Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking. Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features. Design, setting, and participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled. Main outcomes and measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype. Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus. Conclusions and relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies

General intellectual impairment in chronic right hemisphere damaged patients with anosognosia: A group study

The study evaluates the possible relations between cognitive impairment, persisting anosognosia for hemiplegia and peripersonal neglect. Thirty eight chronic right hemisphere stroke patients were divided in three age-and education-matched groups: A (n=13) patients with left hemiparesis, peripersonal neglect, and anosognosia for hemiplegia; B (n = 12) patients with left hemiparesis and peripersonal neglect, and C (n=13) patients with left hemiparesis only. We used MMSE and WAIS Verbal IQ and verbal subtests to assess cognitive impairment in patients, in order to avoid a bias due to visuospatial deficit, which is common in patients with neglect. VIQ, Information, Digit Span and Vocabulary WAIS subtests as well as MMSE were found to be significantly lower in group A versus group B. No difference was found in any test between groups B and C, indicating a general worse cognition in patients compared to those without anosognosia for hemiplegia. Patients with anosognosia for hemiplegia also showed larger brain lesions and, more frequently, frontal, parietal, temporal and basal ganglia involvement, particularly if they had low verbal IQ, indicating a relationship between cognitive impairment, persisting anosognosia for hemiplegia and large right hemisphere lesions. \ua9 2012 Psychology Press

Natalizumab significantly improves cognitive impairment over three years in MS: Pattern of disability progression and preliminary MRI Findings

Previous studies reported that Multiple Sclerosis (MS) patients treated with natalizumab for one or two years exhibit a significant reduction in relapse rate and in cognitive impairment, but the long term effects on cognitive performance are unknown. This study aimed to evaluate the effects of natalizumab on cognitive impairment in a cohort of 24 consecutive patients with relapsing remitting MS treated for 3 years. The neuropsychological tests, as well as relapse number and EDSS, were assessed at baseline and yearly for three years. The impact on cortical atrophy was also considered in a subgroup of them, and are thus to be considered as preliminary. Results showed a significant reduction in the number of impaired neuropsychological tests after three years, a significant decrease in annualized relapse rate at each time points compared to baseline and a stable EDSS. In the neuropsychological assessment, a significant improvement in memory, attention and executive function test scores was detected. Preliminary MRI data show that, while GM volume did not change at 3 years, a significantly greater parahippocampal and prefrontal gray matter density was noticed, the former correlating with neuropsychological improvement in a memory test. This study showed that therapy with Natalizumab is helpful in improving cognitive performance, and is likely to have a protective role on grey matter, over a three years follow-up

Persistence of the effects of attention and executive functions intensive rehabilitation in relapsing remitting multiple sclerosis

Background: Neuropsychological rehabilitation efficacy in multiple sclerosis (MS) is a currently investigated issue. We reported, in a single blind controlled study, that an intensive short duration cognitive training of attention and executive functions significantly improves the treated functions and reduces depression in MS. The persistence of these effects over time are unknown. Objective: To evaluate the persistence over time of neuropsychological improvement due to cognitive training nine months after rehabilitation onset. Methods: This is a single blind randomized controlled study. 24 MS patients were randomly assigned to experimental group (n=13) and received PC assisted neuropsychological treatment for three months, or to control group (n=11), receiving no treatment. Patients were submitted to neuropsychological evaluation, depression and quality of life questionnaires at baseline, three months and nine months later. Results: Nine months follow up compared to baseline evaluation shows a statistically significant improvement (p<0.05) in attention, information processing and executive functions tests (PASAT 3\u2033, COWA/S, WCSTpe), in depression and quality of life questionnaires in rehabilitated patients only. reliable change index (RCI) and modified RCI confirmed the clinical significance of this improvement in rehabilitated patients. Conclusions: Three months intensive neuropsychological rehabilitation of attention, information processing and executive functions induces a long lasting and clinically relevant neuropsychological improvement over time and a persistent depression and quality of life amelioration in patients with RR MS. \ua9 2012 Elsevier B.V

Longitudinal serum neurofilament light chain (sNfL) concentration relates to cognitive function in multiple sclerosis patients

