Effects of trihexyphenidyl on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson's disease: An fNIRS study.

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Trihexyphenidyl (marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Parkinson's disease. It was approved by the FDA for the treatment of Parkinson's in the US in 2003.

Artane has been shown to have several sides effects, some similar to Parkinson's symptoms, in particular people who are older or who have psychiatric conditions may become confused or develop delirium.

Despite growing concerns about Trihexyphenidyl causing cognitive decline in tremor-dominant Parkinson disease patients, the underlying neural correlates remain unclear. Therefore, the authors investigated the effects of this drug on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson disease by utilizing functional near-infrared spectroscopy.

The authors recruited 30 patients with tremor-dominant Parkinson disease, including 15 patients receiving the treatment and 15 patients not receiving Trihexyphenidyl.

The researchers performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms.

They measured brain activation elicited from the verbal fluency task and changes in amplitude of low-frequency fluctuations at rest to investigate executive function and spontaneous neural activity, respectively. In addition, the authors examined the relationship between altered activation during task and resting state and neuropsychological and clinical data.

Compared with tremor-dominant Parkinson disease patients not taking Trihexyphenidyl, tremor-dominant Parkinson disease patients taking the treatment showed no differences on neuropsychological tests.

However, there was insufficient activity of the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and the orbitofrontal cortex related to the frontoparietal network at rest.

Furthermore, functional near-infrared spectroscopy results were positively correlated with scores of multiple cognitive domain functions.

These findings suggest that Trihexyphenidyl treatment may lead to prefrontal dysfunction in tremor-dominant Parkinson disease patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity.

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Acting on the diet or the microbiome can help relieve the symptoms of Parkinson's disease.

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Patients have long said that diets can relieve symptoms of diseases such as Alzheimer's and Parkinson's. Many ALS patients take supplements in varying amounts and types. These claims have long been derided by scientists, yet scientists are now starting to change their minds.

The authors of a new scientific article therefore investigated whether a high fiber diet influences microglial function in mouse models of Parkinson's disease that overexpress α-synuclein. These mice are called ASO (α-synuclein overexpressing) mice.

Parkinson's disease is a disease characterized by α-synuclein pathology and/or dopamine deficiency resulting from degeneration of the substantia nigra (a region of the midbrain).

Although Parkinson's disease is primarily classified as a brain disorder, 70-80% of patients experience gastrointestinal symptoms, primarily constipation, but also abdominal pain and increased intestinal permeability which usually manifest in prodromal stages (Forsyth et al. 2011; Yang et al 2019).

Braak postulated nearly 20 years ago that α-synuclein aggregation can begin in the gastrointestinal tract or olfactory bulb, and eventually reach the brainstem, substantia nigra, and neocortex via the vagus nerve ( Braak et al. 2003). A growing body of evidence supports the potential for gut-to-brain spread of α-synuclein pathology in rodents (S. Kim et al. 2019; B. Liu et al. 2017; Svensson et al. 2015).

The vagus nerve, a long winding nerve, is a major two-way information signaling pathway between the gut and the brain. Vagotomy is the surgical section of the pneumogastric nerve, or vagus nerve, at the level of the abdomen. Vagotomy has been used for decades and most patients who have had such surgery and are still alive are now elderly. A Swedish registry study investigated the risk of Parkinson's disease in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect.

The scientists found that the risk of Parkinson's disease was indeed reduced in patients who underwent a complete truncal vagotomy, whereas there was no risk reduction in those who underwent a selective vagotomy. The risk of Parkinson's disease is also reduced after truncal vagotomy compared to the general population. These epidemiological findings are important and support the hypothesis that Parkinson's disease begins in the gut and not initially in the brain. This provides further evidence for the involvement of the vagus nerve in disease development.

Many important chemical compounds (nowadays we say "molecular" to make it sound important) are produced in the intestine and end up in the brain via the bloodstream. Many of them are made or have their production regulated by gut microbes.

These include short chain fatty acids tryptophan, leptin and ghrelin. Short chain fatty acids include butyrate, propionate and acetate. Butyrate is a known inhibitor of histone deacetylases (HDACs) and in doing so acts as an epigenetic regulator. Cytokines, key immune-regulating molecules produced in the gut, can travel through the bloodstream and influence brain function, particularly in regions of the brain where the blood-brain barrier is deficient.

Among other effects, microbial food metabolites can modulate the activation of microglia, these nerve cells which are essential for the survival of neurons are implicated in Parkinson's disease. Microglia respond to signals from inside the brain, but also receive information from the periphery, including the gut microbiome (Abdel88 Haq et al. 2019). Microglia from germ-free adult mice show an immature gene expression profile and do not respond adequately to immunostimulants (Erny et al. 2015; Thion et al. 2018). However, if these germ-free mice are fed a mixture of short-chain fatty acids, microglial maturation is restored (Erny et al. 2015).

The gut microbiota is a virtual organ that produces a myriad of molecules needed by the brain and other organs. Humans and microbes are in a symbiotic relationship, humans feed the microbes, and microbes in turn provide essential molecules.

