MS-related Cognitive Impairment Research Articles

The Diagnostic Role of Brain MRI in Detection of Multiple Sclerosis Related Cognitive Impairment

Background: Cognitive impairment (CI) is a common manifestation of multiple sclerosis (MS), which can severely affect patients’ and their families’ life. Early suspicion and detection of CI can improve general medical management of MS patients. Objectives: To correlate MS related CI to cortical brain lesions using brain magnetic resonance imaging (MRI). Materials and Methods: Cognitive impairment was detected using mini mental state examination (MMSE); Neurological examination and brain MRI were performed for all patients. Correlation was calculated between disease cortical burden detected by MRI and CI. Results: Fifty-three patients with proven MS were scanned by brain MRI; 69.8% of them had cognitive impairment diagnosed with MMSE. The presence and severity of cognitive impairment was correlated to cortical brain lesion. Cognitive impairment was not correlated with non-cortical brain lesions or neurological physical disability measured by Expanded Disability Status Scale (EDSS). Conclusions: Presence of brain frontal cortical lesions detected by MRI in MS patients can predict subsequent development of MS-related CI.

Yakovlev's Basolateral Limbic Circuit in Multiple Sclerosis Related Cognitive Impairment.

In 1948, Paul Yakovlev described an additional limbic circuit located basolateral to James Papez's circuit (1937) and included orbitofrontal cortex, amygdala, and dorsomedial nucleus of thalamus. This circuit is shown to be an important component of subcortical cognitive abilities. We aimed to demonstrate this circuit in a multiple sclerosis (MS) cohort using diffusion tensor imaging (DTI) and evaluate its role in MS-related cognitive impairment (CI). We enrolled cognitively intact (n = 10) and impaired (n = 36) MS patients who underwent a comprehensive cognitive assessment; the minimal assessment of cognitive function in MS (MACFIMS) and structural magnetic resonance imaging. Correlation analyses between volumetric and DTI-derived values of the orbitofrontothalamic (OFT), amygdalothalamic tracts (ATTs), and dorsomedial nucleus of thalamus and CI index derived from MACFIMS were computed after adjustment for age, education, and lesion load. We observed a consistent trend between CI index and bilateral dorsomedial nucleus' mean diffusivity (MD) (r = .316; P = .02), left OFT Fractional anisotropy (FA) (r = -.302; P = .02), MD (r = .380; .006), and radial diffusivities (RDs) (r = .432; P = .002), also with right ATT FA (r = -.475; P = .0006) and left ATT FA ( = -.487; P = .0005). After Bonferroni correction, correlations of left OFT RD and right and left ATT FA with CI were found to be significant. Our study provides in vivo DTI delineation of Yakovlev's historical basolateral limbic circuit and establishes a role in MS-related CI. These findings may potentially pave the way for future clinical studies using targeted invasive and noninvasive neurostimulation modalities for CI in MS.

Timed instrumental activities of daily living in multiple sclerosis: The test of everyday cognitive ability (TECA)

ObjectiveCognitive impairment is a common symptom of multiple sclerosis (MS) that can lead to declines in daily functioning. Timed instrumental activities of daily living (TIADLs) have been useful to bridge between cognitive testing and real-world functioning in disorders such as Alzheimer's disease and other dementias. However, these have not been standardized for general use, and the tasks that are typically employed have not been sensitive to the detection of milder forms of cognitive deficits. We developed a test of ten TIADLs tasks to measure a broader range of functioning, entitled the “Test of Everyday Cognitive Ability” or TECA, and tested its utility in a diverse sample of participants with MS. MethodTECA performance was characterized in n = 177 participants with MS and compared to healthy controls (n = 49). A subset from each group received repeated administration. In addition, all participants completed a standard battery of neuropsychological measures. ResultsTECA performances were significantly different between MS and control participants. Further, MS participants with cognitive impairment performed significantly slower relative to those MS participants without impairment. ConclusionsThe TECA is a TIADLs assessment appropriate for use in those with MS as it includes a broad range of task difficulties, requires minimum motor involvement, and is sensitive to MS-related cognitive impairment. The TECA is a brief and repeatable test of TIADLs and its ease of administration makes it suitable for both clinical practice and research settings.

Quantitative Limbic System Mapping of Main Cognitive Domains in Multiple Sclerosis.

Cognitive impairment (CI) is common in multiple sclerosis (MS), but underlying mechanisms and their imaging correlates are not completely understood. The gray and white matter structures of the limbic system (LS) play crucial roles in different aspects of cognition. To investigate their role in MS related CI, and since a detailed evaluations are lacking in the literature, we used a comprehensive neuroimaging approach to evaluate CI's correlations with the main components of the LS. Ten non-cognitively impaired MS patients and 30 MS patients with diagnosed CI, who underwent a comprehensive neuropsychological evaluation were included in the analysis. Microstructural integrity, volumetry of main limbic gray and white matter structures and cortical thickness were assessed for associations with CI. Fornix and cingulum/cingulate cortices were found to be the strongest correlates of CI in MS. As expected, LS' gray and white matter structures were involved in various cognitive functions. Uncinate fasciculi showed significant correlation with verbal and visuospatial learning and memory, phonemic and semantic fluency; hippocampi with visuospatial skills, phonemic and semantic fluency, executive functions, and processing speed; thalami with verbal learning, visuospatial skills, semantic fluency; and amygdala with verbal recognition discrimination. This comprehensive neuroimaging approach elucidated the role of the main limbic structures in cognitive functions associated with MS-related CI.

Efficacy of group cognitive rehabilitation therapy in multiple sclerosis.

Cognitive impairment occurs in 40%-65% of patients with multiple sclerosis (MS). Several techniques for cognitive rehabilitation (CR) in these patients have been evaluated; however, the results have been controversial. In this study, we investigated the efficacy of group compensatory CR in patients with MS-related cognitive impairment. Thirty-four female patients with diagnosed relapsing-remitting MS and evidence of impaired cognitive function were included and randomized to intervention (n=17) and control (n=17) groups. CR intervention consisted of eight 2-hour sessions of comprehensive group CR over a 4-week period that focused on improvement of memory, attention, and executive function. As placebo, the control group received the same number of non-therapeutic group sessions. Assessment of cognitive function was performed before intervention (pretest), at the end of intervention (post-test), and 3months later (follow-up). The study population included 34 patients with a mean age of 35.5years. Statistical comparison of memory assessments at 3-month follow-up showed significantly higher scores in the CR group than in the control group (93.33 vs 86.40 for Addenbrooke's Cognitive Examination test and 16.58 vs 12.00 for visual memory, 19.32 vs 14.05 for verbal memory, and 51.28 vs 44.41 for general scores on the Memory Functioning Questionnaire test, respectively). Wisconsin card sorting test score comparison showed significantly lower total time consumption in the CR group than in the control group (308.1 vs 340.8seconds, respectively). Behavior rating inventory of executive function-adultscores in all four subtests were significantly higher in the CR group than in the control group (40.25 vs 55.4 for behavioral regulation index, 51.16 vs 68.6 for metacognition index, and 97.41 vs 124.00 for global executive composite, respectively). Attention was the only domain in which we did not observe any significant variation between groups in terms of post-test and follow-up scores. This study supports the efficacy of group CR in the improvement of cognitive function in patients with MS.

The Influence of Cognitive Impairment on the Fitness-Cognition Relationship in Multiple Sclerosis.

Cognitive processing speed impairment (PSI) is common and debilitating in persons with multiple sclerosis (MS). Exercise training has been proposed as a behavioral approach for possibly managing MS-related processing speed dysfunction, largely based on cross-sectional studies of the relationship of cardiorespiratory fitness and cognitive processing speed. However, there is minimal evidence supporting exercise training as a treatment for MS-related PSI, as the vast majority of the existing studies have examined exercise and cardiorespiratory fitness effects on cognition in samples of noncognitively impaired persons with MS. To that end, the current cross-sectional investigation examined whether cardiorespiratory fitness was differentially associated with processing speed in persons with MS with and without PSI. Sixty-four persons with MS undertook the Symbol Digit Modalities Test for establishing groups with and without MS-related PSI, a modified flanker task for measuring processing speed performance, and an incremental exercise test to exhaustion on a cycle ergometer for measuring cardiorespiratory fitness in a single testing session. Bivariate correlations were performed on cardiorespiratory fitness and processing speed outcomes in PSI group subsamples. In the sample without PSI, cardiorespiratory fitness was not significantly associated with processing speed (P = 0.08). However, in the sample with PSI, cardiorespiratory fitness was significantly associated with processing speed (P = 0.01), such that lower cardiorespiratory fitness was strongly associated with slower processing speed. This study provides preliminary evidence of a significant association between cardiorespiratory fitness and processing speed in persons with MS-related PSI. Such an investigation provides the first direct support for aerobic exercise training as a possible behavioral approach for managing/treating MS-related cognitive impairment, beyond merely improving cognitive performance.

DT MRI microstructural cortical lesion damage does not explain cognitive impairment in MS

Objective: We combined double inversion recovery (DIR) and diffusion tensor (DT) magnetic resonance imaging (MRI) to quantify the severity of cortical lesion (CL) microstructural tissue abnormalities in a large cohort of relapse-onset multiple sclerosis (MS) patients and its contribution to cognitive dysfunction. Methods: DIR, DT, dual-echo, and three-dimensional (3D) T1-weighted scans were acquired from 149 MS patients and 40 controls. Cognitively impaired (CI) patients had ⩾2 abnormal neuropsychological tests. Diffusivity values in CLs, cortex, white matter (WM) lesions, and normal-appearing (NA) WM were assessed. Predictors of cognitive impairment were identified using a random forest analysis. Results: Compared to controls, MS patients had lower normalized brain volume (NBV), gray matter volume (GMV), WM volume, lower fractional anisotropy (FA), and higher mean diffusivity in cortex and normal-appearing white matter (NAWM). A total of 44 (29.5%) patients were CI. Compared to cognitively preserved (CP), CI patients had higher T2 WM lesion volume (LV), lower NBV and GMV, and more severe diffusivity abnormalities in WM lesions, cortex, and NAWM. CL measures did not differ between CI and CP patients. Cortex FA, age, disease duration, T2 WM LV, and GMV best predicted MS-related cognitive impairment (C-statistic = 0.88). Conclusion: “Diffuse” GM and NAWM damage and WM lesions, rather than intrinsic CL damage, contribute to cognitive impairment in MS.

The Montreal Cognitive Assessment (MoCA) as a screening test for cognitive dysfunction in multiple sclerosis

ABSTRACTThis study investigates the utility of the Portuguese version of Montreal Cognitive Assessment (MoCA) as a screening-method for identifying cognitive dysfunction (CD) in multiple sclerosis (MS). The 118 participants with comprehensive neuropsychological assessment were divided into two subgroups: (I) MS group (n = 59) and (II) control group (n = 59). The MS patients were classified as cognitively intact (n = 26) or impaired (n = 33, 56%). The results indicated that the MoCA is a psychometrically valid instrument in assessment of MS patients. The Multiple Linear Regression analyses highlighted the significant influence of Modified Fatigue Impact Scale and Irregular Word Reading Test on MoCA performance. The MoCA total score showed a good discriminative capacity between cognitively impaired and cognitively intact subjects. In addition, there were significant differences in MoCA cognitive domain scores between groups. The MoCA total score cut-off point for identifying CD in MS patients was a score below 26 points (AUC = 0.837, CI = 0.736–0.937). A proposed EM-MoCA-Subscore for identifying the MS-related cognitive impairment (max. score = 19 points, cut-off <17 points, AUC = 0.871, CI = 0.784–0.958), can reduce administration time for cognitive screening in clinical settings. The MoCA is a useful and sensitive instrument to identify the MS-related cognitive impairment.

Cognitive Impairment in Multiple Sclerosis: Clinical Manifestation, Neuroimaging Correlates, and Treatment.

Cognitive impairment is found in up to 70% of patients with multiple sclerosis (MS). Once thought of as a variant of subcortical dementia with a characteristic set of deficits, we now know that MS-related cognitive impairment can have many faces. This conceptual change in neuropsychology is embedded in a paradigm shift in the neuroscientific understanding of MS over the past 25 years: Partly based on modern neuroimaging techniques, the classical view of MS as an inflammatory demyelinating disease affecting the white matter of the central nervous system has been extended. In particular, many studies have shown that the MS pathology also includes neurodegeneration, and that gray matter structures such as the cerebral cortex can also show focal lesions, atrophy, or both. The authors present an updated summary of the clinical manifestation and neuroimaging correlates of cognitive impairment in MS, and discuss the relatively few treatment options available to date.

Dose-dependent inhibition of GCPII to prevent and treat cognitive impairment in the EAE model of multiple sclerosis

There are no treatments for cognitive impairment in multiple sclerosis (MS). Novel treatments can be evaluated in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS that displays both physical and cognitive impairments. Inhibition of the neuropeptidase glutamate carboxypeptidase II (GCPII) has previously been shown to ameliorate cognitive impairment in EAE, but dosing has not yet been optimized and only a prevention treatment paradigm has been explored. In the study described herein, the dose response of the GCPII inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was evaluated for preventing cognitive impairment in EAE mice. Mice were immunized and received daily injections of vehicle or 2-PMPA (10, 30, 100, or 300mg/kg) from the time of immunization (i.e. day 0). Although no doses of the drug altered physical disease severity, the 100mg/kg dose was most efficacious at preventing cognitive impairments in Barnes maze performance. Dose-related increases in brain NAAG levels were observed in post-mortem analysis, confirming target engagement. Using the 100mg/kg dose, we subsequently evaluated 2-PMPA׳s ability to treat EAE-induced symptoms by commencing treatment after the onset of physical signs of EAE (i.e. day 14). Mice were immunized for EAE and received daily injections of vehicle or 100mg/kg 2-PMPA starting two weeks post-immunization. Significant improvements in both cognitive performance and increases in brain NAAG levels were observed. GCPII inhibition is a promising treatment for cognitive impairment in MS, and doses providing equivalent exposures to 100mg/kg 2-PMPA in mice should be evaluated in clinical studies for the prevention and/or treatment of MS-related cognitive impairment.

Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights.

Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS) that has only recent gained considerable attention. Clinical neuropsychological studies have made apparent the multifaceted nature of cognitive troubles often encountered in MS and continue to broaden our understanding of its complexity. Radiographic studies have started to decipher the neuroanatomic substrate of MS-related cognitive impairment and have shed light onto its pathogenesis. Where radiographic studies have been limited by inadequate resolution or non-specificity, pathological studies have come to the fore. This review aims to provide an overview of the nature of cognitive impairment typically seen in MS and to explore the literature on imaging and pathological studies relevant to its evolution. In particular, the relative contributions of gray (i.e., cerebral cortex, hippocampus, thalamus and basal ganglia) and white matter to MS-related cognitive impairment will be discussed and the importance of interconnectivity between structures highlighted. The pressing need for longitudinal studies combining standardized neuropsychometric, paraclinical and radiographic outcomes obtained during life with post-mortem tissue analysis after death is presented.

Association of Multiple Sclerosis Related Cognitive Impairment with an MRI Derived Composite Score

Background: MRI-derived metrics such as atrophy, burden of disease (BOD), and cortical lesions (CL) have independently been reported to be associated with Multiple Sclerosis (MS) related cognitive impairment (CI). Composite scores combining some of these individual metrics have also been shown to improve correlations with MS-related physical disability; however the value of a composite score for MS-related CI has not yet been evaluated. In this study we assessed the relationship between CI and a quantitative composite score constructed from MRIderived metrics to include total white matter lesion volume, CL number, and normalized cerebrospinal fluid (nCSF), a measure of brain atrophy. Methods: Thirty three (n=33) patients underwent neuropsychological testing and were classified into CI groups using a 4-point severity scale (0, 1, 2, 3) where zero indicates non-impaired, “1” represents borderline, “2” represents mild, and “3” represents moderate CI. Images obtained at 3T were segmented into tissue and lesion compartments from which BOD and nCSF were quantitatively measured. CL number was identified visually by consensus. BOD, nCSF, and CL number were then transformed to z-scores: zBOD, znCSF and zCL, and a composite score “Z3”was constructed from these measures. The associations between Z3 and CI and the individual transformed measures (z-scores) and CI were evaluated via ordinal logistic regression. Results: Z3 was significantly associated with CI (OR=1.443, 95% Confidence Interval: 1.048-1.987, p=0.024) with a slightly larger OR than any individual measure. Of the individual measures, only BOD had a significant association with CI (OR=1.064, 95% Confidence Interval: 1.008-1.123, p=0.025). No significant association was found between atrophy or CL and CI. Conclusion: The Z3 score is associated with increased CI severity. This association was mainly driven by BOD. Larger studies are needed to assess the potential advantage of a composite score over measures of white matter lesion burden alone.

