In most of the organs of our body, the lymphatic system is responsible for conducting lymph between different parts of the body. The lymphatic system processes an average of 3 liters of lymph per day. Lymph lies between the blood vessels and the cells. The lymphatic system provides a return route to the blood vessels for lymph. Lymph also allows immune cells to circulate in the lymph nodes, allowing immune surveillance of body tissues.

It was historically believed that the brain and meninges lacked a lymphatic vascular system. For more than a century, the dominant hypothesis was that the flow of cerebrospinal fluid, could replace peripheral lymphatic functions and play an important role in the clearance of extracellular fluids.

It was recently discovered (2014) by Jonathan Kipnis and other scientists that a pathway connects the glymphatic system (a recently discovered central nervous system waste disposal system) to the meningeal compartment, which surrounds the brain and the spinal cord. enter image description here

Pathologically, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are all characterized by progressive loss of neurons, cognitive decline, motor impairments, and sensory loss.

Collectively, these diseases fall into a broad category called proteopathies due to the common assembly of misfolded or aggregated intracellular or extracellular proteins. According to the dominant hypothesis of Alzheimer's disease, the aggregation of amyloid-beta in extracellular plaques leads to neuronal loss and cerebral atrophy which is the hallmark of Alzheimer's dementia.

For 2O years anti-amyloid clinical trials failed. Recently an anti-amyloid drug, Biogen and Eisai's aducanumab, has shown mixed efficacy in clinical trials in slowing cognitive decline.

A research team led by pioneers such as Jonathan Kipnis, offers a possible explanation for these disappointing clinical results. Jonathan Kipnis describes the meningeal lymphatic system as a waste disposal system for the central nervous system. If aducanumab or other drugs targeting misfolded proteins break these aggregates, but the debris cannot be removed due to deficiencies in the meningeal lymphatic system, then the patient's condition cannot improve.

Therefore improving the function of lymphatic drainage may have a positive impact on the effectiveness of this type of medication. To test this theory, Kipnis and his colleagues used versions of aducanumab and another drug targeting amyloids, BAN2401, in a mouse model of Alzheimer's disease.

Mice with impaired lymphatic drainage systems showed a higher accumulation of beta-amyloid plaque than controls with intact drainage systems. They also displayed a decreased influx of antibody drugs into the brain from the surrounding fluid. Changes in a type of immune cell in the brain called microglia, which shed dying cells and other debris, was also observed. When the lymphatic drainage was blocked it caused the microglia to go into an inflammatory state.

To explore the therapeutic potential of drugs acting on the meningeal lymphatic system, scientists combined aducanumab or BAN2401 with a C-virus-mediated vascular endothelial growth factor, in hopes of expanding the network of meningeal lymphatics. Mice treated with this therapy showed significantly reduced beta-amyloid accumulation compared to those who received only anti-amyloid drugs.

These findings suggest that it may be possible to develop drugs that target microglia and blood vessels in the brain - both of which are important in Alzheimer's disease - by modulating lymphatic vessel function.

Advertisement


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Dans la plupart des organes de notre corps, les vaisseaux lymphatiques sont chargés de conduire la lymphe entre les différentes parties du corps. Le système circulatoire humain traite en moyenne 20 litres de sang par jour. 17 litres de sang sont ensuite réabsorbés dans les vaisseaux sanguins, mais trois litres subsistent entre les vaisseaux sanguins et les cellules. Le système lymphatique fournit pour ces trois litres, une voie de retour vers les vaisseaux sanguins. La lymphe permet aussi aux cellules immunitaires de circuler dans les ganglions lymphatiques, ce qui permettant une surveillance immunitaire des tissus corporels. On croyait historiquement que le cerveau et les méninges étaient dépourvus de système vasculaire lymphatique. Pendant plus d'un siècle, l'hypothèse dominante était que l'écoulement du liquide céphalo-rachidien, qui entoure, mais n'entre pas en contact direct avec le parenchyme, pourrait remplacer les fonctions lymphatiques périphériques et jouer un rôle important dans la clairance des solutés extracellulaires.

