Combination of anodal tDCS of the cerebellum with a goal-oriented motor training to treat cervical dystonia: a pilot case series.

Background: Transcranial Direct Current Stimulation (tDCS) of the cerebellum shows promise for the treatment of dystonia. Specific motor rehabilitation programs have also been developed in this context. However, the combination of these two approaches has not yet been evaluated to determine their therapeutic potential. Methods: We report a series of 5 patients with cervical dystonia (CD) poorly controlled by botulinum toxin injections. They were initially treated by a protocol of repeated daily sessions (for 3 or 5 days) of cerebellar anodal tDCS (cer-atDCS) applied alone. In a second time, additional protocols of cer-atDCS were performed in combination with a program of goal-oriented motor training exercises (Mot-Training), specifically developed for the treatment of CD. The clinical impact of the procedures was assessed on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Results: Compared to baseline, the maximum percentage of TWSTRS total score improvement was 37% on average after cer-atDCS performed alone (p = 0.147, not significant) and 53% on average after cer-atDCS combined with Mot-Training (p = 0.014, significant). The TWSTRS pain and functional handicap subscores also improved after the combined protocol. A score of (+3) to (+5) was rated on the TWSTRS response scale after cer-atDCS performed alone or the combined protocol, corresponding to a moderate to striking improvement on dystonia and pain. This improvement lasted longer after the combined protocol than after cer-atDCS alone (3.4 vs. 1.4 months on average, p = 0.011). Conclusion: The combination of cer-atDCS with Mot-Training produced a greater and more prolonged improvement than the application of cer-atDCS alone. Such a combined therapeutic procedure is easy to perform and opens important perspectives in the long-term treatment of CD. These results remain to be confirmed by a randomized sham-controlled trial on a larger sample.

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.).

Contacting the gut: Mitochondria-associated Endoplasmic Reticulum Membranes in the Enteric Nervous System.

Changes in the connections between the endoplasmic reticulum (ER) and mitochondria, as well as alterations in mitochondria-associated ER membrane (MAM) signalling, have been documented in various neurodegenerative diseases affecting the brain. Despite the growing recognition of the significance of the gut-brain axis in neurodegenerative conditions, there has been no prior investigation into the biology of MAM within the enteric nervous system (ENS). Our recent research reveals, for the first time, the existence of connections between the ER and mitochondria within enteric neurons. Additionally, we observed alterations in the dynamics of these connections in the enteric neurons from a mouse model exhibiting age-related neurodegeneration. These findings provide the first detailed characterization of MAM in the ENS under physiological conditions and in a mouse model of age-associated neurodegeneration and shed new light on the potential role of enteric MAM in the context of neurodegenerative disorders.

Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-Synuclein Aggregation.

BACKGROUND: The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease. METHODS: Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients. RESULTS: STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process. CONCLUSIONS: These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characterization of mitochondria-associated ER membranes in the enteric nervous system under physiological and pathological conditions.

Alterations in endoplasmic reticulum (ER)-mitochondria associations and in mitochondria-associated ER membrane (MAM) behavior have been reported in the brain in several neurodegenerative diseases. Despite the emerging role of the gut-brain axis in neurodegenerative disorders, the biology of MAM in the enteric nervous system (ENS) has not previously been studied. Therefore, we set out to characterize the MAM in the distal colon of wild-type C57BL/6J mice and senescence-accelerated mouse prone 8 (SAMP8), a mouse model of age-related neurodegeneration. We showed for the first time that MAMs are widely present in enteric neurons and that their association is altered in SAMP8 mice. We then examined the functions of MAMs in a primary culture model of enteric neurons and showed that calcium homeostasis was altered in SAMP8 mice when compared with control animals. These findings provide the first detailed characterization of MAMs in the ENS under physiological conditions and during age-associated neurodegeneration. Further investigation of MAM modifications in the ENS in disease may provide valuable information about the possible role of enteric MAMs in neurodegenerative diseases.NEW & NOTEWORTHY Our work shows for the first time the presence of contacts between endoplasmic reticulum and mitochondria in the enteric neurons and that the dynamic of these contacts is affected in these cells from an age-related neurodegeneration mouse model. It provides new insights into the potential role of enteric mitochondria-associated endoplasmic reticulum membrane in neurodegenerative disorders.

