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,(What the fuck are those treatments? Useless since you didn't point to where those treatments are listed.) 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.
-
Judy George
covers neurology and neuroscience news for MedPage Today, writing about
brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy,
autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep,
pain, and more. Follow
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.
