How Brain Atrophy and Delirium Team Up to Accelerate Post-Surgery Cognitive Decline in Older People Without Dementia

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Contributed by Michele Cavallari, MD, PhD, Center for Neurological Imaging, Brigham and Women’s Hospital; Harvard Medical School; and Marcus Institute for Aging Research, Hebrew SeniorLife; Boston, MA.

Rationale and Objective

Postoperative delirium is a common acute confusional state, affecting up to half of older surgical patients [1] and is an established independent risk factor for dementia [2]. We know that people with dementia are more susceptible to delirium, and that delirium can accelerate cognitive decline in these individuals. Importantly, older patients who are cognitively normal before surgery, can also develop postoperative delirium and long-term cognitive decline (LTCD) after surgery [3]. However, the neural substrates of this association are unclear. Neurodegenerative changes associated with pre-clinical dementia are possible contributors.

This blog presents results from the SAGES study, a large NIH-funded project led by Dr. Inouye, aimed at understanding why older adults without dementia at the time of surgery develop postoperative delirium and cognitive decline [4]. Through neuroimaging methods, particularly magnetic resonance imaging (MRI), we assessed brain atrophy to determine whether brain tissue loss is associated with postoperative delirium and cognitive decline.

Brain atrophy, which reflects tissue loss due to neurodegeneration, is often observed in Alzheimer’s disease (AD) and other forms of dementia [5]. Of note, brain atrophy can become apparent before the clinical onset of dementia. Previous studies have demonstrated that the presence of brain atrophy at the time of surgery is linked to higher risks of developing delirium and LTCD [6]. Growing evidence, including our own findings, suggests that this relationship holds true even for surgical patients without preexisting dementia [7].

Our previous findings were based on the analysis of SAGES participants with cognitive assessments over 3 years after surgery and, similar to most of the previous research, a single preoperative MRI scan. In this study, we went further by investigating the relationship between brain atrophy rates from MRI acquired before and one-year after surgery and cognitive performance assessed over 6 years after surgery [8].

Methods and Results

Each patient underwent an MRI prior to surgery and one year after surgery. Delirium occurrence and severity were assessed once a day, for the duration of the hospital stay, starting from the first day after surgery, using the confusion assessment method (CAM) [9], supplemented by a validated chart review method [10]. Cognition was assessed by the general cognitive performance (GCP) score before surgery and at 11 follow-up time points over 6 years after surgery [11].

Among the 117 elective surgery patients included in this analysis (average age 79 years), 29 (25%) experienced postoperative delirium. We used MRI to measure the thickness of the cerebral cortex, the layer of grey matter at the surface of the brain, in two non-overlapping regions – the AD signature and the aging signature. Previous studies validated atrophy measures of those signature regions as indicators of grey matter loss linked to AD pathology and cognitive aging, respectively [12, 13].

In the SAGES cohort [8], the observed annual decrease in cortical thickness was 0.2 mm (1.7% with respect to baseline) for the AD signature (p = 0.09) and 0.4 mm (1.7% with respect to baseline) for the aging signature (p = 0.01). The development of greater atrophy at one year was associated with faster slopes of LTCD over six years after surgery for both the AD signature [beta (95% CI) = 0.24 (0.06–0.42, p < 0.01) points of GCP/mm of cortical thickness] and aging signature [beta (95% CI) = 0.55(0.07–1.03, p = 0.03] points of GCP/mm of cortical thickness.

Contrary to our hypothesis, atrophy rates were not significantly different between participants who experienced postoperative delirium and those who did not. However, we did find a significant interaction with delirium severity in the association between the rate of brain atrophy and LTCD [AD-signature: beta (95% CI) = 0.04 (0.00–0.08), p = 0.04; aging signature: beta (95% CI) = 0.08 (0.03–0.12), p < 0.01]. These findings suggest that the rate of cortical atrophy and the severity of delirium are independent, synergistic factors contributing to postoperative LTCD in older adults.

Conclusions and Future Directions

Our findings carry both cautionary and reassuring implications for older people undergoing elective surgery. The main takeaway is that brain atrophy and postoperative delirium severity are synergistically associated with an increased risk of future cognitive decline in older adults without dementia at the time of surgery. Both the AD signature and the vulnerable aging signature were linked to worse long term cognitive outcomes, suggesting that the mechanisms driving postoperative cognitive decline are multifactorial and involve AD pathology as well as other age-related neurodegenerative processes. Defining the impact of non-AD neuro-degenerative diseases and their associated neuropathological correlates with postoperative outcomes warrants future investigation.

Interestingly, we did not find a significant difference in the rate of brain atrophy over one year between patients who developed delirium and those who did not. The rate of cortical brain atrophy we report is comparable to the rate of cortical grey matter loss due to aging reported in other observational studies. This is an encouraging finding, suggesting that for older people without dementia undergoing the types of elective surgeries we studied (primarily orthopedic), the risk of surgery-related brain injury may be lower than feared. This aligns with our previous results from the SAGES study, where we observed no major incident neuroradiological events, such as strokes, at the one-year follow-up [14]. Although these results are promising, they are preliminary and need to be confirmed by further studies, ideally with non-surgical control groups to better isolate the effects of surgery and delirium.

While MRI is a valuable tool for advancing our understanding of postoperative delirium and cognitive decline, its high cost remains a barrier to routine clinical use. However, advances in technology and increased accessibility to MRI could accelerate the integration of neuroimaging markers into clinical settings. Emerging artificial intelligence technologies have the potential to transform care for surgical patients by automating the detection and quantification of brain changes and ultimately improving the accuracy and speed of risk assessments for postoperative delirium and cognitive decline.

