Prospective acceptability of digital therapy for major depressive disorder in France: multicentric real-life study.

BACKGROUND: Major depressive disorder is one of the leading causes of disability worldwide. Recently, the WHO has highlighted the negative impact of recent crises (COVID-19 pandemic, war in Ukraine, economic crisis). Although most international guidelines recommend psychological and psychosocial interventions as a first-line treatment for mild to moderate depression, access remains limited in France due to limited availability of trained clinicians, high costs for patients in a context of non-reimbursement and fear of stigmatisation. Therefore, online blended psychological treatment such as deprexis® could improve access to care for people with depression. It has several advantages such as easy access, scalability and is supported by evidence. OBJECTIVE: This study aims to evaluate the real-life acceptability of a deprexis® for people with depression in France, outside of a reimbursement pathway. METHODS: DARE was designed as a multicentre cross-sectional study in which deprexis® was offered to any patient meeting the inclusion criteria during the fixed inclusion period June 2022-March 2023. Inclusion criteria were: 1/ depression, 2/ age between 18 and 65 years, 3/ sufficient French language skills, 4/ access to internet with a device to connect to the deprexis® platform. Exclusion criteria were previous or current diagnosis of bipolar disorder, psychotic symptoms and/or suicidal thoughts during the current episode. The primary objective is to measure the prospective acceptability of deprexis®, a new digital therapy. Secondary objectives are to examine differences in acceptability according to patient and clinician characteristics and to identify reasons for refusal. All investigators received video-based training on deprexis® prior to enrolment to ensure that they all had the same level of information and understanding of the programme. RESULTS: 245 patients were eligible (56.3% women and 56.3% single). Mean age 40.7+-14.1 years. 78% had moderate to severe depression (according to PHQ-9). More than half of the population had another psychiatric comorbidity (excluding bipolar disorder, psychotic disorders and suicidal ideation). 33.9% of patients accepted the idea of using deprexis® and the main reason for refusal was financial, at 83.3%. Multivariate logistic regression identified factors that might favour acceptability of deprexis®. Among these, being in a couple, being treated with an antidepressant or having a low severity level favoured acceptance of deprexis®. CONCLUSIONS: DARE is the first French study aiming at evaluating prospective acceptability of a Digital therapy in the treatment of depression. The main reason for refusal of deprexis® was financial. DARE will allow a better identification of factors influencing it in a natural setting. This study highlights the importance of investigating factors that may be associated with the acceptability of digital interventions, such as marital status, medication use and severity of depression.

Brain dysfunction in gait disorders of Caribbean atypical Parkinsonism and progressive supranuclear palsy patients: A comparative study.

INTRODUCTION: Gait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorders in Caribbean AP and PSP-RS patients. METHODS: We assessed gait and balance using clinical scales and gait recordings in 16 Caribbean AP and 15 PSP-RS patients and 17 age-matched controls. We measured the grey and white matter brain volumes on 3 T brain MRI images. We performed a principal component analysis (PCA) including all the data to determine differences and similarities between groups, and explore the relationship between gait disorders and brain volumes. RESULTS: Both Caribbean AP patients and PSP-RS have marked gait and balance disorders with similar severity. In both groups, gait and balance disorders were found to be most strongly related to structural changes in the lateral cerebellum, caudate nucleus, and fronto-parietal areas. In Caribbean AP patients, gait disorders were also related to additional changes in the cortex, including frontal, insular, temporal and cuneus lobes, whereas in PSP-RS patients, additional white matter changes involved the mesencephalon and parahippocampal gyrus. CONCLUSION: Gait and balance disorders in Caribbean AP patients are mainly related to dysfunction of cortical brain areas involved in visuo-sensorimotor processing and self-awareness, whereas these signs mainly result from premotor-brainstem-cerebellar network dysfunction in PSP-RS patients, brain areas involved in initiation and maintenance of locomotor pattern and postural adaptation.

