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Cognitive dysfunction is associated with an increased risk of parkinsonism, and should be considered a prodromal sign of Parkinson's disease, researchers argued.

In an analysis of data from 7,386 participants in the Rotterdam Study, poor global cognition at baseline was associated with an almost twofold higher risk of incident parkinsonism (HR 1.79, 95% CI 1.37 to 2.33) compared normal cognitive functioning at baseline, according to Arfan Ikram, MD, PhD, of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and colleagues.

This association remained robust after 8 years (HR 1.59, 95% CI 1.02 to 2.59) of follow-up, and after excluding patients with the onset of dementia before parkinsonism (HR 1.72, 95 % CI 1.28 to 2.27), the study authors reported online in .

Ikram and colleagues noted that in Movement Disorder Society criteria for prodromal Parkinson's disease, cognitive loss was "not included as a variable because of the absence of prospective evidence of predictive value."

Their results, however, in conjunction with "other published studies, suggest that cognitive dysfunction now warrants inclusion as a prodromal marker."

Overall, patients were a mean age of 65 at enrollment and 57% were women. The investigators followed 98% of patients until Jan. 1, 2015, and by that time, 79 patients were diagnosed with incident parkinsonism (1.1%). Of these, the majority received a diagnosis of probable Parkinson's disease (72%). Among patients with incident parkinsonism, 30% also developed dementia -- 10 before and 14 after the onset of parkinsonism.

In addition to global cognition findings, researchers also found that individual components of cognition were associated with incident parkinsonism:

• Letter-digit substitution (HR 1.59; 95% CI 1.22-2.04)
• Verbal fluency (HR 1.61, 95% CI 1.23-2.08)
• Interference task Stroop color word test (HR 1.56, 95% CI, 1.25-1.96)

They also found that participants who had both cognitive dysfunction and subtle motor signs at baseline had a 3.3-fold increased risk of incident parkinsonism. Indeed, almost half of patients (49.4%) who received a diagnosis of incident parkinsonism during follow-up already had subtle motor features at baseline, cognitive dysfunction at baseline, or both, the researchers said.

They argued that the findings extend those from their previous nested -- also embedded within the Rotterdam Study -- showing that poor executive functioning and subtle motor signs are more common among patients with prodromal Parkinson's disease.

"Although our previous publication documented the temporal association, it could not be used to estimate risk with a single measure, which is needed to further refine for prodromal Parkinson's disease," Ikram and colleagues wrote. "In the present project, we used a prospective design based on a single global cognitive function measure, which allowed us to assess how common poor cognitive functioning is in patients with prodromal parkinsonism, both in isolation and in combination with subtle motor features."

But in an accompanying editorial, Ethan Brown, MD, and Caroline Tanner, MD, PhD, of the University of California San Francisco, noted that when study participants with subtle motor signs at baseline were removed from the analysis, the association between cognitive impairment and increased risk of parkinsonism was no longer significant.

The only participants with cognitive impairment who were at risk of developing Parkinson's disease were those who had one parkinsonism feature at baseline -- a subtle motor sign, the editorialists wrote. This doesn't meet the two-feature criteria for classification of parkinsonism even though it does provide evidence for premorbid motor features, they added.

"These findings suggest that both motor and cognitive changes can be observed many years before the clinical diagnosis of parkinsonism, and the possibility of these patients having very early Parkinson's disease cannot be ruled out."

Early and accurate identification of prodromal Parkinson's is a , the editorialists emphasized, adding that it represents "an essential step toward the overall goal of slowing disease progression."

"Intervening at the earliest stages of Parkinson's may provide the best chance for slowing disease progression and maintaining function," they wrote. "Clarification of the early course of Parkinson's disease with studies such as this may allow identification in time to change the course of disease."