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

1. Alzheimer's disease and anaesthesia: implications for the central cholinergic system Br J Anaesth 2006; 97: 445-52 R4 정준영

2. Alzheimer’s disease • Common form of dementia • Characterized by • Cortex amygdale and hippocampus 로 innervation 하는 basal forebrain cholinergic neurons 의 degeneration • Difficulty in maintaining and sustaining attention • Profound cognitive impairment (loss of memory and learning ability) • Four different forms • Delirium, delusions, depressed mood and uncomplicated. • The course of the disease • Fluctuant, and cognitive impairment, personality change, psychotic symptoms, incontinence, gait and motor disturbance, seizures and myoclonus • Increases mortality of the population affected, by up to 40%

3. Increasing longevity • Increase in the number of patients with AD • Prevalence • Increases markedly after the age of 65 • General anaesthetic agents, and several drugs administered during anaesthesia • Interact with the central cholinergic system • Degenerative diseases of the brain • Associated with deficits in the cholinergic system

4. AD and central cholinergic system • All regions of the cerebral cortex receive intense cholinergic innervation. • High cognitive functions • strictly related to molecular events • The cholinergic hypothesis of memory dysfunction in the elderly : Based on two central notions. • Wide variety of cognitive processes (particularly those involved in learning and memory)를 forebrain cholinergic system 이 담당 • The age-related cognitive deficit는 이러한 forebrain cholinergic system 의 functional integrity 의 감소에 의함

5. Cognitive functions과 central cholinergic system 과의 연관성에 대한 animal and human research • Acute or chronic treatment with nicotine or nicotinic agonists improves memory performance of rats • Nicotinic antagonists 가 memory and learning 을 감소시킬 수 있다 • Epidemiological studies on patients who smoke • Nicotine 이 cognitive processes, 집중력 향상, verbal and non-verbal information 의 습득에 도움 • Relationship between AD and the central cholinergic system • AD pts에서 cholinergic neurotransmission 과 cognitive function 저하가 동반됨

6. Cognitive impairments • Cortical cholinergic transmission 의 감소와 cerebral blood flow (CBF) 의 perfusion deficit 의 결과로 발생 • CBF • Nicotinic acetylcholine receptors (nAChRs) neurotransmission으로 조절됨 • Decrease → white matter lesions (WML) • frequent in both Alzheimer's and ischemic disease. • The degeneration of cholinergic neurons • Earlier, pathological events in AD, • Involves the structures of the basal forebrain cholinergic system (BFCS) . • The BFCS : nucleus basalis of Meynert (NBM), the horizontal and vertical diagonal bands of Broca (HDBB and VDBB) and the medial septal (MS) nucleus.

7. In AD pts. the brain demonstrates the following features: • Extracellular beta-amyloid (beta-A) peptide-containing plaques, intracellular neurofibrillary tangles, astrocytic gliosis, reactive microglia and inflammation, and neuronal and synaptic losses • Beta-A • Derives from an amyloid precursor protein (APP) by proteolytic cleavage • Bind nAChRs and cause neuronal damage by different mechanisms • Acetylcholine 의 합성과 분비를 억제 • Inhibiting pyruvate deydrogenase(that generates Acetyl-CoA from pyruvate), and glucose uptake. • Cholinergic neurotransmission 과 Ach의 neuromodulatory effect를 방해 • Soluble form of beta-A ↑ : predictor of synaptic degeneration in AD pts • Insoluble beta-A : related to cognitive impairment

8. Cholinergic pathway: receptor, topography, functions • Cholinergic receptors • Nicotinic (nAChRs) and muscarinic (mAChRs) receptors • nAChRs • Ligand-gated cation channels • 11 genes encode for neuronal nAChRs subunits, • 8 of these genes encode for alpha subunits (α2-α9); 3 non-alpha genes encode for beta units (β2-β4). • composed generally of two alpha and three beta subunits. • agonist binding in the specific site → change their conformation and open the inner pore, permitting cations to flow. • Peripheral and central nervous system 모두에서 발현됨 • The neuromuscular junction이 주된 peripherical location이나 ganglionic cells 과 non-neuronal cell에도 존재 • α4β2 and α7 receptor subtypes : 가장 잘 밝혀짐 • α7 receptor subtypes are presynaptic, while α4β2 are both presynaptic and postsynaptic

