New Biomarker for Alzheimer's Disease Diagnostic (BALTAZAR)

Plasma Abeta Peptides and the Risk of Alzheimer's Disease. Diagnostic Performance and Predictive and Prognostic Values of Measurements of Plasma Amyloid Peptides Concentrations for the Diagnosis of Alzheimer's Disease

The aim of this study is to examine the relationship between plasma putative biomarkers for Alzheimer's disease (i.e. Ab40 amyloid and total Ab42 amyloid, free, bound, free/bound, truncated, sAPPα) and :

• the risk of conversion of individuals with Mild Cognitive Impairment (MCI) into Alzheimer's disease (AD),
• the Alzheimer's disease progression rate.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment; Alzheimer's Disease
• Intervention / Treatment: Biological: biomarkers, MRI and CSF

Detailed Description

Rational Whether there are biological markers of Alzheimer's disease (AD) is crucial for adequate targeting and appropriate management of the disease. The aim of our study is to examine diagnostic performance and predictive and prognostic values of new plasma markers of AD.

Results of studies on the predictive value of plasma concentrations of Aβ40 and 42 amyloid peptides for incident AD are not straightforward. Discrepancies in these results may be due to the fact that total peptide concentrations have been measured. One recent study suggests that plasma free Aβ peptide concentration and particularly low-density lipoprotein receptor-related protein (LPR) as like as free Aβ/total Aβ ratio would be more reliable and discriminant.

Main objective of the study To examine the association between plasma free Aβ peptide concentration and (1) the risk of conversion of subjects with Mild Cognitive Impairment (MCI) into Alzheimer's disease (AD) and (2) the risk of worsening of the disease in patients with mild and moderate stages of AD.

Secondary objectives

• To examine the association of total peptid Aβ concentration, free Aβ/Total Aβ ratio, and trunked plasmatic Aβ to the risk of incident AD in MCI subjects, and to the risk of worsening of the disease in mild and moderate AD patients,
• To examine the association between serum sAPP concentration and the risk of incident AD in MCI subjects, and the risk of worsening of the disease in mild and moderate AD patients,
• To compare the time evolution of concentrations of these biomarkers to Alzheimer's disease progression rate which will be assessed on the basis of neuropsychological examinations and MRI examination of hippocampal atrophy,
• To examine the association between serum and cerebrospinal fluid (CSF) concentrations of AD biomarkers in subgroup of participants who undergo lumbar puncture,
• To examine the association between neuroimaging data (cerebral volume, hippocampal volume, cerebrovascular lesions and plasma and CSF AD biomarkers' concentrations,
• To constitute blood and plasma banks, gene bank and CSF bank for future studies on other biomarkers of AD.

Design and Methods Longitudinal multicenter study including 1300 subjects with amnestic impairment (MCI, n=650 and AD, n=650) derived from the main French national Memory Resources and Research Centers.

Participants will undergo at baseline and every 6 months a neurological examination, a neuropsychological assessment (and an oculomotor examination for those included from Broca Hospital).

Alzheimer disease biomarkers' measurements will be performed at inclusion and at the end of the study. For those MCI participants who convert to dementia, the end of the study will correspond to the AD conversion period.

A Magnetic Resonance Imaging (MRI) scan will be performed at inclusion and at the end of the study for MCI subjects who convert into AD.

A lumbar puncture on an outpatient basis will be performed at study entry in all participants who will give an informed consent for this examination in absence of contraindication.

• Study Type: Interventional
• Enrollment (Actual): 1067
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • APHP, Hôpital Broca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

MCI group :

• ≥ 70 years

• MCI diagnosis : New criteria (Petersen, PORTET*)

  1. cognitive complaint from the patient, family, or both,
  2. report by the subject or reporter of a decline in cognitive or functional performance, relative to previous abilities,
  3. cognitive disorders evidenced by clinical evaluation: impairment in memory or another cognitive domain,
  4. cognitive impairment without any repercussion on daily life, even if the subject reports difficulties concerning complex daily activities,
  5. no dementia
• Having signed an informed consent form
• Fluent in French

AD group :

• ≥ 45 years
• AD diagnosis (DSM IV-TR et NINCDS-ADRDA)
• Mild to moderate (MMSE > 15)
• Having signed an informed consent form
• Caregiver/informant to provide information on patient

Exclusion Criteria:

