Testing for the tau protein in blood could help predict the outlook for the rare and deadly Creutzfeldt-Jakob disease (CJD), a discovery that also has implications for research in Alzheimer's disease and other neurodegenerative disorders, researchers reported in JAMA Neurology on May 6.
Tau is a protein associated with neuronal damage, and previous research has found elevated tau levels in patients with CJD. But tau levels are typically obtained through cerebrospinal fluid (CSF), acquired via lumbar puncture -- an invasive procedure. What if tau could be measured through blood samples instead?
Blood testing of total tau (t-tau) was found to be a unique predictor of survival in patients with sporadic CJD (sCJD), and it is more convenient than other methods for estimating a patient's prognosis, reported a team led by Adam Staffaroni, PhD, a neuropsychologist at the University of California, San Francisco (UCSF) Memory and Aging Center.
"These findings further bolster the value of blood-based biomarkers based on their minimally invasive and relatively inexpensive nature and build on prior studies that suggested patients with sCJD and controls can be discriminated with relatively high accuracy using blood-based assays," the group wrote.
The results promise to improve clinical care and help ensure that clinical trials in neurodegenerative diseases are adequately powered, according to the researchers. However, the findings still need to be validated in larger studies before they can be put into practice.
Getting a handle on a grim diagnosis
CJD belongs to a family of human and animal prion (abnormal forms of cellular proteins) diseases. Like Alzheimer's and Huntington's disease, it causes psychiatric symptoms and decline, but it does so much more quickly.
According to the U.S. National Institutes of Health (NIH), only 350 cases of CJD are reported annually; on average, CJD occurs at about age 60, and individuals with the disease rarely live past a year. The sporadic type of CJD is the most common, accounting for 85% of cases. CJD is typically diagnosed through electroencephalography, CSF diagnostics, and magnetic resonance imaging (MRI), with confirmation in autopsy after death.
Baseline total tau on CSF tests and a polymorphism at the codon 129 genotype are currently used to help predict how long patients will live, but there has been interest and some research published about the potential for blood testing as a noninvasive biomarker for CJD and other neurological disorders, Staffaroni and colleagues noted.
In the current study, the researchers sought to determine the utility of plasma and CSF biomarkers compared with other characteristics of CJD by evaluating patients referred to the UCSF Memory and Aging Center with probable or pathology-proven disease between 2004 and 2018. On average, CJD patients live for four months, but lifespan is highly variable, with some surviving for weeks and others for years, the authors noted.
"Accurate prediction of disease duration has implications for clinical management, helping patients and families prepare for the disease course," they wrote. "Accurate prediction of survival time also affects clinical trial design, as stratifying patients based on expected disease course can improve a trial's power, thereby reducing costs and ultimately maximizing the number of trials that can be funded. This is especially germane in sCJD, given the rarity of the disease and variable survival time."
In addition to blood and CSF tests, the researchers assessed five other factors associated with survival:
- Genotyping of the prion protein gene at codon 129
- The Barthel index, a measure of ability to carry out daily life activities
- The Medical Research Council (MRC) prion disease rating scale, which assesses cognitive function as well as life activities
Of these five factors, three -- codon 129 genotyping and scores on the Barthel index and the Medical Research Council scale -- significantly correlated with the length of survival, with lower levels of function predicting a faster disease course, Staffaroni and colleagues reported.
The plasma total tau level and the Barthel index each had independent value for predicting length of life, a statistically significant finding, they wrote. And as with plasma biomarkers, the CSF t-tau level remained associated with survival after controlling for the Barthel index and codon 129 genotype, the researchers noted.
"The correlation between CSF and plasma t-tau level, together with the concordance of CSF and plasma t-tau level in predicting survival time, further strengthens our finding that plasma tau level may be a useful biomarker in this cohort," they wrote.
Building the evidence base for plasma tau
The UCSF investigators wrote that the data are in line with prior research, in that plasma t-tau correlated with the rate of disease progression, matching a study of 45 patients by Thompson et al (Journal of Neurology, Neurosurgery & Psychiatry, September 2018, Vol. 89:9, pp. 955-961). Plasma t-tau did not correlate with survival in that study, they noted, but Thompson and colleagues had not controlled for baseline functional severity.
In the UCSF study, the plasma t-tau level did correlate with survival regardless of functional severity at baseline. Furthermore, the researchers found that the level of plasma neurofilament light (NfL), the level of CSF t-tau, the ratio of t-tau to phosphorylated tau, and the level of neuron-specific enolase (NSE) were also significantly associated with the length of survival, but less so than plasma t-tau.
"Importantly, when baseline functional status and plasma t-tau levels were modeled together, both were strong, independent predictors of survival time," the group wrote. "This suggests that clinical measures and plasma t-tau level could be combined to further improve prediction accuracy."
What this means for Alzheimer's
The results still need to be validated in a larger cohort, and assays are currently only available for research use, though commercial tests are in development. Elevated plasma t-tau is found in patients with many other conditions, including the neurodegenerative diseases Alzheimer's and frontotemporal dementia, as well as acute brain injuries. However, its value as a biomarker has been questioned in other diseases like Alzheimer's partly because the plasma t-tau levels did not match the CSF t-tau levels, Staffaroni and colleagues wrote.
"One explanation for the high correlation between CSF and plasma tau level in sCJD is that the rapidity and amount of neurodegeneration may result in continuous, high quantities of tau in the periphery that overcome the peripheral mechanisms of elimination," the researchers wrote. "Others have argued that higher plasma t-tau concentrations in sCJD may be driven by preterminal cases having higher t-tau levels."
CJD is an excellent model for treatments targeting the prion-like pathogenesis of neurodegeneration, Staffaroni et al wrote, adding that "rapid decline in prion disease may allow clinical trials to detect a drug effect more quickly than trials enrolling patients with slowly progressing conditions."
"This study adds to research in other dementia disorders, such as Alzheimer disease, suggesting that blood-based assays may revolutionize the way that neurodegenerative diseases are diagnosed and monitored," they wrote.
As with Alzheimer's, the field needs to standardize methods for testing, optimize cutoff points, and replicate the research before moving these biomarkers into the clinic or using them in clinical trials, the authors advised.