Identification of Biomarkers Sensitive to Disease Progression in Patients With Mild Cognitive Impairment
THE STUDY WILL BE A TWO-PART RESEARCH
PART A and PART A extended:
- To implement a "common" MRI acquisition protocol in multiple centers across Europe (Pharma-COG partners).
- Apply the common MRI protocol on phantoms and human subjects to characterize, compare and minimize test-retest variability across the MR sites of WP5 for all the quantitative metrics that will be later assessed on patients.
PART B: By collecting clinical, biochemical, neuroimaging, neuropsychological and neurophysiological data in Mild Cognitive Impairment patient, we aim to:
- To develop a biomarker MATRIX (made of a combination of biological secondary endpoints) which is more sensitive than the changes observed in the loss of hippocampal volume (primary endpoint) and correlate with the neuropsychological progression and conversion (clinical secondary endpoints).
- To develop a biomarker MATRIX (made of a combination of biological secondary endpoints) at baseline which is more predictive of the loss of hippocampal volume (primary endpoint) and neuropsychological progression (clinical secondary endpoint) in MCI patients.
- To harmonize the biomarker MATRIX collection and qualify multiple centres across Europe
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Identification of Biomarkers Sensitive to Disease Progression in Patients With Mild Cognitive Impairment: a Two-part Clinical Study. PartA: Multisite MRI Acquisition, Protocol Harmonization. PartB: Identification of Biomarkers Sensitive to Disease Progression in Patients With Mild Cognitive Impairment: a Clinical Study|
- Part A: Magnetic Resonance Imagery protocol [ Time Frame: Two times: One measure at day 1 ] [ Designated as safety issue: No ]
The Magnetic Resonance Imagery protocol comprises a localiser or scout run, 4 structural-volumetric MRI sequences (i.e. 2 MP-RAGE, 1 FLAIR and 1 T2*), a resting state functional MRI acquisition (i.e. rsfMRI), a diffusion tensor scan (i.e. DTI) that will be conducted at the magnetic field strength of 3T and a quantitative assessment of brain perfusion changes with a sequence of Arterial Spin Labelling (i.e. ASL) . The field map will be used for geometric distortion correction of the fMRI data.
The main parameter of "efficacy" will be the reliability of the acquired MRI data (in terms of their correct acquisition and limited variability).
- Part B: Changes of the hippocampal volume [ Time Frame: 2 or 3 times: every 18 months during 2 or 3 years (T0, T18 and/or T36) ] [ Designated as safety issue: No ]The primary endpoint will be changes of the hippocampal volume between the two groups (differentiated by the level of amyloid β1-42 in the cerebro-spinal fluid) and within the same group over time.
- Part B: Clinical assessment [ Time Frame: Every 6 months (screening, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
- Mini-Mental State Examination (MMSE) (general cognitive functioning)
- Clinical Dementia Rating (CDR)
- Medical History
- Physical exam
- Neurological exams
- Hachinski ischemic scale (differentiate Alzheimer's type dementia and multi-infarct dementia)
- Geriatric Depression Scale (Depressive symptoms)
- Functional Assessment Questionnaire (FAQ) (Activities of daily living)
- Neuropsychiatric Inventory Questionnaire (NPI-Q) (Behaviour)
- Part B: Neuropsychology [ Time Frame: Every 6 months (screening, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
- Clock Drawing and Copying Test (Executive functions and planning abilities)
- Rey Auditory Verbal Test (AVLT) (Memory)
- Logical Memory Test I - Immediate Recall (Memory)
- Digit Span Forward (Memory)
- Digit Span Backward (Memory)
- CANTAB Battery (visuospatial functions)
- Letter fluency (Language)
- Category Fluency (Language)
- Boston Naming Test (BNT) (Language)
- Trail Making Test (Attention)
- Digit Symbol Substitution Test (Processing speed)
- Part B: Neurophysiology [ Time Frame: Every 6 months (T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]Electro-Encephalography in several conditions
- Part B: Magnetic Resonance Imagery and functional MRI [ Time Frame: Every 6 months (screening, T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]The protocol comprises a localiser or scout run, 2 structural-volumetric MRI sequences (i.e. MPRAGE and FLAIR), one 2D structural analysis (i.e. T2*) a resting state functional MRI acquisition (i.e. rs-fMRI), a diffusion tensor scan (i.e. DTI) that will be conducted at the magnetic field strength of 3T and a quantitative assessment of brain perfusion changes with a sequence of Arterial Spin Labelling (i.e. ASL only in T18 and T24 timepoints for available patients).
- Part B: Blood drawing [ Time Frame: Every 6 months ] [ Designated as safety issue: No ]
- ApoE (T0 only)
- β amyloid in plasma (T0, T6, T12, T18, T24, T30 and T36)
- Plasma and lymphocytes biomarkers (T0, T6, T12, T18, T24, T30 and T36)
- PKC conformation (T0 and T18/T36)
- amyloid β1-42 binding on erythrocytes (T0 and T18/T36)
- Platelet APP-CTF (intracellular APP metabolites)(T0, T6, T12, T18, T24, T30 and T36)
- RNA splicing analysis (T0, T6, T12, T18, T24, T30 and T36)
- Part B: Actigraphy [ Time Frame: Every 6 months (T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]Assessment of changes in position and acceleration for up to several weeks providing measures of activity. Additionally, sleep/wake and circadian rhythmicity can objectively be estimated from the recorded data by algorithms.
