A Smell Test for Parkinson’s Disease?

Of all our senses, smell is the most mysterious. Yet, despite our lack of understanding, it seems that the nose knows when there is something wrong with the brain. It is now clear that loss of the sense of smell is an early marker for Parkinson’s disease and other neurodegenerative conditions. Simple smell tests can help clinicians diagnose Parkinson’s more accurately, and a series of recent studies further suggest that they could be used to sniff out at-risk patients earlier.

First described in 1871, Parkinson’s is chiefly thought of as a movement disorder characterized by slow movements, rigidity, and tremor. It is becoming increasingly clear, however, that Parkinson’s also involves various non-motor symptoms, including cognitive impairment, sleep disturbances, and altered smell, taste, and vision.

Clinicians recognized that Parkinson’s involves loss of the sense of smell in the 1970s, but reliable  tests for olfactory dysfunction did not become available until the mid-1980s. The development of such tests renewed neurologists’ interest in olfaction, and it quickly became apparent that loss of smell affects the vast majority of people with Parkinson’s.

“There is good evidence that [loss of the sense of smell] may precede the cardinal signs of Parkinson’s disease by decades,” says Andrew Lees, professor of neurology at University College London, adding that formal testing of smell function shows that at least 80 percent of Parkinson’s patients experience loss of smell. “Some people are now prepared to consider it as part of the syndrome, along with rigidity and rest tremor.”

Smell tests are already being used in the clinic to distinguish between Parkinson’s   and related “chameleon” conditions, which mimic its symptoms and are often mistaken for it, to help clinicians make the right diagnosis. “We use a scratch-and-sniff test in the clinic to support the clinical diagnosis of Parkinson’s,” says Less, “and to distinguish it from chameleons like essential tremor, monogenetic recessive Parkinsonism, and multiple system atrophy, where smell is often preserved.”

Loss of Smell = Higher Risk

Research also suggests that simple smell tests could potentially be used to identify people who are at risk of developing Parkinson’s up to 10 years before they are diagnosed. A Dutch study published in 2004 looked at 361 first-degree relatives of Parkinson’s patients, none of whom exhibited any symptoms of the disease. The researchers asked them to perform a combination of smell detection, identification and discrimination tasks, and found that those with a poor sense of smell had at least a 10 percent increase in risk of developing Parkinson’s during the subsequent five years.

These same participants also exhibited significantly reduced levels of the dopamine transporter in parts of the brain that degenerate in the disease, as determined by an imaging technique called single photon emission computed tomography (SPECT), at the start of the study.

A more recent longitudinal study shows that a simple scratch-and-sniff test could identify people who are at risk long before they receive a diagnosis. Epidemiologist HongLei Chen of Michigan State University and his colleagues recruited more than 2,500 older participants involved in the interdisciplinary Health, Aging and Body Composition Study, tested their ability to identify common odors such as cinnamon, gasoline, lemon, and onion, and then divided them, based on their test scores, into three groups – those with a good sense of smell, medium, or a poor one.

The researchers followed their participants, via telephone interviews and visits to the clinic, for an average of nearly 10 years—longer than any other previous study of this kind—and found that those with a poor sense of smell were nearly five times more likely to develop Parkinson’s than those with a good sense of smell. Of the 764 participants with a poor sense of smell, 26 went on to develop the disease, compared with nine of those with a medium sense of smell and seven of those with a good one.

Common Mechanisms?

Olfactory dysfunction occurs in other neurodegenerative diseases; another recent study shows that home-dwelling older adults with normal cognition who have difficulty identifying odors have a higher risk of developing Alzheimer’s disease or some other form of dementia five years later. Citing this pattern, a few researchers have proposed the Olfactory Vector hypothesis of neurodegenerative disease, which theorizes that Alzheimer’s and Parkinson’s are caused by environmental agents such as viruses and toxins entering the brain through the nose.

The olfactory system does seem to serve as a bellweather for overall brain health. People with Parkinson’s have significantly reduced numbers of glomeruli, the spherical olfactory bulb structures at which smell information is transmitted from the nose to the brain. We still do not know if this is the case for other neurodegenerative diseases, however, and the exact relationship between olfactory dysfunction and brain degeneration is far from clear.

While loss of the sense of smell is “an early marker and likely an integral part of Parkinson’s disease development,” Chen says, there’s nothing to say that olfactory dysfunction causes brain degeneration.

There are problems with using smell as a diagnostic marker for Parkinson’s and other neurodegenerative diseases, too, the main one being one that olfactory dysfunction can occur as a result of many other causes. “Sinus disease and head injuries can cause it,” explains Lees, “so it is not very specific.” As a result, 15 percent to 25 percent of older people have a diminished sense of smell, but only a small number of these will go on to develop Parkinson’s or dementia.

A smell test for Parkinson’s would therefore need to reliably distinguish between loss of smell associated with neurodegeneration and that which occurs as a result of other causes. “Narrowing down this common symptom specifically to neurodegenerative diseases will be very important, and we need a better understanding of the factors involved in the development and progression of olfactory impairment prior to a clinical diagnosis,” says Chen.

“We also need to further characterize the olfactory impairment that is relevant to neurodegeneration, by documenting alternative causes, such as nasal infections, and by considering additional markers of early neurodegeneration, such as sleep problems and constipation.”