The pharmacology of blinatumomab: state of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Bispecific drugs (BDs) belong to the family of immunotherapies along with checkpoint inhibitors and CAR-T cells. In the field of oncology, BDs are designed to simultaneously bind a tumour antigen on the one side and an antigen present on the surface of effector cells on the other. This review summarizes the information available to date on the first marketed BiTE-format bispecific antibody, blinatumomab BLINCYTO® in acute lymphoblastic leukaemia. METHODS: A literature search was conducted in the PubMed database by including studies published in English using the term blinatumomab. Furthermore, bibliographies of selected references were also evaluated for relevant articles. Clinical trial (CT) data were retrieved from clinicaltrials.gov (ongoing trials, adverse events [AEs]) and global pharmacovigilance data were retrieved from VigiBase®. RESULTS AND DISCUSSION: Blinatumomab is a fusion protein which consists of two single-chain variable fragments arranged in tandem: the first binds the CD19 surface antigen of all B cells and the second targets the CD3 antigen of T cells. Binding of blinatumomab to B and T cells induces apoptosis of B cells after secretion of granzymes and perforins by T cells. T-cell activation results in secretion of pro-inflammatory cytokines and upregulation of activation markers and adhesion molecules on the surface of T cells. The major CTs that led to an indication show increased overall survival with blinatumomab with better efficacy in patients in haematological remission with minimal residual disease ≥10-3 . The major AEs are cytokine release syndrome, neurotoxicity and hypogammaglobulinemia. The three most frequent system organ classes in CTs are haematological, gastrointestinal and general disorders. These results are also found in VigiBase® but neurological disorders and infections appear more frequently in real life. WHAT IS NEW AND CONCLUSION: This review summarizes the current knowledge of blinatumomab in the literature. The subject of many CTs is to improve the route of administration and expand the indications for treatment.

COVID-19 Presentation and Outcomes among Cancer Patients: A Matched Case-Control Study.

It has been suggested that cancer patients are at higher risk of contracting COVID-19 and at higher risk of developing a severe form of the disease and fatality. This study's objectives were to measure the excess risk of mortality and morbidity of patients with cancer among patients hospitalized for a SARS-CoV-2 infection, and to identify factors associated with the risk of death and morbidity among cancer patients. All first cancer patients hospitalized for COVID-19 in the two main hospitals of the Lyon area were included. These patients were matched based on age, gender, and comorbidities with non-cancer control patients. A total of 108 cancer patients and 193 control patients were included. The severity at admission and the symptoms were similar between the two groups. The risk of early death was higher among cancer patients, while the risk of intubation, number of days with oxygen, length of stay in ICU, and length of hospital stay were reduced. The main factors associated with early death among cancer patients was the severity of COVID-19 and the number of previous chemotherapy lines. The outcomes appear to be driven by the severity of the infection and therapeutic limitations decided at admission.

DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study.

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

Social cognitive impairment in early Parkinson's disease: A novel "mild impairment"?

INTRODUCTION: Social cognition (SC) deficit has recently been described in the early stages of Parkinson's disease (PD), but findings remain unclear. Our objective was to determine the frequency of SC impairment in newly-diagnosed PD patients and whether it is independent of Mild Cognitive Impairment (MCI). METHODS: We enrolled 109 patients with idiopathic PD diagnosed within the previous four years (ICEBERG cohort) and 39 healthy participants. SC was evaluated using the Mini-Social Cognition and Emotional Assessment (Mini-SEA) that allows a multi-domain assessment of SC. Relationships between SC and clinical characteristics, global cognitive efficiency, mood, anxiety, apathy and impulse control disorders, were also evaluated. RESULTS: 30% of patients had significant socio-emotional impairment. Moreover, SC deficit in isolation was 3.5 times more frequent than MCI in isolation (20.2% vs 5.5% respectively). Both emotion identification and Theory of Mind were impaired compared to healthy participants. No effect of age, level of education, disease severity, dopamine replacement therapy, or global cognitive efficiency were found. Only scores on the Frontal Assessment Battery were correlated with SC abilities. CONCLUSION: SC impairment is frequent in early PD and should be given more consideration. It often occurs in the absence of any other cognitive disorder and may represent the most common neuropsychological deficit in early-stage PD. In line with the definition of PD-MCI criteria, we consider the addition of a sixth MCI sub-type termed "Mild Social Cognition Impairment (MSCI)". Further studies are required to validate the addition of this new MCI domain.

Microarray analysis identifies defects in regenerative and immune response pathways in COPD airway basal cells.

