To determine objectively the degree of olfactory disturbance, we biopsied the olfactory mucosa from patients who complained of anosmia. The olfactory disturbances in this study were caused by choanal atresia, chronic sinusitis, viral inflammation, and head trauma, as well as by congenital and idiopathic anosmia. The biopsy specimens were examined by light microscopy and the degree of mucosal degeneration present was classified according to five grades. The clinical courses of the patients studied paralleled the changes found in the olfactory mucosa.

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The role of nerve growth factor (NGF) in neurotrophic support for the extrinsic innervation of the nasal and oral mucosae was investigated in keratin 14 (K14) - NGF transgenic mice in which NGF was overexpressed in K14-synthesizing cells. K14 immunoreactivity was localized in the epithelial basal cells of the whisker pad skin, the hard palate, the floor of the ventral meatus, and the anterior tongue that are stratified squamous epithelia, and also in basal cells of the vomeronasal, olfactory, and respiratory epithelia that are non-stratified epithelia. In transgenic mice, NGF expression was identified and confined primarily to the basal cells of stratified epithelia. The nasal mucosae including the vomeronasal, olfactory, and respiratory mucosae, and the glands associated with the vomeronasal organ received a greater innervation of protein gene product 9.5-immunoreactive extrinsic fibers in transgenic animals than nontransgenic controls. An increased density of calcitonin gene-related peptide-immunoreactive extrinsic fibers was observed in the nonsensory epithelia of the vomeronasal organ, the olfactory sensory and respiratory epithelia in transgenic animals. Our results indicated that the hyperinnervation of the nasal and oral mucosae by extrinsic neurons is due at least partially to target-derived NGF synthesis and release by K14-expressing basal cells.

The present study deals with the immunohistochemical detection of four brain-derived proteins and cytokeratin in the normal olfactory mucosa of humans and guinea pigs. Neurofilament protein immunoreactivity was found in the olfactory vesicles, dendrites, and perikaryon of receptor cells, and in thick nerve bundles located deep in the lamina propria. The antiserum to neuron-specific enolase (NSE) selectively stained olfactory receptor cells throughout the length of the bundles. The NSE immunoreactivity also was recognized in nerve bundles of various sizes throughout the lamina propria. Glia-specific S-100 protein immunoreactivity was present in Bowman's glands as well as in all nerve bundles in the lamina propria, but not in any cellular elements constituting the olfactory epithelium. Immunoreactivity for spot-35 protein, which was considered to be specific for cerebellar Purkinje cells, was found in flasklike cells (microvillar cells) occurring near the free surface of the epithelium. The basal cells in the olfactory and respiratory epithelium were stained positively with a cytokeratin antiserum.

Characteristic changes that appear in the biopsied olfactory mucosa of patients with Alzheimer's disease (AD) were examined with immunohistochemical staining. Specimens were obtained from patients with clinical diagnoses of AD. Patients with vascular dementia and age-matched patients without dementia were used for controls. In most AD cases, neurofibrillary tangle-like abnormal tau protein (Tau) immunoreactivity was seen in the dendrites and perikarya of the olfactory receptor cells and in the nerve bundles. A senile plaque-like extracellular mass was found in the olfactory epithelium, and it reacted strongly to an anti-Tau antiserum and weakly to an anti-amyloid-beta protein antiserum. Ubiquitin (Ubq) immunoreactivity was also observed in the dendrites. Tau immunoreactivity of the perikarya and extracellular mass, and Ubq immunoreactivity were especially characteristic of the olfactory mucosa of AD patients. From these results, it is clear that the same pathologic changes in the brain are also present in the olfactory mucosa of patients with AD. Not only disruption of the central olfactory pathway, but also an olfactory disturbance of AD patients is caused by peripheral changes. Furthermore, an olfactory mucosal biopsy could be a useful method for a definitive diagnosis of AD.