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.

The Neuroregenerative Capacity of Olfactory Stem Cells Is Not Limitless: Implications for Aging

“…In apparent contrast to the regenerative capacity exemplified by the manipulations described above, our group and others have shown that the OE of elderly humans often contains large areas of the epithelium devoid of neurons and GBCs (Nakashima et al, 1984;Holbrook et al, 2005. Moreover, the same has been noted in aged mice (Kondo et al, 2009;Van de Bittner et al, 2017).…”

“…In the case of the olfactory epithelium (OE), a pseudostratified neuroepithelium lining the nasal cavity, tissue stem cells are activated in response to damage and can replace cells that were lost, including the olfactory sensory neurons (OSNs). The regenerative capacity for OE stem cells after injury has been reported in several injury models (Graziadei et al, 1979;Morrison and Costanzo, 1989;Schwob et al, , 1999. Two separate populations of basal cells act as stem cells in the OE.…”

“…Although various diseases and environmental factors may contribute, one study re-ports that Ͼ60% of the population between the ages of 65 and 80 years and 80% of those Ͼ80 years of age have olfactory impairment. Age is arguably the number one cause of olfactory impairment (Doty et al, 1984) and anosmia has been identified as a predictor of 5-year mortality in people between 57 and 85 (Pinto et al, 2014).…”

“…The first are the globose basal cells (GBCs), among which are the active stem cell population responsible for day-to-day maintenance of the neuronal population (Graziadei and Graziadei, 1979) and which can regenerate the entire epithelium after epithelial injury (Huard et al, 1998;Chen et al, 2004). The second group are the horizontal basal cells (HBCs), which are a reserve stem population that is activated by severe direct epithelial injury and can also regenerate the OE under the appropriate conditions (Leung et al, 2007;Schnittke et al, 2015).…”

Seeing how we smell

“…In this issue, Van de Bittner et al describe a promising step toward solving this problem (5). Specifically, the authors discovered and characterized a new PET radiotracer, [ 11 C]GV1-57, which, they conclude, labels the mature olfactory sensory neurons (OSNs) of the olfactory epithelium, the tissue involved in recognizing smells ( Figure 1).…”