Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Clinical heterogeneity of neuro-inflammatory PET profiles in early Alzheimer's disease.

The relationship between neuroinflammation and cognition remains uncertain in early Alzheimer's disease (AD). We performed a cross-sectional study to assess how neuroinflammation is related to cognition using TSPO PET imaging and a multi-domain neuropsychological assessment. A standard uptake value ratio (SUVR) analysis was performed to measure [18F]-DPA-714 binding using the cerebellar cortex or the whole brain as a (pseudo)reference region. Among 29 patients with early AD, the pattern of neuroinflammation was heterogeneous and exhibited no correlation with cognition at voxel-wise, regional or whole-brain level. The distribution of the SUVR values was independent of sex, APOE phenotype, early and late onset of symptoms and the presence of cerebral amyloid angiopathy. However, we were able to demonstrate a complex dissociation as some patients with similar PET pattern had opposed neuropsychological profiles while other patients with opposite PET profiles had similar neuropsychological presentation. Further studies are needed to explore how this heterogeneity impacts disease progression.

Location-weighted versus Volume-weighted Mismatch at MRI for Response to Mechanical Thrombectomy in Acute Stroke.

Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27; P = .02) and eloquent infarction core was negatively associated with good response (OR, 0.85; 95% CI: 0.77, 0.95; P = .004), while noneloquent mismatch was not associated with good response (OR, 1.03; 95% CI: 0.98, 1.07; P = .20). Moreover, adding eloquent metrics improved the prediction accuracy (AUC, 0.73; 95% CI: 0.65, 0.81) compared with clinical variables alone (AUC, 0.65; 95% CI: 0.56, 0.73; P = .01) or a target mismatch profile (AUC, 0.67; 95% CI: 0.59, 0.76; P = .03). Conclusion Location-weighted infarction core and mismatch on diffusion and perfusion MRI scans improved the identification of patients with acute stroke who would benefit from mechanical thrombectomy compared with the volume-based target mismatch profile. Clinical trial registration no. NCT03045146 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Nael in this issue.

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study.

AIM: Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes. METHODS: In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models. RESULTS: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P   = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P  = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P  <  0.0001) and apoA-I (r = 0.33, P  <  0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P   = 0.012). CONCLUSION: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.

Lung Ultrasound to Assist ICU Admission Decision-Making Process of COVID-19 Patients With Acute Respiratory Failure.

There is only low-certainty evidence on the use of predictive models to assist COVID-19 patient's ICU admission decision-making process. Accumulative evidence suggests that lung ultrasound (LUS) assessment of COVID-19 patients allows accurate bedside evaluation of lung integrity, with the added advantage of repeatability, absence of radiation exposure, reduced risk of virus dissemination, and low cost. Our goal is to assess the performance of a quantified indicator resulting from LUS data compared with standard clinical practice model to predict critical respiratory illness in the 24 hours following hospital admission. DESIGN: Prospective cohort study. SETTING: Critical Care Unit from University Hospital Purpan (Toulouse, France) between July 2020 and March 2021. PATIENTS: Adult patients for COVID-19 who were in acute respiratory failure (ARF), defined as blood oxygen saturation as measured by pulse oximetry less than 90% while breathing room air or respiratory rate greater than or equal to 30 breaths/min at hospital admission. Linear multivariate models were used to identify factors associated with critical respiratory illness, defined as death or mild/severe acute respiratory distress syndrome (Pao2/Fio2 < 200) in the 24 hours after patient's hospital admission. INTERVENTION: LUS assessment. MEASUREMENTS AND MAIN RESULTS: One hundred and forty COVID-19 patients with ARF were studied. This cohort was split into two independent groups: learning sample (first 70 patients) and validation sample (last 70 patients). Interstitial lung water, thickening of the pleural line, and alveolar consolidation detection were strongly associated with patient's outcome. The LUS model predicted more accurately patient's outcomes than the standard clinical practice model (DeLong test: Testing: z score = 2.50, p value = 0.01; Validation: z score = 2.11, p value = 0.03). CONCLUSIONS: LUS assessment of COVID-19 patients with ARF at hospital admission allows a more accurate prediction of the risk of critical respiratory illness than standard clinical practice. These results hold the promise of improving ICU resource allocation process, particularly in the case of massive influx of patients or limited resources, both now and in future anticipated pandemics.

