A friend told me that his father could never smell cookies or coffee—a seemingly harmless idiosyncrasy that was frequently the subject of family jokes. No one had any idea that the olfactory deficits could be linked to Parkinson’s disease, and everyone was surprised by the diagnosis when motor symptoms appeared years later.

Olfactory deficits in Parkinson’s disease have been noted in the biomedical literature since at least the mid-1970s¹/early 1980s.² In a 1983 study that compared patients with Parkinson’s disease and matched controls, researchers found that olfactory deficits were not related to age or cognitive function at the time of testing, and proposed that they were a nonmotor symptom of the disease.³

Nearly two decades later, Braak and colleagues found that the olfactory bulb is one of the first neural structures to be affected by synucleinopathy in Parkinson’s disease.⁴ This led to the suggestion that an unknown environmental pathogen may enter the body through the olfactory system to cause the disease.⁵ A decade later, we still don’t know whether this is the case, but this hypothesis and the research that led to it transformed the way people think about Parkinson’s disease pathology.

Today, researchers are attempting to better characterize the olfactory deficits in Parkinson’s disease to determine whether they can be used to aid diagnosis and prognosis. A recent study found that individuals with Parkinson’s disease scored significantly worse on the Sniffin’ Sticks test than did several other groups, including healthy controls, individuals with multiple system atrophy, and individuals with progressive supranuclear palsy.⁶ Other studies have linked olfactory deficits in Parkinson’s disease to future cognitive decline.^7,8 Indeed, reduced olfactory identification has been associated with mild cognitive decline in a large population of non-demented, elderly individuals, suggesting that the association may apply more generally to the aging population.⁹

Olfactory deficits associated with Parkinson’s disease can be studied more molecularly in experimental models, and the fruit fly has frequently been used due to the relative ease of introducing genetic mutations. Reduced olfactory discrimination has been documented in two different fruit fly models, those with LRRK2 mutations and those with PINK1 mutations.^10,11 However, the two genetic models showed opposite electrical responses to olfactory stimuli. These results are intriguing and remind us that there is much left to learn about genes, olfaction, and Parkinson’s disease.

References

1. Ansari KA, Johnson A: Olfactory function in patients with parkinson’s disease. J Chronic Dis. 1975;28(9):493-497. https://www.ncbi.nlm.nih.gov/pubmed/1176578
2.  Korten JJ, Meulstee J: Olfactory disturbances in parkinsonism. Clin Neurol Neurosurg. 1980;82(2):113-118. https://www.ncbi.nlm.nih.gov/pubmed/6254709
3.  Ward CD, Hess WA, Calne DB: Olfactory impairment in parkinson’s disease. Neurology. 1983;33(7):943-946. https://www.ncbi.nlm.nih.gov/pubmed/6683381
4.  Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U: Staging of the intracerebral inclusion body pathology associated with idiopathic parkinson’s disease (preclinical and clinical stages). J Neurol. 2002;249 Suppl 3(III/1-5. https://www.ncbi.nlm.nih.gov/pubmed/12528692
5.  Hawkes CH, Del Tredici K, Braak H: Parkinson’s disease: A dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33(6):599-614. https://www.ncbi.nlm.nih.gov/pubmed/17961138
6.  Krismer F, Pinter B, Mueller C, Mahlknecht P, Nocker M, Reiter E, Djamshidian-Tehrani A, Boesch SM, Wenning GK, Scherfler C, Poewe W et al: Sniffing the diagnosis: Olfactory testing in neurodegenerative parkinsonism. Parkinsonism Relat Disord. 2016. https://www.ncbi.nlm.nih.gov/pubmed/27890451
7.  Schrag A, Siddiqui UF, Anastasiou Z, Weintraub D, Schott JM: Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed parkinson’s disease: A cohort study. Lancet Neurol. 2017;16(1):66-75. https://www.ncbi.nlm.nih.gov/pubmed/27866858
8.  Fullard ME, Tran B, Xie SX, Toledo JB, Scordia C, Linder C, Purri R, Weintraub D, Duda JE, Chahine LM, Morley JF: Olfactory impairment predicts cognitive decline in early parkinson’s disease. Parkinsonism Relat Disord. 2016;25(45-51. PMC4825674. https://www.ncbi.nlm.nih.gov/pubmed/26923521
9.  Liang X, Ding D, Zhao Q, Guo Q, Luo J, Hong Z, Shanghai Aging S: Association between olfactory identification and cognitive function in community-dwelling elderly: The shanghai aging study. BMC Neurol. 2016;16(1):199. PMC5073423. https://www.ncbi.nlm.nih.gov/pubmed/27765032
10.  De Rose F, Corda V, Solari P, Sacchetti P, Belcari A, Poddighe S, Kasture S, Solla P, Marrosu F, Liscia A: Drosophila mutant model of parkinson’s disease revealed an unexpected olfactory performance: Morphofunctional evidences. Parkinsons Dis. 2016;2016(3508073. PMC5018337. https://www.ncbi.nlm.nih.gov/pubmed/27648340
11.  Poddighe S, De Rose F, Marotta R, Ruffilli R, Fanti M, Secci PP, Mostallino MC, Setzu MD, Zuncheddu MA, Collu I, Solla P et al: Mucuna pruriens (velvet bean) rescues motor, olfactory, mitochondrial and synaptic impairment in pink1b9 drosophila melanogaster genetic model of parkinson’s disease. PLoS One. 2014;9(10):e110802. PMC4207759. https://www.ncbi.nlm.nih.gov/pubmed/25340511