Can an injured brain change who we are?
What creates the nuances of our personalities or the fabric of our character? Historically, the ancient Egyptians attributed these traits to our hearts. However, today we understand that our brains are the drivers of who we are (
Ziskind et al., 2004). A jumble of neural connections storing every memory and moment of our lives in order to shape us into who we are as individuals. This is evidenced by years of peer-reviewed publications in the neuroscience field, yet this concept becomes problematic in the context of brain injury (
Simon et al., 2020,
Valk et al., 2020,
Smith et al., 2019). In other words, when we injure an arm, we perceive ourselves and one another as the same person. Yet when we injure our brain, our personalities and the very character that makes us who we are can change forever.
What is neurodegeneration?
An example of a progressive brain injury is neurodegeneration. Neurodegeneration is characterized by the destruction of the central or peripheral nervous system and can be caused by many diseases. Neurodegeneration is devastating to the patient and their families. While many neurodegenerative diseases have no cure, early intervention can drastically slow down the cognitive decline in the patient and extend their quality of life. However, early intervention is complex and rarely done since we do not have meaningful and accessible biomarkers for definitive diagnoses at these early stages of neurodegeneration, also referred to as mild cognitive impairment (MCI). In addition, identifying biomarkers specific enough to differentiate between various neurodegenerative diseases has been a challenge since many clinical features overlap among numerous diseases (
Ashton et al., 2020). Thus, understanding the molecular differences between what is driving the pathology of these neurodegenerative diseases is imperative as we work toward developing specific, reliable, and accessible biomarkers as a robust tool for definitive diagnosis and early intervention to improve the outcome of patients their families struggling with neurodegenerative disease.
A neurodegenerative disease that plagues the world is Alzheimer's disease (AD). The pathologic hallmark of AD is the buildup of amyloid-β (Aβ) plaques in the brain, which are protein aggregates that ultimately disrupt brain function. Individuals with AD will progress from their normal baseline cognitive abilities through subtle changes of the preclinical stages to apparent symptoms of brain dysfunction. The preclinical stages, or MCI, are defined by differences in cognitive abilities, impairment in one or more cognitive domains than expected for the patient's age and education, preservation of independence in functional capacities, and no significant impairment in social or occupational functioning. This early stage then progresses to AD dementia, which eventually impairs the ability to perform activities of daily living that they were previously independently performing due to cognitive deficits (
alz.org). Other neurodegenerative diseases that are important to study are Parkinson's disease (PD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), all of which are also characterized by aggregation of abnormal proteins in the nervous system. They are often referred to as aggregopathies, meaning that they exhibit aggregation of one or more of six essential proteins: Aβ, the prion protein (PrPSc), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) or fused in sarcoma (FUS) (
Ashton et al., 2020).
What are the current methods and challenges of testing for neurodegenerative diseases?
The current methods of diagnosis for these diseases often are not sensitive enough for early detection, and thus by the time of diagnosis, significant neurodegeneration has occurred for decades. Except for genetic testing (for example, autosomal dominant mutations in the APOE gene), clinicians have had to rely on patient reports of cognitive decline, which is unreliable and inconsistent, as well as invasive and expensive testing methods to properly diagnose a patient. For example, Aβ imaging via PET scan by which radioactive tracers such as Florbetapir (18F) are injected into the patient and bind to Aβ in the person's brain to be seen on imaging. However, these PET Scans are not always definitive because neurodegenerative diseases can look similar via PET scan, thus, making targeted treatment challenging to create the best outcome for the patient based on their specific disease. Tau or amyloid testing of the patient's cerebrospinal fluid (CSF) is also a method for diagnosis. However, it is quite invasive given the nature of extracting CSF safely. Furthermore, these biomarkers are still present for a variety of neurodegenerative diseases, resulting in inconclusive diagnoses. Taken together, the need for next-generation biomarkers to detect the onset of neurodegenerative diseases and distinguish between pathologies is a fundamental next step in science and healthcare.
What are the next-generation biomarkers, and how can they help?
Given the invasiveness and ambiguity of the current biomarkers, identifying more specific and accessible biomarkers is critical for early interventions and treatments of neurodegenerative diseases. For example, blood-based biomarkers may offer a more accessible method for identifying biomarkers in patients early. One potential blood-based biomarker is a protein called neurofilament light chain (NFL). NFL is released when nerve cells are damaged and can be found in the CSF and the blood of patients with neurodegenerative disease. NFL levels are elevated in individuals with prodromal AD and familial AD compared to healthy controls (
Ashton et al., 2020). In addition, advances in ultra-sensitive immunoassays for measuring truncated amyloid precursor protein (APP ΔC31), Aβ, and total tau/phosphorylated tau, have demonstrated that blood-based biomarker screening is a practical tool for identifying AD in particular.
For example, since the truncated protein APP ΔC31 is a contributor to neuronal death in AD,
Poksay et al. (2017) used Enzo's
APP ΔC31 ELISA kit, the first-to-market kit to quantify APP ΔC31, to measure this protein biomarker in patient plasma as well as testing small molecule inhibitors to decrease the levels of APP ΔC31 in AD-affected individuals. For further study, Enzo has validated the APP ΔC31 ELISA kit to quantify this analyte in cell lysates and cerebrospinal fluid with high specificity and a large dynamic range (Figure 1A, B). These data are promising as a potential method for early detection and intervention. Moreover, circulating phosphorylated Tau proteins have been detected using antibodies such as
[pSer262] Tau polyclonal antibody, which detects Tau protein that has been phosphorylated at serine 262, a hallmark of AD (
Liu et al., 2005). Another notable blood-based biomarker that might help to distinguish and diagnose neurodegenerative diseases is the Aβ42/Aβ40 ratio. Clinical data show that this ratio is lower in AD dementia and prodromal AD patients than in healthy controls (
Ashton et al., 2020).
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Figure 1. STypical standard curve produced using the APP ΔC31 ELISA kit standard, with large dynamic range (A). The parallelism between the recombinant assay standard and various matrices spiked with APP ΔC31 showing specificity and sample recovery with the kit (B) Full application note can be found here.
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While next-generation biomarkers (such as the aforementioned blood-based biomarkers) are beginning to emerge and be utilized in the clinic, further research is needed to validate the current blood-based biomarkers as well as develop and validate new targets for early intervention and diagnosis.
How can Enzo support the development of next-generation biomarkers and neurology research?
Enzo Life Sciences has been your valued partner in scientific research for decades. Enzo's strong portfolio of products to support your neurological research will enable high-quality data and the progression of your research. Enzo offers a variety of tools to investigate cutting-edge biomarkers and drivers of neurological disease and degeneration. The table below summarizes a few key examples of Enzo's tools and the diseases they address.
Do you need help with your neurology research? Contact our
application scientists at Enzo Life Sciences!
