Cognitive Issues in Pediatric Multiple Sclerosis

Multiple sclerosis (MS) is one of the leading causes of disability in young adults. The onset of MS during developmental age makes pediatric patients particularly susceptible to cognitive impairment, resulting from both disease-related damage and failure of age-expected brain growth. Despite different test batteries and definitions, cognitive impairment has been consistently reported in approximately one-third of pediatric patients with MS. However, the lack of a uniform definition of cognitive impairment and the adoption of different test batteries have led to divergent results in terms of cognitive domains more frequently affected across the cohorts explored. This heterogeneity has hampered large international collaborative studies. Moreover, research aimed at the identification of risk factors (e.g., demographic, clinical, and radiological features) or protective factors (e.g., cognitive reserve, leisure activities) for cognitive decline is still scanty. Mood disorders, such as depression and anxiety, can be detected in these patients alongside cognitive decline or in isolation, and can negatively affect quality of life scores as well as academic performances. By using MRI, cognitive impairment was attributed to damage to specific brain compartments as well as to abnormal network activation patterns. However, multimodal MRI studies are still needed in order to assess the contribution of each MRI metric to cognitive impairment. Importantly, longitudinal studies have recently demonstrated failure of age-expected brain growth and of white matter (WM) and gray matter (GM) maturation plays a relevant role in determining cognitive dysfunction, in addition to MS-related direct damage. Whether these growth retardations might result in specific cognitive profiles according to the age at disease onset has not been studied, yet. A better characterization of cognitive profiles in pediatric MS patients, as well as the definition of neuroanatomical substrates of cognitive impairment and their longitudinal evolution are needed to develop efficient therapeutic strategies against cognitive impairment in this patient population.

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Cognitive Profile and Its Evolution in a Cohort of Multiple System Atrophy Patients

Frontiers in Neurology ◽

10.3389/fneur.2020.537360 ◽

2020 ◽

Vol 11 ◽

Author(s):

Luisa Sambati ◽

Giovanna Calandra-Buonaura ◽

Giulia Giannini ◽

Ilaria Cani ◽

Federica Provini ◽

...

Keyword(s):

Cognitive Impairment ◽

Multiple System Atrophy ◽

Cognitive Decline ◽

Sleep Disturbances ◽

Disease Onset ◽

Cognitive Profile ◽

Cognitive Domain ◽

Neuropsychological Evaluation ◽

Cognitive Profiles ◽

Executive Deficits

Introduction: Cognitive decline is not a characteristic feature of multiple system atrophy (MSA), but recent evidence suggests cognitive impairment as an integral part of the disease. We aim to describe the cognitive profile and its progression in a cohort of patients with MSA.Methods: We retrospectively selected patients referred to our department with a clinical diagnosis of MSA who were evaluated at least once a year during the course of the disease and underwent a comprehensive neuropsychological evaluation.Results: At the first evaluation (T0), 37 out of 60 patients (62%) were cognitively impaired, mainly (76%) in attention and executive functioning. Thirteen patients were impaired in one cognitive domain and 24 in more than one cognitive domain. Six out of the 24 had dementia. Twenty patients underwent a follow-up evaluation (T1) after a mean of 16.6 ± 9.3 months from the first evaluation (T0). Eight out of 20 patients were cognitively normal at both T0 and T1. Seven out of 12 patients presented with stable cognitive impairment at T1, while cognitive decline progressed in five patients. Patients with progression in cognitive decline performed significantly worse at T0 than cognitively stable patients. Education was significantly different between patients with and without cognitive impairment. No other differences in demographic and clinical variables and autonomic or sleep disturbances were found. Patients with dementia were older at disease onset and at T0 and had lower education and disease duration at T0 compared to those in other groups.Conclusions: In patients with MSA, we observed three different cognitive profiles: normal cognition, stable selective attention-executive deficits, and progressive cognitive deficits evolving to dementia. The detection of cognitive impairment in patients with suspected MSA suggests the need for comprehensive and longitudinal neuropsychological evaluation.

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Childhood multiple sclerosis is associated with reduced brain volumes at disease onset and brain growth failure

10.26226/morressier.59a3ed9fd462b8028d8941e6 ◽

2017 ◽

Author(s):

Frederik Bartels

Keyword(s):

Multiple Sclerosis ◽

Disease Onset ◽

Growth Failure ◽

Brain Growth ◽

Brain Volumes

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Selecting the most important self-assessed features for predicting conversion to mild cognitive impairment with random forest and permutation-based methods

Scientific Reports ◽

10.1038/s41598-020-77296-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jaime Gómez-Ramírez ◽

Marina Ávila-Villanueva ◽

Miguel Ángel Fernández-Blázquez

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Random Forest ◽

Cognitive Decline ◽

Social Life ◽

Healthy Aging ◽

Personal Information ◽

Disease Onset ◽

Subjective Cognitive Decline ◽

Comorbid Condition

AbstractAlzheimer’s Disease is a complex, multifactorial, and comorbid condition. The asymptomatic behavior in the early stages makes the identification of the disease onset particularly challenging. Mild cognitive impairment (MCI) is an intermediary stage between the expected decline of normal aging and the pathological decline associated with dementia. The identification of risk factors for MCI is thus sorely needed. Self-reported personal information such as age, education, income level, sleep, diet, physical exercise, etc. is called to play a key role not only in the early identification of MCI but also in the design of personalized interventions and the promotion of patients empowerment. In this study, we leverage a large longitudinal study on healthy aging in Spain, to identify the most important self-reported features for future conversion to MCI. Using machine learning (random forest) and permutation-based methods we select the set of most important self-reported variables for MCI conversion which includes among others, subjective cognitive decline, educational level, working experience, social life, and diet. Subjective cognitive decline stands as the most important feature for future conversion to MCI across different feature selection techniques.

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Associations between cognitive impairment at onset and disability accrual in young people with multiple sclerosis

Scientific Reports ◽

10.1038/s41598-019-54153-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Antonio Carotenuto ◽

◽

Marcello Moccia ◽

Teresa Costabile ◽

Elisabetta Signoriello ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Young People ◽

Clinical Outcomes ◽

Cognitive Abilities ◽

Early Onset ◽

Visual Memory ◽

Cox Regression ◽

Disease Onset

AbstractDifferently from the adult multiple sclerosis (MS) population, the predictive value of cognitive impairment in early-onset MS is still unknown. We aim to evaluate whether cognitive performances at disease onset predict disease progression in young people with MS. This is a retrospective study on early onset (<25 years) MS patients, who had a baseline cognitive evaluation at disease onset. Demographic and longitudinal clinical data were collected up to 7 years follow up. Cognitive abilities were assessed at baseline through the Brief Repeatable Battery. Associations between cognitive abilities and clinical outcomes (occurrence of a relapse, and 1-point EDSS progression) were evaluated with stepwise logistic and Cox regression models. We included 51 patients (26 females), with a mean age at MS onset of 17.2 ± 3.9 years, and an EDSS of 2.5 (1.0–6.0). Over the follow-up, twenty-five patients had at least one relapse, and 7 patients had 1-point EDSS progression. Relapse occurrence was associated with lower 10/36 SPART scores (HR = 0.92; p = 0.002) and higher WLG scores (HR = 1.05; p = 0.01). EDSS progression was associated with lower SDMT score (OR: 0.70; p = 0.04). Worse visual memory and attention/information processing were associated with relapses and with increased motor disability after up to 7-years follow-up. Therefor, specific cognitive subdomains might better predict clinical outcomes than the overall cognitive impairment in early-onset MS.

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A systematic review of resting state functional MRI connectivity changes and cognitive impairment in multiple sclerosis

10.1101/2021.03.18.21253878 ◽

2021 ◽

Author(s):

Danka Jandric ◽

Anisha Doshi ◽

Richelle Scott ◽

David Paling ◽

David Rog ◽

...

Keyword(s):