The phyla Bacteroidetes and Firmicutes represent approximately 80% of total human gut microbiota. The genera of the Firmicutes phylum include Clostridium, Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminicoccus. The phylum Bacteroidetes mainly includes the genera Bacteroides and Prevotella.

The phylum Actinobacterium is dominated by the genus Bifidobacterium. Bifidobacteria and lactobacilli are generally considered beneficial bacteria and are frequently sold as probiotic supplements. Strains of the genus Clostridium or lipopolysaccharide taxa such as Enterobacteriaceae have been associated with disease states in many neurodegenerative diseases including ALS (Charcot's disease).

Similarly but somewhat controversially, the Firmicutes/Bacteroidetes ratio, which explores the relationship between the two dominant phyla, has been associated with various neurodegenerative pathologies.

So, the intestinal microbiome is altered in Parkinson's disease. It is found in mice models of Parkinson's disease (the mice have been genetically engineered to carry a disease resembling that of Parkinson's) that the fecal levels of short-chain fatty acids are different in mice with Parkinson's disease and mice. healthy. It is the intestinal bacteria that transform dietary fiber into short-chain fatty acids by fermentation.

The authors designed personalized high-fiber diets, each containing 20% ​​of a prebiotic blend of two or three dietary fibers designed to support the growth of 5 distinct gut bacterial taxa and stimulate the production of short-chain fatty acids based on of faecal fermentation in vitro.

The scientists then observed broad changes at the microbial phylum and genus level after administration of a prebiotic diet, displaying an increase in Bacteroidetes and a decrease in Firmicutes in mice fed a prebiotic diet, resulting in a lower Firmicutes ratio. /Bacteroidetes (F/B) that has been associated with general features of metabolic health.

Interestingly, Bacteroidetes have been shown to be reduced in Parkinson's patients compared to age-matched controls, suggesting that the prebiotic may counteract this effect (Unger et al. 2016). Additionally, they observed a decrease in proteobacteria, a phylum often increased in dysbiosis and inflammation and elevated in fecal samples from patients with Parkinson's disease (Keshavarzian et al. 2015; Shin, Whon, and Bae 2015).

A fiber-rich prebiotic diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice.

Meanwhile, the gut microbiome of ASO mice adopts a health-correlated profile upon prebiotic treatment, which also reduces microglial activation.

Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum reveals increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to their wild-type counterparts on a standard diet.

Prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of microglia's disease-associated protective macrophage (DAM) subsets. Microglia are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for development, maintenance and proliferation (Elmore et al. 2014).

To test the opposite effect: If depletion of microglia eliminated the beneficial effects of prebiotics, the authors added PLX5622 to the diet of mice aged 5 to 22 weeks and quantified the number of IBA1+ microglia in various brain regions. PLX5622 is a brain-penetrating CSF1R inhibitor that can deplete microglia with no observed effects on behavior or cognition (Elmore et al. 2014).

Depletion of microglia using a CSF1R inhibitor effectively eliminated the beneficial effects of prebiotics and restored motor deficits in ASO mice despite a prebiotic diet.

These studies reveal a novel microglia-dependent interaction between diet and motor Parkinson's disease in mice, findings that may have implications for neuroinflammation and Parkinson's disease.

Prebiotics present a potentially promising therapeutic approach, as diet contributes significantly to the composition of the microbiome and epidemiological evidence has linked high fiber diets to reduced risk of developing Parkinson's disease (Boulos et al 2019).

While increased vegetable intake and adherence to a Mediterranean diet are associated with a lower risk of Parkinson's disease, people consuming a low-fiber, highly processed Western diet have an increased risk of being diagnosed with Parkinson's disease. (Alcalay et al. 2012; Gao et al. 2007; Molsberry et al. 2020).

Several ongoing clinical trials are exploring the beneficial effects of probiotics and prebiotics on Parkinson's disease outcomes. Acting on the diet or the microbiome can help relieve the symptoms of Parkinson's disease.

Agir sur le régime alimentaire ou le microbiome, peut aider à soulager les symptômes de la maladie de Parkinson.

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Depuis longtemps des patients disent que des régimes alimentaires peuvent soulager des symptomes pour des maladies telles que Alzheimer ou Parkinson. Nombre de malade de la SLA prennent des suppléments en quantité et genre très variés. Ces affirmations ont longtemps été moquées par les scientifiques, pourtant ceux-ci commencent maintenant à changer de point de vue.

Les auteurs d'un nouvel article scientifique ont donc étudié si un régime riche en fibres influence la fonction microgliale chez des souris modèles de la maladie de Parkinson qui surexpriment l'α-synucléine. Ces souris sont appelée souris ASO (α-synuclein overexpressing).

La maladie de Parkinson est une maladie éventuellement caractérisée par une pathologie de l'α-synucléine et/ou un déficit en dopamine résultant de la dégénérescence de la substantia nigra (une région du mésencéphale).

Bien que la maladie de Parkinson soit principalement classée comme un trouble cérébral, 70 à 80 % des patients présentent des symaladie de Parkinsontômes gastro-intestinaux, principalement de la constipation, mais également des douleurs abdominales et une augmentation de la perméabilité intestinale qui se manifestent généralement dans les stades prodromiques (Forsyth et al. 2011 ; Yang et al 2019).

