Memory Impairment In Multiple Sclerosis Research Articles

Intrathecal B cell activation and memory impairment in multiple sclerosis

BackgroundCognitive impairment (CI) is a common and disabling feature of people with multiple sclerosis (pwMS), but its underlying mechanisms are heterogenous and not fully understood. A role of infiltrating immune cells in the meninges and brain parenchyma has been hypothesized. This study aimed to explore the hypothesis that intrathecal B cells might influence cognitive performance in pwMS. MethodsA retrospective study was performed on 39 newly diagnosed pwMS who underwent cerebrospinal fluid (CSF) analysis. Kappa (κ)-index was measured as a biomarker of intrathecal B cell activation. Cognitive performance was assessed using the Brief Repeatable Battery of Neuropsychological Tests (BRBN). Brain T2 lesions number (T2LN) and volume (T2LV) together with brain, cortical grey matter, thalamic and hippocampal volumes were calculated to account for MRI-visible damage. Resultsκ-index was higher in pwMS with verbal memory impairment (median 99.6, range 58.5–195.2 vs. median 37.2, range 2.3–396.9, p < 0.001), and it was negatively associated with BRBN tests exploring verbal memory and information processing speed. In multivariate models, higher κ-index was confirmed to be independently associated with worse scores of BRBN tests exploring verbal memory and with a higher probability of verbal memory impairment. ConclusionIntrathecal B cells might drive memory impairment in pwMS independently of brain damage visible on MRI scans.

The nature of memory impairment in multiple sclerosis: understanding different patterns over the course of the disease.

Memory deficit is one of the most common and severe cognitive impairments in patients with multiple sclerosis and can greatly affect their quality of life. However, there is currently no agreement as to the nature of memory deficit in multiple sclerosis. This cross-sectional study, carried out at the Dr. Josep Trueta and Santa Caterina hospitals in Girona (Spain), was designed to determine the semiology of verbal memory deficit in the different stages of the disease. To this end, a modification of Rey's verbal auditory test was created by introducing two recognition trials between the five learning trials, thus monitoring what happens in terms of acquisition versus the retrieval of information during the learning phase. Linear regression models were used to evaluate verbal episodic memory performance between-groups adjusting results by age, sex, educational level, and the presence of anxiety and/or depressive symptoms. 133 patients with multiple sclerosis, clinically isolated syndrome, and radiologically isolated syndrome and 55 healthy controls aged 18-65 years were assessed. It was observed that the memory processes of multiple sclerosis patients worsen with the progression of the disease. In this respect, patients in pre-diagnostic phases (radiologically isolated syndrome and clinically isolated syndrome) show no differences in verbal episodic memory compared to the healthy controls. Patients in the inflammatory stage (relapsing-remitting multiple sclerosis) show a previously learned information retrieval deficit, while patients in progressive stages (secondary progressive multiple sclerosis and primary progressive multiple sclerosis) do not even correctly acquire information. These results provide significant information to assist in understanding the nature of memory deficits in multiple sclerosis over the course of the disease. These results are discussed in terms of possible cognitive rehabilitation strategies depending on the evolutive stage and are related to neuropathological mechanisms involved in the progression of the disease.

A CSF biomarker of intrathecal B cells activation correlates with memory impairment in multiple sclerosis

Cognitive impairment (CI) is a common clinical feature of multiple sclerosis (MS), but its pathophysiology is only partially known. Cerebrospinal fluid (CSF) biomarkers, by reflecting the ongoing pathology, may help in better understanding the determinants of CI in MS. Kappa free light chain index (k-index) is a sensitive biomarker of intrathecal B cells activation. Herein, we investigated the association between k-index and cognitive performance in MS patients.

Insights on the Relationship Between Hippocampal Connectivity and Memory Performances at the Early Stage of Multiple Sclerosis.

