Structural brain changes in post-COVID condition and its relationship with cognitive impairment, 2024, Pacheco-Jaime et al.

SNT Gatchaman

SNT Gatchaman

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Structural brain changes in post-COVID condition and its relationship with cognitive impairment
Pacheco-Jaime, Laura et 52 al.

It has been estimated that ~4% of individuals infected with SARS-CoV-2 will be diagnosed with post-COVID condition. Previous studies have evidenced the presence of cognitive dysfunction and structural brain changes in infected individuals; however, the relationship between structural changes and cognitive alterations in post-COVID condition is still not clear. Consequently, the aim of this work is to study structural brain alterations in post-COVID condition patients after almost 2 years of infection and their likely relationship with patients' cognitive impairment. Additionally, the association with blood biomarkers and clinical variables was also explored.

One hundred and twenty-eight individuals with post-COVID condition and 37 non-infected healthy controls from the Nautilus Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575) underwent structural brain magnetic resonance imaging and a comprehensive neuropsychological assessment. A subsample of 66 post-COVID participants also underwent blood extraction to obtain levels of blood biomarkers. Cortical thickness and subcortical volumes were obtained and analysed using FreeSurfer (v7.1). FMRIB Software Library software (v6.0.4) was used to perform grey matter voxel-based analysis and to study microstructural white matter integrity.

Patients with post-COVID performed significantly worse in working and verbal memory, processing speed, verbal fluency and executive functions, compared to healthy controls.

Moreover, patients with post-COVID showed increased cortical thickness in the right superior frontal and the right rostral middle frontal gyri that negatively correlated with working memory performance. Diffusion tensor imaging data showed lower fractional anisotropy in patients in the right superior longitudinal fasciculus, the splenium and genu of the corpus callosum, the right uncinate fasciculus and the forceps major, that negatively correlated with subjective memory failures.

No differences in blood biomarkers were found. Once patients were classified according to their cognitive status, post-COVID clinically cognitively altered presented increased cortical thickness compared to those classified as non-cognitively altered.

In conclusion, our study showed that grey and white matter brain changes are relevant in this condition after almost 2 years of infection and partly explain long-term cognitive sequelae. These findings underscore the critical importance of monitoring this at-risk population over time.

Link | PDF (Brain Communications) [Open Access]
 
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The disparate findings are acknowledged by the authors:
(paragraphs and bolding. added)
In 2022, a longitudinal MRI work performed a region of interest-based analyses in a large sample of 394 infected participants from the UK Biobank, and found reductions of cortical thickness (CTh) in memory and olfactory-related brain.16

Recently Petersen et al.,17 reported slightly higher mean cortical CTh in individuals recovered from SARS-CoV-2 infection compared to healthy controls (HC), but differences were not statistically significant.

Beyond studies including infected individuals, as the ones mentioned above, there is a growing interest in understanding the long-term sequelae in actual PCC. Nevertheless, evidence related to structural brain abnormalities in this condition is scarce and controversial.

In this regard, two recent studies reported opposite results, whereas Serrano del Pueblo et al.,18 found thinner CTh in long-COVID participants with neurological symptoms in the left temporal gyrus, compared to infected–recovered controls, Besteher et al.,19 reported higher CTh in patients with long-COVID in extended cortical regions, compared to HC.

Disparities are also found in studies evaluating grey matter (GM) volume. While a cross-sectional study found larger GM volume in participants long-COVID suffering from neuropsychiatric symptoms in fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia and thalamus in both hemispheres, compared to HC using a voxel-based morphometry (VBM) approach;20 another study found decreased volumes of the left thalamus, putamen and pallidum in individuals suffering post-COVID fatigue using a region of interest-based subcortical analysis.21Even some studies have not found significant differences in GM volume between patients with long-COVID and subjective cognitive complains and controls using a VBM approach.22

Differences in sample recruitment and the use of diverse methodologies or differences in evolution time from infection may be causing the discrepancies when studying structural brain changes in this condition, hindering the reaching of agreement on them.
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You've answered but I was just about to say:

I'd have to check but my sense is that we've seen more papers claiming increase than decrease, at least in LC. Papers suggesting decrease tend to get more air time though as everyone thinks this means dementia, and they start propagating on social media.

There are quite a few structural and functional imaging studies coming through, so it's hard to know which are worthwhile posting as threads. Although I haven't read it I thought this one was worthwhile given it's from a big group.

