Muscarinic receptors in basal ganglia in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease.
Derivatives of the muscarinic antagonist 3-quinuclidinyl-4-iodobenzilate (QNB), particularly [123I]-(R,R)-I-QNB, are currently being assessed as in vivo ligands to monitor muscarinic receptors in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), relating changes to disease symptoms and to treatment response with cholinergic medication. To assist in the evaluation of in vivo binding, muscarinic receptor density in post-mortem human brain was measured by autoradiography with [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB and compared to M1 ([3H]pirenzepine) and M2 and M4 ([3H]AF-DX 384) receptor binding. Binding was calculated in tissue containing striatum, globus pallidus (GPe), claustrum, and cingulate and insula cortex, in cases of AD, DLB, Parkinson's disease (PD) and normal elderly controls. Pirenzepine, AF-DX 384 and (R,S)-I-QNB binding in the striatum correlated positively with increased Alzheimer-type pathology, and AF-DX 384 and (R,R)-I-QNB cortical binding correlated positively with increased Lewy body (LB) pathology; however, striatal pirenzepine binding correlated negatively with cortical LB pathology. M1 receptors were significantly reduced in striatum in DLB compared to AD, PD, and controls and there was a significant correlation between M1 and dopamine D2 receptor densities. [3H]AF-DX 384 binding was higher in the striatum and GPe in AD. Binding of [125I]-(R,R)-I-QNB, which may reflect increased muscarinic M4 receptors, was higher in cortex and claustrum in DLB and AD. [125I]-(R,S)-I-QNB binding was higher in the GPe in AD. Low M1 and D2 receptors in DLB imply altered regulation of the striatal projection neurons which express these receptors. Low density of striatal M1 receptors may relate to the extent of movement disorder in DLB, and to a reduced risk of parkinsonism with acetylcholinesterase inhibition.
Piggott
Margaret A
MA
MRC/University of Newcastle Centre in Clinical Brain Ageing, MRC Building, Newcastle General Hospital, Westgate Road, NE4 6BE, Newcastle-upon-Tyne, UK. m.a.piggott@ncl.ac.uk
Owens
Jonathan
J
O'Brien
John
J
Colloby
Sean
S
Fenwick
John
J
Wyper
David
D
Jaros
Evelyn
E
Johnson
Mary
M
Perry
Robert H
RH
Perry
Elaine K
EK
D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D001345:Autoradiography; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D005260:Female; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007457:Iodine Radioisotopes; D020961:Lewy Body Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011813:Quinuclidinyl Benzilate / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon
D007457:Iodine Radioisotopes; D018727:Muscarinic Antagonists; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; C065959:AFDX 384; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate