Possible Biomarker for Cognitive Decline in Parkinson's

Pauline Anderson

September 25, 2013

Researchers are reporting what may be a potentially novel means of identifying patients with Parkinson's disease (PD) at increased risk for cognitive impairment.

A new pilot study suggests that lipids involved in ceramide metabolism were elevated in patients with PD compared with controls and are highest among patients with PD who had mild cognitive impairment (MCI) or dementia.

These preliminary results point to the importance of ceramide metabolism in the pathophysiology of sporadic PD, said lead author Michelle M. Mielke, PhD, associate professor, epidemiology and neurology, Mayo Clinic, Rochester, Minnesota.

"I'm excited about this," she told Medscape Medical News. "I think it opens up a whole new avenue of research. We can look at this pathway and see if it's related to the development of PD as well as whether it's a specific biomarker for cognitive impairment in PD."

The study was small, but if its results are replicated, "it could be very important," said Dr. Mielke. "Right now we don't have any biomarkers or predictors of who is going to develop cognitive impairment. I think in a lot of cases, cognitive impairment is more of a problem than some of the motor symptoms in Parkinson's disease."

The study was published online September 18 in PLOS ONE.

Diagnostic Criteria

Dr. Michelle M. Mielke

Mutations in the gene coding for glucocerebrosidase (GBA) — which metabolizes glucosylceramide, a monohexosylceramide, into glucose and ceramide — is the most common genetic risk factor for sporadic PD. GBA mutation carriers are more likely to have an earlier age at onset and to develop cognitive impairment and dementia. The authors thought that lipids involved in ceramide metabolism might also be altered in PD non-GBA mutation carriers and associated with worse cognition.

The study included 26 cognitively normal patients with PD, 14 patients with PD who had MCI, 12 patients with PD and dementia, and 5 cognitively normal controls without PD or other neurologic conditions. Patients with PD were aged 45 to 80 years, had no diagnosis of another neurologic disease, and had a Mini-Mental State Examination score of 18 or greater. None of the patients were GBA carriers.

Diagnosis of PD MCI followed level 1 recommendations of the Movement Disorders Society Task Force guidelines, and diagnosis of PD dementia was based on level II recommendations. From extracted plasma, researchers determined levels of sphingolipids (ceramide, monohexosylceramide, and lactosylceramide) that are involved in glucosylceramide metabolism.

The analysis showed that sphingolipid levels did not correlate with age, sex, age at PD onset, or levodopa equivalence dose.

Compared with controls, patients with PD had significantly higher (P < .05) levels of nearly all ceramide, monohexosylceramide, and lactosylceramide species compared with controls. None of these lipid levels differed between patients with PD and MCI and those with dementia, so researchers combined these groups.

This combined cognitively impaired PD group had significantly higher levels of certain ceramide and monohexosylceramide species (all P < .05) compared with cognitively intact patients with PD. The levels were highest in patients with PD who had either MCI or dementia.

Plasma total low-density and high-density lipoprotein cholesterol and triglyceride levels did not significantly differ between patients with PD and controls in the study, indicating that the differences in ceramide and monohexosylceramide levels were not due to a global lipid effect.

"[I]t is likely that the ceramide pathway is significantly altered in the disease process, " the authors write. "We speculate that higher levels of these lipids may be a marker of more diffuse and severe alpha-synuclein deposition in the brain, leading to PD with cognitive impairment or dementia."

Depressive Symptoms

Among patients with PD, the study found significant positive correlations between multiple species of ceramides and monohexosylceramides and depressive symptoms measured by the geriatric depression scale (GDS), suggesting that plasma ceramides could be an indicator or predictor of depression in PD.

Knowing which patients with PD are more prone to cognitive impairment could affect treatment decisions for depression down the road, said Dr. Mielke. For example, these patients have a less successful outcome with deep-brain stimulation, she said.

Interestingly, patients with PD who had a GBA mutation tend to not only be more cognitively impaired than non-GBA carrier patients with PD but also have more depression and behavioral features, said Dr. Mielke.

Although the results were highly significant despite the small sample size, replication is needed to confirm the findings, said Dr. Mielke.

"This is the first study that has really looked at this, so we need to replicate it in a much larger study and also conduct a longitudinal study to see what the predictive values of these lipids are."

She added that she and her colleagues are working on obtaining funding to try to replicate the results in a group of 500 patients with PD.

Once the results are validated, levels of these lipids could be used as a potential biomarker and this pathway could become a treatment target, said Dr. Mielke.

The relevant pathway could affect a variety of other neurodegenerative conditions in addition to PD, said Dr. Mielke.

Novel Findings

For a comment on this study, Medscape Medical News reached Professor David J. Burn, director, Institute for Ageing and Health, and professor of movement disorders neurology, Newcastle University Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.

Dr. Burn thought the study had "interesting and novel" findings that are welcome and potentially valuable.

"A biomarker to determine patients with PD at risk of cognitive decline and dementia, and also to monitor objectively a response to therapeutic interventions, would clearly be of enormous value," he said.

If the finding of similar plasma lipid levels in patients with PD and MCI and those with dementia is confirmed, it would suggest that "the marker might be more one of trait rather than state," noted Dr. Burn.

"This, in turn, would raise questions as to its utility if the levels do not change appreciably as cognitive decline progresses. In future studies, it will be important to define PD-MCI more rigorously, using level II rather than level I criteria."

Dr. Burn added that it's also important to determine test-retest reliability and to explore why depression also seemed to correlate with lipid markers.

He also agreed that because the numbers in the study groups were relatively small, the findings should be replicated in larger cohorts and from a range of geographic locations.

This work was supported by grants from the National Institute on Aging and from George P. Mitchell and the late Cynthia W. Mitchell. The DEMPARK study was being funded by an unrestricted grant from Novartis and a grant from the International Parkinson Fonds (Deutschland) GmbH (IPD). The continuation of the study (LANDSCAPE) is part of the Competence Network Degenerative Dementias (KNDD), which is funded by the German Federal Ministry of Education and Research. Dr. Mielke reports she has received grant funding from the National Institutes of Health, Lewy Body Dementia Association and Alzheimer's Drug Discovery Foundation, and the Walter S. and Lucienne Driskill Foundation.

PLOS One. Published online September 18, 2013. Abstract



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