Parkinson's Disease, Impulsive-Compulsive Behaviors, and Health-Related Quality of Life.

OBJECTIVE: A large body of literature has examined the links between the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) and the development of "impulsive-compulsive behaviors (ICBs)." Little is known regarding the link between the development of ICBs and health-related quality of life (HRQOL). We aimed to explore the factors that are associated with poorer HRQOL, especially in relation to DRT-induced ICBs, in a sample of PD patients. METHODS: This PARKADD (PARK: PARKinson's disease; ADD: behavioral ADDictions) study was a prospective case‒control study initially designed to assess the factors associated with ICBs in PD patients. A prospective clinical follow-up was added, aiming to capture the long-term evolution of HRQOL in relation to ICBs occurring or worsening after the beginning of PD. We focused on sociodemographic and PD characteristics and the history or presence of ICBs. HRQOL was measured using the Parkinson's Disease Questionnaire-8. A multivariate linear regression was performed to identify factors related to poorer HRQOL. RESULTS: A total of 169 patients were eligible for the follow-up study. The presence of an ICB, a higher levodopa equivalent daily dose (LEDD) and a longer PD duration were significantly associated with poorer HRQOL, with an interaction between LEDD and PD duration. CONCLUSION: The presence of an ICB was related to poorer HRQOL and should be considered a crucial factor for the management of PD patients. Several studies were recently published that provide guidelines for the management of these patients, with recommendations based on two key principles: prevention and specific treatment.

Wake and non-rapid eye movement sleep dysfunction is associated with colonic neuropathology in Parkinson's disease.

STUDY OBJECTIVES: The body-first Parkinson's disease (PD) hypothesis suggests initial gut Lewy body pathology initially propagates to the pons before reaching the substantia nigra, and subsequently progresses to the diencephalic and cortical levels, a disease course presumed to likely occur in PD with rapid eye movement sleep behavior disorder (RBD). We aimed to explore the potential association between colonic phosphorylated alpha-synuclein histopathology (PASH) and diencephalic or cortical dysfunction evidenced by non-rapid eye movement (NREM) sleep and wakefulness polysomnographic markers. METHODS: In a study involving 43 patients with PD who underwent clinical examination, rectosigmoidoscopy, and polysomnography, we detected PASH on colonic biopsies using whole-mount immunostaining. We performed a visual semi-quantitative analysis of NREM sleep and wake electroencephalography (EEG), confirmed it with automated quantification of spindle and slow wave features of NREM sleep, and the wake dominant frequency, and then determined probable Arizona PD stage classifications based on sleep and wake EEG features. RESULTS: The visual analysis aligned with the automated quantified spindle characteristics and the wake dominant frequency. Altered NREM sleep and wake parameters correlated with markers of PD severity, colonic PASH, and RBD diagnosis. Colonic PASH frequency also increased in parallel to probable Arizona PD stage classifications. CONCLUSIONS: Colonic PASH is strongly associated with widespread brain sleep and wake dysfunction, suggesting an extensive diffusion of the pathologic process in PD. Visual and automated analyses of polysomnography signals provide useful markers to gauge covert brain dysfunction in PD. CLINICAL TRIAL: Name: SYNAPark, URL: https://clinicaltrials.gov/study/NCT01748409, registration: NCT01748409.

Wake and non-rapid eye movement sleep dysfunction is associated with colonic neuropathology in Parkinson's disease.

