PET Imaging Shows Aging Reduces Human Brain Ascorbic Acid Transport via Choroid Plexus

A prospective positron emission tomography investigation has demonstrated that ascorbic acid transport from blood across the choroid plexus into cerebrospinal fluid can be directly visualized and quantified in living humans, revealing a significant age-related decline in transport function. Ascorbic acid serves as an essential water-soluble antioxidant within the human brain, supporting synaptic homeostasis, cellular redox balance, and neurotransmitter synthesis. Because the human body cannot synthesize ascorbic acid, the central nervous system depends entirely on carrier-mediated transport across the blood-cerebrospinal fluid barrier to maintain vital physiological levels. Using 6-deoxy-6-[18F]fluoro-L-ascorbic acid as a dedicated radiolabeled probe, researchers successfully tracked the real-time movement of this essential micronutrient analog across ventricular barrier structures. The clinical results establish that functional uptake and ventricular delivery decrease significantly with advancing age, providing the first in vivo evidence of human choroid plexus transport changes across adulthood.

The choroid plexus forms the primary blood-cerebrospinal fluid barrier and acts as the central site of cerebrospinal fluid secretion, regulating fluid composition through active solute carriers. Under baseline physiological conditions, choroid plexus epithelial cells sustain cerebrospinal fluid ascorbic acid concentrations four to ten times higher than blood plasma, while maintaining intraneuronal concentrations approximately two hundred times plasma levels. This steep concentration gradient depends on a coordinated cellular mechanism: sodium-dependent vitamin C transporter 2 at the basolateral membrane takes up ascorbic acid from circulation, while glucose transporter 12 at the apical membrane exports it into the ventricular cerebrospinal fluid. While mouse autoradiography and rabbit kinetic studies confirmed the choroid plexus as the primary entry site, the transport dynamics of these carrier proteins in living humans remained unmeasured due to a lack of noninvasive imaging tools.

Traditional magnetic resonance approaches cannot capture active transporter activity within the blood-cerebrospinal fluid barrier. Structural volumetric magnetic resonance imaging, dynamic contrast-enhanced imaging, and arterial spin labeling detect macrostructural dimensions and barrier integrity, but they cannot measure transporter-mediated solute fluxes. Although proton magnetic resonance spectroscopy noninvasively detects cerebral ascorbic acid concentrations, its spatial resolution cannot capture dynamic transport within small choroid plexus structures. Positron emission tomography resolves these constraints by tracking radiotracer kinetics across living tissues. The radiotracer 6-deoxy-6-[18F]fluoro-L-ascorbic acid was originally designed and evaluated to image malignancies expressing high levels of sodium-dependent vitamin C transporter 2, such as thyroid cancer. Because this radiopharmaceutical shares the in vivo biodistribution of natural ascorbic acid and demonstrates prompt choroid plexus uptake followed by ventricular accumulation, researchers recognized its potential as a targeted molecular probe to evaluate choroid plexus transport kinetics in living humans.

To evaluate this imaging strategy, investigators conducted a prospective secondary analysis utilizing data gathered between May 2024 and September 2024 under trial registration ChiCTR2300076126. Approved by the local ethics committee under Declaration of Helsinki principles with written informed consent, the primary trial enrolled thyroid cancer patients. The secondary analysis included patients without neurological disorders who underwent static scans starting thirty to ninety minutes post-injection or dynamic scanning initiated immediately after administration. Patients were excluded for pregnancy, breastfeeding, neurological symptoms, brain computed tomography abnormalities like tumors or infarction, or poor scan quality. The final analysis evaluated 161 participants with a mean age of 48.0 ± 15.7 years, comprising 71 men and 90 women. Eight participants completed dynamic scanning, while 153 underwent static scanning protocols.

All imaging sessions were conducted on a digital uMI 780 positron emission tomography and computed tomography scanner without requiring patient fasting. Each subject received an intravenous injection of 259 to 370 megabecquerels of 6-deoxy-6-[18F]fluoro-L-ascorbic acid. For the eight participants undergoing dynamic brain imaging, list-mode acquisition commenced immediately upon tracer injection and continued for forty-five minutes. Axial computed tomography scans (120 kV, 100–200 mAs, 2.68-mm thickness, 1.34-mm interval) provided attenuation correction and anatomical localization. Frame-wise rigid registration to CT images was performed using SimpleITK software version 2.5.0 for motion correction without dedicated head holders.

For the 153 static imaging participants, whole-body PET/CT began between thirty and ninety minutes post-injection (mean start time 57.4 ± 13.6 minutes; range 33–89 minutes). Axial computed tomography parameters were 120 kV, smart 100–200 mAs, 1.25-mm slice thickness, and 1.25-mm slice interval. Emission data were acquired over six bed positions at 1.5 minutes per position. Static PET volumes were reconstructed using a Bayesian penalized likelihood algorithm with attenuation correction. Workstation review of coregistered images provided anatomical visualization of the ventricular system, enabling consistent quantification of tracer accumulation across the choroid plexus and cerebrospinal fluid.

Image analysis was independently executed by two nuclear medicine physicians with eleven and five years of experience, blinded to clinical details. Baseline computed tomography was evaluated to record choroid plexus calcification, defined by high-density areas in either ventricle. Partial-volume correction was omitted because computed tomography did not provide sufficiently accurate choroid plexus boundaries. In dynamic datasets, volumes of interest were outlined on the choroid plexus of the lateral and fourth ventricles guided by the five-to-six-minute frames. Spherical cerebrospinal fluid volumes of interest measuring approximately six millimeters in diameter were placed in the anterior horns of the lateral ventricles and the fourth ventricle superior to the choroid plexus, approximately ten millimeters away to prevent overlap. Standardized uptake values were derived, and area under the curve across zero to forty minutes was calculated using the trapezoid method. Observer agreement proved excellent, yielding intrarater intraclass correlation coefficients between 0.96 and 0.99 and interrater coefficients between 0.92 and 0.98.