Il a été récemment découvert (2014) par Jonathan Kipnis et d'autres scientifiques qu'une voie relie le système glymphatique (un système récemment découvert d'élimination des déchets du système nerveux central) au compartiment méningé. Les méninges sont les trois membranes qui enveloppent le cerveau et la moelle épinière. enter image description here Pathologiquement, les maladies neurodégénératives telles que la sclérose latérale amyotrophique, la maladie d'Alzheimer, la maladie de Parkinson et la maladie de Huntington sont toutes caractérisées par la perte progressive des neurones, le déclin cognitif, les déficiences motrices et la perte sensorielle.

Collectivement, ces maladies entrent dans une large catégorie appelée protéopathies en raison de l'assemblage commun de protéines intracellulaires ou extracellulaires mal repliées ou agrégées. Selon l'hypothèse dominante de la maladie d'Alzheimer, l'agrégation de l'amyloïde-bêta en plaques extracellulaires entraîne la perte neuronale et l'atrophie cérébrale qui est la marque de la démence d'Alzheimer.

Un médicament anti-amyloïde, Biogen et l’aducanumab d’Eisai, a montré une efficacité mitigée lors d’essais cliniques pour ralentir le déclin cognitif, tandis que plusieurs candidats similaires n’ont tout simplement pas réussi à démontrer un bénéfice.

Une équipe de recherche dirigée par des pionniers tels que Jonathan Kipnis, propose une explication possible à ces résultats cliniques décevants.

Jonathan Kipnis décrit le système lymphatique méningé comme un système d’évacuation des déchets produits par le système nerveux central.

Si l'aducanumab ou d'autres médicaments visant des protéines mal repliées, rompent ces agrégats mais que les débris ne peuvent pas être éliminés en raison de déficiences du système lymphatique méningé, l'état du patient ne peut pas s'améliorer. L'amélioration de la fonction du drainage lymphatique pourrait donc avoir un impact positif sur l'efficacité de ce type de médicaments.

Pour tester cette théorie, Kipnis et ses collègues ont utilisé des versions d’aducanumab et d’un autre médicament ciblant les amyloïdes, BAN2401, dans un modèle murin de la maladie d’Alzheimer.

Les souris avec des systèmes de drainage lymphatiques altérés ont montré une accumulation plus élevée de plaque bêta-amyloïde que les témoins avec des systèmes de drainage intacts. Les souris présentant un drainage lymphatique altéré ont également montré une diminution de l'afflux des médicaments dans le cerveau.

Les chercheurs ont également observé des changements dans un type de cellule immunitaire du cerveau appelée microglie, qui éliminent les cellules mourantes et d'autres débris. Un drainage lymphatique obturé a fait passer la microglie à un état inflammatoire.

Pour explorer le potentiel thérapeutique de médicaments agissants sur le système lymphatique méningé, les scientifiques ont combiné l'aducanumab ou BAN2401 avec un facteur de croissance endothélial vasculaire médié par un virus-C, dans l'espoir d'élargir le réseau des vaisseaux lymphatiques méningés.

Les souris traitées par cette thérapie ont montré une accumulation de bêta-amyloïde significativement réduite par rapport à celles qui n’ont reçu que les médicaments anti-amyloïdes.

Ces résultats suggèrent qu'il pourrait être possible de développer des médicaments qui ciblent la microglie et les vaisseaux sanguins du cerveau - qui sont tous deux importants dans la maladie d'Alzheimer - en modulant la fonction des vaisseaux lymphatiques.

Advertisement


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Cardiovascular fitness reflects an organism's ability to supply oxygen to organs such as muscles and the brain. As this ability decreases, the general metabolism becomes less able to adapt easily to varying demands as hemoglobin decreases, venous return deteriorates, stroke volume deteriorates.

The benefits of good cardiovascular fitness for physical health are well documented, and good cardiovascular fitness is also beneficial for the structural integrity of the brain. Although it is often associated with healthy lifestyle behaviors such as physical activity, cardiovascular fitness is not necessarily correlated with it.

Cortical thinning associated with aging in the frontotemporal regions has been associated with cognitive decline in both healthy individuals and those with dementia. No cure currently exists for these dementias.

