The cerebrospinal fluid (CSF) pulsates through small, fluid-filled channels known as perivascular spaces during the day and night. These channels surround the blood vessels in the brain and serve to flush out neuroinflammations and other neurological wastes. A disruption to this vital process can lead to neurological dysfunction, cognitive decline, or developmental delays.
For the first time, researchers Dea Garic, PhD, and Mark Shen, PhD, from the Department of Psychiatry at UNC School of Medicine, discovered that infants with abnormally enlarged perivascular spaces are 2.2 times more likely to develop autism compared to infants with similar genetic risk. Their research also found that enlarged perivascular spaces in infants are associated with sleep problems seven to ten years after diagnosis.
„These findings suggest that perivascular spaces could serve as an early marker for autism,“ said Garic, Assistant Professor of Psychiatry and member of the Carolina Institute for Developmental Disabilities (CIDD).
The researchers studied infants at a higher risk of developing autism because they had an older sibling with autism. They observed these infants between the ages of 6 and 24 months before an autism diagnosis was reached. Their study, published in JAMA Network Open, found that thirty percent of infants who later developed autism showed enlarged perivascular spaces at 12 months. By the age of 24 months, almost half of the infants diagnosed with autism had enlarged perivascular spaces.
Significance of Cerebrospinal Fluid and Sleep
For the past ten years, research on the vital functions of cerebrospinal fluid in regulating brain health and development has been revitalized. Shen’s lab was the first to report an excess volume of cerebrospinal fluid in infants who later developed autism at the age of 6 months. The current study showed that excess cerebrospinal fluid volume after 6 months was associated with enlarged perivascular spaces after 24 months.
Every six hours, the brain emits a CSF wave that flows through perivascular spaces to potentially prevent harmful neuroinflammatory proteins, such as amyloid beta, from accumulating in the brain. The CSF clearance process is particularly efficient while we sleep, as most of the CSF circulation and clearance occurs during sleep.
However, sleep disturbances can reduce CSF clearance from perivascular spaces and lead to dilation or enlargement. This has only been studied in animal studies or human studies in adults so far. This is the first study of its kind in children.
Based on Shen’s earlier research, Garic hypothesized that cerebrospinal fluid anomalies in infancy would be associated with later sleep problems. The current sleep analysis found that children with enlarged perivascular spaces at the age of two were more likely to experience sleep problems in school.
„As autism is strongly associated with sleep problems, we were in the unique position to examine cerebrospinal fluid dynamics and sleep. It was truly amazing to observe such a strong association that was separate over such a long period in childhood. But it really shows that perivascular spaces not only have early-life effects but also long-term effects.“
Dea Garic, PhD, lead author of the article.
New Clinical Relevance in Infancy
The research was conducted in association with the Infant Brain Imaging Study (IBIS), a nationwide network of researchers focused on brain development, autism, and related developmental disorders. The network consists of five universities, with the main site being the University of North Carolina at Chapel Hill.
For their study, Garic and Shen analyzed 870 MRI scans from IBIS to measure excess cerebrospinal fluid volume and enlarged perivascular spaces. MRI scans were taken of babies during natural sleep at the ages of six, 12, and 24 months to observe changes over time.
The infant brain undergoes rapid development during this period. It was previously believed that measuring perivascular spaces was only clinically relevant in age-related disorders in older adults, such as dementia. These findings suggest that younger populations may need to be considered and monitored for this type of brain anomaly.
„Our findings were remarkable, as neuroradiologists usually consider enlarged perivascular spaces as a sign of neurodegeneration in adults, but this study reported them in toddlers,“ said Garic. „This is an important aspect of brain development in the first few years of life that should be monitored.“
Future Studies and Opportunities
Garic and Shen believe that excess cerebrospinal fluid volume stagnates or clogs and does not circulate as efficiently through the brain as it should. For their next research project, the researchers plan to use MRI scans again to measure cerebrospinal fluid in the brain of a sleeping infant, this time focusing on the physiology and speed of cerebrospinal fluid flow through the brain.
The research team is also collaborating with other staff to quantify the size of perivascular spaces and the severity of behavioral consequences. The team also plans to expand their research to neurogenetic syndromes associated with autism, such as fragile X syndrome and Down syndrome.
„Overall, our research has shown that cerebrospinal fluid anomalies in the first year of life can have downstream effects on a variety of consequences, including later autism diagnosis, sleep problems, neuroinflammation, and possibly other developmental disorders,“ Shen said.
University of North Carolina Health Care
Garic, D., et al. (2023). Enlarged perivascular spaces in infancy and autism diagnosis, cerebrospinal fluid volume, and later sleep problems. JAMA Network Open. doi.org/10.1001/jamanetworkopen.2023.48341.