Immune Biomarkers May Better Classify Patients, Direct Therapy, Study Says

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Biomarkers of brain inflammation could provide a useful means for classifying Parkinson’s and Alzheimer’s patients and defining the mechanisms underpinning each person’s disease.

Testing for these biomarkers could support clinicians in providing precision medicine, by helping people with the progressive neurodegenerative disorders to choose treatments with a greater chance of benefiting them, based on their individual characteristics.

The study, “Multicenter Alzheimer’s and Parkinson’s disease immune biomarker verification study,” was published in the journal Alzheimer’s & Dementia.

Typically, diseases such as Parkinson’s are defined largely on the basis of patients’ symptoms. But while individuals share the same diagnosis, the underlying molecular and cellular causes of their illness may differ.

This also could explain why treatments do not work equally for all patients. Using these individual differences to identify patient groups may help clinicians choose more tailored treatment choices.

Many researchers propose that neurodegenerative illnesses could be defined on the basis of their molecular features, before evident symptoms occur in later stages of the disease.

To address this hypothesis, the AETIONOMY project, an European public-private partnership funded by the Innovative Medicines Initiative, is exploring potential molecular classifiers for Alzheimer’s and Parkinson’s.

Candidate markers include tracers of neuroinflammation, meaning trackers of the inflammatory reactions occurring in the brain and spinal cord, which comprise the central nervous system, or CNS.

Neuroinflammation probably begins early in neurodegenerative diseases, when the immune system senses the presence of misshaped or aggregated proteins — including beta-amyloid in Alzheimer’s, or alpha‐synuclein in Parkinson’s.

The formation of abnormal clumps of each of these proteins in the brain is believed to be at the root cause of each disease. In Parkinson’s, alpha-synuclein proteins clump together in aberrant aggregates termed protofibrils, which are toxic and thought to play an important role in the death of nerve cells (neurodegeneration).

In the first stages of the disease, these aggregates are known to activate immune cells called microglia and other supportive cells in the brain, known as astroglia. Later, immune reactivity — in which the body mistakenly attacks its own healthy cells — propagates in response to nerve cell death, with immune signals released as a consequence of the damage.

A team of researchers involved in the AETIONOMY project now sought to identify neuroinflammation-specific biomarkers. They screened 227 samples of cerebrospinal fluid or CSF, the fluid that surrounds the brain and spinal cord, collected from Alzheimer’s and Parkinson’s patients.

The goal was to look for relationships between the levels of these markers and patients’ characteristics — for example, age and sex — as well as their link with markers of neurodegeneration, such as tau, and measures of disease progression, like the Hoehn and Yahr scale for Parkinson’s.

People without dementia and patients diagnosed with mild cognitive impairment also were included for comparison.

The researchers specifically focused on 21 selected immunity markers. These included chemical messengers known as cytokines or chemokines, namely YKL‐40, TGF‐beta1, IP‐10, MCP‐1, MIF, and MIP‐1beta. The immune receptors sIl‐1RAcP, sAXL, sTyro3, sTREM2, sTNF‐RI/II, and sICAM‐1 also were targeted, as well as other complement and innate immune factors, including C-reactive protein and C1q, C3, C3b, C4, B, H, and properdin.

The findings were highly reproducible and consistent with previous findings. However, they revealed that immune markers were more tightly related to neurodegeneration — reflected by the levels of the protein tau — than having a diagnosis of Alzheimer’s, Parkinson’s, or mild cognitive impairment.

This suggests that such biomarkers may work better to discriminate the mechanisms underlying each patient’s illness.

Age was the “most striking covariate” with a “strong influence” on immunity markers. Older patients had increased levels of most immune proteins, and also tended to have more advanced disease.

The individual’s sex also influenced marker levels, as did APOE genetic variants — one of the strongest genetic risk factors for Alzheimer’s and a proposed risk factor for Parkinson’s — and center‐specific factors, or variations from the different centers from which patient data was obtained.

“These results are supportive of the use of mechanism‐based disease taxonomies [classifications] in addition to clinical features,” the researchers said.

Ageing seems to have a strong link with increased neuroinflammation; thus it should be taken into account when translating marker results to clinical practice or studies, the team said.

“Immunity biomarker levels in CSF reflect molecular and cellular pathology [disease characteristics] rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration,” the researchers concluded.

Looking ahead, the researchers reaffirm the need to characterize patients not only by symptoms but also by molecular markers that reflect their complex neurodegenerative disorders.

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