05 Nov 2021

Parkinson’s disease is the second most common neurodegenerative disease, and the vast majority of people with it have no underlying mutation. More common still is progressive parkinsonism—a disorder marked by the characteristic symptoms of PD but without overt neurodegeneration. What causes these syndromes? Five new studies are drawing attention to this problem, underscoring aspects over which people have some control.

One, published October 27 in Neurology, reported that deaths due to PD rose sharply over the past two decades in the United States, and three JAMA Neurology papers investigated specific health and lifestyle contributors. One reported that in Denmark, influenza infection nearly doubled the risk of developing PD more than a decade later. A South Korean study reported that physical activity warded off death due to PD, and a little Swedish study issued a call of “Shall We Dance.” Finally, a U.S. study reported that the burden of white-matter hyperintensities—a hallmark of cerebrovascular pathology—correlated with the severity and progression of parkinsonism.

Observational studies cannot cinch causal links between these health factors and parkinsonian disorders. Still, they point to a constellation of factors that could be involved.

In the United States, Death from Parkinson's on the Rise
A paper published October 27 in Neurology reports a rise in deaths associated with PD in the United States. Led by Wei Bao of University of Iowa in Iowa City, researchers combed the National Vital Statistics System, a nationwide death registry, for deaths due to PD between 1999 and 2019. They found that age-adjusted mortality increased, from 5.4 deaths per 100,000 people in 1999 to 8.8 in 2019. PD mortality differed among demographic groups, with twice the incidence in men as in women, and higher rates in non-Hispanic white people than in other racial or ethnic groups. PD mortality was higher among urban dwellers than those living in rural areas. However, the extent to which PD mortality increased—by about 2.4 percent per year—was similar across demographic groups.

“This highlights the urgency of more investments finding disease-modifying treatments for PD and other neurodegenerative diseases of brain,” commented Shahram Oveisgharan of Rush University Medical Center in Chicago.

Influenza: A Harbinger of Future Parkinson's?
Published October 25 in JAMA Neurology, a study led by Noelle Cocoros of Harvard Medical School asked whether influenza or other infections influence a person's risk of developing PD years later. A connection between viral infection and PD has been debated for decades (Olsen et al., 2018). The idea that influenza in particular could initiate the disease process gained traction when researchers proposed a link between the 1918 flu pandemic and a rise in PD incidence years later (Poskanzer and Schwab, 1963). Cocoros and colleagues hypothesized that, given the long preclinical phase of PD, if influenza infection did somehow set the disease in motion, it would take at least a decade for symptoms to surface.

To test their hypothesis, they turned to records from the ample Danish National Patient Registry, which recorded all diagnoses and procedures associated with hospitalizations in Denmark since 1977, and all hospital-based outpatient clinic visits since 1995.

First, the researchers identified 10,271 people who had been diagnosed with PD between 2000 and 2016, and age-matched them to 51,355 controls. The incidences of cardiovascular disease, diabetes, Crohn’s disease, ulcerative colitis, and lung cancer were similar between cases and controls. However, people with PD were 1.73 times likelier than controls to have been infected with influenza at least a decade prior. That odds ratio increased—to 1.91—when the interval between infection and PD diagnosis was at least 15 years. The numbers may be an understatement, because the records captured only flu cases that led to a hospital visit or, after 1995, an outpatient clinic visit.

For the other types of infection, the trend was different. Pneumonia, gastrointestinal and male genital infections, and septicemia associated with PD within five years of infection, but most of these links vanished after 10 years from infection. Besides influenza, only urinary tract infections correlated with a PD diagnosis more than 10 years out; however, this trend became stronger for infections closer to PD diagnosis. These findings for infectious agents other than influenza imply that reverse causality could be afoot, the authors suggested. In other words, as people approach PD diagnosis, they may become more vulnerable to various infections.

For influenza, the findings are consistent with a causal relationship, but cannot prove it. If influenza did cause PD in some people, how would it do so? “The potential mechanisms of action—on the highest level—include viral entry into the central nervous system, which may be influenza-strain-specific, with resulting neuroinflammation,” Cocoros told Alzforum. Cytokines triggered by the immune response to the infection could also affect the aging brain, she added (Aug 2009 news). Cocoros noted that, if there is a causal link between influenza and PD, flu vaccination should reduce PD risk.