One potential intervention against the structural decline of the brain associated with aging is to intervene towards midlife on certain aspects of physical health, such as cardiovascular health.

As a measure of the maximum rate at which the body can use oxygen, cardiovascular fitness reflects how efficiently the respiratory and circulatory systems deliver oxygenated blood to the body during active times.

Better cardiovascular fitness has been associated with structural features of gray matter in the brain.

Frontotemporal atrophy is indeed a common archetype of pathological aging and is considered to be one of the main causes of dementia (Fjell et al., 2015; Cox et al., 2021).

Research suggests that aging-related deterioration in white matter structural integrity may be a better signal of later cognitive decline and mild cognitive impairment than gray matter, because white matter may be more sensitive to early aspects of disorderly aging.

Studies examining the links between cardiovascular form and white matter, particularly in younger or cognitively healthy cohorts, where changes in the microstructural integrity of white matter might ignore small distributed changes that might not survive correction for multiple comparisons in the same tract.

Another possible reason for the mixed results seen could be the confusion of cardiovascular fitness with healthy lifestyle behaviors like physical activity.

Lifestyle interventions designed to improve cardiovascular fitness often do so indirectly, for example by increasing physical activity. However, increasing healthy lifestyle habits is not necessarily correlated with better cardiovascular fitness (d'Arbeloff, 2020).

Previous studies using self-report measures of healthy behaviors as an indicator of cardiovascular fitness when examining associations with white matter structural integrity may have yielded different results from studies using direct measures of cardiovascular condition (Sexton et al., 2016; d'Arbeloff, 2020).

In "Midlife Cardiovascular Fitness Is Reflected in the Brain's White Matter" Tracy d'Arbeloff, Ahmad R Hariri and colleagues from New Zealand and USA, used data from members of the Dunedin study to examine possible differential associations between distributed white matter integrity and the two healthy living behaviors (N = 854) and cardiovascular fitness (N = 801). ) in quarantine.

The authors explored possible links between a putative biomarker, the distributed integrity of the brain's white matter, and two intervention targets, cardiovascular fitness and healthy living behaviors, in midlife.

At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO2Max; N = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (N = 854).

Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO2Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA.

The findings of the authors suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting dementia.

Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues. In the brain, alpha-synuclein is found mainly at the tips of neurons in specialized structures called presynaptic terminals.

The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (Parkinson's disease) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of Parkinson's disease.

In 2007, Braak and co-authors advanced a ‘dual-hit hypothesis’ about the pathogenesis of idiopathic Parkinson's disease, according to which an unknown pathogen akin to a slow-virus may enter the nervous system through both the nasal and intestinal mucosae, eventually resulting in a cascade of neurodegenerative events in the brain. enter image description here

In 2018 Killinger, Labrie and colleagues reported that in two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, they observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset.

After studying 48 subjects without Parkinson disease, they also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD.

In this new study by Yuhua Chen, Feng Yu and colleagues in University of Science and Technology of China in Hefei, investigated appendix abnormality in patients with Parkinson's disease.

The scientists assessed appendix morphology in 100 patients with Parkinson's disease and 50 control subjects by multislice spiral computed tomography. They analyzed the clinical characteristics of patients with Parkinson's disease with diseased appendices, which was confirmed in seven patients by histopathological analysis.

Chronic appendicitis-like lesions were detected in 53% of patients with Parkinson's disease, but these were not associated with the duration of motor symptoms.

Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder are known risk factors for Parkinson's disease.

The seven patients with Parkinson's disease who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation.

These results indicate an association between chronic appendicitis-like lesions and Parkinson's disease, and suggest that α-Syn accumulation in the diseased appendix occurs in Parkinson's disease. The appendix may play a role in the pathogenesis of Parkinson's disease, but the exact mechanism remains unclear. The appendix could be a source of pathological α-syn that propagates to the central nervous system, but a “second-hit” may be required for this phenomenon to occur. Factors like chronic inflammation, microbiome perturbations, formation of α-syn truncation products, and impaired cellular clearance of α-syn aggregates may serve to promote the generation and spread of pathology from the appendix to the brain. The vagus nerve, compromised BBB integrity, and/or age-dependent degeneration of the CNS lymphatic system may be routes by which α-syn seeds accumulate in the brain.

