Early cognitive dysfunction may be a significant risk factor for future risk for parkinsonian disorders, including Parkinson’s disease (PD), new research suggests.
Among more than 7300 study participants, those with low overall cognitive scores at baseline were at significantly greater risk for incident parkinsonism and for probable PD 8 years later than those with higher baseline scores.
Risk for parkinsonism was also increased for those with poor scores on a range of different types of tests, including letter-digit substitution and verbal fluency.
“The findings suggest that cognitive dysfunction can be considered a sign of prodromal PD,” the investigators, led by Sirwin K.L. Darweesh, MD, Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands, write.
Dr Darweesh told Medscape Medical News that although the investigators were not surprised to see the association between poor cognitive function and “short-term risk” of parkinsonism, it was interesting to see that the risk went beyond an 8-year interval.
“Furthermore, our observation that diverse domains of cognition, including executive, attention, cognitive speed, and memory, are already implicated in prodromal parkinsonism patients extends prior observations” in those with clinical parkinsonism, he said.
The findings were published online September 25 in JAMA Neurology.
“Growing Urgency”
Although previous research has shown that patients with PD often have cognitive dysfunction, “there is a scarcity of data on cognitive functioning before parkinsonism diagnosis,” the authors write.
“In clinical parkinsonism patients, most notably those with Parkinson’s disease, damage to the brain is already quite advanced at the time of diagnosis, rendering them less susceptible to putative disease-modifying interventions,” added Dr Darweesh.
“As a consequence, there is a growing sense of urgency to unravel the prodromal phase of common parkinsonism diseases.”
For the current analysis, the investigators assessed 7386 participants in the prospective, population-based Rotterdam Study (57.4% women; mean age, 65.3 years). Baseline cognition was assessed between January 2002 and December 2008 by using a battery of tests.
In the study cohort, 1.1% developed incident parkinsonism during a mean follow-up of 8.3 years. Of these participants, 72.2% were diagnosed with probable PD, and 30.4% had comorbid dementia.
In the 24 patients who had comorbid dementia, 10 developed it before onset of parkinsonism, while the others developed it afterwards.
Results showed that the participants who had low global cognition scores at baseline were more likely to have incident probable PD than those with higher scores at baseline (adjusted hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.11 – 2.08). Changes in semantic fluency were also associated with probable PD (HR, 1.35).
The following table shows that low scores on several cognitive tests were significantly associated with increased risk for parkinsonism.
Table. Risk Factors for Incident Parkinsonism
| Low Baseline Scores for: | HR (95% CI) |
|---|---|
| Global cognition | 1.79 (1.37 – 2.33) |
| Letter-digit substitution | 1.59 (1.22 – 2.04) |
| Verbal fluency | 1.61 (1.23 – 2.08) |
| Inverted interference task on Stroop color word test | 1.56 (1.25 – 1.96) |
The association between poor baseline global cognition scores and incident parkinsonism remained significant past 8 years (HR, 1.59; 95% CI, 1.01 – 2.59). Even after exclusion of the participants who developed dementia, the HR was still a significant 1.72.
The likelihood ratio for parkinsonism development was 2.66 for those who had both cognitive impairment and “subtle motor signs” at baseline (95% CI, 1.64 – 4.32).
“Our data provide important insight” into the link between cognitive dysfunction and risk of parkinsonism within the general population, “especially given the fact that, to our knowledge, only 2 community-based studies have previously published data on this topic,” write the investigators.
Changing the Disease Course
In an accompanying editorial, Ethan G. Brown, MD, and Caroline M. Tanner, MD, PhD, both from the Movement Disorders and Neuromodulation Center at the University of California, San Francisco, write that the Rotterdam Study “provides an excellent setting” for looking into these issues.
“Because this is a large, community-wide cohort with low attrition, the results are broadly applicable,” the editorialists write.
However, noted limitations include the following: “the neuropsychological assessment was not as thorough as currently recommended” for assessing cognition in PD; the primary outcome was development of parkinsonism, including vascular and medication-induced versions, instead of development of PD; and “the study design precluded specialist adjudication of all PD diagnoses.”
Still, “these findings have numerous implications,” Dr Brown and Dr Tanner write.
They note that the association between changes in semantic fluency and probable PD echoes previous results and underlines the importance of giving this type of test early on. Another key finding was that patients with mild cognitive impairment, especially those with subtle motor signs, may have prodomal PD.
“This recognition can allow physicians to screen for falls or other nonmotor aspects of PD in these cases and provide early treatment for these symptoms,” they write.
“Intervening at the earliest stage of PD may provide the best chance for slowing disease progression and maintaining function. Clarification of the early course of PD with studies such as this may allow identification in time to change the course of disease.”
The analysis was supported by Stichting ParkinsonFonds. The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission; the Netherlands Genomics Initiative; and the Municipality of Rotterdam. The study authors have disclosed no relevant financial relationships. Dr Brown receives compensation for serving on the Fellowship Advisory Board for AbbVie Inc. Dr Tanner reports receiving grants from the Michael J Fox Foundation, the Parkinson’s Disease Foundation, the Department of Defense, Sage Bionetworks, and the National Institutes of Health; compensation for serving on Data Monitoring Committees for Biotie Therapeutics, Voyager Therapeutics; and Intec Pharma; and consulting fees from Neurocrine Biosciences, Adamas Therapeutics, and PhotoPharmics.
JAMA Neurol. Published online September 25, 2017. Abstract, Editorial
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