Anesthesia Raises

Dementia Risk
Among Elderly Patients

Danu Soesilowati MD Sp.An

 Introduction
With advances development in health care and
increasing quality of life, the population of older
adults is increasing in most countries
Older Adult
Advancing age is the strongest risk factor for the
development of dementia, and dementia has been
identified as a major current health care challenge
In many exposure to anesthesia and surgery could
increase the risk of developing Alzheimer’s
disease (AD). While the exact pathogenesis of AD
remains unknown.
Dementia
Postoperative cognitive dysfunction (POCD),
characterized by the impairment of recent
memory, concentration, language
comprehension. There is a perception that
POCD may increase risk for dementia and
Alzheimer’s disease (AD)
 POCD in humans is generally considered to be a short-lived condition
where normal function returns within days,
while cognitive changes may persist for weeks or longer. It remains unclear whether this decline simply
unmasks the early stages of dementia or if it is a predictor of later dementia

.
Regardless, with clinical features similar to those observed in patients with dementia,
the incidence of long-term postoperative cognitive impairment raises concerns that anesthesia and surgery
may accelerate the onset and progression of dementia.2
 Brain-Aging Process:
From Microscopic Mechanisms to Macroscopic Consequences

The tissue differences between a young and old The mitochondrial dysfunction plays a
brain include the progressive fundamental role that leads to the
immunosenescence with a complement continuous release of proinflammatory
activation; chronic proinflammation with an mediators, resulting loss of the
overexpression of inflammatory proteins and neuroprotective capability of the
multifactorial mitochondrial persistent microglial cells
dysfunction.6,7

The frontier between healthy and pathologically degenerative brain aging seems to consist of the
progressivity and intensity of the complex triple senescent mechanisms, even more so now because
there is evidence between brain cellular injury and cognitive decline after surgery. In addition, whereas
the normal brain-aging process involves more adaptive factors leading to
neuroprotective or neurorestorative mechanisms,
 Patophysiology of Dementia
Definition
Dementia is a syndrome in which there is
01
deterioration in cognitive function (i.e. the
ability to process thought) beyond what
might be expected from normal ageing.
Patophysiology
Dementia is a chronic, progressive decline 02
in brain function. A prominent feature is
memory impairment, but dementia also
involves deterioration of other cognitive,
behavioural and emotional functions.
Diagnose
06
The diagnostic criteria for dementia as the 03
development of cognitive or neuropsychiatric
symptoms that are associated with a decline
in the individual’s previous level of
functioning, cognitive domains
Laboratory
Some biomarker changes can include either
04 decreased levels of amyloid-beta (Aβ),
together with increased total tau or
phosphorylated tau in the cerebrospinal fluid
(CSF) of the individual.
Anesthetic
05 An in vitro study showed that the
volatile anesthetics halothane and
isoflurane increase oligomerization
and cytotoxicity of amyloid
peptides.
Plaques
One of the features of AD is ‘plaques’ (clumps of
proteins) that form in the brain. Recent studies have
found that some anaesthetic drugs increase the rate at
which plaques form in brain cells in animal
experiments.
Scheme of how anesthesia causes AD

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 INHALATIONAL ANESTHESIA
The two most important
histological features of
AD are :
• Formation of extracellular amyloid plaques, composed
predominantly of Aβ, and intraneuronal neurofibrillary
tangles (NFT), composed of aberrantly
• Hyperphosphorylated tau proteins assembled into
paired helical filaments (PHF)

ISOFLURANE

An in vitro study demonstrated that isoflurane promotes the oligomerization of Aβ and increases its toxicity A
combination of inhaled anesthetics and hypoxia may activate caspases and induce apoptosis, increasing the
overall level of amyloid proteins.
Xie et al reported that exposure to 2% isoflurane for 6 h induces apoptosis, alters the processing of APP and
leads to an increased production of Aβ peptides in H4 human neuroglioma cells stably transfected to express
human wild-type full-length APP (H4-APP cells)
 SEVOFLURANE
Sevoflurane induces identical cellular and histological effects to isoflurane.

