Les scientifiques ont tendance à considérer les maladies de façon très schématiques et très compartimentées, Alzheimer serait uniquement caractérisé par des pertes de mémoires, Parkinson par des troubles moteurs, la SLA par la paralysie musculaire.

En réalité les symptomes des maladies neurodégénératives sont peu différenciés. Les malades d'Alzheimer n'ont pas de troubles de mémoire permanent, alors qu'on catégorize leur maladie comme une démence, ils peuvent démontrer des raisonnement précis. Ils éprouvent aussi des hallucinations et souvent des troubles moteurs de type Parkinsonien. Les malades de Parkinson eux ont des hallucinations, et peuvent évoluer vers une démence. Les malades de la SLA maladie de Lou Gherig/Charcot) ont montrent souvent des troubles moteurs comme le clonus, une certaine forme de démence pour au moins un tiers d'entre eux. Une forme de démence (FTD) a d'ailleurs une proximité avec la SLA sur le plan moléculaire.

Les manifestations psychotiques affectent plus de la moitié des personnes atteintes de la maladie de Parkinson à un certain stade de l’évolution de leur maladie et peuvent être profondément perturbatrices, contribuant à une mortalité et une morbidité accrues, ainsi qu’à la détresse des soignants. Si ces hallucinations ont leur origine dans la maladie, elles sont aussi des effets secondaires de l'usage à long terme des médicaments antiparkinsoniens.

La psychose lors de la maladie de Parkinson, apparaît comme le plus grand facteur de risque de placement en maison de retraite chez les patients parkinsoniens. Cependant, il n'existe pas de critères diagnostiques universellement acceptés de la psychose lors de la maladie de Parkinson. Habituellement on met l'accent sur certains symptômes caractéristiques durant au moins un mois : hallucinations, délires, illusions et faux sentiment de présence.

Les hallucinations visuelles sont des perceptions visuelles anormales sans stimulus physique visuel, contrairement aux illusions visuelles qui sont des perceptions erronées de stimuli visuels réels. Ce sont par exemple des hallucinations de présence (une sensation qu'une autre personne est présente à proximité alors qu'il n'y a personne), ou des images fugaces et vagues dans la vision périphérique. Bien qu'il y est eu de nombreuses études sur la sujet, des chercheurs Lithuaniens ont cherché à évaluer la prévalence des hallucinations mineures dans une cohorte composée de patients atteints de maladie de Parkinson et de témoins sains.

Il n'y avait pas de différences significatives dans la démographie des groupes maladie de Parkinson et témoins. La majorité des patients parkinsoniens présentaient une atteinte bilatérale sans incapacité grave.

Au total, 16 patients (la moitié) atteints de maladie de Parkinson et 4 sujets témoins (un dixième) ont présenté au moins une hallucination mineure. Parmi les personnes qui ont signalé une hallucination mineure, les patients atteints de maladie de Parkinson ont signalé des illusions visuelles et des hallucinations de présence nettement plus fréquemment que les sujets témoins. Les hallucinations de passage étaient de deux fois plus fréquentes dans le groupe de malade de Parkinson que dans le groupe de contrôle.

Parmi les 16 participants ayant signalé des illusions visuelles, la moitié d'entre eux n'ont ressenti qu'un seul type d'illusion visuelle. Dans le groupe maladie de Parkinson, les illusions visuelles les plus fréquemment rapportées étaient les illusions visuelles complexes, l'akinétopsie et la pélopsie, tandis que dans le groupe témoin, la pélopsie était l'illusion visuelle la plus fréquemment rapportée.

L'akinétopsie se produit souvent avec une traînée visuelle (palinopsie), des images rémanentes étant laissées à chaque image du mouvement.

La palinopsie décrit des images comme des auras, des scintillements, des points lumineux comme s'il neigeait.

Les patients parkinsoniens qui ont signalé des illusions visuelles avaient tendance à avoir une durée de maladie plus longue et un dosage de Levodopa plus élevé.

Currently, available therapies for the treatment of Parkinson's disease fail to provide lasting and predictable relief of motor symptoms without significant risk of adverse events. Patients with Parkinson's disease report significantly less satisfaction with treatment than patients with other chronic diseases, particularly because of unpredictable motor fluctuations. Patients may experience motor fluctuations, including a sudden and unpredictable drop in efficiency. In addition, treatment with levodopa causes very serious side effects.

Therefore, new therapies for the treatment of Parkinson's disease are expected to have durable and predictable efficacy, provide effective control of motor symptoms, and improve significant adverse events associated with current therapies. Currently available dopamine treatments work either by increasing dopamine levels (e.g. levodopa, COMT and MAO-B inhibitors) or by directly activating dopamine receptors in the striatum, an area deep in the brain.

