Current Approaches to

Management of Cognitive

Impairment in MS

John DeLuca, Ph.D.

Senior Vice President for Research

Kessler Foundation

West Orange, New Jersey, USA

Professor, Department of Physical Medicine & Rehabilitation

Department of Neurology

Rutgers, New Jersey Medical School

Newark, New Jersey, USA

Disclosures

• Advisory board for Biogen IDEC

• Speaker, EMD Serono

• Grant funding, Biogen IDEC

• Grant funding, EMD Serono

• Grant funding, NMSS

• Grant funding, CMSC

Overview

• Cognitive Rehabilitation

• Exercise

• Medication

Cognitive Rehabilitation

Cognitive Rehabilitation Studies

42 total studies

63% of all studies

RR and PMS Participants in Cognitive

Rehabilitation Studies

38 total studies: 4 unknown

0

10

20

30

40

50

60

70

80

90

100

Frequency Percent Progressive S’s in study

RED= RR; BLUE= Progressive

15 studies

989 persons with MS

Support effectiveness of memory intervention on:

Objective assessments of immediate and long term follow-up

QOL in immediate follow-up

Cochrane Database of Systematic Reviews 2016, Issue 3

Evidenced Based Cognitive Rehabilitation for

Persons with Multiple Sclerosis: An Updated

Review of the Literature from 2007-2016

Y. Goverover, N.D. Chiaravalloti, A. O’Brien, J. DeLuca

ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

(2017), doi: 10.1016/j.apmr.2017.07.021.

Classified studies on level of evidence based on AAN criteria for therapy trials

Yielded 40 studies (2007-2016)

contrasts with 16 studies (ALL prior years)

Results:

1 Practice Standard Learning/Memory

2 Practice Guidelines Attention, nonspecific tx

5 Practice Options Learning/Memory; Attention

Goverover et al (2017) Archives Physical Medicine & Rehab

# of studies 40 16

Class I 6 (15%) 4 (25%)

Class II 9 (23%) 5 (31%)

Class III/IV 25 (63%) 7 (44%)

2007-2016* All years prior 2007**

Vast majority of all studies are positive

**O’Brien et al (2008) Archives Physical Medicine & Rehab

* Goverover et al (2017) Archives Physical Medicine & Rehab

Cognitive Rehabilitation: Behavioral Approaches

Sample RCT results

Computer-assisted rehabilitation of

attention in patients with multiple

sclerosis: results of a randomized

double blind trial

M.P. Amato1 , B. Goretti1, E. Portaccio1, R.G. Viterbo2, P.

Iaffaldano2, M. Trojano2

1Department of Neurological and Psychiatric Sciences, University of Florence,

Italy 2Department of Neurological and Psychiatric Sciences, University of Bari,

Italy

Amato et al., 2014, MSJ

Attention Training RCT

• OBJECTIVE: To assess efficacy of a

computerized program for retraining

of impaired attention in MS

• Multicenter RCT (n=88)

• RR only – (impaired on attention)

• Randomly assigned to:

– Specific computerized training (SCT)

– Aspecific computerized training (ACT)

• Class I evidence

Amato et al., 2014, MSJ

PASAT Results

ACT

SCT

ACT

SCT

Effect for Time: F=12.19; p<0.001

Effect for Time*Group; F=6.50; p=0.002

Effect for Time: F=21.6; p<0.001

Effect for Time*Group; F=7.37; p=0.001

Amato et al., 2014, MSJ

SCT

ACT

Effect for Time: F=11.43; p<0.001

Effect for Time*Group; F=2.67; p=0.072

There was no significant

effect of the SCT on the other

neuropsychological tasks

(p>0.12)

SDMT Results

Amato et al., 2014, MSJ

Learning and Memory

• RCT examine efficacy self-generation learning program (self-GEN trial) in MS

• 6-session behavioral intervention teaching self-generation techniques to

improve learning and memory in persons with MS

• 35 learning and memory impaired MS randomized:

• treatment group (n=19)

• Active placebo control (n=16)