Braak a postulé il y a près de 20 ans que l'agrégation l'α-synucléine peut commencer dans le tractus gastro-intestinal ou le bulbe olfactif, et finalement atteindre le tronc cérébral, la substantia nigra et le néocortex via le nerf vague (Braak et al. 2003). De plus en plus d'éléments corroborent le potentiel de propagation de l'intestin au cerveau de la pathologie l'α-synucléine chez rongeurs (S. Kim et al. 2019 ; B. Liu et al. 2017 ; Svensson et al. 2015).

Le nerf vague, un long nerf sinueux, est une voie majeure de signalisation d'informations bidirectionnelles entre l'intestin et le cerveau. La vagotomie est la section chirurgicale du nerf pneumogastrique, ou nerf vague, au niveau de l'abdomen. La vagotomie été utilisée pendant des décennies et la plupart des patients qui ont subi une telle chirurgie et qui sont encore en vie sont maintenant des personnes âgées. Une étude de registre suédoise a étudié le risque de maladie de Parkinson chez les patients ayant subi une vagotomie et a émis l'hypothèse que la vagotomie tronculaire est associée à un effet protecteur.

Les scientifiques ont constaté que le risque de maladie de Parkinson était en effet diminué chez les patients ayant subi une vagotomie tronculaire complète, alors qu'il n'y avait pas de réduction du risque chez ceux qui avaient subi une vagotomie sélective. Le risque de maladie de Parkinson est également diminué après une vagotomie tronculaire par rapport à la population générale. Ces résultats épidémiologiques sont importants et soutiennent l'hypothèse selon laquelle la maladie de Parkinson commence dans l'intestin et non initialement dans le cerveau. Cela fournit une preuve supplémentaire de l'implication du nerf vague dans le développement de la maladie.

De nombreux composants chimiques (de nos jours, nous disons "moléculaires" pour que cela sonne important) importants sont produits dans l'intestin et se retrouvent dans le cerveau via la circulation sanguine. Beaucoup d'entre eux sont fabriqués ou ont leur production régulée par des microbes intestinaux.

Ceux-ci comprennent les acides gras à chaîne courte, le tryptophane, la leptine et la ghréline. Les acides gras à chaîne courte comprennent le butyrate, le propionate et l'acétate. Le butyrate est un inhibiteur connu des histone désacétylases (HDAC) et, ce faisant, agit comme un régulateur épigénétique. Les cytokines, molécules clés de régulation immunitaire produites au niveau de l'intestin, peuvent voyager via la circulation sanguine et influencer la fonction cérébrale, en particulier dans les régions du cerveau où la barrière hémato-encéphalique est déficiente.

Entre autres effets, les métabolites microbiens alimentaires peuvent moduler l'activation de la microglie, or ces cellules nerveuses qui sont indispensables à la survie des neurones sont impliquées dans la maladie de Parkinson. La microglie répond aux signaux provenant de l'intérieur du cerveau, mais reçoit également des informations de la périphérie, y compris du microbiome intestinal (Abdel88 Haq et al. 2019). La microglie de souris adultes exemptes de germes présente un profil d'expression génique immature et ne répond pas adéquatement aux immunostimulants (Erny et al. 2015 ; Thion et al. 2018). Cependant, si l'on nourrit ces souris exemptes de germes avec un mélange d'acides gras à chaîne courte, la maturation microgliale est restaurée (Erny et al. 2015).

Le microbiote intestinal est un organe virtuel qui produit une myriade de molécules dont le cerveau et d'autres organes ont besoin. Les humains et les microbes sont dans une relation symbiotique, les humains nourrissent les microbes, et à leur tour, les microbes fournissent des molécules essentielles aux humains.

Les phylums Bacteroidetes et Firmicutes représentent environ 80 % du microbiote intestinal humain total. Les genres du phylum Firmicutes comprennent Clostridium, Lactobacillus, Bacillus, Clostridium, Enterococcus et Ruminicoccus. Le phylum Bacteroidetes comprend principalement les genres Bacteroides et Prevotella. Le phylum Actinobacterium est dominé par le genre Bifidobacterium. Les bifidobactéries et les lactobacilles sont généralement considérés comme des bactéries bénéfiques et sont fréquemment vendus comme suppléments probiotiques. Des souches du genre Clostridium ou des taxons de lipopolysaccharides tels que les Enterobacteriaceae ont été associées à des états pathologiques dans beaucoup de maladies neurodégénératives y compris la SLA (maladie de Charcot).

Bien que ce soit quelque peu controversé, de façon siilaire le ratio Firmicutes/Bacteroidetes, qui explore la relation entre les deux phylums dominants, a été associé à diverses pathologies neurodégénératives.

Or le microbiome intestinal est altéré dans la maladie de Parkinson. On constate chez les souris modèles de la maladie de Parkinson (on a par génie génétique infligé à ces souris une maladie ressemblant à celle de Parkinson) que les niveaux fécaux des acides gras à chaîne courte sont différent chez les souris malades de Parkinson et les souris saines. Or ce sont les bactéries intestinales qui transforment par fermentation les fibres alimentaires en acides gras à chaîne courte.

Les auteurs ont donc conçus des régimes personnalisés riches en fibres, chacun contenant 20 % d'un mélange prébiotique de deux ou trois fibres alimentaires conçu pour favoriser la croissance de 5 taxons bactériens intestinaux distincts et stimuler la production d'acides gras à chaîne courte sur la base d'une fermentation fécale in vitro.

Les chercheurs ont alors observé de vastes changements au niveau du phylum microbien et du genre après l'administration d'un régime prébiotique, affichant une augmentation des Bacteroidetes et une diminution des Firmicutes chez les souris nourries avec un régime prébiotique, entraînant une baisse du rapport Firmicutes/Bacteroidetes (F/B) qui a été associé à des caractéristiques générales de la santé métabolique.

Curieusement, il a été démontré que les Bacteroidetes sont réduits chez les patients parkinsoniens par rapport aux témoins du même âge, ce qui suggère que le prébiotique peut contrer cet effet (Unger et al. 2016). De plus, ils ont observé une diminution des protéobactéries, un phylum souvent augmenté dans la dysbiose et l'inflammation et élevé dans les échantillons fécaux de patients atteints de maladie de Parkinson (Keshavarzian et al. 2015 ; Shin, Whon et Bae 2015).

Un régime prébiotique riche en fibres atténue les déficits moteurs et réduit l'agrégation de l'α-synucléine dans la substantia nigra des souris.

Parallèlement, le microbiome intestinal des souris ASO adopte un profil corrélé à la santé lors du traitement prébiotique, ce qui réduit également l'activation microgliale.

L'analyse ARN-seq unicellulaire de la microglie de la substantia nigra et du striatum révèle une signalisation pro-inflammatoire accrue et des réponses homéostatiques réduites chez les souris ASO par rapport à leurs homologues de type sauvage suivant un régime standard. L'alimentation prébiotique inverse les états microgliaux pathogènes chez les souris ASO et favorise l'expansion des sous-ensembles de macrophages protecteurs associés à la maladie (DAM) de la microglie.

La microglie dépend de la signalisation du récepteur du facteur 1 stimulant les colonies (CSF1R) pour le développement, le maintien et la prolifération (Elmore et al. 2014).

Pour tester l'effet inverse: Si l'épuisement de la microglie à élimine les effets bénéfiques des prébiotiques, les auteurs ont ajouté PLX5622 au régime alimentaire de souris âgées de 5 à 22 semaines et quantifié le nombre de microglies IBA1+ dans diverses régions du cerveau. PLX5622 est un inhibiteur pénétrant dans le cerveau du CSF1R qui peut épuiser la microglie sans effets observés sur le comportement ou la cognition (Elmore et al. 2014).

L'épuisement de la microglie à l'aide d'un inhibiteur de CSF1R a effectivement éliminé les effets bénéfiques des prébiotiques et rétablit les déficits moteurs des souris ASO malgré un régime prébiotique.

Ces études révèlent une nouvelle interaction dépendante de la microglie entre l'alimentation et les symaladie de Parkinsontômes moteurs chez la souris, des découvertes qui pourraient avoir des imaladie de Parkinsonlications pour la neuroinflammation et la maladie de Parkinson.

Les prébiotiques présentent une approche thérapeutique potentiellement prometteuse, car le régime alimentaire contribue de manière significative à la composition du microbiome et des éléments épidémiologiques ont établi un lien entre les régimes riches en fibres et le risque réduit de développer la maladie de Parkinson (Boulos et al. 2019). Alors qu'une consommation accrue de légumes et l'adhésion à un régime méditerranéen sont associées à un risque plus faible de maladie de Parkinson, les personnes consommant un régime occidental pauvre en fibres et hautement transformé présentent un risque accru de diagnostic de maladie de Parkinson (Alcalay et al. 2012 ; Gao et al. 2007 ; Molsberry et al. 2020). Plusieurs essais cliniques en cours explorent les effets bénéfiques des probiotiques et des prébiotiques sur les résultats liés à la maladie de Parkinson. Agir sur le régime alimentaire ou le microbiome, peut aider à soulager les symptômes de la maladie de Parkinson.

Parkinsonism in a sample of patients with amyotrophic lateral sclerosis

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Numerous studies have suggested that the medical classification of many neurodegenerative diseases (Alzheimer's, ALS, Parkinson's, many dementias) is artificial because patients may have biomarkers involving up to four comorbidities.

The coexistence of amyotrophic lateral sclerosis (ALS) with clinical forms of Parkinson disease (PD), although uncommon, is found to a greater degree than one would expect by chance. The pathological mechanisms of ALS and Parkinson disease are still not understood, and the coexistence of these two diseases suggests that they could share mechanisms in common.

In this publication, authors from Colombia, Brazil, USA present a sample of patients with clinically definitive or probable ALS who were evaluated with single-photon emission computed tomography (SPECT/TRODAT) and compared with non-ALS controls. SPECT is a nuclear medicine tomographic imaging technique using gamma rays.