What predicts poor outcome after successful thrombectomy in early time window?

BACKGROUND: Half of the patients with large vessel occlusion (LVO)-related acute ischemic stroke (AIS) who undergo endovascular reperfusion are dead or dependent at 3 months. We hypothesize that in addition to established prognostic factors, baseline imaging profile predicts outcome among reperfusers. METHODS: Consecutive patients receiving endovascular treatment (EVT) within 6 hours after onset with Thrombolysis In Cerebral Infarction (TICI) 2b, 2c and 3 revascularization were included. Poor outcome was defined by a modified Rankin scale (mRS) 3-6 at 90 days. No mismatch (NoMM) profile was defined as a mismatch (MM) ratio ≤1.2 and/or a volume <10 mL on pretreatment imaging. RESULTS: 187 patients were included, and 81 (43%) had a poor outcome. Median delay from stroke onset to the end of EVT was 259 min (IQR 209-340). After multivariable logistic regression analysis, older age (OR 1.26, 95% CI 1.06 to 1.5; p=0.01), higher National Institutes of Health Stroke Scale (NIHSS) (OR 1.15, 95% CI 1.06 to 1.25; p<0.0001), internal carotid artery (ICA) occlusion (OR 3.02, 95% CI 1.2 to 8.0; p=0.021), and NoMM (OR 4.87, 95% CI 1.09 to 22.8; p=0.004) were associated with poor outcome. In addition, post-EVT hemorrhage (OR 3.64, 95% CI 1.5 to 9.1; p=0.04) was also associated with poor outcome. CONCLUSIONS: The absence of a penumbra defined by a NoMM profile on baseline imaging appears to be an independent predictor of poor outcome after reperfusion. Strategies aiming to preserve the penumbra may be encouraged to improve these patients' outcomes.

ASCOD Phenotyping of Stroke With Anterior Large Vessel Occlusion Treated by Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Determining the mechanism of large vessel occlusion related acute ischemic stroke is of major importance to initiate a tailored secondary prevention strategy. We investigated using the atherosclerosis, small vessel disease, cardiac source, other cause, dissection (ASCOD) classification the distribution of the causes of large vessel occlusion related acute ischemic stroke treated by mechanical thrombectomy. METHODS: This was a predefined substudy of the FRAME (French Acute Multimodal Imaging to Select Patient for Mechanical Thrombectomy). Each patient underwent a systematic etiological workup including brain and vascular imaging, electrocardiogram monitoring lasting at least 24 hours and routine blood tests. Stroke mechanisms were systematically evaluated using the atherosclerosis, small vessel disease, cardiac source, other cause, dissection grading system at 3 months. We defined single potential cause by one cause graded 1 in a single domain, possible cause as a cause graded 1 or 2 regardless of overlap, and no identified cause without grade 1 nor 2 causes. RESULTS: A total of 215 patients (mean age 70±14; 50% male) were included. A single potential cause was identified in 148 (69%). Cardio-embolism (53%) was the most frequent, followed by atherosclerosis (9%), dissection (5%) and other causes (1%). Atrial fibrillation accounted for 88% of C1. Overlap between grade 1 causes was uncommon (3%). Possible causes were identified in 168 patients (83%) and 16 (7%) had no cause identified after the initial evaluation. CONCLUSIONS: Cardio-embolism, especially atrial fibrillation, was the major cause of large vessel occlusion related acute ischemic stroke. This finding emphasizes the yield of paroxysmal atrial fibrillation detection in those patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03045146.

Metabolic and cardiovascular adaptations to an 8-wk lifestyle weight loss intervention in younger and older obese men.

