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Delirium is associated with cognitive decline and subsequent dementia, and rises in plasma total Tau (tTau) and neurofilament light (NfL), providing links to Amyloid-Tau-Neurodegeneration (ATN) pathophysiology. We investigated whether changes in delirium severity after surgery correlated with changes in cerebrospinal fluid (CSF) ATN biomarkers. Thirty-two thoracic vascular surgical patients were recruited into a prospective biomarker cohort study with assessment of delirium severity and incidence (NCT02926417). CSF (n = 54) and plasma (n = 118) samples were sent for biomarker analysis for tTau, phosphorylated tau-181 (pTau) (plasma n = 53), NfL, and amyloid-β 42/40 ratio (Ab42/40-ratio). The primary outcome was the correlation of preoperative to postoperative change in ATN biomarkers with the highest postoperative Delirium Rating Scale-98 score. CSF and plasma biomarkers all increased postoperatively (all P < .05, n = 13 paired preoperative-postoperative samples). Delirium severity was associated with peak changes in CSF tTau (P = .007, r = 0.710) and pTau (P = .01, r = 0.667) but not NfL (P = .09, rho = 0.491) or Ab42/40-ratio (P = 0.18, rho = 0.394). Sensitivity analysis with exclusion of subjects with putative spinal cord ischaemia shifted the NfL result to significance (P < .001, rho = .847). Our data show that changes in tau and biomarkers of neurodegeneration in the CSF are associated with delirium severity. These data should be considered hypothesis generating and future studies should identify if these changes are robust to confounding.

Altered predictive coding may underlie the reduced auditory mismatch negativity amplitude observed in patients with dementia. We hypothesized that accumulating dementia-associated pathologies, including amyloid and tau, lead to disturbed predictions of our sensory environment. This would manifest as increased reliance on “observed” sensory information with an associated increase in feedforward, and decrease in feedback, signaling. To test this hypothesis, we studied a cross-sectional cohort of participants who underwent positron emission tomography imaging and high-density EEG during an odd-ball paradigm, and used dynamic casual modeling and Bayesian statistics to make inferences about the neuronal architectures (generators) and mechanisms (effective connectivity) underlying the observed auditory evoked responses. Amyloid-β imaging with [C-11] Pittsburgh Compound-B PET were qualitatively rated using established criteria. Tau-positive PET scans, with [F-18]MK6240, were defined by a MK-6240 standardized uptake value ratio positivity threshold at two standard deviations above the mean of the Amyloid(−) group in the entorhinal cortex (entorhinal MK-6240 SUVR > 1.27). The cross-sectional cohort included a total of 56 participants (9 and 13 participants in the Tau(+) and Amyloid(+) subgroups, respectively: age interquartile range of [73.50 - 75.34] and [70.5–75.34] years, 56% and 69% females, respectively; 46 and 43 participants in the Tau(-) and Amyloid(-) subgroups, respectively: age interquartile range of [62.72–72.5] and [62.64–72.48] years, 67% and 65% females, respectively). Mismatch negativity amplitudes were significantly smaller in Tau+ subgroup than Tau- subgroup (cluster statistics corrected for multiple comparisons: p = 0.028). Dynamic causal modelling showed that tau pathology was associated with increased feedforward connectivity and decreased feedback connectivity, with increased excitability of superior temporal gyrus but not inferior frontal regions. This effect on superior temporal gyrus was consistent with the distribution of tau disease on PET in these participants, indicating that the observed differences in mismatch negativity reflect pathological changes evolving in preclinical dementia. Exclusion of participants with diagnosed mild cognitive impairment or dementia did not affect the results. These observational data provide proof of concept that abnormalities in predictive coding may be detected in the preclinical phase of Alzheimer’s disease. This framework also provides a construct to understand how progressive impairments lead to loss of orientation to the sensory world in dementia. Based on our modeling results, plus animal models indicating that Alzheimer’s disease pathologies produce hyperexcitability of higher cortical regions through local disinhibition, mismatch negativity might be a useful monitor to deploy as strategies that target interneuron dysfunction are developed.

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Electroencephalography signatures of amyloid-β (Aβ), tau, and neurodegenerative pathologies would aid in screening for, tracking progression of, and critically, understanding the pathogenesis of dementia. We hypothesized that slowing of the alpha peak frequency, as a signature of hyperpolarization-activated cyclic nucleotide gated “pacemaker” channel activity, would correlate with amyloid and tau pathology burden measured by amyloid (Pittsburgh Compound B) and tau (MK-6240) PET or CSF biomarkers. We also hypothesized that EEG power would be associated with neurodegeneration (CSF neurofilament light and hippocampal volume). Wakeful high-density EEG data were collected from 53 subjects. Both amyloid-β and tau pathology were associated with slowing in the alpha peak frequency [Pittsburgh Compound B (+) vs. Pittsburgh Compound B (-) subjects, p = 0.039 and MK-6240(+) vs. MK-6240(-) subjects, p = 0.019]. Furthermore, slowing in the peak alpha frequency correlated with CSF Aβ42/40 ratio (r2=0.270; p = 0.003), phosphoTau (pTau181, r2=0.290; p = 0.001) and pTau181/Aβ42 (r2=0.343; p < 0.001). Alpha peak frequency was not associated with neurodegeneration. Higher CSF neurofilament light was associated with lower total EEG power (r2=0.136; p = 0.018), theta power (r2=0.148; p = 0.014) and beta power (r2=0.216; p = 0.002); the latter was also associated with normalized hippocampal volume (r2=0.196; p = 0.002). Amyloid-tau and neurodegenerative pathologies are associated with distinct electrophysiological signatures that may be useful as mechanistic tools and diagnostic/treatment effect biomarkers in clinical trials.