Dopamine is a neurotransmitter that modulates a variety of human functions such as motion, cognition, emotions, and the peristaltic reflexes in the gastrointestinal tract. The transport of this molecule at the neuron pre- and postsynaptic junctions is mediated by an axonal membrane dopamine transporter (DAT) that regulates dopamine levels within the synaptic cleft.

Development of various imaging ligands that specifically bind to DAT has been of interest to understand the functioning of these transporters and also to diagnose and monitor the treatment of Parkinson disease. TRODAT was shown to have a high sensitivity and specificity to measure the gradual loss of DAT in Parkinson disease patients.

Patients with clinically definite or probable ALS were assessed with the amyotrophic lateral sclerosis functional rating scale (ALSFRS) to define severity and had their demographic data collected. The TRODAT results of patients with ALS were compared with those of patients with a diagnosis of Parkinson disease with less than 10 years of duration, and with patients with a diagnosis of others movement disorders not associated with neurodegenerative diseases.

A total of 75% of patients with ALS had TRODAT results below the levels considered normal; that was also true for 25% of the patients in the control group without neurodegenerative disease, and for 100% of the patients in the Parkinson disease group. A statistically significant difference was found between patients with ALS and the control group without neurodegenerative disease in the TRODAT values < 0.05.

Conclusions: This study fits with the neuropathological and functional evidence that demonstrates the existence of nigrostriatal dysfunction in patients with ALS.

Sometimes ALS and Parkinson's are associated, for example in a unique neurodegenerative disease found on the island of Guam which is attributed to a toxin in cycad flour.

Progressive degeneration of functionally related groups of neurons occurs in certain infective, toxic, nutritional and genetically determined neurological diseases. It also takes place in normal aging, and several of the regions that undergo selective decay with the passage of time.

One (old) hypothesis that I like, is that features associated with Parkinson's disease, Alzheimer's disease, and ALS may be non-specific indicators of neuronal "disease", with certain morphological markers tending to appear more frequently in particular circumstances and particular regions associated with the pathology of particular diseases.

Community-based high-intensity cycling improves disease symptoms in individuals with Parkinson's disease

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Regular and long-term engagement in aerobic exercise protocols hold promise in slowing the progression of Parkinson's disease. It is recommended that people with PD participate in a minimum of 90–150 min of moderate to vigorous aerobic exercise per week.

Regular program attendance and pedalling at a relatively high cadence may be key variables in mitigating Parkinson's disease symptoms.

The aim of the project describe by authors of a new article, was to monitor exercise behaviour and evaluate its effect on disease progression over a 6 month period in 50 people with Parkinson disease. It was implemented at five community exercise facilities (two in northern Washington and three in central Colorado) from 2019–2020.

The Movement Disorders Society-Unified Parkinson's disease Rating Scale Motor III and other motor and non-motor outcomes were gathered at enrollment and following 6 months of exercise. Attendance, heart rate, and cadence data were collected for each exercise session. enter image description here

On average, people with Parkinson disease attended nearly two-third of the offered PFP classes. The MDS-UPDRS III significantly decreased over the 6-month exercise period and immediate recall significantly improved.

Other motor and non-motor metrics did not exhibit significant improvement. Participants who attended most available classes experienced the greatest improvement in MDS-UPDRS III scores.

Consistent attendance and pedalling at a relatively high cadence may be key variables to Parkinson disease symptom mitigation. Improvement in clinical ratings coupled with lack of motor and non-motor symptom progression over 6 months provides rationale for further investigation of the real-world, disease-modifying potential of aerobic exercise for people with Parkinson disease.

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Gut-oriented disease modifying therapy for Parkinson's disease.

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Neuropathology studies have shown that the Parkinson's disease, one of the most common neurodegenerative disorders, may start from the gut enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis.

Metabolomic analysis revealed different gut microbiomes and gut metabolites in patients with Parkinson disease compared with unaffected controls.

Currently, although dopaminergic treatments and deep brain stimulation can provide some symptomatic benefits for motor symptoms of the disease, but as the disease progresses, these medications become less effective, while at the same time amplifying Parkinson's symptoms (tremor, hallucinations).

Patients whose disease begins in the gut may benefit most from interventions that target the gut microenvironments. In this review, the authors summarize the currently available evidence for targeting the gut microbiota in Parkinson disease.

This includes:

  • Probiotics such as Lactobacillus rhamnosus GG, Bifidobacterium animalis lactis, Lacobacillus plantarum PS128 , Clostridium butyricum, Bifidobacterium bifidum, L. fermentum, Lactobacillus reuteri, lactis Probio-M8, and Lactobacillus acidophilus. Nota Bene: L. acidophilus, B. bifidum, L. reuteri, L. fermentum reduced gene expressions of inflammatory markers (IL-1, IL-8, TNF-α) and increased expressions of TGF-β and PPAR-γ in the blood of participants. Abnormal insulin-related signaling pathway was observed in people with Parkinson disease and PPAR-γ plays a vital role in the regulation of many signaling pathways, including regulating insulin sensitivity, carbohydrate and lipid homoeostasis and mitochondrial biogenesis.

