New therapeutic implications from latest CFR research

SAN FRANCISCO, CA 5/12/14. CFR investigators recently reported new insight into what causes the significant variability in levels of progranulin previously observed among individuals. Led by postdoctoral fellow Dr. Andra Nicholson in the lab of senior author and CFR Investigator Dr. Rosa Rademakers at the Mayo Clinic in Jacksonville, FL, the new study analyzed progranulin levels in plasma and cerebral spinal fluid (CSF) from 345 individuals and identified multiple contributions to this variability.

“We confirmed the conundrum we’d suspected would be there, based on the highly variable levels of progranulin between individuals that we had previously measured,“ said Dr. Nicholson.

Mutations in progranulin cause frontotemporal dementia by reducing the amount of circulating progranulin protein by more than half. In fact, Rademakers and colleagues previously reported that measuring plasma progranulin levels is an accurate way to identify individuals with progranulin mutations. Given this reduction, finding a drug that can restore progranulin levels to normal levels is the focus of numerous initiatives to treat FTD caused by progranulin mutations.

Blood is much easier to obtain than CSF, thus researchers were hopeful that measuring blood progranulin levels would be a reliable indicator of CSF progranulin levels. However, Dr. Nicholson and colleagues’ new work revealed that while CSF and plasma progranulin levels do correlate, this correlation is very small. Drugs often have difficulty entering the brain because of a selectively penetrant blood brain barrier that separates the brain from the bloodstream. Dr. Nicholson’s work revealed that to accurately understand a drug’s effect on altering progranulin levels in the brain, progranulin must be measured in CSF, not blood.

“Measuring progranulin in blood is a fail-safe way to determine if a patient is a mutation carrier,” said Dr. Nicholson, “but we advise caution when using blood progranulin levels as a reflection of brain progranulin levels.”

Dr. Nicholson and colleagues asked what might contribute to the difference in progranulin levels between individuals and determined that age, gender, and plasma progranulin levels accounted for only 6% of the variability in CSF. DNA differences were responsible for an additional 12%, resulting from changes in a region of the progranulin gene previously shown to affect the levels of this protein. What accounts for the remaining 82% of variability in CSF between individuals remains unknown, but Dr. Nicholson and colleagues proposed environmental factors such as inflammation state or fasting may influence levels.