Elsevier

NeuroImage

Volume 40, Issue 3, 15 April 2008, Pages 1056-1063
NeuroImage

Nicotinic α4β2 receptor binding in dementia with Lewy bodies using 123I-5IA-85380 SPECT demonstrates a link between occipital changes and visual hallucinations

https://doi.org/10.1016/j.neuroimage.2008.01.010Get rights and content

Abstract

Introduction

To investigate in vivo differences in the distribution of α4β2 subtypes of nAChR using the ligand 123I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in DLB and similarly aged controls.

Methods

Thirty-one subjects (15 DLB and 16 controls) underwent 123I-5IA-85380 and perfusion (99mTc-exametazime) SPECT scanning. Patient scans were compared to scans of control subjects on a voxel-by-voxel basis using SPM2.

Results

Compared to controls, significant reductions in relative 123I-5IA-85380 uptake were identified in frontal, striatal, temporal and cingulate regions in DLB. Elevation of scaled 123I-5IA-85380 uptake in occipital cortex was observed in DLB relative to controls, as well as being associated with DLB subjects with a recent history of visual hallucinations. Changes in 123I-5IA-85380 SPECT in DLB were different from perfusion.

Conclusion

Reductions in normalised 123I-5IA-85380 uptake in DLB were distinct from their perfusion deficits. Significant increase in occipital lobe uptake was present in DLB, a change most pronounced in subjects with a recent history of visual hallucinations. The findings directly link cholinergic changes in occipital lobe to visual hallucinations in DLB.

Introduction

Acetylcholine (ACh) is widely distributed within the human brain and has important roles in attention, memory and cognition (Volkow et al., 2001). One of the main classes of acetylcholine receptors (AChR) are nicotinic acetylcholine receptors (nAChR), which have also been implicated in memory, cognitive and sensory processes (Jones et al., 1999). nAChR consist of eight alpha (α2–α9) and three beta (β2–β4) subunits of which the major subtypes in humans are the α4β2 and α7 subtypes (Le Novere and Changeux, 1995). Reductions in nAChR have been reported in various neurodegenerative disorders, including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) (Perry et al., 1995).

Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia in later life, accounting for 15–20% cases. It is characterised clinically by attentional fluctuation, recurrent visual hallucinations and motor features of parkinsonism and histopathologically by cortical and sub-cortical Lewy bodies (McKeith et al., 1996). DLB is also known to be associated with marked cholinergic deficits (Perry et al., 1993, Tiraboschi et al., 2000). Several nicotinic radioligands have been used to explore various subunits of nAChR in DLB postmortem. Studies have shown that 3H-epibatidine and 3H-nicotine, ligands for a broad range of nAChR subtypes, are reduced in temporal (Gotti et al., 2006), striatal (Gotti et al., 2006), mid-frontal (Reid et al., 2000) and thalamic (Court et al., 1999) regions in DLB relative to controls. 125Iα-bungarotoxin, a ligand used to visualise α7 nicotinic receptors was also found to be depleted in DLB in mid-frontal and thalamic areas (Court et al., 1999, Reid et al., 2000), but preserved in temporal cortex (Gotti et al., 2006). Other studies have revealed loss of the α6/α3 selective nAChR in striatum and thalamus using 125Iα-conotoxinMII in DLB compared to controls (Ray et al., 2004). In addition, the marker 125I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) has been used to assess α4β2 nAChR in DLB, where receptor loss relative to controls was observed in tissues of striatum, entorhinal cortex as well as substantia nigra (Pimlott et al., 2004).

Autopsy studies in DLB are limited in that their examination of receptor distributions has not been explored as yet in the whole brain, while results inevitably indicate changes associated with end stage disease. Information regarding at what stage changes occur, how they progress over time and to what extent they are associated with clinical features requires in vivo imaging studies. Such studies to date have been limited by the non-selectivity of available nAChR ligands, though 11C-nicotine PET has demonstrated abnormalities in AD (Kadir et al., 2006, Nordberg et al., 1995). More recently, a specific ligand for the α4β2 receptor has become available and applied as a SPECT tracer (123I-5IA-85380) in studies of baboons (Musachio et al., 1999), normal humans (Fujita et al., 2002) and those with Parkinson’s disease (Fujita et al., 2006).

A striking feature of previous functional imaging studies in DLB is the consistency with which occipital (Brodmann area (BA) 17–19) and posterior parietal (precuneus, BA7) hypoperfusion and hypometabolism has been observed. Such findings have been linked by some to the presence of visual hallucinations (Imamura et al., 1999, Mori et al., 2006), but this has not been a consistent finding (Lobotesis et al., 2001, Pasquier et al., 2002). Functional abnormalities in occipital cortex remain unclear since structural imaging in this area is normal and the occipital lobe is not a major site of Lewy body pathology, although a recent study has shown the presence of Lewy body pathology in the secondary visual pathway (BA18–19) in DLB (Yamamoto et al., 2006).

In the present study we investigated differences in normalised 123I-5IA-85380 SPECT binding in vivo between DLB and similar aged controls and comparing this to the regional cerebral blood flow (rCBF) pattern obtained from 99mTc-exametazime SPECT scanning. We hypothesised that in DLB relative 123I-5IA-85380 uptake would be reduced in frontal, temporal and striatal regions in accordance with previous neuropathology. Moreover, from previous reports linking muscarinic acetylcholine upregulation in occipital lobe in DLB (Colloby et al., 2006), and the probable connection between muscarinic receptor and visual function due to its localisation in the primary visual cortex (Rodriguez-Puertas et al., 1997, Rossner et al., 1993), we further hypothesised a possible association between cholinergic nicotinic function (123I-5IA-85380 uptake) in occipital lobe and visual hallucinations in DLB.

Section snippets

Subjects

The sample consisted of 31 non-smoking (> 10 years) subjects (15 DLB, 16 normal elderly controls). Patients were obtained from a community-dwelling population of patients who had been referred to geographically based local old age psychiatry services. Normal controls were recruited from among friends and spouses of patients included in this and other research studies. All subjects underwent 123I-5IA-85380 and 99mTc-exametazime SPECT scanning. The study was approved by the local research ethics

Subject characteristics

Table 1 shows demographic characteristics of DLB and controls. Using analysis of variance (ANOVA) for two populations (equivalent to two sample t-test), groups were matched for age (F1,29 = 0.5, p = 0.5), while as expected significant differences were observed between DLB and controls in MMSE (F1,29 = 22.2, p < 0.001), CAMCOG (F1,29 = 31.3, p < 0.001) and UPDRS III (F1,29 = 94.4, p < 0.001) scores. Groups were also matched for sex (χ2 = 1.2, df = 1, p = 0.3). Depression scale used was the depression sub-item score

Discussion

We have examined relative 123I-5IA-85380 uptake, as a measure of the α4β2 receptor, in DLB patients compared to similarly aged controls using in vivo 123I-5IA-85380 SPECT imaging. Significant loss of uptake was found bilaterally in the striatum, left superior temporal gyrus, and right inferior frontal gyrus and cingulate. These results show a different pattern of loss compared to rCBF and appear to be broadly in agreement with previous autopsy evaluations using α4β2 affinity nicotinic receptor

Acknowledgments

We thank the Alzheimer’s Society for financial support. The authors report no conflicts of interest. We thank staff at the Regional Medical Physics Department, Nuclear Medicine Section, Newcastle General Hospital and all members of the clinical research team who helped with patient recruitment.

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