Effects of subthalamic nucleus stimulation and levodopa on decision‐making in Parkinson's disease

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Multiple System Atrophy: Phenotypic spectrum approach coupled with brain 18-FDG PET

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Subthalamic nucleus stimulation, dopaminergic treatment and impulsivity in Parkinson's disease

International audienceBackground: Deep brain stimulation of the subthalamic nucleus (STN DBS) is known to increase response speed and lower response accuracy in Parkinson's disease (PD) patients. It has been proposed that this speed-accuracy tradeoff is due to enhanced sensitivity of the motor system to sensory information. An alternative possibility is that this effect is due to weakened suppressive processes. The two alternative interpretations can be tested by analyzing the electromyographic activity (EMG) of the response agonists when the patients perform conflict reaction time tasks. In those tasks, fast subthreshold muscle impulses often occur in the agonist of the incorrect response. These impulses are partial errors that are suppressed before being behaviourally committed.Material and Methods: Here we analyzed the EMG of the response agonists recorded while sixteen PD patients performed a Simon task that elicits prepotent response tendencies so as to decipher (i) whether STN DBS affects the expression and/or suppression of subthreshold muscle impulses that are critical for action control and (ii) the interaction between dopaminergic treatment and STN DBS. The patients were tested On and Off STN DBS and On and Off dopaminergic medication in a full factorial design.Results: STN DBS not only impaired the proficiency to suppress subliminal action impulses (p = 0.01) but also favoured the muscular expression of fast incorrect impulses (p<0.001). Dopaminergic treatment only affected the action impulses suppression (p = 0.02) and did not change the effect of STN DBS on impulsive action control.Conclusion: Contrary to a recent proposal, STN DBS impaired rather than improved action control by weakening erroneous impulse suppression, whether the patients were On or Off their usual medication. These findings are discussed in light of a recent proposal (Servant M, White C, Montagnini A, Burle B, 2015) that reconciles partial errors with accumulation-to-bound models of decision making. Our results suggest that medication specifically lowers the mechanical threshold while STN DBS lowers the mechanical threshold and to a lesser extent the EMG-threshold

Subthalamic stimulation breaks the balance between distal and axial signs in Parkinson’s disease

International audienceIn Parkinson's disease (PD), the effects of both L dopa and subthalamic deep brain stimulation (STN-DBS) are known to change cost-valuation. However, this was mostly studied through reward-effort task involving distal movements, while axial effort, less responsive to treatments, have been barely studied. Thus, our objective was to compare the influence of both L dopa and STN-DBS on cost-valuation between two efforts modalities: vowel production (as an example of axial movement) and hand squeezing (as an example of distal movement). Twelve PD patients were recruited to participate in this study. The task consisted in deciding whether to accept or reject trials based on a reward-effort trade-off. Participants performed two blocks with hand squeezing, and two with vowel production, in the four treatment conditions (L dopa On/Off; STN-DBS On/Off). We found that STN-DBS changed the ratio difference between hand and phonation efforts. Vowel production effort was estimated easier to perform with STN-DBS alone, and harder when associated with L dopa. The difference between hand and phonation efforts was correlated with quality of life in Off/Off and On L dopa alone conditions, and with impulsive assessment On STN-DBS alone. We highlighted that STN-DBS could introduce an imbalance between the actual motor impairments and their subjective costs. With this finding, we also suggest paying particular attention to the different treatment effects that should be expected for axial and distal movement dysfunctions

Incobotulinum toxin A in Parkinson's disease with foot dystonia: A double blind randomized trial

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Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis

Trial of botulinum toxin for isolated or essential head tremor

International audienceBackground: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials.Methods: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24.Results: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia.Conclusions: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.)

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases.We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography.Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers.This study evidences an age-dependent increase of β-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases

Heterogeneity of PD-MCI in candidates to subthalamic deep brain stimulation: associated cortical and subcortical modifications

International audienceBackground: Parkinson’s disease mild cognitive impairment (PD-MCI) is frequent and heterogenous. There is no consensus about its influence on subthalamic deep brain stimulation (STN-DBS) outcomes. Objective: To determine the prevalence of PD-MCI and its subtypes in candidates to STN-DBS. Secondarily, we sought to identify MRI structural markers associated with cognitive impairment in these subgroups. Methods: Baseline data from the French multicentric PREDISTIM cohort were used. Candidates to STN-DBS were classified according to their cognitive performance in normal cognition (PD-NC) or PD-MCI. The latter included frontostriatal (PD-FS) and posterior cortical (PD-PC) subtypes. Between-group comparisons were performed on demographical and clinical variables as well as on T1-weighted MRI sequences at the cortical and subcortical levels. Results: 320 patients were included: 167 (52%) PD-NC and 153 (48%) PD-MCI patients. The latter group included 123 (80%) PD-FS and 30 (20%) PD-PC patients. There was no between-group difference regarding demographic and clinical variables. PD-PC patients had significantly lower global efficiency than PD-FS patients and significantly worse performance on visuospatial functions, episodic memory, and language. Compared to PD-NC, PD-MCI patients had cortical thinning and radiomic-based changes in the left caudate nucleus and hippocampus. There were no significant differences between the PD-MCI subtypes. Conclusion: Among the candidates to STN-DBS, a significant proportion has PD-MCI which is associated with cortical and subcortical alterations. Some PD-MCI patients have posterior cortical deficits, a subtype known to be at higher risk of dementia

High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

International audiencePurpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation