ALLFTD Neuropsychological Assessment

Katya Rascovsky, PhD On behalf of the ALLFTD Neuropsychology Work Group

1 Overview

• Introduction • FTLD-NACC module for differential diagnosis • UDS3 in familial FTD • Longitudinal modeling of FTLD-NACC in familial FTD • Changes to NIH-Examiner administration • Tablet-based assessment • Data quality issues/error checks • Discussion and conclusions Challenges

• Clinical heterogeneity

• Pre-symptomatic vs. symptomatic

• Cross-sectional vs. longitudinal Depends on question • Differential diagnosis (specific) • Earliest detectable change (sensitive) What is ideal? • Longitudinal tracking (sensitive, wide range, limited floor, ceiling, learning effects) • Clinical trials (target population)

• Time / frustration

What is practical? • Shared instruments • Personnel / training / reliability • Readily available Global / Visuospatial / Memory

Domain ALLFTD GENFI CReATe Global Cognitive Montreal Cognitive Mini-Mental State Examination Edinburgh Cognitive and Assessment (MoCA) (MMSE) Behavioral Screen (ECAS) Visuospatial / Benson Complex Figure Copy Benson Complex Figure Copy Constructional Block Design Judgment of Line Orientation (JOLO) Episodic Memory Benson Complex Figure Benson Complex Figure (Delayed Recall) (Delayed Recall)

California Verbal Learning Test Free and Cued Selective Rey Auditory Verbal Learning – Short Form (CVLT-SF) Reminding Test (FCSRT) Test (RAVLT)

Craft Story (Immediate & Logical Memory Recognition Delayed Recall) Doors from Doors and People Test Language Domain ALLFTD GENFI CReATe Language Phonemic Fluency (F-L words)* Phonemic Fluency (F-A-S Phonemic Fluency (F-S-P words)* words)* Category Fluency (Animals & Vegetables)* Category Fluency (Animals)* Category Fluency (Animals & Actions)* Multilingual Naming Test* Boston Naming Test (30 item – modified) Boston Naming Test (30 item)

Word Reading – Regular and Camel and Cactus Test (32 item) North American Adult Reading Irregular Words Test Revised (NART-R) Noun and Verb Naming Subtests Writing Fluency Index (Animals Semantic Word Picture Matching and Actions) Test Semantic Associates Test Northwestern Anagram Test- SF Sentence Reading Sentence Repetition WM & Executive Functions Domain ALLFTD GENFI CReATe Working Number Span Test (Forward & Digit Span Test (Forward & Back) ECAS Digit Span (Back) memory Back)

EXAMINER Working Memory Factor • Dot Counting • N-back (1-back) • N-back (2-back)

Attention / Trial Making Test A Trial Making Test A Trial Making Test A Processing Speed Digit Symbol Test Executive / Trial Making Test B Trial Making Test B Trial Making Test B cognitive flexibility EXAMINER Cognitive Control D-KEFS Color-Word Interference Oral Trails Index Factor Test Modified Wisconsin Card • Flanker Sorting Test (MWCST) • Set Shifting

UDS3: % total A/L participants 100

999 60 998 997

50 996 995

40 ceiling

% total participants total % range floor 30

0 Craft IV Benson C Digits FC Digits BC Animals TMT-A TMT-B Craft DV Benson DR MINT VF-F

Year 1 data from 10/19 data freeze (n=1,396) 100 100 90 90

80 80 70 999 70 999 998 998 60 60 997 997 50 50 996 996 40 40 995 995 30 30

UDS3 % CDR 0 ceiling UDS3 % CDR 1 ceiling 20 20 range range 10 10 floor floor 0 0

100 100

90 90

80 80

70 999 70 999 998 60 998 60 997 997 50 50 996 996 40 40 995 995 UDS3 % CDR 3 30 30 UDS3 % CDR 2 ceiling ceiling 20 20 range range 10 floor 10 floor 0 0 FTLD-NACC: % total A/L participants

100

70 999 60 998 997

50 996 995

40 ceiling % total participants total % range floor 30

0 Regular W Irregular W WPMT Sem Assoc NWAT S Repetition S Reading Noun N Verb N Year 1 data from 10/19 data freeze (n=1,396) 100 100 90 90