Multiple Sclerosis ◽

Systematic Review ◽

Cognitive Impairment ◽

Functional Mri ◽

Resting State ◽

Narrative Synthesis ◽

Clear Link ◽

Study Methodology ◽

Definition Of ◽

Substantial Heterogeneity

Cognitive impairment is common in multiple sclerosis (MS) and resting state functional MRI (rs-fMRI) functional connectivity (FC) is increasingly used to study its pathophysiology. However, results remain difficult to interpret, showing both high and low FC associated with cognitive impairment. We conducted a systematic review of rs-fMRI studies in MS to understand whether the direction of FC change relates to cognitive dysfunction, and how this may be influenced by the choice of methodology. Embase, Medline and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS. Fifty-seven studies were included in a narrative synthesis. Of these, 50 found an association between cognitive impairment and FC abnormalities. Worse cognition was linked to high FC in 18 studies, and to low FC in 17 studies. Nine studies found patterns of both high and low FC related to poor cognitive performance, in different regions or for different MR metrics. There was no clear link to increased FC during early stages of MS and reduced FC in later stages, as predicted by common models of MS pathology. Throughout, we found substantial heterogeneity in study methodology, and carefully consider how this may impact on the observed findings. These results indicate an urgent need for greater standardisation in the field, in the choice of MRI analysis and the definition of cognitive impairment. Through this we will be closer to using rsfMRI FC as a biomarker in clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS.

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Variable course of Unverricht-Lundborg disease

Neurology ◽

10.1212/wnl.0000000000004518 ◽

2017 ◽

Vol 89 (16) ◽

pp. 1691-1697 ◽

Cited By ~ 8

Author(s):

Laura Canafoglia ◽

Edoardo Ferlazzo ◽

Roberto Michelucci ◽

Pasquale Striano ◽

Adriana Magaudda ◽

...

Keyword(s):

Risk Factors ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Time Course ◽

Proportional Hazards ◽

Cell Damage ◽

Age At Onset ◽

Disease Onset ◽

Rank Test ◽

Genetically Determined

Objective:To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset.Methods:We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model.Results:Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline.Conclusions:A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.

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Selecting the most important self-assessed features for predicting conversion to Mild Cognitive Impairment with Random Forest and Permutation-based methods

10.1101/785519 ◽

2019 ◽

Cited By ~ 4

Author(s):

Jaime Gómez-Ramírez ◽

Marina Ávila-Villanueva ◽

Miguel Ángel Fernández-Blázquez

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Random Forest ◽

Cognitive Decline ◽

Social Life ◽

Healthy Aging ◽

Personal Information ◽

Disease Onset ◽

Subjective Cognitive Decline ◽

Comorbid Condition

ABSTRACTAlzheimer’s Disease (AD) is a complex, multifactorial and comorbid condition. The asymptomatic behavior in the early stages makes the identification of the disease onset particularly challenging. Mild cognitive impairment (MCI) is an intermediary stage between the expected decline of normal aging and the pathological decline associated with dementia. The identification of risk factors for MCI is thus sorely needed. Self-reported personal information such as age, education, income level, sleep, diet, physical exercise, etc. are called to play a key role not only in the early identification of MCI but also in the design of personalized interventions and the promotion of patients empowerment. In this study we leverage on The Vallecas Project, a large longitudinal study on healthy aging in Spain, to identify the most important self-reported features for future conversion to MCI. Using machine learning (random forest) and permutation-based methods we select the set of most important self-reported variables for MCI conversion which includes among others, subjective cognitive decline, educational level, working experience, social life, and diet. Subjective cognitive decline stands as the most important feature for future conversion to MCI across different feature selection techniques.

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Age of Onset as a Moderator of Cognitive Decline in Pediatric-Onset Multiple Sclerosis

Journal of the International Neuropsychological Society ◽

10.1017/s1355617714000642 ◽

2014 ◽

Vol 20 (8) ◽

pp. 796-804 ◽

Cited By ~ 21

Author(s):

Banafsheh Hosseini ◽

David B. Flora ◽

Brenda L. Banwell ◽

Christine Till

Keyword(s):

Multiple Sclerosis ◽

Cognitive Decline ◽

Social Status ◽

Cognitive Reserve ◽

Disease Onset ◽

Rate Of Change ◽

Childhood And Adolescence ◽

Younger Age ◽

Pediatric Onset ◽

Cognitive Maturation

AbstractCognitive impairment is often reported in pediatric-onset multiple sclerosis (MS). Using serial cognitive data from 35 individuals with pediatric-onset MS, this study examined how age at disease-onset and proxies of cognitive reserve may impact cognitive maturation over the course of childhood and adolescence. Neuropsychological evaluations were conducted at baseline and up to four more assessments. Of the 35 participants, 7 completed only one assessment, 5 completed two assessments, 13 completed three assessments, 10 completed four or more assessments. Growth curve modeling was used to assess longitudinal trajectories on the Trail Making Test-Part B (TMT-B) and the Symbol Digit Modalities (SDMT; oral version) and to examine how age at disease onset, baseline Full Scale IQ, and social status may moderate rate of change on these measures. Mean number of evaluations completed per patient was 2.8. Younger age at disease onset was associated with a greater likelihood of cognitive decline on both the TMT-B (p=.001) and SDMT (p=.005). Baseline IQ and parental social status did not moderate any of the cognitive trajectories. Findings suggest that younger age at disease-onset increases the vulnerability for disrupted performance on measures of information processing, visual scanning, perceptual/motor speed, and working memory. Proxies of cognitive reserve did not protect against the progression of decline on these measures. Young patients with MS should be advised to seek follow-up cognitive evaluation to assess cognitive maturation and to screen for the potential late emergence of cognitive deficits. (JINS, 2014, 20, 1–9)

