Disturbances of consciousness in dementia with Lewy bodies associated with alteration in nicotinic receptor binding in the temporal cortex
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 (; 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.
References (47)
The fall and rise of neuronal α-bungarotoxin binding proteins
Trends in Pharmacological Science
(1992)Comments to session on electrophysiological aspects of cholinergic mechanisms
Progress in Brain Research
(1993)- et al.
Convergent artichortical cholinergic activities in ageing and Alzheimer’s disease
Neurobiology of Ageing
(1992) - et al.
Acetylcholine in mind: A neurotransmitter correlate of consciousness
Trends in Neuroscience
(1999) - et al.
A clinically & pathologically distinct form of Lewy body dementia in the elderly
Journal of Neurological Science
(1990) - et al.
Nicotine receptors are located on lateral geniculate nucleus terminals in cat visual cortex
Brain Research
(1987) - et al.
Location of nicotinic and muscarinic cholinergic and mu-opiate receptors in rat cerebral neocortex: Evidence from thalamic and cortical lesions
Brain Research
(1992) - et al.
Immunohisto- and cytochemical localization of cortical nicotinic cholinoceptors in rat and man
Brain Research
(1989) - et al.
Immunohistochemical localization of nicotinic β 2 and α 4 receptor subunits in normal human brain and in individuals with Lewy body and Alzheimer’s disease: Preliminary observations
Neuroscience Lettters
(1998) A possible role for cholinergic neurons of the basal forebrain and pontomesencephalon in consciousness
Consciousness and Cognition
(1997)