  • Prebiotics: Prebiotics are non-digestible food ingredients, generally attributed to dietary fibers, that selectively stimulate the growth or activity of some genera of microorganisms to beneficially affect the host's health. One recent open-label clinical trial with 87 participants showed improvement of non-motor symptom scores, reduced fecal inflammatory marker of calprotectin and increased fecal butyrate in patients with PD who received prebiotic supplement with resistant starch compared to those without prebiotic intervention.

  • Fecal microbiota transplantation: Indeed it's hard to identify the characteristics of a "good" fecal microbiata in the case of Parkinson. Increased abundance of Blautia and Prevotella and lower abundance of Bacteroidetes may be of some interest.

  • Live biotherapeutic products: Two gut bacterial strains, Parabacteroides distasonis (MRX0005) and Megasphaera massiliensis (MRX0029) may help patients. Genetically modified strains are studied on animal models

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Spinal cord stimulation therapy for patients with Parkinson's disease and gait problems (STEP-PD): study protocol for an exploratory, double-blind, randomised, placebo-controlled feasibility trial.

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This new publication discusses a future (small) clinical trial (NCT05110053) of spinal cord stimulation therapy for patients with Parkinson's disease. Spinal cord stimulation is not new, there are even devices on the market for this purpose. enter image description here The imaging analyzes that this study will produce, will make it possible to define a subgroup of patients with Parkinson's disease who will have benefited from the treatment and will help to define rules about when using this therapy in order to avoid unnecessary interventions.

Parkinson's disease is a chronic neurodegenerative disease that affects nearly 8 million people worldwide. Parkinson's disease manifested by the classic triad bradykinesia (Slowness of initiation of movement (slowness of initiation of voluntary movement), rigidity and tremor. These symptoms can, at least in the early stages of the disease, be treated effectively with dopamine replacement therapy, however, as the disease progresses, more debilitating symptoms appear, including gait problems, postural instability, and falls.

Unfortunately, the onset of these symptoms represents a major step in the progression of Parkinson's disease, resulting in loss of autonomy, deterioration in quality of life and a marked increase in mortality. These disabling symptoms often respond poorly to dopamine medications and advanced therapies, including deep brain stimulation of the subthalamic nucleus (DBS). enter image description here Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, via implanted electrodes, to specific targets in the brain (the cerebral nucleus) for treatment movement disorders, including Parkinson's disease. illness, essential tremor, dystonia, and other conditions such as obsessive-compulsive disorder (OCD) and epilepsy. Its underlying principles and mechanisms are not fully understood.

Other stimulation methods have been considered by other teams such as the use of infrared, ultrasound (Magnetic resonance-guided focused ultrasound) or low-frequency sounds, or magnetic fields (Transcranial Current Magnetic Stimulation) or electric current continuous or alternating (Transcranial Current Stimulation), or even radio frequencies.

Spinal cord stimulation is a surgical treatment used as a treatment for chronic neuropathic pain that is unresponsive to other conventional treatments. Several studies have shown improved walking function in patients with Parkinson's disease following spinal cord stimulation for back pain. More recently, a small number of Parkinson's disease patients with gait dysfunction (without back pain) have been treated with encouraging initial results on gait function and with few adverse events.

Spinal cord stimulation assumes that by delivering electrical current at a certain frequency, intensity, latency and specific location, the physiological functioning of targeted areas of the spinal nerve can be restored. The most common complication of spinal cord stimulation is related to lead migration, followed by infections which, sooner or later, could lead to new surgeries. CSF leak and device failure are less common complications.

The method involves introducing one or more electrodes into the epidural space through which electrical impulses are transmitted into the epidural space. The electrodes are connected to a neurostimulator placed under the skin of the abdomen. The contact between the electrodes and the neurostimulator leads to the stimulation of the posterior parts of the spinal cord and the patient then feels a "tingling sensation", where he felt intense pain. In this therapy, in which electrical impulses prevent or relieve the sensation of pain, no nerves are damaged. In addition, with a single movement of the hand, the patient can turn the device on and off, as well as regulate the force in order to obtain the desired stimulation.

This future spinal cord stimulation clinical trial, which is being planned for patients with Parkinson's disease (STEP-PD), aims to assess the safety and feasibility of burst spinal cord stimulation as a treatment gait disorders in the Parkinson's disease.

This trial will investigate possible changes after spinal cord stimulation in cholinergic activity and glucose metabolic patterns of cortex and associative cortical-subcortical loops with positron emission tomography.

A total of 14 patients will be assessed using clinical rating scales and gait assessments at baseline, and at 6 and 12 months after spinal cord stimulation implantation. They will also receive serial 18F-deoxyglucose and PET scans to assess the effects of spinal cord stimulation on cortical/subcortical activity and brain cholinergic function.

The first two patients will be included in an open-label pilot study while the others will be randomized to receive active treatment or placebo (no stimulation) for 6 months. From then on, the entire cohort will enter an open-label active treatment phase for 6 months.

