More Evidence Links Poor Sense of Smell to Parkinson's Up to 10 Years Later

Pauline Anderson

September 07, 2017

People with a poor sense of smell have an increased risk for Parkinson's disease (PD), and the association is strongest among men and whites, results of new research suggest.

The study extends the association between olfactory dysfunction and PD risk, already noted in previous research, to almost 10 years and to blacks.

Dr Honglei Chen

"Doctors need to pay attention to poor sense of smell in elderly patients," lead study author, Honglei Chen, MD, PhD, Epidemiology Branch, National Institute of Environmental Health Sciences, and Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, told Medscape Medical News.

He added that unlike visual impairment or hearing impairment, clinicians may not take notice of declining sense of smell in their patients.

Even though there are no preventive treatments for PD, there's "huge clinical interest" in identifying neurodegenerative diseases early on because this might spur development of potential protective therapies, said Dr Chen.

The study was published online September 6 in Neurology.

Earlier research in the field primarily focused on white participants and had relatively short follow-up — typically less than 4 or 5 years.

For this analysis, Dr Chen and his colleagues evaluated sense of smell in relation to incident PD among participants in the Health, Aging and Body Composition (Health ABC) study. In 1997-1998, this study enrolled well-functioning community-dwelling individuals aged 70 to 79 years in Pittsburgh, Pennsylvania, and in Memphis, Tennessee.

Participants were followed regularly and evaluated for sense of smell at a single time point —the year 3 clinical examination in 1999-2000 (baseline) — using the Brief Smell Identification Test (BSIT).

A short version of the 40-item Pennsylvania Smell Identification Test, the BSIT asks participants to scratch and smell 12 odorants, one at a time, and to identify the correct one from among four possible choices. Researchers gave 1 point for each correct answer, with a total score ranging from 0 to 12. A higher score indicates a better sense of smell.

Investigators categorized participants into tertiles according to their sense of smell, with the highest tertile, indicating better olfaction, as reference.

The BSIT includes a question about history of head injury, defined as "hit in the head hard enough to make you faint." Various studies have identified head injury as a risk factor for PD and often also as a risk factor for a poor sense of smell, said Dr Chen.

At enrollment, study participants were asked about physician-diagnosed PD, and over the course of the study, investigators collected information on medication use and hospitalizations. Two movement disorder specialists reviewed all the data and came to a consensus about PD status.

Researchers followed participants from baseline to the date of PD diagnosis, death, last contact, or August 31, 2012, whichever came first. The analyses included 2462 participants (1510 white and 952 black participants).

Over an average of 9.8 years of follow-up, the researchers identified 42 incident PD cases, including 30 among white and 12 among black participants.

Poor olfaction predicted a higher risk for PD. Compared to those in the highest tertile on the BSIT, those testing in the lowest tertile had increased risk for PD (hazard ratio [HR], 4.8; 95% confidence interval [CI], 2.0 - 11.2; P for trend = 0.00001), after adjustment for sex and race.

The association did not change much after additional adjustment for study site, education, smoking, coffee drinking, general health status, and history of head injury (HR, 5.1; 95% CI, 2.1 - 11.9).

Race Differences

The researchers looked at black and white participants separately. Research suggests that compared to whites, blacks have a lower incidence of PD but a poorer sense of smell.

The results showed that poor sense of smell was clearly associated with higher PD risk in white participants and, although a similar association was suggested for black participants, it was not statistically significant.

It's important to be "really cautious" about interpreting this result because the sample size is small — only 12 black participants developed PD, said Dr Chen.

"Although this is probably the first data that includes a reasonable number of black PD patients, the data are still fairly limited and preliminary."

Dr Chen pointed out that while 80% to 90% of people may develop dysfunction in their sense of smell before getting a PD diagnosis, only a small proportion of those with poor sense of smell progress to PD.

"A poor sense of smell may be caused by a variety of reasons, and we suspect that PD-related neurodegeneration is only a small fraction of it."

It's possible that the cause for a poor sense of smell "is more diverse and complex among black participants compared to whites," said Dr Chen.

The researchers also looked at men and women separately. Men are more likely to be diagnosed with PD than women, with estrogen possibly being a protective factor, said Dr Chen. At the same time, men are more likely to have a poor sense of smell, although the reasons for this "have not been carefully examined."

Although olfaction was statistically associated with higher PD risk in both sexes, the strength of the association was twice as strong in men. This, said the authors, suggests that poor sense of smell may be a better predictor of PD in men than in women.

In an analysis stratified by the length of follow-up, the researchers found significant associations for both the first 5 years of follow-up and afterward. In analyses that excluded the first years of follow-up, the association remained at a similar strength for the first 6 years of follow-up (HR range, 4.1 - 5.0) but then the HR decreased to 2.9.

Dr Chen stressed the importance of identifying early symptoms of PD. Patients could then make lifestyle changes — such as more exercise — to improve their quality of life. Also, knowing early PD signs may inform research into identifying treatments for the disease.

Some researchers believe that PD begins in the olfactory structure, where α-synuclein pathology first develops, and then progresses much later to the midbrain, which leads to motor symptoms and then to a PD diagnosis.

But more research is needed to assess how the sense of smell changes over time before a PD diagnosis and how other symptoms in prodromal PD — for example, rapid eye movement sleep disorder and constipation — are involved, said Dr Chen.

"I think we need to move in several related directions in order to understand prodromal PD."

Longest Follow-up

In an accompanying editorial, Gene L. Bowman, ND, MPH, Department of Nutrition and Brain Health, Nestle Institute of Health Sciences, Lausanne, Switzerland, and the Brain Institute, Department of Neurology, Oregon Health & Science University, Portland, noted that the follow-up in the current study is the longest to date.

The new paper also includes "important data" on a large cohort of African Americans, said Dr Bowman.

The observation that black participants have a higher prevalence of hyposmia — the reduced ability to smell and to detect odors — yet lower incidence of PD needs further clarification, said Dr Bowman. Such clarification, he added, might determine whether African Americans are less familiar with the odorants used in a smell test, or whether there's a true biological explanation for the associations.

A limitation of the study is that hyposmia has several explanations beyond neurodegeneration, such as chronic rhinosinusitis. Future studies can provide more insight into the cause of the olfactory dysfunction, said Dr Bowman.

Obtaining more details on which aspects of smell are impaired — for example, detection, identification, or intensity — would help clinicians focus on the most relevant smell tests, said Dr Bowman.

Aparna Wagle Shukla, MD, associate professor, and director of investigator initiated clinical trials, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, also commented on the new research for Medscape Medical News.

Dr Wagle Shukla called the new epidemiologic study "important" and noted that it has "several interesting features."

For example, she said, the study identified impaired olfaction as an important risk factor for PD, especially in older white men, and it showed poorer olfaction to be associated with PD beyond the first several years of follow-up.

As well, she said, the research indicated that the association seemed to diminish in strength over time.

Dr Wagle Shukla also found it interesting that older black men had poorer olfaction compared with older white men but didn't have an increased risk for PD.

The sex-based differences uncovered by the study were also noteworthy for Dr Wagle Shukla.

Whether impaired olfaction is a true marker of prodromal PD "will become clear with future investigations," she said.

Wissam Deeb, MD, Department of Neurology, University of Florida, also commented on the findings. 

"The authors have done an excellent job in trying to identify PD and ruling out alternative diagnoses, such as neuroleptic-induced parkinsonism or restless leg syndrome," Dr Deeb noted.

"A major limitation of the study, as noted by the authors, is the retrospective design and the small sample size, especially the black incident PD cases of only 12," he said. "There are multiple confounding factors that can limit the value of the information, especially the level of education and smoking. As also noted by the authors, there is no direct evaluation for other sino-nasal causes."

As the authors also note, the added value of the study is in specifically evaluating the BSIT in the black US population, he said. "Unfortunately, there was only a small number of incident black PD patients to make any conclusions."

Despite the limitations of the retrospective evaluation and the small incident PD sample size, Dr Deeb concluded, "the study adds to the accumulating evidence that anosmia or hyposmia can be prodromal signs of PD. Larger, prospective studies focusing on racial, educational, and sex differences in regards to BSIT are warranted."

Dr Chen serves on the editorial boards of the American Journal of Epidemiology, International Journal of Molecular Epidemiology and Genetics, and American Journal of Neurodegenerative Disease. Dr Bowman is a scientific advisor to the Horizon 2020 European Union–funded PROPAG-AGEING project, whose aim is to identify novel biomarkers for earlier diagnosis of Parkinson disease; received National Institutes of Health/National Institute on Aging support for a clinical trial in age-related cognitive decline; and is an employee of Nestle Institute of Health Sciences. D r Wagle Shukla has disclosed no relevant financial relationships.

Neurology. Published online September 6, 2017. Abstract, Editorial

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