Basal ganglia cholinergic and dopaminergic function in progressive supranuclear palsy

Abstract

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative disorder. In contrast to Parkinson's disease (PD) and dementia with Lewy bodies (DLB), replacement therapy with dopaminergic and cholinergic agents in PSP has been disappointing. The neurochemical basis for this is unclear. Our objective was to measure dopaminergic and cholinergic receptors in the basal ganglia of PSP and control brains. We measured, autoradiographically, dopaminergic (dopamine transporter, 125I PE2I and dopamine D2 receptors, 125I epidepride) and cholinergic (nicotinic alpha4beta2 receptors, 125I 5IA85380 and muscarinic M1 receptors, 3H pirenzepine) parameters in the striatum and pallidum of pathologically confirmed PSP cases (n=15) and controls (n=32). In PSP, there was a marked loss of dopamine transporter and nicotinic alpha4beta2 binding in the striatum and pallidum, consistent with loss of nigrostriatal neurones. Striatal D2 receptors were increased in the caudate and muscarinic M1 receptors were unchanged compared with controls. These results do not account for the poor response to dopaminergic and cholinergic replacement therapies in PSP, and suggest relative preservation of postsynaptic striatal projection neurones bearing D2/M1 receptors.

Parkinson's disease: clinical features and diagnosis

“…Although differences in the density of postsynaptic dopamine receptors in patients with PD or other atypical parkinsonian disorders have been used to explain the poor response to levodopa therapy in the latter group, this may not be the only explanation. Recent positron emission tomography imaging studies have shown relative preservation of dopamine receptors in PSP,136 suggesting downstream changes as a possible mechanism for the lack of response. Furthermore, patients with MSA often have excellent initial responses but frequently develop levodopa related orofacial dyskinesias and lose antiparkinsonian efficacy.…”

Preliminary studies of differential impairments of the dopaminergic system in subtypes of progressive supranuclear palsy

“…Overall, IBZM scans showed that the D2 receptor was well preserved in PSP-P and PD patients and significantly reduced in RS patients. Different subtypes of PSP are postulated to reflect various involvements of the striatal D2 receptor, which were presented in the earlier studies [5,[14][15][16].…”

“…However, other imaging studies of PSP [10,11] showed that DAT activity impairment was relatively severe in the caudate nucleus. The activities of D2 receptor were reduced in most patients with PSP [12,13], but it was normal, slightly reduced, or even elevated in some cases of PSP [5,[14][15][16]. These inconsistent results of the D2 receptor might be explained by the lumping of both RS and PSP-P subtypes in PSP patients in earlier studies.…”

The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases

“…We have recently demonstrated no significant difference in the M1 receptors in the striatum of patients with PSP compared with controls. 12 This suggests preservation of the medium spiny neurones bearing these receptors, which are predominantly involved in the indirect pathway (projecting to the external globus pallidus (GPe)). M2 receptors are found presynaptically on striatal cholinergic interneurones, and also on corticostriatal and thalamostriatal afferents.…”