80 80 999 999 70 70 998 998 60 60 997 50 50 997 996 40 40 996 30 995 30 995 FTLD % CDR 1 FTLD % CDR 0 CDR % FTLD 20 ceiling 20 ceiling 10 range 10 range 0 floor 0 floor

100 100 90 90 80 80 999 999 70 70 998 998 60 60 50 997 50 997 40 996 40 996 30 995 30 995 FTLD % CDR 3 CDR % FTLD FTLD % CDR 2 CDR % FTLD 20 ceiling 20 ceiling 10 range 10 range 0 floor 0 floor Examiner: % total A/L participants

100

70 999 60 998 997

50 996 995

40 ceiling % total participants total % range

30 floor

0 N1B N2B Dot Count Set shift Flanker Ex F words Ex Animals Year 1 data from 10/19 data freeze (n=1,396) 100 100

90 90

80 80 999 999 70 998 70 998 60 997 60 997

50 996 50 996 995 40 995 40 ceiling ceiling 30 30 range

range Examiner % CDR 1 Examiner Examiner % CDR 0 20 20 floor floor 10 10

0 0 N1B N2B Dot Count Set shift Flanker Ex F words Ex Animals N1B N2B Dot Count Set shift Flanker Ex F words Ex Animals

100

100 90 90

80 999 80 999 70 998 70 998 60 997 60 997 50 996 50 996

40 995 40 995 ceiling 30 ceiling Examiner Examiner % CDR 2 30 Examiner Examiner % CDR 3 range range 20 20 floor floor 10 10 0 0 N1B N2B Dot Count Set shift Flanker Ex F words Ex Animals N1B N2B Dot Count Set shift Flanker Ex F words Ex Animals Criteria for Evaluation of Clinical and other Measures

• Differential diagnosis: Does it differentiate between clinical syndromes? Useful in how many syndromes? • Disease progression: Does it change over time in asymptomatic or symptomatic individuals? Effect size? • Clinical meaningfulness: Does it reflect something a participant or family would consider important? (regulatory) • Biologically informative: Does it reveal something informative about the disease process, prediction of decline, etc.? • Too early to decide: Seems promising, but need more data. Evaluation of cognitive assessments

Measure Helps with Changes over Clinically Informs More info differential dx time meaningful Biology needed to decide UDS3

FTLD-NACC

NIH-Examiner

CVLT-SF

Tablet

Yes and/or established Maybe and/or unclear No or N/A Conclusions

• When choosing clinical instruments: • Define population • Define goal • Balance ideal / practical • Multilevel battery • New technology CVLT-SF

CVLT-SF Delay CVLT Recog 100 100

90 90

80 80

70 70

60 60

50 50

40 40

30 30

20 20

10 10

0 0 cdr 0 cdr 0.5 cdr 1 cdr 2 cdr 3 Total cdr 0 cdr 0.5 cdr 1 cdr 2 cdr 3 Total

floor range ceiling 995 996 997 998 999 floor range ceiling 995 996 997 998 999 Longitudinal Evaluation of Familial Cohort (LEFFTDS) – UDS 3.0 Battery

Julie Fields Nellie Brushaber, Jeremy Syrjanen, Walter Kremers, Brad Boeve Test Battery

• Common tests (or analogs), known and validated • Updated norms • Battery utilized nationwide Sample Summary

