The pathophysiology of<unk>  is still not well understood, despite extensive research. Animal models The lack of animal models that are relevant to<unk>  has left many key questions in<unk>  pathophysiology unanswered. Earliest rodent models of<unk>  used atropine (a muscarinic acetylcholine receptor blocker) to induce cognitive and electroencephalography (EEG) changes similar to<unk> , and other anticholinergic drugs, such as biperiden and hyoscine, have produced similar effects. Along with clinical studies using various drugs with anticholinergic activity, these models have contributed to a "cholinergic deficiency hypothesis" of<unk> . Profound systemic inflammation occurring during sepsis is also known to cause<unk>  (often termed sepsis-associated encephalopathy). Animal models used to study the interactions between prior degenerative disease and overlying systemic inflammation have shown that even mild systemic inflammation causes acute and transient deficits in working memory among diseased animals. Prior dementia or age-associated cognitive impairment is the primary predisposing factor for clinical<unk>  and "prior pathology" as defined by these new animal models may consist of synaptic loss, abnormal network connectivity, and "primed microglia" brain macrophages stimulated by prior neurodegenerative disease and aging to amplify subsequent inflammatory responses in the central nervous system (CNS). Cerebrospinal fluid Studies of cerebrospinal fluid (CSF) in<unk>  are difficult to perform. Apart from the general difficulty of recruiting participants who are often unable to give consent, the inherently invasive nature of CSF sampling makes such research particularly challenging. However, a few studies have exploited the opportunity to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery. A 2018 systematic review showed that, broadly,<unk>  may be associated with neurotransmitter imbalance (namely serotonin and dopamine signaling), reversible fall in somatostatin, and increased cortisol. The leading "neuroinflammatory hypothesis" (where neurodegenerative disease and aging leads the brain to respond to peripheral inflammation with an exaggerated CNS inflammatory response) has been described, but current evidence is still conflicting and fails to concretely support this hypothesis. Neuroimaging Neuroimaging provides an important avenue to explore the mechanisms that are responsible for<unk> . Despite progress in the development of magnetic resonance imaging (MRI), the large variety in imaging-based findings has limited our understanding of the changes in the brain that may be linked to<unk> . Some challenges associated with imaging people diagnosed with<unk>  include participant recruitment and inadequate consideration of important confounding factors such as history of dementia and/or depression, which are known to be associated with overlapping changes in the brain also observed on MRI. Evidence for changes in structural and functional markers include: changes in white-matter integrity (white matter lesions), decreases in brain volume (likely as a result of tissue atrophy), abnormal functional connectivity of brain regions responsible for normal processing of executive function, sensory processing, attention, emotional regulation, memory, and orientation, differences in autoregulation of the vascular vessels in the brain, reduction in cerebral blood flow and possible changes in brain metabolism (including cerebral tissue oxygenation and glucose hypometabolism). Altogether, these changes in MRI-based measurements invite further investigation of the mechanisms that may underlie<unk> , as a potential avenue to improve clinical management of people suffering with this condition. Neurophysiology Electroencephalography (EEG) allows for continuous capture of global brain function and brain connectivity, and is useful in understanding real-time physiologic changes during<unk> . Since the 1950s,<unk>  has been known to be associated with slowing of resting-state EEG rhythms, with abnormally decreased background alpha power and increased theta and delta frequency activity. From such evidence, a 2018 systematic review proposed a conceptual model that<unk>  results when insults/stressors trigger a breakdown of brain network dynamics in individuals with low brain resilience (i.e. people who already have underlying problems of low neural connectivity and/or low neuroplasticity like those with Alzheimer's disease). Neuropathology Only a handful of studies exist where there has been an attempt to correlate<unk>  with pathological findings at autopsy. One research study has been reported on 7 patients who died during ICU admission. Each case was admitted with a range of primary pathologies, but all had acute respiratory distress syndrome and/or septic shock contributing to the<unk> , 6 showed evidence of low brain perfusion and diffuse vascular injury, and 5 showed hippocampal involvement. A case-control study showed that 9<unk>  cases showed higher expression of HLA-DR and CD68 (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of astrocyte activity) than age-matched controls; this supports a neuroinflammatory cause to<unk> , but the conclusions are limited by methodological issues. A 2017 retrospective study correlating autopsy data with MMSE scores from 987 brain donors found that<unk>  combined with a pathological process of dementia accelerated MMSE score decline more than either individual process.
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