Study Objectives: The body-first Parkinson's disease (PD) hypothesis suggests initial gut Lewy body pathology that propagates to the pons before reaching the substantia nigra, and subsequently progresses to the diencephalic and cortical levels. This disease course may also be the most likely in PD with rapid eye movement sleep behavior disorder (RBD). Objectives: We aimed to explore the potential association between colonic phosphorylated alpha-synuclein histopathology (PASH) and diencephalic or cortical dysfunction evidenced by non-rapid eye movement (NREM) sleep and wakefulness polysomnographic markers. Methods: In a study involving 43 patients with PD who underwent clinical examination, rectosigmoidoscopy, and polysomnography, we detected PASH on colonic biopsies using whole-mount immunostaining. We performed a visual semi-quantitative and automated quantification of spindle and slow wave features of NREM sleep, and the wake dominant frequency, and then determined Braak and Arizona stage classifications for PD severity based on sleep and wake electroencephalographic features. Results: The visual analysis aligned with the automated quantified spindle characteristics and the wake dominant frequency. Altered NREM sleep and wake parameters correlated with markers of PD severity, colonic PASH, and RBD diagnosis. Colonic PASH frequency also increased in parallel to presumed PD Braak and Arizona stage classifications. Conclusions: Colonic PASH in PD is strongly associated with widespread brain sleep and wake dysfunction, pointing toward likely extensive diffusion of the pathological process in the presumptive body-first PD phenotype. Visual and automated analyses of polysomnography signals provide useful markers to gauge covert brain dysfunction in PD. Statement of Significance: The presence of gut synucleinopathy in Parkinson's disease can be linked to the body-first hypothesis in its pathophysiology. This study, performed in a cohort of 43 patients with Parkinson's disease that underwent clinical assessment, rectosigmoidoscopy and polysomnography, provides evidence that colonic neuropathology in Parkinson's disease is associated with widespread brain dysfunction, as evaluated by wake and non-rapid eye movement sleep polysomnographic markers. Our results support the assumption of an extensive diffusion of the pathological process to diencephalic and neocortical structures in the presumptive body-first phenotype. They also suggest the use of routine polysomnography in phenotyping patients with Parkinson's disease. Future studies should investigate the brain diffusion pattern and its sleep markers in the hypothesized brain-first phenotype of Parkinson's disease.

Are LRRK2 mysteries lurking in the gut?

Gut-brain axis and inflammation are two hot topics in Parkinson's disease (PD). In this setting, the leucine-rich repeat kinase 2 (LRRK2) gene, which encodes the eponym protein, has attracted much attention. LRRK2 is not only the gene most commonly associated with Parkinson's disease but also a susceptibility gene for Crohn's disease (CD), thereby suggesting that it may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. In contrast to the accumulated data on LRRK2 in the central nervous system (CNS), research on LRRK2 in the digestive tract is still in its infancy, and the scope of the present review article is therefore to review existing studies on LRRK2 in the gastrointestinal tract in both physiological and pathological conditions. In light of current data on LRRK2 in the gastrointestinal tract, we discuss if LRRK2 could be or not regarded as a molecular link between gut inflammation, Parkinson's disease, and Crohn's disease, and we suggest directions for future research.

Tau expression and phosphorylation in enteroendocrine cells.

Background and objective: There is mounting evidence to suggest that the gut-brain axis is involved in the development of Parkinson's disease (PD). In this regard, the enteroendocrine cells (EEC), which faces the gut lumen and are connected with both enteric neurons and glial cells have received growing attention. The recent observation showing that these cells express alpha-synuclein, a presynaptic neuronal protein genetically and neuropathologically linked to PD came to reinforce the assumption that EEC might be a key component of the neural circuit between the gut lumen and the brain for the bottom-up propagation of PD pathology. Besides alpha-synuclein, tau is another key protein involved in neurodegeneration and converging evidences indicate that there is an interplay between these two proteins at both molecular and pathological levels. There are no existing studies on tau in EEC and therefore we set out to examine the isoform profile and phosphorylation state of tau in these cells. Methods: Surgical specimens of human colon from control subjects were analyzed by immunohistochemistry using a panel of anti-tau antibodies together with chromogranin A and Glucagon-like peptide-1 (two EEC markers) antibodies. To investigate tau expression further, two EEC lines, namely GLUTag and NCI-H716 were analyzed by Western blot with pan-tau and tau isoform specific antibodies and by RT-PCR. Lambda phosphatase treatment was used to study tau phosphorylation in both cell lines. Eventually, GLUTag were treated with propionate and butyrate, two short chain fatty acids known to sense EEC, and analyzed at different time points by Western blot with an antibody specific for tau phosphorylated at Thr205. Results: We found that tau is expressed and phosphorylated in EEC in adult human colon and that both EEC lines mainly express two tau isoforms that are phosphorylated under basal condition. Both propionate and butyrate regulated tau phosphorylation state by decreasing its phosphorylation at Thr205. Conclusion and inference: Our study is the first to characterize tau in human EEC and in EEC lines. As a whole, our findings provide a basis to unravel the functions of tau in EEC and to further investigate the possibility of pathological changes in tauopathies and synucleinopathies.

