Many toddlers diagnosed with autism at two years of age had a substantially greater amount of extra-axial cerebrospinal fluid (CSF) at six and 12 months of age, before diagnosis is possible, a research network led by UNC School of Medicine’s Joseph Piven, MD has found. They also found that the more CSF at six months - as measured by MRI - the more severe the autism symptoms were at two years of age.
The findings point to faulty cerebrospinal fluid flow as one of the possible causes of autism for a large subset of people.
“The CSF is easy to see on standard MRIs and points to a potential biomarker of autism before symptoms appear years later. We also think this finding provides a potential therapeutic target for a subset of people with autism,"
said Piven, co-senior author of the study, the Thomas E. Castelloe Distinguished Professor of Psychiatry, and director of the Carolina Institute for Developmental Disabilities (CIDD).
Cerebrospinal Fluid Functions
Until the last decade, the scientific and medical communities viewed cerebrospinal fluid as merely a protective layer of fluid between the brain and skull, not necessarily important for proper brain development and behavioral health. But scientists then discovered that CSF acted as a crucial filtration system for byproducts of brain metabolism.
First author Mark Shen, PhD, CIDD postdoctoral fellow, said:
“We know that CSF is very important for brain health, and our data suggest that in this large subset of kids, the fluid is not flowing properly. We don’t expect there’s a single mechanism that explains the cause of the condition for every child. But we think improper CSF flow could be one important mechanism."
Every day, brain cells communicate with each other. These communications cause brain cells to continuously secrete byproducts, such as inflammatory proteins that must be filtered out several times a day. The CSF handles this, and then it is replenished with fresh CSF four times a day in babies and adults.
High Autism Risk
The researchers enrolled 343 infants, 221 of which were at high risk of developing autism due to having an older sibling with the condition. Forty-seven of these infants were diagnosed with autism at 24 months, and their infant brain MRIs were compared to MRIs of other infants who were not diagnosed with autism at 24 months of age.
The six-month olds who went on to develop autism had 18 percent more CSF than six-month olds who did not develop autism. The amount of CSF remained elevated at 12 and 24 months. Infants who developed the most severe autism symptoms had an even greater amount of CSF - 24 percent greater at six months.
Also, the greater amounts of CSF at six months were associated with poorer gross motor skills, such as head and limb control. David G. Amaral, director of research at the UC Davis MIND Institute, said:
“Normally, autism is diagnosed when the child is two or three years old and beginning to show behavioral symptoms; there are currently no early biological markers. That there’s an alteration in the distribution of cerebrospinal fluid that we can see on MRIs as early as six months, is a major finding."
The researchers found that increased CSF predicted with nearly 70 percent accuracy which babies would later be diagnosed with autism. It is not a perfect predictor of autism, but the CSF differences are observable on a standard MRI.
“In the future, this sort of CSF imaging could be another tool to help pediatricians detect risks for autism as early as possible,” Shen said.
“We can’t yet say for certain that improper CSF flow causes autism. But extra-axial CSF is an early marker, a sign that CSF is not filtering and draining as it should. This is important because improper CSF flow may have downstream effects on the developing brain; it could play a role in the emergence of autism symptoms."
The National Institutes of Health, Autism Speaks, and the Simons Foundation funded the research.
Mark D. Shen, Sun Hyung Kim, Robert C. McKinstry, Hongbin Gu, Heather C. Hazlett, Christine W. Nordahl, Robert E. Emerson, Dennis Shaw, Jed T. Elison, Meghan R. Swanson, Vladimir S. Fonov, Guido Gerig, Stephen R. Dager, Kelly N. Botteron, Sarah Paterson, Robert T. Schultz, Alan C. Evans, Annette M. Estes, Lonnie Zwaigenbaum, Martin A. Styner, David G. Amaral, Joseph Piven Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants who Later Develop Autism Biological Psychiatry, 2017; DOI: 10.1016/j.biopsych.2017.02.1095
Image: Right: MRI of a baby at 6 months who was diagnosed with autism at 2 years. The dark space between the brain folds and skull indicate increased amounts of cerebrospinal fluid. Left: MRI of a baby who was not diagnosed with autism at age 2. Credit: Carolina Institute for Developmental Disabilities (UNC-Chapel Hill)