Developing More Effective Paradigms for Assessing and Monitoring Cognitive Change Across the MCI and PreMCI Spectrum

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1 Developing More Effective Paradigms for Assessing and Monitoring Cognitive Change Across the MCI and PreMCI Spectrum David A. Loewenstein, PhD Rosie Curiel PsyD Sara Czaja, PhD University of Miami School of Medicine

2 Limitation of Widely Used Memory Measures In Early Detection of Cognitive Impairment 1) Many measures and cognitive paradigms underlying them have been around for several generations 2) There is tremendous variability in MCI patients because of different levels of attention to the task, different learning strategies and cognitive reserve 3) Measures that have performed well in the evaluation of dementia or late MCI may not optimal measures for assessing early MCI and PreMCI states

3 Limitation of Widely Used Memory Measures In Early Detection of Cognitive Impairment (Continued) 4) May not fully capture different aspects of memory 5) Subjects are not used as their own controls but are rather compared to group averages 6) Lack of sensitivity across the range of MCI and PreMCI states makes many cognitive instruments limited across the entire range of MCI

4 What is the Importance of Good Cognitive Assessment In Clinical Trials? Recent guidelines forwarded by the FDA suggest they will not consider the approval of a medication using a biomarker as a surrogate outcome measure in AD (at any stage of the illness) until there is widespread evidence-based agreement that an effect on a particular biomarker is reasonably likely to predict clinical benefit. Such benefit will most likely need to be identified and measured as individuals transition from normal to Pre- MCI or MCI states that are associated with risk of progression to AD.

5 How do we Develop the Most Effective Memory Assessment Instruments for Clinical Trials? We need to develop paradigms that are maximally sensitive Different subtests capture different ranges of cognitive severity in MCI and PreMCI states. Cognitive markers should line up with sensitive biomarkers in MCI and PreMCI states.

6 How do we Develop the Most Effective Memory Assessment Instruments for Clinical Trials? Individual variability caused by differences in attention, education, culture and learning strategies can be minimized by employing techniques such as controlled learning. Constructs such as proactive and retroactive interference in the context of maximum storage allows us to compare a person s performance to their optimal capability. Assessment must be computerized for optimal portability, reliability in administration and applicability to the early stages of AD.

7 Can we construct a Cognitive Stress Test To Measure Subtle Cognitive Dysfunction? A Potential Model: Vulnerability to Semantic Interference as an Early Marker of Alzheimer s Disease

8 Semantic Interference Test (SIT) Loewenstein, et al., (2004) Journal of the International Neuropsychological Society (1)

9 SEMANTIC INTERFERENCE TEST (SIT) (Loewenstein, Acevedo and Duara et al, 2004) Ten common objects are presented and recalled over three learning trials Introduce 10 additional objects for recall which are semantically related to items on 1 st list (e.g., fork for spoon; comb for brush) Proactive Interference- Old learning interferes with new List B learning Retroactive Interference- New List B Learning interferes with recall of original targets

10 Interference Effects In Learning and Memory We are not dealing with any type of interference, we are dealing with : SEMANTIC INTERFERENCE

11 Sensitivity and Specificity of the SIT in the early Detection of MCI-AD MCI-AD Sensitivity= 84.6% Normal Elderly Specificity= 96.2%

12 SIT Longitudinal Findings (Loewenstein, D.A., Acevedo, A., Agron, J. & Duara, R. ( Dementia and Geriatric Cognitive Disorders, 2007) Relative to a wide array of neuropsychological measures List B recall (susceptible to proactive interference) was more highly predictive of decline from MCI to dementia over an average 30 month period

13 Amyloid Scanning In AD Subject and Healthy Normal Subject Miller B & Heflin L (2008)

14 Association Between Florbetapir SUVR, SIT and Different Memory Measures in 17 Nondemented Community Dwelling Persons with Memory Complaints Fuld Object Memory Evaluation Delayed Logical Memory For Passages SIT List B (subject to proactive interference) Short-Delay List A Cued Recall (subject to retroactive interference) SUVR Total Anterior Cingulate Posterior Cingulate r= -.08 r= -.16 r= -.25 r=-.48 r=-.57* r=--.57* r=-.64 ** r=-.72 ** r=-.66 * r=--.43 r=-. 49 r=-. 69***

15 Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L)

16

17 Examiner: You will see 15 words, one at a time. The words will be fruits, musical instruments, or articles of clothing. Each time I show you a word, I want you to read it out loud. Later on, I am going to ask you to tell me, from memory, all of these words, which will be fruits, musical instruments or articles of clothing. Read each word out loud so that you can remember it later.

