Critical Illness Clinical Trial
Official title:
Perioperative Research Into Memory GENomics in the Intensive Therapy Unit: Alzheimer's (PRIMoGenITA): The Genomics of Cognitive Impairment After Admission to a Burns Intensive Care Unit
The current central dogma of long-term cognitive impairment after intensive care admission
suggests an underlying neuroinflammatory dysregulation affecting neuronal function. This
pathological process has not been fully elucidated and there has been little research into
its genetic associations.
Alzheimer's disease (AD) causes cognitive impairment through a process of abnormal beta
amyloid deposition and neuronal death through localised activation of the innate immune
system. It is the most prevalent disease affecting cognition. The Apolipoprotein E (APOE)
gene is implicated in the progression of late-onset Alzheimer's disease and is a recognised
neuroinflammatory modulator. It is possible that young individuals exposed to high levels of
inflammation may experience an acceleration of this process. This study sets out to look for
an association between APOE-∈4 possession and poor cognitive outcome after a major burn
injury and intensive care admission.
Long-lasting post-operative cognitive dysfunction (POCD) is now a well-recognised
complication of surgery, anaesthesia and critical care. It has been shown that cognitive
impairment in critical care survivors can be worse than cohorts diagnosed with Mild Cognitive
Impairment and approaching those suffered moderate Traumatic Brain Injury. POCD most
significantly impacts upon the elderly, comorbid and those with pre-existing cognitive
impairment, and has a socially and psychologically significant impact on quality of life.
The current central dogma suggests an underlying neuroinflammatory dysregulation affecting
neuronal function. However, the underlying pathological processes have not yet been fully
elucidated. Although some risk factors have been recognised we cannot accurately predict
outcome, suggesting other unidentified determinants. The discovery of further risk factors
would allow new insights into the underlying mechanism, and open up future avenues of
investigation and potential interventions.
Thus far, little work has been performed looking into the impact of genomics on cognitive
outcome after critical care. There are an estimated 20,000 protein coding genes in the human
genome. Such large numbers of whole exome sequence variables necessitate using either an
extremely large population or testing a small number of candidate genes. Critical Care
research is hampered by small population sizes, ruling out whole genome analysis. The ideal
candidate gene would be a known modulator of neuroinflammation, synthesised in the central
nervous system (or able to traverse the blood-brain barrier) and have a known association
with cognitive impairment. In terms of feasibility it should have relatively high incidence
allele proportions, and be modifiable for in order to test any association for causality.
The most common gene associated with cognitive impairment is APOE, which codes for
apolipoprotein E (ApoE). There are three common alleles of the APOE gene: APOE-∈2, APOE-∈3
and APOE-∈4. Possession of an APOE-∈4 allele increases the risk of developing late-onset
Alzheimer's Disease. ApoE demonstrates immunomodulatory properties both systemically and in
the central nervous system. It is secreted by astrocytes and oligodendrocytes after brain
injury and is implicated in the cholesterol distribution necessary for membrane growth after
axonal injury. ApoE-deficient murine glial cultures express more nitric oxide (NO) and Tissue
Necrosis Factor α (TNFα) after simulated injury (LPS / closed head injury) than wild-type
cells. Incubating the deficient glial cultures in recombinant apoE suppresses the TNF-α
expression. This suppression occurred to a much greater extent with recombinant apoE-∈3 and
apoE-∈2 than with apoE-∈4. Finally, microglia treated with secreted amyloid precursor protein
α (sAPP-α, a secreted derivative of β amyloid precursor protein (β-APP)) will produce higher
levels of activation markers and enhance the production of neurotoxins. This effect can be
blocked by prior incubation apoE3, but not with apoE4. Administration of peripheral ApoE
mimetic peptide (a truncated protein able to traverse the blood brain barrier) suppresses
systemic and brain Il-6 and TNFα levels. Lastly, ApoE isoforms also have different affects on
cholinergic neuron destruction, through increased synthesis and reduced elimination of
amyloid beta.
Critical care patients typically experience systemic inflammation secondary to sepsis,
surgery or trauma, or a combination of the three. Central nervous system (CNS) ApoE mRNA
expression is upregulated in wild-type mice exposed to repeated restraint stress. As such, it
is possible that APOE genotype may influence cognitive outcome through mediation of the
neuroinflammatory response. The APOE-∈4 allele is known to increase the risk of POD after
surgery and to increase the duration of delirium in the intensive care unit (ITU). The
presence and duration of post-operative delirium (POD) are recognised predictors of long-term
cognitive impairment (LTCI). Neither the incidence of delirium nor LTCI according to APOE
genotype have been investigated in critical care patients.
More recently, burns intensive care (BICU) survivors have also been shown to develop LTCI
following discharge with an associated reduction in quality of life.
The incidence of cognitive impairment amongst severe burns patients is comparable to ARDS
cohorts, but in a younger and less comorbid group. Patients with severe burns develop large
magnitude systemic inflammatory reactions secondary to their injury. This is perpetuated by
multiple surgeries and a high incidence of nosocomial infections. This cohort provides a
unique group of relatively young individuals with comparable injuries and minimal pre-morbid
comorbidity or cognitive impairment. As such, they represent a less varied population than
general adult ITUs. It is also unusual to find evidence of AD, vascular dementia or
Parkinson's dementia in younger age brackets. This reduces the confounding factors that
typically impede critical care clinical research and any association between APOE-∈4 and ITU
LTCI may therefore infer a common pathological process.
We hypothesise that severe burn patients who possess an APOE ε4 allele are more susceptible
to long term cognitive impairment following their injuries, and that this will impact
significantly on their quality of life.
With this study we aim to: assess neurocognitive function following a severe burn; more
specifically processing speed, executive function, working memory, immediate recall and
delayed recall; assess our sample population APOE genotype; and investigate the association
between APOE genotype and cognitive function.
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