Within the striatum, dopamine acts on two distinct populations of receptors, primarily the D1/D5 and D2/D3 receptors, which differ in the neuronal populations on which they are expressed and in the G proteins to which they are coupled. Dopamine therefore promotes movement by acting:

• on D1/D5 receptors to activate direct pathway striatal neurons
• by acting on the D2/D3 receptors to inhibit the MSNs of the indirect pathway to release the inhibitory brake on the motor power.

Together, these two parallel circuits coordinate targeted motor control in the healthy brain. Progressive loss of dopamine signaling in Parkinson's disease leads to disturbances in the balance of direct and indirect pathway activation and subsequent dysregulation of striatal output.

It was hypothesized that targeting dopamine D1/D5 receptors (without targeting D2/D3 receptors) would produce strong motor benefits with reduced risk of D2/D3 receptor-related adverse events, but the development of Selective D1 agonists have previously been hampered by intolerable cardiovascular adverse events and poor pharmacokinetic properties.

Partial agonism at D1/D5 has shown promise in alleviating motor symptoms, potentially without the adverse events associated with selective D2/D3 dopamine agonists (e.g., confusion, sleep disturbances, impulsivity, hallucinations) and dopamine agonists fully selective D1/D5.

However, even activation of extrastriatal D1/D5 receptors, particularly those located outside the central nervous system, can also produce adverse effects such as cardiovascular and dyskinetic problems.

Tavapadon, a highly selective partial agonist of the D1 and D5 receptors, has been studied for some time for use in early to advanced Parkinson's disease. Early clinical and preclinical evidence suggests that tavapadon offers the potential to provide robust, durable, and predictable motor control via selective activation of direct striatal pathways, associated with a reduced risk of adverse events seen with prior dopamine agonists in due to its D1/D5 selectivity and its partial agonist properties.

Tavapadon is a highly selective partial agonist of the dopamine D1 and D5 receptors, with little or no functional activity at the D2, D3 or D4 receptors.

Tavapadon may also have advantages over previously studied fully selective D1/D5 dopamine agonists, not only in terms of sustained motor benefit, but also in terms of reduced risk of bothersome dyskinesias. The preclinical study of tavapadon was conducted in non-human primates with MPTP-induced Parkinson's disease who had previously developed dyskinesias in response to long-term levodopa treatment. The administration of tavapadon, alone or in combination with levodopa, then allowed powerful control of motor symptoms accompanied by a reduction in dyskinesia.

Thursday 18, the company Cerevel (which is in the process of being acquired by Abbvie) communicated on the good results of a phase 3 trial (TEMPO-3) among patients suffering from Parkinson's disease. Subjects were required to receive a stable dose of levodopa for at least four weeks before screening and continue taking the drug in combination with tavapadon or placebo once the trial began. The TEMPO-3 trial evaluated the effectiveness, safety and tolerability of tavapadon as an adjunct treatment to levodopa (LD) in adults. A total of 507 adults aged 40 to 80 participated in the trial. All had a confirmed diagnosis of Parkinson's disease, showed motor fluctuations, and were receiving a stable dose of LD for at least 4 weeks before screening. Patients were randomized to receive either tavapadon in addition to LD, titrated to 5-15 milligrams, or placebo and LD, orally once daily.

During the 27-week trial, patients who took tavapadon went significantly more time without bothersome uncontrolled and involuntary movements, known medically as dyskinesia, than their peers on placebo. The study, which collected data using a self-completed family diary on the status of motor function, showed that people taking the drug went 1.7 hours without bothersome dyskinesia, compared to 0.6 hours in the control group.

Cerevel also reported a significant reduction in the length of time patients experienced symptoms, but has not yet shared data on this secondary endpoint. Likewise, the biotech said the molecule was generally well tolerated, unsurprisingly, and that most side effects were mild or moderate. But we must wait for a more in-depth review of the safety data before medical meetings.

Full results from the TEMPO-3 study will be submitted for presentation at future medical meetings and used to support regulatory submissions of tavapadon as a treatment for Parkinson's disease. Initial results from Phase 3 monotherapy trials for tavapadon, TEMPO-1, and TEMPO-2, are expected in the second half of 2024. Cerevel is also conducting a fourth open-label extension (OLE) trial (TEMPO-4) to evaluate the long-term safety and tolerability of tavapadon.

These various announcements are part of a roadmap of updates on tavapadon which includes regulatory submissions and the main results of two phase 3 studies testing the molecule as a monotherapy obviously with a view to an application for marketing authorization on the market.

