Association of symptoms of neuropsychological long COVID with imaging and plasma biomarkers, 2026, Nakase et al

[forestglip]

Association of symptoms of neuropsychological long COVID with imaging and plasma biomarkers

Spoiler: Authors

Nakase, Taizen; Takano, Yumi; Nomura, Shuko; Baek, Hae Woon; Takayama, Shin; Ono, Rie; Abe, Michiaki; Ishii, Tadashi; Tatewaki, Yasuko; Taki, Yasuyuki

Highlights
• Neuropsychological long COVID i.e. “brain fog” were investigated by biomarkers.
• Cognitive impairments related to abnormal rCBF in the occipital lobe.
• Psychological symptoms related to abnormal rCBF in the parietal lobe.
• Increase of plasma NFL and GFAP was observed in relation to cognitive impairments.
• Imaging and blood biomarkers may elucidate brain damage of “brain fog”.

Abstract

Background
Some patients recovered from COVID-19 may experience cognitive and psychological symptoms, such as “brain fog” or neuropsychological long COVID, and its mechanism is unclear.

Objective
This study aimed to investigate the mechanism of brain damage in neuropsychological long COVID using imaging and blood biomarkers.

Methods
Patients who met the criteria on the “brain fog” screening questionnaire and provided informed consent were enrolled in this study (n = 33; mean age 38.5 years). All participants were examined using magnetic resonance imaging, single-photon emission computed tomography (assessment of regional cerebral blood flow [rCBF]), and blood biomarkers.

Neuropsychological tests (Montreal Cognitive Assessment-Japanese version [MoCA-J], Trail Making Test [TMT], Frontal Assessment Battery, Digital Symbol Coding [DSC] test, State-Trait Anxiety Inventory [STAI], and Self-Rating Depression Scale [SDS]) were performed simultaneously.

Results
Significant correlations were observed between the MoCA-J score and decreased rCBF in the left occipital lobe and increased rCBF in the right occipital lobe (p < 0.05), between the STAI score and decreased rCBF in the right parietal lobe (p < 0.05), and between the SDS score and decreased rCBF in the right parietal lobe (p < 0.05).

The MoCA-J and DSC scores were correlated with plasma levels of neurofilament light chain (p < 0 0.05). The TMT time correlated with plasma glial fibrillary acidic protein levels (p < 0.01).

Conclusion
This study was a cross-sectional and could not distinguish pathological abnormalities. However, as correlations of neuropsychological long COVID with specific brain regions and plasma biomarkers have been elucidated, conducting a case-control analysis may be worthwhile.

Web | DOI | PDF | Journal of the Neurological Sciences | Open Access

 

[forestglip]

There's a comment, but the details are behind a paywall:

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Comment on “Association of Symptoms of neuropsychological long COVID with imaging and plasma biomarkers”

Shukla, Ankita; Brahma, Pratyush Kumar; Rajput, Dharmendra Singh

Web | DOI | Journal of the Neurological Sciences

 

[SNT Gatchaman]

There's a comment, but the details are behind a paywall:

It's clearly AI bullshit, written (supposedly) by three pharmaceutical researchers who wouldn't have any relevant overlap even if they were real people.

1. Dr. Ankita Shukla 1
Professor, Millennium College of Pharmacy, Bhopal, Madhya Pradesh, India
Email: awasthiankita696@gmail.com

2. Pratyush Kumar Brahma 2|*
Assistant Professor, Department of Pharmaceutical Chemistry (Quality Assurance),
School of Pharmacy, Rai University, Ahmedabad – 382260, Gujarat, India
Email: researchdoctor05@gmail.com

3. Dr. Dharmendra Singh Rajput 3
Professor, Department of Pharmaceutics, Mittal Institute of Pharmacy, Bhopal – 462010, Madhya Pradesh, India
Email: dr.dsr141@gmail.com

I'll reproduce the whole letter as an example, and because honestly what even is copyright in this situation?

We read with interest the article by Nakase et al. [1]. examining the association between neuropsychological symptoms of long COVID (“brain fog”) and imaging and plasma biomarkers. The authors are to be commended for their multimodal approach combining neuropsychological testing, IMP-SPECT imaging, and plasma biomarkers in a relatively young cohort, addressing a clinically important and poorly understood condition.

A notable strength of this study was the identification of region-specific cerebral blood flow (rCBF) alterations associated with cognitive and psychological symptoms. The observed association between MoCA-J scores and asymmetric occipital lobe perfusion, together with correlations between anxiety and depressive symptoms and reduced right parietal rCBF, provides a plausible neurobiological framework linking visuospatial processing and attentional networks to the subjective experience of brain fog. These findings extend prior reports of frontoparietal and basal ganglia involvement in post-COVID neurocognitive syndromes by highlighting the potential hemispheric imbalance within the visual–attentional pathways [2].

The biomarker results were also intriguing. The correlations between plasma neurofilament light chain (NFL) and cognitive performance, as well as between glial fibrillary acidic protein (GFAP) and executive task performance, suggest subtle neural or glial alterations, even in the absence of overt structural MRI abnormalities [3]. However, the directionality of these associations, particularly the positive correlation between higher NFL levels and better cognitive scores, raises important questions. While the authors appropriately acknowledge this unexpected finding, further discussion regarding potential peripheral versus central sources of NFL, compensatory neural mechanisms, or temporal effects related to the recovery phase would strengthen the interpretation.

Several methodological considerations warrant further discussion. First, the lack of a control group limits causal inference, particularly given the reliance on machine-embedded reference databases for rCBF comparison [4]. Case–control or longitudinal designs would help determine whether the observed perfusion patterns represent persistent pathology, compensatory changes, or transitional recovery states. Second, the relatively small sample size increased the risk of type I error, especially given the number of regional and biomarker correlations examined. Future studies incorporating corrections for multiple comparisons or hypothesis-driven regional analyses may improve robustness.

Despite these limitations, this study provides valuable evidence that neuropsychological long COVID is associated with measurable functional and biological alterations, even when conventional MRI findings are unremarkable. The integration of functional imaging with blood-based biomarkers represents a promising strategy for objectifying brain fog symptoms and may ultimately aid in patient stratification and monitoring.

Overall, Nakase et al. offer an important contribution to the evolving understanding of COVID–related cognitive dysfunction. Larger, controlled, and longitudinal investigations are essential to validate these findings and clarify their clinical and prognostic significance.

 

[SNT Gatchaman]

Small numbers (n=33) but they noted a bimodal age distribution (two age peaks) in females —

In this study, most participants were in their 40s, which is consistent with patient profiles reported in other countries. Male participants were evenly distributed across age groups ranging from their 20s to 60s; however, female participants were concentrated in their teens and 40s. As no notable differences in comorbidities were observed between males and females, this difference was assumed to be caused by variations in sex hormones or resilience to inflammation.

Females are the dark bars.