Dementia-Related Brain Changes Possibly Promoted by Critical Illnesses

A 16,000-patient assessment found that infection alone, excluding critical illness, is associated with reduced brain volume later in life.

While it can’t yet be proven that brain structure changes and the acceleration of cognitive decline processes associated with Alzheimer disease are promoted by critical illness and major infection, a team of investigators at Johns Hopkins Medicine suggest that is the case.

In an assessment of the roles of hospitalization due to critical illness and major infection in brain structure changes, the Johns Hopkins investigators utilized data from the Atherosclerosis Risk in Communities Study (ARIC) to observe brain structure changes underlying cognitive decline and dementia in association with critical illness and infection.

In the ARIC study, nearly 16,000 participants aged 45 to 64 years old from Maryland, North Carolina, Minnesota, and Mississippi were originally enrolled, with data including magnetic resonance imaging (MRI) scans that showed brain structure in addition to a large cohort of participants followed over a 24-year period. Five medical exams and structured interviews were also included in the large cohort.

Due to the study’s long follow-up period, the team was able to obtain hospitalizations over many years, making the study especially rigorous since Alzheimer disease takes decades to evolve and time to diagnose, noted lead investigator Keenan Walker, PhD, postdoctoral fellow in the Department of Neurology at the Johns Hopkins University School of Medicine

In order to assess evidence of atrophy and damage to so-called white matter, Walker and his team focused on a subset of ARIC subjects who were administered a brain MRI during the final medical exam. A survey of medical records from hospital admissions throughout the ARIC study, 5 in-person exams, and annual telephone contact with participants were also used to collect data.

By using an internationally defined classification of disease codes (or ICD-9 codes) used for insurance billing purposes, the team identified critical illness that included shock, severe sepsis, acute respiratory failure, hypotension, respiratory or cardiac arrest, and the need for cardiopulmonary resuscitation prolonged ventilation.

The number of major infections—including septicemia, other bacterial infection, and pneumonia—were also identified by the team in the same way.

From the 1689 total participants included in the analysis, 1214 (72%) were hospitalized, 47 (4%) had a critical illness and 165 (14%) had a major infection. In addition, 60% were women, 28% were African-American, and 5% met criteria for dementia. At the first visit, the participants’ age was 52.7 years.

Upon analysis, the team observed a 9% greater white matter hyperintensity volume and significantly lower integrity of white matter microstructure associated with hospitalization during the follow-up period, regardless of the reason.

In the 1214 hospitalized patients who had 1 or more critical illness, a 3% smaller brain volume in brain regions was also observed. Such regions include those like the hippocampus, which is implicated in Alzheimer disease.

Major infection was associated with both 10% larger brain ventricle volume and smaller brain volume in regions vulnerable to Alzheimer’s disease (2% smaller).

In general, the team found that infection alone (excluding critical illness) was associated with reduced brain volume later in life.

Looking forward, Walker and his team plan to assess how inflammation in the brain and systemic inflammation relates to each hospitalization.

Based on an accumulating body of research, the investigators surmise that brain inflammation caused by critical illness and infection may lead to the observed reduction in brain volume. In conjunction, these altercations in the brain are suspected to open the door for cognitive decline and Alzheimer disease.

The study, "Association of Hospitalization, Critical Illness, and Infection with Brain Structure in Older Adults," was published online in the Jounal of the American Geriatrics Society.