Powell TP (1980) An electron microscopic study of the types and proportions of neurones in the cortex of the motor and visual areas of the cat and rat. Brain 103:245–258

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Schmitt HP (2001) Frontotemporal dementia: evidence for impairment of ascending serotonergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method. Acta Neuropathol (Berl) 101:256–270

    CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Alan Cross, Anil Misra, Sophie Petit-Zeman, Michelle Qume and Gary Stratman for carrying out some of the assays. Drs S. Afzal, S. Al-Sarraj, Atik Baborie and Bala Doshi and Professors Peter Lantos and Robert Perry kindly helped with the collection and classification of material. DMB is grateful to Oxford University for the award of a McDonnell Visiting Fellowship whilst preparing this manuscript for publication. We also thank Joanna Wilkinson for her help in preparing the manuscript.

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Correspondence to P. T. Francis.

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Bowen, D.M., Procter, A.W., Mann, D.M.A. et al. Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy. Psychopharmacology 196, 603–610 (2008). https://doi.org/10.1007/s00213-007-0992-8

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  • DOI: https://doi.org/10.1007/s00213-007-0992-8

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