Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET

Abstract

Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with 18 F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Methods: Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with 18 F-THK5117. Ten subjects additionally underwent 11 C-Pittsburgh compound B ( 11 C-PiB) PET scanning, and 8 were 11 C-PiB-positive. Ventricular time-activity curves of 18 F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels. Results: For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

Perivascular spaces, glymphatic dysfunction, and small vessel disease

“…However, mice lacking functional vascular endothelial growth factor receptor 3 (VEGFR3), a critical regulator of lymphangiogensis, develop LN hypoplasia and demonstrate decreased clearance of tracers injected into the brain(95). Reduced CSF clearance at the nasal mucosa in humans has also been linked to AD and increased Aβ burden(97). These data suggest that disruption of peripheral efflux sites significantly affect CNS solute clearance.…”

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

“…Some of those, such as lactate, tau, and Aβ, have been implicated in dementia development [90,140,141]. In addition to being a consequence of Aβ pathology, impairments in CSF clearance and the glymphatic system could promote Aβ accumulation [15,142]. By using in vivo MRI of gadolinium-based contrast agent injected into the CSF, Gaberel and collaborators found that ischemic stroke in rodents leads to a decrease of CSF circulation through perivascular spaces, which could be explained by a decrease of arterial pulsation after artery occlusion [17,143].…”

Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis

“…Given the close connection between CSF flow and the glymphatic system, 11 C-PiB PET could also serve as an in-vivo marker of glymphatic system function. Here we aim to replicate previous results that showed decreased lateral ventricular 11 C-PiB signal magnitude in Alzheimer's disease compared to controls (19) and to extend the method to mild cognitive impairment and multiple sclerosis patient groups.…”

“…Standardized uptake value ratios (SUVRs) from 50 to 70 minutes were calculated for the gray matter and lateral ventricle ROIs for each subject from both datasets using cerebellum or a supervised reference region for the AD/MCI and multiple sclerosis datasets, respectively. For consistency with a previous study (19), area-under-curve (AUC) from 35 to 80 minutes was also calculated for the lateral ventricle ROI for a subset of the AD/MCI dataset. AUC35-80 was also calculated for the lateral ventricle ROI for all subjects in the multiple sclerosis dataset.…”

“…11 C-PiB is a neutral lipophilic benzothiazole PET tracer and is used to image A plaques in Alzheimer's disease (17) and, more recently, to quantify in vivo myelin loss and regeneration in multiple sclerosis (18). 11 C-PiB PET has also recently been used to quantify CSF clearance in humans (19). Small molecule radiotracers enter the CSF of the lateral ventricles either directly from the blood through a thick layer of epithelial cells that make up the choroid plexuses or from the brain parenchyma via diffusion through the ependymal cells that line the adult ventricular system (10).…”