Regional hippocampal vulnerability in early multiple sclerosis: a dynamic pathological spreading from dentate gyrus to CA1

"This is the peer reviewed version of the following article: Planche, V., Koubiyr, I., Romero, J. E., Manjon, J. V., Coupé, P., Deloire, M., ... & Tourdias, T. (2018). Regional hippocampal vulnerability in early multiple sclerosis: Dynamic pathological spreading from dentate gyrus to CA 1. Human brain mapping, 39(4), 1814-1824., which has been published in final form at https://doi.org/10.1002/hbm.23970. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] Background: Whether hippocampal subfields are differentially vulnerable at the earliest stages of multiple sclerosis (MS) and how this impacts memory performance is a current topic of debate. Method: We prospectively included 56 persons with clinically isolated syndrome (CIS) suggestive of MS in a 1-year longitudinal study, together with 55 matched healthy controls at baseline. Participants were tested for memory performance and scanned with 3T MRI to assess the volume of 5 distinct hippocampal subfields using automatic segmentation techniques. Results: At baseline, CA4/dentate gyrus was the only hippocampal subfield with a volume significantly smaller than controls (p < .01). After one year, CA4/dentate gyrus atrophy worsened (-6.4%, p < .0001) and significant CA1 atrophy appeared (both in the stratum-pyramidale and the stratum radiatum-lacunosum-moleculare, -5.6%, p < .001 and -6.2%, p < .01, respectively). CA4/dentate gyrus volume at baseline predicted CA1 volume one year after CIS (R-2 = 0.44 to 0.47, p < .001, with age, T2 lesion-load, and global brain atrophy as covariates). The volume of CA4/dentate gyrus at baseline was associated with MS diagnosis during follow-up, independently of T2-lesion load and demographic variables (p < .05). Whereas CA4/dentate gyrus volume was not correlated with memory scores at baseline, CA1 atrophy was an independent correlate of episodic verbal memory performance one year after CIS (beta = 0.87, p < .05). Conclusion: The hippocampal degenerative process spread from dentate gyrus to CA1 at the earliest stage of MS. This dynamic vulnerability is associated with MS diagnosis after CIS and will ultimately impact hippocampal-dependent memory performance.ARSEP Foundation; Bordeaux University Hospital; TEVA Laboratories; French Agence Nationale de la Recherche, Grant/Award Numbers: ANR-10-LABX-57, ANR-10-LABX-43, ANR-10-IDEX-03-02, ANR-10-COHO-002; UPV, Grant/Award Numbers: UPV2016-0099, TIN2013-43457-R; Ministerio de Economia y competitividadPlanche, V.; Koubiyr, I.; Romero Gómez, JE.; Manjón Herrera, JV.; Coupe, P.; Deloire, M.; Dousset, V.... (2018). Regional hippocampal vulnerability in early multiple sclerosis: a dynamic pathological spreading from dentate gyrus to CA1. 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: MR and cognitive decline in RRMS

International audienceThe main predictors of cognitive changes over 7 years are baseline diffuse brain damage and progressive central brain atrophy over the 2 years after MS diagnosis

Mult Scler.

Background: The Brief Computerized Cognitive Assessment in Multiple Sclerosis (BCCAMS) is a short neuropsychological battery for persons with multiple sclerosis (PwMS). Objectives: The main objective of the study is to validate the BCCAMS. Methods: PwMS and healthy subjects (HS) were evaluated using the BCCAMS which include two computerized tests, the Computerized Speed Cognitive Test and the Computerized Episodic Visual Memory Test (CEVMT), a newly developed visuospatial memory test, and the French learning test. The Minimal Assessment of Cognitive Function in MS (MACFIMS), including the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) tests, was also administered. Regression-based norms of the BCCAMS were calculated in 276 HS. BCCAMS was compared with BICAMS and MACFIMS for detection of cognitive impairment (CI). Results: Out of 120 PwMS, CI was detected using the BCCAMS, BICAMS (one impaired test), and MACFIMS (two impaired tests) in 59.1%, 50%, and 37.9%, respectively. The BCCAMS produced the same predictive value as that of the BICAMS battery for detecting CI in the MACFIMS. Conclusion: This study validated the BCCAMS as a validated computerized short assessment for information processing speed and learning in MS. © The Author(s), 2021

Rev Neurol (Paris)

Background: Cognitive impairment is important to consider in the assessment of multiple sclerosis (MS) patients. A short battery of cognitive assessment, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), has been developed to address the need for rapid assessment by combining 3 tests assessing the main cognitive spheres reached in MS. Objectives: To establish regression-based norms of the BICAMS in French speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS). Methods: In all, 123 PwMS including 40 with relapsing-remitting MS, 41 patients with secondary progressive MS and 42 with primary progressive MS and 276 HS were evaluated by the BICAMS including 3 tests, the Symbol Digit Modalities Test (SDMT), the French Verbal learning test (FVLT) a French-adapted memory test, (or the California Verbal Learning Test (CVLT) at retesting) and the Brief Visuo-Spatial Memory Test (BVMT-R). The standards for these tests were established in the healthy population using a multiple regression technique. Validity in MS was measured. Results: Regression-based norms of BICAMS tests have been established in the HS population. 50.4% of PwMS have impairment for at least one BICAMS test (-1.5SD on the Z-score). The most common pathological test was the FVLT altered in 36.6% of patients, followed by the SDMT and the BVMT-R. The re-test reliability was good for the various BICAMS tests, 0.891 for SDMT, 0.781 for FVLT/CVLT and 0.669 for BVMT-R. Conclusion: This study establishes the validity of the BICAMS as a short and easy to apply battery for a brief assessment of the speed of information processing and episodic memory in MS

