Founding Chairman S.Andrea Multiple Sclerosis Center
Sapienza University, Rome, Italy
Has served on scientific advisory boards for Novartis, Merck Serono, Biogen, Sanofi-Genzyme, Roche, Alexion, Bristol Myers, Almirall and Actelion and has received funding for travel and speaker honoraria from Novartis, Merck Serono, Biogen, Sanofi-Genzyme, Roche, Actelion, Almirall, Alexion, and receives research support from Merck Serono, Biogen Idec, Roche and Almirall.
Cognition in MS: a marker of silent progression
'At a certain stage of the disease, patients with MS may show marked enfeeblement of the memory; conceptions are formed slowly (information processing speed); the intellectual and emotional faculties are blunted in their entirety‘
(1877) lectures on the diseases of the nervous system, London
Cognition in MS: a marker of silent progression
• Two components of disability accumulation: either relapseassociated worsening (RAW) or progression independent of relapse activity (PIRA)
• Underlying progression is present from MS inception in all patients to varying degrees
Cognition in MS: a marker of silent progression
100 Patients (%)
RRMS (N = 50) SPMS (N = 30) 20
60
40
80 0
Impairment of cognitive domains in patients with RRMS and SPMS1 Patients in an outpatient clinic in Greece evaluated with a computerised battery of tests 83% 63% 77% 67% 67% 53% Reaction time Trail making test A* Trail making test B* Psychomotor speed Cognitive flexibility Verbal fluency semantic
1.
2.
Matias-Guiu JA et al. Front Neurol 2017
Cognition in MS: a marker of silent progression
Cognitive impairment was more common among patients with SPMS than in those with RRMS 1,2
1212 patients with MS (mean age, 41.1 years); 784 women [64.7%]
196 healthy control individuals (mean age, 40.4 years); 130 women [66.3%]
Five cognitive phenotypes were identified:
• Preserved cognition [19.4%]
• Mild-verbal memory/semantic fluency [29.9%]
• Mild-multidomain [19.5%]
• Severe-executive/attention [13.8%]
• Severe-multidomain involvement [17.5%]
De Meo E G, et al.,Jama Neurol Apr 78 (4): 1-12 ; (2021)
An Isolated Cognitive Relapse (ICR) leads to poorer long-term cognitive test scores compared with no ICR1
Baseline Relapse 6 months…
Baseline Relapse 6 months…
Change from baseline in the difference between relapsing patients and stable patients in raw SDMT score.
In each study, the relapsing group recovers after the relapse time point, to varying degrees, seldom returning to a difference score of 0.
ICRI , isolated cognitive relapse; MSNQ, Multiple Sclerosis Neuropsychological Questionnaire; SDMT, Symbol Digit Modalities Test
1. Pardini M, et al. J Neurol Neurosurg Psychiatry 2014;85:1035-1037;
2. Benedict RHb, et al. Mult Scler 2021; 27:71-78
Cognition in MS: a marker of silent progression
What are the underlying pathological mechanisms?
Chronic/trapped inflammation
• Meningeal inflammatory aggregates
• Slow expansion of pre-existing lesions
• Subpial cortical demyelination
• Diffuse white matter injury
MS disease progression
Loss of functional reserve
• Higher educational attainment moderates the effect of T2 lesion load and third ventricle width on cognition in MS, suggesting increased cognitive reserve provides protection
• Actively enhancing cognitive reserve might reduce or prevent cognitive problems in MS in parallel to disease modifying drugs
Pinter D, et al. PLoS One 2014;9:e87567
Cognition in MS: a marker of silent progression
Each MS lesion may have an impact on cognition through various mechanisms including:
• Chronic inflammation
• Disruption of the neuronal/axonal compartments
• Oxidative stress
• Alterations in the cerebral metabolism
Changes in Cortico-Cortical and Cortico-Subcortical connectivity
Cognition in MS: a marker of silent progression
Unraveling the substrates of cognitive impairment in multiple sclerosis: A multiparametric structural and functional magnetic resonance imaging study
by using random forest analysis evaluating regional white matter (WM) lesions, WM fractional anisotropy (FA) abnormalities, gray matter (GM) atrophy and RS functional connectivity (FC)
(a) r. superior longitudinal fasciculus (100%),
(b) l.anterior thalamic radiation (93.4%),
(c) l.posterior corona radiata (78.5%),
d) l.medial lemniscus (74.2%),
e) l.inferior longitudinal fasciculus (70.4%),
f) l.optic radiation (68.7%),
g)ri.middle cerebellar peduncle (60.6%)
h) r.optic radiation (53.5%);
a) splenium of the corpus callosum (64.3%),
b) l. optic radiation (61.0%),
c) body of the corpus callosum (51.9%)
d) fornix (50.9%);
a) l. precuneus (91.4%),
b) r. cerebellum crus I (84.4%),
c) r. caudate nucleus (78.6%),
d) l.thalamus (76.2%)
e) l.supplementary motor area (59.8%).
