After weeks after weeks of uninteresting publications in neurodegenerative diseases, two publications, at last, are a bit above the lot.

Plateaus in ALS

The first article is about genetic analysis of cases of ALS reversal, or maybe it's not reversals but long duration plateaus in the disease course. As usual with the use of "reversal" word, Dr. Bedlack is involved.

He and his team found that in approximately 1% of patients, there is a plateau phase where the disease stops progressing for a long time. Studying those patients might teach new information. Bedlack and colleagues think they found that those patients have a different genetic code in areas related to insulin growth factor (IGF-1).

IGF-1 was tested in ALS a long time ago, and some interesting results were obtained. It was at a time were the criteria to judge if a clinical trial succeeded were much more stringent than today. Maybe it would be interesting to revisit these trials.

there is also the possibility that an IGF-1 therapy works with 1% of patients, but not with other patients.

Mitigating hydroxyl radicals and excess iron in Parkinson's disease

The other article is about the role of Iron in Parkinson's disease. Its writing style is not academic, yet the authors claim they were able to improve the state of disease in three Parkinson's patients by making them inhale (for one and a half hours!) a gas mixture containing hydrogen. They say hydrogen could dissolve in blood, reach the brain (it is a tiny molecule), and chelate unmetabolized iron.

The authors explain that when there are too many iron ions in the brain for ferritin to mitigate its oxidative effect, the iron ions are released into brain cells and mitochondria. Hydroxyl radicals (HO) with strong oxidizing power are produced, resulting in cellular and mitochondrial damage. In the views of the authors, hydrogen reacts with hydroxyl radicals resulting in water, so the toxicity of hydroxyl radicals is mitigated.

Yet it's not clear to me, why iron ion deposition results in hydroxyl radicals and what happens to iron after hydrogen reacts with hydroxyl radicals.

Iron toxicity in neurodegenerative diseases and aging has been suspected for a long time, yet all chelating drugs that were tried were unable to significantly change the course of the disease.

Some people advocate for Parkinson's patients to consume mannitol. Many individuals affected by the disease began consuming daily oral mannitol. Self-reported outcomes included an improved sense of smell, a reduction in the dose of PD medications, and general improvement in well-being. A clinical trial was done at Hadassah Medical Center in Israel by David Arkadir and colleagues.

The lobby group CliniCrowd was probably instrumental in this decision.

The study lasted 36 weeks and included four dose escalations of oral mannitol (manufacturer Roquette, France) or dextrose as a placebo from 2.5 g to a maximal dose of 18 g per day. The COVID-19 pandemic in 2020 dramatically slowed the recruitment rate in the 3rd year of the clinical trial and led to the decision to earlier trial termination. They did not observe a clear reduction in Parkinson's symptoms. It is possible that a longer exposure would enable clinically to demonstrate disease modification. Anyway, such a high dose of mannitol is not without innuendoes, mannitol is hypertonic, it forces water to be excreted from cells. Yet the mechanism by which mannitol reduces α-synuclein accumulation in PD models was still unknown.

In 2022 another study showed that glycation agents (sugars) can ameliorate α-synuclein folding. Glycation is increased in the brains of hyperglycemic patients. Alpha-synuclein (αSN), a central player in the etiology of Parkinson’s disease, can be glycated so reducing αSN fibril formation. The best glycating agents were unfortunately toxic, but one agent was mildly efficacious while not toxic: Mannose.

Mannitol, while usually derived from fructose, can also be derived from a mannose by reduction. In the human body, mannose residues are used to assemble N-glycans by adding them to a dolichol phosphate (Dol-P) core in the Endoplasmic Reticulum (ER) of cells.

There's a growing body of research suggesting a connection between abnormal N-glycans and neurodegenerative diseases like Alzheimer's and Parkinson's. N-glycans are sugar chains attached to proteins in a specific way, and changes in their structure or abundance seem to play a role in these diseases. This means the sugar chains are either attached differently, have different structures, or are present in abnormal amounts.

N-glycans can influence how proteins fold, interact with other molecules, and get transported within cells. In a recent publication, scientists analyzed neurons in iPSC midbrain cultures derived from patients with Parkinson's disease and they discovered the disruption of a metabolic pathway, the hexosamine pathway. The hexosamine pathway is important for protein synthesis, transport, and folding in the neuron's endoplasmic reticulum. The hexosamine pathway produces N-linked glycans, essential molecules that support protein folding in the endoplasmic reticulum.

