Identifying economically viable tidal sites within the Alderney Race through optimization of levelized cost of energy.

Costs of tidal stream energy generation are anticipated to fall considerably with array expansion and time. This is due to both economies of volume, where arrays comprising of large numbers of turbines can split fixed costs over a greater number of devices, and learning rates, where the industry matures and so arrays of the same size become cheaper due to lessons learned from previous installations. This paper investigates how tidal energy arrays can be designed to minimize the levelized cost of energy (LCOE), by optimizing not only the location but also the number of devices, to find a suitable balance between decreased costs due to economies of volume and diminishing returns due to global blockage effects. It focuses on the Alderney Race as a case study site due to the high velocities found there, making it a highly suitable site for large-scale arrays. It is demonstrated that between 1 and 2 GW could be feasibly extracted as costs in the tidal industry fall, with the LCOE depending greatly on the assumed costs. A Monte-Carlo analysis is undertaken to account for variability in capital and operational cost data used as inputs to the array optimization. Once optimized, the estimated P50 LCOE of an 80 MW array is £110/MWh. This estimate aligns closely with the level of subsidy considered for tidal stream projects in the Alderney Race in the past. This article is part of the theme issue 'New insights on tidal dynamics and tidal energy harvesting in the Alderney Race'.

Anisotropic mesh adaptivity for multi-scale ocean modelling.

Research into the use of unstructured mesh methods in oceanography has been growing steadily over the past decade. The advantages of this approach for domain representation and non-uniform resolution are clear. However, a number of issues remain, in particular those related to the computational cost of models produced using unstructured mesh methods compared with their structured mesh counterparts. Mesh adaptivity represents an important means to improve the competitiveness of unstructured mesh models, where high resolution is only used when and where necessary. In this paper, an optimization-based approach to mesh adaptivity is described where emphasis is placed on capturing anisotropic solution characteristics. Comparisons are made between the results obtained with uniform isotropic resolution, isotropic adaptive resolution and fully anisotropic adaptive resolution.

Focus on phosphoarginine and phospholysine.

Protein phosphorylation is a common signaling mechanism in both prokaryotic and eukaryotic organisms. Whilst serine, threonine and tyrosine phosphorylation dominate much of the literature there are several other amino acids that are phosphorylated in a variety of organisms. Two of these phosphoamino acids are phosphoarginine and phospholysine. This review will focus on the chemistry and biochemistry of both phosphoarginine and phospholysine. In particular we focus on the biological aspects of phosphoarginine as a means of storing and using metabolic energy (in place of phosphocreatine in invertebrates), the chemistry behind its synthesis and we examine the chemistry behind its highenergy phosphoramidate bond. In addition we will be reporting on the incidence of phosphoarginine in mammalian cells. Similarly we will be reviewing the current findings on the biology and the chemistry of phospholysine and its involvement in a variety of biological systems.

Focus on phosphohistidine.

Phosphohistidine has been identified as an enzymic intermediate in numerous biochemical reactions and plays a functional role in many regulatory pathways. Unlike the phosphoester bond of its cousins (phosphoserine, phosphothreonine and phosphotyrosine), the phosphoramidate (P-N) bond of phosphohistidine has a high DeltaG degrees of hydrolysis and is unstable under acidic conditions. This acid-lability has meant that the study of protein histidine phosphorylation and the associated protein kinases has been slower to progress than other protein phosphorylation studies. Histidine phosphorylation is a crucial component of cell signalling in prokaryotes and lower eukaryotes. It is also now becoming widely reported in mammalian signalling pathways and implicated in certain human disease states. This review covers the chemistry of phosphohistidine in terms of its isomeric forms and chemical derivatives, how they can be synthesized, purified, identified and the relative stabilities of each of these forms. Furthermore, we highlight how this chemistry relates to the role of phosphohistidine in its various biological functions.

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

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.

Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia.

Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.

A study of the serotonin transporter in the prefrontal cortex in late-life depression and Alzheimer's disease with and without depression.

Previous studies investigating the serotonin transporter (SERT) in depression have been inconsistent and included a large proportion of subjects who had committed suicide. In Alzheimer's disease studies have generally reported a reduction in SERT density but have not compared Alzheimer's disease subjects with and without comorbid major depression. We conducted a post mortem study of SERT density in the prefrontal cortex in normal elderly, a group of elderly depressed subjects and in Alzheimer's disease subjects with and without major depression. A post mortem study comparing SERT density in the prefrontal cortex in elderly controls (n = 10), subjects with major depression (n = 8) and subjects with Alzheimer's disease with (n = 9) and without (n = 5) comorbid major depression. We used autoradiography to measure the density of [3H]CN-IMI binding (non-specific binding determined with citalopram) to the SERT in the prefrontal cortex. We found a marked reduction in specific SERT binding in the prefrontal cortex in Alzheimer's disease subjects compared with both control (P = 0.002) and depressed subjects (P = 0.004) but no difference in SERT binding between depressed and control subjects or between Alzheimer's disease subjects with and without depression. Our study confirms previous reports of a reduction in SERT binding in Alzheimer's disease but indicates this reduction is not greater in Alzheimer's disease subjects who also have had major depression. In a group of subjects more typical of late-life depression we did not identify any alterations in SERT density.

Estimating population size of endangered brush-tailed rock-wallaby (Petrogale penicillata) colonies using faecal DNA.

The brush-tailed rock-wallaby (Petrogale penicillata) is an endangered species in southeastern Australia and many of the remaining populations are declining. The steep rocky habitat and shy nature of the species make it difficult to obtain data on population parameters such as abundance and recruitment. Faecal pellet counts from scat plots are commonly used to monitor population trends but these are imprecise and difficult to relate to absolute population size. We conducted a noninvasive genetic sampling 'mark-recapture' study over a 2-year period to identify individuals from faecal DNA samples and estimate the population size of four brush-tailed rock-wallaby colonies located in Wollemi National Park, New South Wales. Scat plots in rock-wallaby colonies were used as sample collection points for this study. Two separate population estimates were carried out for three of the colonies to determine if we could detect recruitment and changes in population size. We determined that there was one large colony of an estimated 67 individuals (95% confidence interval: 55-91) and three smaller colonies. Monitoring of the smaller colonies also detected possible population size increases in all three. Our results indicate that faecal DNA analysis may be a promising method for estimating and monitoring population trends in this species particularly when used with a traditional field survey method.

Population structure of brush-tailed rock-wallaby (Petrogale penicillata) colonies inferred from analysis of faecal DNA.

Genetic data obtained using faecal DNA were used to elucidate the population structure of four brush-tailed rock-wallaby (Petrogale penicillata) colonies located in Wollemi National Park, New South Wales. The results suggested that the four sampled colonies are genetically differentiated and do not form a panmictic unit. Based on assignment tests, approximately 5% of sampled individuals were inferred to be dispersers and both male and female migrants were detected. Multilocus spatial autocorrelation analyses provided evidence for increased philopatry among females compared to males within the largest colony in the valley. Females in close spatial proximity were more genetically similar than expected under a random distribution of females, and females separated by more than 400 m were less genetically similar than expected. In contrast, there was no evidence of a significant clustering of related males. This suggests that within-colony dispersal is male biased. We also investigated the best strategies for conserving genetic diversity in this population. All of the four sampled colonies were found to contain distinct components of the genetic diversity of the Wolgan Valley P. penicillata population and loss of any colony is likely to result in the loss of unique alleles. Conservation and management plans should take into account that these colonies represent genetically differentiated discrete subpopulations. This approach is also the best strategy for maintaining the genetic diversity of the populations in this valley.

Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [(125)I]alpha-conotoxinMII in the striatum and thalamus.

The presence of alpha6 subunit containing nicotinic acetylcholine receptors on nigrostriatal dopaminergic neurons has been demonstrated in rodents and monkeys. [(125)I]alpha-conotoxinMII is a radioligand that binds to alpha6, and also alpha3 subunits of nicotinic acetylcholine receptors (nAChRs). In the present study, we have compared the distribution of [(125)I]alpha-conotoxinMII binding in post mortem human tissue from four groups of patients: individuals with dementia with Lewy bodies displaying extra-pyramidal features (DLB + EPF), DLB without extra-pyramidal features (DLB - EPF) Parkinson's disease without dementia (PD) and age-matched controls. Reduced binding was observed in the putamen and caudate in PD and both DLB groups. In DLB patients, the decline was greater in DLB + EPF compared to DLB - EPF group. The declines in nicotinic receptor binding in the striatum were in part paralleled by reductions in the striatal dopamine transporter. In the thalamus, [(125)I]alpha-conotoxinMII binding was significantly reduced in the centromedian nucleus in both DLB groups, and also in the parafascicular nucleus in the DLB - EPF group. In DLB + EPF and PD patients, there was decreased binding in the ventral lateral nucleus. This study demonstrates alterations of alpha6 and/or alpha3 nAChRs binding in DLB and PD, which are likely to relate to extra-pyramidal symptoms.

Cholinergic systems in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and subcortical dementia. Pathologically, there is abnormal accumulation of tau protein. Cholinergic deficits are thought to underlie the postural instability and cognitive impairment of PSP, but trials of cholinergic agonists and cholinesterase inhibitors have failed to show improvement in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related areas of the brain, are damaged in PSP, leading to specific clinical deficits. Cholinergic dysfunction is related to loss of cholinergic interneurons in the striatum, compounded by reduced inputs into the circuits from other cholinergic nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. Normal cholinergic transmission requires the presence of intact cholinergic neurons capable of releasing sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.

Has CONSORT improved the reporting of randomized controlled trials in the palliative care literature? A systematic review.

BACKGROUND: In 1996, the CONSORT (CONsolidated Standards Of Reporting Trials) statement for the reporting of clinical trials was produced, based on empirical evidence regarding bias. AIMS: This study assessed the quality of reporting of randomized controlled trials (RCTs) in the palliative care literature. METHODS: Three specialist journals were hand searched for RCTs. A checklist was devised based on CONSORT recommendations. Two investigators independently assessed all the trials against this checklist. The trials were grouped into time cohorts of five years and quality comparisons made. Trials looking at pain were compared with those trials looking at other aspects of palliative care. RESULTS: Ninety-three RCTs were identified. The number of trials has increased over time: nine in the first cohort, 37 in the second and 47 in the last cohort. The number of patients in the individual trials has also increased over time. Generally, the reporting quality was poor, particularly the areas of allocation concealment, randomization technique and intention to treat analysis, where there is empirical evidence, that it leads to trial bias. Although there were more pain papers than non-pain papers, the quality of reporting was only better for blinding and intention to treat analysis. CONCLUSION: The quality of reporting of RCTs in the palliative care literature is generally poor. However, there has been an increase in the number and the size of RCTs being carried out. This shows recognition of the importance of an evidence base in palliative care. However, in order to guide clinical decision making, future trials need to improve the quality of their reporting by adhering to the CONSORT statement.

Nicotinic acetylcholine receptor distribution in Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and vascular dementia: in vitro binding study using 5-[(125)i]-a-85380.

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.

Nicotinic receptors in the putamen of patients with dementia with Lewy bodies and Parkinson's disease: relation to changes in alpha-synuclein expression.

A reduction in nicotinic receptor (nAChR) binding has previously been observed in putamen in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The present study demonstrates no concommitant reduction in the expression of alpha2-alpha7, beta2 and beta3 nAChR subunit proteins. Alphasynuclein, which can interfere with membrane protein function and is a key constituent of PD and DLB pathology, was increased (insoluble fraction) in both disorders, although nAChR binding loss did not correlate with alpha-synuclein expression within patient groups. The results point to a possible abnormality of striatal nicotinic receptor assembly in PD and DLB.

Clinical presentations in monozygotic twins with dementia with Lewy bodies.

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.

Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia.

The laminar cortical distribution of the [125I]alpha-bungarotoxin, [3H]cytisine and [3H]epibatidine nicotinic acetylcholine receptor ligands was investigated by quantitative autoradiography in autopsy tissue from the cingulate, orbitofrontal and temporal cortices of control and schizophrenia subjects matched for age and smoking history. Different laminar binding patterns were observed for the various nicotinic ligands both in schizophrenic and control brains. [125I]alpha-Bungarotoxin binding was distributed homogeneously across all cortical layers in all three brain regions, with highest binding densities in the cingulate cortex. [3H]Cytisine and [3H]epibatidine binding varied across the cortical ribbon, with high binding in layers I, III, V and VI, within the three cortical regions. A significantly reduced [125I] alpha-bungarotoxin binding (-54%) was observed in the cingulate cortex of schizophrenia subjects, in comparison with normal individuals who smoked tobacco. In the same brain region also a significantly higher [3H]cytisine binding (48-77%) was observed in nearly all layers, except for layer I of the schizophrenia subjects, when compared to normal individuals with a history of tobacco use. No significant changes in [3H]epibatidine binding was observed within the individual cortical layers between control subjects and patients with schizophrenia, but when calculated as a whole region (i.e. measurements performed across the whole cortical ribbon), the temporal cortex showed a significant increase in [3H]epibatidine binding in schizophrenia subjects compared to control subjects. The results suggest opposite changes of the alpha4beta2 and alpha7 nicotinic receptor subtypes in the cingulate cortex of patients with schizophrenia which might reflect involvement of two different nicotinic receptor mechanisms in schizophrenia brain.

Nicotinic receptor abnormalities in Alzheimer's disease.

Loss of cortical nicotinic acetylcholine receptors with high affinity for agonists (20-50%) in patients with Alzheimer's disease is a common finding. Recent immunochemical analyses indicate that this deficit is predominantly associated with the loss of alpha4 subunits (30-50%), although modest reductions of alpha3 may occur in some individuals (25-29%). No reduction of beta2 subunit protein expression or levels of alpha3 and alpha4 messenger RNA has been reported. Decline in cortical [(125)I]alpha-bungarotoxin binding and alpha7 protein expression does not appear to be as extensive or widespread as the loss of alpha4 (0-40%), with no reduction in messenger RNA expression. In the thalamus, there was a trend for reduced [(3)H]nicotine binding in the majority of nuclei (0-20%) in Alzheimer's disease; however, there was a significant decline in [(125)I]alpha-bungarotoxin binding in the reticular nucleus. In the striatum [(3)H]nicotine binding was reduced in Alzheimer's disease, and although neuroleptic medication accentuated this change, it occurred in those free of neuroleptics. Changes in nicotinic acetylcholine receptors in Alzheimer's disease are distinct from those in normal aging and are likely to contribute to clinical features and possibly neuropathology.

Visual hallucinations are associated with lower alpha bungarotoxin binding in dementia with Lewy bodies.

Patients with dementia with Lewy bodies (DLB) commonly experience psychotic symptoms, most notably visual hallucinations. Previously, it has been shown that visual hallucinations in DLB are associated with reduced cortical choline acetyltransferase activity, a marker of cholinergic innervation, but not with predominantly postsynaptic muscarinic M1 receptor binding. In the present investigation, nicotinic acetylcholine receptor (nAChR) levels in the temporal cortex (Brodmann's areas [BA] 20 and 36) were measured in a group of 24 prospectively assessed DLB patients; comparisons were made between groups with or without visual and auditory hallucinations and delusional misidentification. Visual hallucinations and delusional misidentification were associated with lower [(125)I]alpha bungarotoxin binding in areas 36 and 20 (P<.05), but not with changes in [(3)H]epibatidine binding. There were no significant associations with auditory hallucinations. [(3)H]epibatidine, but not [(125)I]alpha bungarotoxin, binding for all DLB cases was reduced compared to controls (P<.001). Loss of cortical alpha 7 nicotinic receptors may contribute to hallucinations and delusional misidentification in DLB, with implications for treatment and understanding the mechanisms of psychotic symptoms in dementia.

Delusions associated with elevated muscarinic binding in dementia with Lewy bodies.

The relation between disturbances of cholinergic neurotransmission and delusions (DELs) has not been investigated in degenerative dementias such as dementia with Lewy bodies (DLB). A cohort of dementia patients were assessed with standardized clinical evaluations (including the Columbia University Scale for Psychopathology in Alzheimer's Disease), which were repeated annually until death. DLB was confirmed neuropathologically in 21 patients. Neurochemical evaluation included M1 receptor autoradiography (pirenzepine binding), biochemical measurement of choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) histochemistry in brain regions hypothesized to be involved in the genesis of psychosis. Compared with 11 age-matched controls, CHAT and pirenzepine levels were most extensively reduced in the temporal and parietal neocortex of DLB patients. In Brodmann area 36, DELs were significantly associated with elevated pirenzepine binding (131.0 vs 93.5, t = 2.7), whereas visual hallucinations were associated with significant reductions in ChAT (1.7 vs 2.5, t = 2.5). There were no significant associations with other areas or with cholinesterase. Although DELs and visual hallucinations were both linked with disturbances in cholinergic neurotransmission, the nature of the associations was different. Upregulation of the postsynaptic muscarinic receptor may be central in the genesis of DELs, with important treatment implications.

Alpha and beta nicotinic acetylcholine receptors subunits and synaptophysin in putamen from Parkinson's disease.

It is well established that nicotinic receptors in the mammalian striatum are involved in modulation of the release of several neurotransmitters, including dopamine. In addition, nicotinic receptors with high affinity for agonists have generally been found to be reduced in the striatum in Parkinson's disease. In the present study antibodies have been used to examine which subunits contribute to the striatal nicotinic receptor loss in Parkinson's disease, and whether the reduction in [(3)H]nicotine binding correlates with synaptic loss. Autopsy tissue from the putamen of 12 Parkinson's disease cases and 12 age-matched control subjects was analysed by immunoblotting using antibodies against recombinant peptides specific for alpha3, alpha4, alpha7, beta2 and beta4 nicotinic acetylcholine receptor (nAChR) subunits and the synaptic marker synaptophysin, in conjunction with assessment of [(3)H]nicotine binding by autoradiography. The data indicate that there is no loss of alpha3, alpha4, alpha7 and beta2 immunoreactivity in the putamen in Parkinson's disease, despite a highly significant reduction in [(3)H]nicotine binding. An intense signal of beta4 immunoreactivity was found in human dorsal root ganglia, but not in temporal cortex or putamen samples. Synaptophysin immunoreactivities were also similar in Parkinson's disease and control cases. These results suggest that the loss of nicotine binding in the putamen in Parkinson's disease may involve an nAChR subunit (e.g., alpha5 and/or alpha6) other than those investigated. Alternatively, the results could reflect impaired subunit assembly at the plasma membrane.