title: Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis.
abstract: BACKGROUND
  Neuropsychiatric behaviours in Alzheimer's disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms.
  
  
  OBJECTIVE
  To correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD.
  
  
  METHODS
  [(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms.
  
  
  RESULTS
  [(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden.
  
  
  CONCLUSIONS
  This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.
authors: Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Outram Road, Outram Park 169608, Singapore.
authors: S W Y
authors: SW
authors: Tsang
authors: P T
authors: PT
authors: Francis
authors: M M
authors: MM
authors: Esiri
authors: P T H
authors: PT
authors: Wong
authors: C P L H
authors: CP
authors: Chen
authors: M K P
authors: MK
authors: Lai
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000523:psychology*; D000818:Animals; D016466:CHO Cells; D015331:Cohort Studies; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D010880:Piperidines / Q000494:pharmacology*; D011618:Psychotic Disorders / Q000150:complications / Q000378:metabolism* / Q000523:psychology*; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium