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In Population-Based Study, Researchers Find Cardiovascular Risk Factors Associated with Increased Risk of Parkinson's

Article In Brief

In an analysis of Medicare claims, researchers found an association between a number of cardiovascular risk factors and subsequent development of Parkinson's disease. But the study authors and independent commentators emphasized that the findings did not find a causal link between cardiovascular risk and Parkinson's.

In a large population-based analysis of Medicare claims, researchers have unearthed an association between most cardiovascular risk factors and a subsequent diagnosis of Parkinson's disease (PD), according a study published online in the August 29 issue of Annals of Neurology.

“In practice, I think these findings are an impetus for physicians to adequately identify, monitor, and manage cerebrovascular risk factors, many of which are modifiable, such as hypertension, hyperlipidemia, and obstructive sleep apnea,” lead author Benjamin R. Kummer, MD, assistant professor of neurology at the Icahn School of Medicine at Mount Sinai, told Neurology Today.

“I also think it's key to emphasize that we haven't established causality in this study, but that further confirmatory investigations suggest a promising avenue of research in the intersections between cerebrovascular and neurodegenerative disorders,” he said.

Dr. Kummer conducted the research when he was a vascular neurology fellow at Weill Cornell Medicine in New York City.

Study Design

Dr. Kummer and his colleagues analyzed data from the claims of one million randomly-selected Medicare beneficiaries aged 66 or older for five years. They checked to see whether the beneficiaries had been diagnosed with prior stroke, atrial fibrillation, heart disease, hyperlipidemia, hypertension, diabetes, heart failure, peripheral vascular disease, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, obstructive sleep apnea, tobacco use, or alcohol use.

In addition, they mined the data for those with idiopathic PD as determined by at least two separate outpatient claims containing the ICD-9-CM diagnosis code 332.0 and at least one of the diagnoses had to have been made by a neurologist.

As one point of comparison, the researchers also evaluated associations between those with any of the aforementioned cerebrovascular risk factors and a subsequent diagnosis of Alzheimer's disease (AD), which has been linked to cerebrovascular risk factors in previous studies. Claims with an ICD-9-CM diagnosis code of 331.0 qualified someone as having AD. They excluded those with a psychotic disorder diagnosis, vascular dementia, or other non-AD dementia.

Of the one million Medicare beneficiaries followed for a mean of 5.2 years, 15,531 (1.5 percent) were diagnosed with PD, and 81,974 (7.9 percent) were diagnosed with AD. Among those diagnosed with PD, 3,645 patients (23.5 percent) also had an AD diagnosis. The mean age of patients subsequently diagnosed with PD was 76 years [SD = 6.2], and for those patients not diagnosed with AD it was 76 [SD = 7.2].

Dr. Kummer and his team found that most of the cerebrovascular risk factors, including prior stroke (HR=1.55; 95 percent CI=1.39-1.72), were associated with the subsequent diagnosis of PD. The extent of these associations were similar, but lessened, as compared with the associations between cerebrovascular risk factors and AD, according to the report.

With the exception of alcohol abuse and hyperlipidemia, all evaluated cerebrovascular risk factors were associated with the diagnosis of PD. Of the cerebrovascular risk factors, obstructive sleep apnea had the strongest association with subsequent PD (HR=1.65, 95 percent CI=1.56-1.75).

The associations between cerebrovascular risk factors and PD were robust even after excluding patients with non-AD dementias, screening for AD or psychotic disorders, and restricting to PD diagnoses made by neurologists (n=10,285, or 66 percent of PD cases in the primary analysis), according to the findings.

But what could be behind the association between cerebrovascular risk and PD? Dr. Kummer noted that “we know that PD is caused by the death of neurons in specific brain areas that initiate movement on a cellular level, and that PD is associated with the accumulation of a misfolded protein called alpha-synuclein that forms Lewy bodies in neurons. While our study did not directly investigate molecular or cellular mechanisms, one possibility to explain our findings is that exposure to cerebrovascular risk factors, in increasing the risk for neuronal injury, may in turn somehow promote the accumulation of misfolded protein, or the propagation of misfolded protein from one affected neuron into other adjacent neurons, which is a hallmark of disease progression in PD.”