BACKGROUND: Airway basal cells are specialised stem cells and regenerate airway epithelium. Airway basal cells isolated from patients with COPD regenerate airway epithelium with an abnormal phenotype. We performed gene expression analysis to gain insights into the defective regenerative programme in COPD basal cells. METHODS: We conducted microarray analysis and compared COPD versus normal basal cells to identify differentially regulated genes (DEGs) and the enriched biological pathways. We determined the correlation of DEGs with cell polarisation and markers of ciliated and goblet cells. HOXB2 was knocked down in 16HBE14o- cells and monitored for polarisation of cells. HOXB2 expression in the lung sections was determined by immunofluorescence. RESULTS: Comparison of normal and COPD basal cell transcriptomic profiles highlighted downregulation of genes associated with tissue development, epithelial cell differentiation and antimicrobial humoral response. Expression of one of the tissue development genes, HOXB2 showed strong correlation with transepithelial resistance and this gene was downregulated in COPD basal cells. Knockdown of HOXB2, abrogated polarisation of epithelial cells in normal cells. Finally, HOXB2 expression was substantially reduced in the bronchial epithelium of COPD patients. CONCLUSIONS: Defect in gene signatures involved in tissue development and epithelial differentiation were implicated in COPD basal cells. One of the tissue developmental genes, HOXB2, is substantially reduced in bronchial epithelium of COPD patients. Since HOXB2 contributes to airway epithelial cell polarisation, we speculate that reduced expression of HOXB2 in COPD may contribute to abnormal airway epithelial regeneration in COPD.

Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles. OBJECTIVE: To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS. METHODS: Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes. RESULTS: We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (ß = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups. CONCLUSION: GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.

Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis.

Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.

Glucocorticoid receptors signaling impairment potentiates amyloid-ß oligomers-induced pathology in an acute model of Alzheimer's disease.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-ß oligomers (oAß), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAß impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAß potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed-forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing Aß and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.

French validation of the questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS).

INTRODUCTION: The management of impulse control disorders (ICDs) in Parkinson's disease (PD) relies on their early identification, allowing adjustment of antiparkinsonian treatment before these manifestations lead to major social, financial or legal consequences. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) is an English-developed and -validated PD-specific rating scale constructed to support the rating of ICDs and related disorders and the assessment of changes in symptom severity over time, but it has not to date been validated in French. METHODS: We conducted an observational, multicenter, cross-sectional study among a subset of patients (n = 280) from the Drug Interacting with Genes in PD (DIG-PD) cohort, aiming to assess psychometric properties of the French version of QUIP-RS: acceptability, internal consistency, factor analysis, reproductibility and hypotheses testing. In addition to this scale, the following measures were applied: MDS-Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination, Frontal Assessment Behavior, and Ardouin Scale of Behavior in Parkinson's Disease (ASBPD). RESULTS: Cronbach's alpha coefficient was 0.72 and ranged from 0.25 to 0.55. Regarding test-retest reliability and inter-rater reliability, the Lin concordance coefficient for items was higher than 0.58. The correlations between QUIP-RS and ASBPD were moderate to high except for dopaminergic addiction and hobbyism (r = 0.41 and 0.40 respectively, p < 0.001). No clinically significant correlation was found between QUIP-RS total score (and items) and other scales. CONCLUSION: The French version of the QUIP-RS appears to be a valid, reliable, and precise instrument for the assessment of ICDs and related disorders in PD. REGISTRATION NUMBER: clinicaltrials.gov number NCT01564992.

Quality of life predicts outcome of deep brain stimulation in early Parkinson disease.

OBJECTIVE: To investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications. METHODS: We performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-up with disease-specific QOL (39-item Parkinson's Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) (UPDRS-III "off" and "on" medications, UPDRS-IV) were conducted to determine predictors of change in PDQ-39-SI. RESULTS: PDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups (p < 0.05). The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group. CONCLUSION: Impaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS. CLINICALTRIALSGOV IDENTIFIER: NCT00354133.

Dynamic changes of DNA methylation and lung disease in cystic fibrosis: lessons from a monogenic disease.

AIM: To assess whether DNA methylation levels account for the noninherited phenotypic variations observed among cystic fibrosis (CF) patients. PATIENTS & METHODS: Using the 450 K BeadChip, we profiled DNA methylation in nasal epithelial cells collected from 32 CF patients and 16 controls. RESULTS: We detected substantial DNA methylation differences up to 55% (median ß change 0.13; IQR: 0.15-0.11) between CF patients and controls. DNA methylation levels differed between mild and severe CF patients and correlated with lung function at 50 CpG sites. CONCLUSION: In CF samples, dynamic changes of DNA methylation occurred in genes responsible for the integrity of the epithelium and the inflammatory and immune responses, were prominent in transcriptionally active genomic regions and were over-represented in enhancers active in lung tissues. ( Clinicaltrials.gov NCT02884622).

Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial.

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

New selective glucocorticoid receptor modulators reverse amyloid-ß peptide-induced hippocampus toxicity.

In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-ß peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment.

Executive functioning and risk-taking behavior in Parkinson's disease patients with impulse control disorders.