The phase 2 LixiPark trial (NCT03439943) showed that treatment with lixisenatide (Adlyxin, Sanofi), a glucagon-like peptide-1 receptor agonist used as a therapy for diabetes, may have resulted in less progression of motor disability compared with placebo at 12 months in patients with early Parkinson disease (Parkinson’s disease) but was associated with gastrointestinal adverse effects. The results of this recent trial add further evidence to exenatide’s potential as a drug that might slow the progression of Parkinson’s and pave the way for the larger phase III clinical trial that is currently underway;

Diabetes mellitus is a risk factor for Parkinson's disease. UK's Cure Parkinson’s has been at the forefront of exenatide’s journey as a potential treatment for Parkinson’s from the outset. They funded the first clinical study of exenatide in people with Parkinson’s. This was a year-long pilot study in 2008 involving 45 people with Parkinson’s. Those who took exenatide did not experience the decline in their movement that is normally seen due to Parkinson’s. Actually, these participants improved a little. Crucially, some of these benefits were still present when measured one year after the participants had stopped taking exenatide, giving hope that this medicine had interfered with the underlying disease process, rather than simply masking symptoms.

Liraglutide is another drug that belongs to a class of medicines called Glucagon-like peptide 1 (GLP-1) receptor agonists. In addition to treating T2 diabetes and obesity, this class of drugs has another interesting property: taming inflammation. In animal models of Parkinson’s, liraglutide has shown strong neuroprotective effects.

Based on this, Cure Parkinson’s in 2017 funded Professor Michele Tagliati to undertake a phase II randomized, double-blind, placebo-controlled clinical trial of liraglutide in people with Parkinson’s.

70 participants were given either once-daily injections of liraglutide or placebo injections for 52 weeks. The study was primarily designed to assess changes in symptoms whilst off Parkinson’s medication for 12 hours before the assessments. Movement (motor), non-motor, and cognitive symptoms were assessed along with several secondary measures, including quality of life and daily activities. The primary analysis of the results included 37 people with Parkinson’s on liraglutide and 18 on the placebo drug.

Non-motor symptoms, activities of daily living, and quality of life appeared to significantly improve in the group on liraglutide treatment. However, there was no clear difference in motor symptoms between those on liraglutide and those on the placebo; it was noted that there appeared to be a strong placebo effect in this study, meaning the participants, even though none was aware they were taking the placebo drug, believed they were experiencing therapeutic results. This is consistent with the often-reported association of more invasive treatments causing a stronger placebo effect.

The research team also reported a significant lowering of body mass index (BMI) and average blood glucose levels in the active drug group, which are not desirable for patients in general. Interestingly, significant mobility improvements were reported by people taking liraglutide in their quality of life experiences, and this was more than in the placebo group.

In this new phase II of lixisenatide trial, the effect of lixisenatide was assessed on the progression of motor disability in persons with Parkinson’s disease.

Participants with Parkinson’s disease 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 endpoint 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 endpoints included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent.

A total of 156 patients 40 to 75 years old with early Parkinson’s disease (diagnosed less than 3 years earlier) on stable symptomatic medications without motor complications were randomized 1:1 (with 78 assigned to each group) to subcutaneous injections of 20 µg lixisenatide or placebo once daily for 12 months, followed by a 2-month washout period. Patients randomized to lixisenatide received 10 μg/day for 14 days and then 20 μg/day administered by once-daily subcutaneous injections for 12 months. If patients were unable to tolerate the dose of 20 μg/day, it would have been reduced to 10 μg/day. Patients were expected to remain on a stable dosage of antiparkinsonian medications for at least the first 6 months of the trial, and optimally for the entire 14 months of follow-up. An interesting feature of the trial was that the drug was tested both during ON and OFF levodopamine periods.

MDS-UPDRS scores at baseline were approximately 15 in both groups.

• At 12 months, scores on the MDS-UPDRS had changed by −0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group.

• 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 endpoints did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%.

What is lixisenatide?

Lixisenatide is a once-daily injectable GLP-1R agonist that is used in the treatment of Type 2 diabetes (brand name ‘Lyxumia’ in the EU and ‘Adlyxin’ in the USA). Lixisenatide can cross the blood-brain barrier.

What is a GLP-1R agonist?

Glucagon-like peptide 1 receptor agonists (or GLP-1R agonists) are a class of drugs used in the treatment of Type 2 diabetes. They act by mimicking the action of a naturally produced gut hormone called GLP-1 in the body. GLP-1 is produced by cells lining the intestines when food and drink is consumed, stimulating insulin to be released by the pancreas. Insulin helps cells absorb glucose from our food (sugar) to be used as energy.