• 453 family members with known mutation – MAPT, GRN, C9orf72

• 321 at least 2 visits

• Follow-up to 4.5 years Baseline/Follow-up Characteristics FTLDCDR_GLOBAL 0.0 0.5 1 + Total (N=304) (N=61) (N=88) (N=453) P-value Genetic status, n (%) <.00011 C9 61 (20.1%) 25 (41.0%) 40 (45.5%) 126 (27.8%) GRN 33 (10.9%) 6 (9.8%) 20 (22.7%) 59 (13.0%) MAPT 45 (14.8%) 12 (19.7%) 22 (25.0%) 79 (17.4%) NONE 165 (54.3%) 18 (29.5%) 6 (6.8%) 189 (41.7%) Baseline age <.00012 N 304 61 88 453 Median (Range) 44.0 (18.0, 80.0) 56.0 (28.0, 80.0) 62.0 (32.0, 75.0) 51.0 (18.0, 80.0) Mean (SD) 45.0 (13.76) 55.6 (11.23) 59.6 (10.00) 49.3 (14.19) Baseline age at onset 0.02992 N 13 50 88 151 Median (Range) 44.0 (16.0, 65.0) 53.0 (12.0, 71.0) 55.0 (16.0, 72.0) 53.0 (12.0, 72.0) Mean (SD) 42.4 (15.01) 50.9 (10.74) 52.6 (12.46) 51.2 (12.40) Sex, n (%) 0.25781 0 125 (41.1%) 32 (52.5%) 39 (44.3%) 196 (43.3%) 1 179 (58.9%) 29 (47.5%) 49 (55.7%) 257 (56.7%) Ed (Years) 0.04372 N 304 61 88 453 Median (Range) 16.0 (11.0, 22.0) 14.0 (11.0, 20.0) 16.0 (12.0, 20.0) 16.0 (11.0, 22.0) Mean (SD) 15.6 (2.42) 14.8 (2.54) 15.5 (2.44) 15.5 (2.45) Total years of follow-up <.00012 N 304 61 88 453 Median (Range) 1.7 (0.0, 4.3) 1.2 (0.0, 4.5) 1.0 (0.0, 4.2) 1.3 (0.0, 4.5) Mean (SD) 1.7 (1.26) 1.5 (1.39) 1.0 (1.04) 1.5 (1.26) 1Chi-Square p-value ; 2Kruskal-Wallis p-value Baseline Cognitive (Global, Attn/Exec)

FTLDCDR_GLOBAL 0.0 0.5 1 + Total (N=304) (N=61) (N=88) (N=453) P-value MoCA – Total (Z) <.00012 N 304 59 75 438 Median (Range) 0.0 (-7.0, 2.9) -1.8 (-8.6, 2.3) -4.1 (-19.6, 1.0) -0.6 (-19.6, 2.9) Mean (SD) -0.2 (1.65) -1.6 (2.19) -5.4 (4.36) -1.3 (3.08) Number Span Forward - Correct Trials (Z) <.00012 N 303 60 74 437 Median (Range) 0.0 (-3.7, 2.3) -0.3 (-2.0, 2.0) -1.1 (-3.4, 2.3) -0.3 (-3.7, 2.3) Mean (SD) 0.0 (1.03) -0.2 (0.88) -1.1 (0.99) -0.2 (1.09) Number Span Backward - Correct Trials (Z) <.00012 N 303 60 73 436 Median (Range) -0.1 (-2.6, 2.6) -0.4 (-2.6, 2.8) -1.7 (-3.8, 1.0) -0.4 (-3.8, 2.8) Mean (SD) -0.1 (1.05) -0.2 (1.15) -1.6 (1.00) -0.3 (1.20) TMT A (Z) <.00012 N 304 60 69 433 Median (Range) 0.1 (-11.9, 2.2) -0.8 (-14.2, 1.5) -3.1 (-20.5, 0.7) -0.2 (-20.5, 2.2) Mean (SD) -0.2 (1.42) -1.6 (2.65) -4.4 (4.88) -1.0 (2.92) TMT B (Z) <.00012 N 304 60 48 412 Median (Range) 0.0 (-8.2, 2.2) -1.0 (-14.1, 1.4) -3.2 (-12.3, 1.1) -0.3 (-14.1, 2.2) Mean (SD) -0.2 (1.28) -1.9 (3.17) -3.8 (3.37) -0.9 (2.33)

2Kruskal-Wallis p-value Baseline Cognitive (Language)

