Hospitalizations, Critical Illness Linked to Dementia-Related Brain Changes

Deborah Brauser

October 24, 2018

Hospitalization, especially the number of stays, critical illness, and major infection are all significantly linked to altered brain structures commonly associated with Alzheimer's disease (AD), new imaging research suggests.

Dr Keenan Walker

A prospective cohort study of more than 1600 adult participants showed that all-cause hospitalization was significantly associated with greater white matter hyperintensity (WMH) volume 24 years later. It was also linked to lower white matter microstructural integrity, as shown in lower fractional anisotropy (FA) and higher mean diffusivity volumes.

In addition, there was a dose-dependent relationship between number of hospital stays and greater WMH volume, lower total and regional brain volumes, and lower white matter integrity.

Critical illness and major infection among the hospitalized participants were also significantly linked to smaller volumes in the "AD signature region" ― brain regions commonly vulnerable to AD, such as the hippocampus.

"Our finding that just being hospitalized itself was associated with some changes in the brain's white matter was probably the most surprising," lead author Keenan A. Walker, PhD, postdoctoral fellow in the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

"You don't really think of noncritical hospitalization for nonneurological events as having an effect on the brain structure," said Walker.

"Another surprise was the size of the relationship between major infection and critical illness and brain structure. We found that having one of these was actually equal to having one of the major risks for Alzheimer's disease, in terms of its contribution to structural brain changes," he added.

The findings were published online recently in the Journal of the American Geriatrics Society.

Possible Mechanism

"Accumulating evidence suggests that acute illness may play a significant and previously unrecognized role in promoting or accelerating neurodegenerative disease in older adults," write the investigators.

Although cognitive dysfunction and dementia have been associated before with prior hospital stays, acute infection, and critical illness, "the mechanism for these associations is poorly understood," they add.

"One hypothesis is that events associated with hospitalization may initiate or exacerbate pathophysiological processes that underlie structural neurodegenerative changes, increasing the risk of cognitive and functional decline and, ultimately, dementia," the researchers write.

They previously published results from the Atherosclerosis Risk in Communities (ARIC) study showing that cognitive decline and large ventricular size were linked to hospitalization over an 11-year period.

Since that time, "an older and significantly larger group of participants" returned for 3-Tesla brain MRIs as part of the ARIC Neurocognitive Study.

For the current analysis, the investigators assessed 1689 of these participants (aged 44 to 66 years at study baseline; mean age, 52.7 years; 60% women), who underwent MRIs "to quantify" brain volumes, as measured using diffusion tensor imaging. The mean age at MRI was 76 years, and all were followed through annual telephone calls and surveillance of local hospitals over a 24-year period.

"AD signature region was derived by calculating the combined volumes of the parahippocampal gyrus, entorhinal cortex, inferior parietal lobules, hippocampus, and precuneus," the investigators report.

Of the participants, 1214 (72%) had at least one hospitalization during the follow-up period, and 14% had a major infection, defined as septicemia, bacterial infection, or pneumonia.

In addition, 4% had had a critical illness, defined as one of the following: acute respiratory failure, hypotension, shock, severe sepsis, cardiopulmonary resuscitation, respiratory or cardiac arrest, or prolonged ventilation. Also, 5% met criteria for a diagnosis of dementia.

Effect Greater Than Genetic Risk

Results showed that all-cause hospitalization vs no hospitalization was significantly associated with the following:

  • Greater WMH volume (standard deviation [SD], 0.12; 95% confidence interval [CI], 0.00 - 0.24; P = .05);

  • Lower FA (SD, -0.17; 95% CI, -0.27 to -0.06; P = .003); and

  • Greater mean diffusivity (SD, 0.16; 95% CI, 0.07 to -0.25; P < .001).

Number of hospital stays was also associated with smaller total brain volume (P trend = .002), smaller AD signature region volume (P trend = .048), lower white matter microstructural integrity (P trend < .001), and greater WMH volume (P trend = .018).

"Although significantly lower WM integrity was observed in individuals with 2 to 3 hospitalizations, significantly smaller brain volumes were detectable only in participants with 4 to 5 hospitalizations," the researchers report.

Among the hospitalized patients, for those with major infection, AD signature region volumes were 2% smaller (SD, -1.28 cm3; 95% CI, -2.21 to -0.35; P = 007) and ventricular volumes were 10% larger (SD, 3.79 cm3; 95% CI, 0.81 - 6.77; P = .01); whereas critical illness was significantly linked only to smaller AD signature region volumes (3% smaller volumes; SD, -1.64 cm3; 95% CI, -3.16 to -0.12; P = .03).

In addition, "the magnitude of the effect of critical illness on AD signature region volume was more than twice that of a single APOE Ɛ4 allele," write the investigators. The effect of hospitalized infection on this type of volume was about 1.5 that of a single APOE Ɛ4 allele.

"Whereas all-cause hospitalization was primarily associated with lower white matter integrity, critical illness and major infection were associated with smaller brain volume, particularly within regions implicated in AD," summarize the researchers.

"Our findings were observed after adjusting for demographic and physiological variables, medical comorbidity, and APOE genotype and remained after participants with dementia were excluded," they add.

Supports Anecdotal Evidence

Walker said in a press release that the study was not designed to determine cause and effect. He noted that limitations include its observational design, the possibility of undetected or misclassified billing codes, and a lack of data on possible comorbidities, such as delirium.

Still, he said that the findings do indicate strong associations.

"In order to maintain brain health in older adulthood, it is important to maintain bodywide health. Some of the events that can land you in the hospital may serve as risk factors for dementia," he said.

He told Medscape Medical News that the take-home message is that the current imaging findings support previous anecdotal findings.

"It's been seen that some people who are middle aged or older who go to the hospital or are hospitalized for pneumonia or have a critical illness like sepsis seem to be not the same afterwards. They're more forgetful or they have trouble getting back to work in the same capacity," Walker said.

"Our findings add validity to what people have been noticing in terms of how these events, which seem nonneurological, can actually have a pretty sizable impact on brain structure," he said. "It may also support the idea that these events may actually promote Alzheimer's-related pathology."

In addition, the results suggest that, "especially in older adults with these illnesses, we should focus on monitoring their brain health and assessing them for potential cognitive deficits that can have negative impacts on their lives," Walker concluded.

The study was funded by the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Centers for Research Resources, and the National Center for Advancing Translational Sciences. Dr Walker has reported no relevant financial relationships. A full list of disclosures for the other study authors are in the original article.

J Am Geriatr Soc. Published online September 24, 2018. Abstract

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