9. mAChRs • Ligand-gated K+ channels with a metabotropic function. • Classified into five different subtypes (M1-M5), • M1, M3 and M5 subtypes • Postsynaptic receptors • Coupled with a G-protein alpha subunit (11/q) • Generates diacylglycerol and inositol 1,4,5-triphosphate (IP3) • M2 and M4 subtypes • Presynaptic receptors • Autoreceptors both in cholinergic and in dopaminergic neurons • Coupled with the G-protein alpha • Inhibits the adenylate cyclase • Stimulates the phospholipase C and the inward rectifying K current. • Receptor binding by agonists causes the activation of several cytoplasmatic and nuclear factors

11. Anaesthesia, anaesthetic agents and the central cholinergic system • The cholinergic system • One of the most important modulatory neurotransmitter systems in the brain • Conscious awareness의 주 요소인 selective attention을 조절 • ACh • One of the main neurotransmitters • High cognitive functions (memory, learning, dendrite arborization, neuronal development and differentiation) 을 조절 • Psychopharmacological and pathological evidence • Supports the concept of a ‘cholinergic component’ of conscious awareness. • Brain mediation of anaesthesia is still not clear • Sensitivity of cholinergic receptors to anaesthetic drugs • Various stages of narcosis (e.g. amnesia, inattentiveness, hypnosis)에 주된 영향

12. During general anaesthesia • Decrease in ACh release and depression of cholinergic transmission → General anaesthetics의 all the desirable effects (such as loss of consciousness, pain, voluntary movements and memory)유발 • The main effect of anaesthetic agents on nAChRs is inhibitory • 마취중 투여되는 대부분의 약제는 nicotinic and muscarinic receptor 모두에 작용 • The volatile anaesthetics • desflurane, isoflurane and sevoflurane • 용량 의존성으로 both nicotinic and muscarinic receptors 에 bind • Barbiturates • Strong competitive antagonists of mAChRs • propofol • 임상 용량 이상의 농도에서만 nAChRs and mAChRs 에 작용

13. The opioids • morphine and fentanyl : block mAChRs and nAChRs • Remifentanil : do not interfere with ACh release • Atracurium and laudanosine(atracurium and cisatracurium metabolite) • Activate α4β2 nAChRs during and for several hours after general anaesthesia • AChRs에 작용해 central cholinergic transmission을 억제하는 마취약제들이 postoperative cognitive dysfunction and delirium 을 유발 할 수 있다 • Neuronal transmission이 저하된 AD pts에서 마취약제를 선택하는데 문제가 될 수 있다

14. Anaesthesia and development of AD: is there a relationship? • The risk of AD and exposure to anaesthesia : no association • The risk of AD and the number of surgical operations : no association • Multiple exposures to GA do NOT increase the risk of AD • Inhalation anaesthesia • Dementia와 같은 neurodegenerative disorders 와 관련 • Associated with long-term cognitive problems • May enhance beta-A oligomerization rates • Propofol • Inhibits oligomerization at low concentrations • Enhances beta-A toxicity at very high concentrations • The incidence of postoperative cognitive dysfunction (POCD) • Increased after cardiac surgery

15. Genetic factor • Apolipoprotein E (APOE)

16. Clinical aspects related to anaesthetic management • Elderly patients require a careful evaluation of their physical and mental status. • Careful mental status evaluation 이 필수 • Dementia 나 mild cognitive impairments (MCI) 발생 가능 • Systemic impairments (e.g. cardiovascular, pulmonary, renal, endocrine and metabolic) 가 많다. • Chronic disease, smoking, alcohol and environmental toxins • Patients affected by AD or MCI • Careful management 를 요함 • Preoperative progression of disease and postoperative care and support를 고려 • 투여 약제의 pharmacokinetic and pharmacodynamic change의 가능성과 unfavourable drug interactions 을 주의

17. Conclusions • Involvement of anaesthesia in the development of AD • Controversal • Drugs given during anaesthesia • Interfere with cholinergic function in the brain • Neurotoxic effects of several anesthetics • Inhaled anaesthetics • enhance peptide oligomerization and cytotoxicity of AD-associated peptides • Propofol • inhibits oligomerization at low concentrations • enhances only at very high concentrations • does not enhance beta-A toxicity

18. Difficulties to draw any conclusions • anaesthesia is not administered as a sole procedure • Surgical stress may accelerate development of clinical signs and symptoms of AD • New clinical and experimental evidence is required to help anaesthetists make the best choice of anaesthetics for the patient with AD