References

  1. Inouye, S.K., 2006. Delirium in older persons. N. Engl. J. Med. 354, 1157–1165. doi.org/10.1056/NEJMra052321.
  2. Inouye, S.K., Marcantonio, E.R., Kosar, C.M., Tommet, D., Schmitt, E.M., Travison, T.G., Saczynski, J.S., Ngo, L.H., Alsop, D.C., Jones, R.N., 2016. The short-term and long-term relationship between delirium and cognitive trajectory in older surgical patients. Alzheimers Dement. 12, 766–775. doi.org/10.1016/j.jalz.2016.03.005.
  3. Kunicki ZJ, Ngo LH, Marcantonio ER, Tommet D, Feng Y, Fong TG, Schmitt EM, Travison TG, Jones RN, Inouye SK, 2023. Six-Year Cognitive Trajectory in Older Adults Following Major Surgery and Delirium. JAMA Intern Med. 183(5):442-450. doi: 10.1001/jamainternmed.2023.0144.
  4. Schmitt, E.M., Marcantonio, E.R., Alsop, D.C., Jones, R.N., Rogers, S.O., Fong, T.G., Metzger, E., Inouye, S.K., 2012. Novel risk markers and long-term outcomes of delirium: the successful aging after elective surgery (SAGES) study design and methods. J. Am. Med. Dir. Assoc. 13 doi.org/10.1016/j.jamda.2012.08.004
  5. Ikram, M.A., Vrooman, H.A., Vernooij, M.W., Heijer, T. den, Hofman, A., Niessen, W.J., van der Lugt, A., Koudstaal, P.J., Breteler, M.M.B., 2010. Brain tissue volumes in relation to cognitive function and risk of dementia. Neurobiol. Aging 31, 378–386. doi.org/10.1016/J.NEUROBIOLAGING.2008.04.008.
  6. Kant, I.M.J., Slooter, A.J.C., Jaarsma-Coes, M., van Montfort, S.J.T., Witkamp, T.D., Pasma, W., Hendrikse, J., de Bresser, J., 2021. Preoperative MRI brain phenotypes are related to postoperative delirium in older individuals. Neurobiol. Aging 101, 247–255. doi.org/10.1016/j.neurobiolaging.2021.01.033.
  7. Racine, A.M., Gou, Y., Fong, T.G., Marcantonio, E.R., Schmitt, E.M., Travison, T.G., Inouye, S.K., Jones, R.N., 2018. Correction for retest effects across repeated measures of cognitive functioning: a longitudinal cohort study of postoperative delirium. BMC Med. Res. Methodol. 18 doi.org/10.1186/S12874-018-0530-X.
  8. Cavallari M, T Touroutoglou A, Katsumi Y, Fong TG, Schmitt E, Travison TG, Shafi MM, Libermann TA, Marcantonio ER, Alsop DC, Jones RN, Inouye SK, Dickerson BC; SAGES study group Relationship between cortical brain atrophy, delirium, and long-term cognitive decline in older surgical patients. Neurobiol Aging. 2024 Aug;140:130-139. doi:10.1016/j.neurobiolaging.2024.05.008. Epub 2024 May 18. PMID: 38788524
  9. Wei, L.A., Fearing, M.A., Sternberg, E.J., Inouye, S.K., 2008. The confusion assessment method: a systematic review of current usage. J. Am. Geriatr. Soc. doi.org/10.1111/j.1532-5415.2008.01674.x
  10. Saczynski JS, Kosar CM, Xu G, Puelle MR, Schmitt E, Jones RN, Marcantonio ER, Wong B, Isaza I, Inouye SK. A Tale of Two Methods: Chart and Interview Methods for Identifying Delirium. J Am Geriatr Soc. 2014; 62: 518-24. PMCID: PMC3959564
  11. Gross, A.L., Jones, R.N., Fong, T.G., Tommet, D., Inouye, S.K., 2014. Calibration and validation of an innovative approach for estimating general cognitive performance. Neuroepidemiology 42, 144–153. doi.org/10.1159/000357647.
  12. Dickerson, B.C., Stoub, T.R., Shah, R.C., Sperling, R.A., Killiany, R.J., Albert, M.S., Hyman, B.T., Blacker, D., Detoledo-Morrell, L., 2011. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 76, 1395–1402. doi.org/10.1212/WNL.0B013E3182166E96.
  13. Bakkour, A., Morris, J.C., Wolk, D.A., Dickerson, B.C., 2013. The effects of aging and Alzheimer’s disease on cerebral cortical anatomy: specificity and differential relationships with cognition. Neuroimage 76, 332–344. doi.org/10.1016/J.NEUROIMAGE.2013.02.059.
  14. Cavallari, M., Dai, W., Guttmann, C.R.G., Meier, D.S., Ngo, L.H., Hshieh, T.T., Fong, T.G., Schmitt, E., Press, D.Z., Travison, T.G., Marcantonio, E.R., Jones, R.N., Inouye, S.K., Alsop, D.C., 2017. Longitudinal diffusion changes following postoperative delirium in older people without dementia. Neurology 89, 1020–1027. doi.org/10.1212/WNL.0000000000004329.

Suggested Citation

Cavallari, Michele. How Brain Atrophy and Delirium Team Up to Accelerate Post-Surgery Cognitive Decline in Older People Without Dementia; November 2024, Available at: https://deliriumnetwork.org/how-brain-atrophy-and-delirium-may-accelerate-post-surgery-cognitive-decline/ (accessed today’s date)

Posted in Delirium Research.

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