FTLDCDR_GLOBAL 0.0 0.5 1 + Total (N=304) (N=61) (N=88) (N=453) P-value Letter Fluency (Z) <.00012 N 189 54 68 311 Median (Range) -0.1 (-2.1, 3.2) -0.8 (-3.2, 1.6) -2.2 (-4.0, 0.8) -0.6 (-4.0, 3.2) Mean (SD) -0.1 (1.00) -0.7 (1.02) -2.0 (1.17) -0.6 (1.28) Category Fluency (Z) <.00012 N 189 54 65 308 Median (Range) -0.2 (-2.9, 3.4) -0.8 (-3.8, 1.9) -2.2 (-5.4, 2.3) -0.7 (-5.4, 3.4) Mean (SD) -0.2 (1.09) -0.8 (1.16) -2.3 (1.55) -0.8 (1.45) MINT (Z) <.00012 N 303 60 72 435 Median (Range) -0.1 (-9.1, 1.4) -0.4 (-6.4, 1.2) -2.8 (-18.5, 0.8) -0.4 (-18.5, 1.4) Mean (SD) -0.4 (1.25) -0.8 (1.56) -4.1 (4.61) -1.1 (2.60) Benson Complex Figure Copy (Z) <.00012 N 302 58 77 437 Median (Range) 0.1 (-3.9, 1.3) 0.0 (-4.1, 1.3) -0.7 (-13.9, 1.2) 0.0 (-13.9, 1.3) Mean (SD) -0.1 (1.00) -0.5 (1.42) -1.3 (2.57) -0.3 (1.52) 2Kruskal-Wallis p-value Baseline Cognitive (Learning/Memory)

FTLDCDR_GLOBAL 0.0 0.5 1 + Total (N=304) (N=61) (N=88) (N=453) P-value Craft Story Recall – Immediate (Z) <.00012 N 303 58 69 430 Median (Range) -0.2 (-3.3, 2.4) -0.7 (-3.7, 1.9) -1.7 (-3.9, 1.3) -0.4 (-3.9, 2.4) Mean (SD) -0.2 (1.03) -0.6 (1.28) -1.6 (1.42) -0.5 (1.24) Craft Story Recall – Delay (Z) <.00012 N 301 58 68 427 Median (Range) -0.2 (-2.8, 2.8) -0.7 (-3.3, 1.8) -1.7 (-3.5, 1.9) -0.4 (-3.5, 2.8) Mean (SD) -0.1 (1.03) -0.6 (1.20) -1.6 (1.37) -0.4 (1.23) Benson Complex Figure – Recall (Z) <.00012 N 302 58 74 434 Median (Range) -0.0 (-3.3, 1.9) -0.6 (-4.7, 1.8) -1.4 (-6.4, 1.1) -0.2 (-6.4, 1.9) Mean (SD) -0.1 (1.06) -0.7 (1.24) -1.8 (1.71) -0.5 (1.38) 2Kruskal-Wallis p-value Baseline Cognitive Pair-wise Comparisons FTLD-CDR 0 FTLD-CDR 0.5 vs 0.5 vs 1+

MoCA <.0001 <.0001

Number Span Forw NS <.0001

Number Span Back NS <.0001

TMT A <.0001 <.0001

TMT B <.0001 .0002

Letter Flu .0017 <.0001

Cat Flu .002 <.0001

MINT NS <.0001

Benson Copy NS .05

Craft Imm .02 .0002

Craft Del .005 <.0001

Benson Del .0006 <.0001

Data Summary

• Baseline: tests do discriminate between FTLD-CDR groups (0 vs 0.5 vs 1+)

• Cross-sectionally by mutation: insufficient data

• Longitudinally by mutation: trends towards worse cognitive performance consistent with FTLD-CDR, especially in the 1+ group Questions of Interest

• Does cognition differ at baseline among MAPT, GRN, C9orf72 gene carriers and non-mutation carriers? • Does cognition change over time within groups? • Can we identify predictors of change in global FTLD-CDR?

Phenoconverters (as of 8/2019)

• Out of 264 gene mutation carriers – Must not convert back to normal • Definition 1: FTLD-CDR or MIR (not always available) of 0 converts to > 0 – 21/264 (8%) • All but 2 in concordance with Definition 2 (both had CDR-MIR discrepancies) • Definition 2: Convert from Clinically Normal to Primary Neurological dx – 22/264 (8%) • 3 discordant from Definition 1 , 2 who converted to either PD or ALS dx

FTLD Module & NIH-EXAMINER in f-FTLD

Adam Staffaroni, PhD UCSF Memory and Aging Center

Criteria for Evaluation of Clinical and other Measures

• Completed FTLD-Module and FTLD-CDR

• Family Gene: MAPT, GRN, C9orf72

• 423 participants w/ 973 timepoints

• No mutation, CDR = 0: n = 161 (352 visits) • Base FTLD-CDR = 0: n = 136 (344 visits) • Base FTLD-CDR = 0.5: n = 42 (106 visits) • Base FTLD-CDR = 1+: n = 77 (150 visits)

Word Reading Test – Regular and Irregular Corr w/ WRAT: .55 Corr w/ WRAT: .75 Total correct (0-30) as well as number of semantic paraphasias, other errors, and “regularization” of irregular words

FTDWORRC Freq. Percent

14 6 1.92 15 307 98.08

Total 313 100.00

FTDWORIC Freq. Percent

11 3 0.96 12 7 2.24 13 19 6.07 14 78 24.92 15 206 65.81

Sentence Repetition and Reading

FTDSENAS Freq. Percent

0 1 0.32 2 3 0.96 3 23 7.40 4 117 37.62 5 167 53.70

FTDREAAS Freq. Percent

3 7 2.26 4 33 10.65 5 270 87.10

Semantic Word-picture Matching

Total Correct: 0-20

FTDSEMMT Freq. Percent

19 6 1.92 20 307 98.08

Correlation with PPVT-R: .83

Semantic Associates Test

0-16 Total associations Animals and tools.

FTDSEMSU Freq. Percent

13 1 0.32 15 9 2.88 16 303 96.81

Nouns (16) Noun and Verb Naming Verbs (16) Noun:Verb Ratio

FTDNOUNC Freq. Percent

5 1 0.32 14 3 0.96 15 17 5.47 16 290 93.25

FTDVERBC Freq. Percent

0 1 0.32 12 1 0.32 13 1 0.32 14 5 1.61 15 22 7.07 16 281 90.35

Corr w/ aBNT: .8 Baseline FTLD-CDR ≥ 1 Baseline:-1.47, p<.001 Longitudinal: -.86, p<.001 Sample Size: 3522 Baseline FTLD-CDR ≥ 1 Baseline:-.243, p<.001 Longitudinal: -1.39, p<.001 Sample Size: 1100 Northwestern Anagram Test (Short form)

FTDANATS Freq. Percent

4 1 0.32 5 7 2.27 6 9 2.92 7 8 2.60 8 19 6.17 9 50 16.23 10 214 69.48

Total Correct (0/10); Subject (5) and Object (5) questions Baseline FTLD-CDR ≥ 1 Baseline: -2.3, p <.001 Longitudinal: -.42,p = .04 Sample Size: 1626 Summary • If FTLD-CDR ≤ 0.5: – Poor separation of carriers and non-carriers – No longitudinal differences were statistically or clinically significant

• If FTLD-CDR ≥ 1: – Several tests capture baseline and longitudinal differences in symptomatic mutation carriers, but effect sizes are relatively small (i.e., large sample sizes required)

• Should we continue administering this module if FTLD-CDR < 0.5? NIH-EXAMINER • NIH-commissioned, computerized EF battery (Kramer et al., 2014)

• Quantifies subdomains of EF – Working memory, cognitive control and fluency

• IRT-derived Executive Composite and 3 factor scores – Detects impairments in sporadic FTD (Possin, 2013) and premanifest HD (You, 2014) – Associated with frontotemporal volumes and “real-life” executive symptoms (Possin, 2014) • NIH-Examiner detects XS and longitudinal changes in presymptomatic f-FTLD • Declines are associated with • CDR® + FTLD • Volume loss

CDR® + FTLD ≥ 1: Sample size = 138 (N=27)

Staffaroni et al., 2019 Alzheimer’s & Dementia Missing Data with Increasing Disease Severity

• FTLD-CDR = 0: 625/683 (92%) • FTLD-CDR = 0.5 174/213 (82%) • FTLD-CDR = 1: 141/224 (63%) • FTLD-CDR = 2: 74/199 (37%) • FTLD-CDR = 3: 0/13 (0%)

ALLFTD: Tablet-Based Examiner

• Removed n-back • Supplanted by Running Dots – Maximized trade off between reliability and task length • Shortened Flanker and Set-Shifting • Building new composite score algorithm Evaluation of Questionnaires

Measure Helps with Changes over Clinically Informs More info differential dx time meaningful Biology needed to decide NIH-EXAMINER Secondary?

FTLD-Module ?

Yes and/or established Maybe and/or unclear No or N/A Data Errors

• Neuropsych cleaning Task force

• Study Coordinator calls – Data cleaning initiatives: CVLT/MINT – Review Data Errors

Please contact me with suggestions or oddities you find in while processing data.

