Another possibility is that olfactory dysfunction in neurodegenerative disease patients is due to damage to the basal forebrain cholinergic system, which is involved in the secretion of the neurotransmitter acetylcholine (ACh) in many areas of the brain. This neurotransmitter plays a significant role in attention, memory, and the facilitation of cortical plasticity, including functional recovery following brain injury. Figure 1The basal forebrain cholinergic system sends cholinergic neural projections to the OB and other main brain regions responsible for smell, memory, and cognition. These projection cells keep checking the activity of the immune cells, such as microglia and astrocytes (Doty, 2012).
Damage to neuron cells projecting to the OB can cause the activation of the resident immune cells which will result in immune activation and the secretion of inflammatory mediators such as the cytokine tumor necrosis factor-alpha (TNF). High level of TNF can cause cell damage and even death which can result in olfactory impairment in neurodegenerative diseases. Figure 2In PD and AD diseases, the deficit is present in 85 to 90% of early-stage patients and is associated with decreased activation of central odor processing structures (as measured by functional imaging).
Bellow, is the summary of evidence demonstrating a correlation between olfactory dysfunction and these two neurodegenerative diseases:
In the 1990s, G. Webster Ross and his colleagues at the University of Hawaii administered smell test to 2,276 nonsymptomatic elderly men to investigate the association between olfactory dysfunction and neurodegenerative diseases. The results of this study showed that those subjects whose initial olfactory test scores fell within the bottom 25 percent of the group were five times more likely to develop PD than the rest of the participants. Over four years, 35 were clinically diagnosed with PD (Doty, 2013).
Further support for olfactory involvement in PD came in 2004, when Mirthe Ponsen
In another study, olfactory dysfunction was observed in patients with an abnormal reduction in striatal dopamine transporter binding, who subsequently developed PD (Shivers et al., 1989).In a study conducted by Hawkes and coworkers, it is shown that PD may start in the olfactory system before the damage in the basal ganglia (Hawkes, Shephard, & Daniel, 1999). In another study it has been shown that atrophy in the piriform cortex and OFC is associated with olfactory dysfunction in early PD, becoming thus significant as olfactory damage progresses (Wu et al., 2011).
Researchers have found evidence that there is a connection between olfactory dysfunction and Alzheimers disease. One evidence they have found is beta-amyloid plaques, a biomarker of AD, in both the olfactory system and the central nervous system in AD patients. In a study conducted by the researchers at DGIST, it has been observed that these plaques have a toxic effect on the olfactory senses after six months, even though the cognitive decline was not observed until the 14-month mark (DGIST, 2017).
In another study, researchers compared the BOLD response to the different odorant concentrations between the AD and healthy controls using fMRI, in addition to collecting smell test scores from AD patients and healthy participants. The study demonstrated that significant changes in odor-related BOLD signal are present in AD patients in comparison to healthy controls and the results correlated with the individuals smell test scores which demonstrated an association of olfactory decline with AD pathology (Wang et al., 2010).
In these fMRI studies of AD patients, the degeneration of neural structures responsible for olfactory functions: primary olfactory cortex, hippocampus, insula, thalamus, and hypothalamus, was also observed (Wang et al., 2010).Besides, there is evidence obtained using stereological techniques, that shows an increased number of dopaminergic periglomerular neurons and a significant volumetric decrease in the olfactory bulb in AD patients (Mundiñano, Caballero, Ordóñez, & et al, 2011). A
nother observation is the correlation between olfactory bulb volume and Mini-Mental State Examination in AD patients (Thomann & et al, 2009). Several studies suggest that the transentorhinal cortex, areas involved in memory, emotion, and olfaction, is one of the first brain regions that is damaged by AD (Braak, Braak, & Bohl, 1993).