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

Abstract. Background: 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-4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimers Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons. Objective: To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS. Methods: 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. Results: 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 4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable. Conclusion: The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment.This work was supported in part by a grant from FISM (Federazione Italiana Sclerosi Multipla).     

APOE and risk of cognitive impairment in multiple sclerosis

OBJECTIVES: The APOE gene polymorphism and the -491 A/T polymorphism in its regulatory region have been associated with an increased risk for developing Alzheimer's disease. We examined these polymorphisms in multiple sclerosis (MS) patients, to determine if a genetic predisposition may explain the risk for developing cognitive decline in MS. MATERIAL AND METHODS: Eighty-nine relapsing-remitting and secondary progressive MS patients underwent to a full neuropsychological battery as well as to determination of APOE and -491 A/T polymorphisms. Genetic analysis was also performed in 107 population controls. RESULTS: The APOE polymorphism was not associated with the risk of cognitive impairment in MS patients. The AA genotype of the -491 A/T polymorphism in the APOE regulatory region was more frequent in cognitively impaired than in cognitively preserved MS subjects. CONCLUSION: The AA homozygous state of the -491 A/T polymorphism of the APOE regulatory region is associated with cognitive impairment in patients with MS.     

Brain dysconnectivity relates to disability and cognitive impairment in multiple sclerosis

The pathophysiology of cognitive dysfunction in multiple sclerosis (MS) is still unclear. This magnetoencephalography (MEG) study investigates the impact of MS on brain resting‐state functional connectivity (rsFC) and its relationship to disability and cognitive impairment. We investigated rsFC based on power envelope correlation within and between different frequency bands, in a large cohort of participants consisting of 99 MS patients and 47 healthy subjects. Correlations were investigated between rsFC and outcomes on disability, disease duration and 7 neuropsychological scores within each group, while stringently correcting for multiple comparisons and possible confounding factors. Specific dysconnections correlating with MS‐induced physical disability and disease duration were found within the sensorimotor and language networks, respectively. Global network‐level reductions in within‐ and cross‐network rsFC were observed in the default‐mode network. Healthy subjects and patients significantly differed in their scores on cognitive fatigue and verbal fluency. Healthy subjects and patients showed different correlation patterns between rsFC and cognitive fatigue or verbal fluency, both of which involved a shift in patients from the posterior default‐mode network to the language network. Introducing electrophysiological rsFC in a regression model of verbal fluency and cognitive fatigue in MS patients significantly increased the explained variance compared to a regression limited to structural MRI markers (relative thalamic volume and lesion load). This MEG study demonstrates that MS induces distinct changes in the resting‐state functional brain architecture that relate to disability, disease duration and specific cognitive functioning alterations. It highlights the potential value of electrophysiological intrinsic rsFC for monitoring the cognitive impairment in patients with MS.     

Cognitive impairment in patients suffering from relapsing-remitting multiple sclerosis with EDSS < or = 3.5

OBJECTIVES : Previous papers have mainly demonstrated the presence and the frequency of cognitive impairment in patients suffering from relapsing-remitting multiple sclerosis. The purpose of this study was to investigate subjects with the relapsing-remitting form of the disease and mild clinical disability (EDSS < or = 3.5), so as to quantify this deficit when the illness does not yet interfere with daily living and the ability to work. METHODS : Fifty patients and 50 healthy controls were submitted to a wide neuropsychological battery, including Wechsler Memory Scale I- (WMS), Benton Visual Retention Test D- (BVRT), Raven Coloured Progressive Matrices (RCPM), Kohs' test (KT), Judgement of Lines Orientation H- (JLO), Facial Recognition (FR) and Aachner Aphasie Test (AAT). They also underwent Clinical Depression Scale (CDQ) and State-Trait Anxiety Inventory (STAI). RESULTS : The results show the presence of significant memory impairment on both WMS (P = 0.000) and BVRT (P = 0.000) in patients compared with controls. Patients were also impaired in abstract reasoning and problem-solving deficit (KT P = 0.003; RCPM P = 0.000) and in FR (P = 0.019). Cognitive decline correlated with illness duration (r = 0.761), but was independent of EDSS (r = 0.085). CONCLUSION : Cognitive decline was present even when physical disability was not yet severe, but it was mild and did not limit patients' ability to work. The cognitive impairment outlined was of the subcortical type and correlated with illness duration. This study emphasizes the importance of cognitive examination in clinical practice. It is suggested that a complete neurological examination include tests on memory and abstract reasoning.     

