Blood gene signature predicts risks of Parkinson’s complications

A score derived from gene activity measured in blood samples can predict a higher risk of developing cognitive impairment and gait freezing in people with Parkinson’s disease, according to a study.

The findings demonstrate that gene activity signatures in blood capture aspects of Parkinson’s biology that are not fully explained by neurodegeneration, and may serve as potential biomarkers for cognitive impairment and freezing of gait (a brief, sudden inability to move), the researchers said.

The study, “Peripheral blood transcriptomic signature is associated with cognitive impairment and freezing of gait in Parkinson’s disease: a data-driven approach,” was published in npj Parkinson’s Disease.

Parkinson’s is marked by motor symptoms such as bradykinesia (slowed movement), rigidity, and tremor, along with a range of nonmotor symptoms. The disease varies considerably among patients, and its underlying biology involves several overlapping processes, including clumps of proteins called Lewy bodies, impaired cellular waste clearance, and inflammation.

Because of this complexity, scientists have struggled to identify reliable blood-based biomarkers for diagnosing Parkinson’s and for subtyping or predicting its course.

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Analyzing genes

Researchers in South Korea used RNA sequencing data, a method that captures gene activity, from blood samples drawn from 541 people with Parkinson’s and 180 healthy individuals in the Parkinson’s Progression Markers Initiative database.

The team applied a technique called weighted gene correlation network analysis (WGCNA), which groups genes that tend to switch on and off together into modules, rather than examining single genes in isolation.

From 28,971 genes analyzed, WGCNA identified 27 modules. About one-fourth (26%) of those genes did not fit into any module and were excluded from the analysis. Across all modules, two emerged: one dubbed yellow, comprising 903 genes, and another red, with 527 genes.

Most of these genes showed higher activity in those with Parkinson’s than in controls and were concentrated in pathways related to the immune system and neutrophils (a type of white blood cell). Further enrichment analysis linked these genes to processes involving inflammation, neutrophils, white blood cells more broadly, and osteoclasts (cells involved in bone breakdown).

Both modules were significantly linked to Parkinson’s disease as well as clinical measures including age, the severity of motor and nonmotor symptoms, and cognitive scores on the Montreal Cognitive Assessment.

Using genes from these two modules, the researchers applied a second method, contrastive principal component analysis, to calculate an individual pseudo-temporal (PT) score for each patient. This score reflects how far a person’s blood gene activity deviates from that of healthy controls. Values ranged from 0 to 1, with higher scores indicating greater deviation.

Higher PT scores correlated with several measures, including longer disease duration, worse cognitive abilities, anxiety and depression, cardiovascular problems, gait and balance difficulty, and overall nonmotor symptom burden.

Over a median of eight years, 403 (74.5%) developed freezing of gait, and 119 (22.0%) developed cognitive impairment. Most patients also developed motor complications related to levodopa, such as the drug’s wearing off, or losing efficacy between doses (79.7%) and dyskinesia (61.7%), which is marked by involuntary, erratic movements.

In an adjusted statistical analysis, a higher PT score was independently associated with a 3.43-fold higher risk of freezing of gait and a 7.31-fold higher risk of cognitive impairment. However, the PT score was not associated with wearing off or dyskinesia.

Patients with scores at or above 0.37, the median PT score, were significantly more likely to develop memory problems and freezing of gait over time than those with lower scores.

The researchers said the results raise the possibility that mechanisms such as neuroinflammation may contribute to cognitive impairment and freezing of gait.

“These findings suggest that [gene activity signatures in blood] may capture aspects of [Parkinson’s biology] extending beyond [neurodegeneration], with relevance to long -term outcomes,” the scientists wrote, though they noted that external validation in independent groups is needed before the PT score can be considered for clinical use.