CHEARS

What are biomarkers:

A biomarker is any characteristic that can be accurately measured as an indicator of a normal biological process, a disease process or a biologic response to a treatment or intervention. Biomarkers tracking different molecular pathways along with brain neuroinflammatory endophenotypes or neuroimaging markers, can untangle temporal–spatial dynamics between neuroinflammation and other pathophysiological mechanisms

What is neuroinflammation:

It is defined as the activation of the brain’s innate immune system in response to an inflammatory reaction and is characterised by a host of cellular and molecular changes within the brain, to be precise its an inflammatory response within the brain or spinal cord on nerve tissue mediated as a result of the production of cytokines, chemokines, reactive oxygen species, and secondary messengers. these mediators are produced by resident CNS glia (microglia and astrocytes), endothelial cells, and peripherally derived immune cells. there are immune, physiological, biochemical, and psychological consequences of these neuroinflammatory responses.

Some of the neuroinflammatory disorders including traumatic brain injury, brain tumors, Multiple sclerosis (MS), neurodegenerative diseases, such as Alzheimer's disease (AD) and Huntington's disease (HD); disorders induced by brain injury; and neuropsychiatric disorders, such as depression, schizophrenia, PTSD.

Why biomarkers are used in neurodegeneration?

Biomarkers are used in neuroinflammation to improve the diagnosis to make an earlier diagnosis, make less invasive testing, for faster drug development, and more effective and personalized treatment outcomes.

Biomarkers in neurodegeneration?

large-scale genomic studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4a, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation.

most of these genes are involved in proinflammatory

• · intracellular signaling,

• · cytokines/interleukins/cell turnover,

• · synaptic activity,

• · lipid metabolism,

• · vesicle trafficking

microglia and astrocytes are key cellular drivers and regulators of neuroinflammation

Focussing on cytokines: Cytokines are a large group of proteins, peptides, or glycoproteins that are secreted by cells of the immune system. These proinflammatory cytokines can be evaluated during stress and trauma. During stress or trauma, cytokines like IL-1 beta, IL-6, TNF-alpha, and IFN-gamma will be released, thereby they can be checked in the blood samples these cytokines can initiate inflammatory processes and provoke a variety of signalling cascades in the brain and release stress hormones that could evolve to systemic inflammation. these systemic inflammations could lead to cardiac diseases and metabolic diseases.

• During depression: there can be an elevation of IFN -Ɣ, CRP, TNF-ALPHA, IL4, CCL-2

• On trauma exposure, there can be an increase in IL-1ß, IL-6, IFNɣ, CRP, TNFΑ

• On PTSD there can be an elevation in IL-1ß, IL6, IFNƔ, CRP, TNFΑ.

• On traumatic brain injury are GFAP, UCHL1, S100B, NFL.

• On AD inflammatory biomarkers are associated with either microglia—e.g., soluble trem2 (strem2), monocyte chemoattractant protein-1 (MCP-1), and YKL-40 —or astroglia;YKL-40, are extensively investigated in AD patients

Biomarker-driven treatment in brain diseases?

• Complex trauma-related diseases require biomarkers for their personalized treatment like in the case of PTSD, this condition can be heterogenous therefore it’s important to identify different subtypes however, it has no specific diagnostic tests, no known cure, and no objective diagnostic tests. its diagnosed and treated with a symptom-compare approach, therefore, biological signatures are important to make a treatment stratification and provide with a wider option of precision medicines for the treatment

Measurement of biomarkers:

• There are different assays available for measuring biomarkers, however these have to be categorised as low sensitivity, moderate sensitivity and high sensitivity based on the significance of their results.

• CT or MRI can be biomarkers that can measure changes in the size and function of the brain, as well as levels of certain proteins in brain and cerebrospinal fluid

• Electro encephalogram can be used that can measure the small electrical signals in your brain for understanding the brain activity. Blood tests are other test used to measure these biomarkers.

Need for standardisation of biomarker measurement

• It’s important for scientist to use accurate measurements to identify the biomarkers to make the best practises for assessing these inflammatory markers.It is challenging to get the values of inflammatory markers as they are very low in blood and require highly sensitive assays to be detected.

• Analytical sensitivity or the lowest concentration of cytokines that is detectable varies between assays and individual cytokines

• There are no tools to predict treatment for PTSD, so generally, psychotherapists use evidence base medicines.The best ways to carry out the treatment would be the use of combination -biomarkers, where the use of neuroimaging and verbal memory task so that it can help to categorize patients into psychotherapy responsive or not responsive from a heterogeneous population.

Challenges in obtaining biomarkers

• There are different challenges in understanding biomarkers in several brain conditions such as depression, PTSD, traumatic brain injury, therefore making it difficult for treatment and diagnosis.

• Firstly, it is uneasy to take a biopsy from the brain as well the cost of MRI and CTis quite expensive.

• Secondly, few proteins are highly specific to the brain and those proteins that are brain specific have only a low concentration on blood or spinal fluid which makes it integral for the requirement of any specialized detection assays or specialized tools for measurement.

• Third, many neurological disorders lack animal models that make it difficult to carry the tests, and last but not least, validation of biomarkers is also very difficult.