• Normal cognitive function
• Major depression (according to the DSMIV-TR or MINI or Geriatric depression Scale> 20/30)
• Genetic form of AD (genetic mutation known)
• All other diseases that could interfere with cognitive assessment (Epilepsy, Parkinson's disease, schizophrenia, other dementia)
• Major sensory deficits that could interfere with cognitive assessment (visual and auditory)
• Diseases involving the short-term survival (advanced cancer, unstable heart disease, severe hepatic/respiratory/renal failure)
• Contraindication for MRI, for lumbar puncture (i.e. anticoagulant agents)
• Use of any experimental agent for the duration of the study
• Participation to other biomedical research that could interfere with principal objective of the study
• For MCI patient, use of IchE or memantine medication before inclusion
• Less than 4 years of education
• Illiteracy, is unable to count or to read
• Pregnant women
• Non health insurance affiliation
• Private subjects of freedom by legal or administrative decision
• Contraindication for MRI examination:
• Claustrophobic subject
• Carrying a cardiac pacemaker
• Presence of any ferromagnetic metallic implants or foreign bodies (carrying an internal electrical/magnetic device, carrying a valvular prosthesis)
• Carrying a ventricular valvular

Exclusion criteria specific to the lumbar puncture:

• Taking anticoagulant agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: biomarkers, MRI and CSF; Longitudinal multicenter study including 1300 subjects with amnestic impairment (MCI, n=650 and AD, n=650) derived from the main French national Memory Resources and Research Centers. Participants will undergo at baseline and every 6 months a neurological examination, a neuropsychological assessment (and an oculomotor examination for those included from Broca Hospital). Alzheimer disease biomarkers' measurements will be performed at inclusion and at the end of the study (or the conversion).

Biological: biomarkers, MRI and CSF; MRI at Day 0 and month 24 (or conversion) Biomarkers at Day 0 et month 24 (or conversion) CSF at D0

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean concentration of plasma AB peptides	MCI "converted" (MCI-AD); and stable MCI (MCI-MCI) groups	at t0 and 24 months
plasma levels of Tau protein	Ancillary study :comparison of plasma levels of Tau protein at baseline between MCI converters and MCI non-converters and between rapidly and non-rapidly progressing AD.	t0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean concentration of biomarker	Mean plasma concentration of AB peptides betweenfast decliner AD (decline of 7 points or more in ADAS-cog)and non fast decliner AD groups; Mean concentration of sAPPalpha betweenMCI "converted" (MCI-AD)and stable MCI (MCI-MCI) groups; Mean concentration of sAPPalpha betweenfast decliner AD (decline of 7 points or more in ADAS-cog)and non fast decliner AD groups	t0 and 24 months
MRI	•Relationship between MRI measures (brain volume, hippocampus atrophy, vascular lesions) and biomarkers	T0 + M24 or conversion
Transcriptomics biomarkers	• Relationship between transcriptomics biomarkers and cognitive decline	T0 and 24 months or conversions
Bace peptide	ancillary study	t0
TACE/ADAM17	ancillary study	to
Cathepsin	ancillary study	t0
sAPPβ	ancillary study	t0
Ratio of CSF sAPPβ and CSF sAPPα	ancillary study	t0
Ratio of plasma Aβ and plasma Tau	ancillary study	t0
Plasma Tau	ancillary study	24 months
MRI biomarkers	ancillary study	t0
MRI biomarkers	ancillary study	24 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Olivier Hanon, ph, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Duron E, Vidal JS, Grousselle D, Gabelle A, Lehmann S, Pasquier F, Bombois S, Buee L, Allinquant B, Schraen-Maschke S, Baret C, Rigaud AS, Hanon O, Epelbaum J. Somatostatin and Neuropeptide Y in Cerebrospinal Fluid: Correlations With Amyloid Peptides Abeta1-42 and Tau Proteins in Elderly Patients With Mild Cognitive Impairment. Front Aging Neurosci. 2018 Oct 1;10:297. doi: 10.3389/fnagi.2018.00297. eCollection 2018. Erratum In: Front Aging Neurosci. 2019 Feb 19;11:11.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2010
• Primary Completion (Actual): February 26, 2015
• Study Completion (Actual): March 16, 2018

Study Registration Dates

• First Submitted: March 11, 2011
• First Submitted That Met QC Criteria: March 14, 2011
• First Posted (Estimate): March 15, 2011

Study Record Updates

• Last Update Posted (Actual): November 22, 2021
• Last Update Submitted That Met QC Criteria: November 19, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Biomarker; Mild Cognitive Impairment; Dementia; Cognitive impairment; Longitudinal; Plasma; Memory impairment; Cerebrospinal fluid; Abeta peptide amyloid, saPP alpha; Oculomotor impairment
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: P081205

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No