During normal aging, the overall smell function goes down significantly starting from the sixth decade of age [1]. Understanding age-related functional decline of the central olfactory system (COS) is important, since it is the most dynamic system in the brain and has been shown to involve in prevalent age-related neurodegenerative diseases such as AD and PD [2, 3]. Previous studies have shown that the activity in the COS of the elderly (above age 65 years) is significantly decreased comparing to that of subjects with age younger than 30 years [4-6]. We expected the brain activity in the COS to be age dependent. However there has been no information of aging effect on the functions of this system during normal adulthood and early aging < 65 years. Here we report an olfactory fMRI study to fill the gap of the aging curve in olfactory system.

Human Subjects: 43 cognitively normal healthy subjects (age 22-64 years, 17 male) were studied. All subjects gave written informed consent, which was approved by the local Institutional Review Board.

Data Acquisition: The olfactory function of the subjects was evaluated with the University of Pennsylvania Smell Identification Test. The fMRI study was conducted on a Siemens 3 T scanner with an 8-channel head coil and a BOLD-sensitive EPI sequence: TR/TE/FA = 2000 ms/30 ms/90°, image resolution = 2.8 mm×2.8 mm, 34 4-mm-thick oblique slices parallel to the AC-PC plane, number of acquisition = 239.

Odor Stimulation paradigm: Different to previously used nonspecific olfactory stimulation methods [4-6], in this study, we evaluated the central olfactory activities related to the sniffing of an odor (odor-sniffing) and sniffing of odorless air (odorless-sniffing) separately, trying to identify the specific central olfactory structures, whose specific functions that are age dependent. During the execution of the fMRI paradigm (Fig. 1), the subjects’ respiration trace was monitored and recorded.

Data Processing and Analysis: The respiration data were processed with ONSET [7]. There was no significant difference in the respiration rate and volume during the odor-sniffing or odorless-sniffing periods for each subject. The fMRI data were processed with SPM8 to study the aging effect on the olfactory activation in the central olfactory structures.

There was a significant aging effect on the smell function in this study cohort. The UPSIT score was negatively correlated with age. The fMRI data showed that both odor-sniffing and odorless-sniffing triggered significant activation in the bilateral POC and secondary olfactory structures. There was a significant negative aging effect on the BOLD signal responding to the odor-sniffing in the bilateral DLPFC, left orbitofrontal cortex (OFC), and left insular cortex (Ins); and responding to the odorless-sniffing the structures showed significant negative aging effect were the left OFC and left Ins (Fig. 2). Neither voxel-based nor ROI-based analysis showed any significant age correlation with the BOLD signal in the POC region. When the subjects were separated into different age groups (22-30, 31-40, 41-50, 51-64 years) for comparison, there was no significant difference in the POC activation responding to either odor-sniffing or odorless-sniffing.We demonstrated a significant age-related olfactory functional decline in the COS. Our data showed lateralization in aging effect in the left OFC and left Ins. Generally aging-related pathological changes are symmetric, e.g., the atherosclerosis in the cerebral circulatory system. The lateralization observed here could be related to the functional asymmetry in processing olfactory information between the two hemispheres. Most interestingly, we found that the brain structures whose BOLD signal were negatively correlated with age are the “secondary” olfactory structures, while the BOLD signal in POC showed no significant correlation with age in the cohort including normal adulthood and early aging stages. Our previous data comparing elder subjects greater than 65 years and young adults below 30 years showed that the BOLD signal in the bilateral POC were significantly weaker in the elderly [4]. Taken together, aging effect on the functions of the POC appears to be nonlinear, i.e., the POC functions are relatively stable during normal adulthood and early aging stages and then experience a significant decline in the later aging period. Consist with the smell function decline that measured behaviorally by the smell identification test, the brain activities of the secondary olfactory structures, i.e., bilateral DLPFC, left Ins, and left OFC, significantly decreased with age. There was no significant age correlation with the BOLD signal in the POC region. These results revealed a differential age-related functional decline pattern in the primary and the secondary central olfactory structures in human COS.