Longitudinal Evaluation and Predictors of Decline In Pre-MCI States David Loewenstein PhD, ABPP

1. Longitudinal Evaluation and Predictors of Decline In Pre-MCI States David Loewenstein PhD, ABPP/CN Department of Psychiatry, Miller School of Medicine, University of Miami Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center

2. There is a pressing need for prevention and early treatments of Alzheimer’s Disease (AD) and related disorders Thirty percent of subjects with no symptoms of cognitive impairment during life have AD pathology post-mortem The most effective interventions will require the identification of AD in the earliest possible stages

3. Studies Describing Pre-MCI States Morris et al (2009)- PiB binding among normals increased risk of progression to CDR .5 and a diagnosis of DAT Hypometabolism on PET (Casselli et al., 2008; Mosconi et al., 2008) Abnormal fMRI activation (Xu et al., 2009) Abnormal aß42 and tau levels in CSF (Petrie et al., 2009)

4. Issues to Consider in the Search for Pre-MCI States Based On Behavior Subjective complaints of cognitive impairment may have excellent predictive validity in memory disorders clinics (where base-rates of underlying disease is high) but not be as useful in other community settings Commonly used cognitive measures frequently used in dementia research may not be optimally beneficial for Pre- MCI states Increased sensitivity in diagnostic criteria may be accompanied by an unacceptable loss of specificity

5. Limitation of Current Memory Measures Selection based upon familiarity. Cut-offs on delayed recall of a single paragraph historically used in memory disorders research despite evidence that such measures adversely affected by lack of attention, anxiety or difficulties with hearing. Age corrections for certain measures can be problematic because age is a risk factor for disease Education based norms may not account for quality of education or the fact that years of education means different things in different cultural/educational groups

6. Measures of Learning may be Very Useful in Studies of MCI & Pre-MCI 3-Trial Fuld Object Memory Evaluation (OME) Evaluates memory for actual common objects presented to the patient Culture and educationally fair Distracters (verbal fluency tasks) between acquistion and retrieval trials prevents rehearsal of to-be-remembered targets

7. Semantic Interference Test (SIT: Loewenstein et al., 2003, 2004; Snitz et al., 2010) Ten Objects for Learning on Fuld OME Introduce 10 additional objects for recall which are semantically related to items on 1st Fuld OME list (e.g., fork for spoon; comb for brush) Proactive Interference- Old learning (OME) interferes with new List B learning Retroactive Interference- New List B Learning interferes with recall of semantically related OME targets

8. Previous Studies of the OME and SIT in MCI Fuld OME most predictive of decline from MCI to dementia in a memory disorders clinic patients (Luis et al., 2004) Semantic Interference Score was the most predictive of progression of MCI to dementia over an average of 30+ months in a community-based sample (Loewenstein et al., 2007) Relative to other memory measures, the Fuld OME most highly associated with MTA on MRI in a community sample and least susceptible to age and education effects (Loewenstein et al., 2009)

9. Can We Identify Pre-MCI States In Our Florida ADRC? Unique Aspect of Our Study- The use of an algorithm to systematically combine neuropsychological and clinical data (Duara et al.,2009)

11. Demographic Characteristics of Subject Groups In Florida ADRC (n=369)

13. Change in Diagnosis of 275 Persons over a 2-3 Year Period

14. Baseline Differences among those who Progressed Versus those who did not Progress to Dementia Higher CDR-SB Lower Hippocampal Volume Lower Fuld Object Memory Score (OME) Lower HVLT-R Delayed Recall Lower SIT Interference Score Lower Delayed Paragraph Recall Score Higher UPDRS Score Lower Category Fluency Score Higher Trails B Time Score

15. Step-Wise Cox Regression- Prediction of Progression to Dementia 3-Trial Fuld Object Memory Evaluation (OME) Higher CDR-SB Higher Trails B

16. Most Recent Study-Comparison of Two Pre-MCI States In Progression To (Last Follow-up) From 1 to 3 Years 

17. Step-Wise Cox Regression- Prediction of Pre-MCI Progression to MCI or Dementia 3-Trial Fuld Object Memory Evaluation (OME) Higher Trails B Lower Block Design Score

18. SUMMARY AND CONCLUSIONS Pre-MCI subjects defined by clinical judgment only had more apathy, greater MTA and greater deterioration to a more impaired cognitive state than normal elderly The Fuld OME, followed by Trails B was the strongest predictor of decline from both Pre-MCI to MCI and MCI to Dementia

19. SUMMARY AND CONCLUSIONS Pre-MCI states defined only on the basis of neuropsychological impairment had a similar pattern of decline as Pre-MCI clinical states An algorithmic approach to MCI and identifying Pre-MCI states may be useful Further follow-up of our cohort with Pre-MCI will yield important data with regards to stability of specific predictors over time Many ways to define Pre-MCI, we must discover criteria with the optimal stability and predictive utility

20. Acknowledgements-NIA 1P50AG025711NIA 5R01AG020094 Huntington Potter Jocelyn Agron Ranjan Duara Wendy Acevedo Maria Greig Amy Borenstein Ashok Raj Jim Mortimer John Schinka William Barker Mike Shoenberg Elizabeth Potter Yougui Wu Jessica Banco William Haley Quian Shen