Loss of IQ in the ICU brain injury without the insult

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Summary

Critically ill patients are at high risk of developing serious neurological dysfunctions including delirium and long-term neurocognitive impairment. Here a novel mechanism is proposed for this highly deleterious condition. A growing body of evidence has shown that critical illness and its treatment can lead to de novo cerebral atrophy including white and grey matter abnormalities, delirium, and neurocognitive decline.

In healthy individuals, normal and consistent connectivity between the posterior parietal cortex (PPC), medial temporal lobe (MTL) and prefrontal cortex (PFC) maintains consciousness and normal cognitive functioning. The circuit is innervated, activated and maintained by the ascending reticular activating system (ARAS) arising from the brainstem. As elderly individuals begin to show signs of grey matter atrophy in the PPC, MTL and PFC, functional connectivity between these regions remains intact; however, the strength of the connections is no longer robust as it once was in the healthy CNS. This circuit continues to be activated and maintained via the ARAS. Individuals treated in the ICU are subject to a number of medical and pharmacological challenges which may disrupt normal CNS connectivity. Serious illnesses such as sepsis, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI), as well as sedative and analgesic medications commonly prescribed in the ICU have the potential to disrupt the functional link in the circuit described above. Minor fluctuations in the ARAS (i.e. hyper or hypo activation) may be sufficient in elderly individuals to cause a disruption which surpasses the critical threshold of functional connectivity necessary to maintain normal (i.e. non-delirious) consciousness. In combination with exposure to other ICU related threats to neurocognitive function, prolonged decoupling of this circuit may lead to deleterious neurodegenerative consequences such as excitotoxicity. Over time this has the potential to result in apoptosis and long-term cognitive impairment. Delirium appears to be a good candidate for the causal mechanism of ICU related cognitive decline and may be a critical point of intervention.

Introduction

Increasingly, the quality of one’s life has become the coin of trade compared to survival alone [1]. Recent evidence suggests that critical illness may pose a significant risk for long-term declines in cognitive functioning and has the potential to severely impact the quality and independence of one’s life. Accumulating data has linked critical illness to significant losses in cognitive ability (including loss of IQ), which unfortunately appear in many cases to be permanent [2], [3], [4], [5], [6], [7], [8], [9], [10]. Although the total number of hospital beds has been reduced in the United States over the last 15 years, the number of critical care beds has increased by 26% with the majority of this increase accounted for by the elderly [11]. With the burgeoning number of older individuals in the current population, and the high percentage of elderly admitted to the ICU, this public health issue has become of vital importance. Unfortunately, it is only in the last decade that researchers and clinicians have begun to document the neurocognitive decline associated with this vulnerable population, despite neurologic dysfunction having been studied extensively for other conditions such as coronary artery bypass grafting (CABG) [12]. Other lines of evidence suggest that CNS degradation is not only linked to cognitive loss and declines in quality of life, but is also an independent predictor of mortality in the ICU [13].

Although the exact mechanism or mechanisms by which ICU-related neurological degradation occur remain under investigation, it appears likely that the development of delirium, i.e. an acute cerebral dysfunction, is a major precursor to post-ICU cognitive decline. Recent advances in the study of Alzheimer’s disease (AD) offer a potential new lens from which to conceptualize ICU-related cognitive deficits. In a series of studies, Buckner and colleagues employed multi-modal neuroimaging techniques to examine neuro-molecular (amyloid protean plaque formation) signatures of Alzheimer’s disease [14]. They then observed that plaque formation overlapped with metabolic changes (hypoactivation) and grey matter atrophy in the medial temporal/hippocampal region (MTL), posterior parietal cortex (PPC) and dorsal prefrontal cortex (PFC). Not surprisingly, grey matter degradation in these regions was also observed to correlate with functional blood oxygen level dependent (BOLD) declines in activation for these known mnemonic regions, while engaged in memory tasks. These regions are anatomically and functionally connected [15], [16] and are hypothesized to be critical for maintaining a normal and clear sensorium [16], [17], [18], [19].

Other evidence suggests that the brain’s primary arousal mechanism, the ascending reticular activating system (ARAS) may also play an important role in the modulation of delirium [20]. Excitatory projections originating in the myelencephalon innervate the midbrain and cortex directly and are hypothesized to be critically involved in general attention [20], [21]. As many anesthetic and sedative agents are believed to act on the brainstem, it is possible that perturbation of the ARAS may lead to fluctuating arousal, sensorium, attention and executive functioning ability [9]. Excitatory myelencephalic afferents may therefore be involved in maintaining an equilibrium between top down regulation via cortical structures and bottom up arousal levels originating in the brainstem (see Fig. 1). For older individuals, transient interference in either or both areas could have the potential for major neurocognitive disruption. Gross longitudinal changes in brain physiology are known to impact metabolic cellular mechanisms [14], [22], [23]. If such changes persist for a sufficient length of time, either hyper or hypo metabolic modifications could lead to apoptosis and neuronal degradation. Once again, patients with prior CNS deterioration or insults may be particularly at risk for the hypothesized mechanism depicted in Fig. 1.

Section snippets

Hypothesis

In healthy individuals there is normal and consistent connectivity between the PPC, MTL and PFC [16], [17], [18], [19] (see Fig. 1). This circuit is innervated, activated and maintained by the ARAS arising from the brainstem via the thalamus [14], [20]. As elderly individuals begin to show signs of grey matter atrophy in these regions, functional connectivity remains intact [20]; however, the strength of the connections is no longer as robust as it once was in the healthy CNS [16], [17], [18],

Evaluation of the hypothesis

This hypothesis could be tested using fMRI to examine functional connectivity between the MTL, PPC and PFC in elderly individuals with and without the APOE-ε4 genotype [32]. If this hypothesis is correct, those possessing the genetic risk of the APOE-ε4 should show a relative lower strength of functional connectivity between the three regions of interest compared to controls without the APOE-ε4 genotype. For this design, investigators would also need to document that other anatomically

Consequences of the hypothesis

If these hypotheses are true it would suggest several alternative modes of practice in ICU settings. For example, pharmacologic regimes could be optimized to minimize the perturbation of the ARAS for individuals at risk for the development of ICU delirium (e.g. avoiding the administration of benzodiazepines). If time permitted, individuals could also be screened to determine whether or not they possess the genetic risk of APOE-ε4 and could be administered alternative agents in order to help

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