1. Tony WAEGEMANS, MD UCB Pharma, Belgium

2. TW/ll/2001-15 Washington/MCI 2 MCI as implemented in our study MCI is a very early stage of dementia with as main characteristic a s progressive s cognitive s impairment (a decline from former premorbid level), leading in the vast majority of patients to more severe and overt forms of dementia (AD, VaD, mixed dementia,…). Mild is not equivalent to benign: MCI is malignant in prognosis.

3. MCI is not a "psychometric construct" but a clinical entity. It can be diagnosed using established clinical techniques e.g. dementia staging instruments such as CDR = 0.5 GDS = 3 Such clinical diagnostic measures include s clinical interview s "bedside” mental tests s collateral source information. TW/ll/2001-15 Washington/MCI 3

4. Additional specific psychometric tests may be used s to confirm the diagnosis or s to increase the proportions of patients declining (delayed recall and executive functions or control processes - Orgogozo, 2000). TW/ll/2001-15 Washington/MCI 4

5. Operational definition of MCI Although specific psychometric tests were used as a scientific tool in defining the MCI concept, it is not an ideal instrument for diagnosis s No reliable reference to pre-morbid level possible s Inclusion of perpetual underachievers s Exclusion of subjects declining from a high pre-morbid level Thus a clinical diagnosis is preferred s In line with how a disease is diagnosed - face validity s Can better assess a decline from pre-morbid functioning s Can identify extraneous influences (physical illness, etc) TW/ll/2001-15 Washington/MCI 5

6. The use of cognitive testing in MCI studies Cognitive testing is the ideal endpoint for longitudinal follow-up (detailed and repeated measures of a condition over time). s Sensitive to change s Correlates very closely with  the increasing clinical severity of dementia  cerebral atrophy (the Braak staging)  volumetric MRI measures s It can be done using standardized and well-validated methods TW/ll/2001-15 Washington/MCI 6

7. The endpoint is an assessment of the core problem of such patients : cognitive decline over time. Although in early stages of dementia memory problems may seem predominant, other cognitive functions are also deteriorating in various proportions and varying speeds in individual patients. Thus, evaluations must cover a full range of cognitive aspects : The tests should be choosen to measure the functions in decline in this early stages. The ADAS used in established dementia has s ceiling effect s is not sufficiently sensitive in very mild cognitive decline TW/ll/2001-15 Washington/MCI 7

8. Principal endpoint A complete cognitive battery measuring each key aspect of cognition should be done. Tests of free and cued recall Delayed recall Working memory Executive functions (planning and problem solving) Semantic category fluency Praxis and spatial ability Attention and concentration = more global cognitive functioning Such cognitive battery should result in one composite score covering the global deterioration. TW/ll/2001-15 Washington/MCI 8

9. Parallel to studies in established dementia, there should be a global change evaluation (CIBIC like) and an assessment of instrumental/complex activities of daily living (IADL-MCI). Additional endpoints - CIBIC + - GDS - MMSE - IADL Inventory - MCI-version - Scale for emotional distress (BSI - Brief Symptom Inventory) TW/ll/2001-15 Washington/MCI 9

10. Congrès Mémoire 28-30 Sept., 2000 13 Design Placebo Active Placebo run-in Screening Baseline 6 months 1 year TW/ll/2001-15 Washington/MCI 10 Run-in : to control for a learning effect, if any.

11. Conclusion These are the different elements that we and our Expert Advisory Board propose to be appropriate for evaluating drug effects in MCI, and therefore should be included in potential guidelines. Design : parallel group, placebo-controlled study of 1 year duration. Diagnosis : clinical diagnosis based on staging instruments. Efficacy endpoints : s cognitive decline documented by using a composite score from a global cognitive test battery s supported by a global clinical measure of change, and/or an impact on instrumental or complex activities of daily living TW/ll/2001-15 Washington/MCI 11