J Neurosci Res

Theory of mind (ToM) seems to be affected in multiple sclerosis (MS). MRI studies suggested a role of the amygdala in social cognitive performances. Therefore, we explored the role of the amygdala network in ToM using a multimodal MRI approach. In MS, patients with impaired ToM showed contradictory dysexecutive neuropsychological profile. Therefore, we compared neural networks involved in ToM and executive functions (EFs). Twenty patients with relapsing-remitting MS and 15 matched healthy controls were selected. ToM (Faux Pas test and mind stories) and EFs were assessed within and outside the scanner. All subjects underwent a battery of neuropsychological tests. Multimodal MRI with structural (diffusion imaging) and functional (resting-state and task-based) sequences was used to analyze the role and connections of the amygdala in ToM functioning. Cognitive and ToM performances were similar between patients and controls. Resting-state data revealed decreased connectivity of the left amygdala with frontal areas in patients compared to controls (p < 0.0001). During the task-based functional MRI, patients demonstrated increased connectivity between the amygdala and several cerebellar and left temporal regions (all p < 0.05). The microstructural alterations between the left amygdala and left temporal regions were associated with increased functional connectivity within the same pathway (r = 0.74; p < 0.01). No overlap was observed between functional networks involved in ToM and EFs. Our study demonstrates more connectivity recruitment between the amygdala and cerebellar and temporal regions in MS patients to reach preserved ToM performance. Microstructural abnormalities have been related to this compensatory network. Finally, different networks were involved in EFs and ToM. © 2021 Wiley Periodicals LLC.Observatoire Français de la Sclérose en Plaque

French validation of the Brief International Cognitive Assessment for Multiple Sclerosis

International audienceBackground: Cognitive impairment is important to consider in the assessment of multiple sclerosis (MS) patients. A short battery of cognitive assessment, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), has been developed to address the need for rapid assessment by combining 3 tests assessing the main cognitive spheres reached in MS. Objectives: To establish regression-based norms of the BICAMS in French speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS). Methods: In all, 123 PwMS including 40 with relapsing-remitting MS, 41 patients with secondary progressive MS and 42 with primary progressive MS and 276 HS were evaluated by the BICAMS including 3 tests, the Symbol Digit Modalities Test (SDMT), the French Verbal learning test (FVLT) a French-adapted memory test, (or the California Verbal Learning Test (CVLT) at retesting) and the Brief Visuo-Spatial Memory Test (BVMT-R). The standards for these tests were established in the healthy population using a multiple regression technique. Validity in MS was measured. Results: Regression-based norms of BICAMS tests have been established in the HS population. 50.4% of PwMS have impairment for at least one BICAMS test (-1.5SD on the Z-score). The most common pathological test was the FVLT altered in 36.6% of patients, followed by the SDMT and the BVMT-R. The re-test reliability was good for the various BICAMS tests, 0.891 for SDMT, 0.781 for FVLT/CVLT and 0.669 for BVMT-R. Conclusion: This study establishes the validity of the BICAMS as a short and easy to apply battery for a brief assessment of the speed of information processing and episodic memory in MS

Front Neurol

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.Translational Research and Advanced Imaging Laborator

Mult Scler

Background: The relationship between structural and functional deficits in multiple sclerosis (MS) is unclear. Objective: This study explored structure-function relationships during the 5 years following a clinically isolated syndrome and their role in cognitive performance. Methods: Thirty-two patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years, along with 10 matched healthy controls. We assessed structural (using diffusion tensor imaging) and functional (using resting-state functional magnetic resonance imaging (fMRI)) brain network metrics, clinical and cognitive scores at each follow-up visit. Structural–functional coupling, calculated as the correlation coefficient between strengths of structural and functional networks, was used to assess structure–function relationships. Results: Structural clustering coefficient was significantly increased after 5 years, whereas characteristic path length decreased. Structural connections decreased after 1 year and increased after 5 years. Functional connections and related path lengths were decreased after 5 years. Structural–functional coupling had increased significantly after 5 years. This structural–functional coupling was associated with cognitive and clinical evolution, with stronger coupling associated with a decline in both domains. Conclusion: Our findings provide novel biological evidence that MS leads to a more constrained anatomical-dependant functional connectivity. The collapse of this network seems to lead to both cognitive worsening and clinical disability

Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome

International audienc

Validation of the French version of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS)

International audienceBackground: The Minimal Assessment of Cognitive Function in Multiple sclerosis (MACFIMS) is an internationally recognised battery of neuropsychological tests for patients with multiple sclerosis (MS).Objectives: To establish regression-based norms for the MACFIMS in French-speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS).Methods: 136 PwMS, including 43 with relapsing-remitting MS, 46 with secondary progressive MS and 45 with primary progressive MS, as well as 276 HS were enrolled. Regression-based norms and validity were established for the seven tests of the MACIMS: the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), the French learning test (FLT) a French-adapted memory test (or the California Verbal Learning Test (CVLT) at re-testing), the Judgment of Line Orientation Test (JLO), the 'épreuve de classement de cartes de Champagne' (ECCC), a French adaptation of the DKEF-sorting test, the Brief Visuospatial Memory Test (BVMT-R) and the Controlled Oral Word Association Test (COWAT).Results: Regression-based norms of MACFIMS tests were established in the HS population. The MACFIMS battery was able to identify cognitive impairment (CI) (at least two abnormal tests in different domains) in 32.7% of PwMS. The domains with more frequent impairment were (in descending order): learning followed by IPS, delayed memory, verbal fluency and working memory.Conclusion: This study established the regression-based norms for French subjects of the French adaptation of the MACFIMS and its validity in PwMS