Alternatively (or in addition), immunosurveillance functions of the appendix may contribute to acquiring autoimmunity towards α-syn, including the generation of self-reactive T cells and autoantibodies. Hence, studying the accumulation and possible spreading of α-syn from appendix to brain could help our understanding of the origins of Parkinson's disease.

Here we review recent publications about ALS and try to connect the dots between autophagy, insulin resistance, C9orf72, FUS, proteopathies, mitophagy and defective neuromuscular junction. It seems autophagy dysregulation is central to all those aspects of ALS.

TDP-43

Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models.

There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. In this publication the clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy.

Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance.

Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons.

C9orf72

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders.

Both C9ORF72 and androgen receptors regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles.

In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ.

FUS

The mechanism by which FUS affects the translation of polyribosomes has not been established. In a recent publication, the authors show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, they show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1.

Moreover, they report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin. The scientists also show that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

Stress granules

It was recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS-TDP-43 fibroblasts, and provided a link between SG formation and autophagy.

The authors demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP-43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington's disease (HD) mutations, and SCA2 mutations.

Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post-transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs.

mTOR

The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

As usual it must be underlined that mTOR is important for living beings, and simply inhibiting it is out of question. It would simply further starve motor neurons and exacerbate the disease as shown above.

Advertisement


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

1 doi: 10.3390/ijms21114021. Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA Fiona Limanaqi 1, Carla Letizia Busceti 2, Francesca Biagioni 2, Federica Cantini 1, Paola Lenzi 1, Francesco Fornai 1 2 2 doi: 10.1016/j.nbd.2021.105359. Online ahead of print. Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice Nirma D Perera 1, Doris Tomas 1, Nayomi Wanniarachchillage 1, Brittany Cuic 1, Sophia J Luikinga 1, Valeria Rytova 1, Bradley J Turner 2 3 doi: 10.1074/jbc.RA120.013801. Epub 2020 Oct 20. FUS contributes to mTOR-dependent inhibition of translation Myriam Sévigny 1, Isabelle Bourdeau Julien 1, Janani Priya Venkatasubramani 1, Jeremy B Hui 1, Paul A Dutchak 1, Chantelle F Sephton 2 4 doi: 10.1002/ana.26069. Online ahead of print. Staufen1 in Human Neurodegeneration Sharan Paul 1, Warunee Dansithong 1, Karla P Figueroa 1, Mandi Gandelman 1, Daniel R Scoles 1, Stefan M Pulst 1

An international clinical trial, is investigating whether infrared light can improve symptoms of Parkinson's disease. The experimental results, based on preclinical studies, indeed suggest that brain illumination in the near infrared is likely to slow down this neurodegenerative disease.

Hamilton, Mitrofanis and others had previously reported that wearing headphones equipped with infrared LEDs improved quality of life, although it did not have much effect on motor symptoms.

A medical device system (called Ev-NIRT) has been developed by the French scientists and Boston Scientific Corporation, for intracerebral illumination at 670 nm of the black substance pars compacta (SNpc), and will be tested in this pilot study.

Researchers will assess the feasibility and tolerance of surgery and brain illumination using the Ev-NIRT medical device, in a group of 7 patients with Parkinson's disease in whom the innovative medical device will be implanted. The patients will be followed for 4 years. The device will emit pulses at a wavelength of 670 nm for one minute, with a periodicity of 150 Hz. This burst of pulses will be followed by five minutes of rest. enter image description here

The team, led by neurosurgeon Alim-Louis Benabid of the Clinatec Institute, hopes that exposing this area of ​​the brain to infrared light will protect cells from death. Benabid, along with Pierre Pollak, are the pioneers who developed deep brain stimulation (DBS) in 1987. DBS works by sending electrical impulses into the brain. This invention has changed the lives of thousands of patients, but it has long term side effects.