Do White-Matter Hyperintensities Promote Parkinsonism?
Researchers led by Oveisgharan investigated underlying factors associated with progressive parkinsonism. This condition—marked by slowness, difficulty walking, rigidity, tremor—is more amorphous than Parkinson's disease proper, and its causes are unclear. It is also more common than PD, afflicting approximately half of people over the age of 80. Previously, researchers had reported that among people with parkinsonism, those who also had neurodegenerative or cerebrovascular pathologies progressed faster (Buchman et al., 2019). 

In a November 1 report in JAMA Neurology, Oveisgharan and colleagues investigated what white-matter hyperintensities—a manifestation of cerebrovascular disease visible on MRI scans—might have to do with how severely a person's parkinsonism has progressed. This was a postmortem investigation, which allowed the researchers to confirm the presence or absence of other neurodegenerative pathologies, including PD and AD.

The study included 516 people, 70 percent of them women, who had died with progressive parkinsonism at an average age of 90. The scientists found that a higher burden of white-matter hyperintensities, as measured by MRI scans taken of each participant’s brain after death, correlated both with how fast their parkinsonism had progressed and with how severe their symptoms were at the end of life.

Next, the researchers controlled for other cerebrovascular pathologies, such as microinfarcts, macroinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. This shrank the association between white-matter hyperintensities and parkinsonism progression by 21 percent, but it remained statistically significant. Controlling for other neurodegenerative pathologies—including those of PD and AD—weakened the association by just 8 percent. In all, the findings suggested that WMH burden independently correlated with the severity of parkinsonism.

Oveisgharan hypothesizes that cerebrovascular pathology may exacerbate parkinsonism by inflicting damage on the basal ganglia—an anatomical region tied to parkinsonism—and its connections to other motor regions.

Fortunately, cerebrovascular disease can be prevented to some extent, for example by treatments such as blood-pressure control or statins, Oveisgharan said. Physical activity has also been tied to a lower risk of incident parkinsonism and a slower rate of progression, he added (Oveisgharan et al., 2019). 

When Living With Parkinson's, Activity Staves Off Death
While questions remain about the myriad contributors to PD mortality, two new studies further reinforce a tried-and-true method for staving it off. Yes, exercise. According to a November 1 paper in JAMA Neurology, physical activity associated with longer survival among people with PD. Led by Yong Wook Kim of Yonsei University College of Medicine and Kyungdo Han of Soongsil University, both in Seoul, the study used data from the Korean National Health Insurance System to ask whether level of physical activity—based on self-reports recorded during check-ups every two years—correlated with mortality among people newly diagnosed with PD.

The study included 10,699 people recently diagnosed with PD, and followed them for an average of eight years. During that time, 1,823 died. People who reported being physically active at any level had better chances of survival during follow-up than did those who reported being inactive. Specifically, both light and vigorous exercisers had a 20 percent drop in mortality compared to inactive people, while moderate exercisers enjoyed 34 percent protection. People who were physically active both before and after their diagnosis had the highest level of protection, but even those who took up exercise after their diagnosis reaped benefits.

As with all observational studies, it is impossible to determine whether exercise itself delayed death. “It is possible that PD patients who could not be active had more severe PD stages, which in turn was associated with a higher risk of death,” noted Oveisgharan. “Therefore, randomized clinical trials are required to confirm these findings.”

The researchers propose that, given the known benefits of exercise, people with PD should be encouraged to maintain as much physical activity as they can, noting that even light exercise was tied to a survival benefit.

Don't like the treadmill? Here's an idea. A little study in Sweden reported that among 10 people with PD, dancing improved multiple aspects of their health and quality of life (Gyrling et al., 2021). Dance classes took place in a dance studio, “a place that does not have connotations of rehabilitation or exercise,” the authors wrote. After a 12-week session, participants reported improvement in multiple aspects of mental and physical health, including uplifted mood and confidence, and better sleep.—Jessica Shugart

Comments

1. • Shahram Oveisgharan
     Rush University Medical Center
   • Posted: 06 Nov 2021

   The second most common neurodegenerative disease of the brain, PD manifests mostly by motor phenotypes including tremor, rigidity, bradykinesia, and postural instability. PD is associated with adverse health outcomes, including a higher risk of death.

