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ALLFTD Neuropsychological Assessment 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 90 80 70 999 60 998 997 50 996 995 40 ceiling % total participants total % range floor 30 20 10 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 90 80 70 999 60 998 997 50 996 995 40 ceiling % total participants total % range floor 30 20 10 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 90 80 70 999 60 998 997 50 996 995 40 ceiling % total participants total % range 30 floor 20 10 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
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