MINI Mental MUltiple Sclerosis Examination (MINIMUS): Neuropsychological Screening for MS Patients (P04.112)

Objective: To assess the ability of a short version of the BRB to identify cognitive impairment(CI)in multiple sclerosis(MS). Background The search for a screening of CI in MS is a major undertaking. Recently it has been suggested that three tests of the Brief Repeatable Battery(BRB)can obtain good levels of sensitivity, specificity and accuracy. Design/Methods: We included all the neuropsychological assessments consecutively carried out in six Italian MS Centres. All the patients were diagnosed with MS, aged 18-65 years, and had adequate vision and hearing to undergo the tests. Cognitive performance was assessed through the BRB and the Stroop Test(ST). Failure of a test was defined on the basis of the Italian normative values. CI was defined as the failure of at least 2 tests. Bayesian statistics predicting CI patients were calculated for each test. Results: 1040 Relapsing-Remitting MS patients were included. CI was detected in 467(47%) patients. The tests with higher sensitivity in detecting CI were the Paced Auditory Serial Addition Test(PASAT-3: sensitivity=63.6%;95%CI59.0-68.1), the Symbol Digit Modalities Test (SDMT; sensitivity=57.8;95%CI53.3-62.3), the Word List Generation (WLG: sensitivity=52.4;95%CI47.5-57.3) and the Selective Reminding Test (Long Term Storage -LTS: sensitivity=37.8;95%CI33.3-42.1; Consistent Long Term Retriveal-CLTR: sensitivity=42.4;95%CI37.9-46.9). These tests were combined into four short batteries. The highest sensitivity and accuracy were obtained by the battery including the SRT-LTS, the SRT-CLTR, the PASAT-3 and the SDMT (sensitivity=94.4%; Specificity=84,7%; Accuracy=89.0%). Psychometric properties remained good also for the battery in which the WLG was included instead of the PASAT-3 (Sensitivity=88.4%; Specificity=79,1%, Accuracy=83.4%). This battery requires approximately 12 minutes for administration and no special equipment. Conclusions: In the present study we propose a brief battery based on a short version of the BRB and ST, that may represent a suitable and cost effective tool for screening of MS-related CI. Supported by: In part by Biogen Dompe. Disclosure: Dr. Amato has received personal compensation for activities with Merck Serono, Biogen Dompe, Sanofi-Aventis Pharmaceuticals, and Bayer Schering. Dr. Amato has received research support from Merck Serono, Sanofi-Aventis Pharmaceuticals, Biogen Dompe, and Bayer Schering. Dr. Goretti has nothing to disclose. Dr. Portaccio has received personal compensation for activities with Biogen Idec as an advisory board member.Dr. Portaccio has received research support from Biogen Idec, Merck Serono, Sanofi Aventis, and Bayer Schering Dr. Patti has received personal compensation for activities with Merck-Serono, Bayer Schering, and Dompe Biotec. Dr. Cilia has nothing to disclose. Dr. Gallo has nothing to disclose. Dr. Grossi has nothing to disclose. Dr. Viterbo has received personal compensation for activities with Biogen Idec and Novartis. Dr. Ghezzi has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation and Sanofi-Aventis Pharmaceuticals, Inc. as a speaker. Dr. Roscio has nothing to disclose. Dr. Mattioli has nothing to disclose. Dr. Stampatori has nothing to disclose. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc.

Intracortical lesions by 3T magnetic resonance imaging and correlation with cognitive impairment in multiple sclerosis

Background: Accurate classification of multiple sclerosis (MS) lesions in the brain cortex may be important in understanding their impact on cognitive impairment (CI). Improved accuracy in identification/classification of cortical lesions was demonstrated in a study combining two magnetic resonance imaging (MRI) sequences: double inversion recovery (DIR) and T1-weighted phase-sensitive inversion recovery (PSIR). Objective: To evaluate the role of intracortical lesions (IC) in MS-related CI and compare it with the role of mixed (MX), juxtacortical (JX), the sum of IC + MX and with total lesions as detected on DIR/PSIR images. Correlations between CI and brain atrophy, disease severity and disease duration were also sought. Methods: A total of 39 patients underwent extensive neuropsychological testing and were classified into normal and impaired groups. Images were obtained on a 3T scanner and cortical lesions were assessed blind to the cognitive status of the subjects. Results: Some 238 cortical lesions were identified (130 IC, 108 MX) in 82% of the patients; 39 JX lesions were also identified. Correlations between CI and MX lesions alone (p = 0.010) and with the sum of IC + MX lesions (p = 0.030) were found. A correlation between severity of CI and Expanded Disability Status Scale was also seen (p = 0.009). Conclusion: Cortical lesions play an important role in CI. However, our results suggest that lesions that remain contained within the cortical ribbon do not play a more important role than ones extending into the adjacent white matter; furthermore, the size of the cortical lesion, and not the tissue-specific location, may better explain their correlation with CI.