About ten years ago, John Mitrofanis, a neuroanatomist at the University of Sydney, spent a year studying DBS with Benabid with the aim of creating a similar concept, but using infrared light. Mitrofanis was inspired by infrared headsets, used in the Parkinson's community. enter image description here

Benabid and Mitrofanis, however, felt that light from outside the skull would not penetrate deep enough and that an implantable device had to be created. In 2017, in collaboration with researcher Cécile Moro, they injected 20 macaques with a neurotoxin present in certain recreational drugs (MPTP) and known to cause the symptoms of Parkinson's disease. Scientists exposed nine macaques to near infrared in the midbrain region using an implanted device.

The French study will follow 14 patients with early-stage Parkinson's disease for 4 years, seven of whom will be treated periodically with 670 nanometer pulses of light delivered to the brain via a thin laser diode cable. The other seven patients will not be operated on; an ethics review committee has in fact decided not to subject them to surgery without the possibility of benefit.

Some Parkinson's researchers are skeptical. No one has shown why exposure to infrared should have an effect on cells that never see daylight. Neurons do not have a chlorophyll-based metabolism. Much of the encouraging results seen so far may be the result of the placebo effect, skeptics say.

There are three main hypotheses to explain how photomodulation works.

  • The first recalls that molecules sensitive to light in the body called chromophores are excited by photon stimulation. We now know that hemoglobin, myoglobin and COX are the only 3 chromophores in mammalian tissues capable of absorbing near infrared light (wavelength 600 to 900 nm). However, there is no clear mechanism of action linking these chromophores to the increased ATP synthesis which is observed under light stimulation.

  • The second hypothesis explains that the production of mitochondrial energy is the effect of a reduction in the intra-mitochondrial viscosity of water induced by the near infrared. the reduction in near infrared mediated viscosity decreases the friction that opposes the rotation of ATP synthase and results in a "smoother" rotation of the ATP synthase machinery. This theory is supported by the fact that increases in cellular ATP level are immediate after near infrared stimulation.

  • A third hypothesis suggests that the photoabsorbent pyropherophorbide-a (P-a) metabolite of dietary chlorophyll may facilitate light energy production processes in animals. In the experiments, ATP levels increased only in groups where P-a and near infrared light were co-administered, and not in those where P-a or near infrared were administered in isolation. Given the multiplicity of these competing theories, it is possible that the near infrared exerts its modulatory effects through several mechanisms instead of just one.

The main aim of this new clinical study is to prove that the implant is safe, says Benabid, but the researchers will also assess the progression of the disease. “This must lead to a great improvement,” he says. "There would be no reason to have extensive surgery for only slight improvement."

The major problem with all neuroprotection trials in Parkinson's disease is that diagnosis appears to occur after more than 50% of the dopamine-producing cells have disappeared. Unless the improvement is huge, the signal will be too weak to be detected.

The team will also be looking for clinical benefits. But because researchers assess symptoms of Parkinson's disease by observing patients performing specific tasks, the assessments are largely subjective and symptoms vary over time; everyone has good days and bad. Since the control group will not undergo surgery, it will be particularly difficult to rule out placebo effects.

Un essai clinique international, mais initié depuis la France cherche à savoir si la lumière infrarouge peut améliorer les symptômes de la maladie de Parkinson. Les résultats expérimentaux, basés sur des études précliniques, suggèrent en effet que l'illumination cérébrale dans le proche infrarouge est susceptible de ralentir cette maladie neurodégénérative. Hamilton, Mitrofanis et d'autres avaient précédemment rapporté que le port d'un casque équipé de LEDs infrarouges améliorait l'expression faciale, le traitement auditif, l'engagement dans la conversation, la qualité du sommeil et la motivation, bien que cela n'ait pas eu beaucoup d'effet sur les symptômes moteurs. Ann Liebert de l'Université de Sydney prévoit une étude chez 120 patients utilisant un casque plus sophistiqué.