damage in strategic WM and GM regions explains cognitive impairment in MS
Cognition in MS: a marker of silent progression
Eijlers AJ, et al. Brain 2018;141:2605-2618
Patients with cognitive Impairment (CI) showed a reduction in structural connettivity suggesting the presence of a network collapse or its inability to compensate for such impairment.
It is thought that CI in MS may be the result of a “disconnection syndrome “. MS pathology mainly interrupts structural pathaways connecying remote brain regions playing an important role for global cognition
Red Color shows the most represenative resting state networks:
Zhang J. Et al. Structural and Functional connectivity substrate of cognitive impairment in Multiple Sclerosis. Front Neurol Review July 2021
A) Visual Network / B) Deafault mode network / C) Cerebellum network
D) sensorimotor network / E) Auditory network / F) Executive control network
G) right frontotemporal network / H) left frontotemporal network
Hypometabolism of thalamic and deep cortical gray structures of the temporal lobe is associated with episodic memory dysfunction in MS.
On the other hand, pathological performance on tests designed to assess frontal functions was associated with widespread reduction of glucose metabolism.
Cognition in MS: a marker of silent progression
Longitudinal prospective study correlating baseline cognitive impairment with progression of disability in 45 relapsing-remitting MS (RRMS) patients over a period of 7 years
Multivariate linear regressions showed significant correlations between :
― the change in the EDSS over 5 years and baseline SDMT (r2=0.19, p=0.032)
the change in the EDSS over 7 years and baseline CLTR score (r2=0.17, p=0.05)
Early cognitive impairment may predict disability outcome after several years
EDSS progression over 7 years is explained by the baseline CLTR
Cut-off value : 29
CLTR, consistent long-term retrieval; EDSS, expanded disability status score; MS, multiple sclerosis; RRMS, relapsing remitting multiple sclerosis; SDMT, symbol digits modalities test Deloire M et al. Multiple Sclerosis 2010;16:581–587. Figure adapted with permission from Multiple Sclerosis
Cognition in MS: a marker of silent progression
Early cognitive impairment in multiple sclerosis could predict disability outcome several years later
• Cognitive impairment occurs early in patients with RMS1
– Reliable identification depends on assessment tools used
• The PASAT assesses several cognitive domains, including processing speed, working memory, calculation ability, divided attention, and mental flexibility1,2
• The SDMT assesses processing speed and working memory and is more sensitive and reliable than the PASAT3,4
Cognition in MS: a marker of silent progression
Advantages1
• Very high sensitivity
• Reliable
• Time efficient and easy
• Well tolerated
• Uniform across languages
• Lack of floor and ceiling effects
• Multiple alternate forms
Disadvantage1
• Other functions affected by MS may contribute to performance
Advantage1
• Large amount of data available
Disadvantages1
• Less sensitive than SDMT
• Practice effects
• Ceiling effect
• Poorly tolerated
• Limited by anxiety and math ability
SDMT, Symbol Digit Modalities Test 1. Sumowski JF, et al. Neurology. 2018;90:278-288
Cognition in MS: a marker of silent progression
Baseline cognitive screening
Symbol Digit Modalities Test (SDMT)2 or other validated screening tool as a minimum, is recommended as an integral component of disease monitoring
Annual re-assessment with the same instrument, or more often as needed, is recommended for all adults and children 8 years or older with MS
○ For all adults and children > 8 years with MS
○ For adults who have experienced a first clinical event or have evidence on MRI of asymptomatic white matter lesions that are consistent with MS (RIS), or evidence of early gray matter damage
○ For any patient who reports changes in cognitive functioning
Depression screening to identify mood changes that may be impacting cognition as well as routine monitoring is recommended at least yearly 1,6
CSCT, Computerised cognitive test; MRI, magnetic resonance imaging; MS, multiple sclerosis; mSMT, modified story memory technique; MSNQ, Multiple Sclerosis
Neuropsychological Screening Questionnaire; PS, processing speed; PST, processing speed test; RIS, radiologically isolated syndrome; SDMT, Symbol Digit Modalities Test
1. Kalb R et al. Mult Scler.2018;24:1665–1680. 2. Benedict RH et al. Mult Scler.2017;23:721–733. 3. Ruet A et al. Mult Scler.2013;19:1665–1672; 4. Rao SM et al. Mult Scler 2017; 23:1929–1937. 5. Benedict RH et al. Mult Scler 2004;10: 675
–678. 6. Honarmand K, Feinstein A. Mult Scler.2009;15:1518–1524.
