The most robust measurement of pathology in neurodegenerative conditions is conducted via imaging technologies, but these don’t do well when it comes to the assessment of the more subtle earlier stages of these conditions. Further, imaging is relatively expensive. So for some years researchers have worked to develop a range of less costly, more convenient biomarkers to assess disease risk and disease progress. Progress has been made. Useful blood tests are emerging for Alzheimer’s disease, for example.
Today’s open access paper reviews recent advances and the present state of fluid biomarker assays for neurodegenerative conditions. Being able to use bodily fluids other than cerebrospinal fluid is arguably even more important than moving away from imaging when it comes to cost and convenience; no-one particularly wants to undergo the lumbar puncture procedure needed to access cerebrospinal fluid. Using blood, saliva, and so forth, becomes possible with the development of more sensitive assay technologies, able to detect the much lower levels of molecules related to neurodegeneration found outside the central nervous system.
Fluid-based biomarkers for neurodegenerative diseases
Neurodegenerative diseases are characterized by various pathological mechanisms, such as the accumulation of misfolded proteins, oxidative stress, neuroinflammation, and impaired neuronal signaling. For example, Alzheimer’s disease (AD) is primarily associated with amyloid-beta (Aβ) plaque deposition and intracellular tau protein hyperphosphorylation leading to neurofibrillary tangles, while Parkinson’s disease (PD) involves the accumulation of aggregated alpha-synuclein (α-syn) forming Lewy bodies. In contrast, amyotrophic lateral sclerosis (ALS) is marked by motor neuron loss, and multiple sclerosis (MS) is distinguished by demyelination and axonal damage. Despite varying pathologies, these diseases share common features, such as progressive neuronal loss, a lack of disease-modifying treatments, and the need for early diagnosis to mitigate disease progression. Currently, diagnostic tools such as cognitive assessments and neuroimaging (e.g., magnetic resonance imaging [MRI] and positron emission tomography [PET]) are widely used, but they are often only valid when the disease has reached advanced stages. This creates a need for novel diagnostic and prognostic tools that can detect and stage these diseases in their preclinical stages.
Fluid biomarkers, which can be obtained from bodily fluids like cerebrospinal fluid (CSF), blood, saliva, and urine, offer a non-invasive and potentially more sensitive means of detecting neurodegenerative diseases. Biomarkers are molecules that could reflect underlying pathological changes in the body, such as protein misfolding, neuronal damage, and neuroinflammation, at times even before clinical symptoms emerge. Detecting these changes early through fluid biomarkers may enable the timely trial of interventions which have the potential to slow or prevent disease progression. CSF has been a traditional source for detecting biomarkers of neurodegenerative diseases, as it is in direct contact with the central nervous system. In AD, for example, the CSF biomarkers Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) are well-established indicators of disease pathology. However, the invasive nature of lumbar punctures limits the routine use of CSF biomarkers in clinical practice.
Recent advances in fluid biomarker research have expanded beyond CSF to include blood and saliva, which are more accessible and less invasive. Blood-based biomarkers have gained particular attention, as they allow for repeated measurements over time and are suitable for large-scale population screening. Plasma Aβ42/40 ratios, various p-tau species, and neurofilament light chain (NfL) have shown promise in detecting Alzheimer pathology with accuracies comparable to CSF biomarkers. In PD, the detection of α-synuclein in blood has also demonstrated early diagnostic potential. Additionally, elevated levels of NfL in both blood and CSF have been observed in ALS and MS, making it a valuable marker for neuroaxonal injury across multiple neurodegenerative diseases.
Salivary levels of α-synuclein have been investigated as a potential marker for PD, while Aβ42 and tau proteins in saliva show potential for diagnosing Alzheimer’s. Although concentrations of these biomarkers are lower in saliva compared to blood or CSF, advances in detection technology are improving the sensitivity of salivary biomarkers, making them a potential tool for large-scale screening. Urine biomarkers are also under investigation, with early studies identifying changes in the levels of proteins like Aβ, tau, and oxidative stress markers in the urine of patients with neurodegenerative diseases. Although urinary biomarkers are still in the early stages of research, they offer another non-invasive method for detecting disease-related changes, particularly in resource-limited clinical settings.
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