The number of older obese adults is increasing worldwide. Whether obese adults show similar health benefits in response to lifestyle interventions at different ages is unknown. The study enrolled 25 obese men (body mass index: 31-39 kg/m2) in two arms according to age (30-40 and 60-70 yr old). Participants underwent an 8-wk intervention with moderate calorie restriction (∼20% below individual energy requirements) and supervised endurance training resulting in ∼5% weight loss. Body composition was measured using dual energy X-ray absorptiometry. Insulin sensitivity was assessed during a hypersinsulinemic-euglycemic clamp. Cardiometabolic profile was derived from blood parameters. Subcutaneous fat and vastus lateralis muscle biopsies were used for ex vivo analyses. Two-way repeated-measure ANOVA and linear mixed models were used to evaluate the response to lifestyle intervention and comparison between the two groups. Fat mass was decreased and bone mass was preserved in the two groups after intervention. Muscle mass decreased significantly in older obese men. Cardiovascular risk (Framingham risk score, plasma triglyceride, and cholesterol) and insulin sensitivity were greatly improved to a similar extent in the two age groups after intervention. Changes in adipose tissue and skeletal muscle transcriptomes were marginal. Analysis of the differential response to the lifestyle intervention showed tenuous differences between age groups. These data suggest that lifestyle intervention combining calorie restriction and exercise shows similar beneficial effects on cardiometabolic risk and insulin sensitivity in younger and older obese men. However, attention must be paid to potential loss of muscle mass in response to weight loss in older obese men.NEW & NOTEWORTHY Rise in obesity and aging worldwide are major trends of critical importance in public health. This study addresses a current challenge in obesity management. Do older obese adults respond differently to a lifestyle intervention composed of moderate calorie restriction and supervised physical activity than younger ones? The main conclusion of the study is that older and younger obese men similarly benefit from the intervention in terms of cardiometabolic risk.

Perfusion Imaging and Clinical Outcome in Acute Ischemic Stroke with Large Core.

OBJECTIVE: Mechanical thrombectomy (MT) is not recommended for acute stroke with large vessel occlusion (LVO) and a large volume of irreversibly injured tissue ("core"). Perfusion imaging may identify a subset of patients with large core who benefit from MT. METHODS: We compared two cohorts of LVO-related patients with large core (>50 ml on diffusion-weighted-imaging or CT-perfusion using RAPID), available perfusion imaging, and treated within 6 hours from onset by either MT + Best Medical Management (BMM) in one prospective study, or BMM alone in the pre-MT era from a prospective registry. Primary outcome was 90-day modified Rankin Scale ≤2. We searched for an interaction between treatment group and amount of penumbra as estimated by the mismatch ratio (MMRatio = critical hypoperfusion/core volume). RESULTS: Overall, 107 patients were included (56 MT + BMM and 51 BMM): Mean age was 68 ± 15 years, median core volume 99 ml (IQR: 72-131) and MMRatio 1.4 (IQR: 1.0-1.9). Baseline clinical and radiological variables were similar between the two groups, except for a higher intravenous thrombolysis rate in the BMM group. The MMRatio strongly modified the clinical outcome following MT (pinteraction < 0.001 for continuous MMRatio); MT was associated with a higher rate of good outcome in patients with, but not in those without, MMRatio>1.2 (adjusted OR [95% CI] = 6.8 [1.7-27.0] vs 0.7 [0.1-6.2], respectively). Similar findings were present for MMRatio ≥1.8 in the subgroup with core ≥70 ml. Parenchymal hemorrhage on follow-up imaging was more frequent in the MT + BMM group regardless of the MMRatio. INTERPRETATION: Perfusion imaging may help select which patients with large core should be considered for MT. Randomized studies are warranted. ANN NEUROL 2021;90:417-427.

A French survey on the lockdown consequences of COVID-19 pandemic in Parkinson's disease. The ERCOPARK study.

