Several newly published studies are reporting evidence affirming a growing hypothesis that links inflammation with cognitive deficits. As well as associating inflammation with the cognitive deficits seen in conditions such as bipolar disorder and Alzheimer’s, some research is even suggesting low-grade systemic inflammation in healthy subjects can result in mental sluggishness.

For some time patients suffering from chronic inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease have reported mild cognitive deficits in association with their disease. Despite a number of correlational studies finding connections between inflammation and cognitive performance, homing in on any clear causal links has been a little tricky for scientists.

“Scientists have long suspected a link between inflammation and cognition, but it is very difficult to be clear about the cause and effect,” explains Ali Mazaheri, from the University of Birmingham. “For example, people living with a medical condition or being very overweight might complain of cognitive impairment, but it’s hard to tell if that’s due to the inflammation associated with these conditions or if there are other reasons.”

The experiment

Mazaheri and his team sought to create an experiment that could empirically evaluate the effects of inflammation on specific cognitive processes. Twenty healthy volunteers were recruited and subjected to a double-blind, placebo-controlled experiment.

To induce low-grade systemic inflammation, the subjects were administered a salmonella typhoid vaccine. This vaccine is known to trigger a rapid, albeit small, systemic inflammatory response, but with no broader side effects such as fever. Around six hours after the injection the participants completed a number of cognitive tests while having their brainwave activity measured. Blood samples were also taken at various points to track levels of interleukin-6, a marker of systemic inflammatory activity. Each subject performed the experiment twice, once with a placebo and once with the active vaccine.

The cognitive tests performed in the study were primarily focused on attentional processes. The researchers point out that while similar prior studies have not found experimentally induced inflammation to result in significant cognitive alterations, those studies used “coarse cognitive tests (e.g., digit span forward, digit symbol test, color-word Stroop test) that more likely index memory, learning and other high-level executive functions.” This new study was much more interested in testing visual attention processes. Three particular components of visual attention were evaluated: alerting, orientating, and executive control.

The results revealed the induction of mild systemic inflammation seemed to only affect one of those three processes – alerting. This specific attentional state of arousal involves the ability to focus our cognitive processes on a discreet object or source while filtering out other peripheral bits of information. This result was primarily identified via differences in EEG brainwave activity and not the general cognitive tests.

“Observed in the absence of performance decrements, these novel findings suggest that acute inflammation requires individuals to exert greater cognitive effort when preparing for a task in order to maintain adequate behavioral performance,” the researchers conclude in the published paper.

Mazaheri suggests these results may explain why some people with chronic inflammatory diseases often report feelings of mental sluggishness.

“These results show quite clearly that there’s a very specific part of the brain network that’s affected by inflammation,” says Mazaheri. “This could explain ‘brain fog’.”

The bipolar connection

The University of Birmingham study is primarily exploring mild cognitive consequences from low-grade inflammation. A separate, newly published study has investigated the relationship between cognitive impairment and inflammation in patients suffering from bipolar disorder (BD).

The research, led by scientists from Brigham and Women's Hospital, began by trying to understand what factors could explain why only around 50 percent of patients with bipolar disorder display neurocognitive deficits. The hypothesis was that not only could inflammatory biomarkers be used to identify those BD patients at the greatest risk of cognitive decline, but treating that inflammatory symptom could potentially offer cognitive benefits.

"We know that one person with bipolar disorder may be very different from another, and these findings support this,” says Katherine Burdick, corresponding author on the Brigham study. “Levels of inflammation varied in patients, but among those with high levels of inflammation, we saw the strongest evidence of cognitive impairment."

The causal mechanisms may not be entirely clear but the Brigham team notes the predictive nature of these inflammatory markers in being able to identify cognitive decline, even after accounting for other confounding factors, imply a strong possibility that treating the inflammation could improve BD-related cognitive impairments.

"Cognitive impairment is a core component of bipolar disorder," says Burdick. "Because of its significant role in predicting a person's level of functioning in their everyday lives, this needs to be considered a treatment target. The message here is an optimistic one: This is a marker of something we can actively change, which opens the door for hope."

Assuming inflammation does play a role in acute cognitive impairment, it would be fair to ask what part it may play in longer term neurodegeneration?

Alzheimer's disease and inflammation

A fascinating study published earlier in 2019 suggested a statistically significant link between chronic inflammation in a person’s middle age, and higher rates of cognitive decline in later life. The 20-year study was resolutely correlational, with the researchers suggesting it is unclear whether treating mid-life inflammation would result in slower rates of cognitive decline in old age.

New research, led by the German Centre for Neurodegenerative Diseases (DZNE) and the University of Bonn, is offering some intriguing causal evidence pointing to a possible mechanistic explanation linking inflammation with neurodegeneration. The impressive work looked at a macromolecule called NLRP3 that is found within the brain’s immune cells. NLRP3 is known as an inflammasome, a kind of molecular signal that triggers inflammatory activity.

The current prevailing pathological sign of neurodegeneration, associated with conditions such as Alzheimer’s disease, is the aggregation of toxic proteins in certain parts of the brain. These accumulations of amyloid proteins into plaques, and tau proteins into neurofibrillary tangles, are thought to underpin the neuronal damage that leads to symptoms of dementia.

Prior research from the same German team has suggested the early accumulations of amyloid proteins into plaques could be initially triggered by inflammatory activity mediated by the NLRP3 inflammasome. This new study now affirms the damaging tau pathology is also underpinned by the same inflammatory process.

"Our results indicate that the inflammasome and the inflammatory reactions it triggers, play an important role in the emergence of tau pathology," says Michael Heneka, a senior researcher working on the project. "It appears that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology."

What this finding ultimately means is that inflammatory triggers may kick off the neurodegeneration attributed to Alzheimer’s disease and other amyloid- or tau-related dementias. Heneka suggests this particular inflammasome trigger could be the missing link in understanding how neurodegeneration begins.

"Inflammatory processes promote the development of [amyloid] pathology, and as we have now been able to show, of tau pathology as well. Thus, the inflammasome plays a key role in Alzheimer's and other brain diseases," says Heneka. "The idea of influencing tau pathology is obvious. Future drugs could tackle exactly this aspect by modulating the immune response. With the development of tau pathology, mental abilities decline more and more.”

Science is all about incremental, piecemeal discoveries. Very rarely does one single study offer up a universal answer. These three new studies are certainly not the final word on the topic, but rather they offer rigorous evidence for an increasingly strong hypothesis linking inflammatory processes to both acute cognitive impairment and longer-term cognitive decline.

The University of Birmingham study was published in the journal NeuroImage.

The Brigham and Women’s study was published in the journal Molecular Psychiatry.

The German study was published in the journal Nature.

Sources: University of Birmingham, Brigham and Women’s Hospital, German Centre for Neurodegenerative Diseases