Blood Tests for Alzheimer's Disease: Can Plasma Biomarkers Diagnose and Predict Disease Progression (BLAD)
The Diagnostic and Prognostic Role of Plasma Biomarkers in Alzheimer's Disease
BLAD is a prospective, monocentric, observational epidemiological study with an additional procedure (annual blood draw) evaluating the diagnostic and prognostic performance of plasma biomarkers for Alzheimer's disease (AD) in a large cohort of patients attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital, Milan, Italy.
2000 patients will be enrolled and followed annually for 5 years. A validation sub-study (150 patients) will compare plasma biomarkers against CSF biomarkers as the gold standard.
The study aims to establish plasma biomarkers as a less invasive and more cost-effective alternative to CSF analysis and amyloid-PET for the diagnosis and prognosis of AD.
Přehled studie
Postavení
Podmínky
Intervence / Léčba
Detailní popis
In light of the possible advent of disease-modifying drugs for Alzheimer's disease (AD), reliable biomarkers have been developed in recent years to define the presence of AD pathology at the brain level. The current biological gold standards are cerebrospinal fluid (CSF) biomarkers (CSF-Abeta40, CSF-Abeta42, CSF-pTau, CSF-NfL) and amyloid-PET. Both methods have excellent diagnostic properties but are costly and invasive, limiting their use outside of highly specialized centers.
Plasma biomarkers (plasma-Abeta40, plasma-Abeta42, plasma-pTau-181, plasma-NfL, plasma-ApoE, plasma-ApoE4, plasma-GFAP, plasma-sTREM2, and other plasma neurodegeneration biomarkers) represent a potentially less invasive and more economically accessible alternative. Recent studies have shown that plasma biomarkers can differentiate AD from other neurodegenerative disorders with accuracy comparable to CSF and PET, detect AD pathology in MCI patients, and predict future development of AD dementia in patients with SCD or MCI. However, more research is needed before their widespread use in clinical practice.
The BLAD study is designed as a monocentric, prospective, observational epidemiological study with an additional procedure (annual blood draw for 5 years) and a diagnostic accuracy sub-study (not device-based).
Patients will be recruited among those attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital during routine clinical practice. All enrolled patients will undergo annual blood sampling for 5 years in addition to standard clinical assessments.
A sub-population of 150 patients who undergo lumbar puncture as part of their routine diagnostic workup will enter the validation sub-study. Only those whose CSF biomarkers confirm a biological diagnosis of Alzheimer's disease will continue follow-up; others will exit the sub-study.
The equipment for plasma biomarker measurement (CE-marked medical device) and laboratory kits will be provided on free loan by Fujirebio. No clinical or laboratory data will be shared with Fujirebio.
Statistical analyses will include: log-rank test to compare time to AD development between groups above and below the biomarker threshold; linear stepwise regression models, linear mixed-effects models, and multivariable Cox models to assess the prognostic value of plasma biomarkers; longitudinal generalized linear models for repeated measures or Wilcoxon test to assess biomarker dynamics over time. For the validation sub-study, ROC curve analysis will be performed to assess accuracy, sensitivity, and specificity of plasma biomarkers against CSF gold standard.
Typ studie
Zápis (Odhadovaný)
Kontakty a umístění
Studijní kontakt
- Jméno: Federica Agosta, MD
- Telefonní číslo: 0226433051
- E-mail: agosta.federica@hsr.it
Studijní záloha kontaktů
- Jméno: Giuseppe Magnani, MD
Studijní místa
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Milano
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Milan, Milano, Itálie, 20132
- Nábor
- IRCCS Ospedale San Raffaele - Cognitive Disorders and Dementia Center (CDCD)
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Kontakt:
- Federica Agosta, MD
- Telefonní číslo: 0226433051
- E-mail: agosta.federica@hsr.it
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Kontakt:
- Giuseppe Magnani, MD
-
Vrchní vyšetřovatel:
- Massimo Filippi, Prof, MD
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Dílčí vyšetřovatel:
- Federica Agosta, MD
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Dílčí vyšetřovatel:
- Giuseppe Magnani, MD
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Dílčí vyšetřovatel:
- Giordano Cecchetti, MD
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Dílčí vyšetřovatel:
- Francesca Caso, MD
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Dílčí vyšetřovatel:
- Roberto Santangelo, MD
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Dílčí vyšetřovatel:
- Gioele Spinelli, MD
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Dílčí vyšetřovatel:
- Giulia Rugarli, MD
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Dílčí vyšetřovatel:
- Federico Coraglia, MD
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
- Dospělý
- Starší dospělý
Přijímá zdravé dobrovolníky
Metoda odběru vzorků
Studijní populace
Popis
Inclusion Criteria (main study and sub-study):
- Age greater than or equal to 40 years (patients of childbearing age are admitted).