This one is not yet published —

Multiple Voxel Pattern Analysis Shows Associations Between Chronic Fatigue Syndrome and Cortical Atrophy (2025, Frontiers in Neuroscience)

Here are a few others from the last six months that I don't think have been posted —

Altered corticostriatal connectivity in long-COVID patients is associated with cognitive impairment (2025, Psychological Medicine)

Two-year impact of COVID-19: Longitudinal MRI brain changes and neuropsychiatric trajectories (2025, Psychiatry and Clinical Neurosciences)

Decreases in frequency-dependent intrinsic activity of the default mode network are associated with depression and cognition in patients with postacute sequelae of SARS-CoV-2 infection (2025, Brain Structure and Function)

Executive Function Deficit in Patients with Long COVID Syndrome: A Systematic Review (2025, Heliyon)

Cognitive impact and brain structural changes in long COVID patients: a cross-sectional MRI study two years post infection in a cohort from Argentina (2024, BMC Neurology)

Assessment of Post-COVID-19 Changes in Brain—Clinical and Imaging Evaluation Using MRI Vessel Wall Imaging and Complementary MRI Methods (2024, Journal of Clinical Medicine)

Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection (2024, Nature Scientific Reports)

Sex differences in ACE2, TMPRSS2, and HLA-DQA2 expression in gray matter: Implications for post-COVID-19 neurological symptoms (2024, Preprint: MedRxiv)

Neuroimaging Correlates of Post-COVID-19 Symptoms: A Functional MRI Approach (2024, Diagnostics)

Cerebrovascular Reactivity Assessed by Breath-Hold Functional MRI in Patients with Neurological Post-COVID-19 Syndrome—A Pilot Study (2024, Neurology International)

Comprehensive MRI assessment reveals subtle brain findings in non-hospitalized post-COVID patients with cognitive impairment (2024, Frontiers in Neuroscience)
 
That's quite a list SNT!

Here's the discussion of the issue from this paper:
CTh is cortical thickening

CTh correlated with working memory performance and was identified only in those PCC patients with altered cognition, whereas abnormal microstructural WM integrity was associated with PCC and related with subjective memory but not with objective neuropsychological performance or other clinical variables.
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Regarding the neuroimaging findings, cortical thickening in PCC patients mainly involving the right frontal lobe was found. However, when observing the whole-brain effect sizes, this cortical thickening seemed to be more extensive and bilateral. Similar to our results, Besteher et al.,19 studied a sample of 61 PCC patients and found higher CTh PCC patients compared to non-infected HC but also to controls with prior infection. Petersen et al.,17also showed slightly higher CTh in COVID-19 patients without PCC compared to the HC group, even though differences were not significant after statistical correction. This cortical thickening present in patients with post-COVID may have its origin in a neuroinflammation process caused by the virus entrance in the CNS.

In fact, several studies have proved that SARS-CoV-2 spike S1 subunit can induce by itself a neuroinflammatory response and microglia activation.55,56 Moreover, Besteher et al.,19 reported increased levels of IL-10, IFNγ and sTREM2 in serum related to cortical thickening in patients suffering from post-COVID condition. These results suggest a possible underlying inflammatory process explaining cortical alterations in patients with post-COVID. Interestingly, cognitive impairment present in patients with long-COVID has also been associated with the presence of inflammation and blood brain barrier disruption,57 indicating inflammation could be the cause of brain changes in these patients, that will finally lead to cognitive impairment.

Nevertheless, our study did not find relationship between cortical thickening and inflammation biomarkers, possibly because serum levels of biomarkers tend to normalize over time, hindering their detection months after the viral infection, as other authors have already proposed.58 Importantly, we could not provide cognitive and imaging data at the time of the acute infection, which prevents us from understanding the evolution of this probable neuroinflammation and the distinction between acute and more chronic inflammatory and structural brain changes. Longitudinal studies with data collection during the acute infection or the addition of an infected control group would help to clarify this question.

Our results showing increased CTh are not in line with the longitudinal study by Douaud et al.,59 which reported cortical thinning in the parahippocampal gyrus and the lateral orbitofrontal cortex. Even though this study has been widely cited and referenced by other authors, their participants are not PCC but individuals recovered from COVID-19 infection and their study design is broadly different to ours, which difficult the direct comparison with our study.

Another study reporting lower CTh in PCC patients compared with individuals recovered from COVID-19 infection.18 This mentioned study used a 1.5T scanner to study a smaller sample of PCC participants with neurological symptoms and shorter time since infection in comparison to our participants. Notably, contrary to our results, the authors did not find correlations between cortical thinning and cognition or clinical symptoms. Indeed, we found an association between impaired working memory and cortical thickening in right frontal brain regions. To our knowledge, only one recent study reported correlation between CTh and performance in memory domain.27 However, this study was limited by a small sample of individuals with post-COVID condition, it did not include a control group and used a multiple regression analyses approach based on mean thickness region of interest data, without multiple comparison correction. Overall, the methodological differences and the inclusion of intracranial volume as covariate in the CTh regression analyses could explain the discrepancies between studies.

Moreover, we also found a tendency of CTh to correlate positively with time since infection, potentially indicating patients with a higher time between infection and assessment may have worse structural changes as they have been carrying this PCC longer time with no recovery.
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Hutan said:
That's quite a list SNT!
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Heh. I've only had a chance to read a couple of those and don't wan't to completely swamp the forum. And at this stage, the big picture I think is that the most we can probably say is that LC and ME/CFS seem to cause measurable brain changes. But a bit like the various and sometimes contradictory metabolic findings, perhaps there's a lot of variation in how individuals or particularly structured cohorts might be responding, either as direct effects or with compensations.

Also all these neuroimaging studies are probably a little removed from what we need to know in terms of actionable causative findings. Other imaging studies such as MR lung perfusion (if validated/replicated), could be a little closer to the action and perhaps point to the upstream processes.
 
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