In Vivo Alzheimer Proteomics (PROMARA)

Use of Targeted Quantitative Proteomics and Metabolic Labelling With Stable Isotopes for the Diagnosis and the Investigation of Neurological Disorders and in Particular Alzheimer Disease

In France, an estimated 860 000 patients are affected by Alzheimer Disease (AD) which represents, as in other developed countries, a major public health issue. In many cases, AD diagnosis is uncertain and its clinical evolution unpredictable. The exactitude of the diagnosis is however particularly important in the perspective of the validation and use of new therapeutic strategies in AD. Detection of cerebrospinal fluid (CSF) diagnosis biomarkers fell short in the detection, of atypical/mixed cases, of some differential diagnosis, and in differentiating rapid or slow clinical evolutions. Hence, CSF analysis gives a unique opportunity to detect and validate biomarkers in many neurological disorders. Nevertheless, in medical practice, CSF biological analysis is currently limited to a small number of analytes.Quantitative and targeted mass spectrometry, especially operated in the Multiple reaction monitoring mode (MRM), represents an alternative to immunodetection and could be used to detect specific biomarkers in complex matrices such as plasma by specifically discriminating the proteotypic peptides corresponding to each proteins. Mass spectrometry has also the ability to distinguish and quantify isotopically labelled and unlabeled selected targets. This ability was used in a publication by the group of R. Bateman (Washington University, St Louis, USA) who could, after administering stable isotope-labelled leucine, evaluate Ab synthesis and clearance in humans. This approach has an enormous potential to study the metabolism of proteins within the human CNS and consequently help in the understanding and diagnosis of neurological disorders.The main objective of this program is set up a targeted quantitative mass spectrometry method for existing and stable isotope-labelled CSF biomarkers in the neurological field; exploit this approach for diagnostic purpurses and to gain knowledge in the pathophysiology of diseases.

Study Overview

• Status: Terminated
• Conditions: Parkinson Disease; Brain Trauma; Probable Alzheimer Disease; Neurological Disease Without Cognitive Degradation; Acute Hydrocephaly
• Intervention / Treatment: Other: collection of CSF, blood, urine, saliva; Biological: administration of stable isotope-labelled leucine-

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34295
    • Laboratoire de Biochimie et Protéomique Clinique, CHU Montpellier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Reports written consent, informed and signed by the patient and a trusted person
• Subject member or beneficiary of a social security system

Specific criteria for group 1 and 2B :

• Age between 55 and 85 years old for patients
• Subject with AD or other neurodegenerative disease (frontotemporal dementia, dementia with Lewy bodies, Parkinson disease)
• Subjects with chronic adult hydrocephalus (HCA) requiring depletion lumbar puncture (PL)

Specific criteria for group 2A :

- Adult patient requiring neurosurgery with CSF shunt (subject with brain trauma, acute hydrocephaly) and favorable evolution that allows removal of the shunt

Exclusion Criteria:

• Patient deprived of liberty by judicial or administrative decision
• Major protected by law
• Pregnancy, women of childbearing age with risk of pregnancy, or breast-feeding
• Presence of a transmissible viral disease (HlV, hepatitis B and C)
• Patient included in a clinical trial
• lnadequate cardiac, hepatic or severe renal disfunction
• Disease amino acid metabolism (Leucinose..)

Exclusion Criteria:

• Information clinical and para-clinical insufficient or unavailable
• Patient deprived of liberty by judicial or administrative decision
• Major protected by law
• Pregnancy, women of childbearing age with risk of pregnancy, or breast
• feeding
• Presence of a transmissible viral disease (HIV, hepatitis B and C)
• Patient included in a clinical trial
• Patient exclusion period relative to another protocol or for which the maximum annual compensation of 4500€ has been reached
• Inadequate cardiac, hepatic or severe renal
• Disease amino acid metabolism (Leucinose..)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 60 patients (20 probable AD, 20 Parkinson Disease (PK), 20 neurological disease without cognitive degradation)	Other: collection of CSF, blood, urine, saliva; - administration of stable isotope-labelled leucine : by drip, for group 2A and group 2B. Group 1 (control group) : 1 collection of CSF. Group 2B : 4 collections of CSF, 24 hours after administration of stable isotope-labelled leucin. Group 2A (patients with brain trauma, acute hydrocephaly) : continuous collection of CSF, for 24 to 36 hours
Experimental: Group 2A; 20 patients (patients with brain trauma, acute hydrocephaly), with temporary derivation of the CSF	Biological: administration of stable isotope-labelled leucine-; - administration of stable isotope-labelled leucine : by drip, for group 2A and group 2B. Group 1 (control group) : 1 collection of CSF. Group 2B : 4 collections of CSF, 24 hours after administration of stable isotope-labelled leucin. Group 2A (patients with brain trauma, acute hydrocephaly) : continuous collection of CSF, for 24 to 36 hours
Experimental: Group 2B; 30 patients (15 probable AD, 15 neurological disease without cognitive degradation)	Biological: administration of stable isotope-labelled leucine-; - administration of stable isotope-labelled leucine : by drip, for group 2A and group 2B. Group 1 (control group) : 1 collection of CSF. Group 2B : 4 collections of CSF, 24 hours after administration of stable isotope-labelled leucin. Group 2A (patients with brain trauma, acute hydrocephaly) : continuous collection of CSF, for 24 to 36 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C13 Leucine incorporation in Amyloid peptides (1-40, 1-42) at different time points (in %)	Analysis of labelled samples with mass spectrometry. Data generated will be studied to validate the experimental model and understand the pathophysiology of neurological disorders. A collection of labelled biological samples will also be generated.	1.5 years
C13 Leucine incorporation in detectable peptides generated after trypsin digestion of biological fluids from patients (CSF, blood, urine, saliva) (in %)	C13 Leucine incorporation in detectable peptides generated after trypsin digestion of biological fluids from patients (CSF, blood, urine, saliva) (in %)	1.5 years

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: Assistance Publique - Hôpitaux de Paris; University Hospital, Clermont-Ferrand; International Atomic Energy Agency
• Investigators: Principal Investigator: Sylvain Lehmann, PU-PH, Laboratoire de Biochimie et Protéomique Clinique, IRMB St Eloi, CHRU de Montpellier

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2013
• Primary Completion (Actual): May 22, 2018
• Study Completion (Actual): May 22, 2018

Study Registration Dates

• First Submitted: September 18, 2014
• First Submitted That Met QC Criteria: October 7, 2014
• First Posted (Estimate): October 13, 2014

Study Record Updates

• Last Update Posted (Actual): December 28, 2021
• Last Update Submitted That Met QC Criteria: December 27, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: mass spectrometry; cerebrospinal fluid (CSF); Alzheimer disease (AD); diagnosis biomarkers; targeted quantitative proteomics; stable isotope-labelled leucine
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Wounds and Injuries; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Craniocerebral Trauma; Trauma, Nervous System; Dementia; Tauopathies; Brain Injuries; Parkinson Disease; Brain Injuries, Traumatic; Nervous System Diseases; Alzheimer Disease; Hydrocephalus
• Other Study ID Numbers: 8652