The LixiPark study was led by Prof Olivier Rascol (University of Toulouse) and Prof Wassilios Meissner (University of Bordeaux). LixiPark is a multicenter trial performed at 21 centers of the French NS-Park/FCRIN network.

The study, sponsored by the Toulouse University Hospital, was co-funded by UK charity Cure Parkinson’s, with Van Andel Institute (VAI; in Michigan, US), and the French Ministry of Health, with drug and placebo support from pharmaceutical company Sanofi.

The LixiPark trial was a phase 2 clinical trial. Phase 2 studies often include measures of efficacy to get an idea of whether a treatment is doing what it is supposed to achieve. Phase 3 is the last stage of clinical testing and involves a very large cohort of people affected by the disease being tested for a long time to determine the effectiveness of the potential treatment alongside its long-term safety. A Phase III clinical trial of Lixisenatide in Parkinson's is ongoing.

What will happen next?

UK's Cure Parkinson’s is working with the investigators to plan the next phase of development of GLP-1R agonists for Parkinson’s. They are also awaiting the results of the phase 2 Stockholm study and the phase 3 UK trial of exenatide, another GLP-1R agonist, in Parkinson’s. These results are expected later this year and they will help to inform the next steps for this class of drugs.

Can Parkinson’s patients take lixisenatide? Lixisenatide is still considered to be experimental for use in Parkinson’s and more research is required. There are currently no GLP-1R agonists, including lixisenatide, that are approved for use in Parkinson’s. GLP-1R agonists are also currently considered an experimental class of drugs for Parkinson’s.

There is a wide range of subtle differences between the broader class of GLP-1R agonists and they have not all been tested in Parkinson’s. Some GLP-1R agonists significantly reduce body weight (which might add concerns of frailty for people with Parkinson’s). Some GLP-1R agonists do not cross the blood-brain barrier very well and therefore are not able to have an effect in the brains of people with Parkinson’s. It is important to note that more research is required to better understand these differences in the context of a potential treatment for Parkinson’s.

When are the results expected of the Phase III exenatide trial?

The study finishes in the first half of 2024, so it is hoped that the results will be available in the second half of 2024. Researchers are also waiting for the results of a large clinical trial examining the effects of a two-year course of exenatide in people with Parkinson’s disease.

“There is a number called the 'clinically meaningful threshold' and we should appreciate that the results 'fell short' of this important metric so it is not ready for prime time in patients. In my view we should not rush to prescribe this drug or to try to creatively acquire it for our patients. We have been down this road many times including leukemia drugs, cough syrups and lithium for Parkinson. The data is not yet there to proceed to prescribing,” Michael S. Okun, MD, national medical advisor for the Parkinson's Foundation, told NeurologyLive®. “More importantly, the weight loss associated with GLP-1’s is not desirable in the majority of cases of Parkinson disease and the nausea and vomiting will not be a welcome symptom. The drug and trial is a step in the right direction, though there is much work to do.”

Will effects last?

David Standaert, a neurologist at the University of Alabama at Birmingham, who was not involved in the trial, says it’s important to know whether the effect will last beyond a year.

“We’re all cautious. There’s a long history of trying different things in Parkinson’s that ultimately didn’t work,” he says. A difference of three points in the rating score is a small change, one that many people with Parkinson’s would struggle to notice. What happens at 5 years? Is it 15 points then, or is it still 3? If it’s still 3, then this is not worth it.” He said.

More questions

A bit astonishing is that apparently, French researchers did not record any imaging biomarkers in the study to monitor disease progression and changes with drug administration. Since the trial was conducted in France, data collection regarding race or ethnic group is prohibited by law. The authors only tested 1 dose of lixisenatide, and thus other doses might have better or worse effects in patients with Parkinson’s disease.

As GLP-1 is a naturally produced hormone in the gut, it would have been interesting to search for changes in microbiome. It is well known since Heiko Braak that alpha-synuclein propagation starts in the gut.

GLP-1 inhibitors are also known to reduce inflammation, was inflammation measured? It is not reported.

Among the authors, there were many consultants, who had worked for several pharmaceutical companies, including Abbvie, that has an interest in drugs for Parkinson's disease.

Recently I learned something new in anatomy (I am a noob in anatomy). It's known for some times there are mirror neurons, but there is an interesting subset: The mirror motor neurons. It was mentioned on a forum by a pALS (patient with ALS) who told he rehabilitated his bladder thanks to mirror motor neurons. Near my home in France, there is a center that uses similar techniques for people who unfortunately experienced strokes. Bladder issues are unfortunately common in ALS patients. These issues arise because ALS affects the nerve cells that control the muscles in bladder and sphincter.