The hexosamine pathway (a biological pathway is the way a molecule is created from components) uses glucose and uridine-5’-triphosphate to generate N-linked glycans for protein folding in the endoplasmic reticulum. In Parkinson's midbrain cultures, however, this N-glycosylation process was interrupted, causing protein misfolding and accumulation of α-synuclein.

Accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein.

So as a non-scientist, I can conclude this post by saying that there is some rationality in using mannitol in Parkinson's disease, while it might not be the silver bullet people are waiting for.

In February, a proposal was made to diagnose Parkinson's disease based on the presence of α-synuclein accumulation, even in the absence of specific clinical symptoms. This proposal follows a similar trend observed in other neurodegenerative diseases. Clinically, this approach is somewhat controversial as it would label asymptomatic individuals as diseased. Furthermore, it raises questions about why individuals in good health would seek medical consultation.

This follows a similar trend in other neurodegenerative diseases. This initiative may be driven by the pharmaceutical industry's frustration over unsuccessful clinical trials. By using molecular criteria, clinical trials could achieve higher success rates, despite the persistence of clinical symptoms. This strategy is already evident in the Alzheimer's field, where several drugs have been approved without significantly alleviating symptoms.

This reflects a situation with disease animal models which are successfully cured by many proposed therapies but when those therapies are applied to humans they fail.

The proposal has not been universally welcomed but is likely to gain approval from regulatory bodies due to pressure from patient associations and the pharmaceutical industry to demonstrate progress.

Here is a small list of readers' reactions and answers by authors:

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00211-4/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00212-6/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00213-8/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00214-X/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00215-1/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00217-5/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00222-9/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00225-4/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00233-3/fulltext

From a political and economic perspective, this approach is problematic. It would lead to the treatment of healthy individuals in an already overburdened healthcare system. Additionally, these treatments are expected to be very costly while being ineffective on clinical symptoms.

We went too far into a mechanical and technological vision of medicine led by molecular biology.

Nous sommes dans une période creuse de résultats scientifiques qui durera sans doute tout l'été, aussi voici un résumé d'un article passionnant racontant comment un médecin et chercheur Turque, Sibel Özekmekçi, a développé la maladie de Parkinson, et comment elle a géré cette maladie. L'article qui est consultable à cette adresse a été résumé, traduit et simplifié pour les besoins du format de publication sur PadiracInnovation. En tant que neurologue expérimenté spécialisé dans la maladie de Parkinson (MP) et d’autres troubles du mouvement, l'auteur raconte comment elle a diagnostiqué sa propre maladie de Parkinson, qui a commencé par des symptômes très légers. Dans cet article, elle a choisi de documenter ses observations et ses expériences au cours de ce voyage, en fournissant des informations du point de vue à la fois du patient et du spécialiste.

À travers cet article de synthèse, son objectif était de fournir un compte rendu concis de son parcours scolaire, de son implication professionnelle dans le domaine de la maladie de Parkinson, des premiers symptômes et de la progression de la maladie, des symptômes moteurs et non moteurs associés à la maladie de Parkinson, ainsi que l'impact psychologique de la maladie lors des étapes de reconnaissance, d'acceptation et d'intériorisation.

Après ses études de médecine à la Faculté de médecine d'Istanbul, Sibel Özekmekçi est devenu professeur agrégé et, avec le médecin spécialiste Güneş Kiziltan, ils ont créé le « Groupe de la maladie de Parkinson et des troubles du mouvement » et ont commencé à consulter des patients dans une clinique externe privée.

Dans les années suivantes, ils ont collaboré avec des neurologues et des physiothérapeutes de la Faculté de médecine d'Istanbul de l'Université d'Istanbul pour transmettre les connaissances médicales actuelles sur la maladie de Parkinson aux patients et aux membres de leur famille. Ainsi l'auteur a souvent soigné des patients atteints de la maladie de Parkinson et occasionnellement des patients souffrant de troubles du mouvement.