18 The Subject Needs to Use Cued Recall Over Two Trials to Maximize Storage of the Fifteen Targets

19 Present List A Target Words Belonging to Three Semantic Categories: Fruits Clothing Musical Instruments 2 presentations and 2 cued recall trials of List A Targets 2 presentations and 2 cued recall trials of List B Targets Delayed Cued Recall for List A Targets

20 LASSI-L Findings (Crocco et al., 2013, AJGP; Curiel et al, 2013;JAS) LASSI-L subscales all have extremely high testretest reliabities Strongest Predictors in Logistic Regression and R0C Models is List A2 Cued Recall and List B1 Cued Recall Sensitivity and specificity for MCI versus normal subjects is 87.9%/91.5%

21 Association Between Medial Temporal Atrophy and LASSI-L Measures in 16 MCI Patients MTA Left MTA Right List A1 Cued Recall r= -.43 r= -.40 List A2 Cued Recall r=-.53* r=-.57* List B Cued Recall r=-.75*** r=-.58* Short-Delay A Cued Recall r=-. 04 r=-. 14

22 Association Between Florbetapir SUVR and LASSI-L Measures in 17 Nondemented Subjects with Memory Complaints List A1 Cued Recall r= -.44 SUVR Total List A2 Cued Recall r=-.38 List B1 Cued Recall r=-.15 List B2 Cued Recall r=-. 56* Short Delay Cued Recall r=-.10

23 Association Between SUVR and LASSI-L Measures in 17 Nondemented Subjects with Memory Complaints List A1 Cued Recall List B2 Cued Recall Precuneus Posterior Cingulate Frontal AC Temporal r= -.60 ** r= -.74** r=-.50 r= -.46 r=-. 48 r= -.62 * r=-. 66** r=-.45 r=-. 14 r=-.54*

24 Computerized LASSI-L

25 You will see some words on the next screen. Touch the word that corresponds to the description of the item.

26 Harmonica Spoon Horse Lighter Train Touch the word that is an animal

27 Harmonica Spoon Horse Lighter Train

28 Harmonica Spoon Horse Lighter Train Touch the word that is a musical instrument

29 Harmonica Spoon Horse Lighter Train

30 You will see a set of 4 pictures Touch the picture that corresponds to the word that you saw previously

31

32

33 LASSI-L Computerized CueD & DElayed Recall Version LIST A 1 st Cued Encoding for 15 Semantically Distinct Targets Cued Recall 1 LIST A 2 nd Cued Encoding for 15 Semantically Distinct Targets Cued Recall 2 LIST B 1 st Cued Encoding for 15 Semantically Distinct Targets Cued Recall B Short- Delay Cued Recall A Long Delay Cued A and then Long Delayed Cued B

34 How do we Develop the Most Effective Memory Assessment Instruments for Clinical Trials? We need to develop paradigms that are maximally sensitive Different subtests capture different ranges of cognitive severity in MCI and PreMCI states. Cognitive markers should line up with sensitive biomarkers in MCI and PreMCI states.

35 How do we Develop the Most Effective Memory Assessment Instruments for Clinical Trials? Individual variability caused by differences in attention, education, culture and learning strategies can be minimized by employing techniques such as controlled learning. Constructs such as proactive and retroactive interference in the context of maximum storage allows us to compare a person s performance to their optimal capability. Assessment must be computerized for optimal portability, reliability in administration and applicability to the early stages of AD.

36 RESEARCH TEAM- UM Center on Aging and UM Department of Psychiatry University of Miami Sara Czaja, PhD Philip Harvey, PhD David Loewenstein, PhD Rosie Curiel, PsyD Elizabeth Crocco, MD Samir Sabbag, MD Sankarin Nair, MS Mount Sinai (Miami Beach) Ranjan Duara, MD

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