- Adverse events [ Time Frame: Every 6 months (T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: Yes ]Any changes in the chronicity, severity, action taken, seriousness of a symptom or adverse event will be recorded by a qualified clinician (MD).
|Study Start Date:||December 2011|
|Study Completion Date:||October 2015|
|Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
MCI Patient with Lumbar puncture
PartB: Patients affected by amnestic Mild Cognitive Impairment (aMCI).
Procedure: Lumbar puncture
All the patients will be divided in two groups based on their Aβ 1-42 levels measured in the cerebro-spinal fluid obtained form a lumbar puncture: in low Aβ1-42 (positive aMCI patients CSFP) and high Aβ1-42 (Negative aMCI patients CSFN). The threshold of Aβ1-42 used to divide the patient will be 500 (ng/L) based on Sjogren criteria (2001).
Timeframe of lumbar punctures: every 18 months during 2 years (T0 and T18) or 3 years (T0, T18 and T36).
Other Name: Cerebrospinal fluid puncture
Please refer to this study by its ClinicalTrials.gov identifier: NCT01425957
|Université Lille 2, UL2 - Centre d'investigation clinique / Centre de Ressources biologiques 9301 - INSERM - Centre Hospitalier Régional et Universitaire de LILLE|
|Lille, France, 59307|
|APHM, Hopital de la Timone, Service de Neurologie et Neuropsychologie|
|Marseille, France, 13385|
|INSERM - CHU Purpan|
|Toulouse, France, 31059|
|Hospital and Institute of the University of Duisburg and Essen - Department for Psychiatry and Psychotherapy, LVR Hospital Essen|
|Essen, Germany, 45147|
|University Hospital of Leipzig - Department of Psychiatry|
|Leipzig, Germany, 04103|
|Aristotle University of Thessaloniki, Greek Association of Alzheimer's disease and related disorders, Thessaloniki, Greece|
|Thessaloniki, Greece, 54643|
|IRCCS-FBF - Ordine Ospedaliero San Giovanni di Dio, Fatebenefratelli, Istituto di Ricovero e Cura a Carattere Scientifico|
|Brescia, Provincia Lombardo-Veneta, Italy, 25125|
|Neurofisiologia Clinica IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Padiglione Specialita' piano Fondi|
|Genoa, Italy, 16132|
|IRCCS Fondazione SDN per la Ricerca e l'Alta Formazione in Diagnostica Nucleare di Napoli|
|Napoli, Italy, 80143|
|Dipartimento di Specialità medico-chirurgiche e Sanità Pubblica, Sezione di Clinica Neurologica, Centro Disturbi della Memoria, Perugia, Italy|
|Perugia, Italy, 06132|
|Università Cattolica del Sacro Cuore - Policlinico Agostino Gemelli Istituto di Neurologia - Neuropsychological and Neurorehabilitation Unit|
|Roma, Italy, 00168|
|Amsterdam, Netherlands, 1007MB|
|Institut d'Investigacions Biomèdiques August Pi I Sunyer, IDIBAPS|
|Barcelona, Catalunya, Spain, 08036|
|Study Director:||Giovanni Frisoni, MD, MP||Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni di Dio Fatebenefratelli, Brescia, Italy|
|Principal Investigator:||Mira Didic, MD||Université de la Méditerranée, Service de Neurologie et Neuropsychologie, Marseille France|
|Principal Investigator:||Jose-Luis Molinuevo, PhD||Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain|
|Principal Investigator:||Regis Bordet, MD||Université Lille 2, Lille, France|
|Principal Investigator:||Pierre Payoux, MD||Institut National de la Santé et de la Recherche Médicale, Toulouse, France|
|Principal Investigator:||Peter Schönknecht, MD||Universitätsklinikum Leipzig, Department of Psychiatry and Nuclear Medicine, Leipzig, Germany|
|Principal Investigator:||Jens Wiltfang, MD||Universitaet Duisburg-Essen, Department of Psychiatry and Nuclear Medicine, Duisburg-Essen, Germany|
|Principal Investigator:||Flavio Mariano Nobili, MD||IRCCS Azienda Ospedaliera Universitaria San Martino-IST|
|Principal Investigator:||Magda Tsolaki, MD||Greek Association of Alzheimer's disease and related disorders, Thessaloniki, Greece|
|Principal Investigator:||Lucilla Parnetti, MD||Università di Perugia, Clinica Neurologica, Centro Disturbi della Memoria, Perugia, Italy|
|Principal Investigator:||Paolo Maria Rossini, MD||Università Cattolica del Sacro Cuore, Policlinico Agostino Gemelli, Istituto di Neurologia, Roma, Italy|
|Principal Investigator:||Andrea Soricelli, MD||Istituto di Ricerca Diagnostica e Nucleare, University of Naples Parthenope, Napoli, Italy|
|Principal Investigator:||Philip Scheltens, MD||VUmc Alzheimercentrum|