Treatment options of cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) is a progressive disease of the CNS, characterized by the production of widespread lesions in the brain and spinal cord. Inflammatory demyelination has traditionally been seen as the main disease process in MS; however, axonal damage or loss is increasingly being documented to occur early in the disease. Cognitive deficits can occur independently of physical disability, which complicates their identification and recognition. More recently, cortical demyelination has been identified among possible causes of cognitive impairment in MS. Neuropsychological studies have consistently demonstrated that 40-65% of patients with MS experience cognitive dysfunction, particularly in recent memory, information processing speed, and sustained attention. Early detection of cognitive impairment is essential to enable therapeutic intervention to alleviate symptoms or prevent further cognitive decline, although how best to manage MS-related cognitive impairment is currently unclear. Treatment strategies for cognitive impairment in MS are still in their infancy. This article will summarize several pharmacological attempts to enhance cognitive performances in people with MS.

Diffusion Tensor Imaging Abnormalities in Cognitively Impaired Multiple Sclerosis Patients

Cognitive impairment can add to the burden of disease in patients with multiple sclerosis (MS). The aim of this study was to assess the relative importance of diffusion tensor imaging (DTI) indices derived from normal appearing white matter (NAWM) and grey matter (NAGM) in determining cognitive dysfunction in MS patients. Sixty two MS patients [51 female, mean age = 41 (sd = 9.6) years, median expanded disability status scale (EDSS) = 2.5] meeting modified McDonald criteria for MS underwent neuropsychological testing using the Neuropsychological Screening Battery for MS (NSBMS) and magnetic resonance imaging (MRI, 1.5T GE) that included DTI sequences. Total T1 hypointense and T2 hyperintense lesion volumes were obtained using semi-automated software. Lesion volumes were subtracted from whole-brain parenchyma to obtain measures of NAWM and NAGM. Fractional anisotropy (FA) of NAWM and mean diffusivity (MD) of NAGM were obtained. Cognitive impairment was present in 11 patients (18%). These patients had higher EDSS scores, were less educated, and were more likely to have secondary progressive MS. They also had higher hypointense (p = 0.001) and hyperintense (p = 0.004) lesion volumes, greater NAWM atrophy (p = 0.007), lower FA of total NAWM (p = 0.003), and higher MD of total NAGM (p = 0.015). Using a logistic regression analysis, and after controlling for demographic and disease-related differences between groups, FA of NAWM emerged as a significant predictor of cognitive impairment adding to the variance derived from lesion and atrophy data. This study underlies the important role of normal-appearing brain tissue in the pathogenesis of MS-related cognitive impairment.

Multiple Sclerosis With Predominant, Severe Cognitive Impairment

To describe the characteristics of multiple sclerosis (MS) presenting with severe cognitive impairment as its primary disabling manifestation. Retrospective case series. Tertiary referral center. Patients Patients were identified through the Mayo Clinic data retrieval system (1996-2008) with definite MS (McDonald criteria) and severe cognitive impairment as their primary neurological symptom without accompanying significant MS-related impairment or alternative diagnosis for cognitive dysfunction. Twenty-three patients meeting inclusion criteria were compared regarding demographics, clinical course, and radiological features. Demographic, clinical, and radiological characteristics of the disease. Twelve patients were men. The median age of the first clinical symptom suggestive of central nervous system demyelination was 33 years, and severe MS-related cognitive impairment developed at a median age of 39 years. Cognitive impairment could be dichotomized as subacute fulminant (n = 9) or chronic progressive (n = 14) in presentation, which corresponded to subsequent relapsing or progressive MS courses. Study patients commonly exhibited psychiatric (65%), mild cerebellar (57%), and cortical symptoms and signs (eg, seizure, aphasia, apraxia) (39%). Fourteen of 21 (67%), where documented, smoked cigarettes. Brain magnetic resonance imaging demonstrated diffuse cerebral atrophy in 16 and gadolinium-enhancing lesions in 11. Asymptomatic spinal cord magnetic resonance imaging lesions were present in 12 of 16 patients (75%). Immunomodulatory therapies were generally ineffective in improving these patients. We describe patients with MS whose clinical phenotype is characterized by severe cognitive dysfunction and prominent cortical and psychiatric signs presenting as a subacute fulminant or chronic progressive clinical course. Cigarette smokers may be overrepresented in this phenotype.