Un système de dispositif médical (appelé Ev-NIRT) a été développé pour un éclairage intracérébral à 670 nm de la substance noire pars compacta (SNpc), et sera être testé dans cette étude pilote. Les chercheurs évalueront la faisabilité et la tolérance de la chirurgie et de l'illumination cérébrale grâce au dispositif médical Ev-NIRT, auprès d'un groupe de 7 patients atteints de la maladie de Parkinson auquels sera implanté le dispositif médical innovant. Les patients seront suivis pendant 4 ans. L'appareil émettra pendant une minute des impulsions à une longueur d'onde de 670 nm, avec une périodicité de 150 Hz. Cette salve d'impulsions sera suivie de cinq minutes de repos. enter image description here

L'équipe, dirigée par le neurochirurgien Alim-Louis Benabid de l'Institut Clinatec espère que l'exposition de cette zone du cerveau à la lumière infrarouge protégera les cellules de la mort. Benabid avec Pierre Pollak, sont les pionniers qui ont développé la stimulation cérébrale profonde (DBS) en 1987. DBS fonctionne en envoyant des impulsions électriques dans le cerveau. Cette invention a changé la vie de milliers de patients, mais elle a des effects secondaires à long terme.

Il y a une dizaine d'année, John Mitrofanis, neuro-anatomiste à l'Université de Sydney, avait passé un an à étudier le DBS avec Benabid dans le but de créer un concept similaire, mais utilisant la lumière infrarouge. Mitrofanis était inspiré par les casques à infrarouge, utilisés dans la communauté Parkinson. enter image description here

Benabid et Mitrofanis ont cependant estimé que la lumière provenant de l'extérieur du crâne ne pénétrerait pas assez profondément et qu'il fallait créer un dispositif implantable. En 2017, en collaboration avec la chercheuse Cécile Moro, ils ont injecté à 20 macaques une neurotoxine présente dans certaines drogues récréatives (MPTP) et connue pour provoquer les symptômes de la maladie de Parkinson. Les scientifiques ont exposés neuf macaques à du proche infrarouge dans la région du mésencéphale grâce à un dispositif implanté.

L’étude française suivra 14 patients atteints de la maladie de Parkinson à un stade précoce pendant 4 ans, dont sept seront traités périodiquement avec des impulsions de lumière de 670 nanomètres délivrées au cerveau via un mince câble à diode laser. Les sept autres patients ne seront pas opérés; un comité d'examen éthique a en effet décidé de ne pas les soumettre à une intervention chirurgicale sans possibilité de bénéfice.

Certains chercheurs sur la maladie de Parkinson sont sceptiques. Personne n'a montré pourquoi l'exposition à de l'infrarouge devrait avoir un effet sur des cellules qui ne voient jamais la lumière du jour. Les neurones n'ont pas un métabolisme basé sur la chlorophyle. Une grande partie des résultats encourageants observés jusqu'à présent peuvent être le résultat de l'effet placebo, disent les sceptiques.

Il existe trois hypothèses principales pour expliquer le fonctionnement de la photomodulation.

  • La première rappelle que les molécules sensibles à la lumière du corps appelées chromophores sont excitées par stimulation photonique. On sait maintenant que l'hémoglobine, la myoglobine et la COX sont les 3 seuls chromophores dans les tissus des mammifères capables d'absorber la lumière dans le proche infrarouge (longueur d'onde de 600 à 900 nm). Cependant, il n'y a pas de mécanisme d'action clair liant ces chromophores à l'augmentation de la synthèse d'ATP qui est observée sous stimulation lumineuse.

  • La deuxième hypothèse explique que la production d'énergie mitochondriale est l'effet d'une réduction de la viscosité intra-mitochondriale de l'eau induite par le proche infrarouge. la réduction de la viscosité à médiation proche infrarouge diminue le frottement qui s'oppose à la rotation de l'ATP synthase et entraîne une rotation «plus douce» de la machinerie de l'ATP synthase. Cette théorie est étayée par le fait que les augmentations du niveau d'ATP cellulaire sont immédiates après la stimulation au proche infrarouge.

  • Un troisième hypothese suggére que le métabolite photo-absorbant pyrophéophorbide-a (P-a) du chlorophyl alimentaire pourrait faciliter les processus de production d'énergie par la lumière chez les animaux. Dans les expériences, les niveaux d'ATP n'ont augmenté que dans les groupes où P-a et la lumière proche infrarouge étaient co-administrés, et non dans ceux dans lesquels P-a ou proche infrarouge étaient administrés isolément. Compte tenu de la multiplicité de ces théories concurrentes, il se peut que le proche infrarouge exerce ses effets modulateurs à travers plusieurs mécanismes au lieu d'un seul.

