MILD COGNITIVE IMPAIRMENT
Conditions
Keywords
MEMORY and COGNITIVE IMPAIRMENT, ALZHEIMER DISEASE CONVERSION, Amyloid beta-Peptides
Brief summary
THE STUDY WILL BE A TWO-PART RESEARCH PART A and PART A extended: 1. To implement a common MRI acquisition protocol in multiple centers across Europe (Pharma-COG partners). 2. 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: 1. 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). 2. 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. 3. To harmonize the biomarker MATRIX collection and qualify multiple centres across Europe
Interventions
PROCEDURELumbar 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).
Sponsors
European Union
Qualissima
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
* PART A: Participants will be (i) healthy volunteers (between 50 and 80 years old) and/or (ii) subjects (between 50 and 80 years old), who will perform a 3T-MRI for reasons such as migraine, headache, auditory or visual symptoms, paresthesias, and whose scan will be negative (see
Exclusion criteria
below). Such subjects will be selected and asked to perform additional sequences according to the part A study protocol. * PART B: Specific inclusion criteria: 1. Written Informed Consent to participate in a up to 3 year imaging study 2. Male and female aged between 55-90 years 3. Memory complaint by patient or partner that is verified by a physician. (Memory complains expressed by the patients or their informant that the examiner considers to be relevant and exceed those expected for a patient of their age. The patient may or may not have symptoms of deficiency in other cognitive areas.) 4. Abnormal memory functions documented by scoring 1 SD below the age-adjusted mean on the Logical Memory II subscale, (Delayed Paragraph Recall) from the Wechsler Memory Scale. 5. General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit. 6. Mini-Mental State Exam score between 24 and 30 (inclusive) 7. Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5. 8. Amnestic Mild Cognitive Impairment (MCI) (pure amnestic or multidomain) 9. Geriatric Depression Scale less than 6 10. Hachinski Modified Ischemic scale\< to 4 11. Patient is untreated or under a permitted medication (Cholinesterase inhibitors and memantine, before the enrolment and newly prescriptions during the study, are permitted for aMCI patients.) 12. At least 5 grades education 13. Must speak (language) fluently 14. Have a study partner with 10+ hr/wk contact (can be in person and telephone), accompanies to visits 15. Willing and able to comply with the requirements of the study, as judged by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Magnetic Resonance Imagery protocol | Two times: One measure at day 1 | 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 | 2 or 3 times: every 18 months during 2 or 3 years (T0, T18 and/or T36) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Neurophysiology | Every 6 months (T0, T6, T12, T18, T24, T30 and T36) | Electro-Encephalography in several conditions |
| Part B: Magnetic Resonance Imagery and functional MRI | Every 6 months (screening, T0, T6, T12, T18, T24, T30 and T36) | 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: Clinical assessment | Every 6 months (screening, T6, T12, T18, T24, T30 and T36) | * 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: Actigraphy | Every 6 months (T0, T6, T12, T18, T24, T30 and T36) | 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 | Every 6 months (T0, T6, T12, T18, T24, T30 and T36) | Any changes in the chronicity, severity, action taken, seriousness of a symptom or adverse event will be recorded by a qualified clinician (MD). |
| Part B: Blood drawing | Every 6 months | * 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: Neuropsychology | Every 6 months (screening, T6, T12, T18, T24, T30 and T36) | * ADAS-COG * 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) |
Countries
France, Germany, Greece, Italy, Netherlands, Spain
Outcome results
None listed