BACKGROUND: Serum neurofilament light chain (sNfL) may be used as a biological marker of disease progression in multiple sclerosis (MS), although longitudinal studies correlating cognitive deficits to sNfL are limited. OBJECTIVE: To longitudinally investigate the relation between cognitive dysfunction, sNfL and MRI brain volume in a relapsing remitting MS patients. METHODS: 18 MS patients (9 males and 9 females, mean age 45 years, mean education 12.6 years) all prescribed with interferon beta 1a (44 mcg 3 times per week), are longitudinally evaluated by means of annual clinical exam with EDSS, neuropsychological evaluation with Brief repeatable battery (BRB) and Delis Kaplan Executive function test (DKEFS), dosage of sNfL (SIMOA) and MRI. RESULTS: Here are reported the results of 1 year follow-up. A significantly higher sNfL in MS compared to healthy controls and higher sNfL in patients with greater cognitive impairment were found. Cognitive Impairment Index, memory, executive function tests correlated with sNfL. Gray matter volume resulted unchanged at 1-year follow-up; a weak correlation between some tests' score and selective cortical brain areas was found. CONCLUSION: Our longitudinal pilot study confirms that sNfL are related to cognitive abilities, confirming data of other authors from retrospective studie

The transfer from survey (map-like) to route representations into Virtual Reality Mazes: effect of age and cerebral lesion

Background: To go from one place to another, we routinely generate internal representations of surrounding spaces, which can include egocentric (body-centred) and allocentric (world-centred) coordinates, combined into route and survey representations. Recent studies have shown how both egocentric and allocentric representations exist in parallel and are joined to support behaviour according to the task. Our study investigated the transfer from survey (map-like) to route representations in healthy and brain-damaged subjects. The aim was two-fold: first, to understand how this ability could change with age in a sample of healthy participants, aged from 40 to 71 years old; second, to investigate how it is affected after a brain lesion in a 8 patients' sample, with reference to specific neuropsychological frames. Methods: Participants were first required to perform the paper and pencil version of eight mazes, then to translate the map-like paths into egocentric routes, in order to find the right way into equivalent Virtual Reality (VR) mazes. Patients also underwent a comprehensive neuropsychological evaluation, including a specific investigation of some topographical orientation components. Results: As regards the healthy sample, we found age-related deterioration in VR task performance. While education level and gender were not found to be related to performance, global cognitive level (Mini Mental State Examination), previous experience with computer and fluidity of navigation into the VR appeared to influence VR task results. Considering the clinical sample, there was a difficulty in performing the VR Maze task; executive functions and visuo-spatial abilities deficits appeared to be more relevant for predicting patients' results. Conclusions: Our study suggests the importance of developing tools aimed at investigating the survey to route transfer ability in both healthy elderly and clinical samples, since this skill seems high cognitive demanding and sensitive to cognitive decline. Human-computer interaction issues should be considered in employing new technologies, such as VR environments, with elderly subjects and neurological patients

The Rao's Brief Repeatable Battery version B: Normative values with age, education and gender corrections in an Italian population

The Brief Repeatable Battery (BRB) of Neuropsychological Tests is one of the most widely used instruments to assess cognitive functioning in multiple sclerosis patients. However, to date, normative data for the Italian population are available only for the version A, which limits the use of the battery in longitudinal evaluations. We administered the BRB version B to 132 healthy subjects to obtain normative values taking into account the influences of demographic factors on the test scores and calculating corrections for these relevant factors (age, gender and education). Higher age and educational level were associated with better performance on all the tests. The World List Generation was also influenced by gender, since women performed better than men. Moreover, some tests of the version B seem to be easier than those of version A. Our data can improve the applicability of the BRB for both clinical and research purposes in longitudinal assessments. \ua9 2013 Springer-Verlag Italia

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking. Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features. Design, Setting, and Participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled. Main Outcomes and Measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype. Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: Preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P &lt;.001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P &lt;.001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P &lt;.001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P =.04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P =.02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P =.04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus. Conclusions and Relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies. © 2021 American Medical Association. All rights reserve