Experimental and Clinical Biomarkers for Progressive Evaluation of Neuropathology and Therapeutic Interventions for Acute and Chronic Neurological Disorders

Abstract

This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.

A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration

“…This could potentially clarify the higher frequency of seizures and epileptiform discharges observed in DFP-exposed animals during later recording periods. In addition, widespread axonal sprouting of granule cells is also associated with a lower seizure threshold, leading to the development of SRS and other ictal abnormalities, including discharges, HFOs, inter-ictal spikes in DFP-exposed animals ( Houser, et al 1990 ; Cavazos and Cross, 2006 ; Danzer, 2017 ; Reddy and Abeygunaratne, 2022 ). Moreover, DFP exposure itself can induce cell death, disrupting the balance between apoptosis and neurogenesis within the hippocampus ( Espay, 2014 ; Nardone et al, 2016 ).…”

Empirical Analysis of Drug Targets for Nervous System Disorders

“…1 The high attrition rate can be attributed to several factors including the complexity and heterogeneity of nervous system disorders, as well as the scarcity of validated and easily accessible biomarkers to monitor therapeutic response. 2 The difficulty in predicting clinical efficacy with nervous system disease preclinical models has also contributed to the low success rate in phase II clinical trials, where efficacy is first evaluated in patients. These challenges prompted some pharmaceutical companies to deprioritize and/or restructure efforts on developing new therapeutic agents treating nervous system disorders.…”

“…The clinical success rate of neurological drugs is significantly lower than that of other disease areas when comparing the probability of launch (FDA approval) from entry into phase I clinical trials with a success rate of only 3% over the 2010–2017 time period . The high attrition rate can be attributed to several factors including the complexity and heterogeneity of nervous system disorders, as well as the scarcity of validated and easily accessible biomarkers to monitor therapeutic response . The difficulty in predicting clinical efficacy with nervous system disease preclinical models has also contributed to the low success rate in phase II clinical trials, where efficacy is first evaluated in patients.…”

Cognitive Activity Is Associated with Cognitive Function over Time in a Diverse Group of Older Adults, Independent of Baseline Biomarkers

“…Our objective was to better understand the influence of cognitive activity in older adults with variable cognitive functioning and a range of underlying disease status. Since biomarkers provide a proxy indicator for neuropathology [19], we examined the association of cognitive activity and cognitive function, in the context of three biomarkers.…”