Abstract:
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 3 T 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 (ss = 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.

Abstract:
Neurocognitive disorders leading to progressive cognitive, functional and behavioural impairment are often undiagnosed or diagnosed lately. But tailored care and therapeutics help in implementing secondary and tertiary prevention dynamics aiming at preserving quality of life and delaying, anticipating or preventing behavioural crisis and severe stages of dementia. Moreover, the diagnosis of numerous diseases induces specific care and therapeutics, as well access to research and clinical trials. For the first time, the representatives of the National College of General Practitioners, the French Federation of Memory Centres, the French Federation of Gerontology and Geriatrics, the French Federation of Neurology, the French Society of Psychogeriatrics and the national plan on neurodegenerative diseases propose a graduated and tailored diagnosis strategy involving primary care and specialists of neurocognitive disorders. This strategy has been built in the context of the national plan on neurodegenerative diseases, the European Joint Action 'Act on dementia', and has been consensually agreed after a seminar animated by the National College of General Practitioners in March 2017.

Abstract:
Cognition and health-related quality of life (HRQoL) are early involved in multiple sclerosis (MS). The aim of QUALICIS study was to monitor cognition and HRQoL prospectively in a cohort of clinically isolated syndrome (CIS) patients starting a treatment with subcutaneous beta-1b interferon as a first disease modifying treatment (DMT), and to assess their correlation with the clinical outcome 6years later. Relapse history, EDSS and yearly standardized brain MRI data were also collected. 37 patients were included. Cognition and HRQoL remained stable over treatment period. At baseline, we found that SDMT was moderately correlated to T2 lesion load (r=-0.47, p=0.04). Baseline SDMT was predictive of HRQoL at year 2 (r=0.53, p=0.02). Regarding 6-year outcome, the most specific predictive factor of favorable outcome was achieving 'No Evidence of Disease Activity' (NEDA) status at year 1. In this group, all the patients had a stable EDSS score and none switched to a second line therapy. In the 'non-NEDA' group, 44% of patients experienced EDSS worsening and 38.9% switched to a second line therapy. The number of gadolinium enhancing lesions on baseline scan was the only predictive factor of poor outcome in this subgroup of patients (2 vs. 0.13, p=0.03). Our results suggest that NEDA at 1year could be used to predict long term outcome after initiation of DMT in CIS. For non-NEDA patients, monitoring SDMT and brain atrophy could be potentially relevant, but this should be confirmed on a larger sample.

Abstract:
BACKGROUND: Health-related quality of life (HRQoL) is impaired in multiple sclerosis (MS) but can be improved by disease-modifying therapies such as natalizumab. However, the predictive factors and neuropsychiatric correlates of HRQoL improvement are unknown. METHODS: In this study, 48 patients with relapsing-remitting MS were included in a 3-year open-label, single group, multicenter, clinical trial (NCT01392872). HRQoL was measured by the disease-specific MusiQoL questionnaire, together with physical disability, cognition, fatigue, anxiety and depression scores at baseline, 6months, 12months, 18months and 36months after starting natalizumab therapy. RESULTS: Compared to baseline, global HRQoL, as measured with the index of the MusiQoL, was significantly increased 6months after the beginning of natalizumab therapy, with medium effect-size (58.6+/-16.2 vs 69.8+/-18.9, p<0.001, Cohen's d=0.63). This improvement was maintained over time for up to 3years and mainly concerned activity of daily living, psychological well-being, symptoms and coping (p<0.001 for every dimensions). The variation of global HRQoL after 3years was negatively correlated with the variation of fatigue score (r=-0.44, p=0.015). Furthermore, a higher fatigue score at baseline was correlated with improvement in global HRQoL 3years afterwards (r=0.34, p=0.041), independently of age, educational level, disease duration and disability at baseline (beta=2.45, p=0.020). Disability at baseline, cognitive impairment, anxiety and depression failed to predict or correlate with global HRQoL improvement in multivariate analyses. CONCLUSION: Natalizumab improved HRQoL quickly and sustainably in patients with relapsing-remitting MS. In terms of HRQoL, natalizumab seems to benefit mostly patients with more marked fatigue at baseline.