Correlates of cognitive impairment and depressive mood disorder in multiple sclerosis

The psychopathological status of 25 inpatients suffering from clinically definite multiple sclerosis (MS) according to Poser criteria was assessed by using standardized methods (Structured Clinical Interview for DSM-III-R, Inpatient Multidimensional Psychiatric Scale, Hamilton and Montgomery-Asberg Depression Rating Scales and the Structured Interview for the Diagnosis of Alzheimer Dementia and Dementias of other Aetiology (SIDAM). Magnetic resonance (MRT) (0.5 T; T2-weighted sequence) of the brain was analysed by measuring the ventricular brain ratio (VBR), the area of the corpus callosum (CC) and the extension of hyperintense lesions of the brainstem, the temporal lobes and the brain at all. Six of 25 (24%) of these moderately disabled patients (mean Extended Disability Score (EDSS) 3.3) were diagnosed to suffer from depressive mood disorder (major depression or dysthymia); 2 were demented. In correlation analysis, depression was unrelated to age, gender, duration of illness, status of disability (EDSS) or the results of cognitive assessment. No relationship between the depression scores and the different MRT measures could be identified. The presence or absence of gadolinium enhancement was also uncorrelated to depressive symptoms. Fatigue as measured by the Fatigue Severity Scale was unrelated to depression or subcortical brain atrophy (increased VBR) but significantly correlated to the area of hyperintense MRT changes in brainstem and midbrain. Cognitive impairment (decreased SIDAM scores) was correlated to the total area of hyperintense MRT changes of the brain parenchyma. The type of clinical course (relapsing-remitting vs chronic progredient) was not found to influence the affective or cognitive state in our MS patient's sample.     

Cognitive impairment in multiple sclerosis is associated to different patterns of gray matter atrophy according to clinical phenotype

Objective : To investigate whether cognitive impairment in multiple sclerosis (MS) patients is associated to different patterns of gray matter (GM) atrophy and T2‐visible lesion distribution according to the clinical phenotype. Experimental Design: Twenty‐two relapsing remitting (RR), 29 secondary progressive (SP), and 22 primary progressive (PP) MS patients, and 39 healthy controls underwent high‐field structural magnetic resonance imaging and an extensive neuropsychological battery. Voxel‐wise distribution of GM damage and T2‐lesions was compared between cognitively impaired (CI) and cognitively preserved (CP) patients according to their clinical phenotype. Principal Observations: Thirty‐nine MS patients were CI. In all MS groups, regional GM loss was correlated with cognitive impairment. Different patterns of regional distribution of GM atrophy and T2‐visible lesions were found between CI vs. CP MS patients, according to their clinical phenotype. No areas were significantly more atrophied in CI SPMS vs. CI RRMS patients. Conversely, compared with CI PPMS, CI SPMS patients had a significant GM loss in several regions of the fronto‐temporal lobes, the left hypothalamus and thalami. While in RRMS and SPMS patients there was a correspondence between presence of T2 visible lesions and GM atrophy in several areas, this was not the case in PPMS patients. Conclusion: Distinct patterns of regional distribution of GM damage and T2‐visible lesions are associated with cognitive impairment in MS patients with different clinical phenotypes. The correspondence between lesion formation and GM atrophy distribution varies in the different forms of MS. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Cognitive impairment in amyotrophic lateral sclerosis and its relation to motor disabilities

The performance of patients with amyotrophic lateral sclerosis (ALS) on selective neuropsychological tests was examined in regard to the applicability of such examinations to diagnosis. Eighteen patients with ALS, and 15 age- and education-matched controls were given a battery of tests designed to assess motor and intellectual functions. The ALS group displayed significantly lower scores on all tests than those in the control group. Correlation analyses on the several motor and neuropsychological results in ALS group revealed that there was a significant negative correlation between upper motor symptoms and mini-mental state examination, as well as memory tests.     

Attention impairment in recently diagnosed multiple sclerosis

Patients with multiple sclerosis (MS) experience cognitive disorders which can occur early in the course of the disease. The present study tried to investigate attention abilities of MS patients at the early stage of the disease. Three attention modalities (sustained, simple and complex focused attention) were evaluated. The results show that MS patients at the early stage of the disease presented attentional dysfunction only when the cognitive load of the attention task was high and when controlled information processing was required. This suggests that MS patients probably suffer from a processing resources deficit without modification of the attentional mechanisms.     

