Decreased Functional Connectivity of Olfactory-Related Regions in Parkinson’s Disease Compared to Mild Cognitive Impairment and Healthy Controls

Filippo Cieri, Cleveland Clinic, Las Vegas, United States
Nandy Rajesh, University of North Texas, Dallas, United States
Zhuang Xiaowei, Cleveland Clinic, Las Vegas, United States
Richard Doty, University Pennsilvanya, Philadelphia, United States
Jessica Caldwell, Cleveland Clinic, Las Vegas, United States
Dietmar Cordes, Cleveland Clinic, Las Vegas, United States



Olfactory dysfunction is often an early sign of Parkinson's Disease (PD) and Alzheimer’s Disease (AD). A decreased sense of smell is also present in physiological aging and Mild Cognitive Impairment (MCI), but its patterns of functional connectivity of olfactory-related regions remain unclear. Functional imaging studies are sorely needed to better understand neural correlates of hyposmia. The aims of this study were to examine functional connectivity (FC) and the changing pattern of function abnormalities in healthy controls (HCs) and subjects with MCI, and PD.

Participants and Methods:

Participants and Methods

We included 117 subjects from the Center of Biomedical Research Excellence (COBRE), with 29 HCs (62.1% women = age mean 71 ± 7.0 SD; men = 70.6 ± 6.8 SD), 43 MCI patients (34.9% women = age mean 73.0 ±5.3 SD; men 74.3 ± 5.9 SD) and 45 PD-MCI patients (40% women = age mean 69.44 ± 7.04 SD; men age mean 71.56 ± 7.47 SD). We utilized AAL atlas with 120 ROIs in our analyses, resulting in 7140 networks and corresponding functional network connectivity (FNC) values from resting state fMRI data with 850 time points. FNC values were calculated by extracting average time-series from each ROI and then computing a Pearson correlation between each ROI pair.  For initial assessments, 378 olfactory networks were analyzed.  We restricted our analyses to network pairs with average FNCs above 0.5. This reduced the number of relevant networks to 32.  Finally, for each subject, we calculated the average FNC value for these 32 networks.  This value was used as the outcome variable for our analysis. We performed a multiple regression with average FNC as the outcome and disease status as the predictor.


The regression result was highly significant (p = 0.0007). No statistically significant difference between HC and MCI was found. However, FNC was significantly lower in the PD group (p= 0.004) compared to HCs and MCI patients, especially within and between elements of the limbic system. Brain structures and regions involved included the amygdala, hippocampus, and the, parahippocampal, cingulate, and orbitofrontal regions.


Few studies explore olfaction impairment in physiological and pathological aging, with its neural correlates. We have demonstrated that a distinct olfactory functional network pattern may represent a change involved in PD which deserves more investigation. This research of FC of structures within the olfactory system network suggests the possibility that such measures may be useful in identifying pathophysiological mechanisms. Being the loss of olfaction one of the first symptoms of pathological aging, FC investigation of olfactory-related regions can be helpful to better understand the early signs of hyposmia present in PD,anticipating the diagnostic process and guiding the development of new potential therapy.

Category: Cognitive Neuroscience

Keyword 1: olfaction
Keyword 2: neuroimaging: functional connectivity
Keyword 3: Parkinson's disease