A partir de l'âge de 70 ans des contractions involontaires peu nombreuses sont apparus dans le pouce de sa main droite, et même si elle soupçonnait que certaines d'entre elles pourraient signifier un début de maladie de Parkinson, elle a hésité à se diagnostiquer, car les contractions étaient sporadiques. Elle ne s'y était pas attardée à l'époque, mais en regardant ses photographies prises à cette époque, après le diagnostic, maintenant elle distingue bien la présence d'une légère chute des lèvres du coté droite, ce qui est fréquent chez les patients présentant une maladie de Parkinson. Puis au fil des ans, des douleurs sont apparues dans la région fémorale antérieure de sa jambe droite lors de longues marches. Elle a aussi fait une chute bénigne en bord de mer, mais sans comprendre la raison de cette chute. C'est aussi à cette époque qu'elle a remarqué qu'elle se penchait beaucoup en avant lorsqu'elle se promenait et que sa légère bosse, qui était là depuis l'enfance, avait augmenté de taille. Un jour, alors qu'elle a commencé à avoir des tremblements constants au repos dans le pouce de sa main droite, elle a alors réalisé que le problème était grave. Le tremblement se présentait sous la forme d'une flexion et d'une extension du doigt, mais elle ne voulait pas encore accepter le diagnostic Quelques jours plus tard, elle a également eu un tremblement au repos dans l'index de la main gauche, mais cela ne s'est pas reproduit. De nombreux patients ne consultent pas un médecin à ce stade mais seulement lorsque la maladie progresse et que les symptômes s'accentuent. Elle a alors consulté un collègue spécialiste de cette maladie.

Aux premiers stades, avant l'âge d'environ 60 à 65 ans, des agonistes dopaminergiques sont prescrits tels que le piribédil en deux à trois doses quotidiennes, le pramipexole à action prolongée en dose unique ou des inhibiteurs de la monoamino oxydase-B tels que la rasagiline en dose unique sont recommandés. Chez les personnes âgées et chez les patients de tout âge à un stade avancé de la maladie, la lévodopa, est le médicament le plus couramment administré. Bien qu'âgée alors de 72 ans, elle a cependant préféré se faire prescrire les médicaments adjuvants en raison de la nature légère de ses symptômes et de leur facilité d'utilisation.

Elle n’a pu expliquer le diagnostic à sa fille qu’une vingtaine de jours plus tard, "pour ne pas la bousculer". Sa fille a été très surprise et, bien sûr, très bouleversée par l'ironie du destin, car Sibel Özekmekçi était médecin et exerçait depuis de nombreuses années dans ce domaine. Au cours de sa dernière année et demie d'exercice professionel, elle n'a jamais parlé de sa maladie à ses collègues.

À cette époque, elle a également partagé le diagnostic avec son cher ami psychiatre, le Prof. Şahika Yüksel. Son psychiatre, l'a encouragé à s'ouvrir à ses proches de son état. Ainsi, un an et demi après le diagnostic, elle a commencé à révéler occasionnellement qu'elle était atteinte de la maladie de Parkinson. En effet, en partageant le diagnostic avec d’autres, elle avait l’impression que son fardeau s'allégeait. Elle a alors compris qu’il valait mieux accepter l’apparition des symptômes moteurs.

C'était aussi une relative consolation pour elle de savoir que sa maladie ne faisait pas partie des syndromes « Parkinson plus » dont l'évolution rapide rend les patients handicapés en peu de temps. Les quelques amis qui connaissaient sa maladie et sa fille lui ont conseillé de faire un suivi auprès d'un autre médecin expérimenté. Celui-ci a légèrement augmenté la dose de lévodopa/bensérazide. Pour l'hypersalivation, il a suggéré un collyre au maléate de timolol appliqué sur la langue, qui peut être efficace chez la plupart des patients, mais malheureusement, cela n'a eu aucun effet sur elle. Cependant, des contractions involontaires des fléchisseurs semblables à une dystonie ont commencé au niveau des deuxième et troisième orteils de son pied droit, particulièrement persistantes l'après-midi et le soir. Elle a considéré ces contractions comme une dyskinésie induite par la lévodopa, et elle a commencé à prendre un comprimé d'amantadine.

On sait que les patients atteints de la maladie de Parkinson peuvent présenter de nombreux symptômes non moteurs en plus des symptômes moteurs. Cependant, sans symptômes moteurs, le diagnostic clinique de la maladie est peu probable chez les patients présentant uniquement ces problèmes. Après confirmation du diagnostic elle a pensé que son insomnie, qui durait depuis 20 ans, pourrait être une manifestation présymptomatique et non motrice de la maladie.

Les symptômes qu'elle a personnellement remarqués chez elle, mais qu'elle a seulement reconnu qu'il s'agissait de signes non moteurs de la maladie après avoir posé le diagnostic sont les suivants : - Un sentiment de froid - Beaucoup d’anxiété et de stress extrême. - Elle a du mal à expliquer ses efforts pour cacher le diagnostic à l'époque ; peut-être ne voulais-elle pas susciter la pitié ou attirer l'attention des autres.

Aujourd'hui, sa maladie est bien contrôlée grâce aux médicaments à la dopamine. Bien qu’il n’existe actuellement aucun médicament permettant de ralentir la progression de la maladie de Parkinson, il existe des médicaments qui procurent un soulagement symptomatique. Cependant, même si elle est d’accord avec les récentes observations scientifiques qui montrent que l’exercice ralentit la progression de la maladie, elle doit admettre qu'elle néglige d’en faire régulièrement. Aujourd’hui, parfois, surtout lorsque elle tient un objet lourd, elle éprouve un léger tremblement dans les deux mains. Elle a du mal à se relever après être resté assise longtemps, alors elle préfère se lever souvent et marcher pour surmonter ce problème.

En se qui concerne son futur Sibel Özekmekçi sait que dans la maladie de Parkinson, la diminution partielle de la sérotonine et de la noradrénaline dans le cerveau peut conduire à l’émergence d’une dépression chez de nombreux patients. Il a aussi été souligné la présence de diabète de type II chez les patients atteints pourrait constituer un facteur de risque « prodromique » dans le développement de la maladie.

De même, il a été constaté que l'hypothyroïdie et l'utilisation à long terme de lévothyroxine pouvaient également constituer un risque, et la prévalence de cette maladie s'est avérée élevée chez les patients souffrant d'hyperthyroïdie ainsi que hypothyroïdie. L'auteur doit constamment suivre ses heures de prise de médicaments au cours de la journée et organiser sa vie quotidienne en fonction des intervalles pendant lesquels elle peux manger.

It's well known that reduced exposure to sunlight, during winter months, is associated with depression. The skin, upon UV exposure, produces various cytokines and other signaling molecules that can affect brain function. For instance, it can increase the production of serotonin, a neurotransmitter that regulates mood, appetite, and sleep. In a recent article UV exposure is associated (in mice) with deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Ironically, previous studies show that moderate UV exposure can increase blood urocanic acid levels and enhance learning and memory in the mouse brain via the glutamate biosynthetic pathway. So as usual in biology, there is no single, linear effect of UV exposure.

Dopamine is instrumental in various brain functions and is commonly linked to feelings of pleasure, reward, motivation, and memory. Sustaining a balanced and regulated level of dopamine signaling in the brain is essential since excessive or dysregulated dopamine signaling can harm mental and physical health. Lack of dopamine production in substancia nigra is believed to be causative of Parkinson's disease.

The article discussed today is a small (tiny?) study on 17 mice (9 control and 8 intervention's arm) in Korea. These naked mice allow easy experiments on the skin, application of topical agents, and exposure to UV. To investigate the effects of UV irradiation on hippocampal memory and neurogenesis, mouse skin was irradiated with UV for 6 weeks. After 6 weeks of UV irradiation, the mice underwent behavioral tests. Photoaged mice exhibit impaired cognitive function and neurogenesis.

The scientists analyzed 28 neuropeptides in mouse serum to elucidate the neurotransmitter-mediated mechanisms underlying these skin–brain interactions. Among these neuropeptides, dopamine was the most significantly upregulated. The dopamine level was ~130–145% greater in the serum of UV-irradiated mice than in that of sham-irradiated mice.

The authors measured dopamine levels in the skin and adrenal glands as serum dopamine levels are influenced by the sympathetic nervous system. Dopamine levels in the skin and adrenal glands were significantly greater in UV-irradiated mice than in control mice. In response to UV exposure, no significant changes in dopamine levels were detected in the ventral tegmental area (VTA), substantia nigra (SN), or hippocampus (HPC). However, dopamine levels in the prefrontal cortex (PFC) and hypothalamus (HT) significantly increased.

So unfortunately, it seems UV irradiation would not be useful for patients with Parkinson's disease, as no significant changes in dopamine levels were detected in the ventral tegmental area (VTA), substantia nigra. Yet these mice were exposed to high levels of UV, maybe with moderate levels the effect could be beneficial?

Dopamine levels and cognitive function exhibit an inverted U-shaped relationship, suggesting that cognitive performance can be reduced with either deficient or excessive dopamine. In contrast, peak cognitive function is associated with an optimal dopamine level. Insufficient dopamine can lead to difficulty maintaining attention, reduced motivation, and impaired working memory.

Conversely, excessive dopamine can impair cognitive function, inducing challenges in maintaining a stable focus, as noted in conditions such as schizophrenia, where dopamine pathways are hyperactive.

In conclusion, this is a well-done tiny study that may or may not tell something about the human response to high doses of UV. It might be worth investigating if UV exposure might be beneficial in Parkinson's disease.

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.