Neurons, Nose, and Neurodegenerative Diseases: Olfactory Function and Cognitive Impairment

Abstract

Olfactory capacity declines with aging, but increasing evidence shows that smell dysfunction is one of the early signs of prodromal neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The study of olfactory ability and its role in neurodegenerative diseases arouses much interest in the scientific community. In neurology, olfactory impairment is a potential early marker for the onset of neurodegenerative diseases, but the underlying mechanism is poorly understood. The loss of smell is considered a clinical sign of early-stage disease and a marker of the disease's progression and cognitive impairment. Highlighting the importance of biological bases of smell and molecular pathways could be fundamental to improve neuroprotective and therapeutic strategies. We focused on the review articles and meta-analyses on olfactory and cognitive impairment. We depicted the neurobiology of olfaction and the most common olfactory tests in neurodegenerative diseases. In addition, we underlined the close relationship between the olfactory and cognitive deficit due to nasal neuroepithelium, which is a direct extension of the CNS in communication with the external environment. Neurons, Nose, and Neurodegenerative diseases highlights the role of olfactory dysfunction as a clinical marker for early stages of neurodegenerative diseases when it is associated with molecular, clinical, and neuropathological correlations.

Keywords: anosmia; cognitive dysfunction; nasal neuroepithelium; neurodegenerative disease; neurons; nose; olfactory biomarkers.

Figure 1

Flow chart of articles selection (see methods).

Figure 2

Descriptive anatomy of odorant signal transmission and the human olfactory system. In the box, a focus is on the olfactory system, with neuroepithelium, composed of olfactory sensory neurons that, through the lamina cribrosa plate, establish a synaptic connection with the mitral cells of the olfactory bulb. The axons of the monosynaptic mitral cells that make up the olfactory tract bifurcate at the terminus, fornix, or olfactory cortices. Primarily, the limbic system with the pyriform cortex, amygdala, and entorhinal cortex is involved. (Modified from medical illustration by Patrick J. Lynch).

Figure 3

Higher cognitive abilities, reserved for specific brain regions, are required to identify odors, which, in neurodegenerative diseases, manifest common neuroanatomical defects, up to altered neurotransmission patterns of olfactory pathways, such as for the deposition and accumulation of molecules such as α-synuclein, TDP-43, hyperphosphorylated tau protein, and β-amyloid protein. An important aspect for the clinician, and particularly the otolaryngologist, is the performance of olfactory testing in patients who manifest olfactory disorders. In this context, individuals affected by neurodegenerative diseases should be able to perform non-cognitively complex, short-term tests with few tasks. For this reason, differential diagnosis is recommended for common nasal disorders frequently associated with anosmia or other olfactory disorders so that such disorders can be identified early, as a prodromal symptom of neurodegenerative diseases.