Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder involving motor and cognitive dysfunction. Currently, there is no effective treatment either for symptomatic relief or disease modification. This relates, in part, to a lack of knowledge of the underlying neurochemical abnormalities, including cholinergic receptor status in the basal ganglia.Aim: To measure muscarinic M2 and M4 receptors in the basal ganglia in PSP.Methods: The muscarinic M2 ( presynaptic) and M4 ( postsynaptic) receptors in the striatum, pallidum and adjacent insular cortex were autoradiographically measured in pathologically confirmed cases of PSP (n = 18), and compared with cases of Lewy body dementias (LBDs; n = 45), Alzheimer's disease ( AD; n = 39) and controls ( n = 50).Results: In cases of PSP, there was a reduction in M2 and M4 receptors in the posterior caudate and putamen compared to controls, but no significant changes in the pallidum. Cases with AD showed lower M2 receptors in the posterior striatum. Groups with LBD and AD showed higher M2 binding in the insular cortex compared with controls.Conclusions: The results suggest loss of posterior striatal cholinergic interneurones in PSP, and reduction in medium spiny projection neurones bearing M4 receptors. These results should be taken in the context of more widespread pathology in PSP, but may have implications for future trials of cholinergic treatments.

BACKGROUND:Dementia with Lewy bodies (DLB) is widely recognized as the second most common neurodegenerative cause of dementia in patients over the age of 65. The clinical distinction between DLB and Alzheimers's disease (AD) can be difficult due to the significant clinical overlap between the two disorders. Although the specificity of current consensus criteria is high, the sensitivity of case detection is lower and more variable. In some cases, the diagnosis is only made at postmortem examination.CASE REPORT:Monozygotic twins with the neuropathological diagnosis of Lewy body disease are presented in this report. Despite a very similar presentation and a comparable course of illness, the twins received different clinical diagnoses during life, one DLB and the other AD. This highlights the difficulty of making a clinical diagnosis of DLB, which very much depends on recognizing the features of fluctuation in level of awareness, hallucinations, delusions and the occurrence of falls, and the interpretation of the importance of these signs and symptoms. Pathological examination was virtually identical for the two cases showing the classic neuropathological features of Lewy Body disease.

Based on increasing dream intensity and alterations in neurophysiological activity from waking, through NREM to REM sleep, dreaming appears to correlate with sustained midbrain dopaminergic and basal forebrain cholinergic, in conjunction With decreasing brainstem 5-HT and noradrenergic neuronal activities. This, model, with features in common with the modulatory transmitter models of Hobson et al. and Solms, is consistent with some clinical observations on drug induced alterations in dreaming nod transmitter correlates of delusions.

The human striatum, which receives dopaminergic innervation from the substantia nigra and ventral tegmental area (cell groups A8, A9 and A10), has structural and functional subdivisions both rostrocaudally and dorsoventrally. These relate to motor and non-motor origins of cortical projections and the specific areas of the substantia nigra and ventral tegmental area providing dopaminergic innervation. In the present study, we have evaluated the distribution of a number of dopaminergic parameters in the caudate, putamen and nucleus accumbens at separate coronal levels in a post mortem study in a series of elderly normal individuals aged 55–94 years, with analysis of the effect of post mortem variables. Dopamine D1 receptor density displayed a rostrocaudally declining gradient in the putamen but not in the caudate, such that at levels posterior to the anterior commisure, there was significantly lower D1 binding in the putamen compared to the caudate. The density of dopamine D2 receptors was similar in the putamen and caudate, increasing rostrocaudally. The density of dopamine uptake sites exhibited an increasing rostrocaudal gradient in the caudate, especially ventrally, but not in the putamen, where binding was more constant. The dopamine D3 receptor was concentrated in the ventral striatum, particularly the nucleus accumbens, although there was no evidence of a rostrocaudal gradient. With respect to striosome–matrix compartmentalization, there was no complete segregation, although D1 and D3 receptors were concentrated in striosomes, whereas D2 receptors and uptake sites showed higher density in the matrix. Levels of dopamine were similar in the caudate and putamen, and were significantly elevated at levels including the nucleus accumbens and the anterior commisure. Homovanillic acid and the metabolic index (homovanillic acid/dopamine ratio) were significantly higher in the putamen compared to the caudate, especially at levels from and caudal to the anterior commisure. These distributions of dopamine receptors and metabolic indicators, reflecting the different functional domains of the striatum, are relevant to the interpretation of current in vivo imaging of the dopamine transporter and receptors in neurological and psychiatric disorders. They provide information to assist in the detection of perturbations in expression, in specific diseases, at particular points on rostrocaudal, lateromedial and dorsoventral axes, a level of resolution beyond current neuroimaging capability.

High-affinity nicotine, α-bungarotoxin (αBT) and muscarinic receptor binding was measured in the human hippocampal formation in a series of 57 cases aged between 24 weeks gestation and 100 years. Changes in nicotine receptor binding during development and aging were more striking than differences in αBT and muscarinic binding. Nicotine binding was higher at the late foetal stage than at any other subsequent time in all areas investigated. In the hippocampus a fall in binding then occurred within the first six months of life, with little or no subsequent fall during aging, whereas in the entorhinal cortex and the presubiculum the major loss of nicotine binding occurred after the fourth decade. αBT binding was significantly elevated in the CA 1 region, but in no other region of the hippocampus, in the late foetus, and there was also a fall in αBT binding in the entorhinal cortex during aging from the second decade. The modest changes in total muscarinic binding, which appeared to reflect those in M1 and M3+4 rather than M2 binding, were a rise in the entorhinal cortex between the foetal stage and childhood and a tendency for receptors to fall with age in the hippocampus and subicular complex. These findings implicate mechanisms controlling the expression of nicotinic receptors to a greater extent than muscarinic receptors in postnatal development and aging in the human hippocampus.

Several aspects of movement control by neuronal pathways in the basal ganglia are summarized. Evidence from neurochemical analyses in various neurodegenerative disorders is presented to demonstrate that a severe loss of dopamine in the putamen does not of itself represent a necessary condition for the appearance of extrapyramidal symptoms, and that the appearance of extrapyramidal symptoms or sensitivity to antipsychotics eliciting extrapyramidal symptoms is not solely dependent on a lack of striatal dopamine. The strategies of reduction of cholinergic activity and of reduction of the firing rate of the serotonergic neurons are alternatives to the traditional dopamine replacement therapy in the management of extrapyramidal symptoms. Inhibition of dopaminergic activity by dopamine D2 receptor blockers, as a means of controlling psychotic symptoms is considered inappropriate in disorders such as Lewy body dementia with a potential for increased sensitivity to such medication.