Neurocognitive problems after Covid-19: the "experiment" that may - and should - revolutionize psychiatry (and medicine)

I’ve talked several times about Covid-19, neurocognitive problems and Long Covid. In the last chapter of my book, I share my personal visions about how long covid can revolutionize the way we see neuropsychiatric disorders and how it may change, specifically, the way we approach (and maybe one day treat) new childhood neuropsychiatric conditions (eg, ADHD or autism).

Unfortunately, as the time goes, my ideas are only getting reinforced.

In this systematic review and meta-analysis performed across several databases including MEDLINE/PubMed, PsycINFO, Scopus, medRxiv, and PQDT Global for studies published in English from January 2020 to December 2023, the authorsassessed the risk of developing new-onset dementia (NOD), using Risk Ratio (RR) for measurement. Control groups were categorized as: (i) a non-COVID cohort with other respiratory infections [control group (C1)]; and (ii) a non-COVID cohort with otherwise unspecified health status [control group (C2)]. Follow-up periods were divided into intervals of 3, 6, 12, and 24 months post-COVID.

11 studies (involving 939,824 post-COVID-19 survivors and 6,765,117 controls) were included in the review. Across a median observation period of 12 months post-COVID, the overall incidence of NOD was about 1.82% in the COVID-infected group, compared to 0.35% in the non-COVID-infected group. The overall pooled meta-analysis showed a significantly increased NOD risk among COVID-19 older adult survivors compared to non-COVID-19 controls (RR = 1.58, 95% CI 1.21–2.08). Similar increased NOD risks were observed in subgroup analyses restricted to an observational period of 12 months (RR = 1.56, 95% CI 1.21–2.01), as well as in five studies that employed propensity score matching to sufficiently and effectively control for multiple confounding covariates (RR = 1.46, 95% CI 1.10–1.94). COVID-19 group and C1 group shared a comparably increased risk of developing NOD (overall RR = 1.13, 95% CI 0.92–1.38).

The authors conclude that COVID-19 infection is likely to be a risk factor for developing NOD in older adults over time.

Unfortunately, this conclusion is perfectly supported by several observational studies and imaging studies I previously shared with you in my blog. And now, new studies are proving similar results.

1- This study examined fMRI brain activation patterns during a fatiguing task in those with and without Long Covid. Participants were 10 adults with Long Covidand persistent chronic fatigue (CF) and 10 age- and gender-matched healthy controls. The 2-back working memory task was used during fMRI to induce CF. There were more areas inside and outside the fatigue network that were activated in the Long Covid group as reported CF increased. The relationship between brain activation and scores on the 2-back did differ between groups, with the Long Covid group showing more frontal activation. Findings suggest that individuals with PASC and CF may need to exert greater mental effort during demanding cognitive tasks, reflected in recruitment of a broader network of brain. These conclusion is perfectly in line with the concept of post-exertional malaise triggered by cognitive efforts in patients with long covid (and ME/CFS).

2- in this other study, the authors used structural magnetic resonance imaging (MRI) to examine differences in gray matter thickness for the cortical limbic and the dorsolateral prefrontal cortical regions between patients with Long COVID and healthy controls. Results showed increased cortical thickness in the caudal anterior, isthmus, and the posterior cingulate gyrus as well as the rostral middle frontal gyrus respectively along with higher gray matter volume in the posterior cingulate and the isthmus cingulate in patients with Long COVID. Cortical thickness and gray matter volumes for regions of interest (ROIs) were also associated with the severity measures, clinical dementia rating, and anxiety scores in the Long COVID group. Our findings provide supporting evidence for cortical hypertrophy in Long COVID.

3- In this other study, fifty-two survivors 27 months after infection (mild-moderate group: 25 participants, severe-critical: 27 participants), from a previous community participants, along with 35 healthy controls, were recruited to undergo fMRI scans and comprehensive cognitive function measurements. Participants were evaluated by subjective assessment of Cognitive Failures Questionnaire-14 (CFQ-14) and Fatigue Scale-14 (FS-14), and objective assessment of Montreal Cognitive Assessment (MoCA), N-back, and Simple Reaction Time (SRT). Each had rs-fMRI at 3T. Measures such as the amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were calculated.

Compared with healthy controls, survivors of mild-moderate acute symptoms group and severe-critical group had a significantly higher score of cognitive complains involving cognitive failure and mental fatigue. The rs-fMRI results showed that COVID-19 survivors exhibited significantly increased ALFF values in the left putamen (PUT.L), right inferior temporal gyrus (ITG.R) and right pallidum (PAL.R), while decreased ALFF values were observed in the right superior parietal gyrus (SPG.R) and left superior temporal gyrus (STG.L). Additionally, decreased ReHo values in the right precentral gyrus (PreCG.R), left postcentral gyrus (PoCG.L), left calcarine fissure and surrounding cortex (CAL.L) and left superior temporal gyrus (STG.L). Furthermore, significant negative correlations between the ReHo values in the STG.L, and CFQ-14 and mental fatigue were found. Interpretation: this long-term study suggests that individuals recovering from COVID-19 continue to experience cognitive complaints, psychiatric and neurological symptoms, and brain functional alteration. The rs-fMRI results indicated that the changes in brain function in regions such as the putamen, temporal lobe, and superior parietal gyrus may contribute to cognitive complaints in individuals with long COVID even after 2-year infection.

4- on Nature medicine, e prospective, multicenter study of patients hospitalized with COVID-19 demonstrates objective global cognitive impairment after 12–18 months of follow-up, especially in those who had experienced encephalopathy. The cognitive impairment was associated with increased levels of serum brain injury biomarkers and a reduction in regional brain volume on MRI.

So, what?

The evidence is mounting. SARS-CoV-2 is clearly associated with a higher risk of new-onset neurocognitive problems, including structural and functional brain changes. We know about chronic inflammation and viral persistence as well. If this happens with covid, we cannot exclude this does not happen with other viruses as well. Or in younger children with not-explained new-onset neuropsychiatric conditions. This clearly means, to me, that there is need similar events happen in younger children and to investigate, on a larger basis and even in young children, if early viral infections can lead to neurological childhood problems. This, of course, would happen in a minority of predisposed children. In any case, what about if we would need to revolutionize the concept that viral infections do not need therapies?