New technique tracks a culprit of Alzheimer's in spinal fluid
In their efforts to pick up the disease as early as possible, scientists are searching far and wide through the human body for tell tale signs of Alzheimer’s. A team from the Washington University School of Medicine in St. Louis has come up with a technique it says can detect one of these biomarkers in cerebrospinal fluid, which could lead to earlier diagnoses and more effective treatments.
While Alzheimer’s may become evident and easier to diagnose when the sufferer is exhibiting symptoms such as memory loss and cognitive decline, scientists hope to intervene well before this neurodegeneration takes hold. Blood tests have emerged as a promising way to pursue this by analyzing blood for early biomarkers of the disease, with a number of exciting technologies showing high degrees of accuracy in the last few years.
These types of tests search for signs of proteins called tau and amyloid, which are both implicated in the development of Alzheimer’s disease in the brain. Amyloid proteins build up into what are referred to as plaques, while misfolding tau proteins develop into tangles, both of which are thought to be toxic to the brain’s neurons.
At the center of this new research are tau tangles, which can be detected through PET scans though these are expensive and time-consuming. More specifically, the researchers focused on a key building block of tau tangles called microtubule binding region tau (MTBR), which is an insoluble piece of the final protein.
The hope was to detect MTBR levels by analyzing the cerebrospinal fluid of Alzheimer’s sufferers. Previous efforts to measure MTBR in these fluid samples have come up short, but the authors of the new study believe they have found a new way forward.
The team’s technique involves treating samples of cerebrospinal fluid with a set of chemicals, which works to purify tau, and combines this with mass spectrometry to analyze the contents of the solution.
This method was applied to cerebrospinal fluid from 100 subjects in their 70s. Thirty of these subjects had no cognitive impairment or signs of Alzheimer’s, 58 had amyloid plaques with either no cognitive symptoms or mild or moderate Alzheimer’s dementia, while 12 had cognitive impairment but from unrelated conditions.
The team found that in those with Alzheimer’s, levels of a specific from of MTBR, called MTBR tau 243, were heightened in the cerebrospinal fluid. What’s more, its concentration increased in line with the severity of cognitive impairment and dementia. The researchers followed up on this by tracking some of the subjects over two to nine years, finding that in those with worsening Alzheimer’s, MTBR tau 243 levels continued to significantly increase.
To gain another perspective on the accuracy of the technique, the team drew on PET scans of a group of 35 subjects, 20 with Alzheimer’s and 15 without, which were designed to reveal levels of tau in the brain. The team found that levels of MTBR tau 243 in the cerebrospinal fluid were “highly correlated” with the amounts of tau showing up in the brain scan, suggesting the technique could be a reliable indicator of cognitive decline.
“Right now there is no biomarker that directly reflects brain tau pathology in cerebrospinal fluid or the blood,” says first author Kanta Horie. “What we’ve found here is that a novel form of tau, MTBR tau 243, increases continuously as tau pathology progresses. This could be a way for us to not only diagnose Alzheimer’s disease but tell where people are in the disease. We also found some specific MTBR tau species in the space between neurons in the brain, which suggests that they may be involved in spreading tau tangles from one neuron to another. That finding opens up new windows for novel therapeutics for Alzheimer’s disease based on targeting MTBR tau to stop the spread of tangles.”
The research was published in the journal Brain.