Predictors of Cognitive Loss in Parkinsons Disease

The study covered in this summary was published on medRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

  • Researchers developed a risk score to predict future cognitive decline in patients with Parkinson’s disease (PD). The risk score is based on age, sex, disease duration, and plasma values of albumin, C-reactive protein (CRP), and melanoma inhibitory activity (MIA) protein.

  • Individuals with a risk score in the top quartile had more than four times’ greater risk of developing near-term cognitive decline compared to those in the lowest quartile.

  • MIA is a potential biomarker for cognitive decline in PD.

  • MIA may have a causal role in cognitive decline in PD.

Why This Matters

  • PD, the second most common neurodegenerative disease, affects over five million persons worldwide. Among patients with PD, there is wide variability in cognitive impairment. Biomarkers predictive of PD decline are urgently needed.

  • To the researchers’ knowledge, MIA has not previously been associated with PD.

  • Identification of MIA as a possible causal player in cognitive decline may offer new avenues for research into biologic mechanisms of PD.

Study Design

  • The study used three cohorts in a discovery-replication-validation design to identify proteins associated with cognitive decline in patients with PD. Blood samples were collected between 2013 and 2019. At baseline, no patients had dementia. On the basis of rates of decline in their Montreal Cognitive Assessment (MoCA) scores, individual participants were subsequently classified into fast or slow cognitive decline subgroups.

  • Researchers assessed levels of 1129 proteins in the discovery (n = 108) cohort and 1305 proteins in the replication (n = 83) cohort. Using a linear model that was adjusted for age, sex, and disease duration, they identified which proteins differentiated fast and slow cognitive decline subgroups.

  • On the basis of these results, the investigators developed a model for predicting cognitive decline in PD and then tested the model in the validation cohort (n = 118).

  • The investigators used Mendelian randomization to evaluate whether the top biomarker might have a causal influence on cognitive decline in PD.

Key Results

  • Fast cognitive decline occurred in 28%, 27%, and 20% of the discovery, replication, and validations cohorts, respectively.

  • Nine proteins were associated with rate of cognitive decline. Three of the nine proteins had high potential for use as a clinical biomarker: MIA, CRP, and albumin.

  • A model using MIA, CRP, albumin, age, sex, and duration of disease was moderately accurate in predictng development of cognitive decline. Individuals with a risk score in the third or fourth quartile were more than four times as likely to develop mild cognitive impairment or dementia than those with a score in the lowest quartile.

  • MIA plasma levels were significantly higher in the the fast cognitive decline subgroups in all three cohorts. However, CRP/albumin ratios did not differentiate fast and slow cognitive decline subgroups in the validation cohort.

  • The investigators used a large genetic database to identify single-nucleotide polymorphisms associated with expression of MIA and identified minor alleles of rs2233154. Genotypes of rs2233154 were significantly associated with MIA plasma levels in the replication cohort (P < .0001 for rs2233154CC vs CT; P = .0076 for rs2233154CC vs TT), and in the validation cohort (P < .0001 for rs2233154CC vs CT).

  • In a linear mixed model, rs2233154 genotypes, adjusted for age, sex, disease duration, and baseline MoCA score, were significantly associated with rates of decline in MoCA (P = .0004) in the replication and validation cohorts. The effect was even more marked for individuals with two T alleles.

Limitations

  • Two thirds of the individuals in the study were from a single site. Some findings, such as the CRP/albumin level, were incompletely replicated across cohorts. The model showed only moderate ability to distinguish between fast and slow cognitive decline.

  • In future studies, larger cohorts from multiple sites and at various stages of disease might be utilized to assess performance of the cognitive decline predictor.

Disclosures

  • The study was supported by grants from the National Institutes of Health and a Biomarkers Across Neurodegenerative Diseases (BAND) grant from the Michael J. Fox Foundation/Alzheimer’s Association/Weston Institute.

  • Alice Chen-Plotkin is supported by the Parker Family Chair, the AHA/Allen Institute Brain Health Initiative, and the Chan Zuckerberg Initiative Neurodegeneration Challenge.

This is a summary of a preprint research study, “Plasma MIA, CRP, and Albumin Predict Cognitive Decline in Parkinson’s Disease,” written by Junchao Shen from the University of Pennsylvania and colleagues and published on medRxiv.org. It was provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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