Crosstalk between omega-6 oxylipins and the enteric nervous system: Implications for gut disorders?

The enteric nervous system (ENS) continues to dazzle scientists with its ability to integrate signals, from the outside as well as from the host, to accurately regulate digestive functions. Composed of neurons and enteric glial cells, the ENS interplays with numerous neighboring cells through the reception and/or the production of several types of mediators. In particular, ENS can produce and release n-6 oxylipins. These lipid mediators, derived from arachidonic acid, play a major role in inflammatory and allergic processes, but can also regulate immune and nervous system functions. As such, the study of these n-6 oxylipins on the digestive functions, their cross talk with the ENS and their implication in pathophysiological processes is in full expansion and will be discussed in this review.

LRRK2 expression in normal and pathologic human gut and in rodent enteric neural cell lines.

Leucine-rich repeat kinase 2 (LRRK2) gene, which is the gene most commonly associated with Parkinson's disease (PD), is also a susceptibility gene for Crohn's disease, thereby suggesting that LRRK2 may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. LRRK2 protein has been studied intensely in both CNS neurons and in immune cells, but there are only few studies on LRRK2 in the enteric nervous system (ENS). LRRK2 is present in ENS ganglia and the existing studies on LRRK2 expression in colonic biopsies from PD subjects have yielded conflicting results. Herein, we propose to extend these findings by studying in more details LRRK2 expression in the ENS. LRRK2 expression was evaluated in full thickness segments of colon of 16 Lewy body, 12 non-Lewy body disorders cases, and 3 non-neurodegenerative controls and in various enteric neural cell lines. We showed that, in addition to enteric neurons, LRRK2 is constitutively expressed in enteric glial cells in both fetal and adult tissues. LRRK2 immunofluorescence intensity in the myenteric ganglia was not different between Lewy body and non-Lewy body disorders. Additionally, we identified the cAMP pathway as a key signaling pathway involved in the regulation of LRRK2 expression and phosphorylation in the enteric glial cells. Our study is the first detailed characterization of LRRK2 in the ENS and the first to show that enteric glial cells express LRRK2. Our findings provide a basis to unravel the functions of LRRK2 in the ENS and to further investigate the pathological changes in enteric synucleinopathies.

The intestinal barrier in disorders of the central nervous system.

The intestinal barrier, which primarily consists of a mucus layer, an epithelial barrier, and a gut vascular barrier, has a crucial role in health and disease by facilitating nutrient absorption and preventing the entry of pathogens. The intestinal barrier is in close contact with gut microbiota on its luminal side and with enteric neurons and glial cells on its tissue side. Mounting evidence now suggests that the intestinal barrier is compromised not only in digestive disorders, but also in disorders of the central nervous system (CNS), such as Parkinson's disease, autism spectrum disorder, depression, multiple sclerosis, and Alzheimer's disease. After providing an overview of the structure and functions of the intestinal barrier, we review existing preclinical and clinical studies supporting the notion that intestinal barrier dysfunction is present in neurological, neurodevelopmental, and psychiatric disorders. On the basis of this evidence, we discuss the mechanisms that possibly link gut barrier dysfunction and CNS disorders and the potential impact that evaluating enteric barriers in brain disorders could have on clinical practice, in terms of novel diagnostic and therapeutic strategies, in the near future.

Factors Associated with Dual-Fluency Walk Speed Improvement after Rehabilitation in Older Patients.

