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α3 neuronal nicotinic acetylcholine receptors in neuropsychiatric features of Dementia with Lewy bodies: [125I]-α-conotoxin MII binding in the thalamus and striatum.
Neuroscience Letters 372 (2004) 220–225
Involvement of ␣6/␣3 neuronal nicotinic acetylcholine receptors in neuropsychiatric features of Dementia with Lewy bodies: [125I]-␣-conotoxin MII binding in the thalamus and striatum. Melissa Raya , Iwo Bohra , J. Michael McIntoshb , Clive Ballarda , Ian McKeitha , Sylvie Chalond , Denis Guilloteaud , Robert Perryc , Elaine Perrya , J.A. Courta,∗ , Margaret Piggotta a
d
Institute for Ageing and Health, University of Newcastle upon Tyne, MRC Building, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK b Departments of Biology and Psychiatry, University of Utah, Salt Lake City, USA c Department of Neuropathology, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK INSERM U316, Laboratoire de Biophysique M´edicale et Pharmaceutique, Universit´e Fran¸cois Rabelais, Tours, France Received 12 July 2004; received in revised form 6 September 2004; accepted 20 September 2004
Abstract Dementia with Lewy bodies (DLB) is a neurodegenerative disease associated with a range of neuropsychiatric symptoms and reduced expression of neuronal nicotinic acetylcholine receptors (nAChRs) in neocortex, hippocampus, thalamus and basal ganglia. To determine whether there are selective associations between alterations in ␣6/␣3 neuronal nicotinic acetylcholine receptors (nAChRs) and the two key neuropsychiatric features of DLB, impaired consciousness (IC) and visual hallucinations (VH), quantitative [125 I]-␣-conotoxin MII ([125 I]-␣Ctx MII) autoradiography was undertaken on 28 people with DLB and 15 control cases from the Newcastle Brain Bank. There was a highly significant overall trend for reduced thalamic [125 I]-␣-Ctx MII binding in DLB (p < 0.001), with significant deficits in the centromedian, ventral lateral and ventroposterior medial thalamic nuclei (p < 0.05), together with caudate and putamen (p < 0.001). [125 I]-␣-Ctx MII binding was significantly lower in DLB cases with IC than without IC in the putamen (p < 0.05), however there was no significant association between [125 I]-␣-Ctx MII binding and VH. Reductions in [125 I]-␣-Ctx MII binding in caudate and putamen were paralleled by similar reductions in [125 I]PE2I binding. [125 I]PE2I binding was also significantly lower in DLB cases with IC than without IC in the caudate (p < 0.05) and putamen (p < 0.001). These results demonstrate that deficits in ␣6/␣3 nAChRs occur in specific brain regions in DLB, may in part be related to the loss of dopaminergic neurons and may contribute to the development of impaired consciousness in the disorder. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Dementia with Lewy bodies; Neuronal nicotinic acetylcholine receptors; Thalamus; Striatum; Impaired consciousness; Visual hallucinations
Neuronal nicotinic acetylcholine receptors (nAChRs) form a heterogeneous class of ionotropic receptor with reported roles in attention, cognitive, sensory, reward, pain and motor pathways [21]. The major subtypes in human brain are the ␣7 and ␣42 subtypes although recent studies have demonstrated expression of other nAChR subunits in selected brain regions. ␣6 and ␣3 nAChR subunits are closely homologous in amino acid sequence [27] and ␣6 is selectively expressed ∗
Corresponding author. Tel.: +44 191 4444412; fax: +44 191 4444402. E-mail address: [email protected] (J.A. Court).
0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.09.042
in visual and nigrostriatal dopaminergic pathways in rodents and primates [1,25,42,53]. ␣3 nAChR mRNA is highly expressed in human thalamus [47] and protein expression of both ␣3 and ␣6 nAChR subunits has been demonstrated in human brain [17]. Dementia with Lewy bodies (DLB) accounts for 15–20% of late onset dementia and is characterised by disturbances of consciousness, visual hallucinations, fluctuations in cognition, motor features of parkinsonism [31] and the presence of Lewy bodies in cortical and subcortical regions [31,38]. Extrapyramidal features can be attributed to loss of dopamine
M. Ray et al. / Neuroscience Letters 372 (2004) 220–225
in the striatum [26,39] and reduced neuron density in the substantia nigra pars compacta [38]. Impaired consciousness (IC), associated with fluctuations in cognition, is prevalent in 80–90% of DLB cases [9,31]. Visual hallucinations (VH) are experienced by >80% of DLB patients [4]. nAChR deficits have been described in a number of brain regions in DLB. Reductions in [3 H]nicotine binding (predominantly to ␣42) have been identified in the neocortex [36], thalamic lateral dorsal nucleus [12], striatum [14] and substantia nigra [34]. This has been corroborated by recent evaluation of [3 H]epibatidine [13,29,45] and 5-[125 I]-A-85380 binding [40]. Significant reductions in [125 I]␣-bungarotoxin binding in DLB have also been reported in the thalamic reticular nucleus (Rt) [12] and frontal [45] but not temporal [13] cortex. Investigations of nAChR changes in the temporal cortex (BA 20 and 36) indicate IC is associated with 62–66% higher [3 H]epibatidine binding and VH with reduced [125 I]␣-bungarotoxin binding. The radioligand [125 I]-␣-conotoxin MII ([125 I]-␣-Ctx MII) is selective for ␣6 and/or ␣3 subunit-containing nAChRs and has been used to identify selected nAChR binding sites in a number of species [24,42,51]. In monkeys and mice [125 I]␣-Ctx MII binding sites were predominantly localised to habenula-interpeduncular, visual and nigrostriatal dopaminergic pathways [42]. A recent human study measured highest densities of [125 I]-␣-Ctx MII binding in the optic tract, nucleus accumbens, caudate and putamen with significant reductions in binding occurring in the striatum in Parkinson’s disease (PD) [41]. In the present study we have used [125 I]-␣-conotoxin MII autoradiography to quantify ␣6/␣3 nAChR expression in brains of normal elderly and DLB cases at the level of the posterior striatum and thalamus. DLB cases were clinically and psychologically assessed at annual intervals prior to death enabling correlation of ␣6/␣3 nAChR deficits in specific brain regions with the presence of IC and VH. Clinical assessments for DLB patients included: a standardised psychiatric history (history and aetiology schedule (HAS) [15]; assessment of cognitive function using the Cambridge Assessment of Mental Disorders in the Elderly, section B (CAMCOG) [46]; and a standardised physical examination incorporating the modified Unified Parkinson’s Disease Rating Scale [2]. Occurrence of IC was identified by expert clinical assessment from an operationalized, informant interview, validated against measures of cortical arousal, fluctuating attention and a detailed modified delirium rating scale [49,50]. Definition of the presence and classification of VH was taken from the criteria of Burns et al. [8]. VH were defined as visual percepts in the absence of a stimulus, stipulated as reported to an assessor and not inferred from behaviour. Symptoms were rated as present if they were present for at least 6 months continuously at some stage of the dementia or were present at the assessment prior to death [3]. Brain tissue was obtained from 28 DLB and 15 agematched control cases (Table 1) from the Newcastle Brain Bank with the consent of next of kin and approval of New-
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castle and North Tyneside Research Ethics Committee and the left hemisphere snap frozen at autopsy. Neuropathological diagnosis was according to international DLB consensus criteria [31] using ␣-synuclein immunohistochemistry in formalin fixed tissue from the right hemisphere to demonstrate cortical Lewy bodies. Control cases had no clinical or neuropathological evidence of neurological and psychiatric disorders and did not demonstrate significant vascular pathology. [125 I]-␣-Ctx MII, specific activity 2125 Ci/mmol, was synthesised as previously described [51]. [125 I]-␣-Ctx MII quantitative autoradiography was performed essentially according to Quik et al. [42] with minor modifications. Twenty micrometre cryostat coronal midbrain sections, mounted onto Vecta-bond (Vector Labs, UK) coated slides, were preincubated in binding buffer [containing 144 mM NaCl, 1.5 mM KCl, 2 mM CaCl2 , 1 mM MgSO4 , 20 mM HEPES, 0.1% BSA plus 1 mM phenylmethylsulfonyl fluoride] (pH 7.5) at room temperature for 20 min. This was followed by a 2-h incubation at RT in binding buffer plus 5 mM EDTA, 5 mM EGTA, 10 g/ml aprotinin, leupeptin and pepstatin A and 0.59 nM [125 I]-␣-Ctx MII. Sections were washed three times (40 min each wash) in phosphate buffered saline (pH 7.5) then dipped in distilled water at 4 ◦ C. Non-specific [125 I]-␣-Ctx MII binding was evaluated in the presence of 10 M nicotine and was 44% of the total binding in control putamen. Chemicals used in autoradiography were obtained from Sigma–Aldrich, UK. Sections were air-dried prior to exposure to Kodak Biomax MR film (PerkinElmer, Inc.) together with 125 I autoradiographic microscale standards (Amersham Pharmacia Biotech UK Ltd, UK). Binding was quantified to 125 I standards using MCID Elite image analysis system (Imaging Research Ltd., Interfocus, UK). Three sections for total binding and two sections for non-specific binding were assessed per block of brain tissue and specific binding calculated from the mean of results. Thalamic nuclear and striatal boundaries were evident on [125 I]-␣-Ctx MII autoradiographs and structures identified using a human anatomical atlas [28]. As a measure of dopamine (DA) terminal density DA transporters in caudate and putamen were estimated using [125 I]PE2I in contiguous sections. Autoradiography was performed essentially according to Hall et al. [19] with 90 min incubations in 15pM [125 I]PE2I at 22 ◦ C (in triplicate). Nonspecific binding was determined in 10M GBR12909 and was less than 10% of the total binding. Assessment of differences in overall trends in [125 I]-␣Ctx MII binding in the thalamus between controls versus the whole DLB group and between DLB subgroups was made using two-way analysis of variance (ANOVA) (General Linear Model, Minitab Release 13, Minitab Inc.). When a significant difference was indicated comparisons of binding in individual nuclei were made using two-tailed Student’s t test. This test was also used for two group comparisons in other areas. For three group comparisons (control versus DLB subgroups) one-way ANOVA (Minitab Release 13, Minitab Inc.) with post hoc analysis using Fisher’s comparison of means
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Table 1 Case demographics details for study of [125 I]-␣-Ctx MII binding
Number of cases (n) Age (years) Gender PM delay (hours) MMSE Duration of disease (years) Ex-smokers (n) CERAD Anticholinergic medication (n) Neuroleptic medication (n) Dopaminergic medication (n)
Control
DLB all
DLB + IC
DLB − IC
DLB + VH
DLB − VH
15 80.4 ± 12.0 12F/3M 37.2 ± 22.0 – – 4 – – – –
28 78.5 ± 7.3 12F/16M 39.0 ± 22.5 12.8 ± 7.2 10.4 + 7.6 4 All cases 1 or 0 1 (4 stopped) 3 (3 stopped) 1
12 77.3 ± 6.7 8F/4M 41.2 ± 18.7 14.4 ± 7.9 13.5 ± 8.7 1 All cases 1 or 0 – 3 –
12 78.4 ± 7.9 4F/8M 30.3 ± 23.2 9.2 ± 5.1 6.3 ± 4.0 3 All cases 1 or 0 1 – –
17 76.9 ± 6.9 9F/7M 35.6 ± 22.4 11.7 ± 6.7 8.75 ± 2.8 2 All cases 1 or 0 – 3 1
7 80.1 ± 8.3 3F/4M 37.9 ± 23.5 16.5 ± 12.0 12.7 ± 12.2 2 All cases 1 or 0 – – –
There were four cases for which no neuropsychiatric data was available.
was used. Correlation analysis was by Minitab (Minitab Release 13, Minitab Inc.). In normal human brain [125 I]-␣-Ctx MII binding varied between thalamic nuclei and was highest in the anteroventral nucleus of the thalamus (AV), where it was comparable to that in the striatum (Table 2). Lower levels occurred in mediodorsal (MD), paraventricular (PV), reuniens (Re), parafascicular (Pf), centromedian (CM), ventral anterior (VA), ventral lateral (VL), ventroposterior medial (VPM) and lateral dorsal (LD) thalamic nuclei. Binding was least dense in the thalamic reticular nucleus (Rt) and insular cortex. [125 I]-␣-Ctx MII binding was significantly reduced by 55% in the caudate (p < 0.001) and 76% in the putamen (p < 0.001) in DLB. There was a highly significant overall trend for reduced [125 I]-␣-Ctx MII binding in the thalamus in DLB (F = 35.42, d.f. = 1, 299, p < 0.001) with significantly lower binding occurred in DLB than age-matched controls in the CM (p < 0.05), VL (p < 0.05) and VPM (p < 0.05) thalamic nuclei. There were no differences in [125 I]-␣-Ctx MII binding between DLB and control cases in insular cortex (Table 2). [125 I]-␣-Ctx MII binding was significantly lower in DLB cases with IC (DLB + IC) than DLB cases without IC (DLB − IC) in the putamen (p < 0.01) with a similar (nonsignificant) trend in the caudate. There was also a significant overall trend for reduced binding in DLB + IC compared to DLB − IC in the thalamus (F = 5.89, d.f. = 1, 159, p < 0.05). [125 I]-␣-Ctx MII measurements were significantly lower in DLB ± IC than controls in thalamic CM (F = 4.40, d.f. = 2, 23, p < 0.05), caudate (F = 12.63, d.f. = 2, 32, p < 0.001) and putamen (F = 22.97, d.f. = 2, 33, p < 0.001) (Table 2). Although there was a trend observed for lower [125 I]␣-Ctx MII binding densities in DLB patients without VH (DLB − VH) than with VH (DLB + VH), it did not reach statistical significance in any region examined. Binding was significantly lower in DLB ± VH than controls in the thalamic CM (F = 4.35, d.f. = 2, 23, p < 0.05), caudate (F = 11.80, d.f. = 2, 32, p < 0.001) and putamen (F = 18.08, d.f. = 2, 33, p < 0.001) (Table 3). Comparisons of subgroups of patients with or without auditory hallucinations and with or without
delusions indicated no associations between [125 I]-␣-Ctx MII binding with these features in DLB. [125 I]-␣-Ctx MII binding did not significantly differ between male and female cases in control or DLB groups. There were no significant differences in age and post-mortem delay between the groups. [125 I]-␣-Ctx MII binding did not significantly correlate with post-mortem delay in DLB patients or controls. There were also no consistent correlations with age and [125 I]-␣-Ctx MII binding within the groups. There were no significant differences in MMSE scores between DLB + IC and DLB − IC cases and DLB + VH and DLB − VH cases. [125 I]-␣-Ctx MII binding did not significantly correlate with MMSE scores or disease duration in DLB. Reductions in [125 I]-␣-Ctx MII binding in caudate and putamen in DLB versus controls were paralleled by similar reductions in [125 I]PE2I binding (Table 2). Within DLB cases [125 I]-␣-Ctx MII binding was significantly correlated with [125 I]PE2I binding (p < 0.01 in caudate, p < 0.001 in putamen). When the DLB group was subdivided according to presence of IC [125 I]PE2I binding was significantly lower in caudate (p < 0.05) and putamen (p < 0.001) in DLB cases with IC than without IC (Table 2). The present study is the first to quantify [125 I]-␣-Ctx MII binding in DLB and associate ␣6/␣3 nAChR deficits in specific brain regions with neuropsychiatric features of the disorder. Here we report highly significant reductions in [125 I]-␣-Ctx MII binding in the striatum and thalamus in DLB compared with age-matched controls and significantly lower [125 I]-␣-Ctx MII binding in the putamen of DLB patients with IC than without IC. VH were not associated with lower [125 I]-␣-Ctx MII binding in DLB. Highly significant reductions in striatal [125 I]-␣-Ctx MII binding in DLB patients (both for the DLB group as a whole and subgroups) compared with age-matched controls parallels observations with other ligands with affinity for ␣42 and ␣6/␣3 nAChRs ([3 H]nicotine, [3 H]epibatidine and 5-[125 I]A-85380) [14,29,40]. A proportion of nAChRs are present on dopaminergic neurons in the striatum [11] and its predominant function is the regulation of movement [52]. ␣6/␣3
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Table 2 [125 I]-␣-Ctx MII binding in control and DLB cases and in DLB subgroups with and without impaired consciousness (IC) ([125 I]PE2I binding) Region
Control
Thalamic Rt Thalamic AV Thalamic MD Thalamic PV Thalamic Re Thalamic Pf Thalamic CM Thalamic VA Thalamic VL Thalamic VPM Thalamic LD Caudate [125 I]PE2I binding Putamen [125 I]PE2I binding Insular cortex
0.087 ± 0.050 0.206 ± 0.139 0.134 ± 0.072 0.138 ± 0.083 0.119 ± 0.047 0.171 ± 0.084 0.164 ± 0.085 0.124 ± 0.023 0.132 ± 0.100 0.111 ± 0.030 0.155 ± 0.077 0.187 ± 0.058 0.634 ± 0.093 0.245 ± 0.086 0.649 ± 0.093 0.033 ± 0.015
All DLB 15 7 13 11 9 8 10 5 14 6 13 12 14 13 14 11
0.074 ± 0.051 0.135 ± 0.075 0.088 ± 0.047 0.094 ± 0.053 0.092 ± 0.066 0.100 ± 0.066 0.080 ± 0.057* 0.091 ± 0.058 0.071 ± 0.053* 0.066 ± 0.047* 0.113 ± 0.071 0.084 ± 0.059*** 0.353 ± 0.166*** 0.082 ± 0.070*** 0.233 ± 0.199*** 0.032 ± 0.023
DLB+IC 28 15 26 20 16 15 20 13 22 12 23 27 19 28 20 21
DLB-IC
0.058 ± 0.035 0.110 ± 0.049 0.083 ± 0.049 0.102 ± 0.048 0.091 ± 0.066 0.084 ± 0.063 0.073 ± 0.050* 0.074 ± 0.044 0.051 ± 0.030 – 0.100 ± 0.050 0.073 ± 0.039*** 0.295 ± 0.116***,†† 0.053 ± 0.032***,† 0.105 ± 0.104***,†† 0.053 ± 0.026
12 7 10 9 6 7 8 7 9 – 9 11 10 12 11 10
0.098 ± 0.059 0.158 ± 0.089 0.102 ± 0.043 0.095 ± 0.062 0.070 ± 0.042 0.124 ± 0.076 0.094 ± 0.064* 0.110 ± 0.069 0.089 ± 0.064 – 0.136 ± 0.089 0.107 ± 0.066*** 0.451 ± 0.207*** 0.124 ± 0.076*** 0.413 ± 0.208*** 0.032 ± 0.018
12 8 12 8 7 6 8 6 10 – 10 12 8 12 8 9
Data are presented as means ± S.D. (fmol/mg of protein) with numbers of cases. An overall significant decline in [125 I]-␣-Ctx MII binding occurred in the thalamus in DLB (p < 0.001) and in DLB + IC compared to DLB-IC (p < 0.05) (two-way ANOVA). ∗ Significantly lower than the control group value, p < 0.05. ∗∗∗ Significantly lower than the control group value, p < 0.001. † Significantly lower than the DLB-IC value, p < 0.01. †† Significantly lower than the DLB-IC value, p < 0.001.
nAChRs have been demonstrated, using animal and in vitro studies, to selectively locate on dopaminergic neurons and terminals in this region and mediate DA release [10,22,43]. Correlation of [125 I]-␣-Ctx MII binding and [125 I]PE2I binding in caudate and putamen in the whole DLB group indicates loss of ␣6/␣3 nAChRs is related to the loss of dopaminergic neurons, including dopaminergic projections from the substantia nigra [39]. Comparison of striatal changes in [125 I]-␣-Ctx MII binding in DLB reported here with those previously reported in PD [41] indicates similar deficits occur at posterior levels. However, in contrast reductions in DA uptake sites are less severe in DLB than in PD (e.g., 64 versus 80–90% in posterior putamen). This suggests that either some reduction in [125 I]-␣-Ctx MII binding in DLB is from non-dopaminergic neurons or terminals or that attrition of these nAChRs occurs at an early stage of DA terminal degeneration.
A highly significant overall trend for reduced [125 I]-␣-Ctx MII binding in the thalamus in DLB cases compared to age-matched controls may reflect attrition of nigrostriatal dopaminergic collaterals terminating in thalamic nuclei [16]. However, colocalisation studies using DA uptake site and ␣6 antibodies are required to establish that ␣6 expression is confined to dopaminergic terminals in this region. Statistically significant attenuation of [125 I]-␣-Ctx MII binding was evident in three individual thalamic nuclei; the CM, VL and VPM nuclei in DLB. CM is an intralaminar nucleus with roles in the mediation of consciousness, attention, proprioception, motor and planning acts [7,18]. VL is the principal thalamic relay to motor cortex and has been surgically targeted to relieve parkinsonian symptoms [6,20]. VPM is a somatosensory relay [44], not previously associated with nAChR loss in DLB [12,13].
Table 3 [125 I]-␣-Ctx MII binding in normal human brain and in DLB cases with and without visual (VH) hallucinations Region
Control
Thalamic Rt Thalamic MD Thalamic PV Thalamic CM Thalamic VL Thalamic LD Caudate Putamen Insular cortex
0.087 ± 0.050 0.134 ± 0.072 0.138 ± 0.083 0.164 ± 0.085 0.132 ± 0.100 0.155 ± 0.077 0.187 ± 0.058 0.245 ± 0.086 0.033 ± 0.015
DLB − VH
DLB + VH 15 13 11 10 14 13 12 13 11
0.079 ± 0.048 0.100 ± 0.444 0.111 ± 0.050 0.090 ± 0.057* 0.080 ± 0.053 0.126 ± 0.082 0.083 ± 0.052*** 0.080 ± 0.061*** 0.033 ± 0.021
Data are presented as means ± S.D. (fmol/mg of protein) with numbers of cases. ∗ Significantly lower than the control group value, p < 0.05. ∗∗∗ Significantly lower than the control group value, p < 0.001 (ANOVA: single factor).
17 15 11 11 14 13 17 16 13
0.079 ± 0.064 0.078 ± 0.050 0.075 ± 0.055 0.069 ± 0.060* 0.047 ± 0.053 0.102 ± 0.055 0.112 ± 0.068*** 0.113 ± 0.083*** 0.035 ± 0.026
7 7 6 5 5 6 6 7 6
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The finding that IC in DLB is associated with reduced [125 I]-␣-Ctx MII binding in the putamen and thalamus is novel. [125 I]PE2I binding was also reduced in parallel with [125 I]-␣-Ctx MII binding in DLB + IC versus DLB − IC in caudate and putamen and suggests that changes in the level of consciousness may be associated with greater attrition of nigrostriatal dopaminergic neurons expressing ␣6/␣3 nAChRs and modulation of dopaminergic tone [23]. It is possible that differences in [125 I]PE2I binding between DLB ± IC may also relate to loss of dopaminergic terminals since nigrostriatal dopaminergic neurons project to many thalamic nuclei [16]. However, in the present study we were unable to measure DA uptake sites in the thalamus and these differences between subgroups of DLB may reflect changes in non-dopaminergic elements. It is widely conceived that the development of VH in DLB relates to functional changes in the cholinergic system [35,37]. VH have been associated with reductions in neocortical cholinergic activity [32,33,35] and lower [125 I]␣bungarotoxin binding in BA 20 and 36 of the temporal cortex [13]. In the present study [125 I]-␣-Ctx MII binding was not lower in DLB cases with VH than without VH and it is, therefore, unlikely that ␣6/␣3 nAChRs deficits contribute to any major extent to the development of this feature. There is, currently, no disease-modifying therapy for DLB. Therefore management strategies utilise a range of treatments according to severity of cognitive, psychiatric and motor symptoms of the disorder. Cholinesterase inhibitors are increasingly reported as effective in the treatment of neuropsychiatric feature of DLB [5,30] and one, galantamine, is an allosteric potentiator of ␣64, ␣42 and ␣34 nAChRs [48]. The present investigation quantifies ␣6/␣3 nAChR expression in DLB using [125 I]-␣-Ctx MII autoradiography and makes comparisons between cases with and without IC and VH. Reductions in [125 I]-␣-Ctx MII binding in the striatum and thalamus correlate with the presence of IC in DLB and suggest nicotinic compounds may be a useful treatment approach for this neuropsychiatric feature. Specific regions of striatal and thalamic ␣6/␣3 nAChR deficits may represent potential novel targets for future nicotinic therapy.
Acknowledgements M.R. is supported by a BBSRC CASE studentship, cooperating body Eli Lilly and Co. Ltd., UK. I.B. is supported by an EC grant (NIDE project). J.C., E.K. and M.P. are supported by the MRC, UK.
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Involvement of ␣6/␣3 neuronal nicotinic acetylcholine receptors in neuropsychiatric features of Dementia with Lewy bodies: [125I]-␣-conotoxin MII binding in the thalamus and striatum. Melissa Raya , Iwo Bohra , J. Michael McIntoshb , Clive Ballarda , Ian McKeitha , Sylvie Chalond , Denis Guilloteaud , Robert Perryc , Elaine Perrya , J.A. Courta,∗ , Margaret Piggotta a
d
Institute for Ageing and Health, University of Newcastle upon Tyne, MRC Building, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK b Departments of Biology and Psychiatry, University of Utah, Salt Lake City, USA c Department of Neuropathology, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK INSERM U316, Laboratoire de Biophysique M´edicale et Pharmaceutique, Universit´e Fran¸cois Rabelais, Tours, France Received 12 July 2004; received in revised form 6 September 2004; accepted 20 September 2004
Abstract Dementia with Lewy bodies (DLB) is a neurodegenerative disease associated with a range of neuropsychiatric symptoms and reduced expression of neuronal nicotinic acetylcholine receptors (nAChRs) in neocortex, hippocampus, thalamus and basal ganglia. To determine whether there are selective associations between alterations in ␣6/␣3 neuronal nicotinic acetylcholine receptors (nAChRs) and the two key neuropsychiatric features of DLB, impaired consciousness (IC) and visual hallucinations (VH), quantitative [125 I]-␣-conotoxin MII ([125 I]-␣Ctx MII) autoradiography was undertaken on 28 people with DLB and 15 control cases from the Newcastle Brain Bank. There was a highly significant overall trend for reduced thalamic [125 I]-␣-Ctx MII binding in DLB (p < 0.001), with significant deficits in the centromedian, ventral lateral and ventroposterior medial thalamic nuclei (p < 0.05), together with caudate and putamen (p < 0.001). [125 I]-␣-Ctx MII binding was significantly lower in DLB cases with IC than without IC in the putamen (p < 0.05), however there was no significant association between [125 I]-␣-Ctx MII binding and VH. Reductions in [125 I]-␣-Ctx MII binding in caudate and putamen were paralleled by similar reductions in [125 I]PE2I binding. [125 I]PE2I binding was also significantly lower in DLB cases with IC than without IC in the caudate (p < 0.05) and putamen (p < 0.001). These results demonstrate that deficits in ␣6/␣3 nAChRs occur in specific brain regions in DLB, may in part be related to the loss of dopaminergic neurons and may contribute to the development of impaired consciousness in the disorder. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Dementia with Lewy bodies; Neuronal nicotinic acetylcholine receptors; Thalamus; Striatum; Impaired consciousness; Visual hallucinations
Neuronal nicotinic acetylcholine receptors (nAChRs) form a heterogeneous class of ionotropic receptor with reported roles in attention, cognitive, sensory, reward, pain and motor pathways [21]. The major subtypes in human brain are the ␣7 and ␣42 subtypes although recent studies have demonstrated expression of other nAChR subunits in selected brain regions. ␣6 and ␣3 nAChR subunits are closely homologous in amino acid sequence [27] and ␣6 is selectively expressed ∗
Corresponding author. Tel.: +44 191 4444412; fax: +44 191 4444402. E-mail address: [email protected] (J.A. Court).
0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.09.042
in visual and nigrostriatal dopaminergic pathways in rodents and primates [1,25,42,53]. ␣3 nAChR mRNA is highly expressed in human thalamus [47] and protein expression of both ␣3 and ␣6 nAChR subunits has been demonstrated in human brain [17]. Dementia with Lewy bodies (DLB) accounts for 15–20% of late onset dementia and is characterised by disturbances of consciousness, visual hallucinations, fluctuations in cognition, motor features of parkinsonism [31] and the presence of Lewy bodies in cortical and subcortical regions [31,38]. Extrapyramidal features can be attributed to loss of dopamine
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in the striatum [26,39] and reduced neuron density in the substantia nigra pars compacta [38]. Impaired consciousness (IC), associated with fluctuations in cognition, is prevalent in 80–90% of DLB cases [9,31]. Visual hallucinations (VH) are experienced by >80% of DLB patients [4]. nAChR deficits have been described in a number of brain regions in DLB. Reductions in [3 H]nicotine binding (predominantly to ␣42) have been identified in the neocortex [36], thalamic lateral dorsal nucleus [12], striatum [14] and substantia nigra [34]. This has been corroborated by recent evaluation of [3 H]epibatidine [13,29,45] and 5-[125 I]-A-85380 binding [40]. Significant reductions in [125 I]␣-bungarotoxin binding in DLB have also been reported in the thalamic reticular nucleus (Rt) [12] and frontal [45] but not temporal [13] cortex. Investigations of nAChR changes in the temporal cortex (BA 20 and 36) indicate IC is associated with 62–66% higher [3 H]epibatidine binding and VH with reduced [125 I]␣-bungarotoxin binding. The radioligand [125 I]-␣-conotoxin MII ([125 I]-␣-Ctx MII) is selective for ␣6 and/or ␣3 subunit-containing nAChRs and has been used to identify selected nAChR binding sites in a number of species [24,42,51]. In monkeys and mice [125 I]␣-Ctx MII binding sites were predominantly localised to habenula-interpeduncular, visual and nigrostriatal dopaminergic pathways [42]. A recent human study measured highest densities of [125 I]-␣-Ctx MII binding in the optic tract, nucleus accumbens, caudate and putamen with significant reductions in binding occurring in the striatum in Parkinson’s disease (PD) [41]. In the present study we have used [125 I]-␣-conotoxin MII autoradiography to quantify ␣6/␣3 nAChR expression in brains of normal elderly and DLB cases at the level of the posterior striatum and thalamus. DLB cases were clinically and psychologically assessed at annual intervals prior to death enabling correlation of ␣6/␣3 nAChR deficits in specific brain regions with the presence of IC and VH. Clinical assessments for DLB patients included: a standardised psychiatric history (history and aetiology schedule (HAS) [15]; assessment of cognitive function using the Cambridge Assessment of Mental Disorders in the Elderly, section B (CAMCOG) [46]; and a standardised physical examination incorporating the modified Unified Parkinson’s Disease Rating Scale [2]. Occurrence of IC was identified by expert clinical assessment from an operationalized, informant interview, validated against measures of cortical arousal, fluctuating attention and a detailed modified delirium rating scale [49,50]. Definition of the presence and classification of VH was taken from the criteria of Burns et al. [8]. VH were defined as visual percepts in the absence of a stimulus, stipulated as reported to an assessor and not inferred from behaviour. Symptoms were rated as present if they were present for at least 6 months continuously at some stage of the dementia or were present at the assessment prior to death [3]. Brain tissue was obtained from 28 DLB and 15 agematched control cases (Table 1) from the Newcastle Brain Bank with the consent of next of kin and approval of New-
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castle and North Tyneside Research Ethics Committee and the left hemisphere snap frozen at autopsy. Neuropathological diagnosis was according to international DLB consensus criteria [31] using ␣-synuclein immunohistochemistry in formalin fixed tissue from the right hemisphere to demonstrate cortical Lewy bodies. Control cases had no clinical or neuropathological evidence of neurological and psychiatric disorders and did not demonstrate significant vascular pathology. [125 I]-␣-Ctx MII, specific activity 2125 Ci/mmol, was synthesised as previously described [51]. [125 I]-␣-Ctx MII quantitative autoradiography was performed essentially according to Quik et al. [42] with minor modifications. Twenty micrometre cryostat coronal midbrain sections, mounted onto Vecta-bond (Vector Labs, UK) coated slides, were preincubated in binding buffer [containing 144 mM NaCl, 1.5 mM KCl, 2 mM CaCl2 , 1 mM MgSO4 , 20 mM HEPES, 0.1% BSA plus 1 mM phenylmethylsulfonyl fluoride] (pH 7.5) at room temperature for 20 min. This was followed by a 2-h incubation at RT in binding buffer plus 5 mM EDTA, 5 mM EGTA, 10 g/ml aprotinin, leupeptin and pepstatin A and 0.59 nM [125 I]-␣-Ctx MII. Sections were washed three times (40 min each wash) in phosphate buffered saline (pH 7.5) then dipped in distilled water at 4 ◦ C. Non-specific [125 I]-␣-Ctx MII binding was evaluated in the presence of 10 M nicotine and was 44% of the total binding in control putamen. Chemicals used in autoradiography were obtained from Sigma–Aldrich, UK. Sections were air-dried prior to exposure to Kodak Biomax MR film (PerkinElmer, Inc.) together with 125 I autoradiographic microscale standards (Amersham Pharmacia Biotech UK Ltd, UK). Binding was quantified to 125 I standards using MCID Elite image analysis system (Imaging Research Ltd., Interfocus, UK). Three sections for total binding and two sections for non-specific binding were assessed per block of brain tissue and specific binding calculated from the mean of results. Thalamic nuclear and striatal boundaries were evident on [125 I]-␣-Ctx MII autoradiographs and structures identified using a human anatomical atlas [28]. As a measure of dopamine (DA) terminal density DA transporters in caudate and putamen were estimated using [125 I]PE2I in contiguous sections. Autoradiography was performed essentially according to Hall et al. [19] with 90 min incubations in 15pM [125 I]PE2I at 22 ◦ C (in triplicate). Nonspecific binding was determined in 10M GBR12909 and was less than 10% of the total binding. Assessment of differences in overall trends in [125 I]-␣Ctx MII binding in the thalamus between controls versus the whole DLB group and between DLB subgroups was made using two-way analysis of variance (ANOVA) (General Linear Model, Minitab Release 13, Minitab Inc.). When a significant difference was indicated comparisons of binding in individual nuclei were made using two-tailed Student’s t test. This test was also used for two group comparisons in other areas. For three group comparisons (control versus DLB subgroups) one-way ANOVA (Minitab Release 13, Minitab Inc.) with post hoc analysis using Fisher’s comparison of means
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Table 1 Case demographics details for study of [125 I]-␣-Ctx MII binding
Number of cases (n) Age (years) Gender PM delay (hours) MMSE Duration of disease (years) Ex-smokers (n) CERAD Anticholinergic medication (n) Neuroleptic medication (n) Dopaminergic medication (n)
Control
DLB all
DLB + IC
DLB − IC
DLB + VH
DLB − VH
15 80.4 ± 12.0 12F/3M 37.2 ± 22.0 – – 4 – – – –
28 78.5 ± 7.3 12F/16M 39.0 ± 22.5 12.8 ± 7.2 10.4 + 7.6 4 All cases 1 or 0 1 (4 stopped) 3 (3 stopped) 1
12 77.3 ± 6.7 8F/4M 41.2 ± 18.7 14.4 ± 7.9 13.5 ± 8.7 1 All cases 1 or 0 – 3 –
12 78.4 ± 7.9 4F/8M 30.3 ± 23.2 9.2 ± 5.1 6.3 ± 4.0 3 All cases 1 or 0 1 – –
17 76.9 ± 6.9 9F/7M 35.6 ± 22.4 11.7 ± 6.7 8.75 ± 2.8 2 All cases 1 or 0 – 3 1
7 80.1 ± 8.3 3F/4M 37.9 ± 23.5 16.5 ± 12.0 12.7 ± 12.2 2 All cases 1 or 0 – – –
There were four cases for which no neuropsychiatric data was available.
was used. Correlation analysis was by Minitab (Minitab Release 13, Minitab Inc.). In normal human brain [125 I]-␣-Ctx MII binding varied between thalamic nuclei and was highest in the anteroventral nucleus of the thalamus (AV), where it was comparable to that in the striatum (Table 2). Lower levels occurred in mediodorsal (MD), paraventricular (PV), reuniens (Re), parafascicular (Pf), centromedian (CM), ventral anterior (VA), ventral lateral (VL), ventroposterior medial (VPM) and lateral dorsal (LD) thalamic nuclei. Binding was least dense in the thalamic reticular nucleus (Rt) and insular cortex. [125 I]-␣-Ctx MII binding was significantly reduced by 55% in the caudate (p < 0.001) and 76% in the putamen (p < 0.001) in DLB. There was a highly significant overall trend for reduced [125 I]-␣-Ctx MII binding in the thalamus in DLB (F = 35.42, d.f. = 1, 299, p < 0.001) with significantly lower binding occurred in DLB than age-matched controls in the CM (p < 0.05), VL (p < 0.05) and VPM (p < 0.05) thalamic nuclei. There were no differences in [125 I]-␣-Ctx MII binding between DLB and control cases in insular cortex (Table 2). [125 I]-␣-Ctx MII binding was significantly lower in DLB cases with IC (DLB + IC) than DLB cases without IC (DLB − IC) in the putamen (p < 0.01) with a similar (nonsignificant) trend in the caudate. There was also a significant overall trend for reduced binding in DLB + IC compared to DLB − IC in the thalamus (F = 5.89, d.f. = 1, 159, p < 0.05). [125 I]-␣-Ctx MII measurements were significantly lower in DLB ± IC than controls in thalamic CM (F = 4.40, d.f. = 2, 23, p < 0.05), caudate (F = 12.63, d.f. = 2, 32, p < 0.001) and putamen (F = 22.97, d.f. = 2, 33, p < 0.001) (Table 2). Although there was a trend observed for lower [125 I]␣-Ctx MII binding densities in DLB patients without VH (DLB − VH) than with VH (DLB + VH), it did not reach statistical significance in any region examined. Binding was significantly lower in DLB ± VH than controls in the thalamic CM (F = 4.35, d.f. = 2, 23, p < 0.05), caudate (F = 11.80, d.f. = 2, 32, p < 0.001) and putamen (F = 18.08, d.f. = 2, 33, p < 0.001) (Table 3). Comparisons of subgroups of patients with or without auditory hallucinations and with or without
delusions indicated no associations between [125 I]-␣-Ctx MII binding with these features in DLB. [125 I]-␣-Ctx MII binding did not significantly differ between male and female cases in control or DLB groups. There were no significant differences in age and post-mortem delay between the groups. [125 I]-␣-Ctx MII binding did not significantly correlate with post-mortem delay in DLB patients or controls. There were also no consistent correlations with age and [125 I]-␣-Ctx MII binding within the groups. There were no significant differences in MMSE scores between DLB + IC and DLB − IC cases and DLB + VH and DLB − VH cases. [125 I]-␣-Ctx MII binding did not significantly correlate with MMSE scores or disease duration in DLB. Reductions in [125 I]-␣-Ctx MII binding in caudate and putamen in DLB versus controls were paralleled by similar reductions in [125 I]PE2I binding (Table 2). Within DLB cases [125 I]-␣-Ctx MII binding was significantly correlated with [125 I]PE2I binding (p < 0.01 in caudate, p < 0.001 in putamen). When the DLB group was subdivided according to presence of IC [125 I]PE2I binding was significantly lower in caudate (p < 0.05) and putamen (p < 0.001) in DLB cases with IC than without IC (Table 2). The present study is the first to quantify [125 I]-␣-Ctx MII binding in DLB and associate ␣6/␣3 nAChR deficits in specific brain regions with neuropsychiatric features of the disorder. Here we report highly significant reductions in [125 I]-␣-Ctx MII binding in the striatum and thalamus in DLB compared with age-matched controls and significantly lower [125 I]-␣-Ctx MII binding in the putamen of DLB patients with IC than without IC. VH were not associated with lower [125 I]-␣-Ctx MII binding in DLB. Highly significant reductions in striatal [125 I]-␣-Ctx MII binding in DLB patients (both for the DLB group as a whole and subgroups) compared with age-matched controls parallels observations with other ligands with affinity for ␣42 and ␣6/␣3 nAChRs ([3 H]nicotine, [3 H]epibatidine and 5-[125 I]A-85380) [14,29,40]. A proportion of nAChRs are present on dopaminergic neurons in the striatum [11] and its predominant function is the regulation of movement [52]. ␣6/␣3
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Table 2 [125 I]-␣-Ctx MII binding in control and DLB cases and in DLB subgroups with and without impaired consciousness (IC) ([125 I]PE2I binding) Region
Control
Thalamic Rt Thalamic AV Thalamic MD Thalamic PV Thalamic Re Thalamic Pf Thalamic CM Thalamic VA Thalamic VL Thalamic VPM Thalamic LD Caudate [125 I]PE2I binding Putamen [125 I]PE2I binding Insular cortex
0.087 ± 0.050 0.206 ± 0.139 0.134 ± 0.072 0.138 ± 0.083 0.119 ± 0.047 0.171 ± 0.084 0.164 ± 0.085 0.124 ± 0.023 0.132 ± 0.100 0.111 ± 0.030 0.155 ± 0.077 0.187 ± 0.058 0.634 ± 0.093 0.245 ± 0.086 0.649 ± 0.093 0.033 ± 0.015
All DLB 15 7 13 11 9 8 10 5 14 6 13 12 14 13 14 11
0.074 ± 0.051 0.135 ± 0.075 0.088 ± 0.047 0.094 ± 0.053 0.092 ± 0.066 0.100 ± 0.066 0.080 ± 0.057* 0.091 ± 0.058 0.071 ± 0.053* 0.066 ± 0.047* 0.113 ± 0.071 0.084 ± 0.059*** 0.353 ± 0.166*** 0.082 ± 0.070*** 0.233 ± 0.199*** 0.032 ± 0.023
DLB+IC 28 15 26 20 16 15 20 13 22 12 23 27 19 28 20 21
DLB-IC
0.058 ± 0.035 0.110 ± 0.049 0.083 ± 0.049 0.102 ± 0.048 0.091 ± 0.066 0.084 ± 0.063 0.073 ± 0.050* 0.074 ± 0.044 0.051 ± 0.030 – 0.100 ± 0.050 0.073 ± 0.039*** 0.295 ± 0.116***,†† 0.053 ± 0.032***,† 0.105 ± 0.104***,†† 0.053 ± 0.026
12 7 10 9 6 7 8 7 9 – 9 11 10 12 11 10
0.098 ± 0.059 0.158 ± 0.089 0.102 ± 0.043 0.095 ± 0.062 0.070 ± 0.042 0.124 ± 0.076 0.094 ± 0.064* 0.110 ± 0.069 0.089 ± 0.064 – 0.136 ± 0.089 0.107 ± 0.066*** 0.451 ± 0.207*** 0.124 ± 0.076*** 0.413 ± 0.208*** 0.032 ± 0.018
12 8 12 8 7 6 8 6 10 – 10 12 8 12 8 9
Data are presented as means ± S.D. (fmol/mg of protein) with numbers of cases. An overall significant decline in [125 I]-␣-Ctx MII binding occurred in the thalamus in DLB (p < 0.001) and in DLB + IC compared to DLB-IC (p < 0.05) (two-way ANOVA). ∗ Significantly lower than the control group value, p < 0.05. ∗∗∗ Significantly lower than the control group value, p < 0.001. † Significantly lower than the DLB-IC value, p < 0.01. †† Significantly lower than the DLB-IC value, p < 0.001.
nAChRs have been demonstrated, using animal and in vitro studies, to selectively locate on dopaminergic neurons and terminals in this region and mediate DA release [10,22,43]. Correlation of [125 I]-␣-Ctx MII binding and [125 I]PE2I binding in caudate and putamen in the whole DLB group indicates loss of ␣6/␣3 nAChRs is related to the loss of dopaminergic neurons, including dopaminergic projections from the substantia nigra [39]. Comparison of striatal changes in [125 I]-␣-Ctx MII binding in DLB reported here with those previously reported in PD [41] indicates similar deficits occur at posterior levels. However, in contrast reductions in DA uptake sites are less severe in DLB than in PD (e.g., 64 versus 80–90% in posterior putamen). This suggests that either some reduction in [125 I]-␣-Ctx MII binding in DLB is from non-dopaminergic neurons or terminals or that attrition of these nAChRs occurs at an early stage of DA terminal degeneration.
A highly significant overall trend for reduced [125 I]-␣-Ctx MII binding in the thalamus in DLB cases compared to age-matched controls may reflect attrition of nigrostriatal dopaminergic collaterals terminating in thalamic nuclei [16]. However, colocalisation studies using DA uptake site and ␣6 antibodies are required to establish that ␣6 expression is confined to dopaminergic terminals in this region. Statistically significant attenuation of [125 I]-␣-Ctx MII binding was evident in three individual thalamic nuclei; the CM, VL and VPM nuclei in DLB. CM is an intralaminar nucleus with roles in the mediation of consciousness, attention, proprioception, motor and planning acts [7,18]. VL is the principal thalamic relay to motor cortex and has been surgically targeted to relieve parkinsonian symptoms [6,20]. VPM is a somatosensory relay [44], not previously associated with nAChR loss in DLB [12,13].
Table 3 [125 I]-␣-Ctx MII binding in normal human brain and in DLB cases with and without visual (VH) hallucinations Region
Control
Thalamic Rt Thalamic MD Thalamic PV Thalamic CM Thalamic VL Thalamic LD Caudate Putamen Insular cortex
0.087 ± 0.050 0.134 ± 0.072 0.138 ± 0.083 0.164 ± 0.085 0.132 ± 0.100 0.155 ± 0.077 0.187 ± 0.058 0.245 ± 0.086 0.033 ± 0.015
DLB − VH
DLB + VH 15 13 11 10 14 13 12 13 11
0.079 ± 0.048 0.100 ± 0.444 0.111 ± 0.050 0.090 ± 0.057* 0.080 ± 0.053 0.126 ± 0.082 0.083 ± 0.052*** 0.080 ± 0.061*** 0.033 ± 0.021
Data are presented as means ± S.D. (fmol/mg of protein) with numbers of cases. ∗ Significantly lower than the control group value, p < 0.05. ∗∗∗ Significantly lower than the control group value, p < 0.001 (ANOVA: single factor).
17 15 11 11 14 13 17 16 13
0.079 ± 0.064 0.078 ± 0.050 0.075 ± 0.055 0.069 ± 0.060* 0.047 ± 0.053 0.102 ± 0.055 0.112 ± 0.068*** 0.113 ± 0.083*** 0.035 ± 0.026
7 7 6 5 5 6 6 7 6
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The finding that IC in DLB is associated with reduced [125 I]-␣-Ctx MII binding in the putamen and thalamus is novel. [125 I]PE2I binding was also reduced in parallel with [125 I]-␣-Ctx MII binding in DLB + IC versus DLB − IC in caudate and putamen and suggests that changes in the level of consciousness may be associated with greater attrition of nigrostriatal dopaminergic neurons expressing ␣6/␣3 nAChRs and modulation of dopaminergic tone [23]. It is possible that differences in [125 I]PE2I binding between DLB ± IC may also relate to loss of dopaminergic terminals since nigrostriatal dopaminergic neurons project to many thalamic nuclei [16]. However, in the present study we were unable to measure DA uptake sites in the thalamus and these differences between subgroups of DLB may reflect changes in non-dopaminergic elements. It is widely conceived that the development of VH in DLB relates to functional changes in the cholinergic system [35,37]. VH have been associated with reductions in neocortical cholinergic activity [32,33,35] and lower [125 I]␣bungarotoxin binding in BA 20 and 36 of the temporal cortex [13]. In the present study [125 I]-␣-Ctx MII binding was not lower in DLB cases with VH than without VH and it is, therefore, unlikely that ␣6/␣3 nAChRs deficits contribute to any major extent to the development of this feature. There is, currently, no disease-modifying therapy for DLB. Therefore management strategies utilise a range of treatments according to severity of cognitive, psychiatric and motor symptoms of the disorder. Cholinesterase inhibitors are increasingly reported as effective in the treatment of neuropsychiatric feature of DLB [5,30] and one, galantamine, is an allosteric potentiator of ␣64, ␣42 and ␣34 nAChRs [48]. The present investigation quantifies ␣6/␣3 nAChR expression in DLB using [125 I]-␣-Ctx MII autoradiography and makes comparisons between cases with and without IC and VH. Reductions in [125 I]-␣-Ctx MII binding in the striatum and thalamus correlate with the presence of IC in DLB and suggest nicotinic compounds may be a useful treatment approach for this neuropsychiatric feature. Specific regions of striatal and thalamic ␣6/␣3 nAChR deficits may represent potential novel targets for future nicotinic therapy.
Acknowledgements M.R. is supported by a BBSRC CASE studentship, cooperating body Eli Lilly and Co. Ltd., UK. I.B. is supported by an EC grant (NIDE project). J.C., E.K. and M.P. are supported by the MRC, UK.
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