Longitudinal Study of Cognitive and Emotional Alterations in Amyotrophic Lateral Sclerosis: Clinical and Imaging Data.

Objectives: Extra-motor manifestations occur in 50% of patients with amyotrophic lateral sclerosis (ALS). These mainly concern cognition, emotional processing and behavior. Depression and anxiety are less frequent. Little is known about how these manifestations change as the disease progresses. Similarly, although cortical thinning has been well-documented at disease onset, there are scant data about cortical thinning over time and how this correlates with extra-motor manifestations. The present study therefore assessed cognitive, emotional and psychological state and cortical thinning in a group of patients with ALS at baseline and after a follow-up period. Methods: We assessed executive functions, facial emotion recognition, depressive and anxious symptoms, and cortical thinning in 43 patients with ALS at baseline, comparing them with 28 healthy controls, and 21 of them 9 months later. We looked for links among the extra-motor manifestations and correlations with cortical thickness. Results: At baseline, patients had poor executive function and recognition of complex emotions from the eyes, and more anxious and depressive symptoms than controls. At follow-up, only inhibition abilities had worsened. Cortical thinning was observed in bilateral pre-central regions and other parts of the cerebral cortex at baseline. Over time, it worsened in motor and extra-motor areas. Executive functions correlated with thinning in the middle and inferior frontal gyrus and orbitofrontal cortex. Conclusions: During follow-up, there was little deterioration in extra-motor manifestations and psychological state, despite continuing cortical thinning. Patients with affective Theory of Mind (ToM) changes seemed less depressed than the others. Impaired mental flexibility was subtended by prefrontal regions with cortical thinning.

Neuropsychological management of multiple sclerosis: evaluation of a supervised and customized cognitive rehabilitation program for self-used at home (SEPIA): protocol for a randomized controlled trial.

BACKGROUND: Cognitive and mood disorders negatively impact daily life in patients with multiple sclerosis (MS). Pharmacological treatments did not demonstrate any effect on cognition compared with cognitive rehabilitation (CR). However, if CR programs offer promising results on cognition, they are less consistent concerning mood and quality of life (QoL). In this context, we designed a randomized controlled trial to evaluate the efficacy of an innovative computerized CR program, conducted at home, on QoL. Secondary objectives will estimate the improvement, or the stabilization over time, of patients' cognitive performances and their emotional affects. METHODS: Forty MS patients (relapsing-remitting or secondary progressive forms) who have cognitive impairment will be recruited for the trial (called SEPIA-NCT03471338) and randomly assigned to either the experimental group or the control group. Patients randomly assigned in the experimental group will perform a home-based CR program with psychological support during eight consecutive weeks. CR will be based on computerized cognitive exercises from the PRESCO® software developed by HAPPYneuron©. Training sessions (three sessions of 45 min per week) will consist of short exercises evaluating a broad range of cognitive domains and will be personalized for each patient (tracking tool and supervised guidance). The control group, designed to control for non-specific elements of the intervention, will receive only psychological support consisting of various issues related to MS, such as everyday cognitive-related difficulties or management of emotions. QoL, assessed by the MUSIQOL (Multiple Sclerosis International Quality Of Life) questionnaire, will be evaluated three times (at baseline and after 1 week and 25 weeks after home-based intervention) as well as secondary outcomes measuring self-esteem, cognition, depression, anxiety, metacognition, fatigue, and sleep quality. Given the expected MUSIQOL variation, the inclusion of 20 patients per group (alpha risk 5% and power 80%) will be required. DISCUSSION: Evidence suggests that computerized programs may be a practice option for CR for people with MS, but there is a paucity of studies evaluating QoL. We hope that this innovative program will highlight such benefits over time in patients' daily life. In the future, such programs will allow a wider range of available therapeutic options for MS patients with cognitive impairment and for practitioners in charge of their care. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03471338. Retrospectively registered on 25 April 2018. https://clinicaltrials.gov/ct2/show/NCT03471338?term=NCT03471338&cond=Multiple+Sclerosis&draw=2&rank=1 .

