Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.

Impaired social cognition and fine dexterity in patients with Cowden syndrome associated with germline PTEN variants.

PURPOSE: Cowden syndrome (CS) is an autosomal dominant disease related to germline PTEN variants and is characterised by multiple hamartomas, increased risk of cancers and frequent brain alteration. Since the behaviour of patients with CS sometimes appears to be inappropriate, we analysed their neuropsychological functioning. METHODS: This monocentric study was conducted between July 2018 and February 2020. A standardised neuropsychological assessment, including an evaluation of social cognition, executive functions, language and dexterity, as well as a cerebral MRI were systematically proposed to all patients with CS. Moreover, PTEN variants were identified. RESULTS: Fifteen patients from 13 families were included, with six non-sense (40%), three missense (20%), five frameshift (33.3%) and one splice site (6.6%) variant types. Twelve patients (80%) had altered social cognition: 10 patients had an abnormal modified Faux-Pas score and 5 had Ekman's facial emotions recognition impairment. Nearly all patients (93%) had impaired dexterity. Cerebral MRI showed various cerebellar anomalies in seven patients (46.7%). CONCLUSION: Altered social cognition and impaired fine dexterity are frequently associated with CS. Further studies are needed to confirm these results and to determine whether dexterity impairment is due to the effect of germline PTEN variants in the cerebellum.

Decision-making under risk and ambiguity in adults with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) as well as its most common comorbidities are associated with a higher propensity for risky behaviour in everyday life. However, it is unclear whether this increased risk propensity in real-life contexts translates into a generally increased attitude towards risk. We aimed to assess decision-making under risk and ambiguity based on prospect theory by considering the effects of comorbidities and medication. METHODS: Fifty-four individuals with TS and 32 healthy controls performed risk and ambiguity decision-making tasks under both gains and losses conditions. Behavioural and computational parameters were evaluated using (i) univariate analysis to determine parameters difference taking independently; (ii) supervised multivariate analysis to evaluate whether our parameters could jointly account for between-group differences (iii) unsupervised multivariate analysis to explore the potential presence of sub-groups. RESULTS: Except for general 'noisier' (less consistent) decisions in TS, we showed no specific risk-taking behaviour in TS or any relation with tics severity or antipsychotic medication. However, the presence of comorbidities was associated with distortion of decision-making. Specifically, TS with obsessive-compulsive disorder comorbidity was associated with a higher risk-taking profile to increase gain and a higher risk-averse profile to decrease loss. TS with attention-deficit hyperactivity disorder comorbidity was associated with risk-seeking in the ambiguity context to reduce a potential loss. CONCLUSIONS: Impaired valuation of risk and ambiguity was not related to TS per se. Our findings are important for clinical practice: the involvement of individuals with TS in real-life risky situations may actually rather result from other factors such as psychiatric comorbidities.

The "Neurospeed" game: a fun tool to learn the neurological semiology.

BACKGROUND: Neurological semiology is often considered by medical students as particularly difficult to learn. Finding alternative teaching methods may improve students' motivation and understanding of this field. METHODS: We developed the "Neurospeed", a game to learn neurological syndromes. We assessed its efficiency on short-term learning of neurological syndromes in third-year medical students, through Multiple Choice Questions (MCQs) before and after the game session. Students' satisfaction was evaluated by a satisfaction survey. RESULTS: Out of the 199 third-year medical students of the Faculty of Medicine Sorbonne Paris Nord, 180 attended the Neurospeed in December 2020, and 148 answered 20 Multiple Choice Questions before and after the game, with significant improvement of their score (p < 0.001). Most of the participants agreed that the game was playful, stimulating, and helpful to learn neurological semiology. CONCLUSIONS: Overall, our results show that the Neurospeed game is an interesting tool as a complement to traditional lectures. Further studies are necessary to compare the efficacy of different types of serious games on short-term and long-term learning of neurological semiology.

The sooner the better: clinical and neural correlates of impulsive choice in Tourette disorder.

Reward sensitivity has been suggested as one of the central pathophysiological mechanisms in Tourette disorder. However, the subjective valuation of a reward by introduction of delay has received little attention in Tourette disorder, even though it has been suggested as a trans-diagnostic feature of numerous neuropsychiatric disorders. We aimed to assess delay discounting in Tourette disorder and to identify its brain functional correlates. We evaluated delayed discounting and its brain functional correlates in a large group of 54 Tourette disorder patients and 31 healthy controls using a data-driven approach. We identified a subgroup of 29 patients with steeper reward discounting, characterised by a higher burden of impulse-control disorders and a higher level of general impulsivity compared to patients with normal behavioural performance or to controls. Reward discounting was underpinned by resting-state activity of a network comprising the orbito-frontal, cingulate, pre-supplementary motor area, temporal and insular cortices, as well as ventral striatum and hippocampus. Within this network, (i) lower connectivity of pre-supplementary motor area with ventral striatum predicted a higher impulsivity and a steeper reward discounting and (ii) a greater connectivity of pre-supplementary motor area with anterior insular cortex predicted steeper reward discounting and more severe tics. Overall, our results highlight the heterogeneity of the delayed reward processing in Tourette disorder, with steeper reward discounting being a marker of burden in impulsivity and impulse control disorders, and the pre-supplementary motor area being a hub region for the delay discounting, impulsivity and tic severity.

Impulsive prepotent actions and tics in Tourette disorder underpinned by a common neural network.