Walk speed measured under dual-task conditions (neurocognitive tasks) could reflect patient performance in real-life. Rehabilitation programs are effective in increasing walk speed, but few studies have evaluated the associations between geriatric factors and rehabilitation efficacy under dual-task conditions. Our objective was to investigate the association between geriatric factors and an increase in dual-task walk speed (threshold of 0.1 m/s), after a multidisciplinary rehabilitation program. We performed a retrospective cohort study that included patients aged 75 years and over, who underwent a complete rehabilitation program and who had a neurocognitive assessment at baseline. The primary outcome was the increase in the dual-task (fluency verbal task) walking speed between pre- and post-rehabilitation assessments. In this study, 145 patients were included, with a mean age of 83.6 years old. After rehabilitation, dual-task walk speed increase in 62 (43%) patients. In multivariate analysis, the following factors were associated with an increase in dual-task walk speed: IADL (OR 2.50, 95% CI [1.26; 4.94], p = 0.009), vitamin D level (OR 0.83, 95% CI [0.72; 0.95], p = 0.008), severe sarcopenia (OR 0.00, 95% CI [0.00; 0.32], p = 0.016), depression (OR 15.85, 95% CI [1.32; 190.40], p = 0.029), number of drugs (OR 1.41, 95% CI [1.04; 1.92], p = 0.027), initial dual-fluency walk speed (OR 0.92, 95% CI [0.86; 0.98], p = 0.014) and time interval between initial and final assessments (OR 0.98, 95% CI [0.96; 1.00], p = 0.06). Identifying patients that are less resilient to rehabilitation may promote a centered-patient approach for an individualized and optimized rehabilitation care.

Parkinson's disease and iatrogenic impulsive-compulsive behaviors: A case/non-case study to build a complete model of individual vulnerability.

Background and aims: Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. First-line medications consist of drugs that act by counteracting dopamine deficiency in the basal ganglia. Unfortunately, iatrogenic impulsive-compulsive behaviors (ICBs) can occur in up to 20% of PD patients over the course of their illness. ICBs must be considered multifactorial disorders that reflect the interactions of the medication with an individual's vulnerability and the underlying neurobiology of PD. We aimed to explore the predictive genetic, psychopathological and neurological factors involved in the development of ICBs in PD patients by building a complete model of individual vulnerability. Methods: The PARKADD study was a case/non-case study. A total of 225 patients were enrolled ("ICB" group, N = 75; "no ICB" group, N = 150), and 163 agreed to provide saliva samples for genetic analysis. Sociodemographic, neurological and psychiatric characteristics were assessed, and genotyping for the characterization of polymorphisms related to dopaminergic and opioid systems was performed. Results: Factors associated with "ICBs" were younger age of PD onset, personal history of ICB prior to PD onset and higher scores on the urgency and sensation seeking facets of impulsivity. No gene variant was significantly associated, but the association with the opioid receptor mu 1 (OPRM1) rs1799971 polymorphism was close to significance. Discussion and conclusions: The influence of gene-environment interactions probably exists, and additional studies are needed to decipher the possible role of the opioid system in the development of ICBs in PD patients.

Efficacy and Safety of Electroconvulsive Therapy in Patients With Deep Brain Stimulation: Literature Review, Case Report for Patient With Essential Tremor, and Practical Recommendations.

AIM: Deep brain stimulation (DBS) has proven to be an effective therapy of some treatment-resistant psychiatric disorders and movement disorders. Comorbid depressive symptoms are common and difficult to manage. Treatment with electroconvulsive therapy (ECT) may be required. There are few published cases describing the safety and efficacy of ECT for patients with DBS implants, and there are no available guidelines for administration of ECT in patients with DBS and mood disorders. The current study had 3 aims: (i) to conduct a systematic review of case reports on patients with DBS implants who received ECT; (ii) to report the case of a 69-year-old man with a DBS implant for essential tremor, who required ECT; and (iii) to provide practical recommendations for ECT in patients with DBS implants. METHODS: We conducted a systematic review, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, of existing case reports on patients with DBS implants administered ECT for psychiatric disorders. RESULTS: Our search yielded 25 cases of ECT in patients implanted with DBS systems. In addition, we here describe successful ECT management of major depressive disorder in a patient treated by DBS. We also set forth ECT management guidelines based on points of consensus. The 2 most important practical recommendations are to make sure the DBS system is set to 0 V and turned off before ECT, and to avoid sites near the DBS electrodes. CONCLUSIONS: Electroconvulsive therapy may be an effective and safe treatment for DBS patients with MDD.

