Elsevier

Consciousness and Cognition

Volume 11, Issue 3, September 2002, Pages 461-474
Consciousness and Cognition

Disturbances of consciousness in dementia with Lewy bodies associated with alteration in nicotinic receptor binding in the temporal cortex

https://doi.org/10.1016/S1053-8100(02)00013-2Get rights and content

Abstract

Disturbances of consciousness, including fluctuations in attention and awareness, are a common and clinically important symptom in dementia with Lewy bodies (DLB). In the present study we investigate potential mechanisms of such disturbances of consciousness (DOC) in a clinicopathological study evaluating specific components of the cholinergic system. [3H]Epibatidine binding to the high-affinity nicotinic receptor in the temporal cortex (Brodmann’s areas 20 and 36) differentiated DLB cases with and without DOC, being 62–66% higher in those with DOC (F=4.5,p=.025). The were no differences between DLB patients with or without DOC in 125I-labeled α-bungaratoxin binding to the low-affinity nicotinic receptor, [3H]pirenzepine binding to the muscarinic M1 receptor, or in choline acetyltransferase activity. These findings provide support for the hypothesis that cholinergic activity is an important neural correlate if consciousness and suggest a mechanism of DOC in DLB involving alterations in the nicotinic receptor, composed of predominantly α4 and β2 subunits.

Introduction

Dementia is a disabling and distressing disorder which affects 5% of the population over the age 65 and 20% of those over 80 (Cummings & Benson, 1992), with substantial emotional (Pearlin, Mullen, Semple, & Skaff, 1990) and financial cost (Gray & Fann, 1993). The two most common forms of degenerative dementia are Alzheimer’s disease (AD), which constitutes more than 50% of cases, and dementia with Lewy bodies (DLB), accounting for up to a further 20% (Cummings & Benson, 1992; McKeith et al., 1996).

The concept that patients suffering from degenerative dementia commonly experience marked impairments of consciousness, associated with fluctuating cognition, has become increasingly evident from detailed case reports and clinical experience. The terminology in this area is variable, with overlapping concepts such as disturbances of consciousness, reduced cortical arousal, impaired consciousness, and fluctuating levels of consciousness used to describe this phenomenon; the term disturbances of consciousness (DOC) is employed in the current article (fluctuation is implicit within the concept). Prevalence rates of 80–90% (Byrne, Lennox, Lowe, & Godwin-Austen, 1989; McKeith et al., 1996) have been reported in DLB, unrelated to any underlying medical cause, while 20–25% of AD cases also appear to experience episodes of DOC (Kolbeinsson & Jonsson, 1993).

The consensus criteria for the operationalized clinical diagnosis of DLB (McKeith et al., 1996) describe these episodes as related to “pronounced variations in attention and alertness.” Byrne et al. (1989) described DOC associated with fluctuations in the level of cognitive performance in 12 DLB patients. One DLB sufferer had day-to-day changes of more than 50% on the Mini-Mental State Examination (MMSE), while another patient experienced confusional episodes that were so catastrophic, she varied from being mute, confused, and unable to stand without assistance to being capable of holding a conversation. In another investigation of DLB cases examined by Gibb and colleagues (Gibb, Esiri, & Lees, 1987) one patient was observed to have episodes of stupor with closed eyes, being difficult to rouse, while on other occasions appeared alert and responsive to commands.

The assessment of DOC in dementia has largely relied on expert clinical judgment and a semistandardized scale has been developed (Walker et al., 2000a). Previously, poor interrater reliability has been a major problem although recently, excellent concurrent validity between these semistandardized clinical assessments and both measures of fluctuating attention (measured by evaluating variability in vigilance, simple reaction time, and choice reaction time tasks) and fluctuating delta rhythm on EEG (Walker et al., 2000a, Walker et al., 2000b) has been established. The validation of the clinical assessment method has facilitated cliniconeurochemical studies from a prospectively assessed case register cohort of patients with DLB assessed serially to postmortem.

Cholinergic neurotransmission in the cerebral cortex is severely impaired in DLB, more so than in Alzheimer’s disease (Perry et al., 1994). Acetylcholine has specifically been implicated in the process of conscious awareness (Woolf, 1997; Perry, Walker, Grace, & Perry, 1999). Woolf (1997) has suggested that the cholinergic muscarinic receptor stimulates integrative mechanisms promoted by activation of microtubule associated protein kinase. Perry et al. (1999) reviewed evidence for both muscarinic and nicotinic receptor mechanisms based on the actions of general anesthetics and other drugs affecting consciousness.

Kaufer, Catt, Lopez, and DeKosky (1998) reported two DLB cases who experienced marked remission in DOC with cholinergic therapy (treatment with the cholinesterase inhibitor donepezil). Supporting this observation, in preliminary reports from a double blind placebo controlled trial in which 102 patients were randomized to treatment with the cholinesterase inhibitor rivastigmine or placebo for 20 weeks, at the end of the treatment period patients receiving the cholinesterase inhibitor had significantly less fluctuating confusion on an informant rated diary (McKeith, Del Ser, Anand, Cicin-Sain, & Spiegel, 2000) and significantly less fluctuation in attentional performance (Ballard, McKeith, & Ayre, 2000a), both symptoms closely associated with DOC (Walker et al., 2000a, Walker et al., 2000b).

Disturbances in cholinergic transmission in DLB provide the basis for investigating a potential underlying mechanism of DOC and may also facilitate understanding of neurotransmitter systems involved in normal conscious awareness. In the current study we examined the relationship between DOC and temporal cortical cholinergic parameters [choline acetyltransferase activity (ChAT)], nicotinic receptors (nAChRs), and the M1 muscarinic receptor (mAChRs) in prospectively assessed DLB patients coming to autopsy.

Section snippets

Cases

The study was fully approved by the local human subjects ethical committees. Among a case register cohort of 420 patients, incorporating all clinical referrals of people with dementia to specific geographical catchment areas in Newcastle (Institute for the Health of the Elderly, n=340) and London (Institute of Psychiatry, n=80), 24 consecutive patients who had been assigned a neuropathological diagnosis of DLB at autopsy were studied. Sixteen (67%) were female; the mean age at assessment was 78

Results

Patients with DOC had significantly higher [3H]epibatidine binding in the two areas of temporal neocortex (Brodmann’s areas 20 and 36) compared with patients without DOC (F=4.5,p=.025; Table 3). Autoradiographs illustrating these differences are shown in Fig. 1. Although fewer cases were available for examination, 2- to 2.5-fold differences in [3H]epibatidine binding were also seen in the entorhinal cortex and hippocampal formation between patients with and without DOC (Table 3). [3

Discussion

In this study a prospectively assessed clinical cohort was followed to postmortem to examine potential associations between muscarinic and nicotinic receptor binding and DOC in neuropathologically confirmed DLB cases. The study design has a number of strengths, in particular the use of a validated assessment for DOC at regular intervals until death.

The current findings indicate a selective difference in nicotinic receptor binding in DLB patients associated with DOC. [3H]Epibatidine binding,

Conclusion

The results from this prospective clinicopathological investigation implicate cholinergic mechanisms in DOC, identifying the relative preservation of α4-/β2-containing nicotinic receptors in the temporal cortex and hippocampal formation as a potentially important correlate. These findings may have treatment implications and highlight the need to evaluate DOC as a key outcome parameter in intervention trials with cholinergic therapies. The findings may also focus mechanistic studies on more

Acknowledgements

This study was supported by a Medical Research Council Program Grant.

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