Exposure to 4.1% sevoflurane for 6 h induces apoptosis, alters APP processing and
increases the production of Aβ in H4-APP human neuroglioma cells..
Previous in vivo studies exposed naïve mice to 2.5% sevoflurane for 2 h and observed
increased levels of activated caspases, BACE and Aβ aggregates in the brain at 6, 12,
and 24 h following anesthesia (76).
Also, a combination of 2.1–3% sevoflurane and 60% oxygen for either 2 or 6 h
successfully induced caspase activation and apoptosis, altered APP processing, and
increased the levels of Aβ in the brains of 6-day-old mice

The mechanism of inhalation anesthesia induced neuronal injury includes neuroinflammation, cytosolic calcium
overload with apoptotic pathway activation followed by neuronal death, ROS with resultant mitochondrial damage,
and overexpression of Ab42 oligomer proteins in hippocampal neurons in aged rat
 GA Effects on Dementia Alzheimer
General Anesthesia could theoretically also contribute to cognitive deficits by altering central cholinergic transmission through
nicotinic and muscarinic receptors.

A decrease in acetylcholine
neurotransmission facilitates some of the
desired effects of GA, including analgesia,
amnesia, immobility, and hypnosis.

The present review has summarized previous findings

Some anesthetics inhibit N-methyl-D- on the effects of the commonly used inhaled
aspartate (NMDA) receptors, leading to anesthetics, isoflurane, sevoflurane and desflurane, on
decreased glutamate release and a the accumulation of Aβ peptides, tau
subsequent decrease in excitatory activity. hyperphosphorylation and other AD-like pathologies, in
vitro and in vivo.

It is clear that isoflurane, sevoflurane can induce pro-

However, prolonged exposure to NMDA antagonists,
such as ketamine, may upregulate NMDA receptors
following sustained blockade, which, on removal of drug,
leads to excitotoxicity and apoptosis via an increase in
calcium influx
apoptotic signaling, including caspase activation, and
cause aberrant APP processing, increased synthesis and
accumulation of Aβ, and hyperphosphorylaiton of tau in
cell lines, primary neurons and in vivo in the brain
 Perioperative Hemodynamics and Postoperative Cognitive Decline

• Proper and stable hemodynamics is essential
to maintaining proper cerebral perfusion.
• Intraoperative hypotension (SBP < 80mmHg
or less than 30% of baseline) is associated
with POD and POCD during noncardiac
surgery in elderly patients
• Cerebral autoregulation is a key defense
mechanism of the brain against
hypoperfusion and hyperperfusion.
• Impairment of cerebral autoregulation
may lead to MAP falling outside the
limits of cerebral autoregulation
• Factors affecting cerebral autoregulation
include age, coexisting diseases, and other
factors during the perioperative period.
• Cerebral autoregulatory dysfunction,
endothelial impairment, also contribute to
cognitive impairment and dementia
Anesthetic Neurotoxicity and Postoperative Cognitive Decline
Inhaled Anesthesia
Including isoflurane, sevoflurane, and desflurane may predispose aged rats to
dose-dependent cognitive impairment. Inhalation anesthesia with isoflurane
may induce overexpression of Ab42 oligomer proteins and formation of Ab
plaques in the hippocampus of aged rats at 3 and 7 days following exposure

Intravenous Anesthesia
Propofol causes developmental neurotoxicity in multiple models.
Ketamine may decrease POCD incidence for 1 week following cardiac
surgery via its antiinflammatory effects.12 Furthermore, a subanesthetic
ketamine dose may also attenuate the occurrence of POD and improve
other neurological and psychiatric outcomes

Neurotoxicity
The mechanism of inhalation anesthesia induced neuronal injury includes
neuroinflammation, cytosolic calcium overload with apoptotic pathway
activation followed by neuronal death, in aged rats.
In addition, prolonged isoflurane exposure and repeated exposures to
sevoflurane could result in dose-dependent impairment of spatial task
acquisition in aged rats.12
 Different anesthetic techniques
effects in the risk of
Alzheimer Dementia

• Most reviews indicated that there was limited evidence to suggest any
difference between GA and regional anesthesia for the risk of POCD

• Absence of further evidence to suggest any difference between GA and

regional anesthesia on the incidence of POCD can be explained by the
use of intravenous sedation with regional anesthesia that may increase
the risk and negate the difference

• Mason et al. in their systematic review with meta analysis compared the
influence of general, regional, or combination anesthesia on the
development of POCD and postoperative delirium (POD). They found an
increase in the incidence of POCD but not POD with GA.

