Midlife Systemic Inflammation a Harbinger of Brain Volume Loss

Megan Brooks

November 02, 2017

A new study provides more evidence that midlife systemic inflammation may contribute to brain volume loss and cognitive trouble later in life.

In a large biracial community sample, a higher level of systemic inflammatory markers measured in middle-aged men and women was independently associated with lower regional brain volume and reduced memory more than 2 decades later.

"The findings provide support for inflammation's early pathogenic role in the development of neurodegenerative brain changes associated with late-life cognitive decline, AD [Alzheimer's disease], and other forms of dementia," write Keenan Walker, PhD, Department of Neurology, Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues.

The study was published online November 1 in Neurology.

A Contributing Factor

"The majority of previous studies on this topic have assessed markers of systemic inflammation and neurological integrity simultaneously. As a result, it has been difficult to disentangle whether systemic inflammation was a cause or just an associated feature of late-life brain changes," Dr Walker told Medscape Medical News.

"By demonstrating that markers of systemic inflammation in midlife relate to smaller brain volumes and reduced cognitive functioning decades later, our findings provide support for a causal or contributory role of systemic inflammation. Essentially, these results move us closer to clarifying the temporal relationship between systemic inflammation, cognitive decline, and neurodegeneration," said Dr Walker.

The findings are based on 1633 adults (mean age, 53 years; 60% female; 27% African American) in the Atherosclerosis Risk in Communities Study (ARIC) who had five inflammatory markers measured at baseline: fibrinogen, albumin, white blood cell count, von Willebrand factor, and factor VIII. 

By using all five, the investigators created an inflammation composite score for each participant. Episodic memory and regional brain volumes determined via MRI were assessed 24 years later, when the cohort had an average age of 76.5 years.

Each standard deviation increase in midlife inflammation composite score at baseline was associated with a 532-mm3 smaller AD signature region volume (P = .008), 519-mm3 smaller occipital lobe volume (P = .009), 110-mm3 smaller hippocampal volume (P = .013), and a 1788-mm3 larger ventricular volume (P = .013), as well as reduced episodic memory (P = .046), 24 years after baseline.

The effect of a one–standard deviation increase in the overall inflammation score in midlife on brain volume 2 decades later was similar to the effect associated with having a single APOE ε4 gene that increases the risk for AD, the researchers note.

Compared with adults with no elevated midlife inflammatory markers, those with elevations in three or more markers had, on average, 4.6% smaller hippocampal volumes, 5.3% smaller AD signature region volumes, and 5.7% smaller occipital lobe volumes.

The association between midlife inflammation and late-life brain volume was modified by age and race: Younger adults of white race with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes later on.

Implications and Caveats

The researchers note that the prospective study design, long follow-up, detailed assessment of potentially confounding variables, large sample size, and inclusion of a large African American sample are strengths of the study. However, the current findings should be interpreted within the context of several limitations, they note.

"Although the acute-phase reactants used in the present study represent components of the innate immune system, several of these proteins are implicated in other closely related physiologic process, such as hemostasis, which may also influence brain volume," they write. "Interpretation of the current findings is also limited by the measurement of inflammatory markers at a single time point, as it is unclear whether a single measurement can adequately capture inflammation chronicity." 

Dr Walker said the five inflammatory markers used in the study were chosen for two reasons. First, they have been previously shown to be sensitive markers of nonspecific inflammation in the body and, second, the interleukins and other proinflammatory cytokines were not available.

"We hope to use these findings as a basis to request grant funding to look at interleukins, TNF-α [tumor necrosis factor-α], and other inflammatory mediators. This should give us a more nuanced understanding of the systemic inflammation–brain relationship," he said.

The researchers also caution that interpretation of the contribution of inflammation to neurodegeneration "rests on the assumption that brain volume loss occurred after inflammatory markers were assessed. Although evidence suggests that this is likely the case (brain volume loss accelerates after age 60 years), this cannot be confirmed without the assessment of change over time," they note. They did not have baseline MRI data.

Dr Walker said he believes it's too early to recommend any dramatic changes in practice based on this study.

However, "our findings do suggest that reducing the burden of diseases known to cause chronic inflammation should be a priority for dementia prevention throughout adulthood. It is my hope that these findings will direct future research efforts for dementia prevention and treatment."

Noteworthy Research

Kyle Bourassa, a PhD candidate at the University of Arizona in Tucson, who has studied inflammatory markers and cognitive function but wasn't involved in the current research, said the study is "noteworthy due to the large size of the sample and the fact that they are linking inflammation with brain volume changes specifically."

A recent related study by Bourassa and colleagues found that being overweight or obese leads to clinically meaningful increases in the rate of cognitive decline in association with changes in inflammatory markers in the blood, as reported by Medscape Medical News.

"In our previous study, we examined cognitive measures as our outcome, and while that is useful, being able to link inflammation to specific reductions in the size of brain regions is very interesting," Bourassa said.

Angela Scicutella, MD, PhD, a neuropsychiatrist in Bayside, New York, clinical associate professor, Hofstra Northwell School of Medicine, Hempstead, New York, and member of the American Academy of Neurology, said this study is a "contribution to the literature that already exists and supports the concept that inflammation is a contributing factor."

However, Dr Scicutella said she "would have liked to have seen the MRI at the outset and then later. Not having a baseline was a big problem for me because 24 years is a long time. It's a single time point, so how do you know that it is reflective of almost a quarter of a century? A lot can happen over the years."

"It would also have been nice to know the status of any depressive or anxiety symptoms," which can affect the brain, said Dr Scicutella.

Summing up, Dr Scicutella said the concept that inflammation has a role in neurodegeneration has been shown before, "so I don't think this is new, but they chose a different set of markers.  It also beckons the question, where do we go from here? What do we do about this?"

The study had no commercial funding. Dr Walker, Kyle Bourassa, and Dr Scicutella have disclosed no relevant financial relationships.

Neurology. Published online November 1, 2017. Abstract

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