Possibility of the first fluid biomarker that reflects brain pathology in primary tauopathies

By Dr. Priyom Bose, Ph.D.Reviewed by Danielle Ellis, B.Sc.Nov 28 2022

Tauopathies are a group of neurodegenerative diseases associated with aggregated tau proteins. These diseases typically progress over the years, and their symptoms are linked to neurological impairments. Patients with neurodegenerative diseases and their families are also affected financially and socially.

Background

One of the most common tauopathies is Alzheimer’s disease (AD), which is diagnosed using the cerebrospinal fluid (CSF) biomarker amyloid-β (Aβ) and total and phosphorylated tau. These biomarkers also help evaluate clinical trials. Advancements in positron emission tomography (PET) imaging have enabled the quantification of aggregated Aβ and tau in AD patients’ brains.

Apart from AD, fluid biomarkers or imaging tracers for other tauopathies, such as argyrophilic grain disease (AGD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), globular glial tauopathy, and Pick’s disease (PiD), are not available. Hence, accurate diagnoses of these diseases are challenging. 

Most tauopathies are diagnosed through brain autopsy; therefore, there is an urgent need for antemortem fluid biomarkers to improve the accuracy of clinical diagnosis. Additionally, these biomarkers could also help assess clinical trials for tauopathy therapeutics.

Recent biochemical and structural investigations have indicated that specific tau species contain brain tau aggregates in subtypes of tauopathies. In the adult human brain, six tau splicing isoforms are expressed. These isoforms contain repeat domains(R), such as R1, R3 and R4 (3R) and R1, R2, R3 and R4 (4R) in the microtubule-binding region (MTBR).

Cryogenic electron microscopic (cryo-EM) analysis revealed the presence of distinct tau filament structures in PiD (3R), AD (3R/4R), PSP (4R), CTE (3R/4R), and CBD (4R). It was observed that R3 and R4 repeat domains were frequently present in tau aggregates of tauopathies including AD.

About the study

Besides AD, no fluid biomarkers have been discovered to differentiate subgroups of tauopathies to date. Addressing this gap in research, a recent Nature Medicine study hypothesized that 4R isoform-specific MTBR-tau species accumulate in the patient’s brain of specific subtypes of 4R tauopathies. Furthermore, whether these changes are expressed in the CSF, which could be used to differentiate among subtypes of primary tauopathies, was evaluated.

In this study, two tau fragments, namely, MTBR-tau₂₇₅ and MTBR-tau₂₈₂, were specifically monitored. They were found to be present in the R2 region and were specific to 4R tau splicing isoforms. The diagnostic abilities of MTBR-tau275 and MTBR-tau282 were assessed to analyze their capacity to distinguish between FTLD-tau, FTLD with TAR DNA-binding protein aggregates (FTLD-TDP), control, and different subtypes of tauopathies.

Study findings

The current study focussed on MTBR-tau, which exists in the CSF as a truncated C-terminal tau fragment and contains the core regions of tau aggregates in the brain. Mass spectrometry (MS) and biochemistry analysis revealed distinct tau fragments, i.e., MTBR-tau₂₄₃; R1, MTBR-tau₂₉₉; R2-R3, and MTBR-tau₃₅₄; R4, enriched in varied concentrations in the brains of AD patients with disease progression.

Changes in 4R isoform-specific MTBR-tau₂₇₅ and MTBR-tau₂₈₂ were only found in subsets of 4R and 3R/4R mixed tauopathies. Importantly, these 4R isoform-specific measures remained constant in 3R tauopathy (PiD) and non-tauopathy FTLD (FTLD-TDP). However, it was observed that 4R isoform-specific MTBR-tau₂₇₅ and MTBR-tau₂₈₂, which were normalized to t-tau, decreased in the CSF soluble tau. Subsequently, an enhancement in brain insoluble tau in primary tauopathies, i.e., CBD and FTLD-MAPT P301L, was observed. 

An inverse correlation was determined between MTBR-tau and t-tau in the CSF and the brain. This finding indicates a unidirectional transfer or an equilibrium between soluble CSF MTBR-tau and insoluble brain MTBR-tau in primary tauopathies.

PSP patients have 4R tau aggregates predominantly in subcortical regions, including the thalamus and brain stem. Additionally, AGD pathology was found to be most severe within the medial temporal lobe. Researchers detected that CBD contained widespread and abundant tau pathology in the cerebrum. FTLD-MAPT can promote a significantly high deposition of 4R tau aggregates in glia and neurons in multiple brain regions, such as the neocortex, hippocampus, and substantia nigra.

Compared to CBD, the tau aggregates in PSP contained varied physicochemical properties. Additionally, the equilibrium status between insoluble and soluble forms of these two tauopathies may be different. A repeated lumbar puncture study confirmed that CSF MTBR-tau/t-tau measures were reproducible and stable over four months.

Retrospective clinical syndrome analyses in a pathologically confirmed cohort revealed that CSF MTBR-tau₂₇₅/t-tau and MTBR-tau₂₈₂/t-tau biomarkers could be utilized to detect individuals with CBD with 83% accuracy, irrespective of their clinical symptoms.

Conclusions

The current study revealed that the truncated tau containing MTBR could be detected and quantified in CSF. The CSF soluble concentrations of MTBR-tau fragments, which were correlated with tau PET imaging estimates, indicated the severity of AD. One of this study's most important aspects was identifying the first fluid biomarker that could detect brain pathology in primary tauopathies.

The present study advanced the knowledge of heterogeneous pathophysiology in primary tauopathies. In the future, the current study's findings should positively aid in developing novel therapeutics to manage primary tauopathies.