Dynamic imaging demonstrated that 6-deoxy-6-[18F]fluoro-L-ascorbic acid accumulated rapidly within the choroid plexus of both lateral and fourth ventricles, reaching mean peak standardized uptake values at approximately five minutes post-injection before subsequently declining. Concurrently, tracer levels in ventricular cerebrospinal fluid increased progressively throughout the forty-five-minute scan, while brain parenchyma showed minimal tracer uptake. Semiquantitative time-activity evaluations revealed that tracer activity decreased with age. The area under the curve from zero to forty minutes was significantly higher in younger participants under sixty years than in elderly participants aged sixty and older within the choroid plexus of both lateral and fourth ventricles. In the fourth ventricle, younger participants exhibited a significantly higher uptake slope across the initial ten minutes in the choroid plexus, alongside a significantly steeper accumulation slope in cerebrospinal fluid between ten and forty minutes, indicating reduced carrier extraction and export capacity among older individuals.

All static scans showed visibly elevated tracer accumulation within the choroid plexus, while demonstrating clear age-related reductions in PET metrics. In univariable linear regression analysis, advancing age emerged as a significant predictor of lower standardized uptake values across both choroid plexus and cerebrospinal fluid spaces. Scan-start time was negatively associated with lateral ventricle choroid plexus uptake and positively associated with fourth ventricle cerebrospinal fluid values. Stratified analysis confirmed that the negative association between age and tracer metrics remained consistent across imaging intervals, showing the strongest statistical consistency within the 51-to-70-minute window. Furthermore, participants presenting choroid plexus calcification had significantly lower metrics in the lateral ventricle choroid plexus, fourth ventricle choroid plexus, and lateral ventricle cerebrospinal fluid compared to those without calcification. Conversely, female participants exhibited significantly higher uptake metrics than males in the fourth ventricle choroid plexus and in the cerebrospinal fluid of both lateral and fourth ventricles.

Multivariable linear regression models adjusting simultaneously for sex and choroid plexus calcification confirmed that advancing age was an independent predictor of lower radiotracer metrics. Older age independently predicted reduced maximal and mean standardized uptake values in the choroid plexus as well as in the cerebrospinal fluid across both lateral and fourth ventricles. Increasing age also independently predicted lower cerebrospinal fluid-to-choroid plexus standardized uptake ratios in the lateral ventricles. Following multivariable adjustment, scan-start time retained an independent negative association with lateral ventricle choroid plexus metrics and positive associations with cerebrospinal fluid-to-choroid plexus ratios in both ventricles. Female sex remained an independent predictor of higher cerebrospinal fluid uptake in both ventricles. Sensitivity analyses evaluating spherical volume dimensions across four, six, and eight millimeters in lateral ventricles and four and six millimeters in the fourth ventricle confirmed that cerebrospinal fluid metrics and concentration ratios remained robust regardless of region sizing.

The observed dynamic curve aligns with a sequential transport mechanism where basolateral uptake via sodium-dependent vitamin C transporter 2 is followed by rate-limiting apical release into cerebrospinal fluid via glucose transporter 12. The age-related transport decline corresponds with structural alterations in aging choroid plexus tissue, such as epithelial flattening, microvillus loss, and mitochondrial degeneration, suggesting that volumetric plexus enlargements seen in older adults may reflect non-functional or cystic tissue expansion. Astrocytic recycling of dehydroascorbic acid likely preserves steady-state cortical concentrations despite falling barrier transport, indicating that transport reductions may precede detectable changes in brain parenchyma. Nevertheless, investigators highlighted notable study limitations: the dynamic cohort comprised only eight patients, the sample consisted of individuals evaluated for thyroid cancer rather than healthy volunteers, partial-volume correction was precluded by computed tomography resolution, and dedicated head holders were omitted, indicating that larger studies are needed to determine clinical relevance in neurodegenerative diseases.

Subject of Research: In vivo quantification of human choroid plexus ascorbic acid transport using [18F]FAA PET imaging

Article Title: Ascorbic acid transport via choroid plexus measured with 6-deoxy-6-[18F]fluoro-L-ascorbic acid PET

Article References: Zhang, Y., Lin, X., Deng, H., Long, Y., Yang, T., Jiang, K., Ge, S., He, Q., Zhang, B., Jiang, N., Zha, Z., & Zhang, X. (2026). Ascorbic acid transport via choroid plexus measured with 6-deoxy-6-[18F]fluoro-L-ascorbic acid PET. Fluids and Barriers of the CNS, 23(1), Article 122. https://doi.org/10.1186/s12987-026-00847-w

Image Credits: AI Generated

DOI: 10.1186/s12987-026-00847-w

Keywords: ascorbic acid transport, choroid plexus, blood-cerebrospinal fluid barrier, positron emission tomography, 6-deoxy-6-[18F]fluoro-L-ascorbic acid, [18F]FAA PET, cerebrospinal fluid, aging brain, sodium-dependent vitamin C transporter 2, GLUT12, brain antioxidant, multivariable linear regression, dynamic PET, standardized uptake value, choroid plexus calcification, neuroimaging, kinetic analysis