173 – Brain Gray and White Matter Alterations in Cognitive Long COVID, 2025, McAlpine et al

173 – Brain Gray and White Matter Alterations in Cognitive Long COVID

Lindsay S. McAlpine, Nuno Barros, Allison Nelson, Rafay Khan, Cheryl Lacadie, Shelli Farhadian, Todd Constable, Serena Spudich

[Line breaks added]

Background
Cognitive dysfunction is a common symptom of Long COVID (LC), but its underlying pathobiology is unclear. We hypothesized that multimodal structural brain MRI imaging in people with cognitive LC (c-LC) would demonstrate grey and white matter alterations in brain regions relevant to c-LC symptoms compared to no LC (n-LC) controls.

Methods
Individuals with c-LC (new self-reported cognitive symptoms >3 months after COVID) and n-LC (COVID >3 months prior and no LC) were prospectively enrolled for studies on a single Siemens 3T scanner.

Sequences included 3D T1 MPRAGE (1mm) for cortical gray matter (CGM) volume, 3D FLAIR (1.2mm) for white matter hyperintensity (WMH) volume, and Diffusion Tensor Imaging (DTI) (2mm) for white matter integrity measures fractional anisotropy (FA) and mean diffusivity (MD). Post-processing used Icometrix AI-based software and Bioimage Suite. The Johns Hopkins atlas was used to generate FA and MD for regions of interest (ROI). Analyses used parametric statistics and FDR to correct for multiple comparisons.

Results
23 c-LC (median age 45 years [IQR 41–59], 73% female, 630 days [IQR 365–829] after COVID-19) and 19 n-LC (median age 38 [33 – 44], 73% female, 516 days [IQR 410-797]) were enrolled. The groups differed in age (p=0.03) but were similar in gender, race, and cardiovascular risk factors which were low in prevalence.

CGM volumes were lower in the c-LC group in three key regions: right parietal lobe and supramarginal region (SM), right ventrolateral prefrontal cortex (VLPFC), and left posterior cingulate (for statistics, see Table).

WMH lesion volume was similar between groups (c-LC: 0.65 mL n-LC: 0.65 p:0.90). In the fornix, FA and MD were both altered in the c-LC group compared to n-LC.

In the c-LC group, MD was lower in the left posterior corona radiata and transverse pontine fibers compared to n-LC (Table). There was no difference between groups in the remaining ROIs.

Conclusions
Our finding of specific regional grey and white matter alterations aligns closely with c-LC symptomatology.

The SM is intimately connected to the VLPFC and is involved in articulatory sequencing and language and executive processing; VLPFC is involved in speech production and emotional associations and regulation. Altered CGM in the left cingulate and left corona radiata and DTI measures in the fornix aligns with dysfunction of key memory circuits.

These structural 3T brain MRI findings may serve as biomarkers for diagnostic and mechanistic understanding of c-LC.

Link (Conference on Retroviruses and Opportunistic Infections) [Abstract Only]