While memory impairment in multiple sclerosis (MS) is known to be associated with hippocampal alterations, whether hippocampal networks could dynamically reorganize as a compensation mechanism is still a matter of debate. In this context, our aim was to identify the patterns of structural and functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances in early MS. Thirty-two patients with a first episode suggestive of MS together with 10 matched healthy controls were prospectively explored at baseline, 1 and 5 years follow up. They were scanned with MRI and underwent a neuropsychological battery of tests that included the Selective Reminding Test and the Brief Visual Memory Test Revised to assess verbal and visuo-spatial memory, respectively. Hippocampal volume was computed together with four graph theory metrics to study the structural and functional connectivity of both hippocampi with the rest of the brain. Associations between network parameters and memory performances were assessed using linear mixed-effects (LME) models. Considering cognitive abilities, verbal memory performances of patients decreased over time while visuo-spatial memory performances were maintained. In parallel, hippocampal volumes decreased significantly while structural and functional connectivity metrics were modified, with an increase in hippocampal connections over time. More precisely, these modifications were indicating a reinforcement of hippocampal short-distance connections. LME models revealed that the drop in verbal memory performances was associated with hippocampal volume loss, while the preservation of visuo-spatial memory performances was linked to decreased hippocampal functional shortest path length. In conclusion, we demonstrated a differential impairment in memory performances in the early stages of MS and an important interplay between hippocampal-related structural and functional networks and those performances. As the structural damage increases, functional reorganization seems to be able to maintain visuo-spatial memory performances with strengthened short-distance connections.

Memory in multiple sclerosis: A reappraisal using the item specific deficit approach.

As many as 65% of people with multiple sclerosis (MS) have clinically significant memory impairment, but the nature of this deficit is controversial. Some investigations suggest that an inability to retrieve newly learned information from memory is prominent, whereas others imply that compromised acquisition accounts for impairment. Prior research has not simultaneously evaluated acquisition and retrieval processes in MS, and fewer have attempted to account for initial acquisition when studying retrieval. The Item Specific Deficit Approach (ISDA) offers a method of quantifying acquisition, retrieval, and retention processes, with the latter two mechanisms being adjusted for initial acquisition. To simultaneously quantify acquisition and retrieval abilities, the ISDA was applied to list learning performance in two independent samples of people with MS and corresponding healthy comparison groups. Study 1 included 85 people with MS and 47 healthy individuals. Study 2 involved a separate sample of 79 people with MS and 22 healthy people. They were administered neuropsychological batteries, and participants with MS were classified as globally impaired or unimpaired. The California Verbal Learning Test-II was administered to assess new-learning in both studies, and responses were scored using the ISDA. Both studies revealed that cognitively impaired people with MS manifest weaknesses involving acquisition and retrieval. Nearly identical effect sizes emerged across samples, with cognitive impairment achieving a medium effect upon acquisition and a large effect upon retrieval. These findings accord well with previous research showing diminished acquisition and retrieval among people with MS. The results may also reconcile contradictory findings in the extant literature by showing that memory impairment in MS is not exclusively attributable to either acquisition or retrieval. Rather, both processes may manifest across people with MS. The replication across samples with nearly identical effect sizes implies that these effects are reliable and possess external validity. These data hold implications for memory rehabilitation interventions involving people with MS, and suggest that acquisition and retrieval processes should be addressed in treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The role of hippocampal theta oscillations in working memory impairment in multiple sclerosis.

Working memory (WM) problems are frequently present in people with multiple sclerosis (MS). Even though hippocampal damage has been repeatedly shown to play an important role, the underlying neurophysiological mechanisms remain unclear. This study aimed to investigate the neurophysiological underpinnings of WM impairment in MS using magnetoencephalography (MEG) data from a visual‐verbal 2‐back task. We analysed MEG recordings of 79 MS patients and 38 healthy subjects through event‐related fields and theta (4–8 Hz) and alpha (8–13 Hz) oscillatory processes. Data was source reconstructed and parcellated based on previous findings in the healthy subject sample. MS patients showed a smaller maximum theta power increase in the right hippocampus between 0 and 400 ms than healthy subjects (p = .014). This theta power increase value correlated negatively with reaction time on the task in MS (r = −.32, p = .029). Evidence was provided that this relationship could not be explained by a ‘common cause’ confounding relationship with MS‐related neuronal damage. This study provides the first neurophysiological evidence of the influence of hippocampal dysfunction on WM performance in MS.