BACKGROUND: In 2020 the coronavirus disease 19 (COVID-19) pandemic imposed a total and sudden lockdown. We aimed to investigate the consequences of the first COVID-19 lockdown (mid-March - mid-April 2020) on motor and non-motor symptoms (NMS) in a cohort of French people with Parkinson's disease (PwP). METHODS: PwP were enrolled either by an on-line survey sent from the national France Parkinson association (FP) to reach the French community of PwP or as part of outpatients' telemedicine visits followed by an hospital-based Parkinson Expert Center (PEC). All patients were evaluated using the same standardized questionnaire assessing motor and NMS (including a list of most disabling, new or worsened symptoms and Patient's Global Impression-Improvement scales [PGI-I]) psycho-social queries and quality of life. RESULTS: 2653 PwP were included: 441 (16.6%) in the PEC group and 2122 (83.4%) in the community-based group. Physiotherapy was interrupted among 88.6% of the patients. 40.9% referred a clinical modification of their symptoms. Based on the questionnaire, pain (9.3%), rigidity (9.1%) and tremor (8.5%) were the three most frequently new or worsened reported symptoms. Based on the PGI-I, the motor symptoms were the most affected domain, followed by pain and psychic state. PwP in community-based group tended to have more frequent worsening for motor symptoms, motor complications, pain and confusion than those of the PEC group. CONCLUSIONS: The first COVID-19 lockdown had a negative impact on motor and NMS of PwP. Efforts should be allocated to avoid interruption of care, including physiotherapy and physical activities and implement telemedicine. .

Fluoxetine for the Symptomatic Treatment of Multiple System Atrophy: The MSA-FLUO Trial.

BACKGROUND: There are no effective treatments for multiple system atrophy (MSA). OBJECTIVE: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. METHODS: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. RESULTS: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). CONCLUSION: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society.

Traumatic memory reactivation with or without propranolol for PTSD and comorbid MD symptoms: a randomised clinical trial.

Post-traumatic stress disorder (PTSD) is difficult to treat but one promising strategy is to block memory reconsolidation of the traumatic event. This study aimed to evaluate the efficacy of traumatic memory reactivation under the influence of propranolol, a noradrenergic beta-receptor blocker, in reducing PTSD symptoms as well as comorbid major depression (MD) symptoms. We conducted a double blind, placebo-controlled, randomised clinical trial in 66 adults diagnosed with longstanding PTSD. Propranolol or a placebo was administered 90 min before a brief memory reactivation session, once a week for 6 consecutive weeks. Measures included the SCID PTSD module, the PTSD Check List (PCL-S) and the Beck Depression Inventory-II (BDI-II). PTSD symptoms decreased both in the pre-reactivation propranolol group (39.28%) and the pre-reactivation placebo group (34.48 %). During the 6 treatment sessions, PCL-S and BDI-II scores decreased to similar extent in both groups and there were no treatment differences. During the 3-month follow-up period, there were no treatment effects for the mean PCL-S and BDI-II scores. However, in patients with severe PTSD symptoms (PCL-S ≥ 65) before treatment, PCL-S and BDI-II scores continued to decline 3 months after the end of treatment in the propranolol group while they increased in the placebo group. Repeated traumatic memory reactivation seemed to be effective for PTSD and comorbid MD symptoms. However, the efficacy of propranolol was not greater than that of placebo 1 week post treatment. Furthermore, in this traumatic memory reactivation, PTSD symptom severity at baseline might have influenced the post-treatment effect of propranolol.

Broad white matter impairment in multiple system atrophy.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by the widespread aberrant accumulation of α-synuclein (α-syn). MSA differs from other synucleinopathies such as Parkinson's disease (PD) in that α-syn accumulates primarily in oligodendrocytes, the only source of white matter myelination in the brain. Previous MSA imaging studies have uncovered focal differences in white matter. Here, we sought to build on this work by taking a global perspective on whole brain white matter. In order to do this, in vivo structural imaging and diffusion magnetic resonance imaging were acquired on 26 MSA patients, 26 healthy controls, and 23 PD patients. A refined whole brain approach encompassing the major fiber tracts and the superficial white matter located at the boundary of the cortical mantle was applied. The primary observation was that MSA but not PD patients had whole brain deep and superficial white matter diffusivity abnormalities (p < .001). In addition, in MSA patients, these abnormalities were associated with motor (Unified MSA Rating Scale, Part II) and cognitive functions (Mini-Mental State Examination). The pervasive whole brain abnormalities we observe suggest that there is widespread white matter damage in MSA patients which mirrors the widespread aggregation of α-syn in oligodendrocytes. Importantly, whole brain white matter abnormalities were associated with clinical symptoms, suggesting that white matter impairment may be more central to MSA than previously thought.