Trial registration number: NCT05110053

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Thérapie de stimulation de la moelle épinière pour les patients atteints de la maladie de Parkinson et de troubles de la marche (STEP-PD) : protocole d'étude pour un essai de faisabilité exploratoire, en double aveugle, randomisé et contrôlé par placebo.

- Posted in Thérapie de stimulation de la moelle épinière pour les patients atteints de la maladie de Parkinson et de troubles de la marche (STEP-PD) : protocole d'étude pour un essai de faisabilité exploratoire, en double aveugle, randomisé et contrôlé par placebo. by Français by

Cette nouvelle publication traite d'un futur (petit) essai clinique (NCT05110053) sur la thérapie de stimulation de la moelle épinière pour les patients atteints de la maladie de Parkinson. La stimulation de la moelle épinière n'est pas nouvelle, il existe même sur le marché des dispositifs commercialisés à cet effet. enter image description here Les analyses d'imagerie de cette étude permettront de définir un sous-groupe de patients atteints de maladie de Parkinson qui auront bénéficié du traitement et ainsi de définir des règles quand à l'utilisation de cette thérapie, afin d'éviter des interventions inutiles.

La maladie de Parkinson est une maladie neurodégénérative chronique qui touche près de 8 millions de personnes dans le monde. La maladie de Parkinson se manifestant par la triade classique bradykinésie (Lenteur de l'initiation du mouvement (lenteur de l'initiation du mouvement volontaire), rigidité et tremblement. Ces symptômes peuvent, au moins dans les premiers stades de la maladie, être traités efficacement par une thérapie de remplacement de la dopamine. Cependant, à mesure que la maladie progresse, des symptômes plus débilitants apparaissent, notamment des problèmes de démarche, une instabilité posturale et des chutes.

Malheureusement, la survenue de ces symptômes représente une étape majeure dans la progression de la maladie de Parkinson, entraînant une perte d'autonomie, une détérioration de la qualité de vie et une augmentation marquée de la mortalité. Ces symptômes invalidants répondent souvent mal aux médicaments dopaminergiques et aux thérapies avancées, y compris la stimulation cérébrale profonde du noyau sous-thalamique (DBS). enter image description here La stimulation cérébrale profonde (DBS) est une procédure neurochirurgicale impliquant la mise en place d'un dispositif médical appelé neurostimulateur, qui envoie des impulsions électriques, via des électrodes implantées, à des cibles spécifiques dans le cerveau (le noyau cérébral) pour le traitement des troubles du mouvement, y compris la maladie de Parkinson. maladie, tremblement essentiel, dystonie, et d'autres conditions telles que le trouble obsessionnel-compulsif (TOC) et l'épilepsie. Ses principes et mécanismes sous-jacents ne sont pas entièrement compris. D'autres méthodes de stimulations comme l'utilisation d'infra-rouges, d'ultra-sons (Magnetic resonance-guided focused ultrasound ) ou de sons à basse fréquence, ou de champs magnétiques (Transcranial Current Magnetic Stimulation) ou électriques à courant continue ou alternatif (Transcranial Current Stimulation), ou encore de radio-fréquences ont été considérés.

La stimulation de la moelle épinière est un traitement chirurgical utilisé comme traitement des douleurs neuropathiques chroniques ne répondant pas aux autres traitements conventionnels. Plusieurs études ont montré une amélioration de la fonction de marche chez les patients atteints de maladie de Parkinson suite à une stimulation de la moelle épinière pour douleur dorsale. Plus récemment, un petit nombre de patients atteints de maladie de Parkinson avec un dysfonctionnement de la marche (sans douleur dorsale) ont été traités avec des résultats initiaux encourageants sur la fonction de marche et avec peu de événements indésirables.

La stimulation de la moelle épinière suppose qu'en délivrant un courant électrique à une certaine fréquence, intensité, latence et localisation spécifique, le fonctionnement physiologique des zones ciblées du nerf spinal peut être rétabli grâce à l'action neuromodulatrice. La complication la plus fréquente du stimulation de la moelle épinière est liée à la migration des dérivations, en particulier dans les dérivations quadripolaires, suivie d'infections qui, tôt ou tard, pourraient entraîner des réinterventions. La fuite de LCR et la défaillance du dispositif sont des complications moins courantes.

La méthode consiste à introduire une ou plusieurs électrodes dans l'espace épidural par lesquelles des impulsions électriques sont transmises dans l'espace épidural. Les électrodes sont reliées à un neurostimulateur ou un neuromodulateur, placé sous la peau de l'abdomen. Le contact entre les électrodes et le neurostimulateur entraîne la stimulation des parties postérieures de la moelle épinière et le patient ressent alors une "sensation de picotement", là où il ressentait une douleur intense. Dans cette thérapie, dans laquelle les impulsions électriques empêchent ou soulagent la sensation de douleur, aucun nerf n'est endommagé. En outre, d'un seul mouvement de la main, le patient peut allumer et éteindre l'appareil, ainsi que réguler la force afin d'obtenir la stimulation souhaitée.

