Blood brain barrier and ‘brain fog’

Cognitive difficulties (sometimes referred to as “brain fog”) are a key symptom of ME/CFS – and one of four required for “suspecting ME/CFS” in the 2021 NICE guidelines alongside fatigue, post exertional malaise and unrefreshing sleep. Brain fog is also experienced by many people with long COVID.

In February this year, a team of researchers led by Chris Greene at Trinity College Dublin, published a paper which aimed to investigate whether the blood brain barrier (BBB) – a membrane which carefully regulates movement of molecules between the blood and the brain, may be associated with brain fog in people with long COVID.

Although not always clear from the study – it would appear that the researchers studied:

  • 10 people who had recovered from a COVID-19 infection.
  • 11 people with long COVID who reported brain fog.
  • 11 people who although had long COVID did not report brain fog.

Regrettably, the study team did not include people with ME/CFS, or assess whether participants with long COVID also met ME/CFS diagnostic criteria.

Results suggest that, alongside a hyperactive immune system, there was dysfunction of the BBB in the brains of people with long COVID. Interestingly, BBB dysfunction was able to differentiate people with long COVID who did not report brain fog from those with long COVID who did report brain fog.

The authors of the study state that although the findings may indicate that BBB dysfunction, and ongoing inflammation in the body may play a role in brain fog associated with long COVID, the study was limited by the small sample size used, and also due to the lack of follow up over time. More research looking at BBB dysfunction over time in those with long COVID, and in other “post viral illnesses” is recommended by the research team. 

ME Research UK notes that while this study did not directly consider people with ME/CFS, some of the findings do draw interesting parallels with those in existing research into the disease. For example:

  • In the study there was a strong association of BBB disruption with transforming growth factor (TGFβ)- a protein molecule which regulates a wide variety of cell processes.
    • TGFβ has previously been linked with ME/CFS – In fact, ME Research UK-funded research at the University of Dundee – published in 2004, which found high levels of TGFβ1 in people with the disease.
  • The authors of the recent study state that changes in BBB function not only correlates with changes in brain volume and cortical thickness, but are also closely related to changes in brain structure, and ultimately function.
    • In ME Research UK funded work, Dr Leighton Barnden and his team identified structural brain changes in people with ME/CFS – and those with long COVID, including brainstem volume changes which correlated with measures of pain and breathing difficulty. Like Greene and colleagues, Barnden and his team also highlighted the need for studies that assess changes in brain structure and function over time – here this recommendation was specifically for people with ME/CFS, and those with long COVID.

More research is needed to explore how changes in brain structure and function – particularly investigating whether there may be changes over time, in both those with ME/CFS, and long COVID. 

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