Thank you in advance for your ideas!

Nellie Brushaber https://diginomica.com/us-digital-service-to-nyc-designers-we-need-you [email protected] NACC Socioemotional Questionnaires in ALLFTD

• Behavior Inhibition Scale (BIS): • social self-consciousness and worry • Empathic Concern (IRI-EC) and Perspective Taking (IRI-PT): • emotional and cognitive empathy • Revised Self-Monitoring Scale (RSMS): • ability to detect and react to subtle social cues • Social Behavior Observer Checklist (SBOCL): • clinician observational ratings of aberrant behaviors occurring during a neuropsychological testing session • Social Norms Questionnaire (SNQ): • social semantic knowledge around normative behavior • Geriatric Depression Scale (GDS) from the NACC UDS

RSMS is very sensitive to progression, early

• ALLFTD bvFTD patients (N=475) • Informant reports • 13 item questionnaire

Slope of change of volume w/r/t RSMS score

Toller et al. & ARTFL/LEFFTDS Consortium (In press, Neurology) “Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials.”

SBOCL is sensitive to change, high positive predictive values

Rankin et al. & ARTFL/LEFFTDS Consortium (mss in preparation) NACC Socioemotional Questionnaires in ALLFTD • Three informant-report questionnaire measures are sensitive to early changes regardless of mutation status, and show significant change over the course of the disease (RSMS, IRI, SBOCL) • Two psychiatric measures (one self-report, one informant report) may be sensitive to differences in gene status, with mutation negative individuals developing significantly more psychopathology than mutation positive individuals at CDR=0.5 – BIS (worry) and GDS (depression) are clinically non-redundant, consider keeping both Modernizing testing in ALLFTD • We probably ought to add some face-to-face socioemotional tests to the ALLFTD battery. . .(!) • We also may want to replace some of our neuropsychological measures with better tasks • Electronic data collection has many benefits, particularly for a multisite study like ALLFTD – Increased accuracy over paper-and-pencil based testing – Automated scoring and secure data management – No need for manual data entry – Unified data architecture accelerates data quality checking and release for analysis – Can facilitate multisite collaboration, even internationally – Better monitoring of enrollment statistics by central study administrative core

The best interface for cognitive testing is the tablet

• Computerized testing offers numerous advantages including: • more standardized administration • dynamic stimuli • precise response capture • automated and advanced scoring procedures

• Tablet-based interfaces have been proven to be comfortable even for older adults who have never used computers or smartphones

Modernizing testing in ALLFTD • One potential tablet-based cognitive testing platform: TabCAT (https://memory.ucsf.edu/research-trials/professional/tabcat) – Data infrastructure currently 100% functional for secure multi-site clinical research studies – Includes only non-commercial tests – Already includes: • EXAMINER tests (Dot Counting; Flanker; Set Shifting; Running Dots) • All of the NACC FTLD Module Socioemotional Questionnaires (including patient-facing SNQ, examiner-facing SBOCL) • Additional face-to-face socioemotional measures • Additional executive, memory, visuospatial, and language tasks that could be considered as potential improvements to our existing NP battery

Face-to-face Socioemotional Tasks on TabCAT

Dynamic Affect Recognition Task (DART) • Labeling emotions shown in brief video vignettes • 12 items (2 each of 6 major emotions) 5 minutes • Sensitive to right temporal pole/OFC anatomy/connectivity • Important to test emotion reading in an FTLD study

Radke et al.; Yang et al. (under review) Face-to-face Socioemotional Tasks on TabCAT

Social Interaction Vocabulary Task (SIVT) • Sensitive to deficits in verbal/nonverbal socioemotional semantic knowledge specific to FTLD syndromes • 16 items, easy/ moderate/ difficult, 3 minutes • Norms from confirmed neurologically healthy individuals aged 21-87

TabCAT Line Orientation: dorsal stream visuospatial functioning

Corresponds specifically to right parietal volume, supporting its validity as a dorsal stream VS test

Possin et al., 2018, JAGS TabCAT Match: executive processing speed (replace paper Symbol Digit?)

Corresponds to subcortical and dorsolateral frontal volume, supporting its validity as a test of EF/info processing speed

Possin et al., 2018, JAGS