Les troubles cognitifs

Cognitive impairment is common in multiple sclerosis (MS), occurring at all stages of the disease, even at the earliest, and can be a major source of disability, social impairment, and impoverished quality of life. Cognitive dysfunction is mainly focused on working memory, conceptual reasoning, verbal fluency, speed of information processing, attention and executive function. Measures of information-processing speed appear to be the most robust and sensitive markers of cognitive impairment in MS patients. Cognitive testing in MS patients is complex and cognitive screening tests are time- and cost-saving test instruments. A comprehensive and sensitive cognitive test procedure should be administered to detect cognitive dysfunction, and recent studies demonstrate that single, predominantly speed-related cognitive tests may be superior to extensive and time-consuming test batteries in screening cognitive decline. Additional clinical factors, including disease course, fatigue, and affective disturbance, can impact the degree of MS-related cognitive impairment. Despite weak correlation with disease duration and physical disability status, the degree of cognitive impairment in MS has been related to the extent of topographically specific neuronal tissue damage and loss. Numerous studies have applied conventional and quantitative magnetic resonance imaging (MRI) techniques to correlate the profile and degree of cognitive impairment with various MRI-detectable abnormalities. The burden of MRI-visible lesions does not fully account for the degree of MS-related cognitive impairment. Nonconventional MRI findings suggest the extent of subtle tissue damage in normal-appearing white and grey matter to correlate best with the severity of cognitive impairment in MS patients. Structural MRI approaches have recently been extended by functional MRI studies scrutinizing the brain's ability for adaptive functional reorganization in the presence of widespread tissue damage. Cognitive impairment in MS seems to be not simply the result of tissue destruction, but also a balance between tissue destruction, tissue repair, and adaptive functional reorganization. These findings highlight the need to screen for cognitive deficits in MS patients to conduct potential cognitive rehabilitation intervention.

PASAT in Detecting Cognitive Impairment in Relapsing-Remitting MS

The PASAT, as a part of the Multiple Sclerosis Functional Composite, is used as a sole measure of cognition in multiple sclerosis (MS) clinical trials. In the present study, we evaluated the frequency and characteristics of cognitive impairment among relapsing-remitting MS patients. Using a comprehensive neuropsychological examination as the “golden standard,” we assessed PASAT's sensitivity and specificity in MS-related cognitive impairment as well as factors possibly confounding PASAT performance. Forty-five relapsing-remitting MS patients and 48 healthy controls were studied using PASAT and a comprehensive neuropsychological examination. The frequency of cognitive dysfunction among MS patients was 42%. Cognitive impairment in MS was heterogeneous in nature but characterized, especially, by reduced information-processing ability and memory deficits. PASAT's sensitivity for patients' cognitive impairment was 74% and specificity 65%. Misclassification of cognitive impairment seemed to be associated with self-reported nervousness and poor arithmetic skills. Although PASAT offers satisfactory sensitivity in detecting the presence of cognitive impairment, its specificity may be limited by confounding factors.

Utilization of the auditory consonant trigram test to screen for cognitive impairment in patients with multiple sclerosis: comparison with the paced auditory serial addition test

Several screening methods have been evaluated, but most of them are insensitive to MS-related cognitive impairment. The Auditory Consonant Trigram (ACT) test, which contains core features required for a working memory task, has been used to test neuro-cognitive function in different samples of patients to examine the status of working memory. The aim of the present study was to investigate the correlation between ACT and the Paced Auditory Serial Addition Test (PASAT), and the usefulness of ACT for evaluating the cognitive impairment in MS in a brief visit A total of 109 consecutive patients with definite MS were included. The patients were administered ACT, PASAT and EDSS. Mean PASAT score and mean ACT score were 46.19 +/- 8.51 and 45.30 +/- 9.07, respectively. Correlations between EDSS and PASAT, and EDSS and ACT were moderately strong. The correlation between ACT and PASAT was very strong (r = 0.831, P < 0.01). The mean time required to perform ACT was significantly shorter than PASAT (7.25 +/- 4.72 and 14.70 +/- 6.97 minutes, respectively). In conclusion, as a relatively brief measure of working memory, ACT was well accepted by MS patients and has a strong correlation with PASAT. Thus, ACT might be used for rapid evaluation of cognitive impairment in patients with multiple sclerosis.