Impulse control disorders (ICD) are common in Parkinson's disease (PD) and are associated with dopaminergic medication. The purpose of this study was to investigate executive function and risk-taking behavior in PD patients with ICD. 17 PD patients with ICD (ICD-PD) were compared to 20 PD patients without ICD (CTRL-PD) using neuropsychological and experimental tasks. Executive functions were assessed using standard executive testing (Conner's Performance Test, Modified Wisconsin Card Sorting Test, Trail Making Test and phonological verbal fluency). Subjects were also submitted to an experimental gambling task consisted of three decks of money cards: neutral deck (equal opportunity for gains as losses), winning deck (small amount of money with a positive balance) and loser deck (high amount of money with a negative balance), evaluating risk-taking behavior (number of cards picked in each deck) and valuation of the reward (subjective appreciation of the value of each deck). There was no significant difference in executive functioning between groups. Both groups selected more cards in the losing deck (high amount of money) as compared to the neutral deck (Mann-Whitney test, ICD-PD, p = 0.02; CTRL-PD, p = 0.003) and to the winning deck (Mann-Whitney test, ICD-PD p = 0.0001; CTRL-PD p = 0.003), suggesting an increased risk-taking behavior. Interestingly, we found that ICD-PD patients estimated the value of decks differently from CTRL-PD patients, taking into account mainly the positive reinforced value of the decks (Mann-Whitney test, p = 0.04). This study showed that executive pattern and risk-taking behavior are similar between ICD-PD and CTRL-PD patients. However, ICD-PD patients showed a specific deficit of the subjective estimation of the reward. Links between this deficit and metacognitive skills are discussed.

Evaluation of an integrated multidisciplinary approach in multiple sclerosis care: A prospective, randomized, controlled study.

BACKGROUND: Disabled multiple sclerosis (MS) patients often need intervention of multiple specialists, resulting in a complex organization of care. How this multidisciplinary care should be organized and structured has not been studied. OBJECTIVE: The objective of this article is to address the effectiveness of an integrated multidisciplinary approach versus usual care in MS patients. METHODS: This is a prospective, randomized, controlled, monocentric clinical trial in MS patients. Two treatment strategies were compared: (i) an integrated multidisciplinary (IMD) approach, consisting of a half-day individually tailored comprehensive assessment in the MS clinic; and (ii) a standard care. The primary outcome was the impact of the strategy on quality of life (QoL) measured using the MSIS-29 scale at inclusion and after six months. RESULTS: Fifty MS patients were included. Median MSIS 29 score decreased over six months in the control group (-4.89) and increased in the IMD group (+2.00), with a significant difference between the two groups (p = 0.03). However, in the multivariate analysis, after adjustment of HAD-D and INTERMED score, this difference was no longer significant. CONCLUSIONS: This prospective, randomized study is the first attempt to evaluate the multidisciplinary approach in MS patients. The results show that, contrary to our expectations, an integrated multidisciplinary approach is not superior to usual care on QoL.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease.

OBJECTIVE: To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS: Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS: Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION: In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

Are frontal cognitive and atrophy patterns different in PSP and bvFTD? A comparative neuropsychological and VBM study.

Progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTD) are two clinicohistological entities that share a severe prefrontal syndrome. To what extent do the cognitive syndrome and the location of the underlying brain atrophy unify or segregate these entities? Here, we examined the clinical and radiological patterns of frontal involvement and the neural bases of the cognitive dysfunctions observed in the Richardson form of PSP and the behavioral variant of FTD (bvFTD). The cognitive profile and grey and white matter volume of PSP (n = 19) and bvFTD (n = 16) patients and control participants (n = 18) were compared using a standard battery of neuropsychological tests and voxel-based morphometry (VBM), respectively. Analyses of correlations between neuropsychological and morphometric data were additionally performed. The severity and qualitative pattern of cognitive dysfunction was globally similar between the two patient groups. Grey matter volume was decreased in widespread frontal areas and in the temporal uncus in bvFTD, while it was decreased in the frontal and temporal lobes as well as in the thalamus in PSP. We also found an unexpected involvement of the frontal rectal gyrus in PSP patients compared to controls. Correlation analyses yielded different results in the two groups, with no area showing significant correlations in PSP patients, while several frontal and some temporal areas did so in bvFTD patients. In spite of minor neuropsychological and morphological differences, this study shows that the patterns of cognitive dysfunction and atrophy are very similar in PSP and bvFTD. However, executive dysfunction in these diseases may stem from partially divergent cortical and subcortical neural circuits.