CSF tau levels predict progression in early Parkinson’s, per 8-year study
Protein levels in cerebrospinal fluid tied to motor, cognitive decline
In people with early-stage Parkinson’s disease who had yet to be treated, high levels of the proteins tau and P-tau181 in the cerebrospinal fluid, or CSF — the fluid surrounding the brain and spinal cord — predicted faster motor and cognitive decline, per a new study with eight years of follow-up.
According to the researchers, the “results demonstrated that P-tau181 and [tau] had significant impact on longitudinal cognitive changes” among these Parkinson’s patients. Further, these findings “aligned with the results of longitudinal studies [showing] that tau plays [a] part in cognitive decrease” in people with early Parkinson’s, the team wrote.
One “important finding,” the researchers noted, was that elevated initial levels of P-tau181 and tau in Parkinson’s patients “can predict motor progression, particularly in the initial [disease] stages.”
The study, “Cerebrospinal fluid tau and disease progression in early Parkinson’s disease: an 8-year longitudinal study,” was published in the Journal of Neurology.
Investigating links between CSF tau levels and Parkinson’s progression
A well-established sign of Parkinson’s disease is the formation of toxic aggregates, or clumps, of protein known as Lewy bodies, which mainly contain alpha-synuclein. These clumps trigger the death of brain cells that make dopamine, a nerve cell chemical messenger, giving rise to disease symptoms.
Another protein called tau can also form toxic aggregates, or tau tangles, which is one of the hallmarks of Alzheimer’s disease — the most common cause of dementia. A form of tau called phosphorylated tau181, or P-tau181, has been used as a biomarker to predict cognitive decline in Alzheimer’s patients.
Now, emerging evidence suggests that tau can accelerate the spread of alpha-synuclein clumps and may contribute to motor dysfunction in Parkinson’s patients. Moreover, postmortem analyses of Parkinson’s brain tissue confirmed that elevated tau deposits in certain brain regions correlate with cognitive impairment.
“These findings have heightened interest in examining tau’s role in early [Parkinson’s] patients, especially in motor decline,” the researchers wrote.
To learn more, a team at Sichuan University in China investigated the relationship between total tau, or T-tau, and P-tau181 levels in the CSF and motor and cognitive progression in people with early-stage Parkinson’s.
To this end, they analyzed clinical data from 368 people with Parkinson’s who had yet to be treated. The data were sourced from the Parkinson’s Progression Markers Initiative database (PPMI), a global observational study that aims to identify biomarkers of Parkinson’s progression. A group of 185 age- and sex-matched healthy individuals served as controls.
The median age of the patients was 62.7 years, with a median age at onset of 60.7 and a median disease duration of 4.3 months. Two-thirds of the patients were men. At the study’s start, or baseline, patients had signs of motor dysfunction, as assessed by MDS-UPDRS part 3, and cognitive impairment, as indicated by the Montreal Cognitive Assessment (MoCA).
T-tau, P-tau181, and their ratio, which indicate the extent of tau to P-tau181 conversion, were measured in the CSF collected at baseline and every year for five years thereafter. Alpha-synuclein was assessed yearly for more than three years, and clinical data were available for up to eight years.
Reduced protein levels found for patients vs. controls
According to the analysis, the CSF levels of T-tau and P-tau181 and the ratio of P-tau181 to T-tau were significantly lower in patients than in controls at baseline and at each visit. After adjusting for age at baseline and sex, these levels didn’t change over time.
“In contrast to Alzheimer’s disease, we observed reduced CSF P-tau181, T-tau, and [alpha-synuclein] levels in our [Parkinson’s] patients compared to [controls],” the team wrote.
Higher levels of T-tau and P-tau181 in the CSF of patients significantly predicted a more rapid progression of motor dysfunction and cognitive impairment. A higher P-tau181/T-tau ratio also predicted rapid motor decline but not cognitive decline.
We speculate that P-tau181 and T-tau may influence motor symptoms by interacting with [alpha-synuclein] and promoting protein misfolding, leading to a more rapid progression of motor symptoms.
Likewise, higher CSF T-tau, P-tau181, and their ratios correlated with higher levels of alpha-synuclein in the CSF over time.
“We speculate that P-tau181 and T-tau may influence motor symptoms by interacting with [alpha-synuclein] and promoting protein misfolding, leading to a more rapid progression of motor symptoms,” the team wrote.
The researchers also examined patients’ DaTscans to explore whether CSF tau levels directly reflect the loss of dopamine-producing nerve cells in the brain. This imaging technique helps visualize the dopamine transporter, a protein that moves dopamine molecules back into nerve cells, and can be used to confirm a Parkinson’s diagnosis.
After adjusting for age, sex, disease duration at baseline, and follow-up time, the CSF levels of T-tau and P-tau181 and their ratio did not correlate with DaTscan data.
Therefore, “CSF tau may serve as [a] catalyst for accelerated [alpha-synuclein] deposition, but not directly participate in [nerve cell] degeneration,” the team proposed.
“Elevated baseline CSF P-tau181, T-tau tau and P-tau181/T-tau ratio in early [Parkinson’s] patients predict accelerated motor deterioration, with P-tau181 and T-tau also predicting cognitive decline, potentially through interactions with [alpha]-synuclein,” the researchers concluded. “However, the direct role of tau on [nerve cell] degeneration remains uncertain.”
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