• Class I evidence

Goverover et al, (2017), MSJ

Change pre to post with Self-Gen treatment program

p<.002 p<.03

MIST: Prospective memoryCMT- contextual memory test

Goverover et al, (2017), MSJ

Change pre to post with Self-Gen treatment program

p<.003 p<.02

FAMSFBP

Goverover et al, (2017), MSJ

Memory Retraining in MS

• 86 participants with MS– with objective impairment in new

learning• Method

– Random assignment into two groups:•memory retraining group•control group

– Double blinded conditions

Chiaravalloti et al, 2013, Neurology

Learning by Group: Post-treatment*

CVLT Learning Trials

p=.02, controlling for baseline* No significant groupdifference at baseline

Everyday Life Self-Report

Chiaravalloti et al., Neurology, 2013

56

58

60

62

64

66

68

70

Baseline Immediate Follow-up

FAMS General Contentment FrSBe Total Score, Family Form

Brain changes after behavioral treatment for memory impairment

in MS using fMRI

Changes in Brain Functioning in MS

• Pre-training

• Treatment minus control

• Post-training

• Treatment minus control

Increased activation in frontal and occipital regions in treatment group that is not evident prior to treatment (p<.05)

Chiaravalloti et al., 2012, J Neurol

BOLD activation change from pre- to post-treatment

Chiaravalloti et al., 2012, J NeurolMS – red

HC - blue

parahippocampal gyrus superior temporal gyrus

BOLD activation change from pre- to post-treatment

Chiaravalloti et al., 2012, J NeurolMS – red

HC - blue

middle frontal gyrus precuneus

Increased connectivity from

L Hippocampus to Insula

bilaterally in treatment group

after TX

Increased connectivity from

R Hippocampus to cluster

comprised of:

- L post-central gyrus

- precentral gyrus

- middle frontal gyrus

- cingulate gyrus in tx groupRed line tx; blue line controls

Resting state functional connectivity following cognitive rehabilitation in MS

Leavitt et al, Brain Imaging and Beh, 2012

6 month follow-up

Behavioral Performance

6

7

8

9

10

11

12

13

14control groupmean

treatment groupmean

Pre-

intervention

Post-

intervention

6 months

Post-intervention

CV

LT

S

DF

R P

erf

orm

ance

Dobryakova et al., 2014

MTLOccipital

Gyrus

Rz = -6R

MFG

IPL

x = -33

Area more activate in

the treatment group

vs control group

during memory

encoding

Occipital

GyrusMTL

Rz = 1 MFG

A

x = -42

A

post-intervention x 6months

post-intervention

Brain areas activated in association with encoding

pre-intervention x

post-intervention

Dobryakova et al., 2014

Executive Functions and

Attention

• computer-based intervention (RehaCom) for attention, PS

& EF in RRMS

• 20 RRMS randomized into Treatment vs control:

• Pre (T0) and post (T1) Neuropsych testing

Mattioli et al (2010), J of Neurol Sci

TG: RehaCom cognitive rehabilitation for 12 weeks (1 hr

session, 3 days a week).

CG: no rehabilitation.

Filippi et al, Radiology, 2012

Increased Dorsolateral

PFC bilaterally in

Treatment group after

treatment

MR changes following Cognitive Rehabilitation

In treatment group,

Functional MR changes

Correlated with cognitive

improvement

No structural MR changes

In GM volume or NAWM

observed with treatment

TG ONLY: Increased FC of ACC with:

R MFG

R IPL

correlated with PASAT

CG ONLY: decreased FCC of ACC with

R cerebellum

R ITG

No correlation with cognition

Functional connectivity following Cognitive Rehabilitation

RehaCom – computer-based cognitive rehabilitation. Sessions:

Attention and concentration

Plan a day

Divided attention

reaction behavior

Logical thinking

Cog impaired RR assigned to cog rehab (n=18) or control (n=18)

8 weeks TX, 2x per week

Pre-post RS-FC and structural imaging (brain volume; lesion load)

NO significant pre-post differences on NP in control group

NO significant pre-post differences in brain volume or lesion load in either group

Bonavita et al (2015) J of Neurol

Bonavita et al (2015) J of Neurol

RS-DMN F-connectivity increased

In PCC and inferior parietal cortex

In Treatment group only

RR with impaired PS, attention, WM or EF

assigned to cog rehab (n=12) or control (n=11)

6 weeks TX, 2x per week

Pre-post fMRI during PVSAT; Lesion load

RehaCom – computer-based cognitive rehabilitation.