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BACKGROUND: Hippocampal-dependent memory impairment is frequent and occurs early during the course of multiple sclerosis (MS). While mechanisms responsible for episodic memory dysfunction in patients with MS remain largely unknown, dentate gyrus structure has been suggested as particularly vulnerable at the early stage of the disease. If true, we hypothesized that the pattern separation component of episodic memory (a function known to be critically dependent to dentate gyrus function) would be impaired in patients with early MS (PweMS). METHODS: Thirty eight participants (19 PweMS and 19 healthy controls matched on age, gender and education level) were tested with a behavioral pattern separation task and also for information processing speed and visuospatial episodic memory. RESULTS: We report a significant decrease in pattern separation performance in PweMS compared to healthy controls (27.07 vs. 40.01, p = .030 after Holm-Bonferroni correction, d = 1.02) together with a significantly higher pattern completion rate (56.11 vs. 40.95, p = .004 after Holm-Bonferroni correction, d = 1.07) while no difference was found among groups for information processing speed and 'global' visuospatial episodic memory regarding learning, long-term recall or recognition. CONCLUSION: Our results suggest that behavioral pattern separation task can detect subtle memory decline in patients with MS and argue for early dentate gyrus dysfunction during the course of the disease.

Abstract:
The objective of this study is to evaluate the relationship between social cognition (SC) and cognitive impairment in persons with multiple sclerosis (PwMS). A prospective study was conducted in 60 PwMS, 30 with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS) and 15 with primary progressive MS (PPMS), and in healthy subjects (HS). All subjects were assessed by the Bordeaux Social Cognition Evaluation Protocol (PECS-B) (facial emotion recognition, theory of mind, emotional awareness and cognitive and affective alexithymia), by a large neuropsychological battery and by questionnaires (depression and anxiety). 43.3% of PwMS were impaired for at least one SC test. The proportion of PwMS with at least two impaired SC tests was similar in all three phenotypes (20%). Mean scores differed significantly between PwMS and HS only for the Reading the Mind in the Eyes Test, a test of Theory of Mind (ToM). ANOVA analyses showed an effect of phenotype on emotional awareness scores with lower scores in PPMS as compared to RRMS. ToM performance was significantly correlated (r 2 = 0.56) with executive functions, working memory and episodic memory scores. SC impairment was found in all phenotypes and was more prominent in cognitively impaired MS patients. Executive functions, and working and episodic memory performance accounts for approximately 50% of ToM performance. Emotional awareness is more impaired in progressive MS.

Abstract:
Cerebellar impairment is frequent and predictive of disability in multiple sclerosis (MS). The Nine-Hole Peg Test (NHPT) is commonly used to assess cerebellar symptoms despite its lack of specificity for cerebellar ataxia. Eye-tracking is a reliable test for identifying subtle cerebellar symptoms and could be used in clinical trials, including those involving early MS patients. To evaluate, by the use of eye-tracking, the accuracy of the NHPT in detecting subtle cerebellar symptoms in patients with clinically isolated syndrome with a high risk of conversion to MS (HR-CIS). Twenty-nine patients and 13 matched healthy controls (HC) underwent an eye-tracking protocol. Cerebellar impairment was defined by registration of saccadic intrusions or at least 10 % dysmetria in a saccadic movement recording. These criteria were compared to NHPT performance. Sixteen patients fulfilled saccadic criteria for cerebellar impairment. NHPT performance was significantly increased in HR-CIS patients (p < 0.01) versus HC. However, NHPT performance did not differ between cerebellar and non-cerebellar groups. NHPT performance with the dominant hand could differentiate patients, particularly cerebellar patients, from HC, but it could not discriminate cerebellar from non-cerebellar patients who were classified according to saccadic criteria. These findings should be considered in future clinical trials involving HR-CIS patients.

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