Structural MRI correlates of cognitive impairment in patients with multiple sclerosis

In a multicenter setting, we applied voxel‐based methods to different structural MR imaging modalities to define the relative contributions of focal lesions, normal‐appearing white matter (NAWM), and gray matter (GM) damage and their regional distribution to cognitive deficits as well as impairment of specific cognitive domains in multiple sclerosis (MS) patients. Approval of the institutional review boards was obtained, together with written informed consent from all participants. Standardized neuropsychological assessment and conventional, diffusion tensor and volumetric brain MRI sequences were collected from 61 relapsing‐remitting MS patients and 61 healthy controls (HC) from seven centers. Patients with ≥2 abnormal tests were considered cognitively impaired (CI). The distribution of focal lesions, GM and WM atrophy, and microstructural WM damage were assessed using voxel‐wise approaches. A random forest analysis identified the best imaging predictors of global cognitive impairment and deficits of specific cognitive domains. Twenty‐three (38%) MS patients were CI. Compared with cognitively preserved (CP), CI MS patients had GM atrophy of the left thalamus, right hippocampus and parietal regions. They also showed atrophy of several WM tracts, mainly located in posterior brain regions and widespread WM diffusivity abnormalities. WM diffusivity abnormalities in cognitive‐relevant WM tracts followed by atrophy of cognitive‐relevant GM regions explained global cognitive impairment. Variable patterns of NAWM and GM damage were associated with deficits in selected cognitive domains. Structural, multiparametric, voxel‐wise MRI approaches are feasible in a multicenter setting. The combination of different imaging modalities is needed to assess and monitor cognitive impairment in MS. Hum Brain Mapp 37:1627‐1644, 2016. © 2016 Wiley Periodicals, Inc.     

Cortical lesions at diagnosis predict long-term cognitive impairment in multiple sclerosis: A 20-year study

Background and purpose

Although cognitive impairment (CI) is frequent in multiple sclerosis (MS) patients, few studies (and with conflicting results) have evaluated early predictors of CI in the long term. We aimed at determining associations between early clinical/neuroradiological variables with reference to CI after 20 years of MS.

Methods

We investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and cortical lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were followed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted.

Results

CI patients showed higher focal cortical pathology at diagnosis compared to cognitively normal subjects (p < 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long-term CI. Moreover, number of CLs (especially ≥3) was also strongly associated with long-term CI (≥3 CLs: odds ratio [OR] = 3.7, 95% confidence interval = 1.8–7.5, p < 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve = 0.67, specificity = 75%, sensitivity = 55%) was estimated according to the risk of developing CI.

Conclusions

These results highlight the impact of considering both white and gray matter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI.     

Cognitive deficits in multiple sclerosis: correlations with T2 changes in normal appearing brain tissue

Objectives – Although disease load in multiple sclerosis (MS) often is based on T2 lesion volumes, the changes in T2 of normal appearing brain tissue (NABT) are rarely considered. By means of magnetic resonance, (MR) we retrospectively investigated whether T2 changes in NABT explain part of the cognitive impairment seen in MS and constitute a supplement to traditional measurement of T2 lesion volume. Materials and Methods – Fifty patients with clinically definite MS were included (38 women, 12 men). Patients were MR scanned, neuropsychologically tested, and evaluated clinically with the Kurtzke Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Impairment Scale (MSIS). Voxel‐wise T2 estimates and total T2 lesion volume were tested for correlations with eight cognitive domains, a general cognitive dysfunction factor (CDF), and the two clinical scales. Results – We found distinct clusters of voxels with T2 estimates correlating with CDF, mental processing speed, complex motor speed, verbal fluency, and MSIS. A significant negative correlation was found between total lesion volume and CDF (r = ?0.34, P = 0.02), verbal intelligence (r = ?0.40, P = 0.005), mental processing speed (r = ?0.34, P = 0.03), visual problem solving (r = ?0.40, P = 0.01), and complex motor speed (r = ?0.39, P = 0.01). No significant correlation was detected between total lesion load and the clinical measures EDSS and MSIS. Conclusion – Our results suggest that even in the NABT MR detects changes likely to be associated with an underlying pathology and possibly contributes to the cognitive impairment in MS.     

多发性硬化患者的认知功能障碍及其与头颅MRI病灶的相关性

目的　研究多发性硬化 (MS)患者认知功能障碍的特点及其与头颅MRI病灶的相关性。方法　对 70例MS患者进行韦氏智力量表 (WAIS)测试及头颅MRI检查 ,并用多元回归分析方法对各相关因素进行分析。结果　MS组全量表智商 (FIQ)异常 (<90分 )率为 4 0 %(2 8/70 ) ,与对照组比较差异有显著性 (P <0 0 1)。对智商成绩影响最显著的因素为病变部位 (脑部病变 )。MRI显示病灶的等级与病程呈显著正相关(r=0 348,P <0 0 5 ) ,胼胝体病灶数与FIQ呈负相关 (r=- 0 2 8,P <0 0 5 ) ,其他均无显著相关性 (均P >0 0 5 )。结论　MS患者存在认知障碍 ,MS的病变部位 (脑部病变 )对智能影响最显著 ,头颅MRI所示病灶与MS患者的认知障碍的相关性大多不显著。     