This forum post picked my curiosity and I looked in Pubmed. Indeed there are many sudies that discuss about this kind of rehabilitation technique in ALS and Parkinson's disease. It's called Motor Imagery and there is even a Wikipedia about it.

If you pardon me for grave oversimplification, it's a matter of showing some action to the subject, for example someone is walking, and then asking to the subject to imagine doing the same thing.

The ALS patient told it needed years to regain control of his sphincter, so it's not possible to find some scientific litterature that would enlight us on the results wa can expect with this long duration of rehabilitation, without mentioning that unfortunately many ALS patients do not live that long. Scientists are usually busy people, their studies last between days and a few months as it must coincide with academic time. But there are many studies that mention that even after a few tests, a positive effect can be detected. Here is an example.

A review on Parkinson's disease is less optimistic, it tells of ~5% motor improvement.

I wonder to which extend this Motor Imagery could help to regain some important functionality. Maybe some reinforcement could be added when the imaging process is detected. Apparently even a simple EEG is able to detect this mental state. The article cited above has some additional details on this. It calls also in question why those mirror motor neurons are not striked by the disease as they are probably colocated with upper motor neurons.

Introduction

L'article (en pre-print) discuté aujourd'ui traite de nutrition et de la maladie de Parkinson. La maladie de Parkinson est le deuxième trouble neurodégénératif le plus répandu dans le monde et entraîne une réduction significative de la qualité de vie. Les tendances actuelles en matière d'incidence, de prévalence et de charge de morbidité montrent que le fardeau mondial de la maladie de Parkinson a augmenté.

Les connaissances actuelles suggèrent de façon très générales que la maladie de Parkinson est probablement causée par une interaction entre une prédisposition génétique et la présence de facteurs environnementaux qui peuvent s'accumuler tout au long de la vie, c'est à dire que les scientifiques ont de grandes difficultés à identifier les facteurs à risques. Même le diagnostic semble ne pas faire l'unanimité des chercheurs, pour certains le problème est le manque de production de dopamine dans une certaine zone du cerveau, pour d'autres il s'agit d'une maladie liée à l'accumulation d'une protéine mal-formée: L'alpha-synucléine.

Le fer a peut-être un rôle particulier dans la maladie de Parkinson car il est nécessaire à l'enzyme limitant la production de dopamine. En effet celle-ci, la tyrosine hydroxylase, catalyze la conversion de l'amino acide L-tyrosine vers le L-3,4-dihydroxyphenylalanine (L-DOPA). Pour cela elle a besoin d'oxygène et de fer et aussi de tetrahydrobiopterine comme cofactors. L-DOPA est un precurseur de la dopamine, qui à son tour est un precurseur des neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). De même il existe une relation entre le métabolisme des glucides et celui du fer. Ce qui suggère qu'un métabolisme anormal des glucides puisse avoir une relation avec l'apparition de la maladie de Parkinson.

Les facteurs environnementaux qui se sont avérés liés au risque de maladie de Parkinson comprennent : * Les facteurs associés à un risque réduit de maladie de Parkinson sont le tabagisme, la consommation d'alcool, et la consommation de caféine. De façon moins claire on trouve aussi notamment la vitamine E, les flavinoïdes et le β-carotène ou encore la viande rouge. * Tandis que l'exposition aux pesticides ou aux herbicides et aux blessures à la tête1 sont associés à un risque accru de maladie de Parkinson. Il a également été suggéré que les produits laitiers pourraient augmenter le risque de maladie de Parkinson.

Il existe une relation bien établie entre le microbiome intestinal et la pathogenèse de la maladie de Parkinson. Certaines théories développées sur l'étiologie de la maladie de Parkinson, telles que l'hypothèse de Braak, affirment que la maladie de Parkinson peut commencer dans le système nerveux entérique de l'intestin avant de remonter jusqu'au cerveau. Ces théories sont étayées par des associations connues entre les problèmes gastro-intestinaux prodromiques et le biomarqueur caractéristique de la maladie de Parkinson, l'α-synucléine, dans le système nerveux entérique avant le diagnostic de la maladie de Parkinson.

Fer et maladie de Parkinson

Une accumulation accrue de fer dans des régions comme la substance noire et les noyaux gris centraux et une dyshoméostasie du métabolisme du fer sont des constatations courantes chez les patients parkinsoniens. Malgré cela, les recherches sur le fer alimentaire ont donné des résultats mitigés. Dans l’ensemble, l’apport alimentaire en fer ne semble pas être associé au risque de maladie de Parkinson, mais des analyses de sous-groupes dans les sous-populations occidentales et masculines ont révélé que, dans ces sous-groupes, le fer alimentaire était associé à une augmentation significative du risque de maladie de Parkinson.

