Cognitive Impairment In Multiple Sclerosis Research Articles

Treatment of Cognitive Impairment in Multiple Sclerosis

Cognitive impairment in multiple sclerosis is an increasingly recognized entity. This article reviews the cognitive impairment of multiple sclerosis, its prevalence, its relationship to different types of multiple sclerosis, and its contribution to long-term functional prognosis. The discussion also focuses on the key elements of cognitive dysfunction in multiple sclerosis which distinguish it from other forms of cognitive impairment. Therapeutic interventions potentially effective for the cognitive impairment of multiple sclerosis are reviewed including the effects of disease modifying therapies and the use of physical and cognitive interventions.

Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis

Cognitive dysfunction (affecting particularly attention and working memory) occurs early in patients with multiple sclerosis. Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new brain regions that could limit expression of these deficits. However, lesion studies remind us that functional specializations in the brain make certain brain regions necessary for a given task. We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with multiple sclerosis pathology. We used a version of the n-back task to probe working memory in patients with early multiple sclerosis. We applied a functional connectivity analysis to test whether relationships between relative activations in different brain regions change in potentially adaptive ways with multiple sclerosis. We studied 21 patients with relapsing-remitting multiple sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI. The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls. However, patients showed relatively reduced activation in the superior frontal and anterior cingulate gyri (P > 0.01). Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific brain region assessed (P < 0.001). Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns. Control subjects showed significantly greater correlations between right dorsolateral prefrontal and superior frontal/anterior cingulate activations (P < 0.05). Patients showed correlations between activations in the right and left prefrontal cortices, although this relationship was not significant in healthy controls (P < 0.05). We interpret these results as showing that, while cognitive processing in the task appears to be performed using similar brain regions in patients and controls, the patients have reduced functional reserve for cognition relevant to memory. Functional connectivity analysis suggests that altered inter-hemispheric interactions between dorsal and lateral prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. Together, these results suggest that therapeutic enhancement of the coherence of interactions between brain regions normally recruited (functional enhancement), as well as recruitment of alternative areas or use of complementary cognitive strategies (both forms of adaptive functional change), may limit expression of cognitive impairments in multiple sclerosis.

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Modality-specific aspects of sustained and divided attentional performance in multiple sclerosis

While the prevalence of cognitive impairment in multiple sclerosis is well documented, few studies have systematically investigated the profile of attentional abilities. In the current study, 30 MS participants were assessed on measures of sustained and divided attention and compared to a sample of 30 neurologically intact healthy controls. Performance on visual and auditory unimodal and bimodal trials were conducted for measures of both forms of attention. A three-factor mixed measures analysis of variance (group × task × modality) was conducted. MS participants were impaired relative to controls on all measures of speed and accuracy across unimodal and bimodal trials and more impaired on measures of divided attention than on sustained attention measures. Performance on the bimodal trials was also significantly compromised relative to the unimodal trials especially on the divided attention task. The theoretical and clinical implications of these findings are discussed.

Subjective cognitive complaints relate to mild impairment of cognition in multiple sclerosis

Cognitive impairment is common in multiple sclerosis (MS), but cannot be reliably predicted by physical impairment. The negative impact of cognitive impairment makes early detection important, but subjective cognitive complaints may be attributed to depression. We examined the relationship between subjectively reported and objectively measured cognitive impairment in MS, adjusting for mood. A neuropsychological battery, the Multiple Sclerosis Functional Composite (MSFC), the Mental Health Inventory (MHI), the Modified Fatigue Impact Scale (MFIS), the Perceived Deficits Questionnaire (PDQ) were administered to 136 patients. Demographically-adjusted cognitive scores were calculated. Subjective impairment was defined as PDQ score >2 standard deviations above that for healthy persons. We modeled the relationship of cognitive scores (independent variables) to being subjectively impaired (dependent variable) using logistic regression. Immediate Memory (IM) and Processing Speed Index (PSI) scores were non-linearly related to subjective impairment Patients were less likely to report subjective impairment if their PSI was normal (OR =0.11; 0.02-0.73) or markedly impaired (OR =0.17; 0.03-0.91), compared to mildly reduced PSI. In young patients decreases in IM were associated with increased subjective impairment (OR = 1.25; 1.07-1.47). Subjectively reported impairment reflects subtle declines in PSI and IM independent of mood, fatigue, and physical impairment Cognitive complaints should not be discounted due to depression.

