Delirium appears to act independently of the pathologic processes of classic dementia — and “multiplicatively” — in driving cognitive decline, according to findings from a novel neuropathological study combining data from three population-based cohorts. Delirium has been shown to be a strong predictor of both new-onset dementia and the acceleration of existing cognitive decline, but it has been unclear whether delirium accounts for additional or interrelated pathologic injury, said Daniel H. J. Davis, PhD, of the University College London, and his coinvestigators with the Epidemiological Clinicopathological Studies in Europe Collaborative (JAMA Psychiatry 2017;74:244–51). To better understand the pathologic mechanisms for delirium and dementia and their association with cognitive decline, the research team harmonized patient-level data from three large community-based cohorts — the Cognitive Function and Aging Study, the Cambridge City Over-75s Cohort, and the Vantaa 85+ study. Specifically, they looked at the 987 participants of these cohort studies who were brain donors and had neuropathologic evaluations in addition to repeated Mini-Mental State Examinations (MMSE), detailed dementia evaluations, and either patient interviews or corroborated patient history that revealed whether the patient had ever or never had delirium symptoms. The researchers quantified the trajectories of MMSE change in the 6 years before death in relation to delirium, dementia pathologic burden, and both delirium and pathologic burden. Among the findings: •Neocortical amyloid plaques, vascular pathologic findings, or Lewy bodies (classic dementia pathologic variables) were not significantly different in individuals with and without a history of delirium.•Delirium (in 279 of the 987 individuals) was associated with a mean 2.8-point lower MMSE score 6 years before death.•For the typical 90-year-old with no delirium and no pathologic burden, the mean rate of decline in MMSE scores was 0.35 points per year.•Those with delirium had an additional rate of decline of 0.37 MMSE points/year.•Those showing the pathologic processes of dementia at death had an additional rate of decline of 0.39 MMSE points/year.•Those with both delirium and a high dementia pathologic burden had the greatest decline, with an additional −0.16 MMSE points/year. In total, their estimated rate of decline was 1.27 MMSE points/year (−0.35 base rate, −0.37 points attributable to delirium, −0.39 points attributable to the pathologic burden, and −0.16 points attributable to the interaction). “Delirium in the presence of dementia-related neuropathologic processes was associated with cognitive decline beyond that expected for delirium or the neuropathologic process itself,” the investigators wrote. This means that “delirium may be independently associated with [additional unmeasured] pathologic processes that drive cognitive decline.” In an editorial about the study, Tamara G. Fong, MD, PhD, of the Institute for Aging Research at Harvard Medical School, and two colleagues at Harvard and at Brown University, said that the “substantial sample size, length of follow-up, and availability of neuropathologic data in this study are unprecedented in the field of delirium research.” The “important and novel finding,” they said, “is that the effect of delirium on mental status differences at baseline (6 years before death) and the pace of mental status decline is independent of neuropathologic findings [at death],” they wrote (JAMA Psychiatry 2017;74:212–3). Moreover, they said, the research “highlights that cognitive decline after delirium is not simply acceleration of underlying dementia pathologic processes; rather, there is a synergistic effect of delirium and dementia on the rate of cognitive decline.” This knowledge lays an “important foundation” for research aimed at identifying preventable factors that lead to neuronal injury in delirium and strategies to target such factors, the editorial says, [JAMA Psychiatry doi:10.1001/jamapsychiatry.2016.3812]. That delirium was retrospectively ascertained and by slightly different methods in the three cohort studies is a limitation of their analysis, Davis and colleagues wrote. Moreover, delirium severity, frequency, timing and other related factors were unknown. Neuropathologic assessments in the cohort studies were performed with the investigators masked to clinical data. Moving forward, the study investigators wrote, it will be important to understand whether various dimensions of the “delirium syndrome” — such as duration, severity or cause — have greater effects on cognitive trajectories than others. Christine Kilgore is a freelance writer in Falls Church, VA.
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Nov 4, 2024
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