Comme souvent, certaines études signalent que l'anémie est associée à un risque accru de maladie de Parkinson, tandis que d'autres rapportant le contraire. Ces résultats apparemment contradictoires peuvent suggérer une relation non linéaire dans lequel à la fois, des niveaux faibles et élevés de fer cérébral dans les circuits moteurs sont associés à un risque accru de maladie de Parkinson

Motivation

Bien que des travaux antérieurs aient étudié les habitudes alimentaires des patients atteints de maladie de Parkinson, cela ne fournit pas de compréhension mécaniste de la façon dont les différences alimentaires peuvent entraîner des profils de risque différentiels de maladie de Parkinson. Dans ce nouvel article, des chercheurs étudient les différences en matière de fer dans le cerveau liées aux facteurs alimentaires et liés au mode de vie liés au risque de maladie de Parkinson en utilisant un biomarqueur cérébral spécifique du fer de la maladie de Parkinson, qu'ils appellent PVS cérébral d'hémochromatose. Ce biomarqueur regroupe les signaux d'accumulation de fer provenant des IRM cérébrales T2-w des régions motrices, notamment le cervelet, le thalamus, le caudé et le putamen.

Les auteurs ont cherché à comprendre comment les facteurs alimentaires et ceux liés au mode de vie influence la présence de ce biomarqueur spécifique du fer et comment cela est lié au risque de maladie de Parkinson.

Leurs investigations montrent que les préférences alimentaires en faveur (bizarrement) de l'alcool et la consommation de produits frais sont associées à un risque réduit de maladie de Parkinson, et que l'apport alimentaire et les préférences en faveur des aliments sucrés sont associés à un risque accru de maladie de Parkinson.

Il semblerait qu'une relation existe dans laquelle les nutriments et les préférences alimentaires liés à des niveaux de fer cérébraux plus faibles seraient associés à un risque accru de maladie de Parkinson.

La dérégulation du fer est une caractéristique courante du maladie de Parkinson, et des essais cliniques de la chélation sont en cours comme voie de traitement potentielle pour le maladie de Parkinson et d'autres maladies neurodégénératives.

Par exemple les essais cliniques concernant le défériprone comme traitement de la neurodégénérescence associée à la pantothénate kinase, une maladie génétique liée à une accumulation accrue de fer dans le cerveau et à des symptômes liés au mouvement. Mais ces essais cliniques ont montré que le défériprone n'entraînait qu'une réduction très faible de la progression de la maladie.

Les essais sur la défériprone, un chélateur du fer, pour le traitement de la maladie de Parkinson ont donné des résultats mitigés. La aussi les essais ont montré une réduction de l'accumulation de fer dans certaines zones du cerveau, mais aucune amélioration significative des symptômes.

Sucres et glucides

Dans toutes leurs analyses, les scientifiques ont constaté que les facteurs liés aux glucides dans les préférences et l'apport nutritionnel estimé étaient associés à une diminution du PVS cérébral de l'hémochromatose, à une augmentation du risque de maladie de Parkinson.

La littérature suggère un effet bidirectionnel avec : * a) un taux élevé de fer influençant la régulation glycémique et augmentant le risque de diabète de type II, une maladie principalement causée par une altération aiguë de la régulation glycémique, * b) l'ingestion orale de glucose entraînant des modifications des facteurs du métabolisme du fer résultant en fer périphérique.

Le fer peut jouer un rôle dans le développement de la résistance à l’insuline. La littérature scientifique à ce jour, montre que la dérégulation glycémique et les maladies associées sont liées à un risque accru de maladie de Parkinson et à de pires résultats de la maladie de Parkinson.

Un métabolisme dérégulé du fer pourrait conduire à des envies inadaptées de glucides, ce qui pourrait déréguler conjointement le métabolisme du glucose et du fer, conduisant à une boucle de rétroaction. La dérégulation fragmentée du métabolisme du fer et du glucose peut expliquer pourquoi une manifestation occasionnelle de carence en fer comme le pika, incite à manger des aliments riches en glucides comme l'amidon, le riz non cuit et les pâtes non cuites.

Les sucres et les glucides peuvent également avoir un impact sur le risque de maladie de Parkinson et l’accumulation de fer au niveau du microbiome. Une forte préférence alimentaire pour les sucreries et les glucides peut augmenter les niveaux de bactéries pathogènes opportunistes pro-inflammatoires dans l’intestin, ce qui est fortement lié à un risque accru de maladie de Parkinson. Ce modèle alimentaire est également en corrélation avec la pathologie de la ɑ-synucléine, qui peut émerger d’un état intestinal dysbiotique et pro-inflammatoire.

