Nasal neuron PET imaging quantifies neuron generation and degeneration
Genevieve C. Van de Bittner, … , Mark W. Albers, Jacob M. Hooker
Genevieve C. Van de Bittner, … , Mark W. Albers, Jacob M. Hooker
Published January 23, 2017
Citation Information: J Clin Invest. 2017;127(2):681-694. https://doi.org/10.1172/JCI89162.
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Research Article Aging Neuroscience

Nasal neuron PET imaging quantifies neuron generation and degeneration

Abstract

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics.

Authors

Genevieve C. Van de Bittner, Misha M. Riley, Luxiang Cao, Janina Ehses, Scott P. Herrick, Emily L. Ricq, Hsiao-Ying Wey, Michael J. O’Neill, Zeshan Ahmed, Tracey K. Murray, Jaclyn E. Smith, Changning Wang, Frederick A. Schroeder, Mark W. Albers, Jacob M. Hooker

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Figure 3

[11C]GV1-57 imaging of the mature OSN population during normative development and aging.

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[11C]GV1-57 imaging of the mature OSN population during normative develo...
(A) Representative [11C]GV1-57 PET images (SUV, NIH+white, 3–45 minutes) of male rats administered [11C]GV1-57 (0.93 ± 0.14 mCi) at select ages during postnatal olfactory neurodevelopment and into the OE developmental plateau. Images selected from 7 ages between 1.3 and 15 months old (C). (B) Representative [11C]GV1-57 PET images (SUV, NIH+white, 3–45 minutes) of female mice administered [11C]GV1-57 (0.54 ± 0.11 mCi) at select ages during postnatal olfactory neurodevelopment, maturation, and aging. (C) DVR quantification of [11C]GV1-57 uptake in rats imaged across OSN neurodevelopment and into the OE developmental plateau. Gray box indicates additional [11C]GV1-57 dynamic range. Error bars are ± SEM; n = 3–8 per age. Regression analysis indicates a cubic fit to the data; type III ANOVA with Satterthwaite approximation indicates significant curve fit, P = 1.9 × 10–8. (D) DVR quantification of [11C]GV1-57 uptake in individual rats imaged at 5.5, 9, and 12 months. The slope of each line indicates the rate of OSN influx for a single animal (Supplemental Table 3). (E) DVR quantification of [11C]GV1-57 uptake in mice imaged at 3, 4, 7, 12, and 23 months. Gray box indicates additional [11C]GV1-57 dynamic range. Error bars are ± SEM; n = 2–6 per age. **P < 0.01, ***P < 0.005, using a 2-tailed Student’s t test with Bonferroni correction (α = 0.025) for multiple comparisons. (F) Modeled olfactory neuron population curve using [11C]GV1-57 rodent imaging data from C and E. This model corroborates existing ex vivo OSN data (37–39) that suggest that net OSN influx occurs prior to a midlife OSN population peak with net OSN efflux beyond the peak. The mature OSN drawings depict changes in net OSN population, a result of changes to total OSN-populated area and OSN density across lifespan (37–39). Specifically, a less dense and smaller OE is present at early stages of development, a maximally dense and maximally large OE is present at the OSN population peak, and a less dense but still relatively large OE is present at older ages (37–39). Neuron illustrations were hand-drawn by GCV.