Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.
BACKGROUND
Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD).


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


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-HT(2A) receptors were significantly reduced from control values. Of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), 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-HT(1A) receptor antagonist may be indicated.
Bowen
D M
DM
Department of Neuropathology, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Procter
A W
AW
Mann
D M A
DM
Snowden
J S
JS
Esiri
M M
MM
Neary
D
D
Francis
P T
PT
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010296:Parietal Lobe / Q000378:metabolism / Q000473:pathology; D011180:Postmortem Changes; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012189:Retrospective Studies; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D002795:Choline O-Acetyltransferase; D043643:Receptor, Muscarinic M1; D044282:Receptor, Serotonin, 5-HT1A; D044402:Receptor, Serotonin, 5-HT2A; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid