Alzheimer’s disease and anaesthesia : implications for the central cholinergic system

1. Alzheimer’s disease and anaesthesia :implications for the central cholinergic system British Journal of Anaesthesia 2006;97:445-52 R4 김용일

2. Alzheimer’s disease (AD) • Common form of dementia • Degeneration of basal forebrain cholinergic neurons • Difficulty in maintaining & sustaining attention • Cognitive impairment • Loss of memory, learning ability • Prevalence increses markedly after the age of 65 • Anaesthetists will encounter many patients with AD • General anaesthetic agents & several drugs can interact with the central cholinergic system

3. AD and central cholinergic system • In AD, reduced activity of cholinergic projections to the hippocampus and cortex • Cholinergic hypothesis of memory dysfunction • Forebrain cholinergic systems sustain cognitive process – learning & memory • Decline in the functional integrity  Age-related cognitive deficits • In AD - good correlation between anatomical, biochemical changes and mental test scores • Neuroanatomical and neurochemical systems also degenerated • Difficult to establish a specific relationship

4. AD and central cholinergic system-continued • Cognitive impairments are consequence both of • Marked reduction in cortical cholinergic transmission • Perfusion deficit of cerebral blood flow (CBF) • Nicotinic acetylcholine receptors(nAChRs) – modulate CBF • Decreased CBF causes white matter lesions (WML) • Frequent in both AD & ischemic disease • Reactive astrogliosis & activation of microglia cells • Key source of cytokines, proteases, nitrogen intermediates

5. AD and central cholinergic system-continued • Basal forebrain cholinergic system (BFCS) • Nucleus basalis of Meynert • Horizontal & vertical diagonal bands of Broca • Medial septal nucleus  cholinergic innervations of limbic &cortical brain layers

6. AD and central cholinergic system-continued • BFCS impairments are related to several structural and functional changes • Cholinergicdysfunction  impaired trophic support • Trophic properties of ACh is essential to • Neuronal morphology • Survival promotion in response to neurotoxic changes • Features of brain with AD • Extracellular beta-amyloid(beta-A) peptide-containing plaques • Intracellular neurofibrillary tangles • Astrocyticgliosis • Reactive microglia & inflammation • Neuronal & synaptic losses Interrelationship is poorly understood

7. AD and central cholinergic system-continued • Beta-A may bind nAChRs, cause neuronal damage • Memory impairment may explained by • Ca2+ release • Chronic activation of cellular cascade of extracellular signal-regulated kinase (ERK2) • Derangement of ERK2-MAPK signalling • (MAPK : mitogen-activated protein kinases) • Beta-A interferes cholinergic neurotransmission & neuromodulatory effect of ACh •  Negatively regulates synthesis & release of Ach • Increase in soluble form of beta-A • Predictor of synaptic degeneration in AD • Insoluble beta-A : related to cognitive impairment

8. Cholinergic pathway: receptor, topography, functions • Cholinergic receptors divided into nicotinic (nAChRs) & muscarinic (mAChRs) • nAChRs • Family of ligand-gated cation channels : GABA-A, 5-HT3, glycine receptors • Subunit : 8 genes encode for alpha, 3 genes for beta subunits • Expressed in PNS & CNS • Wide, but non-uniform distribution in brain • Important for central cholinergic neurotransmission • Fast synaptic transmission • Axo-axonic transmission • Modulation of membrane potentials • Regulation of release of excitatory & inhibitory transmitters • ACh, dopamine, GABA, glutamate, norepinephrine, serotonine

9. Cholinergic pathway: receptor, topography, functions- continued • mAChRs • 5 subtypes • M1, M3, M5 – postsynaptic receptors • Second messengers • Increase Ca2+ concentrations • Activate protein kinase C, mitogen-activated protein kinases (MAPKs) pathway, phospholipase A2 & D • M2, M4 – presynaptic receptors • Autoreceptors in cholinergic & dopaminergic neurons • Activation of several cytoplasmatic & nuclear factors • Specific tyrosine kinases • Focal adhesion kinase • MAPK • Extracellular signal-regulated kinases (ERKs) • C-Jun N-terminal kinases (JNKs)

10. Cholinergic pathway: receptor, topography, functions- continued • High cognitive functions strictly related to (memory, learning, neuronal rearrangement & evolution) • Long-term potentiation of neurons • Long-term depression of neurons • Synaptic plasticity of neurons • Maintenance & differentiation of neurons

11. Anaesthesia, anaesthetic agents and the central cholinergic system • ACh regulateshigh cognitive functions • Memory, learning, dendrite arborization, neuronal development & differentiation • ‘cholinergic component’ of conscious awareness • Brain mediation of anaesthesia is still not clear • Sensitivity of cholinergic receptors •  determining various stages of narcosis • (amnesia, inattentiveness, hypnosis) • During general anaesthesia • Decrease in Ach release & depression of cholinergic transmission •  loss of consciousness, pain, voluntary movements & memory • Effects on brain function via binding mAChRs & nAChRs • Nicotinic receptor – involved in mechanism of action of general anaesthetic agents • main effect on nAChRs : inhibitory

12. Anaesthesia, anaestheticagentsand the central cholinergic system- continued • Most of anaesthetic drugs interact with both nicotinic & muscarinic receptors • Volatile anaesthetics : bind both in dose-related manner • Barbiturates : strong competitive antagonists of mAChRs • Propofol : only at high concentration than in clinical use • Acts on mAChRs & nAChRs • Opioids : may block mAChRs & nAChRs • Remifentanil does not interfere with Ach release • Atracurium, metabolite of atracurium & cisatracurium • laudanosine • Activate α4β2 nAChRs • During and for several hours after general anaesthesia • Neuroprotective effects • Patients with AD – compromised neuronal transmission • Particular problems in the choice of anaesthetic drugs • May have different effects on postoperative outcome

13. Anaesthesia and development of AD :is there a relationship? • In a retrospective study • No association between the risk of AD & exposure to anaesthesia in 1 & 5 yr • By Eckenhoff and colleagues • Inhalation anaesthesia • may be implicated in neurodegenerative disorders – dementia • Associated with long-term cognitive problems • Enhance beta-A oligomerization rates • Propofol • Low conc. : inhibits oligomerization • Very high conc. : enhances beta-A toxicity • By Palotas and colleagues • Thiopental & propofol considered safe • Do not facilitate APP (amyloid precursor protein) production • Postoperative cognitive dysfunction – controversial • Increased after cardiac surgery • By Bohnen and colleagues • Anaesthesia– contribute to development of AD • Identify a cumulative exposure to general & spinal anaesthesia before the age of 50 • But did not find a correlation after 50 yr • Possible relationship of exposure at an earlier age

14. Anaesthesia and development of AD :is there a relationship?- continued • Apolipoprotein E • Major genetic susceptibility locus for common forms of AD • 3 common polymorphisms • Epsilon 2 : lowers the risk, increases the age of onset • Epsilon 3, 4 : increases the risk, lowers the age of onset • Associated with • Risk of AD • Recovery of psychological parameters after general cardiac anaesthesia • Possibility that anticholinergic properties of anaesthesia drugs • Alter cellular balance • Facilitating cognitive decline • More studies are required on • Exposure to anaesthesia, predisposing individual factors and development of AD

15. Clinical aspects related to anaesthetic management • Older patient are incresing • Careful evaluation of their physical & mental status • More systemic impairments • Cardiovascular, pulmonary, renal, endocrine & metabolic • Chronic disease, smoking, alcohol & environmental toxins

16. Clinical aspects related to anaestheticmanagement-continued • Patients affected by AD or mild cognitive impairments • Careful management • Informed consent • Relatives should be consulted • Preop. progression of disease • Postop. Care & support • Unfavourable drug interactions • Donepezil - cholinesterase inhibitor • Antagonize atracurium • Galantamine – symptomatic treatment of AD • Used to reverse neuromuscular paralysis induced by tubocurarine-like neuromuscular blocking agents • Tacrine – anticholinesterase (used to manage AD) • In chronic use : resistance to D-tubocurarine • d/t down-regulation of postsynaptic ACh receptors

17. Conclusions • Despite doubts about involvement of anaesthesia in development of AD • Anaesthetic drugs interfere with cholinergic function in brain • Neurotoxic effects of several anaesthetic agents • Inhaled anaesthetic • Enhance peptide oligomerization & cytotoxicity of AD-associated peptides • Further evaluation required • Interaction between neurodegenerative disorders & inhalation anaesthesia • Propofol • Inhibits oligomerization at low conc. • Enhances only at very high conc. • Does not enhance beta-A toxicity • Surgical stress – may accelerate development of AD • Very difficult to draw any conclusions • Anaesthetic agents to be used or avoided in AD  new clinical & experimental evidence is required