Alcool

Il existe également une littérature importante selon laquelle la consommation d’alcool a un impact sur l’absorption et l’accumulation du fer. L’alcool peut entraîner une accumulation accrue de fer dans le cerveau82. L’alcool est connu pour réguler négativement la synthèse de l’hepcidine, une hormone régulatrice du fer, et, en cas de consommation excessive, peut provoquer une surcharge en fer chez des individus par ailleurs hémodynamiquement typiques. En particulier chez les personnes atteintes d’hémochromatose héréditaire, la consommation d’alcool est largement associée à de pires résultats en matière de santé. Des effets similaires sont observés dans d’autres troubles de surcharge en fer comme la bêta-thalasémie.

Exercice physique

Les auteurs ont constaté que les préférences liées à l'exercice sont associées de manière significative à une réduction du risque de maladie de Parkinson et à une réduction du fer cérébral, telles que mesurées avec le PVS cérébral de l'hémochromatose. Evidemment les principaux déficits moteurs de la maladie de Parkinson rendent l'activité physique moins attractive. Mais des niveaux d’activité modérés à élevés se sont avérés associés à un risque plus faible de développer une maladie de Parkinson plus tard dans la vie et les personnes atteintes de maladie de Parkinson qui déclarent une activité physique plus élevée ont une progression plus lente des symptômes et une meilleure qualité de vie.

Céréales et fruits

Les préférences pour les légumes et les fruits étaient associées à une diminution du risque de maladie de Parkinson et à aucune association significative avec le PVS. Ces résultats concordent avec les conclusions d’études antérieures selon lesquelles une consommation élevée de fruits et légumes est liée à un risque plus faible de maladie de Parkinson. Une consommation élevée de fruits et légumes pourrait expliquer une partie des effets protecteurs de la maladie de Parkinson observés dans le régime méditerranéen.

Les préférences liées aux céréales étaient associées à une réduction du fer cérébral. Ce résultat est surprenant étant donné que les céréales sont un véhicule courant pour l’enrichissement en fer. Similairement les grains de céréales peuvent contenir entre 50 et 80 % de glucides en poids, on pourrait donc penser que ce type de nourriture a un effet défavorable sur la maladie de Parkinson. Mais, les céréales et les produits laitiers, généralement consommés avec les céréales, sont riches en inhibiteurs de l'absorption du fer comme l'acide phytique et le calcium, qui réduisent la biodisponibilité du fer en chélatant et en cloîtrant le fer dans le tube digestif. L'interprétation actuelle des auteurs est que les niveaux plus faibles de fer dans le cerveau observés chez les individus préférant les céréales sont dus aux inhibiteurs de l'absorption du fer présents dans ces repas et que l'association qui est observée se produit malgré l'enrichissement en fer des céréales et non à cause de celui-ci.

Conclusion

En conclusion, c'est une étude intéressante, qui montre bien la complexité de la biologie humaine et que les maladies ne se réduisent pas à la carence ou l'excès de quelque molécule, contrairement à ce que le biologie moléculaire laisse entendre.

For a patient, participating in a clinical trial is complicated to organize, in addition, the drugs tested are very rarely effective in the field of neurodegenerative diseases. However, it seems that there are unexpected benefits to volunteering for a clinical trial.

Clinical trials in neurodegenerative diseases are often disappointing, there are probably many reasons for that situation. A core aspect of clinical trials is that the population who received the treatment should be representative of the general population. For logistic reasons, biotechs that have few employees have to subcontract clinical trials. Principal investigators and subcontractors have every reason to select patients who present a textbook-like disease.

Suspecting that the clinical trial population is not representative of real-life patients, an international team wanted to characterize the progression of Parkinson's disease using real-world data to guide the design of clinical trials and identify subpopulations.

The increasing availability of real-world data, and recent advances in natural language processing, particularly large language models, allow for an easier and more granular comparison of populations than before.

This study includes two research populations and two populations derived from real-world data.

The research populations are the Harvard Biomarkers Study (935 patients), which is a longitudinal biomarker cohort study with structured in-person study visits, and finally Fox Insights (36,660 patients), a research study based on the Michael J. Fox Foundation online self-survey.

The real-world cohorts are Optum Integrated Claims electronic health records (157,475 patients), representing large-scale linked medical and claims data and de-identified data from Mass General Brigham (Mass General Brigham, 22,949 patients), a University Hospital.

Structured, anonymized data from Mass General Brigham's electronic health records is augmented using natural language processing with a large language model to extract measures of Parkinson's disease progression. This extraction process is manually validated to verify accuracy.

