In patients with neurodegenerative diseases, there is a spectrum of smell dysfunction ranging from severe loss, as seen in Alzheimer's disease and Parkinson's disease, to relatively little loss, as seen in progressive supranuclear palsy. Given the ubiquitous but varying degrees of olfactory dysfunction among such diseases, it is conceivable that differential disruption of a common primordial neuropathological substrate causes these differences in olfactory function. For example, the amount of damage to forebrain neurotransmitter and neuromodulator circuits, most notably those involving cholinergic transmission, appears to be correlated with quantitative smell test scores across a wide range of neurodegenerative diseases. Thus, a key question is whether damage to such a substrate is the basis for the perceptual differences in olfaction or whether disease-specific or other entities, such as respiratory infections or pollution, are responsible. In light of the early preclinical onset of smell deficits in many neurodegenerative diseases, the answer to this question might provide crucial insight into the cause of disease pathology at its earliest stages of development.
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