Ralph H. B. Benedict, Ph.D., ABPP-CN
Associate Professor of Neurology and Psychiatry
SUNY Buffalo School of Medicine
Jacobs Neurological Institute
Detecting Cognitive Disorders in MS
Outline
Brief History Update: Screening for NP dysfunction Update: Consensus NP Test Battery Clinical Application: Integrating Cognitive
Assessment into Routine Care
MS: MRI T2
Grade 1 Grade 2 Grade 3
Adapted from Rao et al. (1991)Adapted from Rao et al. (1991)
Language SpatialSpatialAbilities
AttentionAttentionSpanSpan
ProcessingProcessingSpeedSpeed
MemoryMemory ProblemProblemSolvingSolving
3030
2525
2020
1515
1010
55
00
8-9%
12-19%
7-8%
22-25%
22-31%
13-19%
SET A
SET B
SET C
“marked enfeeblement of the memory …. conceptions are formed slowly..”
Charcot (1877)
NP Profiles in MS
30
55
4540
60
50
0
10
20
30
40
50
60
language
spatial
mem
ory
atten/wm
executive
premor IQ
Normal (30%)
% ile
60
45
71
60
50
0
10
20
30
40
50
60
language
spatial
mem
ory
atten/wm
executive
premor IQ
Mild Cognitive Disorder (55%)
% ile
2
45
33
19
4550
0
10
20
30
40
50
60
language
spatial
mem
ory
atten/wm
executive
premor IQ
Focal Defect (<5%)
% ile25
2 2 1 1
50
0
10
20
30
40
50
60
language
spatial
mem
ory
atten/wm
executive
premor IQ
Dementia (10-15%)
% ile
A line is drawn through the long axis of the third ventricle, parallel to the inter-hemispheric fissure. The width is measured by drawing a second line perpendicular to the first at its midpoint, and then recording its length.
Third Ventricle Width (TVW)
Brain tissue volume (contour – CSF)
Outer contour of brain surface
Brain parenchymal fractionBrain parenchymal fraction
BPF =BPF =
Bicaudate Ratio (BCR)Bicaudate Ratio (BCR)
•BCR – the minimum BCR – the minimum intercaudate intercaudate distance divided by distance divided by brain width along brain width along same linesame line
•Higher BCR = Higher BCR = atrophyatrophy
Bermel et al., Arch Neurol 2002;59:275-280Bermel et al., Arch Neurol 2002;59:275-280
Brain Lesion Burden or Atrophy: Which MRI Measure Best Predicts Cognitive Impairment in Multiple Sclerosis?Benedict et al. Archives of Neurology. 2004; in press
• 37 MS patients volunteers, 28 controls matched age, educ, gender
• Conventional MRI: T1 LV; FLAIR LV; TVW; BCR; BPF
• Neuropsychological Testing: PASAT; SDMT; CVLT; BVMT; JLO; WCST
• Controls: Premorbid IQ = North American Adult Reading Test (NAART) Depression = Center for Epidemiologic Studies (CES-D)
T1 LV F LV BCR TVW
T1 LV
F LV .89
BCR .56 .49
TVW .50 .47 .80
BPF -.42 -.26 -.68 -.79
Retained MRI variable
Partial r Mult R2
Change in R2 from Block 1
P
CVLT Learning TVW -.44 .26 .15 <.05
CVLT Delay TVW -.45 .44 .14 <.01
BVMT Delay TVW -.47 .42 .17 <.01
PASAT TVW -.57 .44 .26 <.001
SDMT TVW -.71 .57 .43 <.001
Benedict et al, J Neuroimaging. 2004, in press
• 31 MS patients from Benedict et al (AN; 2004) also had informant report NPI profiles
Depression Euphoria* Disinhibition*
T1 .55 .41 --
FLV .47 .35 --
BCR -- -- --
TVW -- .46 .46
BPF -- -.43 -.34
*only NPI scales correlated with cognitive function (eg PASAT r = -.53).
Screening for Cognitive Disorders?
