A study led by NYU Langone Health researchers has found that 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 (AD) and with greater cognitive decline.
The study discovered that patients reporting long COVID had a 10% larger choroid plexus (ChP) than those who had fully recovered from their initial infection with SARS-CoV-2, the virus that causes COVID-19. The results also showed that increased ChP size aligned with blood levels of proteins that increase as Alzheimer’s disease worsens, and with blood levels of other proteins that increase in response to brain injury.
“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,” said Yulin Ge, MD, a professor in the department of radiology at the NYU Grossman School of Medicine. “Physical, molecular, and clinical evidence suggests that a larger ChP may be an early warning sign of future Alzheimer’s-like cognitive decline.”
Co-senior author Ge and colleagues reported on their study in Alzheimer’s & Dementia, in a paper titled “Choroid plexus alterations in long COVID and their associations with Alzheimer’s disease risks,” in which they concluded, “Extending prior volumetric studies, our findings highlight perfusion abnormalities, closely associated with ChP enlargement, as an additional feature of ChP pathology in long COVID … The ChP abnormalities thus represent a promising marker for predicting AD risk.”
Long COVID is a condition in which symptoms of infection with SARS-CoV-2 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. “Neurological manifestations are among the most prominent features of long COVID, including cognitive impairment, sleep disorders, olfactory dysfunction, psychiatric symptoms, and others,” the authors wrote. Long COVID has also been associated with AD-like pathology, including amyloidogenic processes such as accumulation of amyloid-forming peptides, they noted.
Various hypotheses have been proposed for the pathogenesis of long COVID. “Although there is no consensus on a single pathological mechanism, neuroinflammation and immune dysfunction remain key hypotheses regarding the driving factors of the neurological sequelae of this post-viral condition,” the investigators continued.
The choroid plexus (ChP) is a vasculature-rich structure that serves as the primary site for cerebrospinal fluid (CSF) production, regulates immune responses, and maintains the blood-CSF barrier, the authors further explained. The CP regulates immune system responses (inflammation) and waste clearance in the brain. Past studies have shown that SARS-CoV-2 can infect damage the ChP epithelium, leading to blood-CSF barrier leakage. Studies have also reported abnormal CSF findings in long COVID patients with neurological symptoms. “Collectively, these findings underscore the ChP’s pivotal role in neuroimmune regulation and its potential contribution to the neurological manifestations of Long COVID,” the authors stated.
They also noted that recent imaging studies have reported increased ChP volume in long COVID individuals, as well as those with neuroinflammatory disorders, normal aging, and AD patients. However, they pointed out, “… despite extensive research, no studies have explored the structural and perfusion alterations in long COVID and their associations with neurological symptoms and blood biomarkers, to date.”
For their newly reported 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. The study participants underwent advanced brain MRI scans, along with blood tests and cognitive exams. “Cognitive impairment was evaluated using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR) scale,” they explained.
The researchers had multiple objectives. They wanted to analyze structural and perfusion alterations in the ChP among individuals with long COVID, in comparison with recovered individuals, and with healthy controls. They also aimed to explore the relationship between ChP alterations and neurological symptoms in long COVID subjects, and to examine correlations between ChP imaging features and plasma biomarkers associated with neuroinflammation and AD-related pathology.
Their tests revealed that structural changes seen in the ChP blood vessels of long COVID patients both expanded ChP volume and reduced flow through its blood vessels (cerebral blood flow; CBF). “Overall, these patients exhibited enlarged ChP and reduced blood perfusion,” the authors wrote.
The results showed that ChP size increases tracked with blood levels of proteins, including glial fibrillary acidic protein (GFAP), that are elevated in response to brain injury. “GFAP, an astrocytic biomarker, elevated during neuronal injury, glial activation, and scarring, is recently considered as potential biomarker of AD,” the team noted. “Elevated GFAP levels have also been reported in both acute SARS-CoV-2 infection and in long COVID, indicating immune-mediated astroglia injury and hypoxia-driven inflammation may contribute to post-infection neurological sequelae.”
The results in addition found that both ChP volume and CBF were significantly correlated with blood pTau217 levels. “Plasma p-tTau217 is a highly sensitive biomarker for identifying AD, reflecting both amyloid and tau burden,” they stated.
The research team found that patients with larger ChPs performed an average of two percent worse on a standard 30-point screening test, the Mini-Mental State Exam (MMSE), which records changes in memory and attention. “Both ChP volume and CBF were associated with cognitive decline measured with Mini-Mental State Examination and Clinical Dementia Rating,” they stated. “The present study identified that ChP enlargement is positively correlated with increased sleepiness and negatively correlated with lower MMSE scores, which are both pertinent indicators of neurodegenerative or AD-related clinical alterations.”
While the mechanisms behind the findings 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 scar-like 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.
“In conclusion, we identified ChP alterations in long COVID, characterized by enlarged volume and reduced blood flow. These alterations were associated with sleep disturbances, cognitive impairment, and plasma biomarkers of AD, suggesting a potential link to future dementia risk,” the scientists reported.
Acknowledging limitations of their study, the investigators also noted that further studies will be required to confirm their findings and clarify potential implications for AD pathogenesis. “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 co-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 and director of the Center for Cognitive Neurology at NYU Langone Health. “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.”
