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 2

[11C]GV1-57 binds mature OSNs.

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[11C]GV1-57 binds mature OSNs. (A) Representative [11C]GV1-57 PET images...
(A) Representative [11C]GV1-57 PET images (SUV, NIH+white, 3–45 minutes) of 3-month-old mice imaged with no treatment (control) or 2–3 days after unilateral or bilateral anterior bulbectomy. (B) DVR quantification of [11C]GV1-57 uptake in control and bulbectomy-treated mice. Error bars are ± SEM; n = 3–6 per group. One-way ANOVA, F(2, 9) = 8.808, P < 0.01, followed by a 1-tailed Student’s t test, ***P < 0.005. (C and D) Coronal OE sections from a mouse that underwent unilateral anterior bulbectomy and [11C]GV1-57 imaging were immunostained with anti-OMP and stained with DAPI to provide total and OMP+ nuclei counts. OE regions with the greatest damage on the bulbectomy side were paired with the contralateral sham side, and both were counted. (C) OMP+ nuclei were significantly reduced following anterior bulbectomy, and OMP– nuclei numbers were not significantly altered. Error bars are ± SEM; n = 3 tissue sections. ***P < 0.005 using a 2-tailed Student’s t test. NS, P = 0.34 using a 2-tailed Student’s t test. (D) Representative image of an immunostained OE section. White boxes indicate regions used for cell counting. (E) Western immunoblot of the mature OSN population (OMP) in control and bulbectomy-treated mice, using OE tissue from animals imaged with [11C]GV1-57. For this and the following immunoblot analyses, protein marker intensities relative to total protein loaded were used, since the goal was to analyze changes in relative cellular populations, as opposed to alterations in protein expression. n = 2 per group. (F) Significant correlation between [11C]GV1-57 quantification (DVR) and the mature OSN population (OMP) across individual mice (Spearman, r = 0.89, P = 0.033).