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Predict cognitive decline with clinical markers in Parkinson’s disease (PRECODE-1)

Journal of Neural Transmission ◽

10.1007/s00702-019-02125-6 ◽

2019 ◽

Vol 127 (1) ◽

pp. 51-59

Author(s):

Heather Wilson ◽

Gennaro Pagano ◽

Tayyabah Yousaf ◽

Sotirios Polychronis ◽

Rosa De Micco ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Disease Onset ◽

Semantic Fluency ◽

Drug Naïve ◽

Level 1 ◽

Level 2

AbstractOver the course of the disease, about 80% of Parkinson’s disease patients will develop cognitive impairment. However, predictive factors associated with cognitive decline are still under investigation. Here, we investigated which clinically available markers are predictive of cognitive impairment in a cohort of early drug-naïve Parkinson’s disease patients. 294 drug-naïve Parkinson’s disease patients, who were cognitively normal at baseline, were recruited from the Parkinson’s Progression Markers Initiative. At 36-month follow-up, patients were diagnosed with cognitive impairment according to two levels: Level 1 diagnosis was defined as MoCA < 26 and Level 2 diagnosis was defined as MoCA < 26, alongside an impaired score on at least two neuropsychological tests. Predictive variables with a validated cut-off were divided into normal or abnormal measures, whilst others were divided into normal or abnormal measures based on the decile with the highest power of prediction. At 3 years’ follow-up, 122/294 Parkinson’s disease (41.5%) patients had cognitive decline. We found that age at Parkinson’s disease onset, MDS-UPDRS Part-III, Hopkin’s Learning Verbal Test-Revised Recall, Semantic Fluency Test and Symbol Digit Modalities Test were all predictors of cognitive decline. Specifically, age at Parkinson’s disease onset, Semantic Fluency Test and symbol Digit Modalities Test were predictors of cognitive decline defined by Level 2. The combination of three abnormal tests, identified as the most significant predictors of cognitive decline, gave a 63.6–86.7% risk of developing cognitive impairment defined by Level 2 and Level 1 criteria, respectively, at 36-month follow-up. Our findings show that these clinically available measures encompass the ability to identify drug-naïve Parkinson’s disease patients with the highest risk of developing cognitive impairment at the earliest stages. Therefore, by implementing this in a clinical setting, we can better monitor and manage patients who are at risk of cognitive decline.

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Cognitive reserve in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458513498834 ◽

2013 ◽

Vol 19 (9) ◽

pp. 1122-1127 ◽

Cited By ~ 90

Author(s):

James F Sumowski ◽

Victoria M Leavitt

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Disease Burden ◽

Cognitive Reserve ◽

Cerebral Atrophy ◽

White Matter Lesions ◽

Cognitive Status ◽

Vocabulary Knowledge ◽

Future Research ◽

Brain Growth

Cognitive impairment is common among persons with multiple sclerosis (MS), but some patients are able to withstand considerable disease burden (e.g. white matter lesions, cerebral atrophy) without cognitive impairment (cognitive inefficiency, memory decline). What protects these patients from cognitive impairment? We review the literature on cognitive reserve in MS, which shows that heritable (larger maximal lifetime brain growth) and environmental (greater intellectual enrichment) factors attenuate the negative effect of disease burden on cognitive status. That is, persons with larger maximal lifetime brain growth, greater vocabulary knowledge, and/or greater early life participation in cognitive leisure activities (e.g. reading, hobbies) are better able to cope with MS disease without cognitive impairment. We review evidence that benefits of intellectual enrichment on cognitive status may stem from more efficient patterns of brain function. We discuss clinical implications and highlight important unanswered questions for future research on reserve against cognitive impairment in MS.

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