Functional Olfactory Deficits in the Olfactory System of Alzheimer’s Disease and Mild Cognitive Impairment Patients as a Potential Diagnostic Marker

Open Access
Vasavada, Megha M
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
March 10, 2014
Committee Members:
  • Qing X Yang, Dissertation Advisor
  • Paul Joseph Eslinger, Committee Member
  • Patricia Sue Grigson Kennedy, Committee Member
  • Ralph Norgren, Committee Member
  • Alzheimer's disease
  • Mild cognitive impairment
  • olfaction
  • MRI
  • fMRI
Alzheimer's disease affects 5.4 million individuals in the US, causing debilitating memory and cognitive impairment. By the time the disease has clinically manifested itself, the pathology has progressed to the neocortex. Currently, early diagnosis and understanding of Alzheimer’s pathology on functional deficits is the key for the development of therapy. While volumetric measurements of the hippocampus provide excellent diagnostic assistance, post-mortem studies have shown that the earliest pathological markers of Alzheimer’s (amyloid beta plaques and neurofibrillary tangles) are found first in olfactory areas of the brain. Clinically, olfaction is affected in the earliest stages of Alzheimer’s disease and mild cognitive impaired (MCI) patients, a group considered to be at the highest risk for Alzheimer’s. Often olfactory deficits appear prior to the manifestation of cognitive symptoms. Magnetic resonance imaging (MRI) provides the ability to noninvasively examine the functional and structural changes that occur prior to presentation of behavioral symptoms in individuals with Alzheimer’s disease and MCI. Therefore, in this dissertation, MRI techniques were utilized to investigate the involvement of the primary olfactory cortex in Alzheimer’s disease and MCI subjects, and to determine the sensitivity of these techniques as potential diagnostic markers of disease. The same subjects were used in each analysis, therefore the subject information, behavioral tests, and data collection is the same for each chapter. In chapter 2, we used both volumetric and functional MRI (fMRI) measurements to study the diagnostic potential by investigating the primary olfactory cortex. Behavioral tests, including the University of Pennsylvania Smell Identification Test (UPSIT), as well as cognitive tests demonstrated olfactory and memory impairments in both Alzheimer’s and MCI patient groups (one-way Analysis of Variance (ANOVA), P < 0.0001). The volumetric MRI of the primary olfactory cortex showed decreased volume in both Alzheimer’s and MCI subjects compared with age-matched normal controls (one-way ANOVA, P < 0.001). However in terms of both volume measurement and behavioral performance, MCI values ranged between those of Alzheimer’s and those of normal controls. On the other hand, the olfactory fMRI results showed that activation signal change in the primary olfactory cortex was significantly and nearly equally decreased in the Alzheimer’s and MCI subjects when compared with normal controls (one-way ANOVA, P < 0.0001). This suggests that although behavioral and volumetric measurement may be variable in MCI subjects, their activation signal in the brain is already changing. We also established that combining the UPSIT score, hippocampal volume, and activation signal change in the primary olfactory cortex increases the diagnostic specificity and sensitivity of Alzheimer’s and MCI. In chapter 3, the dominant role of the central olfactory system in Alzheimer’s and MCI was established. Whether olfactory deficits in Alzheimer’s disease and MCI are more dominantly due to peripheral or central olfactory system deterioration is unclear. While several studies agree with central olfactory system deterioration based on observations, olfactory fMRI and pathological evidence are inconclusive. The olfactory paradigm used in this study had a visual cue “Smell?” accompanied by either odor presentation or no odor presentation. The presentation with “Smell?” without congruent odor presentation allowed for analysis of the primary olfactory cortex with an afferent stimulus that was perceived as equal to the subjects. The visual and motor systems were not impaired in AD and MCI subjects therefore all no stimulus provided could be perceived as unequal. We hypothesized that if the dysfunction is outside the brain similar activation signal change would be observed in all three groups when the visual cue “Smell?” was presented without congruent odor and group differences would only be found when the visual cue and odor were presented congruently (this is when stimulus is perceived differently between the groups since both MCI and AD subjects have trouble with olfactory function). Without an odorant; however, the normal controls exhibited greater activation signal change compared with both the Alzheimer’s and MCI subjects (one-way ANOVA, P < 0.05). This suggested central olfactory system dominance; however, our study was not able to disprove concomitant dysfunction of the peripheral olfactory system in Alzheimer’s and MCI. In chapter 4, functional connectivity analysis was performed on our olfactory fMRI data to learn further about the olfactory network. Functional connectivity is defined as the correlation of interregional neural interactions during particular tasks or from spontaneous activity during rest. We observed functional connectivity of the piriform was decreased to the striatum, thalamus, and anterior cingulate cortex for both Alzheimer’s and MCI subjects (ANOVA, P < 0.001). The Alzheimer’s group trended toward greater disconnection of the olfactory network compared with MCI subjects, although the difference did not achieve statistical significance. The trend toward preservation of connectivity in MCI subjects may explain their observed higher behavioral function. Therefore, we conclude that the central olfactory system is the dominant system involved in Alzheimer’s and MCI patients, and is causing olfactory deficits. We demonstrated that fMRI showed decreased activation in the primary olfactory cortex of MCI subjects, and was in fact similar to the decreased activation of Alzheimer’s disease subjects. This indicates consistent early functional changes in the brains of MCI subjects despite variability in their behavioral and volumetric measurements. fMRI, thus has great potential to be used as an early diagnostic marker in Alzheimer’s disease and MCI, and may also be used to study the progression of disease.