Inflammatory markers in spinal fluid can reflect patients’ cognitive status

Rising CSF levels of T-alpha, particularly, tied to onset of impairment

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by Steve Bryson, PhD |

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Inflammatory biomarkers in the cerebrospinal fluid (CSF) of Parkinson’s disease patients with and without mutations in the GBA gene are at similar levels, and across all patients, higher levels of these markers associate with poorer cognition over time, a study found.

TNF-alpha, a pro-inflammatory molecule, showed particular potential as a predictive biomarker of future cognitive impairment, its researchers wrote.

Higher levels of certain inflammatory biomarkers also were found to associate with more toxic molecules and nerve damage biomarkers in all Parkinson’s patients, irrespective of their mutation status.

A person’s age, sex, and disease duration influenced levels of some inflammatory biomarkers, highlighting the need for age- and sex-specific cutoff values, the researchers added.

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Neuronal loss that marks Parkinson’s may promote inflammatory processes

The study, “Inflammatory CSF profiles and longitudinal development of cognitive decline in sporadic and GBA-associated PD,” was published in the journal npj Parkinson’s Disease.

Parkinson’s is marked by the progressive death of nerve cells in the brain that produce dopamine, a molecule used to send messages between nerve cells. The loss of these neurons is thought to be caused by the accumulation of toxic clumps of the alpha-synuclein protein.

Growing evidence suggests that inflammation plays a role in Parkinson’s development and progression. Inflammation is a typical response to tissue injury, but the ongoing loss of neurons in the brain that marks Parkinson’s may trigger and sustain inflammatory processes and cause further damage.

To better understand Parkinson’s-related inflammation, researchers at the University of Tübingen in Germany measured the levels of 30 inflammatory biomarkers in the CSF, the fluid that surrounds the brain and spinal cord, in 498 Parkinson’s patients: 256 men and 242 women.

Patients’ mean age was 66 and they had been living with the disease for a mean of seven years. Among them, 98 carried mutations in the GBA gene, one of the most common genetic risk factors of Parkinson’s and one linked to a faster cognitive decline.

In patients without GBA mutations, CSF levels of all biomarkers were similar to those with GBA-mutation carriers, regardless of mutation severity, results showed. The exception was TNF-alpha, whose levels were significantly lower in the GBA-mutation patient group.

Among men with Parkinson’s, higher CSF levels of IL-8, IL-18, MCP-1, and MIP-1 beta significantly associated with mild cognitive impairment, as determined using the Montreal Cognitive Assessment.

Higher levels of eotaxin-1 linked with worse motor symptoms, as measured with the Unified Parkinson’s Disease Rating Scale-Part 3.

Elevated CSF levels of alpha-synuclein and other toxic molecules tied to neurodegeneration also were found in men with higher CSF levels of the inflammatory markers ICAM-1, MIP-1 beta, MMP3, SCF, and VEGF. Likewise, these patients had elevated CSF levels of neurofilament light chain (NfL), a biomarker of nerve cell damage.

Neurofilament light chain is a major subunit of neurofilaments, key structural proteins of neurons. When nerve cell fibers are damaged and neurons die, neurofilaments are released into bodily fluids.

Among women with Parkinson’s, higher levels of IL-8, ICAM-1, MMP3, and VEGF associated with poorer cognitive function, while higher IL-8, MCP-1, and VEGF levels were linked to poorer motor function. Elevated ICAM-1 and SCF levels associated with a greater buildup of toxic alpha-synuclein and NfL.

Researchers then assessed potential links between these inflammatory biomarkers and cognitive changes over time.

Onset of cognitive problems tied to significantly higher TNF-alpha levels

Of the 260 patients without GBA mutations and no signs of cognitive impairment when first sampled (a baseline or study start measure), 213 (82%) were followed over time. About one-quarter (27%) developed cognitive impairment after a mean of 3.8 years and a mean disease duration of 11 years.

Among GBA-mutation carriers, 92% of the 59 patients without baseline cognitive problems were followed over time. Among them, 15 patients developed cognitive impairment after a mean of 3.7 years. Their mean disease duration was 10.2 years.

Data from all Parkinson’s patients showed that those who developed cognitive problems over follow-up had significantly higher TNF-alpha levels at baseline than those who did not develop cognitive problems, and significantly higher levels than patients who entered the study with cognitive issues.

In turn, higher VEGF levels at baseline were associated with a delay in the development of cognitive impairment among patients without GBA mutations. In those carrying such mutations, a slower onset of cognitive impairment linked with higher MIP-1 beta baseline levels.

Further analysis found that sex, age and/or disease duration influenced certain inflammatory markers levels related to a delay in cognitive issues, regardless of mutation status.

“We conclude that CSF levels of inflammatory markers are associated with clinical rating scales of motor and cognitive function as well as with levels of neurodegenerative CSF markers,” the researchers wrote.

However, “the majority of these inflammatory CSF markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment,” they added.

“Importantly, we detected a relevant interaction of sex, age and disease duration with the CSF levels of inflammatory markers,” the team wrote, adding that defining “age and sex-specific cut-off values for inflammatory markers … will be highly necessary before planning and interpreting clinical trials.”