Sessions:

Attention and concentration

Divided attention

Vigilance

Stroop Performance

Cerasa et al (2012), Neurorehab & Neural Repair

Tx group vs control showed:

Increased activation in

L posterior parietal cortex

R posterior cerebellar lobule

(group x time interaction)

Cerasa et al (2012), Neurorehab & Neural Repair

A RCT COMPARING SPECIFIC INTENSIVE COGNITIVE

TRAINING TO ASPECIFIC PSYCHOLOGICAL

INTERVENTION IN RRMS: The SMICT study

• 10 MS Centers in Italy

• 45 RRMS randomized:

– specific training (attention/PS or memory or EF) (rehacom)

– aspecific function (psychological intervention)

• Cognitively impaired (at least 1 test of BRB battery:1.5 sd <norm)

• All S’s prescribed interferon beta 1A

• 4 months tx: two 60 min sessions per week

• Outcome: assessment at 1 year on:

– NP battery

– depression (MADRS)

– QOL (MSQoL)

Mattioli et al (2015), Frontiers in Neurology

Cognitive Change from baseline to 1 year:(no group difference on Executive functions, Depression, QOL)

30

35

40

45

50

baseline 1 year

Aspecific

Specific

30

35

40

45

50

baseline 1 year

Aspecific

Specific

10

15

20

25

baseline 1 year

Aspecific

Specific

10

15

20

25

30

35

baseline 1 year

Aspecific

Specific

PASAT 3” SDMT

SPART 10/36 SRT CLTR

Mattioli et al (2015), Frontiers in Neurology

Improvements maintained at 2 years in:

PS

verbal memory

visual memory

24 MS cognitively impaired RRMS randomized to:

Tx: home-based computerized intervention

wait list control

NP testing

RS MRI

Looking at Thalamic RSFC

De Gilio et al (2016), Radiology

Thalamic RS network is disrupted in MS

Decreased cognitive performance associated with increased

thalamocortical connectivity

Maladaptive plasticity

– unable to compensate for tissue damage to prevent cognitive impairment

Home-based cognitive rehabilitation using the internet

Double blind, randomized, active placebo controlled trial

135 MS randomized (all with cognitive impairment)

adaptive online cognitive training n=74

ordinary computer games n=61

Training was remotely delivered and supervised

60 hours over 12 week

Primary outcome:

neuropsychological composite score

Results: significant improvement in Tx group

Class I evidence

Change from pre to post assessment

0

0,1

0,2

0,3

0,4

0,5

0,6

0,5

0,55

0,6

0,65

0,7

0,75

0,8

0,85

0,9

pre post

tx ctl

Mean NP composite z-score Mean rating cognitive improvement

p<.007p<.029

Charvet et al, (2017) PLOS ONE

Evaluate a cognitive rehabilitation ”App” in cognitively impaired MS

“COGNI-TRAcK” – Cognitive Training Kit

For portable devises

28 cognitively impaired MS randomized to:

ADAT-gr: adaptive training – automatic adjustment of task difficulty

CONST-gr: trained at a constant difficulty level

Based on working memory exercises

8 weeks, five 30-min sessions per week

Self-administered at home

Cognitive Rehabilitation and Cognition in MS

• Conclusions– Consistent data to support effectiveness

• Neuropsychological performance

• Functional neuroimaging support

• Future studies– Design studies to look at everyday life

– More studies on long term outcomes

• Ready for clinical practice– Paucity of adequately trained clinicians

Cognitive Rehabilitation in MS

It works!

Exercise

Exercise and Cognition in MS

• Can Exercise training improve cognition in MS?