Mismatch Profile Influences Outcome After Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) is the recommended treatment for acute ischemic stroke caused by anterior circulation large vessel occlusion. However, despite a high rate of reperfusion, the clinical response to successful MT remains highly variable in the early time window where optimal imaging selection criteria have not been established. We hypothesize that the baseline perfusion imaging profile may help forecast the clinical response to MT in this setting. METHODS: We conducted a prospective multicenter cohort study of patients with large vessel occlusion-related acute ischemic stroke treated by MT within 6 hours. Treatment decisions and the modified Rankin Scale evaluation at 3 months were performed blinded to the results of baseline perfusion imaging. Study groups were defined a posteriori based on predefined imaging profiles: target mismatch (TMM; core volume <70 mL/mismatch ratio >1.2 and mismatch volume >10 mL) versus no TMM or mismatch (MM; mismatch ratio >1.2 and volume >10 mL) versus no MM. Functional recovery (modified Rankin Scale, 0-2) at 3 months was compared based on imaging profile at baseline and whether reperfusion (modified Thrombolysis in Cerebral Infarction 2bc3) was achieved. RESULTS: Two hundred eighteen patients (mean age, 71±15 years; median National Institutes of Health Stroke Scale score, 17 [interquartile range, 12-21]) were enrolled. Perfusion imaging profiles were 71% TMM and 82% MM. The rate of functional recovery was 54% overall. Both TMM and MM profiles were independently associated with a higher rate on functional recovery at 3 months Adjusted odds ratios were 3.3 (95% CI, 1.4-7.9) for TMM and 5.9 (95% CI, 1.8-19.6) for MM. Reperfusion (modified Thrombolysis in Cerebral Infarction 2bc3) was achieved in 86% and was more frequent in TMM and MM patients. Reperfusion was associated with a higher rate of functional recovery in MM and TMM patients but not among those with no MM. CONCLUSIONS: In this cohort study, about 80% of the patients with a large vessel occlusion-related acute ischemic stroke had evidence of penumbra, regardless of infarction volume. Perfusion imaging profiles predict the clinical response to MT.

Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.

We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.

Significant Decrease in Hippocampus and Amygdala Mean Diffusivity in Treatment-Resistant Depression Patients Who Respond to Electroconvulsive Therapy.

Introduction: The hippocampus plays a key role in depressive disorder, and the amygdala is involved in depressive disorder through the key role that it plays in emotional regulation. Electroconvulsive therapy (ECT) may alter the microstructure of these two regions. Since mean diffusivity (MD), is known to be an indirect marker of microstructural integrity and can be derived from diffusion tensor imaging (DTI) scans, we aim to test the hypothesis that treatment-resistant depression (TRD) patients undergoing bilateral (BL) ECT exhibit a decrease of MD in their hippocampus and amygdala. Methods: Patients, between 50 and 70 years of age, diagnosed with TRD were recruited from the University Hospital of Toulouse and assessed clinically (Hamilton Depression Rating Scale, HAM-D) and by DTI scans at three time points: baseline, V2 (during treatment), and V3 within 1 week of completing ECT. Results: We included 15 patients, who were all responders. The left and right hippocampi and the left amygdala showed a significant decrease in MD at V3, compared to baseline [respectively: ß = -2.78, t = -1.97, p = 0.04; ß = -2.56, t = -2, p = 0.04; ß = -2.5, t = -2.3, p = 0.04, false discovery rate (FDR) corrected]. MD did not decrease in the right amygdala. Only the left amygdala was significantly associated with a reduction in HAM-D (ρ = 0.55, p = 0.049, FDR corrected). Conclusion: MD is an indirect microstructural integrity marker, which decreases in the hippocampus and the left amygdala, during BL ECT in TRD populations. This could be interpreted as a normalization of microstructural integrity in these structures.

Grey Matter changes in treatment-resistant depression during electroconvulsive therapy.