Screening for MS Cognitive Impairment using a Self-Administered 15-Item QuestionnaireBenedict et al. Multiple Sclerosis. 2003; 9:95-101
Phase I: Item Selection/Reduction
Participants: 100 consecutive clinic patientsMeasure: 68 Items (atten, mem, other, pers/beh)
Scale: 0 (never) to 4 (severe)Procedure: Reduce to 15 Items via Rasch analysis
Correlate with Cognitive FunctionsQuestionnaire
• easily distracted• lose focus when listening• slowed problem solving• trouble describing programs
recently watched• forgetting appointments• forgetting what is read• instructions repeated• reminded to do tasks
• forgetting errands
• difficulty answering questions
• difficulty tracking two things at once
• missing the point of conversations
• difficulty controlling impulses
• laugh/cry with little cause
• talk excessively
MS Neuropsychological Screening Questionnaire (MSNQ)
0 not at all 3 very often & disruptive1 rarely & no problem 4 very often & greatly interferes with
life2 occasionally, seldom a problem
Screening for MS Cognitive Impairment Using a Self-Administered 15-Item Questionnaire
Participants: 50 pts (40 RR), random recruitmentMean age 42, education 15 years
Mean SD Alpha Corr
BDI
Corr
CVLT
Corr
PASAT
Patient Report 22.5 10.2 .93 .53 ns ns
Informant Report 18.4 11.1 .94 ns -.53 -.47
Benedict, et al. Multiple Sclerosis. 2003; 9:95-101
Bayesian Probabilities, Informant Report MSNQ
Sensitivity # TP / # patientsSpecificity # TN / # normalsPositive PP # TP / # positive testsNegative PP # TN / # negative tests
Imp Nrm
MSNQ +
10 1 11
MSNQ -
2 37 39
12 38 50
Sens = .83 Spec = .97PPP = .91 NPP = .95
Processing Speed and Memory Tests
Problems?
small sample, one center
no controls
no test-retest reliability
MSNQ Cross Validation - Methods
85 MS pts, 40 age and education matched normal controls
80% pts with RR course
62% informants were spouses, known pt mean 23 yrs
MSNQ administered to all subjects, 40 MS retest at 1 week
MACFIMS
Depression: CESD-10; BDI-FS
Centers: Jacobs Neurological InstituteBernard Gimbel MS CenterUCSFUCHSC
MSNQ Cross Validation - Reliability
Cronbach’s Alpha Self-Report .94
Cronbach’s Alpha, Informant Report .93
Test-Retest Reliability (r) Self-Report .90
Test-Retest Reliability (r) Informant-Report .93
MSNQ Cross Validation - Validity
Self Inf
COWAT -.17 -.33*
JLO -.44± -.36±
CVLT-II Learning -.37± -.45±
CVLT-II Delay -.42± -.50±
BVMT-R Learning -.46± -.57±
BVMT-R Delay -.45± -.55±
PASAT -.38± -.59±
SDMT -.45± -.58±
D-KEFS Sorting -.30* -.38±
Composite Z -.49± -.64±
CES-D-10 Depression .61± .37±
* p<.05± p<.01
MSNQ Cross Validation – Predictive Validity
SENS SPEC PPV NPV
Self Report .83 .60 .53 .87
Self Report (dep) .80 .68 .73 .75
Informant .87 .84 .74 .92
Informant (2003) .83 .97 .91 .95
Screening is positive, now what?
Minimal Neuropsychological Assessment of MS Patients: A Consensus ApproachBenedict et al. Clinical Neuropsychologist, 2002.
• Ralph Benedict, Ph.D. Co-Chair
• Jill Fischer, Ph.D. Co-Chair
• Cate Archibald, Ph.D.
• Peter Arnett, Ph.D.
• William Beatty, Ph.D.
• Julie Bobholz, Ph.D.
• Gordon Chelune, Ph.D.
• John Fisk, Ph.D.
• Dawn Langdon, Ph.D.
• Lauren Caruso, Ph.D.
• John DeLuca, Ph.D.
• Fred Foley, Ph.D.
• Nicholas LaRocca, Ph.D.
• Frederick Munschauer, M.D.
• Steve Rao, Ph.D.
• Lindsey Vowels, Ph.D.
• Amy Weinstein, Ph.D.
Process:
(1) Review Literature (MS and Psychometric Data) (2) Consensus: Purpose of Minimal Exam Cognitive Domains Psychometric Criteria (3) Rank Order Candidate Tests (4) Propose Directions for Research
Consensus: Psychometric Criteria
Standardized Manual, commercially available
Normative Data Published, large sample, age 20-55
Adequate Range No ceiling or floor effects.
Reliability Moderate/high test-retest reliability.
Criterion Validity Discriminates MS and controls, good sensitivity & specificity.
Alternate Forms Alternate forms are equivalent.
Practical Brief, minimal equipment, minimal confound of neurol signs.
Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS)
Test Cognitive Domain Min
Paced Auditory Serial Addition Test Processing Speed/Working Memory
10
Symbol Digit Modalities Test Processing Speed/Working Memory
5
California Verbal Learning Test Learning and Memory 25
Brief Visuospatial Memory Test Learning and Memory 10
D-KEFS Sorting Test Executive Function 25
Judgement of Line Orientation Test Visual-Spatial Ability 10
Controlled Oral Word Association Test Language and Other Domains 5
Practice Effects, Alternate Forms
Benedict & Zgaljardic. (1998). J Clin Exp Neuropsychol Zgaljardic & Benedict. (2001). Appl Neuropsych, in press
Subjects: 32 healthy volunteers, mean age 63.3, 37% male
Design: Counterbalanced adm of 4 HVLT-R & BVMT-R formsTwo week Test/Retest IntervalRandom assignment to same- and alternate-form conditions
Brief Visuospatial Memory Test - Revised
4
5
6
7
8
9
10
11
12
T-1 T-2 T-3 T-4
Session 1Session 2Session 3Session 4
4
5
6
7
8
9
10
11
12
T-1 T-2 T-3 T-4
Session 1Session 2Session 3Session 4
MACFIMS Validation
373 MS pts (176 clinical referral) 59 age and education matched normal controls 73% pts with RR course
MACFIMS Timed Ambulation, 9-H Peg,Maximum Repetition Rate
CESD-10; BDI-FS Fatigue Severity Scale NEO – Five Factor Inventory Neuropsychiatric Inventory MSQOL-54
Test-Retest Reliability
Alternate Form Testing
r
CVLT-II Learning .77
CVLT-II Delayed Recall .87
CVLT-II Delayed Recognition .77
BVMT-R Learning .80
BVMT-R Delayed Recall .75
BVMT-R Delayed Recognition .60
Sample: MS = 39
Group Discrimination
TEST % impaired
all
% impaired exclude referrals
ANOVA MS v
Control p
Controlled Oral Word Association 17 13 <0.001
Judgement Of Line Orientation 41 35 <0.001
CVLT-II Learning 39 29 <0.001
CVLT-II Delayed Recall 40 27 <0.001
BVMT-R Learning 43 34 <0.001
BVMT-R Delayed Recall 50 39 <0.001
PASAT 43 28 <0.001
Symbol Digit Modalities Test 60 42 <0.001
D-KEFS Sorting Test 57 39 <0.001
Study Design
VocationalStatus
Retained Significant Predictors
FatigueAge,
Education, etc
DiseaseFeatures
PhysicalDisability
Cognitive Function
MoodDisorder
PersonalityBehavior Disorder
MSQOL-54Mental
Composite
MSQOL-54Physical
Composite
1st tier regression models, controlling for any significant demographics
2nd tier regression models, controlling for any significant demographics
Regression Analysis Results
MSQOL-54 PhysicalFatigue Severity Scale (R2=0.57)Center for Epidemiologic Studies Depression Scale (R2change=0.08)EDSS (R2change=0.02)Beck Depression Inventory – Fast Screen for Medical Patients (R2change=0.02)
MSQOL-54 MentalCenter for Epidemiologic Studies Depression Scale (R2=0.68)Fatigue Severity Scale (R2change=0.03)
Vocational StatusSymbol Digit Modalities Test (Wald=12.8)WCST Perseverations (Wald=7.8)NEO Personality Inventory, Informant Report Conscientiousness (Wald=6.7)Disease Duration (Wald=5.3)Judgment of Line Orientation Test (Wald=3.8)
Sample: MS = 120; Control = 44
Patient Care?
Neuropsychological Practice Guidelines
Routine ScreeningIn the Office
RoutineMinimal NP Exam
+MSNQ
MACFIMS
ComprehensiveNP Evaluation
Psychiatry OT, ST
-0.40 .25 0 .5 0 .8
-0 .75
0 .5
-4
-3
-2
-1
0
1
2
z score
Case HJ
0 0 0 0 0 00.3 0 .1 0 .2 0 .5 0 0.102468
1012
me an scoreraw score
Case HJ
Case HJ• age 23, EDSS 2.5, DD = 3.0 yr• CC is fatigue• BDI-FS borderline• TVW=3.0, BPF=0.87
Case BK• age 26, EDSS 4.0, DD = 7.0 yr• CC is situational, needs not met• BDI-FS elevated• TVW=6.4, BPF=0.79
-0.340.24
-1-1.5
-3.1
0.5
-4
-3
-2
-1
0
1
2
z score
Case BK
69
0
69
20.3 0 .1 0 .2 0 .5 0 0.10
2468
1012
me an scoreraw score
Case BK
Thank You
Jacobs Neurological InstituteLawrence Jacobs, MDFrederick Munschauer, MDBianca Weinstock Guttman, MD
Buffalo Neuroimaging Analysis CenterRohit Bakshi, MDRobert Zivadinov, MD
UB NeuropsychologyDavid Shucard, PhD Inna Fishman, MAJanet Shucard, PhD Elizabeth Wahlig, MADominic Carone, PhD Jane Braun, PhDDanielle McCabe, MA
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