Real-time quaking-induced conversion (RT-QuIC), a test for pathological misfolded protein, detected alpha-synuclein in the cerebrospinal fluid (CSF) of patients with isolated rapid-eye-movement (REM) sleep behavior disorder (IRBD), years before clinical symptoms of Parkinson’s disease or dementia with Lewy bodies emerged.
In these patients, RT-QuIC detected misfolded alpha-synuclein in CSF with both sensitivity and specificity of 90%, reported Alison Green, PhD, of the University of Edinburgh in Scotland, and co-authors, in Lancet Neurology. Alpha-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson’s disease or dementia with Lewy bodies.
“The detection of pathological alpha-synuclein preceded the development of clinical symptoms by a mean of 3.2 years, with a range of 6 months to 9 years,” Green said.
“This is the first step towards having a reliable biomarker for early, pre-symptomatic disease which will enable therapeutic interventions, including potential neuroprotective treatments, to start in a more timely manner,” she told MedPage Today.
RT-QuIC was developed initially to detect abnormally folded prion protein. The “technique is based on prion seed-induced misfolding and aggregation of recombinant protein substrate, accelerated by alternating cycles of shaking and rest in fluorescence plate readers,” said Inga Zerr, MD, of the Georg-August University in Göttingen, Germany, in an accompanying editorial.
Seeding activity of misfolded alpha-synuclein had previously been studied in people with Parkinson’s disease and dementia with Lewy bodies using brain tissue, CSF, submandibular gland tissues, olfactory mucosa samples, and skin biopsies, Zerr added.
IRBD can be part of the prodromal stage of Parkinson’s disease and dementia with Lewy bodies. In this study, Green and colleagues evaluated CSF samples obtained from 52 patients who had IRBD confirmed by video polysomnography at a sleep disorders center in Barcelona and 40 matched controls who were free of neurological disease.
Lumbar punctures for CSF were obtained from 2008 to 2017. Mean follow-up from lumbar puncture until the end of the study in 2020 was 7.1 years in the IRBD group and 7.7 years in controls.
During follow-up, 32 patients (62%) were diagnosed with Parkinson’s disease or dementia with Lewy bodies a mean 3.4 years after lumbar puncture, of whom 31 (97%) were alpha-synuclein positive at baseline. Specifically, 16 people developed Parkinson’s (15 of whom were positive for CSF alpha-synuclein), and 16 developed dementia with Lewy bodies (all were positive for CSF alpha-synuclein).
CSF alpha-synuclein RT-QuIC was positive in 47 (90%) of 52 patients and in four (10%) of 40 healthy controls, resulting in a sensitivity of 90.4% (95% CI 79.4–95.8) and a specificity of 90.0% (95% CI 76.9–96.0).
The average interval for people who were alpha-synuclein positive at baseline to convert to clinically defined Parkinson’s or dementia with Lewy bodies was 3.2 years. Patients with IRBD who were alpha-synuclein negative had lower risk for developing Parkinson’s disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were alpha-synuclein positive. During follow-up, none of the controls developed an alpha-synucleinopathy.
“This result clearly demonstrates the potential of the RT-QuIC method to detect alpha-synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies, early before typical clinical manifestation,” Zerr said.
“However, a matter that needs to be addressed further in longitudinal studies is the interpretation of positive test results in a cross-sectional setting,” she continued. “There were four positive test reactions in 40 healthy controls and in 16 patients with IRBD who did not (by the end of the study) develop clinical symptoms indicative of alpha-synucleinopathy. The probability of some participants having a subclinical alpha-synucleinopathy that did not evolve into Parkinson’s disease or dementia with Lewy bodies within the observation period cannot be excluded and requires further investigation.”
Other limitations, Green and co-authors noted, were that the results are based on a single-center study with a fairly small number of participants.
Disclosures
The study was funded by the Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
Green reported no competing interests; co-authors reported relationships with AbbVie, Roche, Takeda, Jazz, UCB, Wave Pharmaceuticals, Teva, Bial, Prevail, Boehringer Ingelheim, Biogen, the Spanish Network for Research on Neurodegenerative Disorders, and the Michael J. Fox Foundation for Parkinson’s Research.
Zerr reported no conflicting interests.