The relationship of cognitive impairment with neurological and psychiatric variables in multiple sclerosis patients

Objective. Cognitive impairment (CI) in multiple sclerosis (MS) can develop any time. CI is associated with the degree of neuronal loss, but disease duration, fatigue, comorbid affective disorder, and drug dose may also affect cognition. Our aim was to assess which cognitive domain was disturbed primarily in mild MS patients and to see whether CI was related with clinical and psychiatric features. Method. Neurological and psychiatric evaluation of 31 MS patients and 31 age, sex, and education-matched healthy controls were made with Structured Clinical Interview for Axis I Disorders (SCID-I). Depression, anxiety, functionality, fatigue, and disability scoring were determined with Hamilton Depression-Anxiety scales, Global Assessment of Functionality, Fatigue Severity and Expanded Disability Status Scales. Cognitive functions were assessed using Mini Mental, Serial Digit Learning, Verbal and Nonverbal Cancellation, Stroop and Rey Auditory Verbal Learning tests. Results. Retrieval from long-term memory and psychomotor speed were significantly worse in MS group. CI was correlated with disease duration, number of attacks, and physical disability but not with depression and anxiety severity. Disease duration predicted disturbances in recall and psychomotor speed, whereas fatigue and disability predicted depression. Conclusion. Psychomotor speed and memory were primarily impaired in MS patients, and CI was closely associated with clinical aspects of MS rather than with depression and anxiety.     

多发性硬化患者的认知功能损害

目的研究多发性硬化(multiplesclerosis,MS)患者认知功能损害的形式、特点及相关影响因素,了解认知功能损害对患者生活功能的影响。方法将66例MS患者分为脊髓型和脑/脑脊髓型两组,另外选择健康对照30名,采用神经心理学测验的方法系统评价记忆、语言、信息处理速度、执行功能及整体认知功能,并进行生活功能评定,所有MS患者同时接受头颅及脊髓磁共振成像(MRI)检查。结果神经心理学测试发现,与健康对照组相比,脑/脑脊髓型MS组瞬时记忆和长延迟记忆受损明显(P<0.05),执行功能损害显著(P<0.01),信息处理速度下降(P<0.01)。单纯脊髓型也存在认知功能损害,以执行功能损害及信息处理速度下降为主(P<0.05)。记忆、执行功能等认知功能测验成绩与头颅MRI所见病变相关(r=-0.319～-0.543,P<0.05)。认知功能测验成绩与病程长短、复发次数无明显相关。执行性画钟作业(CLOX)及Stroop测验反应错误数与扩展功能障碍状态量表(EDSS)有相关性(r=-0.325及0.372,P<0.05)。操作性日常生活能力(IADL)及MS生活影响量表(MSIS29)得分与记忆、执行功能等认知测验成绩呈负相关(r=-0.325～-0.537,P<0.05)。结论MS的认知功能损害以记忆、信息处理速度、执行功能为主,整体认知功能及语言功能相对保存。认知功能损害影响患者的生活功能,与病程长短、复发次数无明显相关。     

Survey-based assessment of the relationship between cognitive impairment and mentally stimulating activity in multiple sclerosis

Objectives: Cognitive impairment (CI) is a common and potentially debilitating component of the disease course in multiple sclerosis (MS). However, therapeutic options remain limited. It is unknown whether cognitively enriching activities reduce the burden of CI in patients with MS, as is found in other neurologic diseases affecting cognition. The aim of this study was to determine whether participation in cognitively enriching activities decreased self-reported CI in MS patients.

Methods: CI and activity levels were reported through electronic surveys completed by MS patients at the Cleveland Clinic. Responses were analyzed by univariable and multivariable regressions to identify factors associated with lower CI.

Results: We received 316 survey responses. Use of an assistive device (β = 4.09; P = 0.033) and Internet use (β = 11.9; P = 0.017) were associated with higher reported CI, while employment correlated with reduced CI (β = ?7.97; P < 0.0001). None of the cognitive activities surveyed were found to reduce CI.

Discussion: This study did not identify a significant impact of cognitively enriching activities on reducing CI, suggesting that other prophylactic or therapeutic approaches should be investigated. A small portion of the population surveyed reported no or minimal CI, suggesting the existence of a resilient population.