New Biomarker for Early Alzheimer’s and Parkinson’s?

Olfactory bulb volume (OBV) was associated with odor identification and mediated the link between volumes of central olfactory brain structures and olfactory function in older adults, a cross-sectional study showed.

Larger OBV was associated with better olfactory function scores on the SIT-12, a 12-item Sniffin’ Sticks smell test, with a difference in score of 0.46 points (95% CI 0.29-0.64), independent of sex, nasal patency, and smoking status, reported Monique Breteler, MD, PhD, of the German Center for Neurodegenerative Diseases in Bonn, and co-authors.

Larger OBV also correlated with larger volumes of several brain regions involved in processing olfactory information, including the amygdala, hippocampus, insular cortex, and medial orbitofrontal cortex. OBV mediated the association between the amygdala, parahippocampal cortex, and hippocampus volumes and olfactory function in older participants.

“This cross-sectional study found that olfactory bulb volume was independently associated with odor identification function and was a robust mediator of the age-dependent association between volumes of central olfactory structures and olfactory function,” Breteler and colleagues wrote in JAMA Otolaryngology–Head & Neck Surgery.

“Thus, neurodegeneration-associated olfactory dysfunction may primarily originate from the pathology of peripheral olfactory structures, suggesting that OBV may serve as a preclinical marker for the identification of individuals who are at an increased risk of neurodegenerative diseases,” they added.

Olfactory structures are affected early in Alzheimer’s disease and Parkinson’s disease, before cognitive symptoms emerge. Impaired olfactory function is among the earliest signs of neurodegenerative disorders and has been associated with cognitive decline in dementia-free older adults.

Olfactory dysfunction also has emerged as one of the earliest and most frequent neurological signs of SARS-CoV-2 infection. “However, little is known about the neuroanatomical basis of olfactory dysfunction in the general population, elucidation of which could not only provide insights into its underlying causes but also facilitate the identification of individuals who are at an increased risk of neurodegenerative conditions,” Breteler and co-authors noted.

The researchers used data from the Rhineland Study, an ongoing population-based cohort study that aims to identify risks and biomarkers for neurodegenerative diseases. Participants were enrolled from March 2016 to October 2017 and underwent 3T brain MRI and olfactory assessment. Smoking and nasal patency information was self-reported and performance on the SIT-12 was used as a proxy for olfactory function.

Analyses included 541 participants with a mean age of 53.6; nearly 57% were women. Increasing age, male sex, and nasal congestion were associated with worse olfactory function on the SIT-12.

Larger volumes of amygdala (difference in OBV 0.12, 95% CI 0.01-0.24), hippocampus (0.16, 95% CI 0.04-0.28), insular cortex (0.12, 95% CI 0.01-0.24), and medial orbitofrontal cortex (0.10, 95% CI 0.00-0.20) were associated with larger OBV. Larger volumes of amygdala (volume × age interaction effect 0.17, 95% CI 0.03-0.30), parahippocampal cortex (0.17, 95% CI 0.03-0.31), and hippocampus (0.21, 95% CI 0.08-0.35) were associated with better olfactory function, but only in older age groups.

There’s a need for better biomarkers to identify people at risk of neurodegenerative disorders, observed Subinoy Das, MD, of the U.S. Institute for Advanced Sinus Care and Research in Columbus, Ohio, in an accompanying editorial. “A decrease in OBV could warn clinicians about the increased risk for neurodegenerative disease and serve as a marker for therapeutic responses to improve smell,” he wrote.

“Much more work is needed,” Das pointed out. “Ideally, the OBV could be replaced with a maximal olfactory bulb width to simplify the measurements for widespread clinical use, and reference ranges based on age and sex will need to be created.”

The study has several limitations, Breteler and colleagues acknowledged. Analyses were based on cross-sectional, not longitudinal, data. Odor identification was used as a proxy for olfactory function, but it is a subtask of the complete olfactory testing battery. Subjective nasal patency assessment may have led to less precise estimates of associations between imaging measures and olfactory function, they added.