Is the Snoezelen method a non-pharmacological alternative for patients with neurocognitive disorders? / La méthode Snoezelen : une alternative thérapeutique chez les patients ayant des troubles cognitifs ?

Neuropsychiatric disorders are one of the frequent complications of neurocognitive disease, and have an impact on the quality of life of patients and caregivers. Non-phamacologic interventions are recommended as first-line treatment. The Snoezelen method is a multisensory stimulation method based on the assumption that acting on sensoriality can improve neuropsychiatric symptoms and thus quality of life, but its level of evidence is controversial. To explore this, we performed a systematic literature review of randomized controlled articles focusing on the use of the Snoezelen method in patients with cognitive disorders. Eighteen studies were included. The clinical outcomes studied were multiple (behavior, mood, cognition, functional capacities and biomedical parameters). When the Snoezelen method was compared to the "standard activities" group, it appears to be effective on short-term behavior. This was more negligible when the method was compared to others non-pharmacological interventions. Although the Snoezelen method could be effective on mood, cognition, and functional abilities, its level of evidence remains low. Furthers mixed studies (quantitative and qualitative) would be an interesting approach to delve into this topic in the most holistic way by integrating the patients, the caregivers and the cost of the method.

La prise en soin des symptômes neuropsychiatriques de patients ayant des troubles neurocognitifs est basée sur des traitements non médicamenteux. Certains auteurs suggèrent que la méthode Snoezelen pourrait être une alternative thérapeutique. L'objectif de cette revue de littérature était de faire une recherche systématique des essais contrôlés et randomisés ayant analysé l'effet de la méthode Snoezelen sur les patients âgés ayant des troubles cognitifs. Le processus de sélection a permis d'inclure 18 études, ayant des méthodologies hétérogènes. Dans plusieurs études, la méthode Snoezelen pourrait avoir un effet bénéfique, à court terme, sur les troubles du comportement, sur l'humeur, la cognition, ou les capacités fonctionnelles. Cependant, la méthode Snoezelen ne semblait pas être supérieure à d'autres interventions non médicamenteuses et certaines études montraient des résultats discordants. Finalement, le niveau de preuve d'efficacité de la méthode Snoezelen reste faible et des études mixtes (quantitatives et qualitatives) seraient intéressantes à mener pour évaluer l'intérêt de la méthode Snoezelen sur des profils spécifiques de patients ayant des troubles neurocognitifs.

Comparison of commercially available antibodies for the detection of phosphorylated alpha-synuclein in primary culture of ENS.

BACKGROUND: It is now well established that phosphorylated alpha-synuclein histopathology, the pathologic hallmark of Parkinson's disease (PD) is not limited to the brain but also extends to the enteric nervous system (ENS). This observation led to the hypothesis that the ENS could play a pivotal role in the development of PD. Research on the enteric synucleinopathy has, however, been hampered by difficulties in detecting phosphorylated alpha-synuclein in the ENS by Western blotting, even when the transferred membrane is fixed with an optimized protocol. This suggests that the available antibodies used in previous studies lacked of sensitivity for the detection of phosphorylated alpha-synuclein at Ser129 in enteric neurons. Here, we evaluated three recent commercially available phospho-alpha-synuclein antibodies and compared them to two antibodies used in previous research. METHODS: The specificity and sensitivity of the 5 antibodies were evaluated by Western blot performed with recombinant alpha-synuclein and with protein lysates from rat primary cultures of ENS. In primary culture of ENS, additional experiments were performed with the most specific antibody in order to modulate alpha-synuclein phosphorylation and to validate its utilization in immunofluorescence experiments. RESULTS: The rabbit monoclonal antibody D1R1R uniquely and robustly detected endogenous phosphorylated alpha-synuclein at Ser129 in rat primary culture of ENS without any non-specific bands, allowing for a reliable analysis of phosphorylated alpha-synuclein regulation by pharmacologic means. CONCLUSIONS AND INFERENCES: Using D1R1R antibody together with the optimized protocol for membrane fixation may help deciphering the signaling pathways involved in enteric alpha-synuclein post-translational regulation in PD.