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EDITORIAL COMMENTARY
Year : 2022 | Volume
: 25
| Issue : 6 | Page : 995-996
CSF P-tau 231 as biomarker in alzheimer's disease
Adreesh Mukherjee, Atanu Biswas
Department of Neurology, Institute of Post Graduate Medical Education and Research (IPGME&R) and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
Correspondence Address:
Atanu Biswas
Department of Neurology, IPGME&R and Bangur Institute of Neurosciences, 52/1A, S.N. Pandit Street, Kolkata - 700 025, West Bengal
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aian.aian_858_22
How to cite this article:Tau, a microtubule-associated protein, plays an important role in the normal function of neuron. Its phosphorylation promotes axonal and synaptic plasticity in the developing brain.[1] However, under pathological condition, hyper-phosphorylation and aberrant assembly of tau protein result in insoluble aggregates which are accompanied by synaptic dysfunction and neural cell death. Neurodegenerative conditions like Alzheimer's disease (AD) and some forms of frontotemporal dementia are examples of tau-pathies.[2]
Despite many other pathophysiological pathways described, amyloid and tau are the two most important molecules considered important in AD pathogenesis. Some of the other pathophysiological substrates are related to the disposal of aggregates from neurons, microglia dysfunction, lipid metabolism, and inflammation.[3] Genome-wide association studies have identified many new genes associated with these pathways, strengthening arguments in favor. Nonetheless, for early and effective disease-modifying therapy, amyloid and tau are the targets and search for reliable biomarker are centered on them.
Tau protein is considered as a promising candidate biomarker for axonal degeneration and neurofibrillary tangle (NFT) formation in AD. However, there are several challenges for molecular characterization of tau in cerebrospinal fluid (CSF). First, in the adult human brain, there exist six different tau isoforms produced from a single gene. Second, this heterogeneity is compounded by extensive posttranslational modifications, including phosphorylation, glycosylation, and oxidation of the protein.[4] There are several serine and threonine phosphorylation sites in tau protein, and phosphorylation is observed in different locations in different diseases. Additionally, concentration of tau in CSF is only 300 ng/ML in healthy individuals and 900 ng/ML in AD subjects. Considering that this quantity is distributed over many different modified forms and six splice variants, the amount available for analysis of each molecular species remains a challenge. However, recent methodologies have enabled for detection of total and phosphorylated tau (P-tau) in CSF.
Several longitudinal studies suggest tau pathology as downstream of the amyloidogenic cascade in AD.[5],[6] Longitudinal studies of carriers of mutation of autosomal dominant genes of AD long before the appearance of symptoms provided insight about how Alzheimer's pathology develops in the brain.[7] This has helped in the postulation of AT (N) hypothesis that suggests that amyloid and tau played an orchestrated role in AD pathogenesis. The search for the early biomarkers has come a long way thereafter. The chemical analysis of CSF to demonstrate low Aβ-42 peptide and high P-tau and total tau (T-tau) and their ratios has offered easy differentiation from other diseases and making a diagnosis of AD. CSF Aβ-42 and P-tau levels are considered as surrogate markers for the amyloid and tau deposition in the brain, which have been proven with correlation studies with amyloid and tau imaging. The attempt to provide a diagnosis in early symptomatic stage as in mild cognitive impairment (MCI) is essential to provide disease-modifying therapies. The anti-amyloid and anti-tau therapies are the key agents that are considered to prevent ongoing neurodegeneration and halt the progression. Although these therapies are yet to be available for regular use in clinical practice, advancement in diagnostics is happening very fast to welcome these therapies.
P-tau has been correlated with NFTs and tau deposition in brain[8] and has been found to differentiate AD from other dementia. Tau phosphorylated at threonine 231 (P-tau 231) differentiated between AD and frontotemporal dementia; tau phosphorylated at serine 181 (P-tau 181) enhanced classification between AD and dementia with Lewy bodies.[9] Total tau or T-tau, however, has not been found to differentiate between AD from other degenerative dementia like FTD and vascular dementia. T-tau seems to be a general marker of damage to cortical axons or neurodegeneration.
Nabizadeh et al.[10] performed a systematic review of CSF P-tau 231 (phosphorylated tau at threonine-231) or CSF P-tau 231 as a diagnostic biomarker for AD and MCI. They compared the CSF level of P-tau 231 between subjects with AD, MCI, and normal control (NC) to assess the possible role of P-tau 231 in distinguishing AD and MCI from normal people. The meta-analysis provided evidence that CSF P-tau 231 levels in AD patients were higher than in MCI patients and NC and were significantly higher in MCI patients compared to NC. The authors argue that CSF P-tau 231 may be used as a reliable biomarker for differential diagnosis of AD and MCI.
There are, however, many unanswered questions. First, no correlation of the biomarker with tau imaging of the patients was performed in the studies quoted. The fact that clinical diagnosis of AD does not always match with the pathological diagnosis is well established. More studies are therefore warranted to make the relationship of CSF P-tau level with tau deposition in cerebral cortex. Second, MCI is a heterogeneous group and does not suggest harboring AD pathology. Inclusion of clinically amnestic MCI supplemented with tau-imaging and comparing the CSF P-tau level would strengthen the argument. Third, age group of subjects in the studies is not matched. Several studies have demonstrated that T-tau and P-tau concentration of CSF varies with age and age-related cutoffs are proposed.[11]
Alzheimer's research is progressing fast to get effective treatment strategies. Despite the failure of many anti-amyloid agents in the last decade, some rays of hope came with the success of newer agents. Many anti-tau agents are also in the pipeline, so also other agents targeting various other pathomechanisms of the disease. A combination therapy with multiple targets would probably be an effective therapy in the coming days. For these to be effective, a correct diagnosis with an effective diagnostic marker is essential. CSF P-tau 231 definitely is a good candidate biomarker for the disease.
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