Detecting Cognitive Impairment in Amyloid-Positive Asymptomatic - PowerPoint PPT Presentation

Detecting Cognitive Impairment in Amyloid-Positive Asymptomatic Populations. Jason Hassenstab, PhD Assistant Professor Neurology and Psychological & Brain Sciences Knight Alzheimer’s Disease Research Center Washington University in St. Louis

Disclosures: Jason Hassenstab Research Support Consultant/Advisory Boards ◉ NIH U19 AG032438 Biogen ◉ NIH U01 AG042791 Lundbeck ◉ NIH P01AG026276 Takeda ◉ NIH P50AG005681 ◉ NIH P01AG003991 Clinical Trials ◉ NIH R01AG046179 Cognition Core Director, Dominantly- ◉ NIH R01AG053267 Inherited Alzheimer Network-Trials ◉ Alzheimer’s Association Unit (DIAN-TU) ◉ GHR Foundation ◉ An Anonymous Foundation I own no stocks or equities in any ◉ BrightFocus Foundation pharmaceutical or biotechnology company

Overview ◉ Basics of AD Prevention Trials ◉ Cognitive Decline in Preclinical to Symptomatic AD ◉ Endpoints in Active and Planned Secondary Prevention Trials ◉ Psychometric characteristics and gold standard measures ◉ Novel Approaches/Innovations

Prevention Trials in AD Pillai & Cummings, 2013 Med Clin N Am

How does cognition change over the course of AD? Bateman et al., 2012 NEJM

Lim et al., 2014 Brain

Papp et al., 2015 Neuropsychologia Petersen et al., 2015 JAMA Neurol

Cognitive Endpoints in Secondary Prevention Trials Cog Domain ADCS-PACC APCC EPAD TOMMORROW* DIAN-TU MMSE Orientation Mental Status MMSE MMSE (5 items) Logical Memory RBANS Immediate Logical Memory RBANS List Recall BVMT-R Delayed Delayed Recall Memory Delayed Recall Episodic Memory RBANS Delayed CVLT-II Long Delay FCSRT Total Recall RBANS Story Recall ISLT Delayed Recall Memory Recall Digit-Symbol Digit-Symbol RBANS Digit Coding Trails B Substitution Substitution Executive Function Digit Span Backward RBANS Language Category Fluency Semantic Memory/Language Letter Fluency RBANS Attention Digit Span Forward Attention Trails A Ravens Matrices Other RBANS Line RBANS Visuospatial Orientation

The ADCS-PACC Measure Ceiling? Floor? Practice Effects? Anectodal MMSE Y N (nowhere to go) FCSRT Free Recall N (rare) Y Y WMS-R Logical N (rare) Y Large Memory Digit-Symbol N (rare) N Minimal Substitution Donohue et al., 2014 JAMA Neurology

Basics of Ceiling and Floor Effects Test is too easy Test is too difficult

Why EVER use a cognitive test with a ceiling or floor effect? MMSE: Ceiling Effect Logical Memory: Floor Effect ◉ “Coin of the Realm” ◉ Narrative recall deficits ◉ Has face validity for clinical commonly reported in AD meaningfulness ◉ Has face validity for clinical ◉ Any decline on MMSE is meaningfulness typically very significant ◉ A score of zero (floor) clinically provides meaningful (but limited) information about dementia severity.

Why EVER use a cognitive test with a ceiling effect? Small baseline SD, large effect sizes, but high error ◉ Composite scores standardize to baseline (z-scores) ◉ Tests with ceiling effects will naturally produce large decline estimates (when they decline) WUSTL DIAN-All DIAN-TU WUSTL ADRC ADRC CDR 0’s (CDR 0-1) PET-PIB+ CDR 0’s CDR 0’s MMSE 29.1 (1.2) 27.8 (3.3) 29.0 (1.2) 28.8 (1.5) (mean, SD) Digit Symbol 62.4 (12.0) 54.7 (18.2) 49.9 (11.1) 46.12 (11.3) (mean, SD)

“Waterfall” Effects Z-score MMSE in Trial Eligible Subjects Z-score Digit Symbol in Trial Eligible Subjects (n=146) (n=146) Estimated Year to Symptom Onset Estimated Year to Symptom Onset

How do ceiling effects impact cognitive composites? AIBL: Error in slope estimates is nearly doubled when including MMSE Lim et al., 2016 Alz Dem DADM

How do ceiling effects impact cognitive composites? Knight ADRC: Error in slope estimates is nearly doubled when including MMSE CDR 0 PIB-PET Negative CDR 0 PIB-PET Positive (n=193) (n=71) Composite Mean Slope (SD) Mean Slope (SD) ADCS-PACC 0.054 (0.24) -0.040 (0.25) (FCSRT, DSST, LMDelayed, MMSE) Knight ADRC PACC 0.031 (0.13) -0.054 (0.17) (FCSRT, DSST, Animal Naming, LMDelayed)

If Cognitive Tests Were Nearly Perfect…

What actually occurs…

Data from Knight ADRC Selective R Reminding: g: Fre ree R Reca call Log ogic ical M l Memory D y Dela layed R Recall ll Age ge Age ge

Using Composites Helps…A Bit DIAN AN E Episodic dic Mem Memory C Composit ite EY EYO