Cognitive impairment predicts limitations in the workplace and in social settings independent of level of physical disability 1
Cognition in MS: a marker of silent progression
Domains of disease activity
MSDM points
Interpretation of MSDM total score
Integrated interpretation
All domains green
No change in therapy, Re-evaluate in 6 months
Relapse
Progression of disability (modified MSFC)
T25FW, 9HPT, LCSLC (panel with 1.25% contrast)
Each test with worsening by 20%
Each test with worsening by 40%
≥2 points = red
1 domain yellow Re-evaluate in ≤3 months
≥2 domains yellow or
≥1 domain red
Consider optimisation/change of therapy
SDMT
Worsening by ≥4 points
Worsening by ≥8 points
Neuropsychology
MRI
• Multiple Sclerosis Decision Model (MSDM), incorporates cognitive status, fatigue, depression and quality of life with standard metrics of relapse rate, disability progression and MRI.
• Treatment optimisation is re-evaluated for deterioration in two functional tests or severe deterioration in one test
9HPT, 9-Hole Peg Test; LCSLC, Low-Contrast Sloan Letter Chart; MRI, magnetic resonance imaging; MSFC, Multiple Sclerosis Functional Composite; SDMT, Symbol Digit Modalities Test; T25FW, Timed 25-Foot WalkStangel M et al. Ther Adv Neurol Disord. 2015;8:3-13.
Cognition in MS: a marker of silent progression
Improving cognitive performance?
Heterogeneity in training response
Campbell et al., 2016
Goverover et al., 2018
Cognition in MS: a marker of silent progression
Included with permission from Penner I-K et al. Presentation at the 6th Congress of the European Academy of Neurology; 23–26 May 2020; Virtual Presentation. EPR3080
Cognition in MS: a marker of silent progression
Overall
• Meta-analysis of 44 studies, including 55 distinct MS patient samples and 7131 patients
• Small-to-moderate positive effect on cognitive test performance of DMTs – g = 0.27, 95% CI = 0.21–0.33
• DMTs are effective in improving cognitive test performance in RRMS
CI, confidence interval; DMT, disease-modifying therapy; MS, multiple sclerosis; RRMS, relapsing-remitting MS.Landmeyer NC et al. Neurology. 2020;94:e2373–e2383
are effective in
• Patients received SC IFN β-1b 250μg or placebo QOD, for 2 years or until a diagnosis of CDMS (BENEFIT Study)
• Cognitive improvements were more pronounced in early treatment versus delayed treatment
BL, baseline; CDMS, clinically definite multiple sclerosis; IFN β-1b, interferon beta-1b; PASAT, Paced Auditory Serial Addition Test; QOD, every other day; SC, subcutaneous Penner IK et al. Mult Scler. 2012;18:1466–1471
Cognition in MS: a marker of silent progression
• Cognitive impairment is a common marker of disease progression
• Structural damage in strategic WM and GM regions explains cognitive impairment
• The importance of screening and monitoring cognitive performance
• Strategy training and disease modified treatment should be beneficial if started early
Cognition in MS: a marker of silent progression
Full Professor of Neurology
Founding Chairman S.Andrea Multiple Sclerosis Center
Sapienza University, Rome, Italy
