a-85380 and Lewy-Body-Disease

Disturbances of consciousness (DOC) are common in dementia with Lewy bodies (DLB). Following previous findings of preserved temporal cortical high-affinity nicotinic binding relating to DOC, we investigated this receptor in thalamus, an area of high nicotinic receptor concentration, implicated in consciousness. 5-[125I]-A-85380 binding, primarily reflecting the alpha4beta2 subtype, was compared in 16 DLB patients with DOC and 6 without DOC, matched for duration and severity of dementia. Binding was higher in patients with DOC compared to patients without DOC in all thalamic nuclei examined, reaching significance in the reticular and ventral anterior thalamic nuclei. Comparing DLB patients with and without DOC to previously reported controls revealed similar binding levels in patients with DOC and lower binding in patients without DOC, reaching significance in the ventral anterior, indicating preserved nicotinic receptor density in DLB patients with DOC. These findings, together with previous neocortical data, implicate nicotinic modulation of thalamo-cortical circuitry as a key component in the control of conscious awareness in DLB.

Topics: Aged; Aged, 80 and over; Azetidines; Consciousness Disorders; Female; Humans; Iodine Radioisotopes; Lewy Body Disease; Male; Neocortex; Neural Pathways; Prospective Studies; Receptors, Nicotinic; Thalamus

Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[(125)I]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125)I]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[(125)I]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-[(125)I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[(125)I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-[(125)I]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Autoradiography; Azetidines; Binding Sites; Brain Diseases; Case-Control Studies; Dementia, Vascular; Female; Humans; In Vitro Techniques; Iodine Isotopes; Lewy Body Disease; Male; Parkinson Disease; Radiochemistry; Receptors, Nicotinic; Tissue Distribution