L'objectif principal de cette nouvelle étude clinique est de prouver que l'implant est sûr, dit Benabid, mais les chercheurs évalueront également la progression de la maladie. «Cela doit induire une grande amélioration», dit-il. «Il n'y aurait aucune raison de faire une intervention chirurgicale étendue pour une amélioration qui ne serait que légère.»

Le problème majeur de tous les essais de neuroprotection dans la maladie de Parkinson est que le diagnostic semble se produire après la disparition de plus de 50% des cellules productrices de dopamine. À moins que l'amélioration ne soit énorme, le signal sera trop faible pour être détecté.

L'équipe recherchera également des avantages cliniques. Mais comme les chercheurs évaluent les symptômes de la maladie de Parkinson en observant les patients effectuant des tâches spécifiques, les évaluations sont largement subjectives et les symptômes varient dans le temps; tout le monde a de bons et de mauvais jours. Étant donné que le groupe témoin ne subira pas de chirurgie, il sera particulièrement difficile d'exclure les effets placebo.

Amyotrophic lateral sclerosis is a non-cell autonomous disease, and motor neuron degeneration is modulated by intracellular and intercellular damages. Or at least this is what tells some scientists, indeed there is an abundance of proposal for ALS etiology and no consensus.

Another dissension point between ALS scientists is if the disease starts in the brain, or in a muscle. The former is the mainstream hypothesis. Both camps have proven again and again that their proposal was the right one.

A third mystery is that scientists almost never bothered to explore the most obvious manifestation of ALS: The muscle wasting.

With the amelioration of tools' performance, scientist's attention is turning to extra cellular vesicles.

Extra cellular vesicles

In the Central Nervous System (CNS), intercellular crosstalk happens among neurons, between neurons and glia or cells of the innate immune system, through different modalities, involving the release into the extracellular space of molecules such as neurotransmitters, neurotrophic factors, metabolites, and mutant proteins encapsulated or not in vesicles.

C9orf72, which presents aberrant hexanucleotide (GGGGCC) expansion in the non-coding region in ALS patients, regulates vesicle trafficking. Other proteins such as SOD1, TDP-43 or FUS are found in vesicles in ALS.

Where we discuss of muscles

Although much less studied than for motor neurons, abnormalities have been also described in skeletal muscle from ALS patients.

Accumulation of misfolded mutant proteins is observed in skeletal muscle.

In line with the pivotal role of defective mitochondrial respiratory chain and oxidative stress in ALS skeletal muscle, increasing levels of PGC‐1α, a transcription coactivator that promotes mitochondrial biogenesis, can improve muscle function even at late stages of the disease.

Skeletal muscle is a major site of glucose storage in the form of glycogen, which is transformed into ATP through glycolysis. The dysfunction of fast‐twitch type IIb myofibres in ALS is consistent with glucose intolerance and insulin resistance reported in ALS patients.

Myofibres from transgenic mice over expressing wild‐type TDP‐43 show impaired insulin‐mediated glucose uptake.

Does muscles kill motor neurons? In ALS, muscles are supposed to die from inactivity as motor neurons do not anymore activate them. A publication on MedRxiv proposes that it is actually the other way round: Muscles kill motor neurons. After all it is well known that many ALS patients were having intense sport activities. And an ALS-like phenotype was observed in mice when exogenous human mutant SOD1 expression was restricted to the skeletal muscle.

The authors of the pre-print, Laura Le Gall, Stephanie Duguez, Pierre Francois Pradat and colleagues, recall that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. So they hypothesized that muscle vesicles may be involved in ALS pathology.

An accumulation of multivesicular bodies was observed in muscle biopsies of 27 sporadic ALS patients.

Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing.

Compared to vesicles from healthy control myotubes, when administered to healthy motor neurons the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. enter image description here

This article may revolutionize the understanding of ALS' etiology.

Advertisement


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Please, to help us continue to provide valuable information: