Divergent CSF   alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy

Abstract

Background Elevated CSF tau is considered a biomarker of neuronal injury in newly developed Alzheimer’s disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of tau species in other primary tauopathies. We assessed CSF tau protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterized by deposition of four microtubule binding repeat (4R) tau with minimal Aβ pathology. Methods 26 normal control (NC), 37 AD, and 24 PSP patients participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total tau, and ptau181. Additional, novel ELISAs targeting different N-terminal and central tau epitopes were developed to examine CSF tau components and to investigate interactions between diagnostic group, demographics, and genetic variables. Results PSP had lower CSF N-terminal and C-terminal tau concentrations than NC and AD measured with both the novel tau ELISAs and the standard AlzBio3 tau and ptau assays. AD had higher total tau and ptau levels than NC and PSP. There was a gender by diagnosis interaction in both AD and PSP for most tau species, with lower concentrations for male compared to female patients. Conclusions CSF tau fragment concentrations are different in PSP compared with AD despite the presence of severe tau pathology and neuronal injury in both disorders. CSF tau concentration likely reflects multiple factors in addition to the degree of neuronal injury.

Genome-wide association study identifies MAPT locus influencing human plasma tau levels

“…3,4 Enigmatically, despite strong genetic links to tau, CSF tau levels are normal or low in other tauopathies such as PSP and some tau gene (MAPT) mutation carriers. 5,6 The recent development of an ultrasensitive assay for tau in peripheral blood makes it feasible to study the relationship between peripheral tau concentrations and tauopathies. 7 In comparison to CSF, plasma tau levels in aging and neurodegenerative disease have not been well studied.…”

Tau Diagnostics and Clinical Studies

“…The CSF tau profile is composed entirely of tau fragments rather than full-length protein, with different fragmentation patterns dependent on disease state and progression (Johnson et al 1997;Meredith et al 2013). CSF tau CTF and NTF levels are decreased in PSP, while increases were observed in AD (Wagshal et al 2015). There is much interest in the use of CSF fragments of tau as a biomarker, with data being presented by Kina Höglund showing that the asparagine endopeptidase mediated-NTF, tau 1-368 (Zhang et al 2014) could potentially act as an AD specific biomarker.…”

Progressieve supranucleaire parese

“…De bepalingen van totaal tau en fosfotau in de liquor cerebrospinalis zullen ook normaal zijn als op dat moment geen specifieke tau-isomeren kunnen worden gemeten. Naar analogie van het verlaagde Ab-42-eiwit in de liquor bij AD is wel gesuggereerd dat totale tauconcentraties bij PSP verlaagd zijn, maar daarover bestaat nog geen consensus [14]. Een marker waarmee PSP zich in elk geval lijkt te onderscheiden van de ziekte van Parkinson is de verhoogde concentratie neurofilament light-chaineiwit dat ook bij onze patiënt werd gevonden [11].…”