• Vanderweyde et al. compared effects of GA and local anesthesia on the

risk of developing AD in patients undergoing either prostate or hernia
surgery. Exposure to GA did not increase the risk of AD, and interestingly
it was associated with a reduced risk of AD when compared to local
anesthesia.
 Different anesthetic techniques effects
in the risk of Alzheimer Dementia

• GA could theoretically also contribute to cognitive deficits by altering

central cholinergic transmission through nicotinic and muscarinic
receptors.
• A decrease in acetylcholine neurotransmission facilitates some of
the desired effects of GA, including analgesia, amnesia, immobility,
and hypnosis

• The inhalation anesthetic isoflurane has been shown to induce

caspase activation and increase Aβ accumulation, which are
associated with the key pathological pathways in AD.
• In contrast, propofol has been reported to have neuroprotective
effects. Zhang et al. compared the effects of isoflurane and propofol
individually and in combination on Aβ oligomerization in vitro and in
vivo.
• Isoflurane alone induced Aβ42 oligomerization, whereas propofol
inhibited the isoflurane-mediated oligomerization of Aβ42
 Different anesthetic techniques effects
in the risk of Alzheimer Dementia

• Other studies investigated the type of postoperative cognitive

decline after total knee arthroplasty (TKA)

• Neuropsychological testing was conducted and the changes in

cerebrospinal fluid (CSF) biomarkers after surgery were evaluated.
Fifteen patients who required bilateral TKA at a 1-week interval
under spinal anesthesia were included.

• Neuropsychological tests were performed twice, concentrations of

CSF amyloid peptide, tau protein, and S100B were measured twice
during spinal anesthesia at a 1-week interval.

• The results suggest that only frontal-executive function declined 1

week after TKA under spinal anesthesia. The CSF biomarker
analysis indicated that TKA under regional anesthesia might not
cause neuronal damage
How to prevent post operative cognitive
dysfunction and dementia
Dexmedetomidine
There are two theories to explain the decreased rates of delirium associated with
sedation of dexmedetomidine: The first theory is based on the intrinsic delirium-
sparing property determined by multiple characteristics of dexmedetomidine. Since
GABA, the primary inhibitory neurotransmitter in the central nervous system seems
to play a key role in the pathogenesis of delirium

COX-2 Inhibitors
Parecoxib was shown to decrease pro-inflammatory markers and POCD
incidence (as assessed using a neurocognitive battery) compared to placebo at 1
week, but not 3 months following. Similarly, a trial of 178 elderly patients showed
that celecoxib reduced pro-inflammatory markers and POCD (determined by
reduction in performance of ≥ 2 of 5 cognitive tests) at 1 week following surgery
compared to placebo

Dexamethasone
As with other steroid hormones, dexamethasone inhibits the infiltration of
leukocytes into the target inflammatory region moreover, it can
downregulate the transcription of cytokines and other cell adhesion
molecules. Although dexamethasone has well-demonstrated anti
inflammatory actions, it is unclear whether it may have an effect on the
development of POCD.
How to prevent post operative cognitive
dysfunction and dementia
N-Acetylcysteine
N-acetylcysteine (NAC) has antioxidant properties which are related to its role as a
precursor for glutathione synthesis. Additionally, in pre-clinical studies, NAC has
been shown to downregulate pro-inflammatory cytokine synthesis including HGMB-
1, upregulate anti-inflammatory cytokine synthesis, and reduce microglial activation.
NAC supplementation can have beneficial cognitive effects for patients with a wide
variety of neurological and psychiatric disorders, including Alzheimer’s

Amantadine
Further, amantadine inhibited surgery induced neuroinflammation on
postoperative day 1. In humans, there is only one randomized clinical trial in the
recruitment phase investigating the use of a 5-day course of amantadine
(beginning with one dose preoperatively) on POCD.22

Statins
Inhibits enzyme that catalyzes the conversion of HMG-CoA to mevalonate, and
is the rate-limiting step of cholesterol synthesis from fatty acids. Statins have
been widely proposed to be beneficial for neurological disorders including
dementia and postoperative delirium.In POCD, a small randomized controlled
trial comparing postoperative statin vs. placebo administration in patients
undergoing on-pump CABG showed a significant reduction in memory
dysfunction (measured by postgraduate institute memory scale) on
postoperative day.
CONCLUSION
There was some research compared patients having a general
anaesthetic with patients having a regional (local anaesthetic)
for the same operation.
These studies have shown that the number of patients who
develop POCD is similar for both types of anaesthetic, but that
delirium may be less common after a regional anaesthetic.

Other studies have looked at different methods of general

anaesthesia, using inhaled versus intravenous anaesthetic
drugs for example, and have shown no difference in the
incidence of POCD.
At present the precise causes of POCD and post-operative
delirium are unknown, and it is likely that there are multiple
causes

Some drugs such as dexmedetomidine, COX-2 inhibitors,

dexamethasone, statins, n-acetylsisteine, amantadine could
reduce post operative cognitive dysfunction incidence but
further studies are needed to confirm
Thank You