1407 Event Related Potentials (ERP's) differentiate cognitive impairments in Multiple Sclerosis (MS) and NeuroBehçet's (NB) Disease

1407 Event Related Potentials (ERP's) differentiate cognitive impairments in Multiple Sclerosis (MS) and NeuroBehçet's (NB) Disease

Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis

Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-epsilon4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer's Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons. To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS. Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms. Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the epsilon4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable. The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment.

Cognitive impairment in multiple sclerosis does not affect reliability and validity of self-report health measures.

Patient self-report health measures have received increasing recognition as supplementary outcome parameters in multiple sclerosis (MS). Given the high prevalence of cognitive problems in this population, reliability and validity of self-report instruments in patient groups with cognitive impairment is essential, especially when using such scales longitudinally. A sample of 80 MS patients with cognitive dysfunction according to Symbol Digit Modalities Test (SDMT) score and 107 unimpaired patients were included in the analyses. Data was available from the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS), the Hospital Anxiety and Depression Scale (HADS), clinical rating scores [Expanded Disability Status Scale (EDSS) and FS (Functional Status) scales, CAMBS (Cambridge MS Basic Score)] and objective tests of upper and lower limb function [Timed 8 Meter Walk (T8) and Nine Hole Peg Test (9HPT)). Both self-report questionnaires showed satisfactory internal consistencies and retest reliability. Pattern and magnitude of correlations with other health status measures supported the validity of both instruments. However, there was a marked discrepancy between subjective and objective measures of cognitive function. Cognitively impaired patients furthermore showed significantly higher depression and anxiety as well as lower quality of life (QoL). The report provides evidence that QoL and affective symptomatology can be reliably assessed in MS patients with cognitive dysfunction. The common pattern of poor correlation between self-rated and objective cognitive function thus appears to be a result of the patients' (adaptive or maladaptive) coping mechanisms rather than being due to inaccurate measurement.

Sex Differences in Cognitive Impairment in Multiple Sclerosis

Multiple sclerosis (MS) is twice as prevalent in females as in males, but the possibility of sex differences in the cognitive sequellae of the disease has not been considered. In this study male patients with MS performed more poorly than female patients on tests of verbal and nonverbal memory, visuospatial construction, and on the Mini Mental State Exam (MMSE) and the Wisconsin Card Sorting Test (WCST). The groups of male and female patients were similar in age, education, and on several measures of neurologic and emotional disturbance. Among normals there are no sex differences on the MMSE and WCST. Sex differences on the memory and visuospatial construction tests were larger in magnitude for the patients than for normal controls, implying that male patients are somehow especially vulnerable to cognitive deficits. Reanalysis of existing databases could clarify questions about the existence and source of cognitive sex differences in MS.

Screening for early cognitive impairment in multiple sclerosis patients using the clock drawing test

The clock drawing test (CDT) is a complex task assessing integrative functions, abstract thinking and visuospatial organization. In the present study we evaluated the CDT as a possible screening instrument for early cognitive impairment in multiple sclerosis (MS) patients. In total, 107 MS patients completed the CDT as well as a battery assessing five cognitive domains. There were 73 female and 34 male participants (mean age 45.4±11.6 years, range 19–69). The majority (76/107) were diagnosed with a relapsing–remitting disease course. Mean expanded disability status scale (EDSS) score was 4.3±2.4 (range 0–8). The CDT was scored on a 1–6 point scale with “1” being a perfect score and “6” reflecting severe disorganization. Mean CDT score was 2.6±1.4. In 53% of patients the CDT was normal while in 11.2% dementia was apparent. The CDT score did not correlate with the total EDSS. Significant correlations were obtained with the mental functional system score of the EDSS (r=0.78; p=0.0001), visual learning and recall, sustained attention and concentration. Our findings demonstrate the sensitivity of the CDT to several cognitive domains. The absence of correlation with total EDSS score coupled with significant correlation with the mental functional system suggests that the CDT may be useful for screening MS patients.

Frontal Cortex Atrophy Predicts Cognitive Impairment in Multiple Sclerosis

The association between regional measures of cortical atrophy and neuropsychological (NP) dysfunction was studied in 35 multiple sclerosis (MS) patients. Patients underwent neurological examination, MRI, and NP testing. Blind quantitative MRI analysis yielded total T2 lesion area (TLA) and third ventricle width (3VW). Cortical atrophy, rated by blind visual inspection, was more extensive in superior frontal and parietal cortices than in other regions. No MRI measures were correlated with depression scores. TLA and 3VW were significantly correlated with each NP test. Cortical atrophy measures for bilateral superior frontal cortex were retained in regression models predicting impairments in verbal learning, spatial learning, attention, and conceptual reasoning. The authors conclude that cerebral atrophy predicts NP impairment while accounting for the influence of TLA or 3VW. Regions of cortex most susceptible to atrophic and cognitive changes in MS are the right and left superior frontal lobes.

Cognitive impairments in multiple sclerosis: a review.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Cognitive impairment (CI) may develop at any time during the course of the disease in the presence or absence of neurological disability. On the basis of comprehensive neuropsychological studies, there is now a consensus among investigators that 45 percent to 65 percent of MS patients suffer from some degree and form of cognitive difficulty. Features of CI include bradyphrenia; impaired attention, concentration and abstract reasoning; reduced manual speed and dexterity; deficits in memory retrieval; and language deficits in both the relapsing-remitting and progressive forms of MS. Impairments in all cognitive domains may result from the diffuse spread of microscopic pathology, although a preferential lobar distribution of plaques can present with a predominant deficit in the corresponding cognitive function. Nevertheless, the severity of CI best correlates with total microscopic and macroscopic disease burden of the brain as defined by recently developed magnetic resonance imaging (MRI) sequences. A disruption of connecting intercortical and subcortical pathways is likely to be the main cause of metabolic and functional abnormalities in neurons. However a direct toxic effect of soluble inflammatory products may also compromise neuronal function and survival. Early treatment of MS with interferons and copaxone can prevent or delay the onset of both neurological and cognitive disabilities by reducing the inflammatory activity and damage in the CNS. Until more powerful neuroprotective agents become available, simple neuropsychological screening and cognitive rehabilitation for memory and language impairments will remain important components in the care of MS patients.

Clinical and MRI assessment of brain damage in MS.

Cognitive impairment in multiple sclerosis (MS), generally in the form of the so-called subcortical dementia, results predominantly by the disruption of communication among cortical and subcortical areas, consequent to white matter damage. Studies with conventional magnetic resonance imaging (MRI) demonstrated that cognitive impairment in MS patients is related to lesion burden, although the strength of this correlation is weak. This can be partially explained by the poor pathological specificity of conventional MRI techniques and by damage in the normal-appearing white matter (NAWM). This interpretation is supported by studies using non-conventional MRI techniques, more specific to the heterogeneous substrates of MS pathology, such as the assessment of hypointense lesion load on T1-weighted scans and the measurement of the magnetization transfer ratio (MTR) of whole brain, MS lesions and NAWM. Other factors, such as the site of MS lesions and the presence of active inflammation, also seem to play an important role.

The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice.

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) is a sensitive measure of cognitive impairment in multiple sclerosis (MS) patients. It consists of the Selective Reminding Test, the 10/36 Spatial Recall Test, the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Test and the Word List Generation Test. We administered one of two parallel versions of the test battery to 140 healthy subjects to produce normative values for both versions. As expected, test scores were influenced by certain variables like age, gender and education. Although constructed as two equivalent versions, for some tests the two versions showed significant differences in test scores, which could not be explained by differences in these variables.

Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological, and MRI findings

OBJECTIVETo explore functional corticocortical connections in multiple sclerosis by means of coherence of the EEG, and to evaluate their correlations with the degree of cognitive impairment and with brain lesion...

Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis

OBJECTIVESTo assess (a) whether the changes in the normal appearing brain tissue (NABT), as revealed by magnetisation transfer (MT) histogram analysis, correlates with cognitive dysfunction in patients with multiple sclerosis...

Correlatos de los estudios de resonancia magnética nuclear con la disfunción cognitiva observada en pacientes con esclerosis múltiple

Studies with conventional magnetic resonance imaging (MRI) support the hypothesis that cognitive impairment in multiple sclerosis (MS) patients is related with the lesion burden. Patterns of frontal lobe cognitive decline were also found to be related with the corresponding regional lesion load, although the total lesion load on T2-weighted MRI scans of the brain seems to be more relevant in determining frontal lobe deficits. Other non-conventional MRI techniques with a higher specificity to the heterogeneous substrates of MS pathology, such as the assessment of hypointense lesion load on T1-weighted scans and the histogram analysis of magnetization transfer ratio maps, have recently been applied to MS cognitive studies. Results from these studies suggest that three factors play a role in the pathogenesis of MS dementia: the burden of MS lesions, the severity of the pathological damage within individual lesions and that of the normal-appearing white matter.

A multiparametric MRI study of frontal lobe dementia in multiple sclerosis

Previous studies achieved conflicting results when correlating magnetic resonance imaging (MRI) abnormalities and cognitive impairment in multiple sclerosis (MS) patients. Recently, the estimation of MS lesion load on T1-weighted images and the analysis of magnetization transfer ratio (MTR) histograms, increased the degree of the correlation between physical disability and MRI findings in MS. We assessed the relationship of conventional and non-conventional MRI-derived measures with frontal lobe dementia in MS. Dual echo, T1-weighted and MT MRI scans of the brain were obtained in 11 MS patients with and in 11 without frontal lobe dementia, matched for age, sex, education and disability. Total (TLL) and frontal (FLL) lesion loads were assessed from T2- and T1-weighted scans. MTR histogram analysis was performed for the whole brain, the frontal lobe and the cerebellum. Median TLL and FLL were significantly higher in cognitively impaired patients on both T2- and T1-weighted scans. The MRI measure that better discriminated the two groups of patients was T1-weighted TLL (median values were 19.1 ml for demented and 1.9 ml for non-demented patients, P=0.006). Average MTR, peak height and location of overall brain and frontal lobe histograms were significantly lower for cognitively impaired than for cognitively intact patients (P values ranged from 0.0001 to 0.001). Cerebellar MTR histogram metrics did not significantly differ in patients with and without cognitive decline. The presence of cognitive decline in MS is associated with the extent and pathological severity of brain MRI abnormalities.

Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis.

This study correlated the extent of abnormalities detected by different magnetic resonance imaging (MRI) techniques [proton density (PD)-weighted, T1-weighted, and magnetization transfer imaging (MTI)] with the overall cognitive, frontal lobe, and memory impairments in patients with MS. There were 30 clinically definite MS patients, with different disease courses. psychoactive/steroid treatments, mood disorders, acute relapse phase. Neuropsychological test results. Total (TLL) and frontal (FLL) lesion loads assessed from PD-weighted, T1-weighted (22 patients), and MTI (22 patients) MRI scans. Average lesion MT ratios (MTR) and analysis of the MTR histograms from brain tissue axial slabs on MTI scans. Patients with frontal lobe deficits (n=15) or memory impairment (n-17) had a higher TLL on PD scans (p=0.04 and p=0.01, respectively). Patients with frontal lobe deficits had higher FLL on PD scans (p=0.01) and TLL on MTI (p=0.03) scans. No significant relationships between the extent of T1-weighted lesion loads and the presence of any neuropsychological impairment. Mean MTR of both MS lesions and whole brain tissue was lower in patients with frontal lobe impairment (p=0.04). MRI lesion loads correlated significantly with some neuropsychological test scores. Lesion loads on PD-weighted MRI and MTI-derived measures are associated with cognitive decline in MS patients. Overall macroscopic and microscopic brain damage is more important than the corresponding regional brain disease in determining deficits of selective cognitive domains.

Pathophysiology of cognitive impairment in multiple sclerosis

Only in the last decade has significant progress been reached in understanding the pathophysiology of cognitive impairment in multiple sclerosis (MS). Edema, inflammation, demyelination and axonal loss may have different consequences on nerve fiber conduction, causing temporal disorganization or disruption of the inputs travelling along the intrahemispheric and interhemispheric connections among associative areas as well as between cortical and subcortical structures involved in mental functions.