CSF production and drainage are vital brain functions with deficiencies contributing to amyloid lesions in murine models of aging and Alzheimer’s disease (AD). We developed a human PET based technology to measure CSF drainage (de Leon et al 2017). Using [18F]-tau tracers we replicated our findings of reduced ventricular CSF drainage in AD and the association with [11C]-PiB PET amyloid accumulation (Li et al 2022). We recently developed an improved PET radiotracer for CSF dynamics [11C]-Butanol, a highly permeable alcohol that does not bind to brain tissues. [11C]-Butanol with a 20min half-life enables unbiased estimates of brain CSF egress. We hypothesized that CSF turnover is reduced in normal elders, associated with amyloid, and that anatomical CSF egress pathways could be identified.
Thirty-two normal subjects between the ages of 20-85y were examined. Dynamic list mode [11C]-Butanol PET, [18F]MK6240, and [11C]-PiB were sequentially obtained and co-registered to MRI. Tracer time activity data were used to model the egress of CSF from brain and extra-cranial sites. We examined known CSF draining regions including: brain, ventricle, nasal turbinates, superior sagittal sinus, optic nerve sheath, and control regions.
Ventricular [11C]-Butanol production and clearance reductions are age associated (r=-.83, p<.01) and reduced in subjects above the median age of 67y (~23%, p<.05). Ventricular CSF egress reductions are associated with global brain amyloid (p<.05), but not global brain tau estimates. Using [11C]-Butanol we identified the optic nerve sheath as a CSF egress site affected by aging.
PET imaging of CSF may provide quantitative evidence for drainage pathways carrying misfolded proteins impacted by age.