- Subjective or objective cognitive complaints, progressive in nature and of suspected neurodegenerative origin.
Mini-Mental State Examination (MMSE) score greater than or equal to 18.
Additional inclusion criterion for the validation sub-study:
- Availability of CSF biomarkers for Alzheimer's disease within 6 months of the blood draw.
Exclusion Criteria (main study):
- Secondary forms of cognitive impairment based on medical history, neurological examination, and neuroimaging findings.
- Pregnancy or breastfeeding.
- Rapidly progressive cognitive decline occurring over weeks or months, typically indicative of prion disease, neoplasia, or metabolic disorders.
- Subjects who require a legal guardian or tutor.
Exclusion Criteria (validation sub-study):
- Secondary forms of cognitive impairment based on medical history, neurological examination, and neuroimaging findings.
- Pregnancy.
- Rapidly progressive cognitive decline occurring over weeks or months, typically indicative of prion disease, neoplasia, or metabolic disorders.
- Subjects who are unable to give informed consent and require a legal guardian or tutor.
Studijní plán
Jak je studie koncipována?
Detaily designu
Kohorty a intervence
Skupina / kohorta |
Intervence / Léčba |
|---|---|
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Main Study Cohort
2000 adult patients attending the Cognitive Disorders and Dementia Center (CDCD) at IRCCS San Raffaele Hospital with subjective or objective cognitive complaints of progressive and suspected neurodegenerative nature.
All patients undergo annual blood sampling for 5 years in addition to standard clinical follow-up.
|
A blood sample is collected once per year for 5 years (additional procedure beyond standard clinical care) for measurement of plasma biomarkers including: Abeta40, Abeta42, Abeta42/Abeta40 ratio, pTau-181, NfL, ApoE, ApoE4, GFAP, sTREM2, and other plasma neurodegeneration biomarkers.
Blood draw is a routine clinical procedure with no specific contraindications.
The only possible side effect is local hematoma at the puncture site.
Plasma biomarker measurement is performed using a CE-marked medical device (Fujirebio, provided on free loan).
Results do not modify the patient's standard diagnostic and therapeutic pathway.
|
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Validation Sub-study Cohort
150 patients from the main cohort who undergo lumbar puncture as part of their routine diagnostic workup and have CSF biomarkers for Alzheimer's disease available within 6 months of blood draw.
Only those with CSF biomarkers confirming a biological diagnosis of Alzheimer's disease continue longitudinal follow-up in the sub-study.
|
A blood sample is collected once per year for 5 years (additional procedure beyond standard clinical care) for measurement of plasma biomarkers including: Abeta40, Abeta42, Abeta42/Abeta40 ratio, pTau-181, NfL, ApoE, ApoE4, GFAP, sTREM2, and other plasma neurodegeneration biomarkers.
Blood draw is a routine clinical procedure with no specific contraindications.
The only possible side effect is local hematoma at the puncture site.
Plasma biomarker measurement is performed using a CE-marked medical device (Fujirebio, provided on free loan).
Results do not modify the patient's standard diagnostic and therapeutic pathway.
|
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Time to progression to all-cause dementia in MCI patients (primary prognostic endpoint)
Časové okno: Annually from baseline up to 5 years
|
Time to clinical progression to all-cause dementia in patients with Mild Cognitive Impairment (MCI) at baseline, assessed using multivariable Cox proportional hazards models.
For each plasma biomarker, patients are divided into two groups (above/below the median) and compared using the log-rank test (cause-specific hazard).
