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Tytuł pozycji:

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.

Tytuł:
Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.
Autorzy:
Vallabh SM; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, 02114, USA. .; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA. .; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA, 02142, USA. .; Prion Alliance, Cambridge, MA, 02139, USA. .
Minikel EV; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, 02114, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA, 02142, USA.; Prion Alliance, Cambridge, MA, 02139, USA.
Williams VJ; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Carlyle BC; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
McManus AJ; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Wennick CD; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Bolling A; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Trombetta BA; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Urick D; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Nobuhara CK; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Gerber J; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Duddy H; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Lachmann I; AJ Roboscreen GmbH, 04129, Leipzig, Germany.
Stehmann C; Australian National CJD Registry, University of Melbourne, Parkville, 3010, Australia.
Collins SJ; Australian National CJD Registry, University of Melbourne, Parkville, 3010, Australia.
Blennow K; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
Zetterberg H; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.; UK Dementia Research Institute, University College London, London, WC1N 3BG, UK.; Department of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UK.
Arnold SE; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, 02114, USA. .; Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA. .
Źródło:
BMC medicine [BMC Med] 2020 Jun 18; Vol. 18 (1), pp. 140. Date of Electronic Publication: 2020 Jun 18.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: [London] : BioMed Central, 2003-
MeSH Terms:
Biomarkers/*metabolism
Neurodegenerative Diseases/*diagnosis
Prion Diseases/*diagnosis
Adult ; Cohort Studies ; Female ; Humans ; Longitudinal Studies ; Male ; Neurodegenerative Diseases/blood ; Neurodegenerative Diseases/cerebrospinal fluid ; Prion Diseases/blood ; Prion Diseases/cerebrospinal fluid ; Reproducibility of Results ; Risk Factors
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Grant Information:
P30 AG062421 United States AG NIA NIH HHS; R21 TR003040 United States TR NCATS NIH HHS; F31 AI122592 United States AI NIAID NIH HHS
Contributed Indexing:
Keywords: Biomarkers; Cerebrospinal fluid; Clinical trial design; Neurodegenerative disease; Neurofilament; Primary prevention; Prion; Real-time quaking-induced conversion; Total tau
Substance Nomenclature:
0 (Biomarkers)
Entry Date(s):
Date Created: 20200620 Date Completed: 20201204 Latest Revision: 20231105
Update Code:
20240105
PubMed Central ID:
PMC7302371
DOI:
10.1186/s12916-020-01608-8
PMID:
32552681
Czasopismo naukowe
Background: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population.
Methods: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months.
Results: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.
Conclusions: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.
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