   Like other major neurodegenerative diseases, no disease-modifying treatment is currently available for PD. Physical activity is a modifiable risk factor associated with a lower risk of PD. However, few studies have examined the association of physical activity in PD patients with risk of death. Using a national registry, Seo Yeon Yoon and colleagues showed that more vigorous physical activity was associated with a lower risk of death in PD patients. Moreover, PD patients who remained physically active over years had a lower risk of death compared with patients who remained in or turned into an inactive state. While findings are promising, several limitations should be considered. The study findings are based on a national registry that did not include patients’ PD severity (such as the Unified PD Rating Scale score). Therefore, it is possible that PD patients who could not be active had more severe PD stages, which in turn was associated with a higher risk of death. Therefore, future randomized clinical trials are required to confirm these findings.

   Infectious diseases have been implicated in the pathogenesis of many diseases including PD. Using the Danish National Patient Registry, Noelle Cocoros and colleagues examined the history of influenza and other infectious diseases with odds of PD. They found that the history of influenza was associated with higher odds of PD if influenza had occurred more than 15 years prior to PD diagnosis. However, this finding was in contrast to the association of other infections with PD, where the association held if infections had occurred less than five years before the PD diagnosis. In addition, the authors did not assess association of influenza vaccine with PD. This requires further studies to rule out a possibility of reverse causality that PD patients are more vulnerable for infections during the prodromal phases of PD.

   Using the U.S. National Vital Statistics System, Shuang Rong and colleagues examined trends of PD mortality in the last 20 years. They found that mortality from PD was increasing by an average 2.4 percent per year, which resulted the number to increase from 5.4 to 8.8 per 100,000 population from 1999 to 2019. This increase was not due to aging, as numbers were age-standardized. With subgroup analysis, they found that the PD mortality had increased in all states, in both men and women, in urban and rural citizens, and in all ethnicities. This study highlights the urgency of more investments finding disease-modifying treatments for PD and other neurodegenerative diseases of brain.   

   View all comments by Shahram Oveisgharan

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Bugs on the Brain—Can Flu Cause Parkinsonism, Neurodegeneration? 17 Aug 2009

Paper Citations

1. Olsen LK, Dowd E, McKernan DP. A role for viral infections in Parkinson's etiology?. Neuronal Signal. 2018 Jun;2(2):NS20170166. Epub 2018 Apr 16 PubMed.
2. POSKANZER DC, SCHWAB RS. COHORT ANALYSIS OF PARKINSON'S SYNDROME: EVIDENCE FOR A SINGLE ETIOLOGY RELATED TO SUBCLINICAL INFECTION ABOUT 1920. J Chronic Dis. 1963 Sep;16:961-73. PubMed.
3. Buchman AS, Yu L, Wilson RS, Leurgans SE, Nag S, Shulman JM, Barnes LL, Schneider JA, Bennett DA. Progressive parkinsonism in older adults is related to the burden of mixed brain pathologies. Neurology. 2019 Apr 16;92(16):e1821-e1830. Epub 2019 Mar 20 PubMed.
4. Oveisgharan S, Yu L, Dawe RJ, Bennett DA, Buchman AS. Total daily physical activity and the risk of parkinsonism in community-dwelling older adults. J Gerontol A Biol Sci Med Sci. 2019 May 2; PubMed.
5. Gyrling T, Ljunggren M, Karlsson S. The impact of dance activities on the health of persons with Parkinson's disease in Sweden. Int J Qual Stud Health Well-being. 2021 Dec;16(1):1992842. PubMed.

Further Reading

Papers

1. Estupinan D, Nathoo S, Okun MS. The Demise of Poskanzer and Schwab's Influenza Theory on the Pathogenesis of Parkinson's Disease. Parkinsons Dis. 2013;2013:167843. Epub 2013 Jun 11 PubMed.