Alexithymia in Amyotrophic Lateral Sclerosis and Its Neural Correlates.

Introduction: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive and extensive motor deficits. Patients may also have cognitive impairments or alteration of emotional processing. Very few studies, however, have looked at deficits in how they experience their own feelings (alexithymia). Methods: We assessed alexithymia in 28 patients with ALS using the 20-item Toronto Alexithymia Scale (TAS-20), comparing them with a control group matched for sex, age, and education level. We took into account both the total score of the TAS-20 and its three subscores corresponding to the three dimensions of alexithymia: Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF), and Externally Oriented Thinking (EOT). Patients also underwent a neuropsychological assessment and anatomical magnetic resonance imaging (MRI) in order to correlate cognitive performances and gray matter volume and level of alexithymia. Results: On average, ALS subjects had a significantly higher total score and DIF sub-score of the TAS-20 than controls indicating an increased alexithymia in patients. Total and DIF Scores correlated significantly and negatively to gray matter volume of the prefrontal cortex, right superior temporal pole and parahippocampal gyri. No correlations were found between scores on executive functions and those on the TAS-20. Conclusion: The first stage of one's own emotional processing seems to be affected in ALS independently of executive dysfunction. This trouble seems to be underpinned by cerebral regions that are well known to be both implicated in alexithymia in healthy subjects and altered in ALS.

Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study.

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 (ß=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.

Neural substrate of cognitive theory of mind impairment in amyotrophic lateral sclerosis.

We now know that amyotrophic lateral sclerosis (ALS) is not restricted to the motor system. Indeed, a large proportion of patients with ALS exhibit cognitive impairment, especially executive dysfunction or language impairment. Although researchers have recently turned their attention to theory of mind (ToM) in ALS, only five studies have been performed so far, and they reported somewhat contradictory results. Moreover, the neural basis of the potential ToM deficit in ALS remains largely unknown. The present study was therefore designed to clarify whether a cognitive ToM deficit is indeed associated with ALS, specify the putative link between cognitive ToM deficits and executive dysfunction in ALS, and identify the dysfunctional brain regions responsible for any social cognition deficits. We investigated cognitive ToM and executive functions in a group of 23 patients with ALS and matched healthy controls, using an original false-belief task and a specially designed battery of executive tasks. We also performed an (18)F-fluorodeoxyglucose positron emission tomography examination. Results confirmed the presence of cognitive ToM deficits in patients compared with controls, and revealed significant correlations between ToM and executive functions, although the cognitive ToM deficit persisted when a composite executive function score was entered as a covariate. Using statistical parametric mapping, we calculated positive correlations between tracer uptake and false-belief scores on a voxel-by-voxel basis in the patient sample. Results showed that the cognitive ToM deficit correlated with the dorsomedial and dorsolateral prefrontal cortices, as well as the supplementary motor area. Our findings provide compelling clinical and imaging evidence for the presence of a genuine cognitive ToM deficit in patients with ALS.

[Cognitive disorders and amyotrophic lateral sclerosis. Beyond motor impairment]. / Troubles cognitifs et SLA. Au-delà de l'atteinte motrice.

Amyotrophic lateral sclerosis (ALS) is a predominantly motor disease that can be associated in half the patients with a cognitive and/or behavioral impairment. Cognitive/behavioral disorders are subclinical in most cases and need specific testing to be diagnosed. They can meet the diagnostic criteria of FTLD in 10-15 % of patients. The occurrence of cognitive/behavioral changes in patients with ALS is taken as evidence of a continuum between ALS and fronto-temporal dementias. The cognitive changes mostly involve executive functions, language and social cognition. Behavioral changes include apathy, disinhibition, lack of empathy and impulsivity. Cognitive/behavioral changes in the course of ALS are related to a shorter survival. Cognitive/behavioral changes may interfere with decision making, particularly end-of-life decisions, and they increase the burden of carers. Cognitive/behavioral changes should be recognized and assessed so as to tailor therapeutic interventions.