INTRODUCTION: 20-30% of depressed patients experience Treatment Resistant Depression (TRD). Electroconvulsive Therapy (ECT) remains the treatment of choice for TRD. However, the exact mechanism of ECT remains unclear. We aim to assess grey matter changes in patients with TRD undergoing bilateral ECT treatment at different points during and after treatment. METHODS: Patients are recruited at the University Hospital of Toulouse. Eligibility criteria include a diagnosis of TRD and an age between 50 and 70 years old. Patients received clinical assessments (Hamilton Depression Rating Scale) and structural scans (MRI) at three points: baseline (within 48 h before the first ECT); V2 (after the first ECT considered effective); and V3 (within 1 week of completing ECT). RESULTS: At baseline, controls had significantly higher cortical thickness than patients in the fusiform gyrus, the inferior, middle and superior temporal gyrus, the parahippocampal gyrus and the transverse temporal gyrus (respectively: t(35)=2.7, p = 0.02; t(35)=2.89, p = 0.017; t(35)=3.1, p = 0.015; t(35)=3.6, p = 0.009; t(35)=2.37, p = 0.031; t(35)=2.46, p = 0.03). This difference was no longer significant after ECT. We showed an increase in cortical thickness in superior temporal gyrus between (i) baseline and V3 (t(62)=-3.43 p = 0.009) and (ii) V2 and V3 (t(62)=-3.42 p = 0.009). We showed an increase in hippocampal volume between (i) baseline and V3 (t(62)=-5.23 p < 0.001) and (ii) V2 and V3 (t(62)=-5.3 p < 0.001). CONCLUSION: We highlight that there are grey matter changes during ECT treatment in a population with TRD compared to a healthy control population. These changes seem to occur after several rounds of ECT.

Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults.

OBJECTIVE: It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project (www.pharmacog.org): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers. METHODS: rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware. RESULTS: In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2-4 Hz) and alpha (8-13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities. CONCLUSIONS: The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness. SIGNIFICANCE: Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia.

Repetitive transcranial magnetic stimulation for functional tremor: A randomized, double-blind, controlled study.

OBJECTIVES: The objective of this study was to compare the effect on functional tremor of active versus sham repetitive transcranial magnetic stimulation and investigate whether the addition of hypnosis might help to prolong any repetitive transcranial magnetic stimulation-induced therapeutic effect. METHODS: We compared the effect of 5 consecutive daily sessions of active/sham repetitive transcranial magnetic stimulation on functional tremor, at 1 and 2 months, in a randomized, double-blind, 2-arm, parallel-controlled study. In a second open-label phase, all patients underwent 3 weekly sessions of hypnosis combined with single sessions of real repetitive transcranial magnetic stimulation. The primary outcome was a change in the Psychogenic Movement Disorder Rating Scale at month 1 when compared with baseline. Secondary outcomes were changes in the Psychogenic Movement Disorder Rating Scale and Tremor subscores, the 36-item Short Form Health Survey, the Self-Report Hospital Anxiety and Depression Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impression Scale assessed at months 1, 2, 6, and 12. RESULTS: A total of 33 outpatients affected by functional tremor were screened, and 18 outpatients fulfilling the inclusion criteria (8 men, 10 women) were randomized. One month after the intervention, the mean Psychogenic Movement Disorder Rating Scale score had decreased in both groups, but the differences from baseline were only significant in the active repetitive transcranial magnetic stimulation group (P < .001). This remained significant at month 2 (P < .001). The significant decrease of the Psychogenic Movement Disorder Rating Scale and Tremor subscores were maintained at months 6 and 12 for the active repetitive transcranial magnetic stimulation group. For the control group, the Psychogenic Movement Disorder Rating Scale score had returned almost to its baseline value by month 2 and remained unchanged at months 6 and 12. CONCLUSION: Repetitive transcranial magnetic stimulation could represent a valuable therapeutic option in the management of functional tremor. © 2019 International Parkinson and Movement Disorder Society.

Naftazone in advanced Parkinson's disease: An acute L-DOPA challenge randomized controlled trial.

INTRODUCTION: There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study. METHODS: We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population. RESULTS: Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ±â€¯3.4 versus 6.7 ±â€¯4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated. CONCLUSIONS: This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration.