Vascular Inflammation in Neuropsychiatric Long COVID, 2026, McAlpine et al

[Mij]

Now published, see post #3

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Abstract
Background: Neuropsychiatric symptoms are prominent and can have a substantial functional impact in many people with Long COVID (LC). The underlying pathophysiology of neuropsychiatric LC (N-LC) is unknown.

Methods: 28 individuals with acute COVID-19 (AC), 50 N-LC (new or worsening neuropsychiatric symptoms >3 months after COVID-19), and 29 post-COVID-19 controls with no LC (>3 months prior) were enrolled. Participants underwent cross-sectional blood testing, and the N-LC and control groups underwent neuropsychiatric testing, including verbal learning and memory, fluency, processing speed, and mental health assessments. Fourteen soluble biomarkers of vascular health were measured in plasma. ANCOVA testing with a Benjamini-Hochberg procedure was used to compare biomarkers between groups adjusting for co-morbidities.

Findings: Participants with N-LC and controls were similar demographically, while the AC group had higher rates of obesity and hypertension. Biomarkers of leukocyte adhesion to the endothelium and endothelial inflammation were elevated in N-LC compared to controls, including L-selectin, ADAMTS13, sP-selectin, and sICAM-1, whereas coagulopathy measures (D-dimer, fibrinogen) did not differ. Most biomarkers were highest in AC and lower in N-LC (AGP, CRP, haptoglobin, SAA, ADAMTS13, PF4, sP-selectin, sVCAM-1, and D-dimer). However, three biomarkers were highest in N-LC compared to AC: Fetuin (vascular calcification), L-selectin (leukocyte adhesion), and α-2 macroglobulin (endothelial adhesion). In N-LC, higher sP-selectin was strongly associated with lower fluency and verbal learning. Lower AGP was strongly associated with lower verbal memory, verbal learning, fluency, mood, and anxiety.

Interpretation: Alterations in biomarkers of vascular inflammation strongly associate with the presence of N-LC. Biomarkers of endothelial adhesion and vascular calcification are only elevated in N-LC compared to both groups, suggesting a pathophysiology distinct from the resolving effects of AC. Biomarkers related to endothelial adhesion and systemic inflammation associate with specific cognitive domains, linking vascular inflammation with brain function. Identifying abnormalities in vascular endothelial function, calcification, and remodeling may lead to therapeutic targets for N-LC.

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[Mortal Machinery]

Looks like this has been accepted for publication and is now available here: LINK

 

[forestglip]

Vascular Inflammation in Neuropsychiatric Long COVID

Lindsay S. McAlpine MD 1 b, Eran F. Shorer MD MSc 2, Jennifer Chiarella BS 1 b, Allison Nelson RN 1 b, Rebecca Veenhuis PhD 2, Alba Azola MD 2, Alfred Lee MD 1, Richard Pierce MD 1, Shelli Farhadian 1 b, Leah H. Rubin PhD 2, Serena S. Spudich MD 1 3 b, for the Yale COVID Mind b, IMPACT Study Groups a

Abstract
The role of vascular inflammation in neuropsychiatric Long COVID (LC) is suspected but not well understood. This study evaluated whether vascular inflammation is present in individuals with neuropsychiatric LC and how it relates to cognitive and mental health symptoms.

This cross-sectional, case-control study included individuals with acute COVID-19 (AC), neuropsychiatric LC, and recovered controls. Participants were enrolled from the COVID Mind Study and the Yale IMPACT Study (hospitalized), and an independent cohort from the Johns Hopkins University (JHU) Long COVID Study.

Fifty individuals with neuropsychiatric LC (new symptoms a median of 368 days post-COVID), 28 with AC, and 29 recovered controls (>3 months post-COVID) were evaluated. All underwent blood sampling and neuropsychiatric testing. The JHU cohort included 114 individuals with late LC (median 1065 days post-COVID illness associated with LC onset) and 31 recovered controls (median 852 days).

Fourteen plasma biomarkers of vascular inflammation were measured. ANCOVA was used to compare groups, adjusting for comorbidities. Non-hospitalized participants completed the Global Neuropsychological Assessment, GAD-7, and PHQ-9.

LC and recovered groups were demographically similar, while AC participants had higher obesity and hypertension rates. LC participants had elevated circulating biomarkers of endothelial, leukocyte, and platelet adhesion (sL-selectin, ADAMTS13, sP-selectin, sICAM-1) compared to recovered controls. Coagulation markers (D-dimer, fibrinogen) did not differ.

Most biomarkers were highest in AC and lower in LC; however, fetuin, sL-selectin, and α-2 macroglobulin were higher in LC than AC. In LC, higher sP-selectin correlated with lower fluency and verbal learning. Lower α1-acid glycoprotein levels were strongly associated with poorer verbal memory, verbal learning, fluency, depression, and anxiety.

In the JHU cohort, late LC and recovered controls showed no differences in biomarkers or demographics, suggesting normalization over time.

Persistent dysregulation at the intersection of inflammation, platelet adhesion, and endothelial dysfunction is strongly linked to neuropsychiatric Long COVID. Elevated markers of endothelial adhesion in LC suggest distinct pathophysiology from AC. These biomarkers correlate with lower fluency and verbal learning, linking vascular dysfunction to brain function. This study underscores the critical need for longitudinal, within-person investigations to elucidate how vascular inflammation evolves over time.

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