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Impairments of Smell in Huntington’s Disease

Impairments of Smell in Huntington’s Disease

Even before a person is diagnosed with Huntington’s Disease (HD) they may already begin experiencing symptoms. Based on recent research, the stages of HD have expanded to include pre-diagnostic stages; these are referred to as the HD prodromes.1 The Huntington’s Disease Society of America (HDSA) currently lists impairments of smell function (formally known as olfactory function) as an indication of the HD Prodrome B.2 

How to measure olfactory function

Traditionally, researchers have used the University of Pennsylvania Smell Identification Test (UPSIT) to study olfactory function in patients.34 The UPSIT is commercially available and produced by Sensonics, Inc. The test consists of four test booklets, with each booklet containing 10 pages.5 For each page, the patient is prompted to scratch off the label and sniff the odor that is released. They are then prompted to select an option from four multiple-choice alternatives provided on the page. The person’s score is calculated as how many correct odor identifications they made out of 40. This is then compared to the normative database of 4,000 individuals with perceived normal olfactory function. The test is able to identify the person’s olfactory function in relation to people in their age and gender group. It is able to provide an indication of normosmia, mild microsmia, moderate microsmia, severe microsmia, and total microsmia. Microsmia is the reduced ability to smell and detect odors whereas normosmia is considered the perceived normal olfactory function.  While briefer versions of this test have been created, the 40-item UPSIT is considered the standard test. The UPSIT has previously been used to evaluate odor identification in people living with Huntington’s Disease.6

The UPSIT has become one of the gold standards in the field for olfactory deficits. For one, it has been proven to have strong internal consistency reliability. 7 This means that all the components included in the test are measuring the same construct or idea, in this case being the olfactory function. The UPSIT has also been favored for its accessibility. It is currently offered in 28 different languages, can be self-administered, and only takes about 10 minutes to complete. 

Olfactory deficits in people diagnosed with HD

People with Huntington’s Disease have been found to have deficits in their smell function – in particular, they tend to have trouble with smell recognition and identification. For instance, while they may still be able to smell, they are unable to distinguish between these smells or they may not remember what a smell is associated with.8 One research group even found that those with HD were less likely to demonstrate disgust to a set of unpleasant odors compared to those without HD.9 This presents an even more difficult challenge, as it pertains to one’s personal health. For example, someone who is unable to recognize smells may not be able to associate when there is a gas leak in a building and would therefore be in danger if not alerted by someone who can smell it. In the research studies that have been conducted, asymptomatic individuals carrying the HD mutation do not tend to present with the same olfactory identification impairment.10 This has traditionally suggested that the olfactory impairments arise with disease onset. 

Possible Causes of Smell Deficit

Previous research has tried to investigate how Huntington’s Disease could be impacting the ability to smell and recognize smells. Research has found that the sensory deficit cannot be fully explained just by the prominent motor deficits associated with HD.

Correlations have been found between the reduced olfactory function and volume reduction of the entorhinal cortex, caudate, and parahippocampal regions.11 The entorhinal cortex is an area of the brain that has been primarily associated with functions such as memory, navigation, and perception of time. The caudate is another area that has been found to help with storing and processing memories – in particular, it serves as a feedback system in which it takes what you have previously learned to inform future actions. Lastly, the parahippocampal region is important in storing memories and then retrieving them. Altogether, the correlation between the smell deficit and these different regions of the brain important for memory help to understand the relationship between the deficit in smell recognition in people diagnosed with HD. 

Researchers have attempted to use mouse-models to explain some of the molecular bases of the deficit. Several different mouse models for HD, including the YAC128 mice, have been genetically modified to more accurately study the HD condition.12 In one study using the YAC128 mice, the researchers found that there were smell deficits present in the YAC128 mice as well as a reduction in the volume of critical brain regions. They also studied the different prevalence of key proteins involved in the immune response and found that there was an increase in neuronal cell death. Specifically, they found an increase in caspase-6 and caspase-8 activity, two proteins that are critical in cell death mechanisms, in the YAC128 mouse model. Altogether, this research study suggested that the olfactory impairments could be related to the reduction in the volume of critical brain areas that coordinate the olfactory system along with neuronal cell death. Another study using the YAC128 mice found that they also demonstrated aggregation of the Huntingtin protein in different brain sections.13 

In another research study, the researchers analyzed another mouse-model system with 140-CAG-repeat mice.14 In this study, they also found that there was a presence of Huntingtin protein aggregates in the olfactory tubercle, olfactory bulb, anterior olfactory nucleus, piriform cortex, and entorhinal cortex; all of these are involved in the function of smell. While the role of the aggregates is still being investigated, the research suggests that it could explain the deficits observed in the people diagnosed with HD. 

Understanding the possible causes of olfactory dysfunction in individuals diagnosed with Huntington’s Disease is still ongoing. However, different research studies have proposed plausible causes. 

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  7. Doty, R. L., Frye, R. E., & Agrawal, U. (1989). Internal consistency reliability of the fractionated and whole University of Pennsylvania Smell Identification Test. Perception & Psychophysics, 45(5), 381-384. doi:10.3758/bf03210709 []
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  9. Mitchell, I. J., Heims, H., Neville, E. A., & Rickards, H. (2005). Huntington’s Disease Patients Show Impaired Perception of Disgust in the Gustatory and Olfactory Modalities. The Journal of Neuropsychiatry and Clinical Neurosciences, 17(1), 119-121. doi:10.1176/jnp.17.1.119 []
  10. Bylsma, F. W., Moberg, P. J., Doty, R. L., & Brandt, J. (1997). Odor identification in Huntington’s disease patients and asymptomatic gene carriers. The Journal of Neuropsychiatry and Clinical Neurosciences, 9(4), 598-600. doi:10.1176/jnp.9.4.598 []
  11. Barrios, F. A., Gonzalez, L., Favila, R., Alonso, M. E., Salgado, P. M., Diaz, R., & Fernandez-Ruiz, J. (2007). Olfaction and neurodegeneration in HD. NeuroReport, 18(1), 73-76. doi:10.1097/wnr.0b013e3280102302 []
  12. Laroche, M., Lessard-Beaudoin, M., Garcia-Miralles, M., Kreidy, C., Peachey, E., Leavitt, B. R., . . . Graham, R. K. (2020). Early deficits in olfaction are associated with structural and molecular alterations in the olfactory system of a Huntington disease mouse model. Human Molecular Genetics, 29(13), 2134-2147. doi:10.1093/hmg/ddaa099 []
  13. Slow, E. J. (2003). Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Human Molecular Genetics, 12(13), 1555-1567. doi:10.1093/hmg/ddg169 []
  14. Menalled, L., Sison, J., Dragatsis, I., Zeitlin, S., & Chesselet, M. (2003, October 6). Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. Retrieved September 10, 2020, from []