– understudied

• Well-established literature in the general population across the lifespan

• Of the existing MS studies

– most are not RCTs

– suffer from significant methodological flaws including• small sample sizes

• poorly-defined interventions

• lack of adequate control groups

• inclusion of cognition as a non-primary outcome

Sandroff, 2015, Neuroscience and Biobehavioral Reviews

Exercise Training and Cognition in MS

• Inconsistent evidence from 5 RCTs of exercise training and cognition in MS:5-9

• Not in-line with literature from the general population on exercise and cognitive function10

• Methodological concerns of MS RCTs

• Need to considering Class II, III, and IV evidence for informing better RCTs (i.e., for

better prescribing exercise training)11,12

5 Oken et al., 2004; 6 Romberg et al., 2005; 7 Briken et al., 2014; 8 Carter et al., 2014; 9 Hoang et al.,2016; 10 Voss et al., 2011; 11 Sandroff, 2015; 12 Sandroff et al., 2016

Sandroff, In Press

1 2 3 4

Sandroff, In Press

Sandroff, In Press

32 MS

16 cognitive Rehab + aerobic exercise

16 aerobic exercise only

6 week intervention

Pre and post neuropsychological testing (BRB)

Results:

Combined group improved significantly more than exercise alone

Cognitive Rehab + Exercise Study

25

27

29

31

33

35

37

39

Cog Reh + Exer Exer

SDMT

23

25

27

29

31

33

35

37

39

41

Cog Reh + Exer Exer

Stroop - Interference

10

12

14

16

18

20

22

Cog Reh + Exer Exer

SPART 10/36

4

4,5

5

5,5

6

6,5

7

7,5

8

Cog Reh + Exer Exer

SPART -Delay

XXXX - pre tx

XXXX – post txJimenez- Morales et al (2017) Rev Neurol

RCT with MS S’s with substantial MS-related mobility disability

EDSS between 4 and 6

Multimodal exercise training

83 MS subjects

43 treatment (aerobic, resistance, balance exercise)

40 active control (minimal exercise: stretching, toning)

6 months or training

Assessment: pre, 3 months, post

Primary outcome: mobility, gait, fitness

Exploratory outcome: Processing speed (SDMT, PASAT)

study not powered on cognition

Intention to treat analysis n=62

PASAT 3” SDMT

p<.05 ns

Sandroff et al (2017) Contemporary Clinical Trials

Exercise and Cognition in MS

• Conclusions– No conclusive data to support effectiveness

• Exercise

• Physical activity

• Physical fitness

• Future studies– Improve methodology

– Design studies to look specifically at cognition

– Replication is required

Pharmacological Approaches

Pharmacological Approaches

• In principle, DMTs potentially improve

cognition

– approved DMTs reduce T2 & T1 brain lesions

– some reduce the progression of brain atrophy

– decrease of inflammatory activity may

contribute to better cognitive performances

• Symptomatic drugs may have specific

effects

• Review RCT’s

Pharmacological Approaches• Methodological problems in DMT RCT’s

– cognition a secondary or even a tertiary outcome

– explorative outcome often single cognitive test

– patients’ cognitive status not an entry criterion

– studies not powered on cognitive parameters

• not appropriate to detect cognitive changes

• observational studies on DMT studies

– vast majority are non-randomized

– small samples with different clinical characteristics

– heterogeneous cognitive assessment tools and outcome

measures

• Results must be viewed with caution

Interferon-beta 1a and 1b

Design Support

BetaseronPliskin et al, 1996

30 MS

placebo vs

control

NO

(1/13 NP yes).

Control problems

BetaseronSheby et al 1998

167 MS

placebo vs

control

NO

AvonexFischer et al 2000

166 MS

placebo vs

control

YES, cog

secondary

outcome

Acetylcholinesterase Inhibitors

Design Support

Physostigmine

Leo & Rao 1988

Crossover RCT

8 MS

YES

Donepezil

Greene et al 2000

17 cog impaired MS ? No placebo

control

Donepezil

Krupp et al 2004

RCT 69 MS YES

Donepezil

Krupp et al, 2011

RCT 120 MS NO

Rivastigmine

Cader et al, 2009

Single blind crossover

15 MS

NO

Rivastigmine

Shaygannejad et al 2008

RCT 60 MS NO

Design Support

Copaxone

Weinstein et al, 1999

NO

Copaxone

Schwid et al, 2007

153 RCT, 10 yr follow-up NO

L-amphetamine

Benedict et al, 2008

19 MS counterbal

within-Subjects

YES

L-amphetamine

Morrow et al, 2009

151 RCT NO primary outcome

YES secondary

outcome

L-amphetamine

Sumowski et al, 2011

136 RCT YES

Ginkgo biloba

Lovera et al, 2007

39 MS RCT NO

Amantadine

Geisler et al, 1996

45 MS parallel group NO

Other Agents and Cognition

Design Support

Memantine

Villoslada et al, 2009

19 MS RCT, crossover worsening

Memantine

Lovera et al, 2010

126 MS RCT, double blind NO, Increased fatigue &

psych symptoms

Memantine

Peyro Saint Paul, 2016

93 MS RCT NO

Tysabri (Natulizumab)

