Real-Time Quaking-Induced Conversion CSF Analysis Useful in Detecting Misfolded Alpha-Synuclein


A-synuclein-positive athletes were similar to α-synuclein-negative athletes on demographics and other serum and blood biomarkers; however, these patients had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula, and right olfactory cortices.

Carmela Tartaglia, MD, FRCPC, associate professor at the University of Toronto

Carmela Tartaglia, MD, FRCPC

In a recently published study of former athletes, the use of an α-synuclein (αSyn) real-time quaking-induced conversion (RT-QuIC) analysis in cerebrospinal fluid (CSF) was effective in detecting misfolded αSyn. Investigators concluded that this approach may be useful as a biofluid marker for Parkinson disease (PD) and dementia with Lewy bodies (DLB), 2 neurodegenerative disorders that share a similar pathological hallmark of misfolded αSyn aggregates.1

The study included 30 former athletes with MRI, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-ß 42 (Aß42), and neurofilament light chain (NfL). Using RT-QuIC, 6 (20%) of these individuals were CSF α-synuclein positive and were not significantly different from α-synuclein-negative participants on measures of demographics, collision, or contact sports history, and clinical features. Although not statistically significant, the mean age of the αSyn RT-QuIC-positive group was 9 years younger than the negative group, and the mean number of total years played was 5 years higher.

The incidence of αSyn pathology in the CSF of this cohort of athletes (mean age, 50 years) was higher than that previously reported in a study of aged healthy controls (13%). "The difference is especially relevant given that age is the single largest risk factor for all proteinopathies, including αSyn pathology, and we found the increased incidence of αSyn pathology in our athlete cohort despite a mean age ~20 years lower than healthy individuals examined in previous reports," senior investigator Carmela Tartaglia, MD, FRCPC, associate professor at the University of Toronto, and colleagues, wrote.

Additional findings showed lower grey matter volumes in multiple areas of the brain among those who tested positive for αSyn RT-QuIC with no known neurological/neurodegenerative comorbidities (n = 5). Affected areas included the right inferior orbitofrontal gyrus, bilateral superior frontal gyri, bilateral anterior and posterior cingulate gyri, bilateral olfactory cortex, bilateral rectus gyri, and bilateral precunus, all with cluster sizes that exceeded 1000 voxels. The largest cluster also had the highest decrease in grey matter volumes (cluster size: 13,373 voxels; peak at 2.9 SD below healthy controls), encompassing the right inferior orbitofrontal, right anterior insula, and right olfactory cortices.


In the group of athletes with no known neurological/neurodegenerative comorbidities, there was a significantly higher Rey Auditory Learning Test long delay z-score in the 5 αSyn RT-QuIC-positive athletes compared with the 16 negative athletes (0.49 [±0.82] vs –0.95 [±0.89], respectively; P = .003). The groups did not differ on CSF biomarkers of p-tau, t-tau, Aß42, NfL, or other scores or premorbid intelligence quotient, memory, attention/speed of processing, or executive function assessments.

In the study, there was 1 clinically diagnosed case of PD, stemming from a participant who was α-Syn RT-QuIC positive. The other 8 cases of neurological/neurodegenerative diseases, all α-Syn RT-QuIC-negative, included 2 cases of biomarker-confirmed Alzheimer disease (AD), 1 pathologically confirmed AD, 1 clinically diagnosed behavioral variant frontotemporal dementia, 1 clinically diagnosed semantic variant primary progressive aphasia, 1 clinically diagnosed cases of amyotrophic lateral sclerosis, 1 pathologically confirmed corticobasal degeneration/CTE, and 1 clinically diagnosed herpes encephalitis.

Hyposmia, a well-established and early non-motor symptom of PD, was not captured in the cohort because of the frequency by which it is seen in traditional contact sport athletes. The study also had some limitations, including the small sample size and low number of females. Additionally, there was no healthy aged-matched control group to compare the incidence of α-Syn RT-QuIC positivity to our athlete cohort.

"Furthermore, in the absence of neuropathological assessment, we cannot confirm the presence of α-Syn aggregates in the brains of our former athletes and can only infer it based on the α-Syn RT-QuIC results in CSF," the study authors noted.1

1. Vasilevskaya A, Martinez-Valbuena I, Anastassiadis C, et al. Misfolded a-synuclein in cerebrospinal fluid of contact sport athletes. Mov Disord. 2023;38(11):2125-2131. doi:10.1002/mds.29621
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