Motor and cognitive progression scores change more rapidly in the Mass General Brigham than in the Harvard Biomarkers Study (median survival to H&Y scale: 5.6 years versus more than 10 years); median decline to mini-exam of mental status 0.28 versus 0.11. In real-world populations, patients are diagnosed more than eleven years later! After diagnosis, in real-world cohorts, treatment with Parkinson's drugs is initiated 2.3 years later on average than for patients in clinical trials.

This study provides a detailed characterization of Parkinson's disease progression in various populations. It delineates systemic discrepancies between patient populations enrolled in research settings and real-world patients. The study shows systematic differences and potential directional biases between research and real-world datasets. Patients in research populations are diagnosed much earlier, start levodopa and other Parkinson's medications earlier, and show slower changes in clinical scales of motor and cognitive progression. Real-world-based populations are diagnosed at older ages, start medications later than research cohorts, and experience more rapid changes in clinical scales.

These discrepancies are likely due to a combination of selection bias, but exact attribution of causes is difficult using existing data. This study emphasizes the need to diligently consider potential biases when planning a clinical trial.

This post is about an interesting hypothesis. Hypotheses abound, yet few a convincing.

Half of patients with Alzheimer's disease, Parkinson's disease, or ALS have insulin resistance. Obesity and diabetes have been linked to neurodegenerative diseases like multiple sclerosis (MS), Alzheimer's (AD), and Parkinson's (PD). This means the cells of their body cannot let the glucose enter them. Glucose is the main energy source as it is converted into ATP. Glucose is for short-term (day) energy needs. Another source of energy is lipids (fat). Lipids are even more dense than glucose energy-wise.

The body needs an enormous amount of energy. With all the lipids in the body of a healthy person, you could charge two Tesla cars! The brain (a part of the CNS) needs 20% of all energy intake.

A new paper argues that cells shift their metabolism from glucose to lipids under stressors. It tells that one notable distinction between glucose and lipid metabolism is in the quantity of oxygen required to generate each ATP molecule. Lipid metabolism needs two times more oxygen than glucose metabolism. The result is two times more damaging ROS (a by-product of metabolism). Studies have shown that oxidative stress and endoplasmic reticulum stress are correlated and can lead to protein misfolding (Abramov et al., 2020). Accumulation of misfolded proteins causes cellular damage and mitochondrial dysfunction and is associated with a range of neurodegenerative diseases, including ALS (misfolded SOD1, TDP-43, C9orf72) (McAlary et al., 2020), Parkinson's disease (misfolded α-synuclein) and Alzheimer disease (misfolded Aβ and Tau) (Abramov et al., 2020).

It explains also the accumulation of iron in patients' brains: To transport oxygen the blood cells need iron, and as the glucose in the blood is not absorbed in cells, it induces a change in microbiota.

It's also well known that SCFAs (including butyrate) have a positive effect on neurodegenerative diseases by their action on microbiota. SCFAs help to restore glucose as the preferred energy substrate. Authors say there are other means to restore glucose as the main source of energy.

What to think about this paper? First, some authors belong to a biotech so we can expect they want to promote their drug: Mitometin. Second, this is a review, this is not even a pre-clinical study, yet some of the authors were involved in pre-clinical studies on this topic. Other groups have written on this topic. What to make of this? Acetyl-CoA carboxylase might be of interest as they produce malonyl-CoA which inhibits the CPT1 gene that regulates lipid metabolism. B7 vitamin is known to convert acetyl-CoA to malonyl-CoA for fatty acid synthesis.

Now you have an opportunity to fast-track the discovery of drugs in some neuro-degenerative diseases.

AstraZeneca, the pharmaceutical company, proposes a challenge in the area of nucleotide repeat expansion disorders, which includes ALS (Charcot/Gehrig) disease, but also Huntington's disease, etc...

Typically you have to be a startup or an academic with a plan to launch a startup because your solution must be translated into practice within a 12–18-month timeframe.

I am willing to provide reasonable help if you hesitate. This will be mostly in terms of shaping your proposal. I believe that AstraZeneca, like other large companies, is not interested in unproven, hypothetical ideas. On the contrary, IMO they search for people with energy and time (and intellectual right) to give blood to ideas where there is a consensus but where nobody cared to develop it in the pre-clinical stage.

I guess also AstraZeneca would prefer a simple implementation, instead of a complex one. So for example, a small molecule proposal would be preferred to a genetic therapy. A compound of two or three existing drugs to an untested drug. You get the idea.

Good luck!

Jean-Pierre Le Rouzic You will find the link to email me at the bottom of this page.