Tourette disorder (TD), which is characterized by motor and vocal tics, is not in general considered as a product of impulsivity, despite a frequent association with attention deficit hyperactivity disorder and impulse control disorders. It is unclear which type of impulsivity, if any, is intrinsically related to TD and specifically to the severity of tics. The waiting type of motor impulsivity, defined as the difficulty to withhold a specific action, shares some common features with tics. In a large group of adult TD patients compared to healthy controls, we assessed waiting motor impulsivity using a behavioral task, as well as structural and functional underpinnings of waiting impulsivity and tics using multi-modal neuroimaging protocol. We found that unmedicated TD patients showed increased waiting impulsivity compared to controls, which was independent of comorbid conditions, but correlated with the severity of tics. Tic severity did not account directly for waiting impulsivity, but this effect was mediated by connectivity between the right orbito-frontal cortex with caudate nucleus bilaterally. Waiting impulsivity in unmedicated patients with TD also correlated with a higher gray matter signal in deep limbic structures, as well as connectivity with cortical and with cerebellar regions on a functional level. Neither behavioral performance nor structural or functional correlates were related to a psychometric measure of impulsivity or impulsive behaviors in general. Overall, the results suggest that waiting impulsivity in TD was related to tic severity, to functional connectivity of orbito-frontal cortex with caudate nucleus and to structural changes within limbic areas.

Differentiating PNES from epileptic seizures using conversational analysis on French patients: A prospective blinded study.

Psychogenic nonepileptic seizures (PNES) resemble epileptic seizures (ES) but are not caused by the occurrence of excessive cortical neuronal discharge. Previous studies in German-, English-, and Italian-speaking patients showed that patients used a different communicative style to talk about their seizures. They demonstrated that the diagnosis between PNES and ES could be predicted using qualitative assessment and a diagnostic scoring aid (DSA). The objective of our study was to evaluate the contribution of linguistic analysis in the differential diagnosis between ES and PNES in a French patient population. During an extended video-electroencephalogram (video-EEG) monitoring, 13 patients presented PNES and 19 patients with ES. Two neurologists blindly and independently analyzed the interview of each patient. Rater 1 predicted the correct diagnosis in 27 of 32 patients (84%) and Rater 2 in 28 of 32 patients (88%). Interrater reliability of qualitative analysis was satisfactory (k = 0.68, interrater agreement = 84.4%). Using a simplified DSA, Rater 1 and Rater 2 would have correctly diagnosed 88% (28/32 patients) and 91 % (29/32) of the cases, respectively. Our blinded prospective study confirms the diagnostic value of conversational analysis, performed by neurologists, to differentiate PNES from ES in French-speaking patients.

Structural and functional abnormalities within sensori-motor and limbic networks underpin intermittent explosive symptoms in Tourette disorder.

BACKGROUND: Intermittent explosive outbursts (IEO), manifesting as sudden episodes of verbal or physical aggression, are frequently present in patients with Tourette disorder (TD) and considered as one of the most disabling symptoms by patients and families. The neuronal correlates of these behaviours are poorly understood, and this was the primary objective of the present study. METHODS: We assessed the presence of IEO in 55 patients with TD and then compared the subgroup of the patients with IEO to those without these manifestations using a multimodal neuroimaging approach. RESULTS: 47% of TD patients presented IEO, which was frequently associated with attention deficit hyperactivity disorder (ADHD). TD patients (without ADHD) with IEO compared to TD without IEO, showed structural changes in the right supplementary motor area as well as in the right hippocampus (increased fractional anisotropy), and in the left orbitofrontal cortex (decreased mean diffusivity). Using these three nodes as seeds for resting state functional connectivity, we showed a lower connectivity within the sensori-motor cortico-basal ganglia network, and an altered connectivity pattern among the orbito-frontal cortex, amygdala and hippocampus. CONCLUSIONS: Overall, our results indicate that TD with IEO is associated with brain dysfunction related to a less efficient top-down control on action selection, and impairments related to emotional regulation, impulse control and aggressive behaviours.

Neural correlates and role of medication in reactive motor impulsivity in Tourette disorder.

Abnormality of inhibitory control is considered to be a potential cognitive marker of tics in Tourette disorder (TD), attention deficit hyperactivity disorder (ADHD), and impulse control disorders. The results of the studies on inhibitory control in TD showed discrepant results. The aim of the present study was to assess reactive inhibitory control in adult TD patients with and without antipsychotic medication, and under emotional stimulation (visual images with positive, neutral and negative content). We assessed 31 unmedicated and 19 medicated TD patients and 26 matched healthy controls using the stop signal task as an index of reactive motor impulsivity and emotional stimulation with the aim to increase impulsivity. We performed a multimodal neuroimaging analysis using a regions of interest approach on grey matter signal, resting-state spontaneous brain activity and functional connectivity analyses. We found a higher reactive motor impulsivity in TD patients medicated with antipsychotics compared to unmedicated TD patients and controls. This propensity for reactive motor impulsivity in medicated TD patients was not influenced by ADHD or emotional stimulation. Neuroimaging results in medicated TD patients suggested that reactive motor impulsivity was underpinned by an increased grey matter signal from the right supplementary motor area and inferior frontal gyrus; decreased resting-state spontaneous activity of the left putamen; higher functional connectivity between the inferior frontal gyrus and the superior temporal gyri (bilaterally); lower functional connectivity between the cerebellum and the right subthalamic nucleus. Taken together, our data suggested (i) a deficit in reactive motor impulsivity in TD patients medicated with atypical antipsychotics that was unrelated to ADHD and (ii) that motor impulsivity was underpinned by structures and by functional connectivity of the fronto-temporo-basal ganglia-cerebellar pathway.