Retest Reliabilities for Common Neuropsychological Tests Test Pearson’s r WMS Logical Memory Delayed Recall 0.71 CVLT Trials 1-5 Total 0.72 CVLT Long Delay Free Recall 0.74 Trailmaking Test Part A 0.66 Trailmaking Test Part B 0.77 Letter Fluency (COWAT) 0.79 WAIS Letter-Number Sequencing 0.73 WAIS Digit Symbol 0.85 Calamia et al., 2013 TCN; Lo et al., 2012, J. Neuropsychology

Reliabilities in DIAN: 1-3 Years Between Assessments Mutation Carriers Mutation Carriers CDR >0 CDR 0 Non-Carriers (n = 92) (n = 167) (n = 171) r (ICC) r (ICC) r (ICC) DIAN Word List Delayed Recall 0.54 0.57 0.40 WMS Logical Memory Immediate Recall 0.81 0.53 0.51 WMS Logical Memory Delayed Recall 0.85 0.58 0.53 Pair Binding (Assoc. Memory) 0.57 0.51 0.58 Trailmaking Test Part A 0.66 0.76 0.42 Trailmaking Test Part B 0.74 0.72 0.58 WAIS Digit Symbol 0.78 0.84 0.88 Letter Fluency (COWAT) 0.84 0.80 0.80 Category Fluency (Animals + Vegetables) 0.75 0.74 0.61

Reliab abiliti ties es i in Knight t ADRC: Annual al Asses essmen ents ts Amyloid Positive Amyloid Negative CDR 0 CDR 0 (n = 95) (n = 155) Test r (ICC) r (ICC) 0.60 0.57 Free and Cued SRT: Free Recall 0.58 0.54 WMS Logical Memory Immediate Recall 0.53 0.59 WMS Logical Memory Delayed Recall 0.46 0.67 Associate Memory 0.67 0.61 Trailmaking Test Part A 0.63 0.71 Trailmaking Test Part B 0.88 0.87 WAIS Digit Symbol 0.47 0.68 Animal Fluency 0.58 0.63 Vegetable Fluency

Novel approaches for detecting amyloid “positivity” in normal older adults

Courtesy Kathryn Papp, MGH. Presented at AAIC 2018

Courtesy Kathryn Papp, MGH. Presented at AAIC 2018

Within-Subject Repeated Measures Tasks Shorter-term repeated measurement tasks: ◉ Accelerated Long-Term Forgetting (ALF) ◉ Associate Learning (Online Repeatable Cognitive Assessment; ORCA) ◉ Measurement “Burst” Designs

Limitations of Traditional Cognitive Assessments Figure courtesy of Martin Sliwinski, PhD

Accelerated Long Term Forgetting Uses a 7-day long term recall paradigm to look at % retention of list, story, and figural memory. Relative to n = 14 noncarriers, n = 21 CDR 0 (EYO -7.2y) carriers had 30% lower retention of word list, 20% lower story retention. **No differences on standard tests between groups Immediate 30-minute 7-day Recognition Recall Recall Recall Weston et al. 2018 Lancet Neurology

Associate Learning: Online Repeated Cognitive Assessment (ORCA) Participants are played a sound and then shown a picture. They guess whether it is a match or not. Test is completed in about ~20mins/day for 6 consecutive days. The proportion of matches vs non- matches increases each day such that associations are learned implicitly. **This version uses Mandarin characters, but can be done with other pictures and words. Example of the training procedure.

Associate Learning: Online Repeated Cognitive Assessment (ORCA) From AIBL: Cohen’s d = 1.9 n = 80 (n = 20 AB+, n = 30 AB-) CDR 0s completed task plus n = 30 Controls (ages 18-40). Significant interaction of group by time. Shows clear evidence that AB+ had reduced learning. Importantly: No difference between AB+/AB- on standard memory Different rates of memory acquisition in young controls, Aβ - older adults, and Aβ+ measures. older adults over 5 days; shading = 95% confidence intervals. Baker et al. Under Review

Measurement “Burst” Design: Ambulatory Research in Cognition (ARC) 7-day “Burst” of Cognitive Assessments M T W Th F S Su Time 7a Test Test Test 8a Test Test 9a Test Test Test 10a 11a Test Test 12p Test Test 1p Test Test Test Test 2p Test Test 3p Test 4p Test Test 5p Test 6p Test 7p 8p Test 9p Test Test 10p Test Test

Reliab ability ty of ARC M Meas asures res Symbols Grids Prices All Participants (n = 208) (n = 208) (n = 113) 0.80 0.38 0.34 Reliability of 1 Test (ICC) 0.91 0.67 0.73 Reliability 1 day (4 tests) 0.96 0.78 0.81 Reliability 2 day (~7 tests) 0.99 0.91 0.90 Reliability 5 day (~16 tests) 0.99 0.93 0.92 Reliability 7 day (~22 tests)

ARC Biomarker Correlations: CSF Amyloid. 100% Cognitively Normal (CDR 0) CSF Amyloid Beta1-42 and ARC smartphone CSF Amyloid Beta1-42 and standard In-clinic assessments (n = 39). assessments (n = 37). r = 0.24, p = 0.13 r = 0.06, p = 0.72

ARC Biomarker Correlations: CSF Tau. 100% Cognitively Normal (CDR 0) CSF Total Tau and ARC smartphone CSF Total Tau and standard In-clinic assessments (n = 39). assessments (n = 37). r = -0.34, p = 0.03 r = -0.06, p = 0.69