The study has greater than 95% power to detect a Hazard Ratio of 2 and approximately 75-80% power for HR of 1.5.
|
Annually from baseline up to 5 years
|
Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Change in MMSE score over time
Časové okno: Annually from baseline up to 5 years
|
Change over time in Mini-Mental State Examination (MMSE) score as a measure of cognitive progression.
A decrease of 5 or more points is considered clinically significant progression of cognitive impairment due to AD.
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Annually from baseline up to 5 years
|
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Conversion from MCI to Alzheimer's disease dementia
Časové okno: Annually from baseline up to 5 years
|
Rate of clinical conversion from Mild Cognitive Impairment (MCI) to Alzheimer's disease dementia over the 5-year follow-up period, assessed at each annual visit.
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Annually from baseline up to 5 years
|
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Longitudinal change in plasma Abeta42/Abeta40 ratio
Časové okno: Annually from baseline up to 5 years
|
Change over time in the plasma Abeta42/Abeta40 ratio, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
|
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Longitudinal change in plasma pTau-181 levels
Časové okno: Annually from baseline up to 5 years
|
Change over time in plasma phosphorylated tau 181 (pTau-181) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
|
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Longitudinal change in plasma NfL levels
Časové okno: Annually from baseline up to 5 years
|
Change over time in plasma neurofilament light chain (NfL) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
|
Annually from baseline up to 5 years
|
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Longitudinal change in plasma GFAP levels
Časové okno: Annually from baseline up to 5 years
|
Change over time in plasma Glial Fibrillary Acidic Protein (GFAP) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
|
Annually from baseline up to 5 years
|
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Longitudinal change in plasma sTREM2 levels
Časové okno: Annually from baseline up to 5 years
|
Change over time in plasma soluble Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
|
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Longitudinal change in plasma Abeta40 levels
Časové okno: Annually from baseline up to 5 years
|
Change over time in plasma beta-amyloid 40 (Abeta40) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
|
Annually from baseline up to 5 years
|
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Longitudinal change in plasma Abeta42 levels
Časové okno: Annually from baseline up to 5 years
|
Change over time in plasma beta-amyloid 42 (Abeta42) levels, assessed using longitudinal generalized linear models for repeated measures or Wilcoxon test.
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Annually from baseline up to 5 years
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Další výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Diagnostic accuracy of plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Area under the ROC curve (AUC), sensitivity, and specificity of plasma Abeta42/Abeta40 ratio in diagnosing Alzheimer's disease, using CSF biomarkers (CSF-Abeta40, CSF-Abeta42, CSF-pTau, CSF-NfL) as the gold standard.
Patients are classified as AD or non-AD based on CSF results.
An AUC of at least 0.80 is expected, with greater than 95% power to reject H0: AUC=0.50 at alpha=0.05.
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Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Diagnostic accuracy of plasma pTau-181 vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Area under the ROC curve (AUC), sensitivity, and specificity of plasma pTau-181 in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Diagnostic accuracy of plasma NfL vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Area under the ROC curve (AUC), sensitivity, and specificity of plasma NfL in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Diagnostic accuracy of plasma GFAP vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Area under the ROC curve (AUC), sensitivity, and specificity of plasma GFAP in diagnosing Alzheimer's disease, using CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
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Optimal diagnostic cut-off values for plasma Abeta40 vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
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Determination of the optimal diagnostic cut-off values for Abeta40 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
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Optimal diagnostic cut-off values for plasma Abeta42 vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for Abeta42 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma Abeta42/Abeta40 ratio vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for Abeta42/Abeta40 ratio biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma pTau-181 vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for pTau-181 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma NfL vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for NfL biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma GFAP vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for GFAP biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma sTREM2 vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for sTREM2 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma ApoE vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for ApoE biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
|
Optimal diagnostic cut-off values for plasma ApoE4 vs CSF gold standard (sub-study)
Časové okno: Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Determination of the optimal diagnostic cut-off values for ApoE4 biomarker using ROC curve analysis against CSF biomarkers as the gold standard.
|
Baseline (at time of lumbar puncture, within 6 months of blood draw)
|
Spolupracovníci a vyšetřovatelé
Sponzor
Vyšetřovatelé
- Vrchní vyšetřovatel: Massimo Filippi, Prof, MD, IRCCS San Raffaele
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
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