L'essai clinique de thérapie de stimulation de la moelle épinière, qui est projeté pour les patients atteints de la maladie de Parkinson (STEP-PD), vise à évaluer l'innocuité et la faisabilité du stimulation de la moelle épinière en rafale comme traitement des troubles de la marche dans la maladie de Parkinson, tels que FoG. Cet essai étudiera les changements possibles après stimulation de la moelle épinière dans l'activité cholinergique et les schémas métaboliques du glucose du cortex et des boucles cortico-sous-corticales associatives avec tomographie par émission de positrons. Un total de 14 patients seront évalués à l'aide d'échelles d'évaluation cliniques et d'évaluations de la marche au départ, ainsi qu'à 6 et 12 mois après l'implantation de la stimulation de la moelle épinière. Ils recevront également des scans en série au 18F-désoxyglucose et au 18FEOBV PET pour évaluer les effets du stimulation de la moelle épinière sur l'activité corticale/sous-corticale et la fonction cholinergique cérébrale. Les deux premiers patients seront inclus dans une étude pilote ouverte tandis que les autres seront randomisés pour recevoir un traitement actif ou un placebo (pas de stimulation) pendant 6 mois. À partir de ce moment, l'ensemble de la cohorte entrera dans une phase de traitement actif en ouvert pendant 6 mois.

Trial registration number: NCT05110053

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What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs.

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Despite the sound epidemiologic and basic science rationales underpinning numerous "disease modification" trials in manifest Parkinson disease, none has convincingly demonstrated that a treatment slows progression.

Rapidly expanding knowledge of the genetic determinants and prodromal features of Parkinson disease now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. enter image description here In this article, the authors outline the principles of drug selection for Parkinson disease prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field.

The scientists describe prototypical, relatively low-risk drug candidates for such trials, tailored to specific at-risk populations ranging from pathogenic or gene variant carriers to those defined by prodromal Parkinson disease and α-synucleinopathy. Their proposal includes caffeine, Ibuprofen, Albuterol, Ambroxol.

Finally, the authors review gene-targeted approaches currently in development targeting clinically manifest Parkinson disease for their potential in future prevention trials.

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Can Terazosin be Repurposed to Treat ALS?

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There were 35 clinical trial of Terazosin, most recents are related to various neurodegenerative diseases. enter image description here

Terazosin, is normally used to treat symptoms of a (non cancerous) enlarged prostate and high blood pressure. It was recently discovered to increase energy levels (in the form of ATP molecules) in the brain by enhancing glycolysis.

Hypertension is prevalent in obese and diabetic patients. As soon as 1991, scientists hypothesized that people with hypertension are also likely to suffer from insulin resistance, glucose intolerance, and hyperinsulinemia.

They noted that commonly used antihypertensive agents, such as thiazide, thiazide-like diuretics, and beta-blockers, are associated with glucose intolerance and increased insulin resistance. In contrast, angiotensin-converting enzyme inhibitors, calcium antagonists, and peripheral alpha-blockers (such as prazosin and terazosin) do not adversely affect glucose tolerance or insulin sensitivity.

Yet Terazosin is not without side effects: Orthostatic hypotension, asthenia, dizziness, faintness and syncope.

Insulin stimulates glycolysis. glycolysis is an anaerobic pathway to make ATP (as opposed to the usual Krebs-cycle way, the citric acid cycle and oxidative phosphorylation).

Fixing the underlying insulin resistance would be nice, but we don't actually understand the biochemical mechanisms behind it enough to do that directly yet. Metformin is probably the closest thing, and it has several other beneficial effects as well, but we don't really understand its mechanism(s) of action either.

In 2019 Terazosin suddenly leapt into a growing pool of drugs that might have a repurposed role in Parkinson’s disease, such as exenatide, salbutamol, ursodeoxycholic acid, nilotinib, deferiprone, and ambroxol.

An article with contributors from many laboratories tell that as Terazosin stimulates glycolysis and increases cellular ATP levels, it may change the course of Parkinson’s disease. In toxin-induced and genetic Parkinson's disease models in mice, rats, flies, and induced pluripotent stem cells, Terazosin increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function.

The scientists also interrogated 2 distinct human databases and found slower disease progression, decreased Parkinson's disease-related complications, and a reduced frequency of Parkinson's disease diagnoses in individuals taking Terazosin and related drugs.

So other teams of scientists tried to replicate this success with other neurodegenerative diseases, including ALS.

In this later case, they increased activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) using Terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.

The scientists found that targeting PGK1, indeed modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour.

Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, Terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.

The team is now inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study to examine the impact of terazosin on key indicators of disease progression. If this proves successful and if they find financial sponsors, they will look to move forward into a full clinical trial.

As usual, ALS mice models are not realistic, they live only 25 days when an healthy mouse lives 2 years (30 times more). As ALS in humans strikes mostly after 50 years old, a realistic mice model should live 14 months before being ill. Indeed this would create insanely long experiments, slow publication rates, and it would be costly. As in the old joke, scientists prefer to look where it's easy even if they know that current neurodegenerative diseases mice models are useless.

Let's cross our fingers, who knows, this time it may work.

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