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“In practice, I think these findings are an impetus for physicians to adequately identify, monitor, and manage cerebrovascular risk factors, many of which are modifiable, such as hypertension, hyperlipidemia, and obstructive sleep apnea.”—DR. BENJAMIN R. KUMMER

Figure

“It is not clear that managing cerebrovascular risks will impact Parkinsons or Alzheimers disease diagnosis or progression. Patients with risk factors for atherosclerosis, diabetes, hypertension and potential future stroke should aggressively manage these issues while the jury deliberates on their meaning in the context of a future neurodegenerative disease.”—DR. MICHAEL S. OKUN

He also pointed to recent research, which suggests that damage to cerebral white matter, which is also associated with exposure to cardiovascular disease risk factors, may be associated with more severe motor outcomes in PD. “Exposure to cardiovascular disease risk factors may have thereby increased the risk of a more debilitating and/or clinically noticeable manifestation of PD,” he said.

As for why obstructive sleep apnea had the strongest association with a subsequent diagnosis of PD, Dr. Kummer noted that obstructive sleep apnea is characterized by “exposing the brain to low oxygen by collapse of the airway, and there is some evidence that there is an association between obstructive sleep apnea and damage to the white matter of the brain—it could therefore serve as a surrogate for the cell injury associated with abnormal oxygen delivery to tissue, which may promote neurodegenerative processes.”

While he acknowledged that the findings could simply reflect the potential inability to completely exclude patients with vascular PD, who typically have a higher rate of cerebrovascular risk factors than those with idiopathic PD, Dr. Kummer noted that multiple sensitivity analyses aimed at excluding this type of error did not substantially change the study findings, suggesting that diagnostic error was unlikely to explain such results.

Expert Commentary

“There seems to be an emerging relationship between stroke and Parkinson's disease although many of the details remain to be worked out,” said Michael S. Okun, MD, FAAN, medical director of the Parkinson's Foundation, professor and chair of neurology, and executive director of the Norman Fixel Institute for Neurological Diseases at the University of Florida College of Medicine.

“We should be cautious not to overinterpret this retrospective cohort study as the results are not strong enough to influence our clinical practice,” Dr. Okun added.

“It is not clear that managing cerebrovascular risks will impact Parkinson's or Alzheimer's disease diagnosis or progression,” he continued. “Patients with risk factors for atherosclerosis, diabetes, hypertension and potential future stroke should aggressively manage these issues while the jury deliberates on their meaning in the context of a future neurodegenerative disease.”

“The relatively weak but positive associations of stroke and diabetes with Parkinson's disease seem to be popping up more frequently in recent studies, and their significance as well as their meaning remain in question,” Dr. Okun said. “Some researchers have even suggested the possibility of Parkinson's disease being a risk factor for the occurrence of stroke. There is more uncertainty than we are comfortable with in moving forward with clinical recommendations, however.”

Janis Miyasaki, MD, FAAN, who is director of the Parkinson and Movement Disorders Program at the University of Alberta and co-director of the Complex Neurologic Symptoms Clinic (Neuropalliative Care), emphasized that the link between cerebrovascular risk and PD in the study is only associative and not causative.

“There is past work that has found that people with previous stroke and diabetes have poorer outcomes in Parkinson's disease,” Dr. Miyasaki told Neurology Today. “Our group is involved in a longitudinal study of Parkinson's disease, Lewy body dementia, and Parkinson's disease dementia for biomarkers and imaging as part of the Canadian Consortium on Neurodegeneration in Aging, and annual imaging is required for our study. We are having some surprising findings that are congruent with this work,” she said.

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“There is past work that has found that people with previous stroke and diabetes have poorer outcomes in Parkinsons disease. Our group is involved in a longitudinal study of Parkinsons disease, Lewy body dementia, and Parkinsons disease dementia for biomarkers and imaging as part of the Canadian Consortium on Neurodegeneration in Aging, and annual imaging is required for our study. We are having some surprising findings that are congruent with this work.”—DR. JANIS MIYASAKI

Dr. Miyasaki noted that “the current manuscript highlights that people with Parkinson disease, if they experience unexpected progression or changes, should have neuroimaging completed. Modifiable risk factors for cerebrovascular disease should be addressed, just as in the non-PD population...This work definitely speaks to neurologists being ever vigilant when assessing people with PD and not simply ascribing all neurologic symptoms to PD.”

Disclosures

Drs. Kummer, Okun, and Miyasaki had no disclosures relevant to the study.

Link Up for More Information

• Kummer BR, Diaz I, Wu X, et al. Associations between cerebrovascular risk factors and Parkinson disease https://onlinelibrary.wiley.com/doi/full/10.1002/ana.25564. Ann Neurol 2019; Epub 2019 Aug 29.