03 Feb 2017

Delirium may seem relatively harmless when it’s an elderly patient who temporarily blanks on who or where they are after an acute trauma, but it is not. Delirium can accelerate ongoing dementia. It can also independently precipitate cognitive decline, according to one of the most comprehensive studies of delirium and dementia to date. In the January 18 JAMA Psychiatry, scientists led by Daniel Davis and Carol Brayne, University of Cambridge, U.K., report that delirium contributes to cognitive decline independently of Aβ, tau, Lewy bodies, or vascular disease. But combined with any of these pathologies, delirium can quadruple the rate of memory loss. “I did not know the interaction was that strong,” said Malaz Boustani of the Sandra Eskenazi Center for Brain Care Innovation in Indianapolis. “It’s like going from 10 mph to 40.” Boustani was not involved in the research.

Davis told Alzforum that the findings are a call to take delirium more seriously. “Until recently, we thought of it as an inconvenient side effect of being ill,” he told Alzforum. “This research suggests that repeated episodes hasten the underlying trajectory of neurodegeneration.”

A quarter of the geriatric patients Davis treats develop delirium, and some are never cognitively the same, he said. Delirium hastens cognitive decline in patients who have Alzheimer’s disease and increases the risk for dementia in older people who become delirious after surgery (May 2009 news; Wacker et al., 2006). But whether delirium worsens neurodegenerative pathology that’s already in the brain, or causes decline through a separate process, or both, was not clear.

To find out, Davis turned to postmortem pathology. He examined samples from almost 1,000 brains donated through three epidemiological studies, two in the U.K. and one in Finland. Each collected data on health, delirious episodes, and scores on the mini-mental state examination (MMSE) in people from the general population. They also included neuropathological findings at autopsy. Davis pored over the available medical records and participant interviews for evidence of self- or physician-reported delirium starting six years before death. He divvied up the sample by whether a person ever had an episode of delirium, and then further by those had either no/mild or moderate/severe amyloid plaques, tau tangles, vascular pathology, or Lewy bodies.

Davis found that people with delirium or pathology declined by a further 0.37 and 0.39 points, respectively, on the MMSE than controls. In people with both delirium and pathology, the score dropped by 0.92 more than controls, or 0.16 points more than dementia and delirium combined. That suggested delirium and pathology interacted to accelerate decline even further.

What processes underlie delirium? It’s not clear, said Davis. However, Willem van Gool of the University of Amsterdam, Netherlands, said the results fit well with a hypothesis he put forward seven years ago with Piet Eikelenboom, Vrije University, Amsterdam. He postulated that delirium is caused by neuroinflammation, degeneration of cholinergic neurons in the brain, or a mix of both (van Gool et al., 2010). “This study does not confirm the hypothesis, but the findings are consistent,” he told Alzforum. Davis agreed, proposing that neurodegeneration could prime microglia, which then cause an inflammatory storm in the brain with a systemic infection or injury. He plans to analyze brain and cerebrospinal fluid samples from these patients to see if inflammatory or other markers correlate with delirium.

“The substantial sample size, length of follow-up, and availability of neuropathologic data in this study are unprecedented,” wrote Tamara Fong, Beth Israel Deaconess Medical Center, Boston, and colleagues in an accompanying editorial. While the analysis obscures the impact of the different types of pathology, few studies on delirium have included neuropathology, leaving shared pathologic mechanisms unknown. “This is why studies such as this one are critical,” they wrote.

Boustani said this study had tremendous health implications. “This creates an amazing impetus for public health agents to focus on delirium prevention as a way to reduce the negative burden on brain health.” Almost half of cases are preventable by simple, inexpensive methods, ensuring people get optimal sleep, pain medication, fluids, and exercise in the hospital, he said (Hshieh et al., 2015). 

“We knew that people with delirium were at greater risk of cognitive decline and dementia, but we knew less about the mechanism,” said Donna Fick of Penn State University, University Park. Incorporating neuropathological assessments allowed the authors to untangle an independent contribution of delirium, she said. Although the authors acknowledge that the studies retrospectively measured delirium and that collection methods differed among the three cohorts, she contended that the authors skillfully analyzed the available data, and that makes for a strong study.

Davis will now prospectively track 2,000 people, collecting high-resolution data on the duration, severity, and causes of delirium that he can then relate to long-term outcomes. “We may be able to understand more about the critical points in the progression of dementia, and that may provide a platform for future intervention,” he said.—Gwyneth Dickey Zakaib 

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References

News Citations

1. Research Brief: Delirium Hastens Cognitive Decline in Alzheimer Disease 11 May 2009

Paper Citations

1. Wacker P, Nunes PV, Cabrita H, Forlenza OV. Post-operative delirium is associated with poor cognitive outcome and dementia. Dement Geriatr Cogn Disord. 2006;21(4):221-7. PubMed.
2. Van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet. 2010 Feb 27;375(9716):773-5. PubMed.
3. Hshieh TT, Yue J, Oh E, Puelle M, Dowal S, Travison T, Inouye SK. Effectiveness of multicomponent nonpharmacological delirium interventions: a meta-analysis. JAMA Intern Med. 2015 Apr;175(4):512-20. PubMed.

Further Reading

News

1. Inhaling Alzheimer’s? Hazy Picture Links Anesthesia, AD 31 Jul 2009
2. Anesthesia and Cognitive Decline: No Link in Longitudinal Study 25 Nov 2009
3. Norepinephrine Fuels Microglial Migration, Aβ Phagocytosis 19 Mar 2010
4. Barcelona: Inflammation—That Two-Faced Beast 19 Apr 2011