Choroid plexus enlargement in Long COVID signals cognitive risk

The increased size of, and lesser blood supply to, a key brain structure in patients with Long COVID tracks with known blood markers of Alzheimer's disease and greater levels of dementia, a new study finds. 

Led by NYU Langone Health researchers, the study concerns the choroid plexus (CP), a network of blood vessels lined by cells that produce cerebrospinal fluid, which cushions the brain and forms a protective barrier between the fluid and the bloodstream. The CP regulates immune system responses (inflammation) and waste clearance in the brain. Past studies show that the COVID-19 virus can damage the cells lining CP blood vessels.

Published online Feb. 10 in Alzheimer's & Dementia, the new work found that patients reporting Long COVID had a 10% larger CP than those who had fully recovered from an initial infection with SARS-CoV-2, the virus that causes COVID-19 disease. Further, CP size increases tracked with blood levels of proteins that increase as Alzheimer's disease worsens, such as pTau217, and with blood levels of others that rise in response to brain injury, like glial fibrillary acidic protein. 

The research team also found that patients with larger CPs performed an average of 2% worse on a standard 30-point screening test, the Mini-Mental State Exam, which records changes in memory and attention.

Our work suggests that long-term immune reactions caused in some cases after an initial COVID infection may come with swelling that damages a critical brain barrier in the choroid plexus. Physical, molecular, and clinical evidence suggests that a larger CP may be an early warning sign of future Alzheimer's-like cognitive decline."

Yulin Ge, MD, senior study author, professor, Department of Radiology, NYU Grossman School of Medicine

Long COVID is a condition in which symptoms of infection with the pandemic virus last for months or even years after the initial infection. About 780 million people worldwide have been infected so far, with some of those experiencing long-term fatigue, brain fog, dizziness, loss of smell or taste, depression, and many other symptoms. 

Linking changes

For the study, the research team recruited 179 participants, including 86 patients with neurological symptoms of Long COVID, 67 people who had fully recovered from COVID-19 without lasting symptoms, and 26 individuals who had never had COVID-19.

Each participant received advanced MRI scans of their brains, which enabled the team to find patterns amid the brain scans, blood tests, and cognitive exams of the three patient groups. 

The tests revealed that structural changes seen in the CP blood vessels of Long COVID patients both expanded CP volume and reduced flow through its blood vessels. While the mechanisms behind this are not yet confirmed, the team's theory is that the changes reflect inflammation-driven CP "vascular remodeling," in which layers of cells lining blood vessels thicken in response to long-term activation by immune cells and signals. Such inflammation comes with surrounding stromal fibrosis, the buildup of scarlike tissue that further hinders blood flow. 
Impaired blood perfusion in the CP may reduce CSF production, lead to waste buildup, and compromise the integrity of the blood-CSF barrier, the study authors say.

"Our next step is to follow these patients over time to see if the brain changes we identified can predict who will develop long-term cognitive issues," said senior study author Thomas Wisniewski, MD, the Gerald J. and Dorothy R. Friedman Professor in the Department of Neurology at the NYU Grossman School of Medicine. "A larger, long-term study will be needed to clarify whether these CP alterations are a cause or a consequence of the neurological symptoms, which promises to better focus treatment design efforts," added Wisniewski, director of the Center for Cognitive Neurology at NYU Langone Health. 

Along with Ge, study authors from the Department of Radiology are first author Huize Pang, Li Jiang, Chenyang Li, and Zhe Sun. In addition to Wisniewski, authors from the Department of Neurology were Jennifer Frontera, Allal Boutajangout, Ludovic Debure, Mobeena Ghuman, Alok Vedvyas, and Arjun Masurkar. 

This research was supported by National Institute on Aging grants R01AG077422, U24 NS135568, and P30AG066512.