In this article series we aim at highlighting the current state of knowledge and the latest developments in the field of Alzheimer’s disease (AD) testing. This chapter looks at neurodegenerative biomarker changes in cerebrospinal fluid.
Other articles in this series:
- Altered proteins in brain neurodegenerative diseases
- How to perform a lumbar puncture
- Handling and transportation of CSF samples
The cerebrospinal fluid (CSF) is the optimal source for biomarkers to establish ante-mortem a link between clinical features and underlying pathologic features.
Brain neurodegenerative diseases (NDD) are commonly classified by distinct clinical presentations, e.g., impairment in cognitive functioning involving anatomical regions showing neuronal dysfunction and loss. Most of these diseases follow a deteriorating course to dementia. Fifty to seventy-five percent of dementia cases are due to Alzheimer’s pathology.
Most cases of disease are sporadic, but some are inherited in a dominant manner. In these cases, the overexpression of mutant proteins rises to disease-associated phenotypes with early occurrence of disease often.
Most frequent neurodegenerative dementias
For some diseases, only the criteria referring to the clinical phenotype are used for subtyping, whereas for others biochemical modifications or gene polymorphisms could also to be considered. The classification gains in confidence based on positive evidence of the presence of pathological protein deposits in brain.
The accumulation of brain pathologies seems to be a nearly inevitable consequence of aging; there is frequently an overlap of concomitant pathologies.
How well do the CSF biomarkers perform diagnostically?
Although a multitude of CSF biomarkers for specific pathologic changes and nonspecific markers of oxidative damage or inflammation involved in neurodegenerative diseases were studied, only three core biomarkers are validated for a differential diagnosis of AD, i.e. Aβ1-42 peptide (Aβ42), total tau (T-tau), and its phosphorylated form (P-tau) measured in vitro using CSF specimens.
CSF α-syn is currently studied for its possible value as a PD biomarker and in the differential diagnosis of NDD, but not validated. Current commercial assays detecting total α-syn levels seem not able to distinguish Lewy body disorders from other neurodegenerative disorders.
The detection of CSF PrPSc is performed only in reference laboratories for prion diseases with the nonspecific 14-3-3 protein. For now, only results of CSF Aβ42 (or CSF Aβ42/40 ratio), T-tau and P-tau can be used in routine clinical setting.
Overview of clinical effectiveness of established Alzheimer’s disease biomarkers
The concomitant pathologies in elderly individuals lead to an artificial clinical subgrouping driven by the dominant clinical phenotype. The common age-associated brain pathologies are amyloid plaques, tangles, ischemic cerebrovascular disease but also microinfarctions, hippocampal sclerosis, α-syn deposits (Lewy bodies), TDP43 inclusions, and argyrophilic grains.
A clinical phenotype (typical, atypical or unclear) and the CSF core biomarkers reflecting the dynamic changes of protein metabolism in the brain help in differentiating pathological neurodegenerative decline from normal aging.
- Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Dubois B, et al. Lancet Neurol. 2021; 20(6): 484-496. Review.
- Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia. Simonsen AH, et al. Alzheimers Dement. 2017; 13(3): 274-284. Review.
- Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Blennow K, et al. Alzheimers Dement. 2015; 11(1): 58-69. Review.
- Biomarker modeling of Alzheimer’s disease. Jack CR Jr, et al. Neuron. 2013; 80(6): 1347-1358. Review.
- Fluid biomarkers in Alzheimer’s disease - current concepts. Rosén C, et al. Mol Neurodegener. 2013; 8: 20. Review