Journals of Gerontology: Biological Sciences cite as: J Gerontol A Biol Sci Med Sci, 2017, Vol. 72, No. 8, 1007–1014 doi:10.1093/gerona/glw104 Advance Access publication June 11, 2016 Original Article Early Aging Effect on the Function of the Human Central Downloaded from https://academic.oup.com/biomedgerontology/article/72/8/1007/2629931 by guest on 27 September 2021 Olfactory System Choice Editor’s Jianli Wang,1 Xiaoyu Sun,1 and Qing X. Yang2 1Department of Radiology, Pennsylvania State University College of Medicine, Hershey. 2Departments of Radiology and Neurosurgery, Pennsylvania State University College of Medicine, Hershey. Address correspondence to Jianli Wang, MD, PhD, Department of Radiology, Pennsylvania State University College of Medicine, Hershey, PA 17033. E-mail: [email protected] Received November 23, 2015; Accepted April 27, 2016 Decision Editor: Rafael de Cabo, PhD Abstract During normal aging process, the smell function declines significantly, starting from the sixth decade of age. While it has been shown that activity in the central olfactory system of seniors responding to odor stimulation is significantly less than that of young people, no information of the aging effect on the functions of this system during normal adulthood and early aging has been gathered. In this study, we used functional magnetic resonance imaging to investigate the olfaction-related brain activity in the central olfactory structures of 43 healthy adult volunteers aged from 22 to 64 years. The participants’ smell identification function was negatively correlated with age (r = −.32, p = .037). Significant negative correlation was observed between age and the olfaction-related activities in the bilateral dorsolateral prefrontal cortex, left insular cortex, and left orbitofrontal cortex (p < .001, corrected with cluster size ≥28 voxels). There was no significant correlation observed between age and the activity in the primary olfactory cortex detected in this age group. These results suggest that age-related functional decline in the human brain is more prominent in the secondary and higher-order central olfactory structures than the primary olfactory cortex in the early aging process. Keywords: Olfaction—Age—Aging—Primary olfactory cortex—fMRI The sense of smell is one of the basic functions that we have to 30) (14,16–18,21). However, no information of aging effect on the perceive the environment around us. During the aging process, the functions of this system during normal adulthood and early aging overall smell function, including odor detection, discrimination, stage has been presented. To fill the gap of the aging curve in the cen- identification, and memory, goes down significantly starting from tral olfactory system, we evaluated a group of normal healthy adults the sixth decade of age (1–10). Multiple factors have been docu- younger than 65 years for the olfactory-related brain activation with mented that may contribute to this age-related functional decrease, functional magnetic resonance imaging (fMRI). Different to the pre- for example, at the peripheral level—the loss of olfactory epithelium viously used nonspecific olfactory stimulation methods (16–18,21), (11,12) and the functional decline of olfactory neurons (13), and in this study, we assessed the central olfactory activities related to at the central level—the atrophy and functional decline of the cen- the sniffing of an odor (odor-sniffing) and the sniffing of odorless tral olfactory system (14–23). Understanding the age-related func- air (odorless-sniffing) separately, trying to identify the specific central tional decline of the central olfactory system is important, since it structures with specific olfactory functions that are age dependent. is the most dynamic system in the brain and has been shown to be involved in the two most common neurodegenerative diseases, that Methods is, Alzheimer’s disease and Parkinson’s disease (24–30), in which olfactory deficits are prevalent and age is a significant risk factor. Human Participants We expected the level of brain activity in the central olfactory Forty-three healthy human volunteers (aged 22–64 years, average system to be age dependent. Previous studies have shown that the 40.9 ± 15.0 years, 17 males, 3 left-handed) with no history of otorhi- activity in the central olfactory system of the elderly (older than 65) is nolaryngological, neurological, memory loss, or psychiatric condi- significantly weaker compared to that of the young (younger than tions were recruited from the local community by advertisement. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. 1007 For permissions, please e-mail: [email protected]. 1008 Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 72, No. 8 There was no significant age distribution difference between the MR image acquisition were synchronized using optical triggers from male and female participants (two-sample t test, p = .43). All the par- the MRI scanner. During the execution of the fMRI paradigm, the ticipants provided written, informed consent prior to participation, participants’ respiration trace was monitored via a pneumatic respi- in accord with the requirements of the Institutional Review Board of ration sensor and recorded at a frequency of 10 Hz together with the the Pennsylvania State University College of Medicine. odor delivery onsets and timing of image acquisition by the olfac- tometer. After fMRI scanning, the participants were asked to confirm Psychophysical Test of Olfactory Function if they sensed odors during the fMRI scans. The olfactory function of each participant was evaluated with the 40-component University of Pennsylvania Smell Identification Test fMRI Study Protocol (UPSIT, Sensonics, Haddon Heights, NJ) prior to the fMRI. The The fMRI study was performed on a Siemens 3 T scanner (Magnetom Downloaded from https://academic.oup.com/biomedgerontology/article/72/8/1007/2629931 by guest on 27 September 2021 UPSIT is a self-administered, forced-choice test for the smell identifi- Trio, Siemens Medical Solutions, Erlangen, Germany) with an eight- cation function. The participant UPSIT scores were analyzed for the channel head coil for signal reception. The participants were posi- aging effect on the smell identification function. tioned in the supine position in a dark environment with their heads fit into a padded head restrainer to minimize motion and to provide Olfactory Stimulation Paradigm correct positioning and comfort. The participants’ respiration and The olfactory stimulation paradigm contained visually prompted sniffing patterns were monitored to exclude any irregular respiration changes. A BOLD signal sensitive T *-weighted echo-planar imaging sniffing with either odorized air (lavender smell, lasting for 6 sec- 2 onds) or odorless air delivered to the nose (Figure 1). Each condi- sequence was used for fMRI image acquisition with repetition time/ tion was repeated 12 times and interleaved with 14–22 seconds echo time/flip angle = 2,000 milliseconds/30 milliseconds/90°, field odorless air at a constant air flow of 6 L/min (3 L/min through the of view = 220 × 220 mm, acquisition matrix = 80 × 80, 30 slices par- odorant chamber when the odorant was delivered). The air flow was allel to the anterior commissure–posterior commissure plane with delivered to the both nostrils simultaneously through Teflon tubing a slice thickness = 4 mm, parallel imaging acceleration factor = 2, (inner diameter 6.35 mm) with a 50% relative humidity at room number of repetitions = 239 with an acquisition time of 7 minutes 58 seconds. In addition, a T -weighted anatomical image was acquired temperature (22°C). The intervals between the odor deliveries were 1 pseudo-randomized to reduce any potential anticipatory effect on with a three-dimensional MPRAGE method with repetition time/ the olfactory system. The stimulation paradigm was executed with echo time/flip angle = 2,300 milliseconds/2.98 milliseconds/9°, field a programmable olfactometer (Emerging Tech Trans, LLC, Hershey, of view = 256 × 256 × 160 mm, acquisition matrix = 256 × 256 × 160, PA), which can deliver odorants to participant’s nostrils accurately image resolution = 1 × 1 × 1 mm, and parallel imaging acceleration without any optical, acoustic, thermal, or tactile cues to the par- factor = 2. ticipant. The olfactometer was located next to the MRI console out of the examination room, while the odorant containers were posi- Data Processing and Analysis tioned next to the MRI scanner. Lavender oil (Givaudan Flavors The respiration trace, odor delivery timing, and image acquisition Corporation, East Hanover, NJ) diluted in 1,2-propanediol (Sigma, timing data were processed with the ONSET software (Olfactory St. Louis, MO) at 0.10% (volume/volume) was used as the olfactory Network Stimulation Editing Tool) for actual stimulation onset and stimulant. Lavender is one of the most effective olfactory stimulants duration vectors (http://www.pennstatehershey.org/web/nmrlab/ with minimal to no propensity to stimulate the trigeminal system resources/software) (33). In addition, the respiration volume was (31,32). The odorant was stored in six 300 mL glass jars, each hold- measured and compared between odor and odorless periods. The ing 50 mL of the odorant. To keep the odor concentration stable dur- respiration volume was estimated with the area under the respiration ing each odor presentation, the source of the odorant