Poor Encoding and Weak Early Consolidation Underlie Memory Acquisition Deficits in Multiple Sclerosis: Retroactive Interference, Processing Speed, or Working Memory?

Learning and memory impairments are common in multiple sclerosis (MS) and may be related to difficulty acquiring (encoding or consolidating) new information. We evaluate the role of retroactive interference and investigate whether minimizing interference immediately following encoding (early during consolidation) will improve MS participants' ability to remember new verbal information. Additionally, we investigate processing speed differences between memory-impaired and unimpaired participants and present an exploratory analysis of how the dual-components of working memory (capacity vs. processing) relate to memory impairment. MS memory-unimpaired (N = 12) and MS memory-impaired participants (N = 12) were compared to healthy controls (N = 15). Interference onset following encoding (early, mid, late, no interference) was manipulated over the retention interval of a verbal learning and memory task. Response times (RT) were recorded during interference trials. MS memory-impaired participants encoded less information and lost proportionally more information over the retention interval (weak consolidation). Lengthening the onset of interference did not benefit memory performance in this sample. Memory performance was unrelated to RT but was related to performance on the Symbol Digit Modalities Test. Primary capacity of working memory did not differ across groups; however, secondary memory processing was reduced for MS memory-impaired participants. Minimizing interference following encoding did not improve memory in this sample. Both initial encoding and early consolidation were reduced for memory-impaired MS participants. Evidence for a relationship between processing speed and memory was mixed and depended on the processing speed assessment used. Memory impairment in MS may be partially due to inefficient processing within working memory.

The importance of hippocampal dynamic connectivity in explaining memory function in multiple sclerosis.

IntroductionBrain dynamics (i.e., variable strength of communication between areas), even at the scale of seconds, are thought to underlie complex human behavior, such as learning and memory. In multiple sclerosis (MS), memory problems occur often and have so far only been related to “stationary” brain measures (e.g., atrophy, lesions, activation and stationary (s) functional connectivity (FC) over an entire functional scanning session). However, dynamics in FC (dFC) between the hippocampus and the (neo)cortex may be another important neurobiological substrate of memory impairment in MS that has not yet been explored. Therefore, we investigated hippocampal dFC during a functional (f) magnetic resonance imaging (MRI) episodic memory task and its relationship with verbal and visuospatial memory performance outside the MR scanner.MethodsThirty‐eight MS patients and 29 healthy controls underwent neuropsychological tests to assess memory function. Imaging (1.5T) was obtained during performance of a memory task. We assessed hippocampal volume, functional activation, and sFC (i.e., FC of the hippocampus with the rest of the brain averaged over the entire scan, using an atlas‐based approach). Dynamic FC of the hippocampus was calculated using a sliding window approach.ResultsNo group differences were found in hippocampal activation, sFC, and dFC. However, stepwise forward regression analyses in patients revealed that lower dFC of the left hippocampus (standardized β = −0.30; p = .021) could explain an additional 7% of variance (53% in total) in verbal memory, in addition to female sex and larger left hippocampal volume. For visuospatial memory, lower dFC of the right hippocampus (standardized β = −0.38; p = .013) could explain an additional 13% of variance (24% in total) in addition to higher sFC of the right hippocampus.ConclusionLow hippocampal dFC is an important indicator for maintained memory performance in MS, in addition to other hippocampal imaging measures. Hence, brain dynamics may offer new insights into the neurobiological mechanisms underlying memory (dys)function.

Prospective memory impairment in multiple sclerosis: a review

Objective: Multiple sclerosis (MS) is a progressive disease of the central nervous system affecting information processing speed, episodic memory, attention, and executive functions. MS patients also often report prospective memory (PM) failures that directly impact their functional autonomy, including professional and social life. The purpose of this paper was to review the literature concerning the assessment and remediation of PM deficits in MS. Method: The literature pertaining to PM impairment in MS was carefully reviewed using PubMed, PsyINFO, and Google Scholar, as well as cross-references from the articles published on this topic. Since PM rehabilitation in MS patients is still in its infancy, this review mainly focuses on studies that have directly assessed PM through various measures including questionnaires, standardized clinical tests, and experimental procedures. Conclusion: This literature review confirms the presence of PM deficits in MS patients, even in the early stages of the disease. A further need for controlled studies on PM assessment and PM interventions in patients with MS is stressed.

Hippocampal dysfunction is associated with memory impairment in multiple sclerosis: A volumetric and functional connectivity study

Background: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients. Objective: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. Methods: Hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (multiple sclerosis impaired (MSi) and multiple sclerosis preserved (MSp), respectively) and healthy controls (HC). A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp, and MSi. Results: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi > MSp > HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. Conclusion: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi).

Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis

Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis.

Memory impairment in multiple sclerosis: Relevance of hippocampal activation and hippocampal connectivity

Background: Memory impairment is frequent in multiple sclerosis (MS), but it is unclear what functional brain changes underlie this cognitive deterioration. Objective: To investigate functional hippocampal activation and connectivity, in relation to memory performance in MS. Methods: Structural and functional magnetic resonance imaging data were acquired for 57 MS patients and 28 healthy controls (HCs), yielding hippocampal measures of volume, lesions, functional activation during a memory task and functional connectivity at rest. Memory function was based on two subtests of a larger neuropsychological test battery and related to hippocampal neuroimaging measures, using linear regression. Results: Hippocampal volume was lower in MS patients, as compared to HCs. In MS, hippocampal activation during the task was increased in cognitively preserved, but decreased in cognitively impaired, patients. Increased hippocampal connectivity was detected in MS patients, as compared to HCs, between the left hippocampus and the right posterior cingulate. Memory impairment in MS was explained (adjusted R2 = 0.27) by male gender, decreased hippocampal activation and increased hippocampal connectivity (p = 0.001). Conclusions: Decreased activation of the hippocampus, increased connectivity and male gender were associated with worse memory performance in MS. These results indicate that increased activation and increased connectivity do not always coincide, and relate differently to cognitive dysfunction in MS.

Emotional and neutral verbal memory impairment in Multiple Sclerosis

BackgroundA defective emotional enhancement of verbal memory (VM) performances has been reported in different neurological diseases. ObjectivesTo assess the emotional enhancement of VM in 22 Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis (MS) and 49 Relapsing (RR) MS patients in comparison to 32 Healthy Controls (HC). MethodsImmediate and delayed recall of VM was assessed using the Selective Reminding Test (SRT). A list of 12 emotionally significant words was used to evaluate the Emotional (E) variants of the SRT. Depressive symptoms were assessed by the Beck Depression Inventory. ResultsThe prevalence of depression did not differ between RRMS and CIS patients. Both patient groups showed poorer (p<0.01) VM performances in comparison to HC in all the SRT tasks, but no difference was found between the two patient groups. Emotionally salient words were more (p<0.0001) recalled than neutral words in HC and CIS, but not in RRMS patients, while performing the immediate recall tasks. Delayed recall was not affected by emotional stimuli in both CIS and RR MS groups. The presence of depressive symptoms did not influence the VM performances. ConclusionsOur results demonstrate a defective emotional enhancement of VM in definite MS and, although to a lesser extent, in CIS patients.

The Nature of Verbal Memory Impairment in Multiple Sclerosis: A List-Learning and Meta-analytic Study

The primary purpose of this study was to test the hypothesis that multiple sclerosis (MS) patients have impaired acquisition rather than a retrieval deficit. Verbal memory impairment in MS was examined in 53 relapsing-remitting MS patients and 31 healthy controls (HC), and in a meta-analysis of studies that examined memory functioning in MS with list-learning tasks. The MS group demonstrated significantly lower acquisition and delayed recall performance than the HC group, and the meta-analysis revealed that the largest effect sizes were obtained for acquisition measures relative to delayed recall and recognition. Our data argue against a retrieval deficit as the sole explanation for verbal memory impairment in MS, and make a consistent case for the position that deficient acquisition contributes to the memory dysfunction of MS patients. Deficient acquisition may result from demyelination in relevant white matter tracts that reduces encoding efficiency as a result of impaired speed of information processing.

Memory impairment in multiple sclerosis is due to a core deficit in initial learning

Persons with multiple sclerosis (MS) suffer memory impairment, but research on the nature of MS-related memory problems is mixed. Some have argued for a core deficit in retrieval, while others have identified deficient initial learning as the core deficit. We used a selective reminding paradigm to determine whether deficient initial learning or delayed retrieval represents the primary memory deficit in 44 persons with MS. Brain atrophy was measured from high-resolution MRIs. Regression analyses examined the impact of brain atrophy on (a) initial learning and delayed retrieval separately, and then (b) delayed retrieval controlling for initial learning. Brain atrophy was negatively associated with both initial learning and delayed retrieval (ps < 0.01), but brain atrophy was unrelated to retrieval when controlling for initial learning (p > 0.05). In addition, brain atrophy was associated with inefficient learning across initial acquisition trials, and brain atrophy was unrelated to delayed recall among MS subjects who successfully acquired the word list (although such learning frequently required many exposures). Taken together, memory deficits in MS are a result of deficits in initial learning; moreover, initial learning mediates the relationship between brain atrophy and subsequent retrieval, thereby supporting the core learning-deficit hypothesis of memory impairment in MS.

Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis

The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Is there a future for donepezil therapy in the treatment of multiple sclerosis-related cognitive impairment?

Evaluation of: Krupp LB, Christodoulou C, Melville P et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology 76(17), 1500–1507 (2011).Cognitive impairment is a core feature of multiple sclerosis (MS), is detectable in up to 65% of patients and represents the most important predictor of the subject’s work and vocational status. The cognitive domains most frequently involved are attention, information processing speed, episodic memory and executive functions. To date, there is no approved drug or evidence-based strategy for the treatment of this disabling condition. Promising findings were provided in a monocentric randomized trial on donepezil – a reversible inhibitor of acetylcholinesterase – for the treatment of MS-related memory impairment. However, a larger multicentric trial failed to confirm any efficacy of donepezil on memory impairment in MS subjects. Possible implications of these findings are discussed in this article.

Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis

The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial temporal atrophy

Background:MRI research in multiple sclerosis (MS) samples reveals pathology in both the cerebral cortex and deep grey matter (DGM). The classical subcortical dementia hypothesis has been ascribed to MS and...

Self-generated learning in people with multiple sclerosis: An extension of Chiaravalloti and DeLuca (2002)

Although memory impairment is common in people with multiple sclerosis (MS), few interventions have been tested to remediate forgetfulness in MS. Chiaravalloti and DeLuca (2002) examined the memory benefit of self-generated encoding over didactic presentation in people with MS and a control group. They found that self-generated encoding enhanced memory of MS patients and a control group alike. The present study extended this finding by examining self-generated encoding in memory-impaired MS patients as well. A control group and MS patients with and without memory impairment learned word-pairs that were either self-generated or didactically presented. All groups remembered more self-generated words than those that were read aloud, and severity of memory impairment failed to moderate this memory benefit. Implications of these findings for cognitive rehabilitation and the nature of memory impairment in MS are discussed.