Mattioli et al, 2011

24 MS quazi-controlled

(Disease severity not matched)

YES

1 year follow-up

Other Agents and Cognition (cont)

Some uncontrolled observational studies have suggested an effect with Natulizumab

Kunkel at al, 2015

Iaffaldano et al, 2012

Pharmacology and Cognition in MS

13 7

No Support Support

Pharmacology and Cognition in MS

Support

Interferons 1 of 3

Acetylcholinesterase

Inhibitors

2 of 6

L-amphetamine 2 of 3

Other agents 2 of 8

Pharmacology and Cognition in MS

• Conclusions– No consistent data to support effectiveness

• DMT’s

• Symptomatic

• Future studies– Design studies to look specifically at cognition

– Replication is required

Overall Conclusions

• Cognitive rehabilitation shows most consistent– Future studies

• Long term effects?

• Impact on everyday life?

• Exercise shows some promise– More studies are required

• No consistent support for pharmacological interventions

What is Needed?

• Improved methodology

• Most studies with RRMS

• More Class I studies

– Active control groups

• Larger samples

• Examine impact on everyday life

• Rehab works for:

– Whom? What? How? When? Dosage? (boosters)

• Multidimensional approach to research and treatment

– Cognitive, medication, exercise

AcknowledgmentsNancy Chiaravalloti, Ph.D.

Yael Goverover, Ph.D.

Jean Lengenfelder, Ph.D.

Glenn Wylie, D.Phil

Nancy Moore, M.S.

James Sumowski, Ph.D.

Victoria Leavitt, Ph.D.

Brian Sandroff, Ph.D.

Thank You

Video Games and Cognitive Rehabilitation

– Can I tell my client to use “brain games” or

“video games” for cognitive rehabilitation?

“A Consensus on the Brain Training Industry… “, accessed (April 29, 2015), http://longevity3.stanford.edu/blog/2014/10/15/the-consensus-on-the-brain-training-industry-from-the-scientific-community/

“We object to the claim that brain games offer consumers a scientifically grounded avenue to reduce or reverse cognitive decline when there is no compelling scientific evidence to date that they do.”

75 Leading Cognitive Psychologists & Cognitive Neuroscientists Representing 48 Universities

Lumosity to Pay $2 Million to Settle FTC Deceptive

Advertising Charges for Its “Brain Training” Program

• “Lumosity preyed on consumers’ fears about age-related cognitive decline, suggesting their games could stave off memory loss, dementia, and even Alzheimer’s disease, But Lumosity simply did not have the science to back up its ads.”

• Lumosity claimed that training would:– 1) improve performance on everyday tasks, in school, at work,

and in athletics

– 2) delay age-related cognitive decline and protect against mild cognitive impairment, dementia, and Alzheimer’s disease

– 3) reduce cognitive impairment associated with health conditions, including stroke, traumatic brain injury, PTSD, ADHD, the side effects of chemotherapy, and Turner syndrome, and that scientific studies proved these benefits.

https://www.ftc.gov/news-events/press-releases/2016/01/lumosity-pay-2-million-settle-ftc-deceptive-advertising-charges

Federal Trade Commission Press release, 1/6/2015

Exercise, Physical Activity, Physical Fitness are Different Constructs

• Exercise, physical activity, & physical fitness often considered a single construct, when by definition, they are related, but separate

• physical fitness refers to an attained set of attributes (i.e., cardiorespiratory fitness, muscular strength, balance, body composition) that relates to the ability to perform physical activity

• Exercise: refers to planned, structured, and repetitive bodily movement done to improve or maintain one or more components of physical fitness

• physical activity refers to any bodily movement produced by skeletal muscles that results in energy expenditure

American College of Sports Medicine (ACSM), 2013